CA2204370A1 - Analyte-controlled liquid delivery device and analyte monitor - Google Patents
Analyte-controlled liquid delivery device and analyte monitorInfo
- Publication number
- CA2204370A1 CA2204370A1 CA002204370A CA2204370A CA2204370A1 CA 2204370 A1 CA2204370 A1 CA 2204370A1 CA 002204370 A CA002204370 A CA 002204370A CA 2204370 A CA2204370 A CA 2204370A CA 2204370 A1 CA2204370 A1 CA 2204370A1
- Authority
- CA
- Canada
- Prior art keywords
- needle
- skin
- sensor
- current
- subject
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
- A61M5/14248—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
- A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
- A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
- A61B5/6848—Needles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/168—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
- A61M5/172—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
- A61M5/1723—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M2005/14204—Pressure infusion, e.g. using pumps with gas-producing electrochemical cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/142—Pressure infusion, e.g. using pumps
- A61M5/14244—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
- A61M2005/14268—Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body with a reusable and a disposable component
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/168—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
- A61M5/172—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
- A61M5/1723—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
- A61M2005/1726—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure the body parameters being measured at, or proximate to, the infusion site
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2205/00—General characteristics of the apparatus
- A61M2205/82—Internal energy supply devices
- A61M2205/8206—Internal energy supply devices battery-operated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
- Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation
Abstract
A liquid delivery device (40) comprising a housing (41) having a lower surface (51) for application to the skin of a subject and having a reservoir (42) and a gas generation chamber (43) therein separated by a displaceable membrane (45). Gas generated by an electrolytic cell (44) under the control of a microprocessor (46) causes the gas generation chamber (43) to expand and the reservoir (42) to contract, thereby discharging a liquid drug, such as insulin, from the reservoir via a hollow delivery needle (49) extending from the lower surface (51). The delivery needle (49) and a sensor needle (48) both extend from the lower surface a sufficient distance so as to penetrate through the epidermis and into the dermis when the housing is pressed against the skin. The sensor needle (48) has an enzymatic coating for the detection of an analyte, such as glucose in the subject's plasma. The delivery needle (49) is made of platinum-iridium, and a current passes between the needles (48, 49) and a potentiostat circuit (47) according to the amount of glucose detected. A
reference electrode (silver/silver chloride) (50) which rests against the subject's skin increases the accuracy of the glucose measurement. The current through the potentiostat circuit (47) is measured by a voltmeter (53) and a signal from the voltmeter (53) is amplified and communicated to the microprocessor (46) which determines the correct rate of delivery of the drug on the basis of the level of analyte detected in the subject's plasma.
reference electrode (silver/silver chloride) (50) which rests against the subject's skin increases the accuracy of the glucose measurement. The current through the potentiostat circuit (47) is measured by a voltmeter (53) and a signal from the voltmeter (53) is amplified and communicated to the microprocessor (46) which determines the correct rate of delivery of the drug on the basis of the level of analyte detected in the subject's plasma.
Description
CA 02204370 1997-0~-02 W O 96tl4026 PCT~CE95/00055 Description Analyte-controlled liquid delivery device and analyte monitor Technical ~leld This invention relates to devices for the delivery of liquid drugs 5 to a subject via the subject's skin, and in particular to "closed loop"
insulin delivery devices, as well as to analyte sensors for use in "closed loop" and "open loop" delivery systems.
Back~round Art Conventional therapy for insulin-dependent diabetes mellitus 10 involves self-~lministered subcutaneous insulin injections a number of times daily (usually two, three or four times). The dosage regime is designed to m~int~in the blood glucose level (glycemia) of the subject between hypoglycemic and hyperglycemic levels, preferably between 3 and 10 rnmol/l, taking into account variations arising as a result of, for 15 example, glucose intake at me~ltimes and glucose elimin~tion during periods of activity.
In order to provide better control of a subject's glycemia, continuous infusion pumps have been developed to deliver glucose at a basal rate. This rate may be pre-prog~ ,ed, or the patient or 20 physician may m~nll~lly control the rate according to the results of successive blood glucose tests (which can be carried out by the patient using apparatus which provides a result within a matter of minutes).
The basal rate is usually supplemented by bolus injections before meal times. Such pumps are known as "open loop" systems.
A subcutaneous catheter is used to deliver insulin from an infusion pump to the patient. The open wound caused by the catheter means that the catheter must be resited every few days. Complications arising from the use of the catheter can include erythemia, abscesses, cellulitus and, occasionally, systemic infection.
CA 02204370 1997-0~-02 W O96tl4026 PCT~E95/00055 Implantable devices are also known. Such devices are generally implanted in the abdomen. Complications arising from the use of implantable devices include infection, particularly of the implantation site, and skin necrosis over the implant.
S "Closed loop" systems comprise an insulin pump controlled by a microprocessor and a glucose sensor linked to the microprocessor.
The rate or frequency of insulin ~ ni~tration is controlled by the microprocessor according to the insl~ eous blood glucose level measured by the sensor. Because a system of feedback ~imil~r to natural homeostatic regulation is used, a closed loop insulin delivery system may also be referred to as an "artificial pancreas".
In general, closed loop systems are not implanted. Many of the known systems are of the so-called bedside type which include a reservoir and a pump for a hypoglycemic agent (such as insulin), a reservoir and pump for a hyperglycemic agent (such as glucagon or glucose), means for injecting each agent into the body, means for measuring the blood glucose levels, means for controlling the delivery of each agent at a rate determined by the measured blood glucose level and a housing cont~ining the reservoirs, pumps, measuring apparatus and controlling means. The size of this type of artificial pancreas means that it is limited to bedside use (which explains the name).
Furthermore, because the means for measuring blood glucose levels requires the collection of blood from the patient, this mode of therapy imposes a heavy burden on the p~tient, so that it is impossible to use the device continuously for a long period of time.
A portable artificial pancreas is known from EP-A-0 098 592.
The artificial pancreas has a reservoir for a blood- sugar control agent and a feed pump adapted to inject the control agent into the subject's body at a rate determined by a microcomputer. The microcomputer receives a signal from a glucose sensor which is inserted into the subject's body, and calculates the required insulin delivery rate from the detected glucose level. The glucose sensor and the injection unit (which includes the reservoir, the pump and the microcomputer), are CA 02204370 1997-0~-02 W O96/14026 PCT/L~5~'~GCSC
separate from one another and the output signal of the sensor is tr~n~mitted to the microcomputer by radio.
In the preferred embo~lim~nt, a detection unit, including the sensor and radio tr~n~mitter, is in the form of a wristwatch having a tube le~tling thererlolll to a catheter which has the blood glucose sensor at the end thereof. The injection unit, which includes a radio receiver for receiving the signal from the detection unit, is adapted to be worn on a belt.
This type of portable artificial pancreas shares the problems associated with open loop systems (i.e. erythemia, abscesses, cellulitus and systemic infection), but the problems are, in fact, m~gnified because two catheters are used instead of one.
Apart from the strictly medical problems associated with existing pumps, a significant amount of pain and trauma is also associated with the application of known devices when the catheter(s) is/are inserted into the skin.
Furthermore, such devices are inconvenient to use and may cause discomfort as the pumps are often quite bulky and are generally wom on a belt or a shoulder strap, as is the case with the injection unit of EP-A-0 098 592.
Although implantable devices have found a limited success in open loop systems, they are unsuitable for use in closed loop systems as a failure of the sensor pump, or controlling equipment, or the blockage of an outlet (which might occur as a result of a build-up of fibrin, for 25 example), can lead to ketoacidosis. A patient using an open loop system will be supplementing the basal rate with bolus injections and may be carrying out regular blood glucose tests as before. Accordingly, there is far less danger of severe hypoglycemia or hyperglycemia occurring if an implanted open loop system fails than would be the case for a 30 patient with an implanted closed loop system.
CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 Portable closed loop systems, such as the system described in EP-A-0 098 592, require a reliable glucose sensor. The sensor employed in EP-A-0 098 592 comprises a pl~tin~lm electrode and a silver electrode. The platinum electrode and silver electrode form part of an S electric circuit in which hydrogen peroxide is electrolysed. The hydrogen peroxide is produced as a result of the oxidation of glucose on a glucose oxidase membrane, and the l;ullelll through the circuit provides a measure of the hydrogen peroxide concentration, and hence the glucose concentration, in the vicinity of the sensor.
The sensor is in the form of a composite electrode comprising both the pl~tinllm and silver electrodes, a glucose oxidase membrane layer, a polyurethane film which is permeable to glucose, oxygen and hydrogen peroxide, and a steel, glass and plastics supporting structure.
The composite electrode is attached to the forward end of the catheter 15 which is inserted into a blood vessel or beneath the skin of the subject.
The accuracy of the electrode (and accordingly, the accuracy of the controlled delivery of insulin or glucagon) depends on the efficient conversion of glucose and oxygen to give gluconic acid and hydrogen peroxide. The amount of hydrogen peroxide must be reliably linked to 20 the amount of available glucose in the bloodstream. False determin~tions may, however, arise with the sensor described in EP-A-0 098 592 because all of the available glucose may not be converted by the glucose oxidase enzyme if there is an insufficient supply of oxygen.
Oxygen is available in dissolved form in the blood and it occurs 25 as a product of the electrolysis of hydrogen peroxide. However, the as~un~>lion that excess oxygen will be available relative to glucose may not be correct. If oxygen is not available in excess, then the amount of available oxygen (not glucose) will be the limiting factor in the reaction and the current provided by the electrode will provide a false 30 determination of the subject's glycemia.
The ultimate intention of manufacturers of closed loop systems is to devise a system which provides the subject's entire insulin CA 02204370 1997-0~-02 WO 96/14026 PCT/lh~ ,/OQ05 requirement without there being any need for self-injection of bolus insulin. Accordingly, any such system must be acceptable to the patient in terms of being as unobtrusive as possible, being minim~lly painful and tr~llm~tic in application and use, providing minimum discomfort 5 during aclmini~tration, as well as being of the utmost reliability and efficiency. These objectives are not met by the devices of the prior art, for the reasons outlined above, and it is an object of the present invention to provide a device having the above-mentioned qualities.
A further aspect of the invention relates to a sensor per se for 10 use in conjunction with an open loop system, to provide an indication that the rate of drug delivery should be varied or that a bolus injection should be atlministered. It can also be used in conventional diabetes therapy to replace the uncomfortable and potentially unreliable and dangerous method of self-~tlmini~tered blood tests at various intervals 15 throughout the day.
One of the primary problems associated with conventional diabetes therapy (i.e. self-injection of insulin, optionally preceded by a blood test) is its susceptibility to human error. A diabetic whose blood level has become unexpectedly hypoglycemic, e.g. as a result of 20 unforeseen or unexpectedly strenuous activity or as a result of prolonged abstinence from sugar-rich nourishment, is in severe danger of entering a hypoglycemic coma. The danger is compounded by the fact that the time lost between onset of hypoglycemic symptoms and an actual comatose state can be very short, and by the fact that 25 hypoglycemia has a profound psychological effect which is superficially similar to drunkenness in that the patient becomes giddy and loses inhibitions and a sense of responsibility. Furthermore, uninformed bystanders may in fact mistake hypoglycemic symptoms for drunkenness.
.
Bearing the above factors in mind, it would be desirable to provide means by which a patient can ascertain his or her blood glucose level as desired without the inconvenience of obtaining a blood sample and carrying out a blood glucose test.
CA 02204370 1997-0~-02 W O96/14026 PCT~E95100055 Another object of this aspect of the invention is the provision of a blood glucose monitor which informs the diabetic (and, optionally, people in the vicinity) that the blood glucose levels are abnormally low or high, as the case may be, thereby allowing the diabetic to take 5 corrective action, such as the intake of a sugar-rich drink, for example or an injection of insulin, depending on whether hypoglycemia or hyperglycemia is indicated.
Bearing in mind that relatively sophisticated and/or costly electronic circuits may be used in such a monitoring device, it is highly 10 desirable to minimi~e the expense involved in manufacturing the device. This is particularly true in the case of a device employing an enzymatic sensor, since such a sensor will probably have quite a short life span necessitating frequent replacement. Even a significantly advantageous invention, improvement or modification will not achieve 15 its commercial potential if, in the opinion of the consumer the expense is not justified by the advantages.
A further problem associated with enzymatic sensors which are intended for use by patients under real life conditions, as opposed to experimental prototypes, is that of sensor degradation. Even if a 20 sensor is calibrated, it can become ~l~m~ged, inefficient or inaccurate as a result of incorrect application, abrasion, manufacturing flaws, changes in enzyme activity with time or changes in the transport properties of protective membranes surrounding the sensor due to interactions with foreign materials.
A paper by Rishpon J. (BioteGhnology and Bioengineering, Vol.
XXIX, pages 204-214 (1987)) deals with improved glucose oxidase enzyme electrodes and provides a method of determining some of the parameters affecting electrode efficiency from the signal obtained. The experiment described uses platinum disc electrodes covered by a glucose oxidase enzyme layer cross-linked to bovine serum albumen.
The electrode is initially held for 10 seconds at 0.0 volts and then stepped to 0.8 volts for 10 seconds. This square wave potential pattem is repeated and the current is measured. The current is digitized and CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 fed to a microcomputer every 200 ~s. These individual current readings were averaged to provide improved resolution, but were nevertheless found to give lln~ti~factory resolution and signal to noise ratio. Accordingly, the current readings were integrated to provide 5 coulometric rather than amperometric data. This coulometric data was then analysed to provide kinetic and transport parameters relating to the electrodes and it was found that the analysed data could be used in the evaluation of various electrode types.
The present invention seeks to provide a deterrnination of sensor 10 quality or degradation when the sensor is used in vivo on an on-going basis without requiring extensive computations and analysis, and providing direct results rather than abstract parameters such as diffusion co-efficients (as obtained by Rishpon).
Yet a further object of the invention is to provide improved 15 signal to noise ratios using direct measurements, without requiring complex multiple measurements, averagings and integrations. In this respect, it should be noted that the background noise in measuring glucose activity may be greatly increased by the presence of materials such as paracetamol which interfere with the accuracy of glucose 20 measurements by the enzymatic sensor. In the amperometric measurements described by Rishpon, unsatisfactory resolution and signal-to-noise ratios were obtained before integration was effected, and it should be noted that each data point on the amperometric graph described by Rishpon as "lm.~ti~factory" in fact represented the 25 averaging of 2500 distinct measurements.
Disclosure of Invention Accordingly, the invention, in a first aspect, provides a liquid delivery device for delivering a liquid drug to a subject via the subject's skin at a rate sufficient to maintain plasma levels of an analyte 30 within a physiologically acceptable range, comprising:
CA 02204370 1997-0~-02 a housing having a lower surface for application to the skin of the subject;
means for holding the housing in position with the lower surface against the subject's skin;
a drug reservoir within the housing;
a hollow delivery needle associated with the drug reservoir extending through the lower surface when the lower surface is in contact with the subject's skin, having an inner end communicating with the drug reservoir and an outer end projecting outwards a sufficient 10 distance so as to penetrate through the epidermis and into the dermis when the housing is pressed ~g~in~t the skin;
means for actively discharging the drug from the reservoir to the subject's skin via the needle;
means for detecting the concentration of an analyte in the 15 subject's plasma and for providing an electrical signal in accordance with the detected concentration, the concentration of said analyte being directly or indirectly related to the amount of drug required by the subject; and means for receiving said electrical signal and for controlling the 20 rate of active discharge of drug in response thereto.
The term "liquid" as used herein includes pure liquids, solutions, suspensions, low-viscosity gels and other flowable compositions. The term "drug" includes pharmaceutical, therapeutic, diagnostic and nutritional agents, and compositions cont~ining such agents.
The device according to the invention is far less painful in application and use if suitable needle dimensions are chosen.
Preferably, the needle is of a suitable length to penetrate the patient's skin either intradermally (i.e. the tip of the needle extends to a point CA 02204370 1997-0~-02 within the dermis) or subcutaneously (the tip of the needle penetrates through the dermis into the underlying tissue).
The device can be pressed against the skin and this action ensures correct insertion of the needle. If a narrow needle, preferably having S an outer diameter of less than 0.2 mm, is used, only the minimum arnount of trauma will be associated with the application of the device.
Furthermore, as the manner of insertion of the needle is invariable (the device is pressed against the skin and the needle always penetrates the skin correctly), the subject can personally apply the 10 device without having to take any particular precautions or without having to receive any medical training. This is not the case with the devices of the prior art, which require, for example, catheters to be inserted intravenously or subcutaneously. In conventional insulin therapy, the patient must be taught to ~lrninister subcutaneous 15 injections, and if sufficient care is not taken the injection may be intravenous or intramuscular rather than strictly subcutaneous, or the needle may hit a bone under the skin. If the injection is delivered to the wrong environment (vein or muscle), the uptake of drug will not occur at the correct rate. The risks associated with these occurrences 20 are significant drawbacks to known systems.
For the above reasons, the invention provides a significant advantage over known closed loop systems, m~king it suitable for -unsupervised use. As the device also has means for holding the housing in position with the lower surface against the subject's skin, the device 25 is completely portable and may be worn inconspicuously on the body under all clothing without requiring a belt or a bracelet-type strap.
Furthermore, as the device is not a two-part system, as is the case with EP-A-0 098 592, the signal may be communicated directly from the means for detecting the blood concentration of an analyte to the 30 means for controlling the rate of active discharge of the drug.
Accordingly, there is no danger of the signal from the sensor being .
WO 96/14026 PCT/IE9510005~i misinterpreted due to radio interference from nearby sources, and the device itself cannot interfere with nearby equipment.
The device is also less expensive to manufacture than the relatively complex portable artificial pancreases of the prior art. It can 5 be disposable and is preferably designed for once-daily ~lministration.
Suitably, the device is applied in the morning and worn throughout the day. It may be removed at night or worn throughout the night. If removed, the subject may inject a conventional night-time dose of insulin or the device may be adapted to deliver a suitable bolus of 10 insulin before removal.
Suitably, the delivery needle extends permanently through the lower surface.
Preferably, however, said delivery needle is recessed within the housing when the lower surface is not in contact with the subject's skin, 15 and the device comprises means for extending the delivery needle through the lower surface so as to project outwards said distance when the housing is pressed against the skin. This may be achieved, for example, by means of a mechanical, electrical or piezoelectric sensor located on the lower surface of the housing, with the sensor means for 20 extending the delivery needle through the lower surface being actuated by the sensor. The extension of the delivery needle is carried out in a consistent and suitable manner when this embodiment is used.
Preferably, the delivery needle penetrates through the derrnis for subcutaneous delivery of the drug. The choice of intradermal or 25 subcutaneous delivery, however, depends on the condition to be treated, the drug to be used and the chosen therapy and dosage regime. For certain drugs, it is preferable to deliver dosages intraderrnally as a depot effect may be desired, i.e. the drug builds up in concentration within the skin layers and is gradually released therefrom to the 30 systemic circulation. With suitable drugs this depot effect can provide therapeutically effective blood levels many hours after the device has been removed.
CA 02204370 1997-0~-02 W O96/14026 PCT/lh~C~
According to a further embodiment of the invention, the means for detecting the plasma concentration of the analyte comprises a sensor needle extending from the lower surface of the housing when the lower surface is in contact with the subject's skin, the sensor needle having an 5 outer end projecting outwards a sufficient distance so as to penetrate through the epidermis and into the dermis when the housing is pressed against the skin.
Thus, the application of the housing can ensure the insertion of both the delivery needle and the sensor needle for the analyte. This is 10 particularly advantageous for the reasons recited above in relation to the delivery needle.
Suitably, the sensor needle extends permanently through the lower surface.
Preferably, the sensor needle is recessed within the housing when 15 said lower surface is not in contact with the subject's skin, and the device comprises means for extending the sensor needle through the lower surface so as to project outwards said distance when the housing is pressed against the skin.
The same means may be used to extend both the delivery needle 20 and the sensor needle siml-lt~nPously through the lower surface when the device is pressed against the skin. Alternatively, each needle may be activated separately as the particular parts of the housing adjacent to the point through which the needles extend comes into contact with the skm.
Suitably, the sensor needle penetrates through the dermis.
It is envisaged that the same needle may be used for the purposes of delivery and analyte sensing. Preferably, however, the delivery and sensor needles are in spaced apart relationship.
CA 02204370 1997-0~-02 In a preferred embodiment, the delivery and sensor needles are electrically conducting and the means for detecting the concentration of an analyte is to measure an electric current between the needles, the circuit being completed upon application of the lower surface to the 5 skin of the subject. The third r~ferellce voltage point kept at a specific voltage compared to the sensor needle an electric circuit comprising a power source connected between the needles, the needles may be entirely formed of conductive material or they may carry a conductive coating or conductive elements therein.
Suitably, the electrical signal provides a measure of the electric current flowing through the circuit.
Suitably, the sensor needle has an enzyme associated therewith, the enzyme being specific to the analyte to be detected and the current through the circuit being dependent on the concentration of a reactant 15 in the enzymatic reaction in the vicinity of the needle.
Preferably, the sensor needle has an enzyme associated therewith, the enzyme being specific to the analyte to be detected and the current through the circuit being dependent on the concentration of a product of the enzymatic reaction in the vicinity of the needle.
The use of an analyte-specific enzyme is particularly advantageous as such an enzyme can be used to detect minute concentrations of analyte in the blood, plasma or tissue of the subject.
The association of an electric c~ ellt with the enzymatic reaction allows a q~ntit~ive evaluation of analyte concentration. The electrical current may, of course, be amplified or analysed as a~ro~-iate by means of any one of a vast range of electronic techniques.
Furthermore, the enzyme allows high concentrations of analyte to be measured equally accurately as only a very small quantity of enzyme can catalyse large amounts of substrate (analyte). Some pure enzymes, for example, can catalyse the transformation of as many as lO,000 to 1,000,000 mols of substrate per minute per mol of enzyme.
Accordingly, only a very small enzyme supply needs to be associated CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 with the needle to ensure total analyte reaction in the vicinity of the needle.
Preferably, the product of the enzymatic reaction is a charged species, or said product spontaneously breaks down to produce a S charged species, or said product reacts catalytically at the surface of the needle to produce a charged species. The term "charged species" as used herein includes ions, protons and electrons. In any of these situations, the production of charged species in the vicinity of the needle allows a current to flow between the electrodes. Accordinglyt 10 the current through the circuit is dependent on the numbers of charged species available to carry current at any time.
Suitably, the product of the enzymatic reaction or a derivative thereof partakes in an electrochemical reaction, the sensor needle acting as one electrode of an electrochemical cell and the delivery needle 15 acting as another electrode. In accordance with Faraday's Laws of Electrolysis, the amount of a substance consumed at an electrode of an electrochemical cell is directly proportional to the current through the cell. Obviously, one would not expect this strict relationship to hold for an electrochemical cell incorporating a complex biological system, 20 but the circuit can nevertheless be calibrated to provide a correlation between the current and the analyte concentration.
Suitably, when the enzymatic reaction requires free oxygen to proceed, the structure of the sensor needle allows oxygen to pass from an inner end thereof which is in commllnication with a supply of 25 oxygen to the exterior surface of that part of the sensor needle which projects from the housing.
Preferably, the needle is a hollow needle open at the outer (skin-penetrating) end to provide communication between the inner end and the enzyme.
30The use of a hollow needle (or of some other structure of needle which allows oxygen to reach the location of the enzyme) confers an CA 02204370 1997-0~-02 W O96/14026 PCT/1~ 005 important advantage over conventional implanted enzyme sensors, as the hollow needle ensures that the rate of reaction is never restricted by a lack of oxygen. The supply of oxygen may be air inside the housing, air outside the housing, an oxygen reservoir within the housing or an S oxygen source (such as an electrochemical cell) inside the housing, to provide a few examples.
Preferably, the enzyme is in the form of an enzyme-containing coating on the surface of the needle.
Further, preferably, the enzyme-cont~ining coating is covered by 10 a protective coating of an analyte-permeable material.
Suitably, said analyte-permeable material is a perflourinated ion-exchange membrane, for example, "Nafion" ("Nafion" is a Trade Mark). This type of material protects the enzyme before and during operation of the device. If the sensor is in the form of a hollow needle, 15 the coating may cover the open end of the needle to prevent fluids from entering the needle.
According to a preferred embodiment, the analyte is glucose, and the drug is selected from glucagon and insulin or analogues thereof.
The insulin used in the device may be chosen to meet the 20 requirements of the patient. It may be bovine, porcine, human or synthetic and it may be short acting or long acting, or it may comprise a mixture of different types of insulin.
Preferably, in this preferred embodiment of the invention, the enzyme is glucose oxidase.
Further, preferably, the product is hydrogen peroxide.
In the preferred embodiment. the hydrogen peroxide is catalysed to produce oxygen, hydrogen ions and electrons and the magnitude of CA 02204370 1997-0~-02 WO 96/14026 PCT/IE9S~GCS~
the current through the circuit is related to the number of electrons produced.
Suitably, the hydrogen peroxide is produced adjacent to a platinum supply, the platinum supply catalysing the oxidation of the 5 hydrogen peroxide. The pl~tin~lm may be in a colloidal dispersion within a coating on the surface of the sensor needle, it may be carried by particles distributed in intim~te admixture with the enzyme supply, it may be provided on the surface of the sensor needle, or the sensor needle may comprise pl~timlm or a platinum alloy such as platinum-10 iridium.
A high degree of accuracy may be achieved if the electric circuit comprises a reference electrode which is adapted to contact the subject's skin and the sensor needle is biased at a fixed potential with respect to the reference electrode.
Suitably, the electric circuit comprises a potentiostat having an operational amplifier which drives a current between the sensor and delivery needles.
Further, preferably, the power source and the sensor needle are connected in series with the positive input of the amplifier, and a 20 resistor and the delivery needle are connected in series with the amplifier output, the reference electrode being connected to the negative input of the arnplifier.
As will be further described below, the potentiostat m~int~in.s the potential of the sensor needle at a preset level with respect to the 25 reference electrode by passing the current between the sensor needle and the delivery needle. Thus, the sensor needle acts as a working electrode and the delivery needle acts as a counter electrode.
The current through the reference electrode is, in a well calibrated potentiostat, minim~l and the current between the working 30 electrode and the counter electrode is independent of the resistance in CA 02204370 1997-0~-02 the "cell" (in this case the skin and tissue between the needles). Thus, the current is limited by the numbers of mobile charged species available to carry current.
Suitably, the current through the circuit is determined by 5 measuring the voltage drop across the resistor.
Preferably, a voltmeter connected across said resistor provides a signal determined by the magnitude of the voltage drop and the signal is amplified and supplied to the means for receiving an electrical signal and for controlling the rate of active discharge of drug in response 1 0 thereto.
Further, preferably, said means for controlling the rate of active discharge is a pre-programmable microprocessor which calculates the required drug dosage from the received signal and which controls the rate of active discharge in order to provide the required dosage.
Optionally, the circuit comprises switching means to allow current to flow intermittently. In this embodiment, the time taken for the current to reach a steady state (if a steady state is reached) can be analysed to determine information regarding the operation of the device. Suitably, therefore, a charge accumulates at the sensor needle when current is prohibited and the charge disperses when current flow begins.
An explanation of how a pulsatile current can be used to derive useful information on transport and kinetic parameters is given in the paper by J. Rishpon referred to above. By using a voltage stepped periodically between 0.0V (10 seconds) and 0.8V (10 seconds) and observing the resultant current specifically by sampling the current at intervals of 200 ,us and integrating the digitized signal to obtain a chronocoulometric response, sensitivity was greatly increased above that available by steady-state measurements. However, sophisticated equipment including a micro-computer was required to digitize, average and integrate the current measurements.
CA 02204370 1997-0~-02 W O96/14026 PCT~E95/0005S
Preferably, the switching means comprises means for intermittently applying a voltage to the sensor needle. Suitably, the voltage is applied as a stepped voltage. As the enzymatic reaction proceeds independently of the current, a charge will accumulate at the 5 sensor needle when the current is switched off. When the current is switched on, the charge is able to disperse, and the current takes the form of a peak which falls away to a steady state level.
Preferably, the current is measured immediately after the stepped voltage is applied. This enables a large current to be measured 10 and improves the signal to noise ratio.
In a preferred embodiment, the circuit further comprises means for comparing the current at different times. This information can be used to evaluate the efficiency and condition of the electrode. In one embodiment, the current is measured twice at times tl and t2 as it falls 15 from a peak level towards a steady state level, given value I(tl) and I(t2). The ratio I(tl)/I(t2) has been found to be a constant which is specific to the electrode and which is independent of the concentration of the analyte being measured. It is also been found that for any given construction of electrode, the ratio will remain constant as long as the 20 electrode is functioning correctly, but when the ability to detect glucose is impaired, the ratio will change. Therefore, repeated measurements of this ratio provide a way of monitoring the quality of the sensor over time and the user can thereby be alerted when the sensor requires replacement.
To facilitate the application of the device, in a preferred embodiment, the lower surface is shaped such that when it is pressed against the skin a substantial proportion of the pressure applied to the skin is directed through the needle tip. Thus, the needle may project permanently from a suitable part of the lower surface or it may be extended from a suitable part of the lower surface when the lower surface is pressed against the skin. Preferably, the shape of the lower surface is adapted to compensate for the elasticity of the skin by the design of the lower surface. Generally, this means that the lower CA 02204370 1997-0~-02 surface is shaped such that a substantial portion of the pressure is directed through the tip of the needle itself rather than through the skin-contacting parts of the lower surface, at least while the housing is being pressed against the skin.
Suitably, for example, the lower surface of the housing may have a convex shape and the hollow needle may extend from the centre of the convexity, or the lower surface may be provided with a protuberance from which the needle projects, or the lower surface may be of a conical shape with the needle extending from the apex of the cone (suitably, this is an inverted cone with a large base-to-height ratio).
Preferably, the means for affixing the housing in position comprises a pressure-adhesive coating on the lower surface thereof.
This allows the device to be far less obtrusive than the sort of device which must be worn on a belt, shoulder strap or bracelet.
Suitably, the delivery and/or sensor needle(s) project outwards of the housing by 0.3-3.0 mm and have an outer diameter of 0.05-0.4 mm, preferably 0.1-0.3 mm, and an inner diameter of 0.02-0.1 mm, preferably 0.05-0.075 mm. Such needle dimensions allow for intradermal or subcutaneous delivery and a small outer diameter ensures that the application of the needle(s) is relatively painless.
In a preferred embodiment of the invention the reservoir is in the form of an expansible-contractible chamber which is expanded when filled with the drug and whi~h can be contracted to dispense the drug therefrom. Suitably, the drug reservoir, when filled, has a volume of the order of 0.2 ml to 10.0 ml.
Further, preferably, the means for actively discharging the drug comprises an electrically controlled gas generator within the housing for generating a gas to contract the drug reservoir in order to discharge the drug therefrom. Suitably, the gas generator is an electrolytic cell. The use of an electrolytic cell is preferred as the CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 generation of gas is highly controllable and is suitable for delivering accurate amounts of the drug, as well as for allowing the delivery of drug to be started and stopped subst~nti~lly inst~nt~neously if pulsatile delivery is required.
As a preferred feature, the device comprises a start button which is depressible in order to energize the gas generator and thereby to start discharging the drug from the drug reservoir.
Suitably, the means for controlling the rate of active discharge comprises an electronic circuit for controlling the time and rate of gas generation, thereby controlling the discharge of the drug from the drug reservolr.
Optionally, the device further comprises a membrane which is permeable to the drug and impermeable to solid impurities, the membrane covering the inner end of the delivery needle.
The invention provides, in a second aspect, a device for monitoring the concentration of an analyte in the plasma of a subject.
comprising:
a housing having a lower surface for application to the skin of the subject;
means for holding the housing in position with the lower surface ~g~in~t the subject's skin;
an electrical detection circuit comprising a power source connected across two electrodes mounted on said lower surface, the circuit being completed upon application of the lower surface to the skin of the subject, one of said electrodes being a sensor needle for penetrating through the epidermis and into the dermis when the lower surface is applied to the skin and having an enzyme associated therewith, said enzyme being specific to the analyte to be detected, and the current through the circuit being directly or indirectly dependent CA 02204370 1997-0~-02 WO 96/14026 PCT/I~5S/~):10~5 on the concentration of the analyte in the vicinity of the sensor needle;
and a communication circuit comprising means for measuring the current through said electrical detection circuit, means for calculating 5 the plasma concentration of the analyte from the measured current and communicating means for communicating the calculated concentration to the subject.
The application of such a device is no more painful, and may, in fact, be less painful, than a conventional pin prick blood test. Unlike 10 such a blood test, however, the device according to the invention need not be repeatedly administered if the blood levels need to be rechecked.
The device may, in fact, be worn in place for continual monitoring over a period of, for example, 12 hours, one day, two days or up to one week. The period is generally limited by the exhaustion of, or a 15 decrease in the efficiency of, the enzyme associated with the sensor needle. The presently preferred frequency of a~mini~tration is once-daily as this ensures that the sensor needle is always in optimum condition and it also allows the subject to change the site of application regularly.
Suitably, the enzyme is glucose oxidase and the analyte to be measured is glucose.
The invention is not, however, limited solely to glucose monitoring devices. Similar enzymatic sensors may suitably be employed if alternative analytes require monitoring.
According to a preferred embodiment, the sensor needle is a working electrode and the other of said two electrodes is a counter electrode in the form of a platinum surface for contact with the subject's skin.
Although the counter electrode can be an invasive electrode (i.e.
a needle) there is no necessity in the present case for a second needle, CA 02204370 1997-0~-02 WO 96/14026 PCT/lh~ 'uG~
and in the interests of comfort, it is preferred to employ a counter electrode which rests against the skin. Preferably, the area of such an electrode is maximised to increase sensitivity. In certain cases, the sensitivity of an electrode resting against the skin may not be sufficient, 5 and, accordingly, an invasive needle may be used.
Preferably, the electrical detection circuit also comprises a reference electrode on the lower surface of the housing, in the form of a silver/silver chloride surface for contact with the subject's skin, and a potentiostat having an operational amplifier which drives a current 10 between the working electrode and the counter electrode.
Such a circuit operates as hereinbefore described with reference to the embodiments of the invention in its first aspect.
According to a particularly preferred embodiment, the housing comprises a first part and a second part, the first part comprising the 15 lower surface and the electrodes and the second part comprising the power source and the comm--nication circuit.
Suitably, the first part is detachably mounted on the second part, such that the first part can be disposed of and replaced and the second part can be reused a number of times.
When a two-part device is used, the costs can be considerably lower. The first part contains all of the disposable elements (adhesive, electrode coatings, etc.), while the second part contains the reusable elements, such as the electronic components, the co..~ icating means and the power source. Although a power source such as a battery must 25 be replaced periodically, it is a relatively permanent element in comparison to an enzymatic sensor. Long-term batteries can be used having a life span of over two years. Accordingly, such batteries can be reused hundreds of times relative to the first part.
CA 02204370 1997-0~-02 W O96/14026 PCTnE95/00055 Suitably~ the communicating means is activated when the calculated analyte plasma concentration falls outside a predetermined range.
Further, suitably, the communicating means comprises an audible 5 alarm.
Thus, an audible alarm can be made to sound if the subject has blood levels approaching those associated with hyperglycemia or hypoglycemia, and corrective action can be taken before any serious condition develops. Preferably, different sounds are emitted by the 10 alarm depending on the condition of the patient. Furthermore, different sounds or louder sounds can be emitted if the situation worsens.
Preferably, the commllnicating means operates continuously to provide a constant indication of the subject's analyte plasma 15 concentration.
Further, preferably, the communicating means comprises a visible display of the analyte concentration. Suitably, the visible display is in the form of a liquid crystal display for indicating the analyte concentration as a numerical value.
Other visible displays are, of course, possible, such as a series of light, with a number of lights lit indicating an approximate blood glucose level, or a dial indicating a nurnerical value relating to the blood glucose level, etc.
One of the most important advantages associated with a device according to the invention is that the patient can check blood glucose levels throughout the day and, through experience, a f~mili~rity can be built up with the patterns of fluctuation in blood glucose level associated with normal daily routine and with extraordinary events such as strenuous exercise, the consumption of different types of foods and drinks and variations in insulin dosage. This will provide a CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 diabetic with an awareness of the effect of various factors on his or her blood glucose levels and preventive action can be taken before it is strictly required. Developing such an association need not be a conscious exercise on the part of the diabetic, because an association of S this type is built up through experience.
Heretofore, diabetic subjects have been able to recognise that blood glucose levels should be increased or decreased, but this is generally as a result of the onset of hyperglycemic or hypoglycemic symptoms. By recognising that corrective action is required before 10 such symptoms develop, the blood glucose levels of the subject will be far more regular.
An additional advantage is that a diabetic subject using a device according to the invention will not mistake unrelated symptoms as being related to abnormally high or low blood glucose levels. An 15 objective check is available which prevents the subject from mistakenly increasing insulin or sugar intake.
Although not explicitly enumerated, many of the features of the invention in its first aspect are suitable for incorporation into the second aspect, as will be apparent to the skilled person. Furthermore, 20 both aspects of the invention can be combined to provide a delivery device with monitoring and display features.
In a third aspect, the invention provides a method of measuring the plasma concentration of an analyte comprising the steps of: a) penetrating the epidermis with an enzymatic sensor which forms part 25 of an electrical circuit, wherein the current through the circuit is dependent on the presence of a species produced by the enzymatic reaction with the analyte; b) supplying a periodic potential to the enzymatic sensor such that current only flows through the electric circuit intermittently; and c) measuring the current shortly after it 30 begins to flow.
CA 02204370 1997-0~-02 W O96/14026 PCT/l~S~CS~
For the reason indicated above and, as will be further illustrated below, this method has been found to provide accurate results in a far simpler and more efficient manner than the chronocoulometric method known from the prior art.
Suitably, the potential is supplied intermittently as a periodic stepped potential, providing a disconnect period and a connect period, thereby giving rise to a peak current at the beginning of the connect period, falling away towards a steady state current level.
In a presently preferred embodiment, the disconnect period is at least one second long and the connect period is at least 20 microseconds long.
Preferably, the connect period is in the range 20-400 microseconds. More preferably it is in the range 40-80 microseconds.
Further, preferably, the disconnect period is in the range 1-15 seconds, more preferably 5-10 seconds.
These periods have been found to provide good results when used with the type of glucose sensor further described below. The disconnect period should be long enough for a substantial amount of the current-dependent species to build up at the electrode, in order to provide a strong peak current at the be~inning of the connect period.
Suitably, the current is measured in the first 15 rnicroseconds of the connect period. Preferably, the current is measured between 0.25 and 10 rnicroseconds after the beginnin~ of the connect period, and most preferably between 0.5 and 3 microseconds after the beginning of the connect period.
By measuring the current early in the connect period, a strong peak current will be obtained, thereby boosting the signal to noise ratio relative to a steady state amperometric measurements. In the method described by Rishpon (supra), measurements were only made every CA 02204370 1997-0~-02 W O96/14026 PCTnE95/00055 200 microseconds. It has been found that the best results are obtained if measurements are made well within 200 microseconds of the start of the connect period, as after 200 microseconds the current will have effectively dropped to a steady state level for many constructions of 5 electrode.
As indicated above in relation to the device, preferably, the method further comprises the steps of measuring the current a second time during the connect period, calc~ ting a ratio between the two measured values, and comparing this ratio to a memorised value or 10 range of values to determine whether the sensor is performing normally. Preferably the second current measurement is made when the current has fallen to a steady-state valve.
Suitably, the method also comprises the step of providing an indication that the sensor is defective if the calculated ratio is different 15 to the memorised value or range of values.
This indication can be effected in many ways, preferably by providing a visible or audible alarm.
Brief description of Drawin~s The invention will be further illustrated by the following 20 description of embodiments thereof, given by way of example only with reference to the accompanying drawings, in which:
Fig. 1 is a cross-section through a liquid delivery device according to the invention;
Fig. 2 is a m~gnified view of a detail of the device of Fig. 1;
Fig. 3 is a cross-section through a second liquid delivery device according to the invention;
Fig. 4 is a view of the underside of the device of Fig. 3;
CA 02204370 1997-0~-02 Fig. S is a schematic representation of the electronic circuit of the device of Fig. 3;
Fig. 6 illustrates an alternative construction of sensor needle for use in a device according to the invention;
S Fig. 7 illustrates a detail of the sensor needle of Fig. 6;
Fig. 8 is a schematic cross section through an embodiment of a device for monitoring plasma glucose levels, according to the second aspect of the invention;
Fig. 9 is a plan view of the underside of the device illustrated in Fig. ~;
Fig. 10 is a perspective view of an actual device of the type schematically illustrated in Fig. 8, before assembly;
Fig. 11 is a perspective view of the device of Fig. 10 when assembled;
Fig. 12 is a diagram of the potential applied to the sensor electrode and the corresponding current obtained from the electrode;
Fig. 13 is a plot of actual current profiles achieved for different glucose concentrations;
Fig. 14 is a plot of in~ t~eous culTent values against glucose concentration showing a linear relationship between current and glucose concentration;
Fig. lS is a plot of the ratio of two instantaneous current re~ling~ taken at different times for various glucose concentrations in respect of three different electrodes, showing CA 02204370 1997-0~-02 W O96/14026 PCT~E95/000~5 how this ratio can be used to evaluate the performance of the electrode;
Fig. 16 is a side cross sectional elevation of a further embodiment of sensor needle for use with the device according S to the invention; and Fig. 17 is a front elevation of the needle of Fig. 16.
Modes for carryin~ out the Invention Fig. 1 shows a device according to the invention, illustrated generally at 10, for use in the controlled delivery of insulin to a "Type 10 1" diabetic subject (i.e. suffering from insulin-dependent diabetes mellitus).
The device 10 comprises a housing 11 Cont~inin~ an insulin reservoir 12 for storing insulin in liquid form (suspension, solution or liquid) and a gas generation chamber 13. Reservoir 12 and gas 15 generation chamber 13 are separated by an elastomeric membrane 14, such that an expansion of gas generation chamber 13 leads to a corresponding contraction of insulin reservoir 12.
A platinum-iridium delivery needle 15 projects through a lower surface 16 of housing 11 by a distance of 2.5 mm. Delivery needle 15 20 is hollow and is open at an inner end 17 to insulin reservoir 12. It is also open at outer end 18 such that, when lower surface 16 of housing 11 is pressed against a subject's skirl, delivery needle 15 penetrates through the epidermis and the dermis, thereby establishing co..... ication between insulin reservoir 12 and the subject's 25 subcutaneous tissue via the hollow needle 15. If a shorter needle is used, communication can be established with the capillary system of the dermis.
Gas generation chamber 13 is provided with an electrolytic cell 19 powered by a battery 20 under the control of a programmable CA 02204370 1997-0~-02 WO 96/14026 PCT/lh5SI'~~ 55 microprocessor 21. Microprocessor 21 controls the rate at which gas is generated in electrolytic cell 19 by the electrolysis of water.
Electrolytic cell 19 has walls of a hydrophobic material which allow gas to permeate therethrough but which retain water within the 5 cell. When gas is generated by electrolytic cell 19, the pressure increases in gas generation charnber 13, causing the volume of chamber 13 to expand with a corresponding contraction of insulin reservoir 12 resulting in insulin being forced out of reservoir 12 through needle 15 (and, in use, into the patient's tissue).
Microprocessor 21 controls the rate of gas generation and, consequently, the rate of insulin delivery, by monitoring the patient's blood glucose level by means of a glucose sensor, indicated generally at 22. Sensor 22 comprises a pl~tinllm-iridium sensor needle 23 extending from lower surface 16 by about 2 mm.
Referring additionally to Fig. 2, it can be seen that sensor needle 23 is hollow and is open at both ends. Inner end 24 leads to a passageway 25 extending through housing 11 to the external atmosphere. Accordingly, outer end 26 of sensor needle 23 is, Yia passageway 25, in comrnunication with a supply of excess oxygen.
20 Needle 23 is coated with a glucose oxidase enzyme coating 27. This entire composite needle structure is covered by a layer of "Nafion" 28 which serves as a protective material, but is permeable to glucose, water, oxygen and hydrogen peroxide. "Nafion" layer 28 also covers open end 26 of stainless steel needle 23, thereby stopping blood from 25 entering and filling the hollow interior of needle 23.
Oxygen within sensor needle 23 can diffuse through "Nafion"
coating 28 into glucose oxidase enzyme layer 27. In addition, glucose and water can also diffuse through "Nafion" layer 28 into glucose oxidase enzyme containing layer 27. The enzyme catalyses the reaction 30 of glucose with oxygen and water, producing gluconic acid and hydrogen peroxide. Accordingly, hydrogen peroxide is produced in enzyme layer 27 surrounding platinum-iridium needle 23 in an amount CA 02204370 1997-0~-02 WO 96/14026 PCT/IE95/OOOS~
which is directly dependent on the amount of available glucose in the bloodstream.
Delivery needle 15 is a coated with a silver/silver chloride layer.
Battery 20 is connected between delivery needle 15 and sensor needle 5 23 via internal connecting wires 31 (Fig. 2) within the housing.
Accordingly, when the needles 15,23 penetrate into the dermis or the subcutaneous tissue, a circuit is closed by the establishment of an electrical connection between the needles 15,23. The circuit is effectively an electrochemical cell, with one electrode being a standard 10 silver/silver chloride electrode in aqueous solution (i.e. needle 23 with its coating immersed in the bloodstream) and the other electrode being a platinum electrode supplied with hydrogen peroxide.
The free mobile charges providing a flow of current through the sensor needle are produced in the catalysed oxidation of hydrogen 15 peroxide on pl~tinllm in the reaction:
H2~2 -~ ~2+ 2H+ + 2e~
The electrons produced in this reaction allow current to flow through the sensor needle 23.
The current through the circuit is limite~l by the numbers of electrons available at sensor needle 23. This means that, since the electrons are produced by hydrogen peroxide oxidation and the hydrogen peroxide is produced by the enzymatic oxidation of glucose, that the current depends on the glucose concentration in the bloodstream.
The current through the circuit is amplified and measured by microprocessor 21. Microprocessor 21, which comprises a stored programme, calculates the precise amount of insulin which must be delivered at any time in order to maintain glucose at the optimum physiological concentration.
CA 02204370 1997-0~-02 W 096/14026 PCT~E95/00055 The microprocessor 21 maintains this concentration by controlling the current flowing through electrolytic cell 19, since any increase or decrease in the amount of gas produced by electrolytic cell 19 results in a corresponding increase or decrease in the amount of 5 insulin injected into the subject via needle 15. In effect, therefore, device 10 acts as an artificial pancreas which contin~l~lly monitors the glucose concentration in the bloodstream and constantly adjusts the on-going rate of insulin ~tlministration to take account of the measured glucose level.
In contrast to prior art devices for the ~lmini~tration of insulin, device 10, which can be affixed to any suitable area of the skin (such as the upper arm or abdomen) is unobtrusive. It is easy and painless to apply; simply by pressing lower surface 16 against the skin, the two needles 15,23 penetrate the skin and an adhesive layer 29, which is 15 provided on lower surface 16, holds the device in place throughout the course of treatment. A device having a diameter of approximately 5 cm and a thickness of approximately 1 cm may contain a sufficient amount of insulin for treatment throughout 12 hours, 1 day, or up to l week.
The insulin used in the device may be chosen to meet the requirements of the patient. It may be bovine, porcine, human or synthetic and it may be short acting or long acting, or it may comprise a mixture of different types of insulin.
The needles 15,23, including the coatings thereon, have an external diameter of 0.2 mm. Accordingly, there are no large, open wounds (as there are with traditional delivery cannulas and sensor irnplants) which may become infected. Additionally, since the site of application can be changed daily, for example, the wounds will heal almost immediately and there is no possibility of either the sensor needle or the delivery needle becoming coated with fibrin.
A preferred embodiment of the invention is illustrated in Fig. 3.
The device, indicated generally at 40, comprises a housing 41 CA 02204370 1997-0~-02 containing an insulin reservoir 42 and a gas generation chamber 43 within which there is provided an electrolytic cell 44. Reservoir 42 and gas generation charnber 43 are separated by an elastomeric membrane 45 such that when gas is generated by electrolytic cell 44, 5 gas generation charnber 43 expands by displacing membrane 45 downwards and thereby contracting insulin reservoir 42 causing the drug to be discharged therefrom.
The rate of generation of gas is controlled by a microprocessor 46 which receives a signal from a glucose sensing apparatus comprising a potentiostat 47 linked to a sensor needle 48 and a delivery needle 49 of the types described above with reference to Figs. 1 and 2. The potentiostat is also connected to a reference electrode 50 on the lower (skin-contacting) surface 51 of housing 41. The arrangement of sensor needle 48, delivery needle 49 and reference electrode 50 on lower surface 51 of housing 41 as illustrated in Fig. 4.
Fig. 5 is a schematic representation of the electronic circuit of device 40. Potentiostat 47 is shown as a dotted outline. It comprises an operational amplifier 51, a power source (Vin) connected between the positive input of operational arnplifier 51 and sensor needle 48 (which 20 acts as the working electrode), and a resistor 52 connected between the output of operational arnplifier 51 and delivery needle 49 (which acts as the counter electrode). Reference electrode 50 is connected to the negative input of the operational amplifier 51.
Potentiostat 47 serves to hold the working electrode 48 at a fixed 25 potential relative to the reference electrode. Since both inputs to the operational amplifier are effectively at the same potential, the potential difference between reference electrode 50 and working electrode 48 is equal to Vin. The current through the amplifier 51, which is dependent on the amount of glucose detected by sensor needle 48, is effectively 30 independent of the resistance of the "cell" between working electrode 48 and counter electrode 49, (at least within the operating range of the operational amplifier).
CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 The current is calculated from the voltage drop across resistor 52 using a voltmeter 53 which provides a signal to microprocessor 46 which interprets the signal as indicating a certain glucose concentration in the tissue surrounding sensor needle 48. Voltmeter 53 actually 5 includes both a floating-input voltmeter and an amplifier connected to the output of the voltmeter to provide a signal of suitable strength to microprocessor 46. One or more power sources (not shown) are also included for the purposes of powering electrolytic cell 44 (Fig.3), the amplifier connected to the voltmeter output, and microprocessor 46.
10 The power source(s) may be that/those used in the potentiostat circuit or separate power source(s) may be provided.
An alternative composition of sensor needle to that illustrated in Fig. 2 is shown in Fig. 6. A hollow stainless steel sensor needle 60 has a single coating layer 61 formed from a casting solution of 15 perflourosulphonic acid polymer, such as the perflourinated ion exchange membrane, "Nafion", glucose oxidase enzyme, and a carbon supported catalyst.
As illustrated in more detail in Fig. 7, the "Nafion" membrane 62 provides an insoluble biocompatible protective matrix for the 20 enzyme 63 retains the enzyme for long term availability in the electrode structure. Membrane 62 also dissolves large quantities of oxygen that is then available adjacent to the enzyme to promote hydrogen peroxide forrnation for signal generation. The carbon supported catalyst is in the form of platinum-loaded carbon particles 64 25 having about 10% by weight of pl~tinllm The particles 64 serve two functions: firstly, the catalytic surface for oxidation of hydrogen peroxide is dispersed throughout the matrix layer 62 within which the hydrogen peroxide is generated; secondly, the carbon support for the catalyst provides an electrically conductive path for electrons produced 30 by the oxidation reaction. An electrode having this type of supporting layer is described in U.S. Patent No. 5,227,042, the disclosure of which is incorporated herein by reference. As U.S. Patent No. 5,227,042 discloses, other catalysts from the platinum group, such as palladium, ruthenium or rodeium can be used in place of platinum.
CA 02204370 1997-0~-02 W O 96/14026 PCT~E95/00055 Fig. 8 is a schematic illustration of an embodiment of the second aspect of the invention, namely a device for monitoring the plasma concentration of an analyte. The device, indicated generally at 50, comprises a housing 51 detachable into a first part 52 and a second part 5 53. The device 50 has a number of features in common with the embodiments of the first aspect of the invention. Specifically, first part 52 of housing 51 has an adhesive lower surface 54 which is provided with a working electrode 55, a counter electrode 56 and a reference electrode 57. The electrodes 56,56,57 are connected to a potentiostat 10 58 as hereinbefore described.
Working electrode 55 is a platinum-iridium needle coated with a glucose oxidase enzyme coating, as previously described. Counter electrode 56 is in the form of a platinum-iridium surface adapted to rest against the subject's skin and reference electrode 57 is in the form 15 of a silver/silver chloride surface adapted to rest against the subject's skin. As previously described, the current passing between working electrode 55 and counter electrode 56 provides a measure of the glucose concentration in the vicinity of working electrode 55. This current is measured by a microprocessor 59 which is calibrated to 20 allow calculation of the glucose plasma concentration from the measured current through potentiostat 58.
Microprocessor 59 is pre-programmed to activate an audible alarm 60 in the case of hyperglycemia or hypoglycemia. These conditions are recognised by the microprocessor if the calculated 25 glucose concentration rises above or falls below a specific range.
Alarm 60 emits different sounds depending on whether hyperglycemia or hypoglycemia is indicated by microprocessor 59. In practice, microprocessor 59 activates audible alarm 60 before the glucose plasma concentration reaches a dangerous level. Thus, the subject, or those 30 supervising the subject, can act in good time by administering glucose-rich food and drink or by aclministering insulin, as the case may be, before corrective action becomes absolutely critical.
CA 02204370 1997-0~-02 Microprocessor 59 also communicates with a liquid crystal display (LCD) 61 which has seven-segment displays to provide a numerical indication of the level of glucose in the subject's plasma.
Thus, if device 50 is worn on a continual basis, the subject can check 5 his or her blood glucose levels at will. In this way, the subject can titrate insulin and/or sugar intake as and when required to provide a plasma glucose profile which more closely resembles that of a healthy individual than that of a self-administering diabetic who self-atlministers insulin according to traditional criteria (i.e. fixed dosages, 10 variable dosages according to the results of occasional blood tests).
Whereas blood tests prior to insulin ~ ni~tration can allow patients to determine optimum dosages, it is impossible for a diabetic to objectively gauge his or her glucose intake requirements between injections, so the diabetic subject is either confined to a strictly 15 controlled diet or else runs the risk of misjudging a safe level of sugar intake.
Battery 62 powers the device and a start button 63 is provided to activate the device after administration to the skin of the subject.
As illustrated, the device 50 is in two parts 52,53 which are 20 separable from one another. First part 52, which is disposable, comprises the three electrodes 55,56,57 and lower surface 54. As the efficiency of the electrodes will decrease over time (in particular, the dependability of the enzymatic sensor or working electrode 55 will not remain stable indefinitely), it is desirable to replace the electrodes on a 25 regular basis. Second part 53 houses all of the reusable elements of the device. Electrical contact is effected between potentiostat 58 and electrodes 55,56,57 by means of two sets of interengagable contacts 64,65 which fit together when first part 52 is mounted on second part 53. Thus, first part 52 can be replaced daily, for example, whereas 30 second part 53 can be reused indefinitely.
Suitably, battery 62 is a long-terrn battery which allows second part 53 to operated continuously over two-three years before CA 02204370 1997-0~-02 W O96/14026 PCT/l~ r5 replacement of battery 62 is necessitated. Microprocessor 59 monitors the power level of battery 62. As battery 62 becomes exhausted, its power decreases and microprocessor 59 activates alarm 60 to provide a special alarm indicating that replacement of battery 62 is necessary.
Push button 63 performs an additional function in that it can be used to reset the alarm when blood glucose levels have moved outside the acceptable range; microprocessor 59 will then only reactivate alarm 60 when calculated glucose levels next move outside the allowable range or, if the levels do not return to norrnal, when the patient's plasma glucose levels worsen appreciably.
Fig. 9 shows a view of the underside of device 50. Thus, lower surface 54 of first part 52 is seen with working electrode 55 (i.e. the enzymatic sensor needle) in the centre. On either side, two approximately semi-circular surfaces 56,57 are indicated by shaded lines. Surface 56 is the platinum-iridium surface of the counter electrode, while surface 57 is the silver/silver chloride surface of the reference electrode. Lower surface 54 is provided with a suitable adhesive to hold device 50 securely in place against the subject's skin.
In Figs. 10 and 11, device 50 of Figs. 8 and 9 can be seen in perspective view. Fig. 10 shows first and second parts 52,53 before assembly. First part 52 has three contacts 65 on the upper surface thereof which receive three complementary contacts (not shown) on the lower surface of second part 53. As indicated in Fig. 11, second part 53 is provided with a liquid crystal display 61 which gives a numerical indication of the blood glucose levels. Beside LCD 61, push button 63 can be seen. An additional feature which is not illustrated in Figs. 8 and 9 is a release liner 64 which covers the lower surface (not visible) of first part 52 before use. Release liner 64 is provided both for safety reasons (i.e. to cover the needle before use) and to ensure that the electrode surfaces are undamaged upon application to the skin of the subject.
CA 02204370 1997-0~-02 W 096/14026 PCT~E95/000~5 Fig. 11 shows device 50 when first part 52 has been mounted on second part 53 to form a single housing 51. First and second parts 52,53 are held together by means of a snap action mechanism (not shown). In use, release liner 64 is then removed and housing 50 is 5 present against the surface of the subject's skin such that the sensor needle (not shown) penetrates through the epidermis and into the dermis (depending on the length of the sensor needle, it may also penetrate through the dermis to the subcutaneous tissue) to allow contact between the enzymatic coating on the sensor needle and the 10 subject's plasma. Contact is also effected between the subject's skin and each of the flat electrodes. Operation of the monitoring device begins when push button 63 is pressed. At the end of 24 hours, first part 52 is snapped away from second part 53 and replaced by a new, identical part for monitoring blood glucose levels throughout the subsequent 24 15 hour/period.
The operation of the measurement circuit has been described above with the working electrode held at a constant potential above the reference electrode. In a more sophisticated embodiment of the invention, however, a potential is only applied intermittently to the 20 working electrode, as indicated in Fig. 12. From Fig. 12 it can be seen that the potential is stepped between a lower value (preferably 0.0 V) where no current will flow, and a higher value (such as 0.6 V) where current is allowed to flow. Fig. 12 is not to scale and the disconnect period is preferably many times longer than the connect period. In a 25 preferred embodirnent, the disconnect period is 3-12 seconds and the connect period is 20-300 microseconds. In the experiments described below, the disconnect period was 7 seconds and the connect period was 60 microseconds.
During the disconnect period, the enzymatic reaction proceeds 30 and hydrogen peroxide builds up at the sensor electrode. Because no potential has been applied and no current is flowing, however, the hydrogen peroxide accumulates continually until the potential is applied allowing a current to flow. As can be seen in the upper half of Fig. 12, CA 02204370 1997-0~-02 the current begins with a peak which then falls away as the hydrogen peroxide is consumed.
Referring additionally to Fig. 13, actual curves obtained using this method can be seen. From these cur~es it will be seen that the peak 5 value is many times greater than the steady state value achieved after, for example, 30 microseconds. If one compares the peak values obtained for glucose concentrations of 0, 1, 2, 4 and 8 mM it can be seen that one can easily distinguish between and measure the peak concentrations, whereas the steady state concentrations are so close 10 together as to be almost indistinguishable. Thus, a greatly improved signal to noise ratio is obtained by applying an intermittent voltage and measuring the current obtained at the peak (or shortly thereafter).
This greatly enhances the accuracy of measurements which can be made using this type of enzymatic sensor, and it has been found that the 15 response of peak current to glucose concentration is effectively linear.
The measurements in Fig. 14 were taken one microsecond after the potential was applied. Each data point therefore represents a single current reading at t = lms ~lS for a given glucose concentration.
The performances of the electrodes were evaluated by measuring 20 the ~ rlcllls Il at t = 1 ~s and I2 at t = 55 ~s and then calculating the ratio Il/I2. This ratio was calculated for each glucose concentration for three different electrodes. One of the electrodes (experiment 101) had degraded and had lost its ability to measure glucose properly, whereas the other two electrodes (experiments 11 1 and 112) were functioning 25 perfectly. It can be seen that the ratio Il/12 in each case is independent of glucose concentration and is equal for the electrodes used in experiments 111 and 112. However, a lower value for Il/I2 was obtained in experiment 101 and is indicative of the loss of performance. While more sophisticated analytical techniques can be 30 based on the principle used to make the Fig. 15 measurements, Fig. 15 represents a very simple but effective method of continuously monitoring electrode performance. The detecting circuit can be designed to sound an alarm or provide a visual indication when the CA 02204370 1997-0~-02 W O96tl4026 PCTAE95/0005 ratio Il/I2 changes by an appreciable amount, thereby indicating that the electrode should be replaced.
For best results it has been found advantageous to measure Il as quickly as possible (e.g. 1-1.5 ~s after the circuit is closed) and to 5 measure 12 when the current has reached steady state (e.g. after 90% of the total connect time has elapsed).
In sllmm~ry, the "pulse sampling method" described above and illustrated by Figs. 12-15 provides the following advantages:
(i) the signal is at least two orders of magnitude higher than 10 with a continuous sampling method. Therefore, less amplification is needed, and higher accuracy is achieved.
(ii) the signal to noise ratio is vastly improved; the noise obtained is less than 10% of the signal. In the continuous sampling (or continuous current) method, the noise is higher than the signal itself 15 and its value is elimin~ted by averaging the samples.
(iii) the pulse sampling method is less sensitive to the presence of substances such as ascorbic acid, uric acid, paracetamol, etc. The reason for this is that enzymatic detection is effected using two reactions: ~lrstly, the chemical reaction where the analyte is converted 20 and a by-product such as hydrogen peroxide is formed; and secondly, an electrochemical reaction, where hydrogen peroxide is consumed and an electric current flows through the electrodes. The chemical reaction takes place whenever the reactants and enzyme are present, while the electrochemical reaction only takes place when the electrode is at a 25 sufficient potential. At that potential, the abovementioned substances also react with the electrode and induce an undesired current that adds to the current generated by hydrogen peroxide decomposition. When using the pulse sampling method, the voltage is intermittently connected to the electrodes. When disconnected, hydrogen peroxide accumulates 30 at the electrode site but the other substances do not accumulate appreciably during these breaks. Therefore, when reconnecting the CA 02204370 1997-0~-02 W O96/14026 PCT/l~g51000 potential, there is an "amplification" of the hydrogen peroxide signal compared to the signal resulting from the other substances and therefore their contribution to noise becomes less significant. This "amplification" of the hydrogen peroxide signal relative to the ascorbic acid/uric acid/paracetamol signals would not exist if the voltage was applied continuously.
(iv) The values, gradient and shape of the pulse carry important information about the condition of the sensor. This can be used to monitor the sensor. In prior art electrodes, the degradation of the sensor would only show as an artificially increased or decreased analyte measurement which would be more likely to be wrongly interpreted as an actual measurement than to be interpreted as an indication of sensor degradation. The ability to distinguish between a false signal and a (l~m~ged sensor means that the sensor according to the invention is far safer than known sensors for use as a measuring tool.
In Figs. 16 and 17, there is indicated, generally at 70, a further embodiment of sensor needle for use with a device according to the invention. The needle 70 comprises a platinum-iridium rod 71 having a bevelled tip 72. The rod 71 is 0.3 mm in diameter.
A transverse bore 73 extends through the thickness of the rod, and bore 73 is filled with an enzyme matrix 74 formed from a casting solution of perflourinated ion exchange membrane ("Nafion"), and glucose oxidase enzyme. A bore 75 extends axially through the length 25 of the rod allowing communication between enzyme matrix 74 and the atmosphere. Bore 75 is 0.1 rnm in diarneter. Each of bores 73 and 75 can be conveniently formed by laser drilling.
Needle 70 works in exactly the same manner as the needles previously described, but provides an advantage in that the enzyme 30 matrix 74 is provided internally of the needle and not as an external coating. This elimin~t~s any tendency for the enzyme layer to be W O96/14026 PCT~E95/00055 ~l~m~ed or scratched during manufacture (i.e. when the needle is affixed to the body of the device).
insulin delivery devices, as well as to analyte sensors for use in "closed loop" and "open loop" delivery systems.
Back~round Art Conventional therapy for insulin-dependent diabetes mellitus 10 involves self-~lministered subcutaneous insulin injections a number of times daily (usually two, three or four times). The dosage regime is designed to m~int~in the blood glucose level (glycemia) of the subject between hypoglycemic and hyperglycemic levels, preferably between 3 and 10 rnmol/l, taking into account variations arising as a result of, for 15 example, glucose intake at me~ltimes and glucose elimin~tion during periods of activity.
In order to provide better control of a subject's glycemia, continuous infusion pumps have been developed to deliver glucose at a basal rate. This rate may be pre-prog~ ,ed, or the patient or 20 physician may m~nll~lly control the rate according to the results of successive blood glucose tests (which can be carried out by the patient using apparatus which provides a result within a matter of minutes).
The basal rate is usually supplemented by bolus injections before meal times. Such pumps are known as "open loop" systems.
A subcutaneous catheter is used to deliver insulin from an infusion pump to the patient. The open wound caused by the catheter means that the catheter must be resited every few days. Complications arising from the use of the catheter can include erythemia, abscesses, cellulitus and, occasionally, systemic infection.
CA 02204370 1997-0~-02 W O96tl4026 PCT~E95/00055 Implantable devices are also known. Such devices are generally implanted in the abdomen. Complications arising from the use of implantable devices include infection, particularly of the implantation site, and skin necrosis over the implant.
S "Closed loop" systems comprise an insulin pump controlled by a microprocessor and a glucose sensor linked to the microprocessor.
The rate or frequency of insulin ~ ni~tration is controlled by the microprocessor according to the insl~ eous blood glucose level measured by the sensor. Because a system of feedback ~imil~r to natural homeostatic regulation is used, a closed loop insulin delivery system may also be referred to as an "artificial pancreas".
In general, closed loop systems are not implanted. Many of the known systems are of the so-called bedside type which include a reservoir and a pump for a hypoglycemic agent (such as insulin), a reservoir and pump for a hyperglycemic agent (such as glucagon or glucose), means for injecting each agent into the body, means for measuring the blood glucose levels, means for controlling the delivery of each agent at a rate determined by the measured blood glucose level and a housing cont~ining the reservoirs, pumps, measuring apparatus and controlling means. The size of this type of artificial pancreas means that it is limited to bedside use (which explains the name).
Furthermore, because the means for measuring blood glucose levels requires the collection of blood from the patient, this mode of therapy imposes a heavy burden on the p~tient, so that it is impossible to use the device continuously for a long period of time.
A portable artificial pancreas is known from EP-A-0 098 592.
The artificial pancreas has a reservoir for a blood- sugar control agent and a feed pump adapted to inject the control agent into the subject's body at a rate determined by a microcomputer. The microcomputer receives a signal from a glucose sensor which is inserted into the subject's body, and calculates the required insulin delivery rate from the detected glucose level. The glucose sensor and the injection unit (which includes the reservoir, the pump and the microcomputer), are CA 02204370 1997-0~-02 W O96/14026 PCT/L~5~'~GCSC
separate from one another and the output signal of the sensor is tr~n~mitted to the microcomputer by radio.
In the preferred embo~lim~nt, a detection unit, including the sensor and radio tr~n~mitter, is in the form of a wristwatch having a tube le~tling thererlolll to a catheter which has the blood glucose sensor at the end thereof. The injection unit, which includes a radio receiver for receiving the signal from the detection unit, is adapted to be worn on a belt.
This type of portable artificial pancreas shares the problems associated with open loop systems (i.e. erythemia, abscesses, cellulitus and systemic infection), but the problems are, in fact, m~gnified because two catheters are used instead of one.
Apart from the strictly medical problems associated with existing pumps, a significant amount of pain and trauma is also associated with the application of known devices when the catheter(s) is/are inserted into the skin.
Furthermore, such devices are inconvenient to use and may cause discomfort as the pumps are often quite bulky and are generally wom on a belt or a shoulder strap, as is the case with the injection unit of EP-A-0 098 592.
Although implantable devices have found a limited success in open loop systems, they are unsuitable for use in closed loop systems as a failure of the sensor pump, or controlling equipment, or the blockage of an outlet (which might occur as a result of a build-up of fibrin, for 25 example), can lead to ketoacidosis. A patient using an open loop system will be supplementing the basal rate with bolus injections and may be carrying out regular blood glucose tests as before. Accordingly, there is far less danger of severe hypoglycemia or hyperglycemia occurring if an implanted open loop system fails than would be the case for a 30 patient with an implanted closed loop system.
CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 Portable closed loop systems, such as the system described in EP-A-0 098 592, require a reliable glucose sensor. The sensor employed in EP-A-0 098 592 comprises a pl~tin~lm electrode and a silver electrode. The platinum electrode and silver electrode form part of an S electric circuit in which hydrogen peroxide is electrolysed. The hydrogen peroxide is produced as a result of the oxidation of glucose on a glucose oxidase membrane, and the l;ullelll through the circuit provides a measure of the hydrogen peroxide concentration, and hence the glucose concentration, in the vicinity of the sensor.
The sensor is in the form of a composite electrode comprising both the pl~tinllm and silver electrodes, a glucose oxidase membrane layer, a polyurethane film which is permeable to glucose, oxygen and hydrogen peroxide, and a steel, glass and plastics supporting structure.
The composite electrode is attached to the forward end of the catheter 15 which is inserted into a blood vessel or beneath the skin of the subject.
The accuracy of the electrode (and accordingly, the accuracy of the controlled delivery of insulin or glucagon) depends on the efficient conversion of glucose and oxygen to give gluconic acid and hydrogen peroxide. The amount of hydrogen peroxide must be reliably linked to 20 the amount of available glucose in the bloodstream. False determin~tions may, however, arise with the sensor described in EP-A-0 098 592 because all of the available glucose may not be converted by the glucose oxidase enzyme if there is an insufficient supply of oxygen.
Oxygen is available in dissolved form in the blood and it occurs 25 as a product of the electrolysis of hydrogen peroxide. However, the as~un~>lion that excess oxygen will be available relative to glucose may not be correct. If oxygen is not available in excess, then the amount of available oxygen (not glucose) will be the limiting factor in the reaction and the current provided by the electrode will provide a false 30 determination of the subject's glycemia.
The ultimate intention of manufacturers of closed loop systems is to devise a system which provides the subject's entire insulin CA 02204370 1997-0~-02 WO 96/14026 PCT/lh~ ,/OQ05 requirement without there being any need for self-injection of bolus insulin. Accordingly, any such system must be acceptable to the patient in terms of being as unobtrusive as possible, being minim~lly painful and tr~llm~tic in application and use, providing minimum discomfort 5 during aclmini~tration, as well as being of the utmost reliability and efficiency. These objectives are not met by the devices of the prior art, for the reasons outlined above, and it is an object of the present invention to provide a device having the above-mentioned qualities.
A further aspect of the invention relates to a sensor per se for 10 use in conjunction with an open loop system, to provide an indication that the rate of drug delivery should be varied or that a bolus injection should be atlministered. It can also be used in conventional diabetes therapy to replace the uncomfortable and potentially unreliable and dangerous method of self-~tlmini~tered blood tests at various intervals 15 throughout the day.
One of the primary problems associated with conventional diabetes therapy (i.e. self-injection of insulin, optionally preceded by a blood test) is its susceptibility to human error. A diabetic whose blood level has become unexpectedly hypoglycemic, e.g. as a result of 20 unforeseen or unexpectedly strenuous activity or as a result of prolonged abstinence from sugar-rich nourishment, is in severe danger of entering a hypoglycemic coma. The danger is compounded by the fact that the time lost between onset of hypoglycemic symptoms and an actual comatose state can be very short, and by the fact that 25 hypoglycemia has a profound psychological effect which is superficially similar to drunkenness in that the patient becomes giddy and loses inhibitions and a sense of responsibility. Furthermore, uninformed bystanders may in fact mistake hypoglycemic symptoms for drunkenness.
.
Bearing the above factors in mind, it would be desirable to provide means by which a patient can ascertain his or her blood glucose level as desired without the inconvenience of obtaining a blood sample and carrying out a blood glucose test.
CA 02204370 1997-0~-02 W O96/14026 PCT~E95100055 Another object of this aspect of the invention is the provision of a blood glucose monitor which informs the diabetic (and, optionally, people in the vicinity) that the blood glucose levels are abnormally low or high, as the case may be, thereby allowing the diabetic to take 5 corrective action, such as the intake of a sugar-rich drink, for example or an injection of insulin, depending on whether hypoglycemia or hyperglycemia is indicated.
Bearing in mind that relatively sophisticated and/or costly electronic circuits may be used in such a monitoring device, it is highly 10 desirable to minimi~e the expense involved in manufacturing the device. This is particularly true in the case of a device employing an enzymatic sensor, since such a sensor will probably have quite a short life span necessitating frequent replacement. Even a significantly advantageous invention, improvement or modification will not achieve 15 its commercial potential if, in the opinion of the consumer the expense is not justified by the advantages.
A further problem associated with enzymatic sensors which are intended for use by patients under real life conditions, as opposed to experimental prototypes, is that of sensor degradation. Even if a 20 sensor is calibrated, it can become ~l~m~ged, inefficient or inaccurate as a result of incorrect application, abrasion, manufacturing flaws, changes in enzyme activity with time or changes in the transport properties of protective membranes surrounding the sensor due to interactions with foreign materials.
A paper by Rishpon J. (BioteGhnology and Bioengineering, Vol.
XXIX, pages 204-214 (1987)) deals with improved glucose oxidase enzyme electrodes and provides a method of determining some of the parameters affecting electrode efficiency from the signal obtained. The experiment described uses platinum disc electrodes covered by a glucose oxidase enzyme layer cross-linked to bovine serum albumen.
The electrode is initially held for 10 seconds at 0.0 volts and then stepped to 0.8 volts for 10 seconds. This square wave potential pattem is repeated and the current is measured. The current is digitized and CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 fed to a microcomputer every 200 ~s. These individual current readings were averaged to provide improved resolution, but were nevertheless found to give lln~ti~factory resolution and signal to noise ratio. Accordingly, the current readings were integrated to provide 5 coulometric rather than amperometric data. This coulometric data was then analysed to provide kinetic and transport parameters relating to the electrodes and it was found that the analysed data could be used in the evaluation of various electrode types.
The present invention seeks to provide a deterrnination of sensor 10 quality or degradation when the sensor is used in vivo on an on-going basis without requiring extensive computations and analysis, and providing direct results rather than abstract parameters such as diffusion co-efficients (as obtained by Rishpon).
Yet a further object of the invention is to provide improved 15 signal to noise ratios using direct measurements, without requiring complex multiple measurements, averagings and integrations. In this respect, it should be noted that the background noise in measuring glucose activity may be greatly increased by the presence of materials such as paracetamol which interfere with the accuracy of glucose 20 measurements by the enzymatic sensor. In the amperometric measurements described by Rishpon, unsatisfactory resolution and signal-to-noise ratios were obtained before integration was effected, and it should be noted that each data point on the amperometric graph described by Rishpon as "lm.~ti~factory" in fact represented the 25 averaging of 2500 distinct measurements.
Disclosure of Invention Accordingly, the invention, in a first aspect, provides a liquid delivery device for delivering a liquid drug to a subject via the subject's skin at a rate sufficient to maintain plasma levels of an analyte 30 within a physiologically acceptable range, comprising:
CA 02204370 1997-0~-02 a housing having a lower surface for application to the skin of the subject;
means for holding the housing in position with the lower surface against the subject's skin;
a drug reservoir within the housing;
a hollow delivery needle associated with the drug reservoir extending through the lower surface when the lower surface is in contact with the subject's skin, having an inner end communicating with the drug reservoir and an outer end projecting outwards a sufficient 10 distance so as to penetrate through the epidermis and into the dermis when the housing is pressed ~g~in~t the skin;
means for actively discharging the drug from the reservoir to the subject's skin via the needle;
means for detecting the concentration of an analyte in the 15 subject's plasma and for providing an electrical signal in accordance with the detected concentration, the concentration of said analyte being directly or indirectly related to the amount of drug required by the subject; and means for receiving said electrical signal and for controlling the 20 rate of active discharge of drug in response thereto.
The term "liquid" as used herein includes pure liquids, solutions, suspensions, low-viscosity gels and other flowable compositions. The term "drug" includes pharmaceutical, therapeutic, diagnostic and nutritional agents, and compositions cont~ining such agents.
The device according to the invention is far less painful in application and use if suitable needle dimensions are chosen.
Preferably, the needle is of a suitable length to penetrate the patient's skin either intradermally (i.e. the tip of the needle extends to a point CA 02204370 1997-0~-02 within the dermis) or subcutaneously (the tip of the needle penetrates through the dermis into the underlying tissue).
The device can be pressed against the skin and this action ensures correct insertion of the needle. If a narrow needle, preferably having S an outer diameter of less than 0.2 mm, is used, only the minimum arnount of trauma will be associated with the application of the device.
Furthermore, as the manner of insertion of the needle is invariable (the device is pressed against the skin and the needle always penetrates the skin correctly), the subject can personally apply the 10 device without having to take any particular precautions or without having to receive any medical training. This is not the case with the devices of the prior art, which require, for example, catheters to be inserted intravenously or subcutaneously. In conventional insulin therapy, the patient must be taught to ~lrninister subcutaneous 15 injections, and if sufficient care is not taken the injection may be intravenous or intramuscular rather than strictly subcutaneous, or the needle may hit a bone under the skin. If the injection is delivered to the wrong environment (vein or muscle), the uptake of drug will not occur at the correct rate. The risks associated with these occurrences 20 are significant drawbacks to known systems.
For the above reasons, the invention provides a significant advantage over known closed loop systems, m~king it suitable for -unsupervised use. As the device also has means for holding the housing in position with the lower surface against the subject's skin, the device 25 is completely portable and may be worn inconspicuously on the body under all clothing without requiring a belt or a bracelet-type strap.
Furthermore, as the device is not a two-part system, as is the case with EP-A-0 098 592, the signal may be communicated directly from the means for detecting the blood concentration of an analyte to the 30 means for controlling the rate of active discharge of the drug.
Accordingly, there is no danger of the signal from the sensor being .
WO 96/14026 PCT/IE9510005~i misinterpreted due to radio interference from nearby sources, and the device itself cannot interfere with nearby equipment.
The device is also less expensive to manufacture than the relatively complex portable artificial pancreases of the prior art. It can 5 be disposable and is preferably designed for once-daily ~lministration.
Suitably, the device is applied in the morning and worn throughout the day. It may be removed at night or worn throughout the night. If removed, the subject may inject a conventional night-time dose of insulin or the device may be adapted to deliver a suitable bolus of 10 insulin before removal.
Suitably, the delivery needle extends permanently through the lower surface.
Preferably, however, said delivery needle is recessed within the housing when the lower surface is not in contact with the subject's skin, 15 and the device comprises means for extending the delivery needle through the lower surface so as to project outwards said distance when the housing is pressed against the skin. This may be achieved, for example, by means of a mechanical, electrical or piezoelectric sensor located on the lower surface of the housing, with the sensor means for 20 extending the delivery needle through the lower surface being actuated by the sensor. The extension of the delivery needle is carried out in a consistent and suitable manner when this embodiment is used.
Preferably, the delivery needle penetrates through the derrnis for subcutaneous delivery of the drug. The choice of intradermal or 25 subcutaneous delivery, however, depends on the condition to be treated, the drug to be used and the chosen therapy and dosage regime. For certain drugs, it is preferable to deliver dosages intraderrnally as a depot effect may be desired, i.e. the drug builds up in concentration within the skin layers and is gradually released therefrom to the 30 systemic circulation. With suitable drugs this depot effect can provide therapeutically effective blood levels many hours after the device has been removed.
CA 02204370 1997-0~-02 W O96/14026 PCT/lh~C~
According to a further embodiment of the invention, the means for detecting the plasma concentration of the analyte comprises a sensor needle extending from the lower surface of the housing when the lower surface is in contact with the subject's skin, the sensor needle having an 5 outer end projecting outwards a sufficient distance so as to penetrate through the epidermis and into the dermis when the housing is pressed against the skin.
Thus, the application of the housing can ensure the insertion of both the delivery needle and the sensor needle for the analyte. This is 10 particularly advantageous for the reasons recited above in relation to the delivery needle.
Suitably, the sensor needle extends permanently through the lower surface.
Preferably, the sensor needle is recessed within the housing when 15 said lower surface is not in contact with the subject's skin, and the device comprises means for extending the sensor needle through the lower surface so as to project outwards said distance when the housing is pressed against the skin.
The same means may be used to extend both the delivery needle 20 and the sensor needle siml-lt~nPously through the lower surface when the device is pressed against the skin. Alternatively, each needle may be activated separately as the particular parts of the housing adjacent to the point through which the needles extend comes into contact with the skm.
Suitably, the sensor needle penetrates through the dermis.
It is envisaged that the same needle may be used for the purposes of delivery and analyte sensing. Preferably, however, the delivery and sensor needles are in spaced apart relationship.
CA 02204370 1997-0~-02 In a preferred embodiment, the delivery and sensor needles are electrically conducting and the means for detecting the concentration of an analyte is to measure an electric current between the needles, the circuit being completed upon application of the lower surface to the 5 skin of the subject. The third r~ferellce voltage point kept at a specific voltage compared to the sensor needle an electric circuit comprising a power source connected between the needles, the needles may be entirely formed of conductive material or they may carry a conductive coating or conductive elements therein.
Suitably, the electrical signal provides a measure of the electric current flowing through the circuit.
Suitably, the sensor needle has an enzyme associated therewith, the enzyme being specific to the analyte to be detected and the current through the circuit being dependent on the concentration of a reactant 15 in the enzymatic reaction in the vicinity of the needle.
Preferably, the sensor needle has an enzyme associated therewith, the enzyme being specific to the analyte to be detected and the current through the circuit being dependent on the concentration of a product of the enzymatic reaction in the vicinity of the needle.
The use of an analyte-specific enzyme is particularly advantageous as such an enzyme can be used to detect minute concentrations of analyte in the blood, plasma or tissue of the subject.
The association of an electric c~ ellt with the enzymatic reaction allows a q~ntit~ive evaluation of analyte concentration. The electrical current may, of course, be amplified or analysed as a~ro~-iate by means of any one of a vast range of electronic techniques.
Furthermore, the enzyme allows high concentrations of analyte to be measured equally accurately as only a very small quantity of enzyme can catalyse large amounts of substrate (analyte). Some pure enzymes, for example, can catalyse the transformation of as many as lO,000 to 1,000,000 mols of substrate per minute per mol of enzyme.
Accordingly, only a very small enzyme supply needs to be associated CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 with the needle to ensure total analyte reaction in the vicinity of the needle.
Preferably, the product of the enzymatic reaction is a charged species, or said product spontaneously breaks down to produce a S charged species, or said product reacts catalytically at the surface of the needle to produce a charged species. The term "charged species" as used herein includes ions, protons and electrons. In any of these situations, the production of charged species in the vicinity of the needle allows a current to flow between the electrodes. Accordinglyt 10 the current through the circuit is dependent on the numbers of charged species available to carry current at any time.
Suitably, the product of the enzymatic reaction or a derivative thereof partakes in an electrochemical reaction, the sensor needle acting as one electrode of an electrochemical cell and the delivery needle 15 acting as another electrode. In accordance with Faraday's Laws of Electrolysis, the amount of a substance consumed at an electrode of an electrochemical cell is directly proportional to the current through the cell. Obviously, one would not expect this strict relationship to hold for an electrochemical cell incorporating a complex biological system, 20 but the circuit can nevertheless be calibrated to provide a correlation between the current and the analyte concentration.
Suitably, when the enzymatic reaction requires free oxygen to proceed, the structure of the sensor needle allows oxygen to pass from an inner end thereof which is in commllnication with a supply of 25 oxygen to the exterior surface of that part of the sensor needle which projects from the housing.
Preferably, the needle is a hollow needle open at the outer (skin-penetrating) end to provide communication between the inner end and the enzyme.
30The use of a hollow needle (or of some other structure of needle which allows oxygen to reach the location of the enzyme) confers an CA 02204370 1997-0~-02 W O96/14026 PCT/1~ 005 important advantage over conventional implanted enzyme sensors, as the hollow needle ensures that the rate of reaction is never restricted by a lack of oxygen. The supply of oxygen may be air inside the housing, air outside the housing, an oxygen reservoir within the housing or an S oxygen source (such as an electrochemical cell) inside the housing, to provide a few examples.
Preferably, the enzyme is in the form of an enzyme-containing coating on the surface of the needle.
Further, preferably, the enzyme-cont~ining coating is covered by 10 a protective coating of an analyte-permeable material.
Suitably, said analyte-permeable material is a perflourinated ion-exchange membrane, for example, "Nafion" ("Nafion" is a Trade Mark). This type of material protects the enzyme before and during operation of the device. If the sensor is in the form of a hollow needle, 15 the coating may cover the open end of the needle to prevent fluids from entering the needle.
According to a preferred embodiment, the analyte is glucose, and the drug is selected from glucagon and insulin or analogues thereof.
The insulin used in the device may be chosen to meet the 20 requirements of the patient. It may be bovine, porcine, human or synthetic and it may be short acting or long acting, or it may comprise a mixture of different types of insulin.
Preferably, in this preferred embodiment of the invention, the enzyme is glucose oxidase.
Further, preferably, the product is hydrogen peroxide.
In the preferred embodiment. the hydrogen peroxide is catalysed to produce oxygen, hydrogen ions and electrons and the magnitude of CA 02204370 1997-0~-02 WO 96/14026 PCT/IE9S~GCS~
the current through the circuit is related to the number of electrons produced.
Suitably, the hydrogen peroxide is produced adjacent to a platinum supply, the platinum supply catalysing the oxidation of the 5 hydrogen peroxide. The pl~tin~lm may be in a colloidal dispersion within a coating on the surface of the sensor needle, it may be carried by particles distributed in intim~te admixture with the enzyme supply, it may be provided on the surface of the sensor needle, or the sensor needle may comprise pl~timlm or a platinum alloy such as platinum-10 iridium.
A high degree of accuracy may be achieved if the electric circuit comprises a reference electrode which is adapted to contact the subject's skin and the sensor needle is biased at a fixed potential with respect to the reference electrode.
Suitably, the electric circuit comprises a potentiostat having an operational amplifier which drives a current between the sensor and delivery needles.
Further, preferably, the power source and the sensor needle are connected in series with the positive input of the amplifier, and a 20 resistor and the delivery needle are connected in series with the amplifier output, the reference electrode being connected to the negative input of the arnplifier.
As will be further described below, the potentiostat m~int~in.s the potential of the sensor needle at a preset level with respect to the 25 reference electrode by passing the current between the sensor needle and the delivery needle. Thus, the sensor needle acts as a working electrode and the delivery needle acts as a counter electrode.
The current through the reference electrode is, in a well calibrated potentiostat, minim~l and the current between the working 30 electrode and the counter electrode is independent of the resistance in CA 02204370 1997-0~-02 the "cell" (in this case the skin and tissue between the needles). Thus, the current is limited by the numbers of mobile charged species available to carry current.
Suitably, the current through the circuit is determined by 5 measuring the voltage drop across the resistor.
Preferably, a voltmeter connected across said resistor provides a signal determined by the magnitude of the voltage drop and the signal is amplified and supplied to the means for receiving an electrical signal and for controlling the rate of active discharge of drug in response 1 0 thereto.
Further, preferably, said means for controlling the rate of active discharge is a pre-programmable microprocessor which calculates the required drug dosage from the received signal and which controls the rate of active discharge in order to provide the required dosage.
Optionally, the circuit comprises switching means to allow current to flow intermittently. In this embodiment, the time taken for the current to reach a steady state (if a steady state is reached) can be analysed to determine information regarding the operation of the device. Suitably, therefore, a charge accumulates at the sensor needle when current is prohibited and the charge disperses when current flow begins.
An explanation of how a pulsatile current can be used to derive useful information on transport and kinetic parameters is given in the paper by J. Rishpon referred to above. By using a voltage stepped periodically between 0.0V (10 seconds) and 0.8V (10 seconds) and observing the resultant current specifically by sampling the current at intervals of 200 ,us and integrating the digitized signal to obtain a chronocoulometric response, sensitivity was greatly increased above that available by steady-state measurements. However, sophisticated equipment including a micro-computer was required to digitize, average and integrate the current measurements.
CA 02204370 1997-0~-02 W O96/14026 PCT~E95/0005S
Preferably, the switching means comprises means for intermittently applying a voltage to the sensor needle. Suitably, the voltage is applied as a stepped voltage. As the enzymatic reaction proceeds independently of the current, a charge will accumulate at the 5 sensor needle when the current is switched off. When the current is switched on, the charge is able to disperse, and the current takes the form of a peak which falls away to a steady state level.
Preferably, the current is measured immediately after the stepped voltage is applied. This enables a large current to be measured 10 and improves the signal to noise ratio.
In a preferred embodiment, the circuit further comprises means for comparing the current at different times. This information can be used to evaluate the efficiency and condition of the electrode. In one embodiment, the current is measured twice at times tl and t2 as it falls 15 from a peak level towards a steady state level, given value I(tl) and I(t2). The ratio I(tl)/I(t2) has been found to be a constant which is specific to the electrode and which is independent of the concentration of the analyte being measured. It is also been found that for any given construction of electrode, the ratio will remain constant as long as the 20 electrode is functioning correctly, but when the ability to detect glucose is impaired, the ratio will change. Therefore, repeated measurements of this ratio provide a way of monitoring the quality of the sensor over time and the user can thereby be alerted when the sensor requires replacement.
To facilitate the application of the device, in a preferred embodiment, the lower surface is shaped such that when it is pressed against the skin a substantial proportion of the pressure applied to the skin is directed through the needle tip. Thus, the needle may project permanently from a suitable part of the lower surface or it may be extended from a suitable part of the lower surface when the lower surface is pressed against the skin. Preferably, the shape of the lower surface is adapted to compensate for the elasticity of the skin by the design of the lower surface. Generally, this means that the lower CA 02204370 1997-0~-02 surface is shaped such that a substantial portion of the pressure is directed through the tip of the needle itself rather than through the skin-contacting parts of the lower surface, at least while the housing is being pressed against the skin.
Suitably, for example, the lower surface of the housing may have a convex shape and the hollow needle may extend from the centre of the convexity, or the lower surface may be provided with a protuberance from which the needle projects, or the lower surface may be of a conical shape with the needle extending from the apex of the cone (suitably, this is an inverted cone with a large base-to-height ratio).
Preferably, the means for affixing the housing in position comprises a pressure-adhesive coating on the lower surface thereof.
This allows the device to be far less obtrusive than the sort of device which must be worn on a belt, shoulder strap or bracelet.
Suitably, the delivery and/or sensor needle(s) project outwards of the housing by 0.3-3.0 mm and have an outer diameter of 0.05-0.4 mm, preferably 0.1-0.3 mm, and an inner diameter of 0.02-0.1 mm, preferably 0.05-0.075 mm. Such needle dimensions allow for intradermal or subcutaneous delivery and a small outer diameter ensures that the application of the needle(s) is relatively painless.
In a preferred embodiment of the invention the reservoir is in the form of an expansible-contractible chamber which is expanded when filled with the drug and whi~h can be contracted to dispense the drug therefrom. Suitably, the drug reservoir, when filled, has a volume of the order of 0.2 ml to 10.0 ml.
Further, preferably, the means for actively discharging the drug comprises an electrically controlled gas generator within the housing for generating a gas to contract the drug reservoir in order to discharge the drug therefrom. Suitably, the gas generator is an electrolytic cell. The use of an electrolytic cell is preferred as the CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 generation of gas is highly controllable and is suitable for delivering accurate amounts of the drug, as well as for allowing the delivery of drug to be started and stopped subst~nti~lly inst~nt~neously if pulsatile delivery is required.
As a preferred feature, the device comprises a start button which is depressible in order to energize the gas generator and thereby to start discharging the drug from the drug reservoir.
Suitably, the means for controlling the rate of active discharge comprises an electronic circuit for controlling the time and rate of gas generation, thereby controlling the discharge of the drug from the drug reservolr.
Optionally, the device further comprises a membrane which is permeable to the drug and impermeable to solid impurities, the membrane covering the inner end of the delivery needle.
The invention provides, in a second aspect, a device for monitoring the concentration of an analyte in the plasma of a subject.
comprising:
a housing having a lower surface for application to the skin of the subject;
means for holding the housing in position with the lower surface ~g~in~t the subject's skin;
an electrical detection circuit comprising a power source connected across two electrodes mounted on said lower surface, the circuit being completed upon application of the lower surface to the skin of the subject, one of said electrodes being a sensor needle for penetrating through the epidermis and into the dermis when the lower surface is applied to the skin and having an enzyme associated therewith, said enzyme being specific to the analyte to be detected, and the current through the circuit being directly or indirectly dependent CA 02204370 1997-0~-02 WO 96/14026 PCT/I~5S/~):10~5 on the concentration of the analyte in the vicinity of the sensor needle;
and a communication circuit comprising means for measuring the current through said electrical detection circuit, means for calculating 5 the plasma concentration of the analyte from the measured current and communicating means for communicating the calculated concentration to the subject.
The application of such a device is no more painful, and may, in fact, be less painful, than a conventional pin prick blood test. Unlike 10 such a blood test, however, the device according to the invention need not be repeatedly administered if the blood levels need to be rechecked.
The device may, in fact, be worn in place for continual monitoring over a period of, for example, 12 hours, one day, two days or up to one week. The period is generally limited by the exhaustion of, or a 15 decrease in the efficiency of, the enzyme associated with the sensor needle. The presently preferred frequency of a~mini~tration is once-daily as this ensures that the sensor needle is always in optimum condition and it also allows the subject to change the site of application regularly.
Suitably, the enzyme is glucose oxidase and the analyte to be measured is glucose.
The invention is not, however, limited solely to glucose monitoring devices. Similar enzymatic sensors may suitably be employed if alternative analytes require monitoring.
According to a preferred embodiment, the sensor needle is a working electrode and the other of said two electrodes is a counter electrode in the form of a platinum surface for contact with the subject's skin.
Although the counter electrode can be an invasive electrode (i.e.
a needle) there is no necessity in the present case for a second needle, CA 02204370 1997-0~-02 WO 96/14026 PCT/lh~ 'uG~
and in the interests of comfort, it is preferred to employ a counter electrode which rests against the skin. Preferably, the area of such an electrode is maximised to increase sensitivity. In certain cases, the sensitivity of an electrode resting against the skin may not be sufficient, 5 and, accordingly, an invasive needle may be used.
Preferably, the electrical detection circuit also comprises a reference electrode on the lower surface of the housing, in the form of a silver/silver chloride surface for contact with the subject's skin, and a potentiostat having an operational amplifier which drives a current 10 between the working electrode and the counter electrode.
Such a circuit operates as hereinbefore described with reference to the embodiments of the invention in its first aspect.
According to a particularly preferred embodiment, the housing comprises a first part and a second part, the first part comprising the 15 lower surface and the electrodes and the second part comprising the power source and the comm--nication circuit.
Suitably, the first part is detachably mounted on the second part, such that the first part can be disposed of and replaced and the second part can be reused a number of times.
When a two-part device is used, the costs can be considerably lower. The first part contains all of the disposable elements (adhesive, electrode coatings, etc.), while the second part contains the reusable elements, such as the electronic components, the co..~ icating means and the power source. Although a power source such as a battery must 25 be replaced periodically, it is a relatively permanent element in comparison to an enzymatic sensor. Long-term batteries can be used having a life span of over two years. Accordingly, such batteries can be reused hundreds of times relative to the first part.
CA 02204370 1997-0~-02 W O96/14026 PCTnE95/00055 Suitably~ the communicating means is activated when the calculated analyte plasma concentration falls outside a predetermined range.
Further, suitably, the communicating means comprises an audible 5 alarm.
Thus, an audible alarm can be made to sound if the subject has blood levels approaching those associated with hyperglycemia or hypoglycemia, and corrective action can be taken before any serious condition develops. Preferably, different sounds are emitted by the 10 alarm depending on the condition of the patient. Furthermore, different sounds or louder sounds can be emitted if the situation worsens.
Preferably, the commllnicating means operates continuously to provide a constant indication of the subject's analyte plasma 15 concentration.
Further, preferably, the communicating means comprises a visible display of the analyte concentration. Suitably, the visible display is in the form of a liquid crystal display for indicating the analyte concentration as a numerical value.
Other visible displays are, of course, possible, such as a series of light, with a number of lights lit indicating an approximate blood glucose level, or a dial indicating a nurnerical value relating to the blood glucose level, etc.
One of the most important advantages associated with a device according to the invention is that the patient can check blood glucose levels throughout the day and, through experience, a f~mili~rity can be built up with the patterns of fluctuation in blood glucose level associated with normal daily routine and with extraordinary events such as strenuous exercise, the consumption of different types of foods and drinks and variations in insulin dosage. This will provide a CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 diabetic with an awareness of the effect of various factors on his or her blood glucose levels and preventive action can be taken before it is strictly required. Developing such an association need not be a conscious exercise on the part of the diabetic, because an association of S this type is built up through experience.
Heretofore, diabetic subjects have been able to recognise that blood glucose levels should be increased or decreased, but this is generally as a result of the onset of hyperglycemic or hypoglycemic symptoms. By recognising that corrective action is required before 10 such symptoms develop, the blood glucose levels of the subject will be far more regular.
An additional advantage is that a diabetic subject using a device according to the invention will not mistake unrelated symptoms as being related to abnormally high or low blood glucose levels. An 15 objective check is available which prevents the subject from mistakenly increasing insulin or sugar intake.
Although not explicitly enumerated, many of the features of the invention in its first aspect are suitable for incorporation into the second aspect, as will be apparent to the skilled person. Furthermore, 20 both aspects of the invention can be combined to provide a delivery device with monitoring and display features.
In a third aspect, the invention provides a method of measuring the plasma concentration of an analyte comprising the steps of: a) penetrating the epidermis with an enzymatic sensor which forms part 25 of an electrical circuit, wherein the current through the circuit is dependent on the presence of a species produced by the enzymatic reaction with the analyte; b) supplying a periodic potential to the enzymatic sensor such that current only flows through the electric circuit intermittently; and c) measuring the current shortly after it 30 begins to flow.
CA 02204370 1997-0~-02 W O96/14026 PCT/l~S~CS~
For the reason indicated above and, as will be further illustrated below, this method has been found to provide accurate results in a far simpler and more efficient manner than the chronocoulometric method known from the prior art.
Suitably, the potential is supplied intermittently as a periodic stepped potential, providing a disconnect period and a connect period, thereby giving rise to a peak current at the beginning of the connect period, falling away towards a steady state current level.
In a presently preferred embodiment, the disconnect period is at least one second long and the connect period is at least 20 microseconds long.
Preferably, the connect period is in the range 20-400 microseconds. More preferably it is in the range 40-80 microseconds.
Further, preferably, the disconnect period is in the range 1-15 seconds, more preferably 5-10 seconds.
These periods have been found to provide good results when used with the type of glucose sensor further described below. The disconnect period should be long enough for a substantial amount of the current-dependent species to build up at the electrode, in order to provide a strong peak current at the be~inning of the connect period.
Suitably, the current is measured in the first 15 rnicroseconds of the connect period. Preferably, the current is measured between 0.25 and 10 rnicroseconds after the beginnin~ of the connect period, and most preferably between 0.5 and 3 microseconds after the beginning of the connect period.
By measuring the current early in the connect period, a strong peak current will be obtained, thereby boosting the signal to noise ratio relative to a steady state amperometric measurements. In the method described by Rishpon (supra), measurements were only made every CA 02204370 1997-0~-02 W O96/14026 PCTnE95/00055 200 microseconds. It has been found that the best results are obtained if measurements are made well within 200 microseconds of the start of the connect period, as after 200 microseconds the current will have effectively dropped to a steady state level for many constructions of 5 electrode.
As indicated above in relation to the device, preferably, the method further comprises the steps of measuring the current a second time during the connect period, calc~ ting a ratio between the two measured values, and comparing this ratio to a memorised value or 10 range of values to determine whether the sensor is performing normally. Preferably the second current measurement is made when the current has fallen to a steady-state valve.
Suitably, the method also comprises the step of providing an indication that the sensor is defective if the calculated ratio is different 15 to the memorised value or range of values.
This indication can be effected in many ways, preferably by providing a visible or audible alarm.
Brief description of Drawin~s The invention will be further illustrated by the following 20 description of embodiments thereof, given by way of example only with reference to the accompanying drawings, in which:
Fig. 1 is a cross-section through a liquid delivery device according to the invention;
Fig. 2 is a m~gnified view of a detail of the device of Fig. 1;
Fig. 3 is a cross-section through a second liquid delivery device according to the invention;
Fig. 4 is a view of the underside of the device of Fig. 3;
CA 02204370 1997-0~-02 Fig. S is a schematic representation of the electronic circuit of the device of Fig. 3;
Fig. 6 illustrates an alternative construction of sensor needle for use in a device according to the invention;
S Fig. 7 illustrates a detail of the sensor needle of Fig. 6;
Fig. 8 is a schematic cross section through an embodiment of a device for monitoring plasma glucose levels, according to the second aspect of the invention;
Fig. 9 is a plan view of the underside of the device illustrated in Fig. ~;
Fig. 10 is a perspective view of an actual device of the type schematically illustrated in Fig. 8, before assembly;
Fig. 11 is a perspective view of the device of Fig. 10 when assembled;
Fig. 12 is a diagram of the potential applied to the sensor electrode and the corresponding current obtained from the electrode;
Fig. 13 is a plot of actual current profiles achieved for different glucose concentrations;
Fig. 14 is a plot of in~ t~eous culTent values against glucose concentration showing a linear relationship between current and glucose concentration;
Fig. lS is a plot of the ratio of two instantaneous current re~ling~ taken at different times for various glucose concentrations in respect of three different electrodes, showing CA 02204370 1997-0~-02 W O96/14026 PCT~E95/000~5 how this ratio can be used to evaluate the performance of the electrode;
Fig. 16 is a side cross sectional elevation of a further embodiment of sensor needle for use with the device according S to the invention; and Fig. 17 is a front elevation of the needle of Fig. 16.
Modes for carryin~ out the Invention Fig. 1 shows a device according to the invention, illustrated generally at 10, for use in the controlled delivery of insulin to a "Type 10 1" diabetic subject (i.e. suffering from insulin-dependent diabetes mellitus).
The device 10 comprises a housing 11 Cont~inin~ an insulin reservoir 12 for storing insulin in liquid form (suspension, solution or liquid) and a gas generation chamber 13. Reservoir 12 and gas 15 generation chamber 13 are separated by an elastomeric membrane 14, such that an expansion of gas generation chamber 13 leads to a corresponding contraction of insulin reservoir 12.
A platinum-iridium delivery needle 15 projects through a lower surface 16 of housing 11 by a distance of 2.5 mm. Delivery needle 15 20 is hollow and is open at an inner end 17 to insulin reservoir 12. It is also open at outer end 18 such that, when lower surface 16 of housing 11 is pressed against a subject's skirl, delivery needle 15 penetrates through the epidermis and the dermis, thereby establishing co..... ication between insulin reservoir 12 and the subject's 25 subcutaneous tissue via the hollow needle 15. If a shorter needle is used, communication can be established with the capillary system of the dermis.
Gas generation chamber 13 is provided with an electrolytic cell 19 powered by a battery 20 under the control of a programmable CA 02204370 1997-0~-02 WO 96/14026 PCT/lh5SI'~~ 55 microprocessor 21. Microprocessor 21 controls the rate at which gas is generated in electrolytic cell 19 by the electrolysis of water.
Electrolytic cell 19 has walls of a hydrophobic material which allow gas to permeate therethrough but which retain water within the 5 cell. When gas is generated by electrolytic cell 19, the pressure increases in gas generation charnber 13, causing the volume of chamber 13 to expand with a corresponding contraction of insulin reservoir 12 resulting in insulin being forced out of reservoir 12 through needle 15 (and, in use, into the patient's tissue).
Microprocessor 21 controls the rate of gas generation and, consequently, the rate of insulin delivery, by monitoring the patient's blood glucose level by means of a glucose sensor, indicated generally at 22. Sensor 22 comprises a pl~tinllm-iridium sensor needle 23 extending from lower surface 16 by about 2 mm.
Referring additionally to Fig. 2, it can be seen that sensor needle 23 is hollow and is open at both ends. Inner end 24 leads to a passageway 25 extending through housing 11 to the external atmosphere. Accordingly, outer end 26 of sensor needle 23 is, Yia passageway 25, in comrnunication with a supply of excess oxygen.
20 Needle 23 is coated with a glucose oxidase enzyme coating 27. This entire composite needle structure is covered by a layer of "Nafion" 28 which serves as a protective material, but is permeable to glucose, water, oxygen and hydrogen peroxide. "Nafion" layer 28 also covers open end 26 of stainless steel needle 23, thereby stopping blood from 25 entering and filling the hollow interior of needle 23.
Oxygen within sensor needle 23 can diffuse through "Nafion"
coating 28 into glucose oxidase enzyme layer 27. In addition, glucose and water can also diffuse through "Nafion" layer 28 into glucose oxidase enzyme containing layer 27. The enzyme catalyses the reaction 30 of glucose with oxygen and water, producing gluconic acid and hydrogen peroxide. Accordingly, hydrogen peroxide is produced in enzyme layer 27 surrounding platinum-iridium needle 23 in an amount CA 02204370 1997-0~-02 WO 96/14026 PCT/IE95/OOOS~
which is directly dependent on the amount of available glucose in the bloodstream.
Delivery needle 15 is a coated with a silver/silver chloride layer.
Battery 20 is connected between delivery needle 15 and sensor needle 5 23 via internal connecting wires 31 (Fig. 2) within the housing.
Accordingly, when the needles 15,23 penetrate into the dermis or the subcutaneous tissue, a circuit is closed by the establishment of an electrical connection between the needles 15,23. The circuit is effectively an electrochemical cell, with one electrode being a standard 10 silver/silver chloride electrode in aqueous solution (i.e. needle 23 with its coating immersed in the bloodstream) and the other electrode being a platinum electrode supplied with hydrogen peroxide.
The free mobile charges providing a flow of current through the sensor needle are produced in the catalysed oxidation of hydrogen 15 peroxide on pl~tinllm in the reaction:
H2~2 -~ ~2+ 2H+ + 2e~
The electrons produced in this reaction allow current to flow through the sensor needle 23.
The current through the circuit is limite~l by the numbers of electrons available at sensor needle 23. This means that, since the electrons are produced by hydrogen peroxide oxidation and the hydrogen peroxide is produced by the enzymatic oxidation of glucose, that the current depends on the glucose concentration in the bloodstream.
The current through the circuit is amplified and measured by microprocessor 21. Microprocessor 21, which comprises a stored programme, calculates the precise amount of insulin which must be delivered at any time in order to maintain glucose at the optimum physiological concentration.
CA 02204370 1997-0~-02 W 096/14026 PCT~E95/00055 The microprocessor 21 maintains this concentration by controlling the current flowing through electrolytic cell 19, since any increase or decrease in the amount of gas produced by electrolytic cell 19 results in a corresponding increase or decrease in the amount of 5 insulin injected into the subject via needle 15. In effect, therefore, device 10 acts as an artificial pancreas which contin~l~lly monitors the glucose concentration in the bloodstream and constantly adjusts the on-going rate of insulin ~tlministration to take account of the measured glucose level.
In contrast to prior art devices for the ~lmini~tration of insulin, device 10, which can be affixed to any suitable area of the skin (such as the upper arm or abdomen) is unobtrusive. It is easy and painless to apply; simply by pressing lower surface 16 against the skin, the two needles 15,23 penetrate the skin and an adhesive layer 29, which is 15 provided on lower surface 16, holds the device in place throughout the course of treatment. A device having a diameter of approximately 5 cm and a thickness of approximately 1 cm may contain a sufficient amount of insulin for treatment throughout 12 hours, 1 day, or up to l week.
The insulin used in the device may be chosen to meet the requirements of the patient. It may be bovine, porcine, human or synthetic and it may be short acting or long acting, or it may comprise a mixture of different types of insulin.
The needles 15,23, including the coatings thereon, have an external diameter of 0.2 mm. Accordingly, there are no large, open wounds (as there are with traditional delivery cannulas and sensor irnplants) which may become infected. Additionally, since the site of application can be changed daily, for example, the wounds will heal almost immediately and there is no possibility of either the sensor needle or the delivery needle becoming coated with fibrin.
A preferred embodiment of the invention is illustrated in Fig. 3.
The device, indicated generally at 40, comprises a housing 41 CA 02204370 1997-0~-02 containing an insulin reservoir 42 and a gas generation chamber 43 within which there is provided an electrolytic cell 44. Reservoir 42 and gas generation charnber 43 are separated by an elastomeric membrane 45 such that when gas is generated by electrolytic cell 44, 5 gas generation charnber 43 expands by displacing membrane 45 downwards and thereby contracting insulin reservoir 42 causing the drug to be discharged therefrom.
The rate of generation of gas is controlled by a microprocessor 46 which receives a signal from a glucose sensing apparatus comprising a potentiostat 47 linked to a sensor needle 48 and a delivery needle 49 of the types described above with reference to Figs. 1 and 2. The potentiostat is also connected to a reference electrode 50 on the lower (skin-contacting) surface 51 of housing 41. The arrangement of sensor needle 48, delivery needle 49 and reference electrode 50 on lower surface 51 of housing 41 as illustrated in Fig. 4.
Fig. 5 is a schematic representation of the electronic circuit of device 40. Potentiostat 47 is shown as a dotted outline. It comprises an operational amplifier 51, a power source (Vin) connected between the positive input of operational arnplifier 51 and sensor needle 48 (which 20 acts as the working electrode), and a resistor 52 connected between the output of operational arnplifier 51 and delivery needle 49 (which acts as the counter electrode). Reference electrode 50 is connected to the negative input of the operational amplifier 51.
Potentiostat 47 serves to hold the working electrode 48 at a fixed 25 potential relative to the reference electrode. Since both inputs to the operational amplifier are effectively at the same potential, the potential difference between reference electrode 50 and working electrode 48 is equal to Vin. The current through the amplifier 51, which is dependent on the amount of glucose detected by sensor needle 48, is effectively 30 independent of the resistance of the "cell" between working electrode 48 and counter electrode 49, (at least within the operating range of the operational amplifier).
CA 02204370 1997-0~-02 W O96/14026 PCT~E95/00055 The current is calculated from the voltage drop across resistor 52 using a voltmeter 53 which provides a signal to microprocessor 46 which interprets the signal as indicating a certain glucose concentration in the tissue surrounding sensor needle 48. Voltmeter 53 actually 5 includes both a floating-input voltmeter and an amplifier connected to the output of the voltmeter to provide a signal of suitable strength to microprocessor 46. One or more power sources (not shown) are also included for the purposes of powering electrolytic cell 44 (Fig.3), the amplifier connected to the voltmeter output, and microprocessor 46.
10 The power source(s) may be that/those used in the potentiostat circuit or separate power source(s) may be provided.
An alternative composition of sensor needle to that illustrated in Fig. 2 is shown in Fig. 6. A hollow stainless steel sensor needle 60 has a single coating layer 61 formed from a casting solution of 15 perflourosulphonic acid polymer, such as the perflourinated ion exchange membrane, "Nafion", glucose oxidase enzyme, and a carbon supported catalyst.
As illustrated in more detail in Fig. 7, the "Nafion" membrane 62 provides an insoluble biocompatible protective matrix for the 20 enzyme 63 retains the enzyme for long term availability in the electrode structure. Membrane 62 also dissolves large quantities of oxygen that is then available adjacent to the enzyme to promote hydrogen peroxide forrnation for signal generation. The carbon supported catalyst is in the form of platinum-loaded carbon particles 64 25 having about 10% by weight of pl~tinllm The particles 64 serve two functions: firstly, the catalytic surface for oxidation of hydrogen peroxide is dispersed throughout the matrix layer 62 within which the hydrogen peroxide is generated; secondly, the carbon support for the catalyst provides an electrically conductive path for electrons produced 30 by the oxidation reaction. An electrode having this type of supporting layer is described in U.S. Patent No. 5,227,042, the disclosure of which is incorporated herein by reference. As U.S. Patent No. 5,227,042 discloses, other catalysts from the platinum group, such as palladium, ruthenium or rodeium can be used in place of platinum.
CA 02204370 1997-0~-02 W O 96/14026 PCT~E95/00055 Fig. 8 is a schematic illustration of an embodiment of the second aspect of the invention, namely a device for monitoring the plasma concentration of an analyte. The device, indicated generally at 50, comprises a housing 51 detachable into a first part 52 and a second part 5 53. The device 50 has a number of features in common with the embodiments of the first aspect of the invention. Specifically, first part 52 of housing 51 has an adhesive lower surface 54 which is provided with a working electrode 55, a counter electrode 56 and a reference electrode 57. The electrodes 56,56,57 are connected to a potentiostat 10 58 as hereinbefore described.
Working electrode 55 is a platinum-iridium needle coated with a glucose oxidase enzyme coating, as previously described. Counter electrode 56 is in the form of a platinum-iridium surface adapted to rest against the subject's skin and reference electrode 57 is in the form 15 of a silver/silver chloride surface adapted to rest against the subject's skin. As previously described, the current passing between working electrode 55 and counter electrode 56 provides a measure of the glucose concentration in the vicinity of working electrode 55. This current is measured by a microprocessor 59 which is calibrated to 20 allow calculation of the glucose plasma concentration from the measured current through potentiostat 58.
Microprocessor 59 is pre-programmed to activate an audible alarm 60 in the case of hyperglycemia or hypoglycemia. These conditions are recognised by the microprocessor if the calculated 25 glucose concentration rises above or falls below a specific range.
Alarm 60 emits different sounds depending on whether hyperglycemia or hypoglycemia is indicated by microprocessor 59. In practice, microprocessor 59 activates audible alarm 60 before the glucose plasma concentration reaches a dangerous level. Thus, the subject, or those 30 supervising the subject, can act in good time by administering glucose-rich food and drink or by aclministering insulin, as the case may be, before corrective action becomes absolutely critical.
CA 02204370 1997-0~-02 Microprocessor 59 also communicates with a liquid crystal display (LCD) 61 which has seven-segment displays to provide a numerical indication of the level of glucose in the subject's plasma.
Thus, if device 50 is worn on a continual basis, the subject can check 5 his or her blood glucose levels at will. In this way, the subject can titrate insulin and/or sugar intake as and when required to provide a plasma glucose profile which more closely resembles that of a healthy individual than that of a self-administering diabetic who self-atlministers insulin according to traditional criteria (i.e. fixed dosages, 10 variable dosages according to the results of occasional blood tests).
Whereas blood tests prior to insulin ~ ni~tration can allow patients to determine optimum dosages, it is impossible for a diabetic to objectively gauge his or her glucose intake requirements between injections, so the diabetic subject is either confined to a strictly 15 controlled diet or else runs the risk of misjudging a safe level of sugar intake.
Battery 62 powers the device and a start button 63 is provided to activate the device after administration to the skin of the subject.
As illustrated, the device 50 is in two parts 52,53 which are 20 separable from one another. First part 52, which is disposable, comprises the three electrodes 55,56,57 and lower surface 54. As the efficiency of the electrodes will decrease over time (in particular, the dependability of the enzymatic sensor or working electrode 55 will not remain stable indefinitely), it is desirable to replace the electrodes on a 25 regular basis. Second part 53 houses all of the reusable elements of the device. Electrical contact is effected between potentiostat 58 and electrodes 55,56,57 by means of two sets of interengagable contacts 64,65 which fit together when first part 52 is mounted on second part 53. Thus, first part 52 can be replaced daily, for example, whereas 30 second part 53 can be reused indefinitely.
Suitably, battery 62 is a long-terrn battery which allows second part 53 to operated continuously over two-three years before CA 02204370 1997-0~-02 W O96/14026 PCT/l~ r5 replacement of battery 62 is necessitated. Microprocessor 59 monitors the power level of battery 62. As battery 62 becomes exhausted, its power decreases and microprocessor 59 activates alarm 60 to provide a special alarm indicating that replacement of battery 62 is necessary.
Push button 63 performs an additional function in that it can be used to reset the alarm when blood glucose levels have moved outside the acceptable range; microprocessor 59 will then only reactivate alarm 60 when calculated glucose levels next move outside the allowable range or, if the levels do not return to norrnal, when the patient's plasma glucose levels worsen appreciably.
Fig. 9 shows a view of the underside of device 50. Thus, lower surface 54 of first part 52 is seen with working electrode 55 (i.e. the enzymatic sensor needle) in the centre. On either side, two approximately semi-circular surfaces 56,57 are indicated by shaded lines. Surface 56 is the platinum-iridium surface of the counter electrode, while surface 57 is the silver/silver chloride surface of the reference electrode. Lower surface 54 is provided with a suitable adhesive to hold device 50 securely in place against the subject's skin.
In Figs. 10 and 11, device 50 of Figs. 8 and 9 can be seen in perspective view. Fig. 10 shows first and second parts 52,53 before assembly. First part 52 has three contacts 65 on the upper surface thereof which receive three complementary contacts (not shown) on the lower surface of second part 53. As indicated in Fig. 11, second part 53 is provided with a liquid crystal display 61 which gives a numerical indication of the blood glucose levels. Beside LCD 61, push button 63 can be seen. An additional feature which is not illustrated in Figs. 8 and 9 is a release liner 64 which covers the lower surface (not visible) of first part 52 before use. Release liner 64 is provided both for safety reasons (i.e. to cover the needle before use) and to ensure that the electrode surfaces are undamaged upon application to the skin of the subject.
CA 02204370 1997-0~-02 W 096/14026 PCT~E95/000~5 Fig. 11 shows device 50 when first part 52 has been mounted on second part 53 to form a single housing 51. First and second parts 52,53 are held together by means of a snap action mechanism (not shown). In use, release liner 64 is then removed and housing 50 is 5 present against the surface of the subject's skin such that the sensor needle (not shown) penetrates through the epidermis and into the dermis (depending on the length of the sensor needle, it may also penetrate through the dermis to the subcutaneous tissue) to allow contact between the enzymatic coating on the sensor needle and the 10 subject's plasma. Contact is also effected between the subject's skin and each of the flat electrodes. Operation of the monitoring device begins when push button 63 is pressed. At the end of 24 hours, first part 52 is snapped away from second part 53 and replaced by a new, identical part for monitoring blood glucose levels throughout the subsequent 24 15 hour/period.
The operation of the measurement circuit has been described above with the working electrode held at a constant potential above the reference electrode. In a more sophisticated embodiment of the invention, however, a potential is only applied intermittently to the 20 working electrode, as indicated in Fig. 12. From Fig. 12 it can be seen that the potential is stepped between a lower value (preferably 0.0 V) where no current will flow, and a higher value (such as 0.6 V) where current is allowed to flow. Fig. 12 is not to scale and the disconnect period is preferably many times longer than the connect period. In a 25 preferred embodirnent, the disconnect period is 3-12 seconds and the connect period is 20-300 microseconds. In the experiments described below, the disconnect period was 7 seconds and the connect period was 60 microseconds.
During the disconnect period, the enzymatic reaction proceeds 30 and hydrogen peroxide builds up at the sensor electrode. Because no potential has been applied and no current is flowing, however, the hydrogen peroxide accumulates continually until the potential is applied allowing a current to flow. As can be seen in the upper half of Fig. 12, CA 02204370 1997-0~-02 the current begins with a peak which then falls away as the hydrogen peroxide is consumed.
Referring additionally to Fig. 13, actual curves obtained using this method can be seen. From these cur~es it will be seen that the peak 5 value is many times greater than the steady state value achieved after, for example, 30 microseconds. If one compares the peak values obtained for glucose concentrations of 0, 1, 2, 4 and 8 mM it can be seen that one can easily distinguish between and measure the peak concentrations, whereas the steady state concentrations are so close 10 together as to be almost indistinguishable. Thus, a greatly improved signal to noise ratio is obtained by applying an intermittent voltage and measuring the current obtained at the peak (or shortly thereafter).
This greatly enhances the accuracy of measurements which can be made using this type of enzymatic sensor, and it has been found that the 15 response of peak current to glucose concentration is effectively linear.
The measurements in Fig. 14 were taken one microsecond after the potential was applied. Each data point therefore represents a single current reading at t = lms ~lS for a given glucose concentration.
The performances of the electrodes were evaluated by measuring 20 the ~ rlcllls Il at t = 1 ~s and I2 at t = 55 ~s and then calculating the ratio Il/I2. This ratio was calculated for each glucose concentration for three different electrodes. One of the electrodes (experiment 101) had degraded and had lost its ability to measure glucose properly, whereas the other two electrodes (experiments 11 1 and 112) were functioning 25 perfectly. It can be seen that the ratio Il/12 in each case is independent of glucose concentration and is equal for the electrodes used in experiments 111 and 112. However, a lower value for Il/I2 was obtained in experiment 101 and is indicative of the loss of performance. While more sophisticated analytical techniques can be 30 based on the principle used to make the Fig. 15 measurements, Fig. 15 represents a very simple but effective method of continuously monitoring electrode performance. The detecting circuit can be designed to sound an alarm or provide a visual indication when the CA 02204370 1997-0~-02 W O96tl4026 PCTAE95/0005 ratio Il/I2 changes by an appreciable amount, thereby indicating that the electrode should be replaced.
For best results it has been found advantageous to measure Il as quickly as possible (e.g. 1-1.5 ~s after the circuit is closed) and to 5 measure 12 when the current has reached steady state (e.g. after 90% of the total connect time has elapsed).
In sllmm~ry, the "pulse sampling method" described above and illustrated by Figs. 12-15 provides the following advantages:
(i) the signal is at least two orders of magnitude higher than 10 with a continuous sampling method. Therefore, less amplification is needed, and higher accuracy is achieved.
(ii) the signal to noise ratio is vastly improved; the noise obtained is less than 10% of the signal. In the continuous sampling (or continuous current) method, the noise is higher than the signal itself 15 and its value is elimin~ted by averaging the samples.
(iii) the pulse sampling method is less sensitive to the presence of substances such as ascorbic acid, uric acid, paracetamol, etc. The reason for this is that enzymatic detection is effected using two reactions: ~lrstly, the chemical reaction where the analyte is converted 20 and a by-product such as hydrogen peroxide is formed; and secondly, an electrochemical reaction, where hydrogen peroxide is consumed and an electric current flows through the electrodes. The chemical reaction takes place whenever the reactants and enzyme are present, while the electrochemical reaction only takes place when the electrode is at a 25 sufficient potential. At that potential, the abovementioned substances also react with the electrode and induce an undesired current that adds to the current generated by hydrogen peroxide decomposition. When using the pulse sampling method, the voltage is intermittently connected to the electrodes. When disconnected, hydrogen peroxide accumulates 30 at the electrode site but the other substances do not accumulate appreciably during these breaks. Therefore, when reconnecting the CA 02204370 1997-0~-02 W O96/14026 PCT/l~g51000 potential, there is an "amplification" of the hydrogen peroxide signal compared to the signal resulting from the other substances and therefore their contribution to noise becomes less significant. This "amplification" of the hydrogen peroxide signal relative to the ascorbic acid/uric acid/paracetamol signals would not exist if the voltage was applied continuously.
(iv) The values, gradient and shape of the pulse carry important information about the condition of the sensor. This can be used to monitor the sensor. In prior art electrodes, the degradation of the sensor would only show as an artificially increased or decreased analyte measurement which would be more likely to be wrongly interpreted as an actual measurement than to be interpreted as an indication of sensor degradation. The ability to distinguish between a false signal and a (l~m~ged sensor means that the sensor according to the invention is far safer than known sensors for use as a measuring tool.
In Figs. 16 and 17, there is indicated, generally at 70, a further embodiment of sensor needle for use with a device according to the invention. The needle 70 comprises a platinum-iridium rod 71 having a bevelled tip 72. The rod 71 is 0.3 mm in diameter.
A transverse bore 73 extends through the thickness of the rod, and bore 73 is filled with an enzyme matrix 74 formed from a casting solution of perflourinated ion exchange membrane ("Nafion"), and glucose oxidase enzyme. A bore 75 extends axially through the length 25 of the rod allowing communication between enzyme matrix 74 and the atmosphere. Bore 75 is 0.1 rnm in diarneter. Each of bores 73 and 75 can be conveniently formed by laser drilling.
Needle 70 works in exactly the same manner as the needles previously described, but provides an advantage in that the enzyme 30 matrix 74 is provided internally of the needle and not as an external coating. This elimin~t~s any tendency for the enzyme layer to be W O96/14026 PCT~E95/00055 ~l~m~ed or scratched during manufacture (i.e. when the needle is affixed to the body of the device).
Claims (87)
1. A liquid delivery device for delivering a liquid drug to a subject via the subject's skin at a rate sufficient to maintain plasma levels of an analyte within a physiologically acceptable range, comprising:
a housing having a lower surface for application to the skin of the subject;
means for holding the housing in position with the lower surface against the subject's skin;
a drug reservoir within the housing;
a hollow delivery needle associated with the drug reservoir extending through the lower surface when the lower surface is in contact with the subject's skin, having an inner end communicating with the drug reservoir and an outer end projecting outwards a sufficient distance so as to penetrate through the epidermis and into the dermis when the housing is pressed against the skin;
means for actively discharging the drug from the reservoir to the subject's skin via the needle;
means for detecting the concentration of an analyte in the subject's plasma and for providing an electrical signal in accordance with the detected concentration, the concentration of said analyte being directly or indirectly related to the amount of drug required by the subject; and means for receiving said electrical signal and for controlling the rate of active discharge of drug in response thereto.
a housing having a lower surface for application to the skin of the subject;
means for holding the housing in position with the lower surface against the subject's skin;
a drug reservoir within the housing;
a hollow delivery needle associated with the drug reservoir extending through the lower surface when the lower surface is in contact with the subject's skin, having an inner end communicating with the drug reservoir and an outer end projecting outwards a sufficient distance so as to penetrate through the epidermis and into the dermis when the housing is pressed against the skin;
means for actively discharging the drug from the reservoir to the subject's skin via the needle;
means for detecting the concentration of an analyte in the subject's plasma and for providing an electrical signal in accordance with the detected concentration, the concentration of said analyte being directly or indirectly related to the amount of drug required by the subject; and means for receiving said electrical signal and for controlling the rate of active discharge of drug in response thereto.
2. A device according to Claim 1, wherein said delivery needle extends permanently through the lower surface.
3. A device according to Claim 1, wherein said delivery needle is recessed within the housing when the lower surface is not in contact with the subject's skin, and the device comprises means for extending the delivery needle through the lower surface so as to project outwards said distance when the housing is pressed against the skin.
4. A device according to any one of Claims 1-3, wherein the delivery needle penetrates through the dermis for subcutaneous delivery of the drug.
5. A device according to any one of Claims 1-4, wherein said means for detecting the plasma concentration of the analyte comprises a sensor needle extending from the lower surface of the housing when the lower surface is in contact with the subject's skin, the sensor needle having an outer end projecting outwards a sufficient distance so as to penetrate through the epidermis and into the dermis when the housing is pressed against the skin.
6. A device according to Claim 5, wherein said sensor needle extends permanently through the lower surface.
7. A device according to Claim 5, wherein said sensor needle is recessed within the housing when said lower surface is not in contact with the subject's skin, and the device comprises means for extending the sensor needle through the lower surface so as to project outwards said distance when the housing is pressed against the skin.
8. A device according to any one of Claims 5-7, wherein the sensor needle penetrates through the dermis.
9. A device according to any one of Claims 5-8, wherein the delivery and sensor needles are in spaced apart relationship.
10. A device according to any one of Claims 5-9, wherein the delivery and sensor needles are electrically conducting and wherein the means for detecting the concentration of an analyte is an electric circuit comprising a power source connected between the needles, the circuit being completed upon application of the lower surface to the skin of the subject.
11. A device according to Claim 10, wherein said electrical signal provides a measure of the electric current flowing through the circuit.
12. A device according to Claim 10 or 11, wherein the sensor needle has an enzyme associated therewith, the enzyme being specific to the analyte to be detected and the current through the circuit being dependent on the concentration of a reactant of the enzymatic reaction in the vicinity of the needle.
13. A device according to Claim 10 or 11, wherein the sensor needle has an enzyme associated therewith, the enzyme being specific to the analyte to be detected and the current through the circuit being dependent on the concentration of a product of the enzymatic reaction in the vicinity of the needle.
14. A device according to Claim 13, wherein said product is a charged species.
15. A device according to Claim 13 or 14, wherein said product spontaneously breaks down to produce a charged species.
16. A device according to any one of Claims 13-15, wherein said product reacts catalytically at the surface of the needle to produce a charged species.
17. A device according to any one of Claims 13-16, wherein said product or a derivative thereof partakes in an electrochemical reaction, the sensor needle acting as one electrode of an electrochemical cell and the delivery needle acting as another electrode.
18. A device according to any one of Claims 13-17, wherein the enzymatic reaction requires free oxygen to proceed and the structure of the sensor needle allows oxygen to pass from an inner end thereof which is in communication with a supply of oxygen to the exterior surface of that part of the sensor needle which projects from the housing.
19. A device according to Claim 18, wherein the needle is a hollow needle open at the outer (skin-penetrating) end to provide communication between the inner end and the enzyme.
20. A device according to any one of Claims 13-19, wherein the enzyme is in the form of an enzyme-containing coating on the surface of the needle.
21. A device according to Claim 20, wherein the enzyme-containing coating is covered by a protective coating of an analyte-permeable material.
22. A device according to Claim 21, wherein said material is a perflourinated ion-exchange membrane.
23. A device according to any preceding claim, wherein the analyte is glucose.
24. A device according to any preceding claim, wherein the drug is selected from glucagon and insulin or analogues thereof.
25. A device according to Claim 23 or 24, when dependent on Claim 10, wherein said enzyme is glucose oxidase.
26. A device according to Claim 13 or any one of Claims 15-25, when dependent on Claim 13, wherein said product is hydrogen peroxide.
27. A device according to Claim 26, wherein the hydrogen peroxide is catalysed to produce oxygen, hydrogen ions and electrons and the magnitude of the current through the circuit is related to the number of electrons produced.
28. A device according to Claim 27, wherein the hydrogen peroxide is produced adjacent to a platinum supply, the platinum supply catalysing the reduction of the hydrogen peroxide.
29. A device according to Claim 28, wherein the platinum is in a colloidal dispersion within a coating on the surface of the sensor needle.
30. A device according to Claim 28, wherein the platinum is carried by particles distributed in intimate admixture with the enzyme supply.
31. A device according to Claim 28, wherein the platinum is provided on the surface of the sensor needle.
32. A device according to Claim 28, wherein the sensor needle comprises platinum.
33. A device according to Claim 28, wherein the sensor needle comprises a platinum alloy such as platinum-iridium.
34. A device according to any preceding claim, when dependent on Claim 10, wherein the electric circuit comprises a reference electrode which is adapted to contact the subject's skin and wherein the sensor needle is biased at a fixed potential with respect to the reference electrode.
35. A device according to Claim 34, wherein the electric circuit comprises a potentiostat having an operational amplifier which drives a current between the sensor and delivery needles.
36. A device according to Claim 35, wherein the power source and the sensor needle are connected in series with the positive input of the amplifier and wherein a resistor and the delivery needle are connected in series with the amplifier output, the reference electrode being connected to the negative input of the amplifier.
37. A device according to Claim 36, wherein the current through the circuit is determined by measuring the voltage drop across said resistor.
38. A device according to Claim 37, wherein a voltmeter connected across said resistor provides a signal determined by the magnitude of the voltage drop and the signal is amplified and supplied to the means for receiving an electrical signal and for controlling the rate of active discharge of drug in response thereto.
39. A device according to any preceding claim, wherein said means for controlling the rate of active discharge is a pre-programmable microprocessor which calculates the required drug dosage from the received signal and which controls the rate of active discharge in order to provide the required dosage.
40. A device according to any preceding claim, when dependent on Claim 10, wherein the circuit comprises switching means to allow current to flow intermittently.
41. A device according to Claim 40, wherein the switching means comprises means for intermittently applying a voltage to the sensor needle.
42. A device according to Claim 41, further comprising means for comparing the current at different times.
43. A device according to Claim 42, wherein the means for comparing the current at different times is integral with the means for controlling the rate of active discharge.
44. A device according to any preceding claim, wherein the lower surface is shaped such that when it is pressed against the skin a substantial proportion of the pressure applied to the skin is directed through the needle tip.
45. A device according to any preceding claim, wherein the means for affixing the housing in position comprises a pressure-adhesive coating on the lower surface thereof.
46. A device according to any preceding claim, wherein the delivery and/or sensor needle(s) project outwards of the housing by 0.3-3.0 mm and have an outer diameter of 0.1-0.4 mm and an inner diameter of 0.05-0.075 mm.
47. A device according to any preceding claim, wherein the reservoir is in the form of an expansible-contractible chamber which is expanded when filled with the drug and which can be contracted to dispense the drug therefrom.
48. A device according to any preceding claim, wherein the drug reservoir, when filled, has a volume of the order of 0.2 ml to 10.0 ml.
49. A device according to Claim 47 or 48, wherein the means for actively discharging the drug comprises an electrically controlled gas generator within the housing for generating a gas to contract the drug reservoir in order to discharge the drug therefrom.
50. A device according to Claim 47, wherein the gas generator is an electrolytic cell.
51. A device according to Claim 49 or 50, further comprising a start button which is depressible in order to energize the gas generator and thereby to start discharging the drug from the drug reservoir.
52. A device according to any one of Claims 49-51, wherein the means for controlling the rate of active discharge comprises an electronic circuit for controlling the time and rate of gas generation, thereby controlling the discharge of the drug from the drug reservoir.
53. A device according to any preceding claim, which further comprises a membrane which is permeable to the drug and impermeable to solid impurities, the membrane covering the inner end of the delivery needle.
54. A device for monitoring the concentration of an analyte in the plasma of a subject, comprising:
a housing having a lower surface for application to the skin of the subject;
means for holding the housing in position with the lower surface against the subject's skin;
an electrical detection circuit comprising a power source connected across two electrodes mounted on said lower surface, the circuit being completed upon application of the lower surface to the skin of the subject, one of said electrodes being a sensor needle for penetrating through the epidermis and into the dermis when the lower surface is applied to the skin and having an enzyme associated therewith, said enzyme being specific to the analyte to be detected, and the current through the circuit being directly or indirectly dependent on the concentration of the analyte in the vicinity of the sensor needle;
and a communication circuit comprising means for measuring the current through said electrical detection circuit, means for calculating the plasma concentration of the analyte from the measured current and communicating means for communicating the calculated concentration to the subject.
a housing having a lower surface for application to the skin of the subject;
means for holding the housing in position with the lower surface against the subject's skin;
an electrical detection circuit comprising a power source connected across two electrodes mounted on said lower surface, the circuit being completed upon application of the lower surface to the skin of the subject, one of said electrodes being a sensor needle for penetrating through the epidermis and into the dermis when the lower surface is applied to the skin and having an enzyme associated therewith, said enzyme being specific to the analyte to be detected, and the current through the circuit being directly or indirectly dependent on the concentration of the analyte in the vicinity of the sensor needle;
and a communication circuit comprising means for measuring the current through said electrical detection circuit, means for calculating the plasma concentration of the analyte from the measured current and communicating means for communicating the calculated concentration to the subject.
55. A device according to Claim 54, wherein the enzyme is glucose oxidase and the analyte to be measured is glucose.
56. A device according to claim 54 or 55, wherein the sensor needle is a working electrode and the other of said two electrodes is a counter electrode in the form of a platinum surface for contact with the subject's skin.
57. A device according to any one of Claims 54-56, wherein the electrical detection circuit also comprises a reference electrode on the lower surface of the housing, in the form of a silver/silver chloride surface for contact with the subject's skin, and a potentiostat having an operational amplifier which drives a current between the working electrode and the counter electrode.
58. A device according to Claim 57, wherein the power source and the sensor needle are connected in series with the positive input of the amplifier and wherein a resistor and the delivery needle are connected in series with the amplifier output, the reference electrode being connected to the negative input of the amplifier.
59. A device according to Claim 58, wherein the current through the circuit is determined by measuring the voltage drop across said resistor.
60. A device according to Claim 59, wherein a voltmeter connected across said resistor provides a signal determined by the magnitude of the voltage drop and the signal is amplified and supplied to the communicating means.
61. A device according to any one of Claims 54-60, wherein the circuit comprises switching means to allow current to flow intermittently.
62. A device according to Claim 61, wherein the switching means comprises means for intermittently applying a voltage to the sensor needle.
63. A device according to Claim 62, further comprising means for comparing the current at different times.
64. A device according to Claim 63, wherein the means for comparing the current at different times is integral with the means for controlling the rate of active discharge.
65. A device according to any one of Claims 54-64, wherein the sensor needle is provided with a conduit permitting communication between the inner skin-contacting end and a source of oxygen.
66. A device according to Claim 65, wherein the source of oxygen is the atmosphere.
67. A device according to any one of Claims 54-66, wherein the housing comprises a first part and a second part, the first part comprising the lower surface and the electrodes and the second part comprising the power source and the communication circuit.
68. A device according to Claim 67, wherein the first part is detachably mounted on the second part, such that the first part can be disposed of and replaced and the second part can be reused a number of times.
69. A device according to any one of Claims 54-68, wherein the communicating means is activated when the calculated analyte plasma concentration falls outside a predetermined range.
70. A device according to any one of Claims 54-69, wherein the communicating means comprises an audible alarm.
71. A device according to any one of Claims 54-70, wherein the communicating means operates continuously to provide a constant indication of the subject's analyte plasma concentration.
72. A device according to any one of Claims 54-71, wherein the communicating means comprises a visible display of the analyte concentration.
73. A device according to Claim 72, wherein the visible display is in the form of a liquid crystal display for indicating the analyte concentration as a numerical value.
74. A method of measuring the plasma concentration of an analyte comprising the steps of:
a) penetrating the epidermis with an enzymatic sensor which forms part of an electrical circuit, wherein the current through the circuit is dependent on the presence of a species produced by the enzymatic reaction with the analyte;
b) supplying a periodic potential to the enzymatic sensor such that current only flows through the electric circuit intermittently; and c) measuring the current shortly after it begins to flow.
a) penetrating the epidermis with an enzymatic sensor which forms part of an electrical circuit, wherein the current through the circuit is dependent on the presence of a species produced by the enzymatic reaction with the analyte;
b) supplying a periodic potential to the enzymatic sensor such that current only flows through the electric circuit intermittently; and c) measuring the current shortly after it begins to flow.
75. A method according to Claim 74, wherein the potential is supplied intermittently as a periodic stepped potential, providing a disconnect period and a connect period, thereby giving rise to a peak current at the beginning of the connect period, falling away towards a steady state current level.
76. A method according to Claim 75, wherein the disconnect period is at least one second long and the connect period is at least 20 microseconds long.
77. A method according to Claim 75 or 76, wherein the connect period is in the range 20-400 microseconds.
78. A method according to any one of Claims 75-77, wherein the disconnect period is in the range 1-15 seconds.
79. A method according to any one of Claims 75-78, wherein the current is measured in the first 15 microseconds of the connect period.
80. A method according to Claim 79, wherein the current is measured between 0.5 and 10 microseconds after the beginning of the connect period.
81. A method according to any one of Claims 75-80, further comprising the steps of measuring the current a second time during the connect period, calculating a ratio between the two measured values, and comparing this ratio to a memorised value or range of values to determine whether the sensor is performing normally.
82. A method according to Claim 81, further comprising the step of providing an indication that the sensor is defective if the calculated ratio is different to the memorised value or range of values.
83. A liquid delivery device, substantially as hereinbefore described with reference to and as illustrated in Figs. 1-5 of the accompanying drawings.
84. A sensor needle for use with a device according to Claim 1 or 54, substantially as hereinbefore described with reference to and as illustrated in Fig. 6 and 7 of the accompanying drawings.
85. A device for monitoring the concentration of an analyte, substantially as hereinbefore described with reference to and as illustrated in Figs. 8-11 of the accompanying drawings.
86. A method for measuring the plasma concentration of an analyte, substantially as hereinbefore described with reference to and as illustrated in Fig. 12 of the accompanying drawings.
87. A device according to Claim 54, further comprising a drug reservoir within the housing, a hollow delivery needle associated with the drug reservoir extending through the lower surface when the lower surface is in contact with the subject's skin, having an inner end communicating with the drug reservoir and an outer end projecting outwards a sufficient distance so as to penetrate through the epidermis and into the dermis when the housing is pressed against the skin, means for actively discharging the drug from the reservoir to the subject's skin via the needle, and means for receiving an electrical signal and for controlling the rate of active discharge of drug in response thereto.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE940865A IE72524B1 (en) | 1994-11-04 | 1994-11-04 | Analyte-controlled liquid delivery device and analyte monitor |
IE940865 | 1994-11-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2204370A1 true CA2204370A1 (en) | 1996-05-17 |
Family
ID=11040560
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002204370A Abandoned CA2204370A1 (en) | 1994-11-04 | 1995-10-27 | Analyte-controlled liquid delivery device and analyte monitor |
Country Status (12)
Country | Link |
---|---|
US (3) | US5807375A (en) |
EP (1) | EP0789540B1 (en) |
JP (1) | JPH10508518A (en) |
AT (1) | ATE205686T1 (en) |
AU (2) | AU693279B2 (en) |
CA (1) | CA2204370A1 (en) |
DE (1) | DE69522821T2 (en) |
IE (1) | IE72524B1 (en) |
NZ (1) | NZ295458A (en) |
TW (1) | TW290442B (en) |
WO (1) | WO1996014026A1 (en) |
ZA (1) | ZA959309B (en) |
Families Citing this family (971)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5593852A (en) | 1993-12-02 | 1997-01-14 | Heller; Adam | Subcutaneous glucose electrode |
CA2219891C (en) | 1995-05-05 | 2002-01-29 | The Perkin-Elmer Corporation | Methods and reagents for combined pcr amplification and hybridization probing assay |
SE9700384D0 (en) * | 1997-02-04 | 1997-02-04 | Biacore Ab | Analytical method and apparatus |
DE69809391T2 (en) | 1997-02-06 | 2003-07-10 | Therasense Inc | SMALL VOLUME SENSOR FOR IN-VITRO DETERMINATION |
US7192450B2 (en) | 2003-05-21 | 2007-03-20 | Dexcom, Inc. | Porous membranes for use with implantable devices |
US7657297B2 (en) * | 2004-05-03 | 2010-02-02 | Dexcom, Inc. | Implantable analyte sensor |
US9155496B2 (en) | 1997-03-04 | 2015-10-13 | Dexcom, Inc. | Low oxygen in vivo analyte sensor |
US6001067A (en) | 1997-03-04 | 1999-12-14 | Shults; Mark C. | Device and method for determining analyte levels |
US7899511B2 (en) | 2004-07-13 | 2011-03-01 | Dexcom, Inc. | Low oxygen in vivo analyte sensor |
US20050033132A1 (en) * | 1997-03-04 | 2005-02-10 | Shults Mark C. | Analyte measuring device |
US8527026B2 (en) | 1997-03-04 | 2013-09-03 | Dexcom, Inc. | Device and method for determining analyte levels |
US6862465B2 (en) | 1997-03-04 | 2005-03-01 | Dexcom, Inc. | Device and method for determining analyte levels |
EP0990151A2 (en) | 1997-06-16 | 2000-04-05 | ELAN CORPORATION, Plc | Methods of calibrating and testing a sensor for (in vivo) measurement of an analyte and devices for use in such methods |
DE19739317A1 (en) * | 1997-09-08 | 1999-03-11 | Conducta Endress & Hauser | Electrical circuit for an electrochemical sensor |
US6117643A (en) * | 1997-11-25 | 2000-09-12 | Ut Battelle, Llc | Bioluminescent bioreporter integrated circuit |
US6036924A (en) | 1997-12-04 | 2000-03-14 | Hewlett-Packard Company | Cassette of lancet cartridges for sampling blood |
US8071384B2 (en) | 1997-12-22 | 2011-12-06 | Roche Diagnostics Operations, Inc. | Control and calibration solutions and methods for their use |
US6893552B1 (en) | 1997-12-29 | 2005-05-17 | Arrowhead Center, Inc. | Microsensors for glucose and insulin monitoring |
US6134461A (en) | 1998-03-04 | 2000-10-17 | E. Heller & Company | Electrochemical analyte |
US6103033A (en) | 1998-03-04 | 2000-08-15 | Therasense, Inc. | Process for producing an electrochemical biosensor |
US6391005B1 (en) | 1998-03-30 | 2002-05-21 | Agilent Technologies, Inc. | Apparatus and method for penetration with shaft having a sensor for sensing penetration depth |
US20040062802A1 (en) * | 1998-04-02 | 2004-04-01 | Hermelin Victor M. | Maximizing effectiveness of substances used to improve health and well being |
US5945123A (en) * | 1998-04-02 | 1999-08-31 | K-V Pharmaceutical Company | Maximizing effectiveness of substances used to improve health and well being |
US7647237B2 (en) | 1998-04-29 | 2010-01-12 | Minimed, Inc. | Communication station and software for interfacing with an infusion pump, analyte monitor, analyte meter, or the like |
US8688188B2 (en) | 1998-04-30 | 2014-04-01 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US8974386B2 (en) | 1998-04-30 | 2015-03-10 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US8480580B2 (en) | 1998-04-30 | 2013-07-09 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US9066695B2 (en) | 1998-04-30 | 2015-06-30 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US8465425B2 (en) | 1998-04-30 | 2013-06-18 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US6175752B1 (en) | 1998-04-30 | 2001-01-16 | Therasense, Inc. | Analyte monitoring device and methods of use |
US6949816B2 (en) * | 2003-04-21 | 2005-09-27 | Motorola, Inc. | Semiconductor component having first surface area for electrically coupling to a semiconductor chip and second surface area for electrically coupling to a substrate, and method of manufacturing same |
US8346337B2 (en) | 1998-04-30 | 2013-01-01 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
WO1999058050A1 (en) | 1998-05-13 | 1999-11-18 | Cygnus, Inc. | Signal processing for measurement of physiological analytes |
US6503231B1 (en) * | 1998-06-10 | 2003-01-07 | Georgia Tech Research Corporation | Microneedle device for transport of molecules across tissue |
AU767122B2 (en) * | 1998-06-10 | 2003-10-30 | Georgia Tech Research Corporation | Microneedle devices and methods of manufacture and use thereof |
US7344499B1 (en) * | 1998-06-10 | 2008-03-18 | Georgia Tech Research Corporation | Microneedle device for extraction and sensing of bodily fluids |
US6558320B1 (en) * | 2000-01-20 | 2003-05-06 | Medtronic Minimed, Inc. | Handheld personal data assistant (PDA) with a medical device and method of using the same |
US6554798B1 (en) | 1998-08-18 | 2003-04-29 | Medtronic Minimed, Inc. | External infusion device with remote programming, bolus estimator and/or vibration alarm capabilities |
DK1166808T3 (en) * | 1998-08-20 | 2004-07-05 | Sooil Dev Co Ltd | Portable automatic syringe assembly and injection needle assembly thereof |
US6338790B1 (en) | 1998-10-08 | 2002-01-15 | Therasense, Inc. | Small volume in vitro analyte sensor with diffusible or non-leachable redox mediator |
EP1135052A1 (en) | 1999-02-12 | 2001-09-26 | Cygnus, Inc. | Devices and methods for frequent measurement of an analyte present in a biological system |
CA2366760A1 (en) * | 1999-04-07 | 2000-10-12 | John T. Kilcoyne | Implantable monitoring probe |
US7806886B2 (en) * | 1999-06-03 | 2010-10-05 | Medtronic Minimed, Inc. | Apparatus and method for controlling insulin infusion with state variable feedback |
US6611707B1 (en) | 1999-06-04 | 2003-08-26 | Georgia Tech Research Corporation | Microneedle drug delivery device |
US6743211B1 (en) * | 1999-11-23 | 2004-06-01 | Georgia Tech Research Corporation | Devices and methods for enhanced microneedle penetration of biological barriers |
US6256533B1 (en) | 1999-06-09 | 2001-07-03 | The Procter & Gamble Company | Apparatus and method for using an intracutaneous microneedle array |
US6312612B1 (en) | 1999-06-09 | 2001-11-06 | The Procter & Gamble Company | Apparatus and method for manufacturing an intracutaneous microneedle array |
US6379324B1 (en) | 1999-06-09 | 2002-04-30 | The Procter & Gamble Company | Intracutaneous microneedle array apparatus |
GB9918839D0 (en) * | 1999-08-11 | 1999-10-13 | Univ Manchester | Sensor devices and analytical methods for their use |
US20020095134A1 (en) * | 1999-10-14 | 2002-07-18 | Pettis Ronald J. | Method for altering drug pharmacokinetics based on medical delivery platform |
US20020156453A1 (en) * | 1999-10-14 | 2002-10-24 | Pettis Ronald J. | Method and device for reducing therapeutic dosage |
US8465468B1 (en) * | 2000-06-29 | 2013-06-18 | Becton, Dickinson And Company | Intradermal delivery of substances |
US20020198509A1 (en) | 1999-10-14 | 2002-12-26 | Mikszta John A. | Intradermal delivery of vaccines and gene therapeutic agents via microcannula |
EP1235611B1 (en) * | 1999-11-15 | 2005-09-07 | Velcro Industries B.V. | Skin attachment member |
US6974437B2 (en) | 2000-01-21 | 2005-12-13 | Medtronic Minimed, Inc. | Microprocessor controlled ambulatory medical apparatus with hand held communication device |
US20030014014A1 (en) * | 2000-02-10 | 2003-01-16 | Zvi Nitzan | Drug delivery device and method |
US6458118B1 (en) * | 2000-02-23 | 2002-10-01 | Medtronic, Inc. | Drug delivery through microencapsulation |
US6612111B1 (en) * | 2000-03-27 | 2003-09-02 | Lifescan, Inc. | Method and device for sampling and analyzing interstitial fluid and whole blood samples |
DE10022398B4 (en) * | 2000-04-28 | 2011-03-17 | Eppendorf Ag | Gas cushion micro-dosing system |
AU2001265056A1 (en) * | 2000-05-26 | 2001-12-11 | The Procter And Gamble Company | Microneedle apparatus used for marking skin and for dispensing semi-permanent subcutaneous makeup |
US6565532B1 (en) | 2000-07-12 | 2003-05-20 | The Procter & Gamble Company | Microneedle apparatus used for marking skin and for dispensing semi-permanent subcutaneous makeup |
US6540675B2 (en) | 2000-06-27 | 2003-04-01 | Rosedale Medical, Inc. | Analyte monitor |
US20050008683A1 (en) * | 2000-06-29 | 2005-01-13 | Becton Dickinson And Company | Method for delivering interferons to the intradermal compartment |
US20040175360A1 (en) * | 2000-06-29 | 2004-09-09 | Pettis Ronald J. | Method for altering drug pharmacokinetics based on medical delivery platform |
US6656147B1 (en) * | 2000-07-17 | 2003-12-02 | Becton, Dickinson And Company | Method and delivery device for the transdermal administration of a substance |
IL137431A0 (en) | 2000-07-20 | 2001-07-24 | Slo Flo Ltd | A new slow release device for controlled delivery of liquid material |
US6553244B2 (en) * | 2000-08-18 | 2003-04-22 | Cygnus, Inc. | Analyte monitoring device alarm augmentation system |
US20040260233A1 (en) * | 2000-09-08 | 2004-12-23 | Garibotto John T. | Data collection assembly for patient infusion system |
ES2287156T3 (en) * | 2000-09-08 | 2007-12-16 | Insulet Corporation | DEVICES AND SYSTEMS FOR THE INFUSION OF A PATIENT. |
US6821281B2 (en) | 2000-10-16 | 2004-11-23 | The Procter & Gamble Company | Microstructures for treating and conditioning skin |
US7828827B2 (en) * | 2002-05-24 | 2010-11-09 | Corium International, Inc. | Method of exfoliation of skin using closely-packed microstructures |
US7131987B2 (en) * | 2000-10-16 | 2006-11-07 | Corium International, Inc. | Microstructures and method for treating and conditioning skin which cause less irritation during exfoliation |
US8641644B2 (en) | 2000-11-21 | 2014-02-04 | Sanofi-Aventis Deutschland Gmbh | Blood testing apparatus having a rotatable cartridge with multiple lancing elements and testing means |
DE10057832C1 (en) | 2000-11-21 | 2002-02-21 | Hartmann Paul Ag | Blood analysis device has syringe mounted in casing, annular mounting carrying needles mounted behind test strip and being swiveled so that needle can be pushed through strip and aperture in casing to take blood sample |
EP1345646A2 (en) | 2000-12-14 | 2003-09-24 | Georgia Tech Research Corporation | Microneedle devices and production thereof |
WO2002050584A2 (en) * | 2000-12-21 | 2002-06-27 | Biovalve Technologies, Inc. | Microneedle array systems |
US6560471B1 (en) | 2001-01-02 | 2003-05-06 | Therasense, Inc. | Analyte monitoring device and methods of use |
JP2002228668A (en) * | 2001-01-31 | 2002-08-14 | Shimadzu Corp | Automatic sampler |
US6663820B2 (en) * | 2001-03-14 | 2003-12-16 | The Procter & Gamble Company | Method of manufacturing microneedle structures using soft lithography and photolithography |
US7041468B2 (en) | 2001-04-02 | 2006-05-09 | Therasense, Inc. | Blood glucose tracking apparatus and methods |
CA2444391A1 (en) * | 2001-04-13 | 2002-10-24 | Becton Dickinson And Company | Methods and devices for administration of substances into the intradermal layer of skin for systemic absorption |
DE10119036C1 (en) | 2001-04-18 | 2002-12-12 | Disetronic Licensing Ag | Immersion sensor for measuring the concentration of an analyte using an oxidase |
US6591124B2 (en) | 2001-05-11 | 2003-07-08 | The Procter & Gamble Company | Portable interstitial fluid monitoring system |
JP4681795B2 (en) | 2001-05-18 | 2011-05-11 | デカ・プロダクツ・リミテッド・パートナーシップ | Fluid pump infusion set |
US8034026B2 (en) | 2001-05-18 | 2011-10-11 | Deka Products Limited Partnership | Infusion pump assembly |
US6793632B2 (en) * | 2001-06-12 | 2004-09-21 | Lifescan, Inc. | Percutaneous biological fluid constituent sampling and measurement devices and methods |
US9795747B2 (en) | 2010-06-02 | 2017-10-24 | Sanofi-Aventis Deutschland Gmbh | Methods and apparatus for lancet actuation |
US7749174B2 (en) | 2001-06-12 | 2010-07-06 | Pelikan Technologies, Inc. | Method and apparatus for lancet launching device intergrated onto a blood-sampling cartridge |
US8337419B2 (en) | 2002-04-19 | 2012-12-25 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
US7682318B2 (en) | 2001-06-12 | 2010-03-23 | Pelikan Technologies, Inc. | Blood sampling apparatus and method |
US9226699B2 (en) | 2002-04-19 | 2016-01-05 | Sanofi-Aventis Deutschland Gmbh | Body fluid sampling module with a continuous compression tissue interface surface |
US7981056B2 (en) | 2002-04-19 | 2011-07-19 | Pelikan Technologies, Inc. | Methods and apparatus for lancet actuation |
ATE485766T1 (en) | 2001-06-12 | 2010-11-15 | Pelikan Technologies Inc | ELECTRICAL ACTUATING ELEMENT FOR A LANCET |
US7025774B2 (en) | 2001-06-12 | 2006-04-11 | Pelikan Technologies, Inc. | Tissue penetration device |
DE60234598D1 (en) | 2001-06-12 | 2010-01-14 | Pelikan Technologies Inc | SELF-OPTIMIZING LANZET DEVICE WITH ADAPTANT FOR TEMPORAL FLUCTUATIONS OF SKIN PROPERTIES |
EP1404234B1 (en) | 2001-06-12 | 2011-02-09 | Pelikan Technologies Inc. | Apparatus for improving success rate of blood yield from a fingerstick |
US9427532B2 (en) | 2001-06-12 | 2016-08-30 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
US20030073609A1 (en) * | 2001-06-29 | 2003-04-17 | Pinkerton Thomas C. | Enhanced pharmacokinetic profile of intradermally delivered substances |
US20050010193A1 (en) * | 2002-05-06 | 2005-01-13 | Laurent Philippe E. | Novel methods for administration of drugs and devices useful thereof |
AUPR632301A0 (en) * | 2001-07-11 | 2001-08-02 | Chee, Frederick Howe-Hui | Infusion apparatus for regulating blood glucose levels |
US20030032874A1 (en) | 2001-07-27 | 2003-02-13 | Dexcom, Inc. | Sensor head for use with implantable devices |
US6702857B2 (en) | 2001-07-27 | 2004-03-09 | Dexcom, Inc. | Membrane for use with implantable devices |
AU2002322761B2 (en) | 2001-07-31 | 2008-08-21 | Scott Laboratories, Inc. | Apparatuses and methods for titrating drug delivery |
US8152789B2 (en) | 2001-10-23 | 2012-04-10 | Medtronic Minimed, Inc. | System and method for providing closed loop infusion formulation delivery |
ATE519420T1 (en) * | 2001-09-11 | 2011-08-15 | Arkray Inc | INSTRUMENT FOR MEASURING A CONCENTRATION OF A COMPONENT IN A LIQUID SAMPLE |
WO2003022330A2 (en) * | 2001-09-12 | 2003-03-20 | Becton, Dickinson And Company | Microneedle-based pen device for drug delivery and method for using same |
US20040087992A1 (en) * | 2002-08-09 | 2004-05-06 | Vladimir Gartstein | Microstructures for delivering a composition cutaneously to skin using rotatable structures |
WO2003024507A2 (en) * | 2001-09-19 | 2003-03-27 | Biovalve Technologies, Inc. | Microneedles, microneedle arrays, and systems and methods relating to same |
EP1471953B1 (en) * | 2001-09-21 | 2011-02-16 | Valeritas, Inc. | Gas pressure actuated microneedle arrays, and systems and methods relating to same |
EP1469903A2 (en) * | 2001-09-28 | 2004-10-27 | BioValve Technologies, Inc. | Microneedle with membrane |
CA2500452A1 (en) * | 2001-09-28 | 2003-04-03 | Biovalve Technologies, Inc. | Switchable microneedle arrays and systems and methods relating to same |
US7429258B2 (en) * | 2001-10-26 | 2008-09-30 | Massachusetts Institute Of Technology | Microneedle transport device |
US20040120964A1 (en) * | 2001-10-29 | 2004-06-24 | Mikszta John A. | Needleless vaccination using chimeric yellow fever vaccine-vectored vaccines against heterologous flaviviruses |
US6989891B2 (en) | 2001-11-08 | 2006-01-24 | Optiscan Biomedical Corporation | Device and method for in vitro determination of analyte concentrations within body fluids |
US6952604B2 (en) | 2001-12-21 | 2005-10-04 | Becton, Dickinson And Company | Minimally-invasive system and method for monitoring analyte levels |
US10080529B2 (en) | 2001-12-27 | 2018-09-25 | Medtronic Minimed, Inc. | System for monitoring physiological characteristics |
US20030125662A1 (en) * | 2002-01-03 | 2003-07-03 | Tuan Bui | Method and apparatus for providing medical treatment therapy based on calculated demand |
US7004928B2 (en) * | 2002-02-08 | 2006-02-28 | Rosedale Medical, Inc. | Autonomous, ambulatory analyte monitor or drug delivery device |
EP1476210B1 (en) | 2002-02-11 | 2008-09-24 | Antares Pharma, Inc. | Intradermal injector |
US8010174B2 (en) | 2003-08-22 | 2011-08-30 | Dexcom, Inc. | Systems and methods for replacing signal artifacts in a glucose sensor data stream |
US8364229B2 (en) | 2003-07-25 | 2013-01-29 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
US7613491B2 (en) | 2002-05-22 | 2009-11-03 | Dexcom, Inc. | Silicone based membranes for use in implantable glucose sensors |
US9282925B2 (en) | 2002-02-12 | 2016-03-15 | Dexcom, Inc. | Systems and methods for replacing signal artifacts in a glucose sensor data stream |
US7828728B2 (en) | 2003-07-25 | 2010-11-09 | Dexcom, Inc. | Analyte sensor |
US8260393B2 (en) | 2003-07-25 | 2012-09-04 | Dexcom, Inc. | Systems and methods for replacing signal data artifacts in a glucose sensor data stream |
US9247901B2 (en) | 2003-08-22 | 2016-02-02 | Dexcom, Inc. | Systems and methods for replacing signal artifacts in a glucose sensor data stream |
US20080172026A1 (en) | 2006-10-17 | 2008-07-17 | Blomquist Michael L | Insulin pump having a suspension bolus |
US7108680B2 (en) * | 2002-03-06 | 2006-09-19 | Codman & Shurtleff, Inc. | Closed-loop drug delivery system |
US20030171738A1 (en) * | 2002-03-06 | 2003-09-11 | Konieczynski David D. | Convection-enhanced drug delivery device and method of use |
US7115108B2 (en) * | 2002-04-02 | 2006-10-03 | Becton, Dickinson And Company | Method and device for intradermally delivering a substance |
US7047070B2 (en) * | 2002-04-02 | 2006-05-16 | Becton, Dickinson And Company | Valved intradermal delivery device and method of intradermally delivering a substance to a patient |
US8221334B2 (en) | 2002-04-19 | 2012-07-17 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for penetrating tissue |
US7226461B2 (en) | 2002-04-19 | 2007-06-05 | Pelikan Technologies, Inc. | Method and apparatus for a multi-use body fluid sampling device with sterility barrier release |
US7175642B2 (en) | 2002-04-19 | 2007-02-13 | Pelikan Technologies, Inc. | Methods and apparatus for lancet actuation |
US9314194B2 (en) | 2002-04-19 | 2016-04-19 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
US7547287B2 (en) | 2002-04-19 | 2009-06-16 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US8579831B2 (en) | 2002-04-19 | 2013-11-12 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for penetrating tissue |
US7563232B2 (en) * | 2002-04-19 | 2009-07-21 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US7291117B2 (en) | 2002-04-19 | 2007-11-06 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US7717863B2 (en) | 2002-04-19 | 2010-05-18 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US7648468B2 (en) | 2002-04-19 | 2010-01-19 | Pelikon Technologies, Inc. | Method and apparatus for penetrating tissue |
US9248267B2 (en) | 2002-04-19 | 2016-02-02 | Sanofi-Aventis Deustchland Gmbh | Tissue penetration device |
US9795334B2 (en) | 2002-04-19 | 2017-10-24 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for penetrating tissue |
US7331931B2 (en) | 2002-04-19 | 2008-02-19 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US8784335B2 (en) | 2002-04-19 | 2014-07-22 | Sanofi-Aventis Deutschland Gmbh | Body fluid sampling device with a capacitive sensor |
US7297122B2 (en) | 2002-04-19 | 2007-11-20 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US7976476B2 (en) | 2002-04-19 | 2011-07-12 | Pelikan Technologies, Inc. | Device and method for variable speed lancet |
US7674232B2 (en) | 2002-04-19 | 2010-03-09 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US7901362B2 (en) | 2002-04-19 | 2011-03-08 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US8702624B2 (en) | 2006-09-29 | 2014-04-22 | Sanofi-Aventis Deutschland Gmbh | Analyte measurement device with a single shot actuator |
US7481776B2 (en) | 2002-04-19 | 2009-01-27 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US7892183B2 (en) | 2002-04-19 | 2011-02-22 | Pelikan Technologies, Inc. | Method and apparatus for body fluid sampling and analyte sensing |
US7229458B2 (en) | 2002-04-19 | 2007-06-12 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US8267870B2 (en) | 2002-04-19 | 2012-09-18 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for body fluid sampling with hybrid actuation |
US7491178B2 (en) | 2002-04-19 | 2009-02-17 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US7909778B2 (en) | 2002-04-19 | 2011-03-22 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US7371247B2 (en) | 2002-04-19 | 2008-05-13 | Pelikan Technologies, Inc | Method and apparatus for penetrating tissue |
US7232451B2 (en) | 2002-04-19 | 2007-06-19 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
CN1655834A (en) * | 2002-05-06 | 2005-08-17 | 贝克顿·迪金森公司 | Method and device for controlling drug pharmacokinetics |
US20060264886A9 (en) * | 2002-05-06 | 2006-11-23 | Pettis Ronald J | Method for altering insulin pharmacokinetics |
US7226978B2 (en) | 2002-05-22 | 2007-06-05 | Dexcom, Inc. | Techniques to improve polyurethane membranes for implantable glucose sensors |
US8996090B2 (en) * | 2002-06-03 | 2015-03-31 | Exostat Medical, Inc. | Noninvasive detection of a physiologic parameter within a body tissue of a patient |
US20040010207A1 (en) * | 2002-07-15 | 2004-01-15 | Flaherty J. Christopher | Self-contained, automatic transcutaneous physiologic sensing system |
EP1539241A2 (en) * | 2002-08-30 | 2005-06-15 | Becton, Dickinson and Company | Method of controlling pharmacokinetics of immunomodulatory compounds |
JP2005538773A (en) * | 2002-09-12 | 2005-12-22 | チルドレンズ ホスピタル メディカル センター | Method and apparatus for injecting drugs without pain |
US7014625B2 (en) * | 2002-10-07 | 2006-03-21 | Novo Nordick A/S | Needle insertion device |
JP4599296B2 (en) * | 2002-10-11 | 2010-12-15 | ベクトン・ディキンソン・アンド・カンパニー | System and method for initiating and maintaining continuous long-term control of the concentration of a substance in a patient's body using a feedback or model-based controller coupled to a single needle or multi-needle intradermal (ID) delivery device |
WO2004041331A1 (en) * | 2002-11-01 | 2004-05-21 | Antares Pharma, Inc. | Administration of insulin by jet injection |
US7381184B2 (en) | 2002-11-05 | 2008-06-03 | Abbott Diabetes Care Inc. | Sensor inserter assembly |
US6800070B2 (en) * | 2002-11-07 | 2004-10-05 | George Mazidji | Lockable tranquilizer bracelet |
EP1583571B1 (en) | 2002-12-23 | 2008-02-13 | M2 Medical A/S | Medical dispensing device for insulin |
US8574895B2 (en) | 2002-12-30 | 2013-11-05 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus using optical techniques to measure analyte levels |
US8771183B2 (en) | 2004-02-17 | 2014-07-08 | Abbott Diabetes Care Inc. | Method and system for providing data communication in continuous glucose monitoring and management system |
US7811231B2 (en) | 2002-12-31 | 2010-10-12 | Abbott Diabetes Care Inc. | Continuous glucose monitoring system and methods of use |
US7228162B2 (en) * | 2003-01-13 | 2007-06-05 | Isense Corporation | Analyte sensor |
US7120483B2 (en) * | 2003-01-13 | 2006-10-10 | Isense Corporation | Methods for analyte sensing and measurement |
IL154243A0 (en) * | 2003-02-02 | 2003-09-17 | Silex Projectors Ltd | Stable infusion device |
US7578954B2 (en) | 2003-02-24 | 2009-08-25 | Corium International, Inc. | Method for manufacturing microstructures having multiple microelements with through-holes |
US7052652B2 (en) | 2003-03-24 | 2006-05-30 | Rosedale Medical, Inc. | Analyte concentration detection devices and methods |
US7134999B2 (en) | 2003-04-04 | 2006-11-14 | Dexcom, Inc. | Optimized sensor geometry for an implantable glucose sensor |
CA2559330A1 (en) * | 2003-04-21 | 2004-11-04 | Stratagent Life Sciences | Apparatus and methods for repetitive microjet drug delivery |
US20060184101A1 (en) * | 2003-04-21 | 2006-08-17 | Ravi Srinivasan | Microjet devices and methods for drug delivery |
CA2523267C (en) | 2003-04-23 | 2013-09-03 | Biovalve Technologies, Inc. | Hydraulically actuated pump for long duration medicament administration |
US7875293B2 (en) * | 2003-05-21 | 2011-01-25 | Dexcom, Inc. | Biointerface membranes incorporating bioactive agents |
US7862519B1 (en) * | 2003-05-21 | 2011-01-04 | Isense Corporation | Easy-to-use multi-use body fluid specimen collection and analyte sensing assembly |
DK1633235T3 (en) | 2003-06-06 | 2014-08-18 | Sanofi Aventis Deutschland | Apparatus for sampling body fluid and detecting analyte |
US8066639B2 (en) | 2003-06-10 | 2011-11-29 | Abbott Diabetes Care Inc. | Glucose measuring device for use in personal area network |
WO2006001797A1 (en) | 2004-06-14 | 2006-01-05 | Pelikan Technologies, Inc. | Low pain penetrating |
CA2529048A1 (en) * | 2003-06-13 | 2005-02-24 | Becton, Dickinson And Company | Improved intra-dermal delivery of biologically active agents |
US7718439B2 (en) | 2003-06-20 | 2010-05-18 | Roche Diagnostics Operations, Inc. | System and method for coding information on a biosensor test strip |
US8206565B2 (en) | 2003-06-20 | 2012-06-26 | Roche Diagnostics Operation, Inc. | System and method for coding information on a biosensor test strip |
US7488601B2 (en) | 2003-06-20 | 2009-02-10 | Roche Diagnostic Operations, Inc. | System and method for determining an abused sensor during analyte measurement |
US7645373B2 (en) | 2003-06-20 | 2010-01-12 | Roche Diagnostic Operations, Inc. | System and method for coding information on a biosensor test strip |
US7645421B2 (en) | 2003-06-20 | 2010-01-12 | Roche Diagnostics Operations, Inc. | System and method for coding information on a biosensor test strip |
US8058077B2 (en) | 2003-06-20 | 2011-11-15 | Roche Diagnostics Operations, Inc. | Method for coding information on a biosensor test strip |
US8148164B2 (en) | 2003-06-20 | 2012-04-03 | Roche Diagnostics Operations, Inc. | System and method for determining the concentration of an analyte in a sample fluid |
US7452457B2 (en) | 2003-06-20 | 2008-11-18 | Roche Diagnostics Operations, Inc. | System and method for analyte measurement using dose sufficiency electrodes |
US8423113B2 (en) | 2003-07-25 | 2013-04-16 | Dexcom, Inc. | Systems and methods for processing sensor data |
US9763609B2 (en) | 2003-07-25 | 2017-09-19 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
US7761130B2 (en) | 2003-07-25 | 2010-07-20 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
US8282549B2 (en) | 2003-12-09 | 2012-10-09 | Dexcom, Inc. | Signal processing for continuous analyte sensor |
JP2007500336A (en) | 2003-07-25 | 2007-01-11 | デックスコム・インコーポレーテッド | Electrode system for electrochemical sensors |
JP4708342B2 (en) | 2003-07-25 | 2011-06-22 | デックスコム・インコーポレーテッド | Oxygen augmentation membrane system for use in implantable devices |
US8275437B2 (en) | 2003-08-01 | 2012-09-25 | Dexcom, Inc. | Transcutaneous analyte sensor |
US8676287B2 (en) | 2003-08-01 | 2014-03-18 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US8060173B2 (en) | 2003-08-01 | 2011-11-15 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US8761856B2 (en) | 2003-08-01 | 2014-06-24 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US7591801B2 (en) | 2004-02-26 | 2009-09-22 | Dexcom, Inc. | Integrated delivery device for continuous glucose sensor |
US20190357827A1 (en) | 2003-08-01 | 2019-11-28 | Dexcom, Inc. | Analyte sensor |
US8845536B2 (en) | 2003-08-01 | 2014-09-30 | Dexcom, Inc. | Transcutaneous analyte sensor |
US9135402B2 (en) | 2007-12-17 | 2015-09-15 | Dexcom, Inc. | Systems and methods for processing sensor data |
US8369919B2 (en) | 2003-08-01 | 2013-02-05 | Dexcom, Inc. | Systems and methods for processing sensor data |
US8626257B2 (en) | 2003-08-01 | 2014-01-07 | Dexcom, Inc. | Analyte sensor |
US8160669B2 (en) | 2003-08-01 | 2012-04-17 | Dexcom, Inc. | Transcutaneous analyte sensor |
US7925321B2 (en) | 2003-08-01 | 2011-04-12 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US7774145B2 (en) | 2003-08-01 | 2010-08-10 | Dexcom, Inc. | Transcutaneous analyte sensor |
US8886273B2 (en) | 2003-08-01 | 2014-11-11 | Dexcom, Inc. | Analyte sensor |
US7920906B2 (en) | 2005-03-10 | 2011-04-05 | Dexcom, Inc. | System and methods for processing analyte sensor data for sensor calibration |
US8233959B2 (en) | 2003-08-22 | 2012-07-31 | Dexcom, Inc. | Systems and methods for processing analyte sensor data |
US20140121989A1 (en) | 2003-08-22 | 2014-05-01 | Dexcom, Inc. | Systems and methods for processing analyte sensor data |
CA2536669A1 (en) * | 2003-08-26 | 2005-03-17 | Becton, Dickinson And Company | Methods for intradermal delivery of therapeutics agents |
AU2012213965B2 (en) * | 2003-09-11 | 2015-10-22 | Labrador Diagnostics Llc | Medical device for analyte monitoring and drug delivery |
EP3851030B1 (en) * | 2003-09-11 | 2024-01-17 | Labrador Diagnostics LLC | Medical device for analyte monitoring |
US8282576B2 (en) | 2003-09-29 | 2012-10-09 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for an improved sample capture device |
EP1680014A4 (en) | 2003-10-14 | 2009-01-21 | Pelikan Technologies Inc | Method and apparatus for a variable user interface |
KR20060099520A (en) | 2003-10-21 | 2006-09-19 | 노보 노르디스크 에이/에스 | Medical skin mountable device |
EP1527792A1 (en) | 2003-10-27 | 2005-05-04 | Novo Nordisk A/S | Medical injection device mountable to the skin |
US7299082B2 (en) * | 2003-10-31 | 2007-11-20 | Abbott Diabetes Care, Inc. | Method of calibrating an analyte-measurement device, and associated methods, devices and systems |
USD914881S1 (en) | 2003-11-05 | 2021-03-30 | Abbott Diabetes Care Inc. | Analyte sensor electronic mount |
WO2005051170A2 (en) | 2003-11-19 | 2005-06-09 | Dexcom, Inc. | Integrated receiver for continuous analyte sensor |
US9247900B2 (en) | 2004-07-13 | 2016-02-02 | Dexcom, Inc. | Analyte sensor |
US7787923B2 (en) * | 2003-11-26 | 2010-08-31 | Becton, Dickinson And Company | Fiber optic device for sensing analytes and method of making same |
US8425417B2 (en) | 2003-12-05 | 2013-04-23 | Dexcom, Inc. | Integrated device for continuous in vivo analyte detection and simultaneous control of an infusion device |
US8423114B2 (en) | 2006-10-04 | 2013-04-16 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
US20080200788A1 (en) * | 2006-10-04 | 2008-08-21 | Dexcorn, Inc. | Analyte sensor |
US8364230B2 (en) | 2006-10-04 | 2013-01-29 | Dexcom, Inc. | Analyte sensor |
US8364231B2 (en) | 2006-10-04 | 2013-01-29 | Dexcom, Inc. | Analyte sensor |
US8532730B2 (en) | 2006-10-04 | 2013-09-10 | Dexcom, Inc. | Analyte sensor |
DE602004029092D1 (en) | 2003-12-05 | 2010-10-21 | Dexcom Inc | CALIBRATION METHODS FOR A CONTINUOUSLY WORKING ANALYTIC SENSOR |
US11633133B2 (en) | 2003-12-05 | 2023-04-25 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
US8425416B2 (en) | 2006-10-04 | 2013-04-23 | Dexcom, Inc. | Analyte sensor |
US8287453B2 (en) | 2003-12-05 | 2012-10-16 | Dexcom, Inc. | Analyte sensor |
US8017145B2 (en) * | 2003-12-22 | 2011-09-13 | Conopco, Inc. | Exfoliating personal care wipe article containing an array of projections |
DE602004016687D1 (en) * | 2003-12-22 | 2008-10-30 | Paul Hadvary | DERIVED SENSOR DEVICE |
US7822454B1 (en) | 2005-01-03 | 2010-10-26 | Pelikan Technologies, Inc. | Fluid sampling device with improved analyte detecting member configuration |
EP1706026B1 (en) | 2003-12-31 | 2017-03-01 | Sanofi-Aventis Deutschland GmbH | Method and apparatus for improving fluidic flow and sample capture |
US7637868B2 (en) * | 2004-01-12 | 2009-12-29 | Dexcom, Inc. | Composite material for implantable device |
EP1713926B1 (en) | 2004-02-06 | 2012-08-01 | Bayer HealthCare, LLC | Oxidizable species as an internal reference for biosensors and method of use |
WO2005079441A2 (en) * | 2004-02-17 | 2005-09-01 | Children's Hospital Medical Center | Injection device for administering a vaccine |
US8808228B2 (en) | 2004-02-26 | 2014-08-19 | Dexcom, Inc. | Integrated medicament delivery device for use with continuous analyte sensor |
WO2005091922A2 (en) * | 2004-03-03 | 2005-10-06 | Becton, Dickinson And Company | Methods and devices for improving delivery of a substance to skin |
WO2005094526A2 (en) | 2004-03-24 | 2005-10-13 | Corium International, Inc. | Transdermal delivery device |
US8792955B2 (en) | 2004-05-03 | 2014-07-29 | Dexcom, Inc. | Transcutaneous analyte sensor |
US8277713B2 (en) | 2004-05-03 | 2012-10-02 | Dexcom, Inc. | Implantable analyte sensor |
WO2005115360A2 (en) * | 2004-05-11 | 2005-12-08 | Becton, Dickinson And Company | Formulations of anti-pain agents and methods of using the same |
US8828203B2 (en) | 2004-05-20 | 2014-09-09 | Sanofi-Aventis Deutschland Gmbh | Printable hydrogels for biosensors |
EP1765194A4 (en) | 2004-06-03 | 2010-09-29 | Pelikan Technologies Inc | Method and apparatus for a fluid sampling device |
US7999435B2 (en) * | 2004-06-14 | 2011-08-16 | Massachusetts Institute Of Technology | Electrochemical actuator |
US7872396B2 (en) * | 2004-06-14 | 2011-01-18 | Massachusetts Institute Of Technology | Electrochemical actuator |
US8247946B2 (en) | 2004-06-14 | 2012-08-21 | Massachusetts Institute Of Technology | Electrochemical actuator |
JP2008503059A (en) | 2004-06-14 | 2008-01-31 | マサチューセッツ・インスティテュート・オブ・テクノロジー | Electrochemical methods, devices, and structures |
US7994686B2 (en) * | 2004-06-14 | 2011-08-09 | Massachusetts Institute Of Technology | Electrochemical methods, devices, and structures |
US7569126B2 (en) | 2004-06-18 | 2009-08-04 | Roche Diagnostics Operations, Inc. | System and method for quality assurance of a biosensor test strip |
WO2006014425A1 (en) | 2004-07-02 | 2006-02-09 | Biovalve Technologies, Inc. | Methods and devices for delivering glp-1 and uses thereof |
US20060015020A1 (en) * | 2004-07-06 | 2006-01-19 | Dexcom, Inc. | Systems and methods for manufacture of an analyte-measuring device including a membrane system |
US8886272B2 (en) | 2004-07-13 | 2014-11-11 | Dexcom, Inc. | Analyte sensor |
US8452368B2 (en) | 2004-07-13 | 2013-05-28 | Dexcom, Inc. | Transcutaneous analyte sensor |
US7783333B2 (en) | 2004-07-13 | 2010-08-24 | Dexcom, Inc. | Transcutaneous medical device with variable stiffness |
US20060016700A1 (en) | 2004-07-13 | 2006-01-26 | Dexcom, Inc. | Transcutaneous analyte sensor |
US8565848B2 (en) | 2004-07-13 | 2013-10-22 | Dexcom, Inc. | Transcutaneous analyte sensor |
WO2006127694A2 (en) * | 2004-07-13 | 2006-11-30 | Dexcom, Inc. | Analyte sensor |
US7946984B2 (en) | 2004-07-13 | 2011-05-24 | Dexcom, Inc. | Transcutaneous analyte sensor |
JP4059238B2 (en) * | 2004-09-16 | 2008-03-12 | ソニー株式会社 | Digital signal processing apparatus and digital signal processing method |
CA2583396C (en) | 2004-10-12 | 2015-06-23 | Bayer Healthcare Llc | Concentration determination in a diffusion barrier layer |
US20060253097A1 (en) * | 2004-10-21 | 2006-11-09 | Braig James R | Methods of treating diabetes |
CN100367906C (en) * | 2004-12-08 | 2008-02-13 | 圣美迪诺医疗科技(湖州)有限公司 | Endermic implantating biological sensors |
US10226207B2 (en) | 2004-12-29 | 2019-03-12 | Abbott Diabetes Care Inc. | Sensor inserter having introducer |
US7731657B2 (en) | 2005-08-30 | 2010-06-08 | Abbott Diabetes Care Inc. | Analyte sensor introducer and methods of use |
US8029441B2 (en) | 2006-02-28 | 2011-10-04 | Abbott Diabetes Care Inc. | Analyte sensor transmitter unit configuration for a data monitoring and management system |
US9743862B2 (en) | 2011-03-31 | 2017-08-29 | Abbott Diabetes Care Inc. | Systems and methods for transcutaneously implanting medical devices |
US20090105569A1 (en) | 2006-04-28 | 2009-04-23 | Abbott Diabetes Care, Inc. | Introducer Assembly and Methods of Use |
US9788771B2 (en) | 2006-10-23 | 2017-10-17 | Abbott Diabetes Care Inc. | Variable speed sensor insertion devices and methods of use |
US9398882B2 (en) * | 2005-09-30 | 2016-07-26 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor and data processing device |
US7697967B2 (en) | 2005-12-28 | 2010-04-13 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor insertion |
US8571624B2 (en) | 2004-12-29 | 2013-10-29 | Abbott Diabetes Care Inc. | Method and apparatus for mounting a data transmission device in a communication system |
US8333714B2 (en) | 2006-09-10 | 2012-12-18 | Abbott Diabetes Care Inc. | Method and system for providing an integrated analyte sensor insertion device and data processing unit |
US9259175B2 (en) * | 2006-10-23 | 2016-02-16 | Abbott Diabetes Care, Inc. | Flexible patch for fluid delivery and monitoring body analytes |
US8512243B2 (en) | 2005-09-30 | 2013-08-20 | Abbott Diabetes Care Inc. | Integrated introducer and transmitter assembly and methods of use |
US9572534B2 (en) | 2010-06-29 | 2017-02-21 | Abbott Diabetes Care Inc. | Devices, systems and methods for on-skin or on-body mounting of medical devices |
US7883464B2 (en) | 2005-09-30 | 2011-02-08 | Abbott Diabetes Care Inc. | Integrated transmitter unit and sensor introducer mechanism and methods of use |
US9636450B2 (en) * | 2007-02-19 | 2017-05-02 | Udo Hoss | Pump system modular components for delivering medication and analyte sensing at seperate insertion sites |
US8652831B2 (en) | 2004-12-30 | 2014-02-18 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for analyte measurement test time |
JP5216328B2 (en) | 2005-01-24 | 2013-06-19 | アンタレス ファーマ インコーポレイテッド | Pre-filled needle assist syringe jet injector |
US7785258B2 (en) * | 2005-10-06 | 2010-08-31 | Optiscan Biomedical Corporation | System and method for determining a treatment dose for a patient |
US8251907B2 (en) | 2005-02-14 | 2012-08-28 | Optiscan Biomedical Corporation | System and method for determining a treatment dose for a patient |
US20060189926A1 (en) * | 2005-02-14 | 2006-08-24 | Hall W D | Apparatus and methods for analyzing body fluid samples |
US8133178B2 (en) | 2006-02-22 | 2012-03-13 | Dexcom, Inc. | Analyte sensor |
US20090076360A1 (en) | 2007-09-13 | 2009-03-19 | Dexcom, Inc. | Transcutaneous analyte sensor |
WO2006102412A2 (en) * | 2005-03-21 | 2006-09-28 | Abbott Diabetes Care, Inc. | Method and system for providing integrated medication infusion and analyte monitoring system |
US8744546B2 (en) | 2005-05-05 | 2014-06-03 | Dexcom, Inc. | Cellulosic-based resistance domain for an analyte sensor |
EP1877116A1 (en) | 2005-04-13 | 2008-01-16 | Novo Nordisk A/S | Medical skin mountable device and system |
US8060174B2 (en) | 2005-04-15 | 2011-11-15 | Dexcom, Inc. | Analyte sensing biointerface |
US8112240B2 (en) | 2005-04-29 | 2012-02-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing leak detection in data monitoring and management systems |
US8840586B2 (en) * | 2006-08-23 | 2014-09-23 | Medtronic Minimed, Inc. | Systems and methods allowing for reservoir filling and infusion medium delivery |
US7905868B2 (en) | 2006-08-23 | 2011-03-15 | Medtronic Minimed, Inc. | Infusion medium delivery device and method with drive device for driving plunger in reservoir |
US8137314B2 (en) * | 2006-08-23 | 2012-03-20 | Medtronic Minimed, Inc. | Infusion medium delivery device and method with compressible or curved reservoir or conduit |
US8277415B2 (en) | 2006-08-23 | 2012-10-02 | Medtronic Minimed, Inc. | Infusion medium delivery device and method with drive device for driving plunger in reservoir |
US20080097291A1 (en) * | 2006-08-23 | 2008-04-24 | Hanson Ian B | Infusion pumps and methods and delivery devices and methods with same |
US8512288B2 (en) | 2006-08-23 | 2013-08-20 | Medtronic Minimed, Inc. | Infusion medium delivery device and method with drive device for driving plunger in reservoir |
US9233203B2 (en) * | 2005-05-06 | 2016-01-12 | Medtronic Minimed, Inc. | Medical needles for damping motion |
US20060264783A1 (en) | 2005-05-09 | 2006-11-23 | Holmes Elizabeth A | Systems and methods for monitoring pharmacological parameters |
US20060263839A1 (en) * | 2005-05-17 | 2006-11-23 | Isense Corporation | Combined drug delivery and analyte sensor apparatus |
US7768408B2 (en) | 2005-05-17 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and system for providing data management in data monitoring system |
US7509156B2 (en) * | 2005-05-18 | 2009-03-24 | Clarian Health Partners, Inc. | System for managing glucose levels in patients with diabetes or hyperglycemia |
EP1893079B1 (en) | 2005-06-08 | 2012-06-27 | SHER, Philip Michael | Fluctuating blood glucose notification threshold profiles and methods of use |
US20060281187A1 (en) | 2005-06-13 | 2006-12-14 | Rosedale Medical, Inc. | Analyte detection devices and methods with hematocrit/volume correction and feedback control |
EP1733676B1 (en) | 2005-06-17 | 2012-08-01 | F. Hoffmann-La Roche AG | Sensor system, arrangement and method for monitoring a compound, in particular glucose in body tissue. |
AU2016213744B2 (en) * | 2005-07-20 | 2017-11-23 | Ascensia Diabetes Care Holdings Ag | Gated amperometry |
KR101321296B1 (en) * | 2005-07-20 | 2013-10-28 | 바이엘 헬스케어 엘엘씨 | Gated amperometry temperature determination |
CN110376269A (en) * | 2005-07-20 | 2019-10-25 | 安晟信医疗科技控股公司 | The method for determining the input signal duration |
AU2013200069B2 (en) * | 2005-07-20 | 2014-06-05 | Ascensia Diabetes Care Holdings Ag | Gated amperometry |
AU2014218413B2 (en) * | 2005-07-20 | 2016-09-15 | Ascensia Diabetes Care Holdings Ag | Gated amperometry |
US8551046B2 (en) | 2006-09-18 | 2013-10-08 | Asante Solutions, Inc. | Dispensing fluid from an infusion pump system |
US7534226B2 (en) | 2005-09-26 | 2009-05-19 | M2 Group Holdings, Inc. | Dispensing fluid from an infusion pump system |
US8852164B2 (en) | 2006-02-09 | 2014-10-07 | Deka Products Limited Partnership | Method and system for shape-memory alloy wire control |
EP1928304B1 (en) | 2005-09-30 | 2012-10-24 | Intuity Medical, Inc. | Catalysts for body fluid sample extraction |
JP5671205B2 (en) | 2005-09-30 | 2015-02-18 | バイエル・ヘルスケア・エルエルシー | Gated voltammetry |
US9521968B2 (en) | 2005-09-30 | 2016-12-20 | Abbott Diabetes Care Inc. | Analyte sensor retention mechanism and methods of use |
US8801631B2 (en) | 2005-09-30 | 2014-08-12 | Intuity Medical, Inc. | Devices and methods for facilitating fluid transport |
WO2007045644A1 (en) | 2005-10-17 | 2007-04-26 | Novo Nordisk A/S | Vented drug reservoir unit |
US7766829B2 (en) | 2005-11-04 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and system for providing basal profile modification in analyte monitoring and management systems |
US9067047B2 (en) | 2005-11-09 | 2015-06-30 | The Invention Science Fund I, Llc | Injectable controlled release fluid delivery system |
US7942867B2 (en) | 2005-11-09 | 2011-05-17 | The Invention Science Fund I, Llc | Remotely controlled substance delivery device |
US7817030B2 (en) | 2005-11-09 | 2010-10-19 | Invention Science Fund 1, Llc | Remote controller for in situ reaction device |
US8998886B2 (en) | 2005-12-13 | 2015-04-07 | The Invention Science Fund I, Llc | Remote control of osmotic pump device |
US8083710B2 (en) * | 2006-03-09 | 2011-12-27 | The Invention Science Fund I, Llc | Acoustically controlled substance delivery device |
US8936590B2 (en) | 2005-11-09 | 2015-01-20 | The Invention Science Fund I, Llc | Acoustically controlled reaction device |
US8273071B2 (en) | 2006-01-18 | 2012-09-25 | The Invention Science Fund I, Llc | Remote controller for substance delivery system |
US8992511B2 (en) | 2005-11-09 | 2015-03-31 | The Invention Science Fund I, Llc | Acoustically controlled substance delivery device |
US7842008B2 (en) * | 2005-11-21 | 2010-11-30 | Becton, Dickinson And Company | Intradermal delivery device |
US20070129620A1 (en) * | 2005-12-02 | 2007-06-07 | Peter Krulevitch | Selectively exposable miniature probes with integrated sensor arrays for continuous in vivo diagnostics |
US20070179436A1 (en) * | 2005-12-21 | 2007-08-02 | Braig James R | Analyte detection system with periodic sample draw and laboratory-grade analyzer |
US11298058B2 (en) | 2005-12-28 | 2022-04-12 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor insertion |
EP1968432A4 (en) | 2005-12-28 | 2009-10-21 | Abbott Diabetes Care Inc | Medical device insertion |
US7774038B2 (en) | 2005-12-30 | 2010-08-10 | Medtronic Minimed, Inc. | Real-time self-calibrating sensor system and method |
US9757061B2 (en) | 2006-01-17 | 2017-09-12 | Dexcom, Inc. | Low oxygen in vivo analyte sensor |
US7736310B2 (en) | 2006-01-30 | 2010-06-15 | Abbott Diabetes Care Inc. | On-body medical device securement |
US11497846B2 (en) | 2006-02-09 | 2022-11-15 | Deka Products Limited Partnership | Patch-sized fluid delivery systems and methods |
US11478623B2 (en) | 2006-02-09 | 2022-10-25 | Deka Products Limited Partnership | Infusion pump assembly |
US11364335B2 (en) | 2006-02-09 | 2022-06-21 | Deka Products Limited Partnership | Apparatus, system and method for fluid delivery |
DE602007013723D1 (en) | 2006-02-09 | 2011-05-19 | Deka Products Lp | SYSTEMS FOR DISPENSING FLUIDS IN PATCH SIZE |
EP1993637A2 (en) * | 2006-02-15 | 2008-11-26 | Medingo Ltd. | Systems and methods for sensing analyte and dispensing therapeutic fluid |
US7885698B2 (en) | 2006-02-28 | 2011-02-08 | Abbott Diabetes Care Inc. | Method and system for providing continuous calibration of implantable analyte sensors |
US7981034B2 (en) | 2006-02-28 | 2011-07-19 | Abbott Diabetes Care Inc. | Smart messages and alerts for an infusion delivery and management system |
US20080140057A1 (en) | 2006-03-09 | 2008-06-12 | Searete Llc, A Limited Liability Corporation Of State Of The Delaware | Injectable controlled release fluid delivery system |
JP5681362B2 (en) | 2006-03-14 | 2015-03-04 | ユニバーシティー オブ サザン カリフォルニア | MEMS device for delivery of therapeutic agents |
US8741230B2 (en) | 2006-03-24 | 2014-06-03 | Theranos, Inc. | Systems and methods of sample processing and fluid control in a fluidic system |
US11287421B2 (en) | 2006-03-24 | 2022-03-29 | Labrador Diagnostics Llc | Systems and methods of sample processing and fluid control in a fluidic system |
CN103239773B (en) | 2006-03-30 | 2015-08-26 | 瓦莱里塔斯公司 | Multi-cartridge fluid delivery device |
US8226891B2 (en) | 2006-03-31 | 2012-07-24 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods therefor |
US7620438B2 (en) | 2006-03-31 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and system for powering an electronic device |
US20070255125A1 (en) | 2006-04-28 | 2007-11-01 | Moberg Sheldon B | Monitor devices for networked fluid infusion systems |
US8073008B2 (en) | 2006-04-28 | 2011-12-06 | Medtronic Minimed, Inc. | Subnetwork synchronization and variable transmit synchronization techniques for a wireless medical device network |
US8251947B2 (en) | 2006-05-03 | 2012-08-28 | Antares Pharma, Inc. | Two-stage reconstituting injector |
EP2020909A2 (en) | 2006-05-08 | 2009-02-11 | Bayer HealthCare LLC | Abnormal output detection system for a biosensor |
US8007999B2 (en) | 2006-05-10 | 2011-08-30 | Theranos, Inc. | Real-time detection of influenza virus |
US20070282246A1 (en) * | 2006-06-05 | 2007-12-06 | Mit, Llp | Iontosonic-microneedle biosensor apparatus and methods |
WO2007143225A2 (en) | 2006-06-07 | 2007-12-13 | Abbott Diabetes Care, Inc. | Analyte monitoring system and method |
JP5241714B2 (en) | 2006-07-07 | 2013-07-17 | プロテウス デジタル ヘルス, インコーポレイテッド | Smart parenteral delivery system |
DE102006033251A1 (en) * | 2006-07-18 | 2008-02-07 | Testo Ag | Protective device for a humidity sensor in an aggressive atmosphere |
US8114023B2 (en) * | 2006-07-28 | 2012-02-14 | Legacy Emanuel Hospital & Health Center | Analyte sensing and response system |
US20110054391A1 (en) * | 2006-07-28 | 2011-03-03 | Ward W Kenneth | Analyte sensing and response system |
US8932216B2 (en) | 2006-08-07 | 2015-01-13 | Abbott Diabetes Care Inc. | Method and system for providing data management in integrated analyte monitoring and infusion system |
US8206296B2 (en) | 2006-08-07 | 2012-06-26 | Abbott Diabetes Care Inc. | Method and system for providing integrated analyte monitoring and infusion system therapy management |
US7828764B2 (en) * | 2006-08-23 | 2010-11-09 | Medtronic Minimed, Inc. | Systems and methods allowing for reservoir filling and infusion medium delivery |
US7811262B2 (en) * | 2006-08-23 | 2010-10-12 | Medtronic Minimed, Inc. | Systems and methods allowing for reservoir filling and infusion medium delivery |
US20080051765A1 (en) * | 2006-08-23 | 2008-02-28 | Medtronic Minimed, Inc. | Systems and methods allowing for reservoir filling and infusion medium delivery |
US7794434B2 (en) * | 2006-08-23 | 2010-09-14 | Medtronic Minimed, Inc. | Systems and methods allowing for reservoir filling and infusion medium delivery |
US7682338B2 (en) * | 2006-08-23 | 2010-03-23 | Medtronic Minimed, Inc. | Infusion medium delivery system, device and method with needle inserter and needle inserter device and method |
US9056165B2 (en) | 2006-09-06 | 2015-06-16 | Medtronic Minimed, Inc. | Intelligent therapy recommendation algorithm and method of using the same |
WO2008030927A2 (en) * | 2006-09-06 | 2008-03-13 | Optiscan Biomedical Corporation | Infusion flow interruption method and apparatus |
DK2083673T3 (en) * | 2006-09-29 | 2012-09-24 | Medingo Ltd | FLUID DISTRIBUTION SYSTEM WITH ELECTROCHEMICAL DETECTION OF ANALYTIC CONCENTRATION LEVELS |
US7831287B2 (en) | 2006-10-04 | 2010-11-09 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
US8275438B2 (en) | 2006-10-04 | 2012-09-25 | Dexcom, Inc. | Analyte sensor |
US8562528B2 (en) | 2006-10-04 | 2013-10-22 | Dexcom, Inc. | Analyte sensor |
US8298142B2 (en) | 2006-10-04 | 2012-10-30 | Dexcom, Inc. | Analyte sensor |
US8447376B2 (en) | 2006-10-04 | 2013-05-21 | Dexcom, Inc. | Analyte sensor |
US8449464B2 (en) | 2006-10-04 | 2013-05-28 | Dexcom, Inc. | Analyte sensor |
US8478377B2 (en) | 2006-10-04 | 2013-07-02 | Dexcom, Inc. | Analyte sensor |
US8202267B2 (en) | 2006-10-10 | 2012-06-19 | Medsolve Technologies, Inc. | Method and apparatus for infusing liquid to a body |
ES2825036T3 (en) * | 2006-10-24 | 2021-05-14 | Ascensia Diabetes Care Holdings Ag | Transient decay amperometry |
US8579853B2 (en) | 2006-10-31 | 2013-11-12 | Abbott Diabetes Care Inc. | Infusion devices and methods |
US20080113391A1 (en) | 2006-11-14 | 2008-05-15 | Ian Gibbons | Detection and quantification of analytes in bodily fluids |
EP2099384B1 (en) * | 2006-11-28 | 2018-09-05 | Roche Diabetes Care GmbH | An insertion device and method for inserting a subcutaneously insertable element into a body |
EP2124726A1 (en) | 2006-12-22 | 2009-12-02 | Medingo Ltd. | Fluid delivery with in vivo electrochemical analyte sensing |
WO2008091602A2 (en) | 2007-01-22 | 2008-07-31 | Corium International, Inc. | Applicators for microneedle arrays |
JP2010517693A (en) | 2007-02-06 | 2010-05-27 | グルメトリクス, インコーポレイテッド | Optical system and method for ratiometric measurement of blood glucose concentration |
US8732188B2 (en) | 2007-02-18 | 2014-05-20 | Abbott Diabetes Care Inc. | Method and system for providing contextual based medication dosage determination |
US8930203B2 (en) | 2007-02-18 | 2015-01-06 | Abbott Diabetes Care Inc. | Multi-function analyte test device and methods therefor |
US8123686B2 (en) | 2007-03-01 | 2012-02-28 | Abbott Diabetes Care Inc. | Method and apparatus for providing rolling data in communication systems |
EP1972267A1 (en) | 2007-03-20 | 2008-09-24 | Roche Diagnostics GmbH | System for in vivo measurement of an analyte concentration |
US9114238B2 (en) | 2007-04-16 | 2015-08-25 | Corium International, Inc. | Solvent-cast microprotrusion arrays containing active ingredient |
EP2146760B1 (en) | 2007-04-30 | 2018-10-10 | Medtronic MiniMed, Inc. | Reservoir filling, bubble management, and infusion medium delivery systems and methods with same |
US7963954B2 (en) | 2007-04-30 | 2011-06-21 | Medtronic Minimed, Inc. | Automated filling systems and methods |
US8434528B2 (en) | 2007-04-30 | 2013-05-07 | Medtronic Minimed, Inc. | Systems and methods for reservoir filling |
US8613725B2 (en) | 2007-04-30 | 2013-12-24 | Medtronic Minimed, Inc. | Reservoir systems and methods |
US8323250B2 (en) | 2007-04-30 | 2012-12-04 | Medtronic Minimed, Inc. | Adhesive patch systems and methods |
US7959715B2 (en) | 2007-04-30 | 2011-06-14 | Medtronic Minimed, Inc. | Systems and methods allowing for reservoir air bubble management |
US8597243B2 (en) | 2007-04-30 | 2013-12-03 | Medtronic Minimed, Inc. | Systems and methods allowing for reservoir air bubble management |
US8461985B2 (en) | 2007-05-08 | 2013-06-11 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US8456301B2 (en) | 2007-05-08 | 2013-06-04 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US7928850B2 (en) | 2007-05-08 | 2011-04-19 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US8665091B2 (en) | 2007-05-08 | 2014-03-04 | Abbott Diabetes Care Inc. | Method and device for determining elapsed sensor life |
WO2008141241A1 (en) | 2007-05-10 | 2008-11-20 | Glumetrics, Inc. | Equilibrium non-consuming fluorescence sensor for real time intravascular glucose measurement |
US20200037874A1 (en) | 2007-05-18 | 2020-02-06 | Dexcom, Inc. | Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise |
US8417311B2 (en) | 2008-09-12 | 2013-04-09 | Optiscan Biomedical Corporation | Fluid component analysis system and method for glucose monitoring and control |
US20100145175A1 (en) * | 2008-08-22 | 2010-06-10 | Soldo Monnett H | Systems and methods for verification of sample integrity |
WO2008150917A1 (en) | 2007-05-31 | 2008-12-11 | Abbott Diabetes Care, Inc. | Insertion devices and methods |
US20080306362A1 (en) * | 2007-06-05 | 2008-12-11 | Owen Davis | Device and system for monitoring contents of perspiration |
WO2008154416A2 (en) * | 2007-06-07 | 2008-12-18 | Microchips, Inc. | Electrochemical biosensors and arrays |
WO2008154312A1 (en) | 2007-06-08 | 2008-12-18 | Dexcom, Inc. | Integrated medicament delivery device for use with continuous analyte sensor |
US8641618B2 (en) | 2007-06-27 | 2014-02-04 | Abbott Diabetes Care Inc. | Method and structure for securing a monitoring device element |
US8160900B2 (en) | 2007-06-29 | 2012-04-17 | Abbott Diabetes Care Inc. | Analyte monitoring and management device and method to analyze the frequency of user interaction with the device |
EP2178584A2 (en) * | 2007-07-26 | 2010-04-28 | Entra Pharmaceuticals Inc. | Skin-patch pump comprising a changing-volume electrochemical actuator |
WO2009016636A2 (en) * | 2007-08-01 | 2009-02-05 | Medingo Ltd. | Portable infusion device provided with means for monitoring and controlling fluid delivery |
US8158430B1 (en) | 2007-08-06 | 2012-04-17 | Theranos, Inc. | Systems and methods of fluidic sample processing |
WO2009029044A1 (en) | 2007-08-24 | 2009-03-05 | Agency For Science, Technology And Research | A system and method for detecting skin penetration |
US20120046533A1 (en) * | 2007-08-29 | 2012-02-23 | Medtronic Minimed, Inc. | Combined sensor and infusion sets |
US9968742B2 (en) * | 2007-08-29 | 2018-05-15 | Medtronic Minimed, Inc. | Combined sensor and infusion set using separated sites |
MX2010003205A (en) | 2007-09-24 | 2010-04-09 | Bayer Healthcare Llc | Multi-electrode test sensors. |
US7967795B1 (en) | 2010-01-19 | 2011-06-28 | Lamodel Ltd. | Cartridge interface assembly with driving plunger |
US9656019B2 (en) | 2007-10-02 | 2017-05-23 | Medimop Medical Projects Ltd. | Apparatuses for securing components of a drug delivery system during transport and methods of using same |
CN101868273B (en) | 2007-10-02 | 2014-10-15 | 莱蒙德尔有限公司 | External drug pump |
US10420880B2 (en) | 2007-10-02 | 2019-09-24 | West Pharma. Services IL, Ltd. | Key for securing components of a drug delivery system during assembly and/or transport and methods of using same |
US9345836B2 (en) | 2007-10-02 | 2016-05-24 | Medimop Medical Projects Ltd. | Disengagement resistant telescoping assembly and unidirectional method of assembly for such |
US9452258B2 (en) | 2007-10-09 | 2016-09-27 | Dexcom, Inc. | Integrated insulin delivery system with continuous glucose sensor |
CA3105353A1 (en) | 2007-10-10 | 2009-04-16 | Optiscan Biomedical Corporation | Fluid component analysis system and method for glucose monitoring and control |
WO2009048607A1 (en) | 2007-10-10 | 2009-04-16 | Corium International, Inc. | Vaccine delivery via microneedle arrays |
EP2211974A4 (en) | 2007-10-25 | 2013-02-27 | Proteus Digital Health Inc | Fluid transfer port information system |
US8417312B2 (en) | 2007-10-25 | 2013-04-09 | Dexcom, Inc. | Systems and methods for processing sensor data |
US8419638B2 (en) | 2007-11-19 | 2013-04-16 | Proteus Digital Health, Inc. | Body-associated fluid transport structure evaluation devices |
EP2227134A2 (en) * | 2007-11-21 | 2010-09-15 | Medingo Ltd. | Hypodermic optical monitoring of bodily analyte |
WO2009076302A1 (en) | 2007-12-10 | 2009-06-18 | Bayer Healthcare Llc | Control markers for auto-detection of control solution and methods of use |
CA2708038A1 (en) | 2007-12-10 | 2009-09-03 | Bayer Healthcare Llc | Slope-based compensation |
WO2009075951A1 (en) | 2007-12-10 | 2009-06-18 | Bayer Healthcare Llc | Rapid-read gated amperometry |
US8290559B2 (en) | 2007-12-17 | 2012-10-16 | Dexcom, Inc. | Systems and methods for processing sensor data |
MX364408B (en) | 2007-12-20 | 2019-04-25 | Univ Southern California | APPARATUS and METHODS FOR DELIVERING THERAPEUTIC AGENTS. |
US8313467B2 (en) | 2007-12-27 | 2012-11-20 | Medtronic Minimed, Inc. | Reservoir pressure equalization systems and methods |
US10188787B2 (en) | 2007-12-31 | 2019-01-29 | Deka Products Limited Partnership | Apparatus, system and method for fluid delivery |
US8881774B2 (en) | 2007-12-31 | 2014-11-11 | Deka Research & Development Corp. | Apparatus, system and method for fluid delivery |
US8900188B2 (en) | 2007-12-31 | 2014-12-02 | Deka Products Limited Partnership | Split ring resonator antenna adapted for use in wirelessly controlled medical device |
US9456955B2 (en) | 2007-12-31 | 2016-10-04 | Deka Products Limited Partnership | Apparatus, system and method for fluid delivery |
WO2009088956A2 (en) | 2007-12-31 | 2009-07-16 | Deka Products Limited Partnership | Infusion pump assembly |
CA2919786C (en) | 2007-12-31 | 2019-10-22 | Deka Products Limited Partnership | Infusion pump assembly |
US10080704B2 (en) | 2007-12-31 | 2018-09-25 | Deka Products Limited Partnership | Apparatus, system and method for fluid delivery |
US8986253B2 (en) | 2008-01-25 | 2015-03-24 | Tandem Diabetes Care, Inc. | Two chamber pumps and related methods |
US8708961B2 (en) | 2008-01-28 | 2014-04-29 | Medsolve Technologies, Inc. | Apparatus for infusing liquid to a body |
WO2009105709A1 (en) | 2008-02-21 | 2009-08-27 | Dexcom, Inc. | Systems and methods for processing, transmitting and displaying sensor data |
US8396528B2 (en) | 2008-03-25 | 2013-03-12 | Dexcom, Inc. | Analyte sensor |
US11730407B2 (en) | 2008-03-28 | 2023-08-22 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US8682408B2 (en) | 2008-03-28 | 2014-03-25 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US8583204B2 (en) | 2008-03-28 | 2013-11-12 | Dexcom, Inc. | Polymer membranes for continuous analyte sensors |
US20090259176A1 (en) * | 2008-04-09 | 2009-10-15 | Los Gatos Research, Inc. | Transdermal patch system |
WO2009126900A1 (en) | 2008-04-11 | 2009-10-15 | Pelikan Technologies, Inc. | Method and apparatus for analyte detecting device |
WO2009137780A2 (en) * | 2008-05-08 | 2009-11-12 | Replenish Pumps, Llc | Implantable pumps and cannulas therefor |
US9849238B2 (en) | 2008-05-08 | 2017-12-26 | Minipumps, Llc | Drug-delivery pump with intelligent control |
WO2009137785A2 (en) * | 2008-05-08 | 2009-11-12 | Replenish Pumps, Llc | Drug-delivery pumps and methods of manufacture |
US8591410B2 (en) | 2008-05-30 | 2013-11-26 | Abbott Diabetes Care Inc. | Method and apparatus for providing glycemic control |
US8924159B2 (en) | 2008-05-30 | 2014-12-30 | Abbott Diabetes Care Inc. | Method and apparatus for providing glycemic control |
WO2009145920A1 (en) | 2008-05-30 | 2009-12-03 | Intuity Medical, Inc. | Body fluid sampling device -- sampling site interface |
US9636051B2 (en) | 2008-06-06 | 2017-05-02 | Intuity Medical, Inc. | Detection meter and mode of operation |
EP2299904B1 (en) | 2008-06-06 | 2019-09-11 | Intuity Medical, Inc. | Medical measurement method |
ES2700861T3 (en) | 2008-07-10 | 2019-02-19 | Ascensia Diabetes Care Holdings Ag | Systems and methods that include amperometric and voltammetric work cycles |
US8700114B2 (en) | 2008-07-31 | 2014-04-15 | Medtronic Minmed, Inc. | Analyte sensor apparatuses comprising multiple implantable sensor elements and methods for making and using them |
ES2738539T3 (en) | 2008-08-05 | 2020-01-23 | Antares Pharma Inc | Multi dose injector |
US9204925B2 (en) * | 2008-08-14 | 2015-12-08 | The Cleveland Clinic Foundation | Apparatus and method for treating a neuromuscular defect |
US7959598B2 (en) | 2008-08-20 | 2011-06-14 | Asante Solutions, Inc. | Infusion pump systems and methods |
DK2626093T3 (en) * | 2008-08-28 | 2014-02-24 | Hoffmann La Roche | DEVICE FOR INCREASING HYPODERMIC insulin absorption |
US9393369B2 (en) | 2008-09-15 | 2016-07-19 | Medimop Medical Projects Ltd. | Stabilized pen injector |
WO2010031059A2 (en) | 2008-09-15 | 2010-03-18 | Deka Products Limited Partnership | Systems and methods for fluid delivery |
US8408421B2 (en) | 2008-09-16 | 2013-04-02 | Tandem Diabetes Care, Inc. | Flow regulating stopcocks and related methods |
EP2334234A4 (en) | 2008-09-19 | 2013-03-20 | Tandem Diabetes Care Inc | Solute concentration measurement device and related methods |
EP2326944B1 (en) | 2008-09-19 | 2020-08-19 | Dexcom, Inc. | Particle-containing membrane and particulate electrode for analyte sensors |
US8708376B2 (en) | 2008-10-10 | 2014-04-29 | Deka Products Limited Partnership | Medium connector |
US8223028B2 (en) | 2008-10-10 | 2012-07-17 | Deka Products Limited Partnership | Occlusion detection system and method |
US8267892B2 (en) | 2008-10-10 | 2012-09-18 | Deka Products Limited Partnership | Multi-language / multi-processor infusion pump assembly |
US8066672B2 (en) | 2008-10-10 | 2011-11-29 | Deka Products Limited Partnership | Infusion pump assembly with a backup power supply |
US8262616B2 (en) | 2008-10-10 | 2012-09-11 | Deka Products Limited Partnership | Infusion pump assembly |
US8016789B2 (en) | 2008-10-10 | 2011-09-13 | Deka Products Limited Partnership | Pump assembly with a removable cover assembly |
US9180245B2 (en) | 2008-10-10 | 2015-11-10 | Deka Products Limited Partnership | System and method for administering an infusible fluid |
US8208973B2 (en) | 2008-11-05 | 2012-06-26 | Medtronic Minimed, Inc. | System and method for variable beacon timing with wireless devices |
US20100145305A1 (en) * | 2008-11-10 | 2010-06-10 | Ruth Alon | Low volume accurate injector |
BRPI0923342A2 (en) | 2008-12-08 | 2016-01-12 | Bayer Healthcare Llc | biosensor system with signal adjustment |
US20100169035A1 (en) * | 2008-12-29 | 2010-07-01 | Medtronic Minimed, Inc. | Methods and systems for observing sensor parameters |
US8152779B2 (en) * | 2008-12-30 | 2012-04-10 | Medimop Medical Projects Ltd. | Needle assembly for drug pump |
US9375529B2 (en) | 2009-09-02 | 2016-06-28 | Becton, Dickinson And Company | Extended use medical device |
EP3677293A1 (en) | 2009-01-12 | 2020-07-08 | Becton, Dickinson and Company | In-dwelling rigid catheter with flexible features |
US8103456B2 (en) | 2009-01-29 | 2012-01-24 | Abbott Diabetes Care Inc. | Method and device for early signal attenuation detection using blood glucose measurements |
US9375169B2 (en) | 2009-01-30 | 2016-06-28 | Sanofi-Aventis Deutschland Gmbh | Cam drive for managing disposable penetrating member actions with a single motor and motor and control system |
US9402544B2 (en) | 2009-02-03 | 2016-08-02 | Abbott Diabetes Care Inc. | Analyte sensor and apparatus for insertion of the sensor |
US20100213057A1 (en) * | 2009-02-26 | 2010-08-26 | Benjamin Feldman | Self-Powered Analyte Sensor |
US9033898B2 (en) | 2010-06-23 | 2015-05-19 | Seventh Sense Biosystems, Inc. | Sampling devices and methods involving relatively little pain |
US9041541B2 (en) | 2010-01-28 | 2015-05-26 | Seventh Sense Biosystems, Inc. | Monitoring or feedback systems and methods |
US20100256524A1 (en) | 2009-03-02 | 2010-10-07 | Seventh Sense Biosystems, Inc. | Techniques and devices associated with blood sampling |
WO2010108116A1 (en) | 2009-03-20 | 2010-09-23 | Antares Pharma, Inc. | Hazardous agent injection system |
US9446194B2 (en) | 2009-03-27 | 2016-09-20 | Dexcom, Inc. | Methods and systems for promoting glucose management |
US9226701B2 (en) | 2009-04-28 | 2016-01-05 | Abbott Diabetes Care Inc. | Error detection in critical repeating data in a wireless sensor system |
US8483967B2 (en) | 2009-04-29 | 2013-07-09 | Abbott Diabetes Care Inc. | Method and system for providing real time analyte sensor calibration with retrospective backfill |
EP3925533B1 (en) | 2009-04-30 | 2024-04-10 | DexCom, Inc. | Performance reports associated with continuous sensor data from multiple analysis time periods |
US9184490B2 (en) | 2009-05-29 | 2015-11-10 | Abbott Diabetes Care Inc. | Medical device antenna systems having external antenna configurations |
GB2471066A (en) * | 2009-06-10 | 2010-12-22 | Dna Electronics Ltd | A glucagon pump controller |
US8613892B2 (en) | 2009-06-30 | 2013-12-24 | Abbott Diabetes Care Inc. | Analyte meter with a moveable head and methods of using the same |
US8344847B2 (en) | 2009-07-09 | 2013-01-01 | Medtronic Minimed, Inc. | Coordination of control commands in a medical device system having at least one therapy delivery device and at least one wireless controller device |
WO2011008966A2 (en) | 2009-07-15 | 2011-01-20 | Deka Products Limited Partnership | Apparatus, systems and methods for an infusion pump assembly |
EP3936032A1 (en) | 2009-07-23 | 2022-01-12 | Abbott Diabetes Care, Inc. | Real time management of data relating to physiological control of glucose levels |
WO2011014704A2 (en) | 2009-07-30 | 2011-02-03 | Tandem Diabetes Care, Inc. | Infusion pump system with disposable cartridge having pressure venting and pressure feedback |
WO2011014851A1 (en) | 2009-07-31 | 2011-02-03 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte monitoring system calibration accuracy |
EP2467797B1 (en) * | 2009-08-18 | 2017-07-19 | MiniPumps, LLC | Electrolytic drug-delivery pump with adaptive control |
US9314195B2 (en) | 2009-08-31 | 2016-04-19 | Abbott Diabetes Care Inc. | Analyte signal processing device and methods |
WO2011026148A1 (en) | 2009-08-31 | 2011-03-03 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods for managing power and noise |
EP3923295A1 (en) | 2009-08-31 | 2021-12-15 | Abbott Diabetes Care, Inc. | Medical devices and methods |
US8487758B2 (en) | 2009-09-02 | 2013-07-16 | Medtronic Minimed, Inc. | Medical device having an intelligent alerting scheme, and related operating methods |
US8157769B2 (en) | 2009-09-15 | 2012-04-17 | Medimop Medical Projects Ltd. | Cartridge insertion assembly for drug delivery system |
US10071198B2 (en) | 2012-11-02 | 2018-09-11 | West Pharma. Servicees IL, Ltd. | Adhesive structure for medical device |
US10071196B2 (en) | 2012-05-15 | 2018-09-11 | West Pharma. Services IL, Ltd. | Method for selectively powering a battery-operated drug-delivery device and device therefor |
WO2011041469A1 (en) | 2009-09-29 | 2011-04-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing notification function in analyte monitoring systems |
EP2482724A2 (en) | 2009-09-30 | 2012-08-08 | Dexcom, Inc. | Transcutaneous analyte sensor |
WO2011041531A1 (en) | 2009-09-30 | 2011-04-07 | Abbott Diabetes Care Inc. | Interconnect for on-body analyte monitoring device |
US20110082711A1 (en) | 2009-10-06 | 2011-04-07 | Masimo Laboratories, Inc. | Personal digital assistant or organizer for monitoring glucose levels |
TWI381862B (en) * | 2009-10-07 | 2013-01-11 | Changhua Christian Hospital | Method and method of hand - push intravenous injection of pharmacokinetic model |
BR112012009196B1 (en) * | 2009-10-19 | 2021-03-30 | Labrador Diagnostics Llc | SYSTEM FOR MODELING THE PROGRESSION OF A DISEASE WITHIN A POPULATION |
US8386042B2 (en) | 2009-11-03 | 2013-02-26 | Medtronic Minimed, Inc. | Omnidirectional accelerometer device and medical device incorporating same |
EP3106871B1 (en) | 2009-11-30 | 2021-10-27 | Intuity Medical, Inc. | A method of verifying the accuracy of the operation of an analyte monitoring device |
US20120296253A1 (en) * | 2009-12-10 | 2012-11-22 | Edward Henry Mathews | Haemodialysis machine retrofit and control installation and use thereof for the treatment of proliferative disorders |
US8574201B2 (en) | 2009-12-22 | 2013-11-05 | Medtronic Minimed, Inc. | Syringe piston with check valve seal |
US8755269B2 (en) | 2009-12-23 | 2014-06-17 | Medtronic Minimed, Inc. | Ranking and switching of wireless channels in a body area network of medical devices |
US8070723B2 (en) | 2009-12-31 | 2011-12-06 | Medtronic Minimed, Inc. | Activity guard |
US8348898B2 (en) | 2010-01-19 | 2013-01-08 | Medimop Medical Projects Ltd. | Automatic needle for drug pump |
US20110184258A1 (en) * | 2010-01-28 | 2011-07-28 | Abbott Diabetes Care Inc. | Balloon Catheter Analyte Measurement Sensors and Methods for Using the Same |
AU2011210648B2 (en) | 2010-02-01 | 2014-10-16 | Otsuka Pharmaceutical Co., Ltd. | Data gathering system |
US8332020B2 (en) | 2010-02-01 | 2012-12-11 | Proteus Digital Health, Inc. | Two-wrist data gathering system |
USD924406S1 (en) | 2010-02-01 | 2021-07-06 | Abbott Diabetes Care Inc. | Analyte sensor inserter |
MX2012010860A (en) | 2010-03-22 | 2013-03-05 | Bayer Healthcare Llc | Residual compensation for a biosensor. |
ES2881798T3 (en) | 2010-03-24 | 2021-11-30 | Abbott Diabetes Care Inc | Medical device inserters and medical device insertion and use procedures |
US8965476B2 (en) | 2010-04-16 | 2015-02-24 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
CN102469941B (en) * | 2010-04-16 | 2016-04-13 | 艾伯特糖尿病护理公司 | Analyze thing surveillance equipment and method |
WO2011140274A2 (en) | 2010-05-04 | 2011-11-10 | Corium International, Inc. | Method and device for transdermal delivery of parathyroid hormone using a microprojection array |
US8337457B2 (en) | 2010-05-05 | 2012-12-25 | Springleaf Therapeutics, Inc. | Systems and methods for delivering a therapeutic agent |
WO2011141907A1 (en) | 2010-05-10 | 2011-11-17 | Medimop Medical Projects Ltd. | Low volume accurate injector |
CA2798938C (en) | 2010-06-07 | 2018-08-07 | Bayer Healthcare Llc | Slope-based compensation including secondary output signals |
FI2575935T4 (en) | 2010-06-07 | 2023-11-23 | Amgen Inc | Drug delivery device |
US8636711B2 (en) | 2010-06-14 | 2014-01-28 | Legacy Emanuel Hospital & Health Center | Stabilized glucagon solutions and uses therefor |
US9215995B2 (en) | 2010-06-23 | 2015-12-22 | Medtronic Minimed, Inc. | Sensor systems having multiple probes and electrode arrays |
CA2803797A1 (en) | 2010-06-25 | 2011-12-29 | Intuity Medical, Inc. | Analyte monitoring methods and systems |
US11064921B2 (en) | 2010-06-29 | 2021-07-20 | Abbott Diabetes Care Inc. | Devices, systems and methods for on-skin or on-body mounting of medical devices |
EP2407193A1 (en) * | 2010-07-12 | 2012-01-18 | Roche Diagnostics GmbH | Medicinal device with multiple part housing |
ES2561824T3 (en) | 2010-07-16 | 2016-03-01 | Seventh Sense Biosystems, Inc. | Low pressure environment for fluid transfer devices |
US20130158482A1 (en) | 2010-07-26 | 2013-06-20 | Seventh Sense Biosystems, Inc. | Rapid delivery and/or receiving of fluids |
WO2012021801A2 (en) | 2010-08-13 | 2012-02-16 | Seventh Sense Biosystems, Inc. | Systems and techniques for monitoring subjects |
US8603033B2 (en) | 2010-10-15 | 2013-12-10 | Medtronic Minimed, Inc. | Medical device and related assembly having an offset element for a piezoelectric speaker |
US8562565B2 (en) | 2010-10-15 | 2013-10-22 | Medtronic Minimed, Inc. | Battery shock absorber for a portable medical device |
US8603032B2 (en) | 2010-10-15 | 2013-12-10 | Medtronic Minimed, Inc. | Medical device with membrane keypad sealing element, and related manufacturing method |
US8474332B2 (en) | 2010-10-20 | 2013-07-02 | Medtronic Minimed, Inc. | Sensor assembly and medical device incorporating same |
US8479595B2 (en) | 2010-10-20 | 2013-07-09 | Medtronic Minimed, Inc. | Sensor assembly and medical device incorporating same |
US8495918B2 (en) | 2010-10-20 | 2013-07-30 | Medtronic Minimed, Inc. | Sensor assembly and medical device incorporating same |
WO2012064802A1 (en) | 2010-11-09 | 2012-05-18 | Seventh Sense Biosystems, Inc. | Systems and interfaces for blood sampling |
US20120157801A1 (en) * | 2010-11-18 | 2012-06-21 | Abbott Diabetes Care Inc. | Adaptor for On-Body Analyte Monitoring System |
US8795230B2 (en) | 2010-11-30 | 2014-08-05 | Becton, Dickinson And Company | Adjustable height needle infusion device |
US8814831B2 (en) | 2010-11-30 | 2014-08-26 | Becton, Dickinson And Company | Ballistic microneedle infusion device |
US9950109B2 (en) | 2010-11-30 | 2018-04-24 | Becton, Dickinson And Company | Slide-activated angled inserter and cantilevered ballistic insertion for intradermal drug infusion |
US8368285B2 (en) | 2010-12-17 | 2013-02-05 | Massachusette Institute Of Technology | Electrochemical actuators |
US8197444B1 (en) | 2010-12-22 | 2012-06-12 | Medtronic Minimed, Inc. | Monitoring the seating status of a fluid reservoir in a fluid infusion device |
US8628510B2 (en) | 2010-12-22 | 2014-01-14 | Medtronic Minimed, Inc. | Monitoring the operating health of a force sensor in a fluid infusion device |
US8469942B2 (en) | 2010-12-22 | 2013-06-25 | Medtronic Minimed, Inc. | Occlusion detection for a fluid infusion device |
US8690855B2 (en) | 2010-12-22 | 2014-04-08 | Medtronic Minimed, Inc. | Fluid reservoir seating procedure for a fluid infusion device |
US8647357B2 (en) | 2011-02-05 | 2014-02-11 | Birch Narrows Development Llc | Lancet device with flexible cover |
WO2012112178A1 (en) | 2011-02-18 | 2012-08-23 | Medtronic,Inc | Modular medical device programmer |
US8352034B2 (en) | 2011-02-18 | 2013-01-08 | Medtronic, Inc. | Medical device programmer with adjustable kickstand |
US9283318B2 (en) | 2011-02-22 | 2016-03-15 | Medtronic Minimed, Inc. | Flanged sealing element and needle guide pin assembly for a fluid infusion device having a needled fluid reservoir |
US9393399B2 (en) | 2011-02-22 | 2016-07-19 | Medtronic Minimed, Inc. | Sealing assembly for a fluid reservoir of a fluid infusion device |
US9463309B2 (en) | 2011-02-22 | 2016-10-11 | Medtronic Minimed, Inc. | Sealing assembly and structure for a fluid infusion device having a needled fluid reservoir |
US11266823B2 (en) | 2011-02-22 | 2022-03-08 | Medtronic Minimed, Inc. | Retractable sealing assembly for a fluid reservoir of a fluid infusion device |
US20120211946A1 (en) | 2011-02-22 | 2012-08-23 | Medtronic Minimed, Inc. | Sealing element for a hollow needle of a fluid infusion device |
US10136845B2 (en) | 2011-02-28 | 2018-11-27 | Abbott Diabetes Care Inc. | Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same |
US8614596B2 (en) | 2011-02-28 | 2013-12-24 | Medtronic Minimed, Inc. | Systems and methods for initializing a voltage bus and medical devices incorporating same |
US9101305B2 (en) | 2011-03-09 | 2015-08-11 | Medtronic Minimed, Inc. | Glucose sensor product and related manufacturing and packaging methods |
US9018893B2 (en) | 2011-03-18 | 2015-04-28 | Medtronic Minimed, Inc. | Power control techniques for an electronic device |
US8564447B2 (en) | 2011-03-18 | 2013-10-22 | Medtronic Minimed, Inc. | Battery life indication techniques for an electronic device |
USD702834S1 (en) | 2011-03-22 | 2014-04-15 | Medimop Medical Projects Ltd. | Cartridge for use in injection device |
DK3575796T3 (en) | 2011-04-15 | 2021-01-18 | Dexcom Inc | ADVANCED ANALYZE SENSOR CALIBRATION AND ERROR DETECTION |
EP2702406B1 (en) | 2011-04-29 | 2017-06-21 | Seventh Sense Biosystems, Inc. | Plasma or serum production and removal of fluids under reduced pressure |
KR102237667B1 (en) | 2011-04-29 | 2021-04-12 | 세븐쓰 센스 바이오시스템즈, 인크. | Delivering and/or receiving fluids |
EP2701598A1 (en) | 2011-04-29 | 2014-03-05 | Seventh Sense Biosystems, Inc. | Systems and methods for collecting fluid from a subject |
US20130158468A1 (en) | 2011-12-19 | 2013-06-20 | Seventh Sense Biosystems, Inc. | Delivering and/or receiving material with respect to a subject surface |
US9008744B2 (en) | 2011-05-06 | 2015-04-14 | Medtronic Minimed, Inc. | Method and apparatus for continuous analyte monitoring |
US8795231B2 (en) | 2011-05-10 | 2014-08-05 | Medtronic Minimed, Inc. | Automated reservoir fill system |
US8636696B2 (en) | 2011-06-10 | 2014-01-28 | Kimberly-Clark Worldwide, Inc. | Transdermal device containing microneedles |
US8496619B2 (en) | 2011-07-15 | 2013-07-30 | Antares Pharma, Inc. | Injection device with cammed ram assembly |
US9220660B2 (en) | 2011-07-15 | 2015-12-29 | Antares Pharma, Inc. | Liquid-transfer adapter beveled spike |
EP3407064B1 (en) | 2011-08-03 | 2020-04-22 | Intuity Medical, Inc. | Body fluid sampling arrangement |
US9775806B2 (en) | 2011-09-21 | 2017-10-03 | Ascensia Diabetes Care Holdings Ag | Analysis compensation including segmented signals |
CA2850148C (en) | 2011-09-27 | 2020-02-25 | Glumetrics, Inc. | Method for functionalizing a porous membrane covering of an optical sensor to facilitate coupling of an antithrombogenic agent |
US9989522B2 (en) | 2011-11-01 | 2018-06-05 | Medtronic Minimed, Inc. | Methods and materials for modulating start-up time and air removal in dry sensors |
US9980669B2 (en) | 2011-11-07 | 2018-05-29 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods |
US8999720B2 (en) | 2011-11-17 | 2015-04-07 | Medtronic Minimed, Inc. | Aqueous radiation protecting formulations and methods for making and using them |
US9317656B2 (en) | 2011-11-23 | 2016-04-19 | Abbott Diabetes Care Inc. | Compatibility mechanisms for devices in a continuous analyte monitoring system and methods thereof |
FI3300658T3 (en) | 2011-12-11 | 2024-03-01 | Abbott Diabetes Care Inc | Analyte sensor methods |
US9610401B2 (en) | 2012-01-13 | 2017-04-04 | Medtronic Minimed, Inc. | Infusion set component with modular fluid channel element |
US9693816B2 (en) * | 2012-01-30 | 2017-07-04 | Covidien Lp | Electrosurgical apparatus with integrated energy sensing at tissue site |
EP2809375B1 (en) | 2012-01-31 | 2021-08-11 | Medimop Medical Projects Ltd. | Time dependent drug delivery apparatus |
WO2013134519A2 (en) | 2012-03-07 | 2013-09-12 | Deka Products Limited Partnership | Apparatus, system and method for fluid delivery |
US8603027B2 (en) | 2012-03-20 | 2013-12-10 | Medtronic Minimed, Inc. | Occlusion detection using pulse-width modulation and medical device incorporating same |
US8603026B2 (en) | 2012-03-20 | 2013-12-10 | Medtronic Minimed, Inc. | Dynamic pulse-width modulation motor control and medical device incorporating same |
US8523803B1 (en) | 2012-03-20 | 2013-09-03 | Medtronic Minimed, Inc. | Motor health monitoring and medical device incorporating same |
US10668213B2 (en) | 2012-03-26 | 2020-06-02 | West Pharma. Services IL, Ltd. | Motion activated mechanisms for a drug delivery device |
US9463280B2 (en) | 2012-03-26 | 2016-10-11 | Medimop Medical Projects Ltd. | Motion activated septum puncturing drug delivery device |
US9072827B2 (en) | 2012-03-26 | 2015-07-07 | Medimop Medical Projects Ltd. | Fail safe point protector for needle safety flap |
WO2013149186A1 (en) | 2012-03-30 | 2013-10-03 | Insulet Corporation | Fluid delivery device with transcutaneous access tool, insertion mechansim and blood glucose monitoring for use therewith |
KR20150011346A (en) | 2012-04-06 | 2015-01-30 | 안타레스 팔마, 인코퍼레이티드 | Needle assisted jet injection administration of testosterone compositions |
WO2013169800A1 (en) | 2012-05-07 | 2013-11-14 | Antares Pharma, Inc. | Injection device with cammed ram assembly |
US9180242B2 (en) | 2012-05-17 | 2015-11-10 | Tandem Diabetes Care, Inc. | Methods and devices for multiple fluid transfer |
US9493807B2 (en) | 2012-05-25 | 2016-11-15 | Medtronic Minimed, Inc. | Foldover sensors and methods for making and using them |
US20130338629A1 (en) | 2012-06-07 | 2013-12-19 | Medtronic Minimed, Inc. | Diabetes therapy management system for recommending basal pattern adjustments |
US9357958B2 (en) | 2012-06-08 | 2016-06-07 | Medtronic Minimed, Inc. | Application of electrochemical impedance spectroscopy in sensor systems, devices, and related methods |
US20150211916A1 (en) * | 2012-06-22 | 2015-07-30 | Mark McGinn | Warning device and method for monitoring alarm status of a vibration level of a piece of rotating machinery having an adaptive alarm indicator |
US9333292B2 (en) | 2012-06-26 | 2016-05-10 | Medtronic Minimed, Inc. | Mechanically actuated fluid infusion device |
US8454562B1 (en) | 2012-07-20 | 2013-06-04 | Asante Solutions, Inc. | Infusion pump system and method |
US8808269B2 (en) | 2012-08-21 | 2014-08-19 | Medtronic Minimed, Inc. | Reservoir plunger position monitoring and medical device incorporating same |
US9682188B2 (en) | 2012-08-21 | 2017-06-20 | Medtronic Minimed, Inc. | Reservoir fluid volume estimator and medical device incorporating same |
US10130767B2 (en) | 2012-08-30 | 2018-11-20 | Medtronic Minimed, Inc. | Sensor model supervisor for a closed-loop insulin infusion system |
US9623179B2 (en) | 2012-08-30 | 2017-04-18 | Medtronic Minimed, Inc. | Safeguarding techniques for a closed-loop insulin infusion system |
US9878096B2 (en) | 2012-08-30 | 2018-01-30 | Medtronic Minimed, Inc. | Generation of target glucose values for a closed-loop operating mode of an insulin infusion system |
US9662445B2 (en) | 2012-08-30 | 2017-05-30 | Medtronic Minimed, Inc. | Regulating entry into a closed-loop operating mode of an insulin infusion system |
US9364609B2 (en) | 2012-08-30 | 2016-06-14 | Medtronic Minimed, Inc. | Insulin on board compensation for a closed-loop insulin infusion system |
US10496797B2 (en) | 2012-08-30 | 2019-12-03 | Medtronic Minimed, Inc. | Blood glucose validation for a closed-loop operating mode of an insulin infusion system |
US9849239B2 (en) | 2012-08-30 | 2017-12-26 | Medtronic Minimed, Inc. | Generation and application of an insulin limit for a closed-loop operating mode of an insulin infusion system |
US9968306B2 (en) | 2012-09-17 | 2018-05-15 | Abbott Diabetes Care Inc. | Methods and apparatuses for providing adverse condition notification with enhanced wireless communication range in analyte monitoring systems |
WO2014053081A1 (en) * | 2012-10-01 | 2014-04-10 | The Hong Kong University Of Science And Technology | Design and manufacture of nonelectronic, active-infusion patch and device for transdermal delivery across skin |
US20140213866A1 (en) | 2012-10-12 | 2014-07-31 | Dexcom, Inc. | Sensors for continuous analyte monitoring, and related methods |
EP2908881A2 (en) | 2012-10-16 | 2015-08-26 | SwissInnov Product Sàrl | Fluid delivery system and methods |
WO2014074621A1 (en) | 2012-11-07 | 2014-05-15 | Glumetrics, Inc. | Dry insertion and one-point in vivo calibration of an optical analyte sensor |
US9265455B2 (en) | 2012-11-13 | 2016-02-23 | Medtronic Minimed, Inc. | Methods and systems for optimizing sensor function by the application of voltage |
US8870818B2 (en) | 2012-11-15 | 2014-10-28 | Medtronic Minimed, Inc. | Systems and methods for alignment and detection of a consumable component |
US10194840B2 (en) | 2012-12-06 | 2019-02-05 | Medtronic Minimed, Inc. | Microarray electrodes useful with analyte sensors and methods for making and using them |
WO2014099907A1 (en) * | 2012-12-18 | 2014-06-26 | Abbott Diabetes Care Inc. | Dermal layer analyte sensing devices and methods |
ES2743404T3 (en) | 2012-12-21 | 2020-02-19 | Corium Inc | Matrix for therapeutic agent supply and manufacturing method |
US9421323B2 (en) | 2013-01-03 | 2016-08-23 | Medimop Medical Projects Ltd. | Door and doorstop for portable one use drug delivery apparatus |
US9522223B2 (en) | 2013-01-18 | 2016-12-20 | Medtronic Minimed, Inc. | Systems for fluid reservoir retention |
US9033924B2 (en) | 2013-01-18 | 2015-05-19 | Medtronic Minimed, Inc. | Systems for fluid reservoir retention |
US9107994B2 (en) | 2013-01-18 | 2015-08-18 | Medtronic Minimed, Inc. | Systems for fluid reservoir retention |
US10426383B2 (en) | 2013-01-22 | 2019-10-01 | Medtronic Minimed, Inc. | Muting glucose sensor oxygen response and reducing electrode edge growth with pulsed current plating |
CA2900672C (en) | 2013-02-11 | 2018-03-27 | Antares Pharma, Inc. | Needle assisted jet injection device having reduced trigger force |
US9308321B2 (en) | 2013-02-18 | 2016-04-12 | Medtronic Minimed, Inc. | Infusion device having gear assembly initialization |
WO2014132239A1 (en) | 2013-02-28 | 2014-09-04 | Kimberly-Clark Worldwide, Inc. | Drug delivery device |
CA2901568C (en) | 2013-02-28 | 2021-02-16 | Kimberly-Clark Worldwide, Inc. | Transdermal drug delivery device |
JP6030803B2 (en) | 2013-03-11 | 2016-11-24 | アンタレス・ファーマ・インコーポレーテッド | Dose syringe with pinion system |
EP2968887B1 (en) | 2013-03-12 | 2022-05-04 | Corium, Inc. | Microprojection applicators |
EP2967531A4 (en) * | 2013-03-14 | 2016-08-24 | Prescient Surgical Inc | Methods and devices for the prevention of incisional surgical site infections |
US9173998B2 (en) | 2013-03-14 | 2015-11-03 | Tandem Diabetes Care, Inc. | System and method for detecting occlusions in an infusion pump |
EP2968118B1 (en) | 2013-03-15 | 2022-02-09 | Corium, Inc. | Microarray for delivery of therapeutic agent and methods of use |
CA2903459C (en) | 2013-03-15 | 2024-02-20 | Corium International, Inc. | Multiple impact microprojection applicators and methods of use |
JP2016518883A (en) * | 2013-03-15 | 2016-06-30 | プロメセオン ファーマ,エルエルシー | Devices, systems, and methods for transdermal delivery of compounds |
AU2014237279B2 (en) | 2013-03-15 | 2018-11-22 | Corium Pharma Solutions, Inc. | Microarray with polymer-free microstructures, methods of making, and methods of use |
EP2968119B1 (en) | 2013-03-15 | 2019-09-18 | Corium International, Inc. | Microarray for delivery of therapeutic agent, methods of use, and methods of making |
US9492608B2 (en) | 2013-03-15 | 2016-11-15 | Tandem Diabetes Care, Inc. | Method and device utilizing insulin delivery protocols |
US8920381B2 (en) | 2013-04-12 | 2014-12-30 | Medtronic Minimed, Inc. | Infusion set with improved bore configuration |
US9237866B2 (en) | 2013-04-29 | 2016-01-19 | Birch Narrows Development, LLC | Blood glucose management |
US9011164B2 (en) | 2013-04-30 | 2015-04-21 | Medimop Medical Projects Ltd. | Clip contact for easy installation of printed circuit board PCB |
US9889256B2 (en) | 2013-05-03 | 2018-02-13 | Medimop Medical Projects Ltd. | Sensing a status of an infuser based on sensing motor control and power input |
US9338819B2 (en) | 2013-05-29 | 2016-05-10 | Medtronic Minimed, Inc. | Variable data usage personal medical system and method |
US9457141B2 (en) | 2013-06-03 | 2016-10-04 | Bigfoot Biomedical, Inc. | Infusion pump system and method |
US10194864B2 (en) | 2013-06-21 | 2019-02-05 | Medtronic Minimed, Inc. | Anchoring apparatus and method for attaching device on body |
US10729386B2 (en) | 2013-06-21 | 2020-08-04 | Intuity Medical, Inc. | Analyte monitoring system with audible feedback |
EP3016629B1 (en) | 2013-07-03 | 2023-12-20 | DEKA Products Limited Partnership | Apparatus and system for fluid delivery |
US9561324B2 (en) | 2013-07-19 | 2017-02-07 | Bigfoot Biomedical, Inc. | Infusion pump system and method |
US9433731B2 (en) | 2013-07-19 | 2016-09-06 | Medtronic Minimed, Inc. | Detecting unintentional motor motion and infusion device incorporating same |
US9402949B2 (en) | 2013-08-13 | 2016-08-02 | Medtronic Minimed, Inc. | Detecting conditions associated with medical device operations using matched filters |
US9880528B2 (en) | 2013-08-21 | 2018-01-30 | Medtronic Minimed, Inc. | Medical devices and related updating methods and systems |
US9889257B2 (en) | 2013-08-21 | 2018-02-13 | Medtronic Minimed, Inc. | Systems and methods for updating medical devices |
US9259528B2 (en) | 2013-08-22 | 2016-02-16 | Medtronic Minimed, Inc. | Fluid infusion device with safety coupling |
KR101494542B1 (en) | 2013-09-10 | 2015-02-23 | 경북대학교 산학협력단 | Gloucose sensor |
US9265881B2 (en) | 2013-10-14 | 2016-02-23 | Medtronic Minimed, Inc. | Therapeutic agent injection device |
US9375537B2 (en) | 2013-10-14 | 2016-06-28 | Medtronic Minimed, Inc. | Therapeutic agent injection device |
US8979799B1 (en) | 2013-10-14 | 2015-03-17 | Medtronic Minimed, Inc. | Electronic injector |
US8979808B1 (en) | 2013-10-14 | 2015-03-17 | Medtronic Minimed, Inc. | On-body injector and method of use |
US9226709B2 (en) | 2013-11-04 | 2016-01-05 | Medtronic Minimed, Inc. | ICE message system and method |
US9267875B2 (en) | 2013-11-21 | 2016-02-23 | Medtronic Minimed, Inc. | Accelerated life testing device and method |
US10569015B2 (en) | 2013-12-02 | 2020-02-25 | Bigfoot Biomedical, Inc. | Infusion pump system and method |
US9750877B2 (en) | 2013-12-11 | 2017-09-05 | Medtronic Minimed, Inc. | Predicted time to assess and/or control a glycemic state |
US9750878B2 (en) | 2013-12-11 | 2017-09-05 | Medtronic Minimed, Inc. | Closed-loop control of glucose according to a predicted blood glucose trajectory |
US9849240B2 (en) | 2013-12-12 | 2017-12-26 | Medtronic Minimed, Inc. | Data modification for predictive operations and devices incorporating same |
US10105488B2 (en) | 2013-12-12 | 2018-10-23 | Medtronic Minimed, Inc. | Predictive infusion device operations and related methods and systems |
US10638947B2 (en) | 2013-12-16 | 2020-05-05 | Medtronic Minimed, Inc. | Use of electrochemical impedance spectroscopy (EIS) in intelligent diagnostics |
US9943256B2 (en) | 2013-12-16 | 2018-04-17 | Medtronic Minimed, Inc. | Methods and systems for improving the reliability of orthogonally redundant sensors |
US9143941B2 (en) | 2013-12-18 | 2015-09-22 | Medtronic Minimed, Inc. | Secure communication by user selectable communication range |
US9779226B2 (en) | 2013-12-18 | 2017-10-03 | Medtronic Minimed, Inc. | Fingerprint enhanced authentication for medical devices in wireless networks |
US9694132B2 (en) | 2013-12-19 | 2017-07-04 | Medtronic Minimed, Inc. | Insertion device for insertion set |
CA2933166C (en) | 2013-12-31 | 2020-10-27 | Abbott Diabetes Care Inc. | Self-powered analyte sensor and devices using the same |
GB2523989B (en) | 2014-01-30 | 2020-07-29 | Insulet Netherlands B V | Therapeutic product delivery system and method of pairing |
US9399096B2 (en) | 2014-02-06 | 2016-07-26 | Medtronic Minimed, Inc. | Automatic closed-loop control adjustments and infusion systems incorporating same |
US9861748B2 (en) | 2014-02-06 | 2018-01-09 | Medtronic Minimed, Inc. | User-configurable closed-loop notifications and infusion systems incorporating same |
US20170065728A1 (en) * | 2014-03-03 | 2017-03-09 | The Penn State Research Foundation | Self-powered enzyme micropumps |
US9388805B2 (en) | 2014-03-24 | 2016-07-12 | Medtronic Minimed, Inc. | Medication pump test device and method of use |
US10034976B2 (en) | 2014-03-24 | 2018-07-31 | Medtronic Minimed, Inc. | Fluid infusion patch pump device with automatic fluid system priming feature |
US9689830B2 (en) | 2014-04-03 | 2017-06-27 | Medtronic Minimed, Inc. | Sensor detection pads with integrated fuse |
US9707336B2 (en) | 2014-04-07 | 2017-07-18 | Medtronic Minimed, Inc. | Priming detection system and method of using the same |
US20150289788A1 (en) | 2014-04-10 | 2015-10-15 | Dexcom, Inc. | Sensors for continuous analyte monitoring, and related methods |
US10441717B2 (en) | 2014-04-15 | 2019-10-15 | Insulet Corporation | Monitoring a physiological parameter associated with tissue of a host to confirm delivery of medication |
US10001450B2 (en) | 2014-04-18 | 2018-06-19 | Medtronic Minimed, Inc. | Nonlinear mapping technique for a physiological characteristic sensor |
US10232113B2 (en) | 2014-04-24 | 2019-03-19 | Medtronic Minimed, Inc. | Infusion devices and related methods and systems for regulating insulin on board |
US10275572B2 (en) | 2014-05-01 | 2019-04-30 | Medtronic Minimed, Inc. | Detecting blockage of a reservoir cavity during a seating operation of a fluid infusion device |
US9681828B2 (en) | 2014-05-01 | 2017-06-20 | Medtronic Minimed, Inc. | Physiological characteristic sensors and methods for forming such sensors |
US10274349B2 (en) | 2014-05-19 | 2019-04-30 | Medtronic Minimed, Inc. | Calibration factor adjustments for infusion devices and related methods and systems |
US10007765B2 (en) | 2014-05-19 | 2018-06-26 | Medtronic Minimed, Inc. | Adaptive signal processing for infusion devices and related methods and systems |
US10152049B2 (en) | 2014-05-19 | 2018-12-11 | Medtronic Minimed, Inc. | Glucose sensor health monitoring and related methods and systems |
US9901305B2 (en) | 2014-06-13 | 2018-02-27 | Medtronic Minimed, Inc. | Physiological sensor history backfill system and method |
US11185627B2 (en) | 2014-07-21 | 2021-11-30 | Medtronic Minimed, Inc. | Smart connection interface |
US10137246B2 (en) | 2014-08-06 | 2018-11-27 | Bigfoot Biomedical, Inc. | Infusion pump assembly and method |
US9717845B2 (en) | 2014-08-19 | 2017-08-01 | Medtronic Minimed, Inc. | Geofencing for medical devices |
US20160051755A1 (en) | 2014-08-25 | 2016-02-25 | Medtronic Minimed, Inc. | Low cost fluid delivery device |
US9919096B2 (en) | 2014-08-26 | 2018-03-20 | Bigfoot Biomedical, Inc. | Infusion pump system and method |
EP3188714A1 (en) | 2014-09-04 | 2017-07-12 | Corium International, Inc. | Microstructure array, methods of making, and methods of use |
US20160071408A1 (en) * | 2014-09-09 | 2016-03-10 | Beijing Lenovo Software Ltd. | Wearable apparatus and data processing method |
US9833563B2 (en) | 2014-09-26 | 2017-12-05 | Medtronic Minimed, Inc. | Systems for managing reservoir chamber pressure |
US9839753B2 (en) | 2014-09-26 | 2017-12-12 | Medtronic Minimed, Inc. | Systems for managing reservoir chamber pressure |
US10279126B2 (en) | 2014-10-07 | 2019-05-07 | Medtronic Minimed, Inc. | Fluid conduit assembly with gas trapping filter in the fluid flow path |
US9592335B2 (en) | 2014-10-20 | 2017-03-14 | Medtronic Minimed, Inc. | Insulin pump data acquisition device |
US9841014B2 (en) | 2014-10-20 | 2017-12-12 | Medtronic Minimed, Inc. | Insulin pump data acquisition device and system |
US9901675B2 (en) | 2014-11-25 | 2018-02-27 | Medtronic Minimed, Inc. | Infusion set insertion device and method of use |
US9833564B2 (en) | 2014-11-25 | 2017-12-05 | Medtronic Minimed, Inc. | Fluid conduit assembly with air venting features |
US9731067B2 (en) | 2014-11-25 | 2017-08-15 | Medtronic Minimed, Inc. | Mechanical injection pump and method of use |
US10195341B2 (en) | 2014-11-26 | 2019-02-05 | Medtronic Minimed, Inc. | Systems and methods for fluid infusion device with automatic reservoir fill |
US9987420B2 (en) | 2014-11-26 | 2018-06-05 | Medtronic Minimed, Inc. | Systems and methods for fluid infusion device with automatic reservoir fill |
US9636453B2 (en) | 2014-12-04 | 2017-05-02 | Medtronic Minimed, Inc. | Advance diagnosis of infusion device operating mode viability |
US9943645B2 (en) | 2014-12-04 | 2018-04-17 | Medtronic Minimed, Inc. | Methods for operating mode transitions and related infusion devices and systems |
US9937292B2 (en) | 2014-12-09 | 2018-04-10 | Medtronic Minimed, Inc. | Systems for filling a fluid infusion device reservoir |
US10307535B2 (en) | 2014-12-19 | 2019-06-04 | Medtronic Minimed, Inc. | Infusion devices and related methods and systems for preemptive alerting |
US10265031B2 (en) | 2014-12-19 | 2019-04-23 | Medtronic Minimed, Inc. | Infusion devices and related methods and systems for automatic alert clearing |
US9717848B2 (en) | 2015-01-22 | 2017-08-01 | Medtronic Minimed, Inc. | Data derived pre-bolus delivery |
US10737024B2 (en) | 2015-02-18 | 2020-08-11 | Insulet Corporation | Fluid delivery and infusion devices, and methods of use thereof |
US9872954B2 (en) | 2015-03-02 | 2018-01-23 | Medtronic Minimed, Inc. | Belt clip |
US9795534B2 (en) | 2015-03-04 | 2017-10-24 | Medimop Medical Projects Ltd. | Compliant coupling assembly for cartridge coupling of a drug delivery device |
US10251813B2 (en) | 2015-03-04 | 2019-04-09 | West Pharma. Services IL, Ltd. | Flexibly mounted cartridge alignment collar for drug delivery device |
US10307528B2 (en) | 2015-03-09 | 2019-06-04 | Medtronic Minimed, Inc. | Extensible infusion devices and related methods |
KR20160115650A (en) * | 2015-03-25 | 2016-10-06 | 삼성전자주식회사 | Wearable electronic device |
WO2016153313A1 (en) | 2015-03-25 | 2016-09-29 | Samsung Electronics Co., Ltd. | Wearable electronic device |
US10449298B2 (en) | 2015-03-26 | 2019-10-22 | Medtronic Minimed, Inc. | Fluid injection devices and related methods |
US10293120B2 (en) | 2015-04-10 | 2019-05-21 | West Pharma. Services IL, Ltd. | Redundant injection device status indication |
US9744297B2 (en) | 2015-04-10 | 2017-08-29 | Medimop Medical Projects Ltd. | Needle cannula position as an input to operational control of an injection device |
US9878097B2 (en) | 2015-04-29 | 2018-01-30 | Bigfoot Biomedical, Inc. | Operating an infusion pump system |
US10130757B2 (en) | 2015-05-01 | 2018-11-20 | Medtronic Minimed, Inc. | Method and system for leakage detection in portable medical devices |
WO2016183493A1 (en) | 2015-05-14 | 2016-11-17 | Abbott Diabetes Care Inc. | Compact medical device inserters and related systems and methods |
US10213139B2 (en) | 2015-05-14 | 2019-02-26 | Abbott Diabetes Care Inc. | Systems, devices, and methods for assembling an applicator and sensor control device |
US9999721B2 (en) | 2015-05-26 | 2018-06-19 | Medtronic Minimed, Inc. | Error handling in infusion devices with distributed motor control and related operating methods |
US10137243B2 (en) | 2015-05-26 | 2018-11-27 | Medtronic Minimed, Inc. | Infusion devices with distributed motor control and related operating methods |
US10575767B2 (en) | 2015-05-29 | 2020-03-03 | Medtronic Minimed, Inc. | Method for monitoring an analyte, analyte sensor and analyte monitoring apparatus |
US10149943B2 (en) | 2015-05-29 | 2018-12-11 | West Pharma. Services IL, Ltd. | Linear rotation stabilizer for a telescoping syringe stopper driverdriving assembly |
EP3302652B1 (en) | 2015-06-04 | 2023-09-06 | Medimop Medical Projects Ltd. | Cartridge insertion for drug delivery device |
US9878095B2 (en) | 2015-06-22 | 2018-01-30 | Medtronic Minimed, Inc. | Occlusion detection techniques for a fluid infusion device having a rotary pump mechanism and multiple sensor contact elements |
US9993594B2 (en) | 2015-06-22 | 2018-06-12 | Medtronic Minimed, Inc. | Occlusion detection techniques for a fluid infusion device having a rotary pump mechanism and rotor position sensors |
US9987425B2 (en) | 2015-06-22 | 2018-06-05 | Medtronic Minimed, Inc. | Occlusion detection techniques for a fluid infusion device having a rotary pump mechanism and sensor contact elements |
US10010668B2 (en) | 2015-06-22 | 2018-07-03 | Medtronic Minimed, Inc. | Occlusion detection techniques for a fluid infusion device having a rotary pump mechanism and a force sensor |
US9879668B2 (en) | 2015-06-22 | 2018-01-30 | Medtronic Minimed, Inc. | Occlusion detection techniques for a fluid infusion device having a rotary pump mechanism and an optical sensor |
US10857093B2 (en) | 2015-06-29 | 2020-12-08 | Corium, Inc. | Microarray for delivery of therapeutic agent, methods of use, and methods of making |
AU2016297823B2 (en) | 2015-07-24 | 2020-10-22 | Sorrento Therapeutics, Inc. | Methods for better delivery of active agents to tumors |
DK3325081T3 (en) | 2015-07-24 | 2021-10-11 | Sorrento Therapeutics Inc | PROCEDURES FOR LYMPHATIC DELIVERY OF ACTIVE SUBSTANCES |
US10463297B2 (en) | 2015-08-21 | 2019-11-05 | Medtronic Minimed, Inc. | Personalized event detection methods and related devices and systems |
US10664569B2 (en) | 2015-08-21 | 2020-05-26 | Medtronic Minimed, Inc. | Data analytics and generation of recommendations for controlling glycemic outcomes associated with tracked events |
US10478557B2 (en) | 2015-08-21 | 2019-11-19 | Medtronic Minimed, Inc. | Personalized parameter modeling methods and related devices and systems |
US10201657B2 (en) | 2015-08-21 | 2019-02-12 | Medtronic Minimed, Inc. | Methods for providing sensor site rotation feedback and related infusion devices and systems |
US10293108B2 (en) | 2015-08-21 | 2019-05-21 | Medtronic Minimed, Inc. | Infusion devices and related patient ratio adjustment methods |
US10576207B2 (en) | 2015-10-09 | 2020-03-03 | West Pharma. Services IL, Ltd. | Angled syringe patch injector |
US9987432B2 (en) | 2015-09-22 | 2018-06-05 | West Pharma. Services IL, Ltd. | Rotation resistant friction adapter for plunger driver of drug delivery device |
US10117992B2 (en) | 2015-09-29 | 2018-11-06 | Medtronic Minimed, Inc. | Infusion devices and related rescue detection methods |
US9992818B2 (en) | 2015-10-06 | 2018-06-05 | Medtronic Minimed, Inc. | Protocol translation device |
CN108472438B (en) | 2015-10-09 | 2022-01-28 | 西医药服务以色列分公司 | Tortuous fluid path attachment to pre-filled fluid reservoirs |
US11666702B2 (en) | 2015-10-19 | 2023-06-06 | Medtronic Minimed, Inc. | Medical devices and related event pattern treatment recommendation methods |
US11501867B2 (en) | 2015-10-19 | 2022-11-15 | Medtronic Minimed, Inc. | Medical devices and related event pattern presentation methods |
US9757511B2 (en) | 2015-10-19 | 2017-09-12 | Medtronic Minimed, Inc. | Personal medical device and method of use with restricted mode challenge |
US10146911B2 (en) | 2015-10-23 | 2018-12-04 | Medtronic Minimed, Inc. | Medical devices and related methods and systems for data transfer |
US10037722B2 (en) | 2015-11-03 | 2018-07-31 | Medtronic Minimed, Inc. | Detecting breakage in a display element |
US10827959B2 (en) | 2015-11-11 | 2020-11-10 | Medtronic Minimed, Inc. | Sensor set |
EP3380061A4 (en) | 2015-11-24 | 2019-07-24 | Insulet Corporation | Wearable automated medication delivery system |
WO2017091584A1 (en) | 2015-11-25 | 2017-06-01 | Insulet Corporation | Wearable medication delivery device |
US10449306B2 (en) | 2015-11-25 | 2019-10-22 | Medtronics Minimed, Inc. | Systems for fluid delivery with wicking membrane |
US9848805B2 (en) | 2015-12-18 | 2017-12-26 | Medtronic Minimed, Inc. | Biostable glucose permeable polymer |
US10327680B2 (en) | 2015-12-28 | 2019-06-25 | Medtronic Minimed, Inc. | Sensor systems, devices, and methods for continuous glucose monitoring |
US10349872B2 (en) | 2015-12-28 | 2019-07-16 | Medtronic Minimed, Inc. | Methods, systems, and devices for sensor fusion |
US10327686B2 (en) | 2015-12-28 | 2019-06-25 | Medtronic Minimed, Inc. | Sensor systems, devices, and methods for continuous glucose monitoring |
US20170181672A1 (en) | 2015-12-28 | 2017-06-29 | Medtronic Minimed, Inc. | Sensor systems, devices, and methods for continuous glucose monitoring |
US10569016B2 (en) | 2015-12-29 | 2020-02-25 | Tandem Diabetes Care, Inc. | System and method for switching between closed loop and open loop control of an ambulatory infusion pump |
DK4238496T3 (en) | 2015-12-30 | 2024-02-26 | Dexcom Inc | TRANSCUTANEOUS ANALYTE SENSOR SYSTEMS AND METHODS |
EP3374900A1 (en) | 2016-01-05 | 2018-09-19 | Bigfoot Biomedical, Inc. | Operating multi-modal medicine delivery systems |
WO2017123525A1 (en) | 2016-01-13 | 2017-07-20 | Bigfoot Biomedical, Inc. | User interface for diabetes management system |
EP3453414A1 (en) | 2016-01-14 | 2019-03-13 | Bigfoot Biomedical, Inc. | Adjusting insulin delivery rates |
JP6513297B2 (en) | 2016-01-21 | 2019-05-22 | ウェスト ファーマ サービシーズ イスラエル リミテッド | Automatic injector, receiving frame and method of connecting cartridge in automatic injector |
JP6885960B2 (en) | 2016-01-21 | 2021-06-16 | ウェスト ファーマ サービシーズ イスラエル リミテッド | Drug delivery device with visual indicators |
US10646643B2 (en) | 2016-01-21 | 2020-05-12 | West Pharma. Services IL, Ltd. | Needle insertion and retraction mechanism |
EP3407780A4 (en) | 2016-01-28 | 2019-09-18 | Klue, Inc. | Method and apparatus for tracking of food intake and other behaviors and providing relevant feedback |
US10790054B1 (en) | 2016-12-07 | 2020-09-29 | Medtronic Minimed, Inc. | Method and apparatus for tracking of food intake and other behaviors and providing relevant feedback |
CN105520288A (en) * | 2016-01-29 | 2016-04-27 | 张银虎 | Intelligent hand ring with dust detection function |
US10363342B2 (en) | 2016-02-04 | 2019-07-30 | Insulet Corporation | Anti-inflammatory cannula |
WO2017160948A1 (en) * | 2016-03-15 | 2017-09-21 | The Trustees Of Columbia University In The City Of New York | Devices and methods for detecting penetration of a semi-permeable membrane |
WO2017161076A1 (en) | 2016-03-16 | 2017-09-21 | Medimop Medical Projects Ltd. | Staged telescopic screw assembly having different visual indicators |
US10765369B2 (en) | 2016-04-08 | 2020-09-08 | Medtronic Minimed, Inc. | Analyte sensor |
US10765348B2 (en) | 2016-04-08 | 2020-09-08 | Medtronic Minimed, Inc. | Sensor and transmitter product |
US10420508B2 (en) | 2016-04-08 | 2019-09-24 | Medtronic Minimed, Inc. | Sensor connections |
CN105796086B (en) | 2016-04-14 | 2019-03-08 | 京东方科技集团股份有限公司 | A kind of intelligent wearable device |
US10589038B2 (en) | 2016-04-27 | 2020-03-17 | Medtronic Minimed, Inc. | Set connector systems for venting a fluid reservoir |
US9970893B2 (en) | 2016-04-28 | 2018-05-15 | Medtronic Minimed, Inc. | Methods, systems, and devices for electrode capacitance calculation and application |
US10426389B2 (en) | 2016-04-28 | 2019-10-01 | Medtronic Minimed, Inc. | Methods, systems, and devices for electrode capacitance calculation and application |
US10324058B2 (en) | 2016-04-28 | 2019-06-18 | Medtronic Minimed, Inc. | In-situ chemistry stack for continuous glucose sensors |
US10086133B2 (en) | 2016-05-26 | 2018-10-02 | Medtronic Minimed, Inc. | Systems for set connector assembly with lock |
US10086134B2 (en) | 2016-05-26 | 2018-10-02 | Medtronic Minimed, Inc. | Systems for set connector assembly with lock |
US9968737B2 (en) | 2016-05-26 | 2018-05-15 | Medtronic Minimed, Inc. | Systems for set connector assembly with lock |
CN109310831B (en) | 2016-06-02 | 2021-11-23 | 西医药服务以色列有限公司 | Three position needle retraction |
US11134872B2 (en) | 2016-06-06 | 2021-10-05 | Medtronic Minimed, Inc. | Thermally stable glucose limiting membrane for glucose sensors |
US11179078B2 (en) | 2016-06-06 | 2021-11-23 | Medtronic Minimed, Inc. | Polycarbonate urea/urethane polymers for use with analyte sensors |
EP3490643B1 (en) | 2016-08-01 | 2021-10-27 | West Pharma. Services Il, Ltd. | Anti-rotation cartridge pin |
US11730892B2 (en) | 2016-08-01 | 2023-08-22 | West Pharma. Services IL, Ltd. | Partial door closure prevention spring |
DE102016214325A1 (en) * | 2016-08-03 | 2018-02-08 | B. Braun Melsungen Ag | Elastomeric reservoir of an infusion pump |
US10449291B2 (en) | 2016-09-06 | 2019-10-22 | Medtronic Minimed, Inc. | Pump clip for a fluid infusion device |
EP3515535A1 (en) | 2016-09-23 | 2019-07-31 | Insulet Corporation | Fluid delivery device with sensor |
US11097051B2 (en) | 2016-11-04 | 2021-08-24 | Medtronic Minimed, Inc. | Methods and apparatus for detecting and reacting to insufficient hypoglycemia response |
US10238030B2 (en) | 2016-12-06 | 2019-03-26 | Medtronic Minimed, Inc. | Wireless medical device with a complementary split ring resonator arrangement for suppression of electromagnetic interference |
US10709834B2 (en) | 2016-12-21 | 2020-07-14 | Medtronic Minimed, Inc. | Medication fluid infusion set component with integrated physiological analyte sensor, and corresponding fluid infusion device |
US10854323B2 (en) | 2016-12-21 | 2020-12-01 | Medtronic Minimed, Inc. | Infusion systems and related personalized bolusing methods |
US10272201B2 (en) | 2016-12-22 | 2019-04-30 | Medtronic Minimed, Inc. | Insertion site monitoring methods and related infusion devices and systems |
US11197949B2 (en) | 2017-01-19 | 2021-12-14 | Medtronic Minimed, Inc. | Medication infusion components and systems |
US10821225B2 (en) | 2017-01-20 | 2020-11-03 | Medtronic Minimed, Inc. | Cannulas for drug delivery devices |
CN110461217B (en) | 2017-01-23 | 2022-09-16 | 雅培糖尿病护理公司 | Systems, devices, and methods for analyte sensor insertion |
US10500135B2 (en) | 2017-01-30 | 2019-12-10 | Medtronic Minimed, Inc. | Fluid reservoir and systems for filling a fluid reservoir of a fluid infusion device |
US10532165B2 (en) | 2017-01-30 | 2020-01-14 | Medtronic Minimed, Inc. | Fluid reservoir and systems for filling a fluid reservoir of a fluid infusion device |
US10363365B2 (en) | 2017-02-07 | 2019-07-30 | Medtronic Minimed, Inc. | Infusion devices and related consumable calibration methods |
US10552580B2 (en) | 2017-02-07 | 2020-02-04 | Medtronic Minimed, Inc. | Infusion system consumables and related calibration methods |
US11207463B2 (en) | 2017-02-21 | 2021-12-28 | Medtronic Minimed, Inc. | Apparatuses, systems, and methods for identifying an infusate in a reservoir of an infusion device |
US10646649B2 (en) | 2017-02-21 | 2020-05-12 | Medtronic Minimed, Inc. | Infusion devices and fluid identification apparatuses and methods |
WO2018156548A1 (en) | 2017-02-22 | 2018-08-30 | Insulet Corporation | Needle insertion mechanisms for drug containers |
US11134868B2 (en) | 2017-03-17 | 2021-10-05 | Medtronic Minimed, Inc. | Metal pillar device structures and methods for making and using them in electrochemical and/or electrocatalytic applications |
US11064951B2 (en) | 2017-03-24 | 2021-07-20 | Medtronic Minimed, Inc. | Patient data management systems and querying methods |
US20180328877A1 (en) | 2017-05-11 | 2018-11-15 | Medtronic Minimed, Inc. | Analyte sensors and methods for fabricating analyte sensors |
KR102388991B1 (en) * | 2017-05-22 | 2022-04-22 | 삼성전자주식회사 | Biosensor, manufacturing method of biosensor and biosignal measuring apparatus |
CN110869072B (en) | 2017-05-30 | 2021-12-10 | 西部制药服务有限公司(以色列) | Modular drive mechanism for a wearable injector |
KR20200067124A (en) | 2017-06-23 | 2020-06-11 | 덱스콤, 인크. | Transdermal analysis sensor, applicator for this, and associated method |
US10856784B2 (en) | 2017-06-30 | 2020-12-08 | Medtronic Minimed, Inc. | Sensor initialization methods for faster body sensor response |
US10596295B2 (en) | 2017-08-28 | 2020-03-24 | Medtronic Minimed, Inc. | Adhesive patch arrangement for a physiological characteristic sensor, and related sensor assembly |
US11412960B2 (en) | 2017-08-28 | 2022-08-16 | Medtronic Minimed, Inc. | Pedestal for sensor assembly packaging and sensor introducer removal |
US11344235B2 (en) | 2017-09-13 | 2022-05-31 | Medtronic Minimed, Inc. | Methods, systems, and devices for calibration and optimization of glucose sensors and sensor output |
WO2019067367A1 (en) | 2017-09-26 | 2019-04-04 | Insulet Corporation | Needle mechanism module for drug delivery device |
US10874300B2 (en) | 2017-09-26 | 2020-12-29 | Medtronic Minimed, Inc. | Waferscale physiological characteristic sensor package with integrated wireless transmitter |
US10525244B2 (en) | 2017-09-28 | 2020-01-07 | Medtronic Minimed, Inc. | Microneedle arrays and methods for fabricating microneedle arrays |
US10524730B2 (en) | 2017-09-28 | 2020-01-07 | Medtronic Minimed, Inc. | Medical devices with microneedle arrays and methods for operating such medical devices |
US11331022B2 (en) | 2017-10-24 | 2022-05-17 | Dexcom, Inc. | Pre-connected analyte sensors |
US20190120785A1 (en) | 2017-10-24 | 2019-04-25 | Dexcom, Inc. | Pre-connected analyte sensors |
CN111683595A (en) * | 2017-11-01 | 2020-09-18 | 血糖监测技术公司 | Method for adjusting a sensor |
WO2019094502A1 (en) | 2017-11-07 | 2019-05-16 | Prescient Surgical, Inc. | Methods and apparatus for prevention of surgical site infection |
US11676734B2 (en) | 2017-11-15 | 2023-06-13 | Medtronic Minimed, Inc. | Patient therapy management system that leverages aggregated patient population data |
US11147931B2 (en) | 2017-11-17 | 2021-10-19 | Insulet Corporation | Drug delivery device with air and backflow elimination |
US11471082B2 (en) | 2017-12-13 | 2022-10-18 | Medtronic Minimed, Inc. | Complex redundancy in continuous glucose monitoring |
US11213230B2 (en) | 2017-12-13 | 2022-01-04 | Medtronic Minimed, Inc. | Optional sensor calibration in continuous glucose monitoring |
WO2019118053A1 (en) * | 2017-12-15 | 2019-06-20 | Stc. Unm | Wearable auto injector |
CN114470420A (en) | 2017-12-22 | 2022-05-13 | 西氏医药包装(以色列)有限公司 | Syringe adapted for cartridges of different sizes |
US11439352B2 (en) | 2018-01-17 | 2022-09-13 | Medtronic Minimed, Inc. | Medical device with adhesive patch longevity |
US11186859B2 (en) | 2018-02-07 | 2021-11-30 | Medtronic Minimed, Inc. | Multilayer electrochemical analyte sensors and methods for making and using them |
US11220735B2 (en) | 2018-02-08 | 2022-01-11 | Medtronic Minimed, Inc. | Methods for controlling physical vapor deposition metal film adhesion to substrates and surfaces |
US11583213B2 (en) | 2018-02-08 | 2023-02-21 | Medtronic Minimed, Inc. | Glucose sensor electrode design |
US11672446B2 (en) | 2018-03-23 | 2023-06-13 | Medtronic Minimed, Inc. | Insulin delivery recommendations based on nutritional information |
GB201804880D0 (en) * | 2018-03-27 | 2018-05-09 | Univ Swansea | Microneedle platform for sensing and delivery |
USD928199S1 (en) | 2018-04-02 | 2021-08-17 | Bigfoot Biomedical, Inc. | Medication delivery device with icons |
US11583633B2 (en) | 2018-04-03 | 2023-02-21 | Amgen Inc. | Systems and methods for delayed drug delivery |
US11147919B2 (en) | 2018-04-23 | 2021-10-19 | Medtronic Minimed, Inc. | Methodology to recommend and implement adjustments to a fluid infusion device of a medication delivery system |
US11158413B2 (en) | 2018-04-23 | 2021-10-26 | Medtronic Minimed, Inc. | Personalized closed loop medication delivery system that utilizes a digital twin of the patient |
WO2019209963A1 (en) | 2018-04-24 | 2019-10-31 | Deka Products Limited Partnership | Apparatus and system for fluid delivery |
CN112236826A (en) | 2018-05-04 | 2021-01-15 | 英赛罗公司 | Safety constraints for drug delivery systems based on control algorithms |
US11367526B2 (en) | 2018-05-07 | 2022-06-21 | Medtronic Minimed, Inc. | Proactive patient guidance using augmented reality |
USD926325S1 (en) | 2018-06-22 | 2021-07-27 | Dexcom, Inc. | Wearable medical monitoring device |
US11761077B2 (en) | 2018-08-01 | 2023-09-19 | Medtronic Minimed, Inc. | Sputtering techniques for biosensors |
US11122697B2 (en) | 2018-08-07 | 2021-09-14 | Medtronic Minimed, Inc. | Method of fabricating an electronic medical device, including overmolding an assembly with thermoplastic material |
US11021731B2 (en) | 2018-08-23 | 2021-06-01 | Medtronic Minimed, Inc. | Analyte sensing layers, analyte sensors and methods for fabricating the same |
US11241532B2 (en) * | 2018-08-29 | 2022-02-08 | Insulet Corporation | Drug delivery system with sensor having optimized communication and infusion site |
US10828419B2 (en) | 2018-09-04 | 2020-11-10 | Medtronic Minimed, Inc. | Infusion set with pivoting metal cannula and strain relief |
US11547799B2 (en) | 2018-09-20 | 2023-01-10 | Medtronic Minimed, Inc. | Patient day planning systems and methods |
US11097052B2 (en) | 2018-09-28 | 2021-08-24 | Medtronic Minimed, Inc. | Insulin infusion device with configurable target blood glucose value for automatic basal insulin delivery operation |
CA3112209C (en) | 2018-09-28 | 2023-08-29 | Insulet Corporation | Activity mode for artificial pancreas system |
US11071821B2 (en) | 2018-09-28 | 2021-07-27 | Medtronic Minimed, Inc. | Insulin infusion device with efficient confirmation routine for blood glucose measurements |
US10980942B2 (en) | 2018-09-28 | 2021-04-20 | Medtronic Minimed, Inc. | Infusion devices and related meal bolus adjustment methods |
US10894126B2 (en) | 2018-09-28 | 2021-01-19 | Medtronic Minimed, Inc. | Fluid infusion system that automatically determines and delivers a correction bolus |
US20200116748A1 (en) | 2018-10-11 | 2020-04-16 | Medtronic Minimed, Inc. | Systems and methods for measurement of fluid delivery |
US10946140B2 (en) | 2018-10-11 | 2021-03-16 | Medtronic Minimed, Inc. | Systems and methods for measurement of fluid delivery |
US11565039B2 (en) | 2018-10-11 | 2023-01-31 | Insulet Corporation | Event detection for drug delivery system |
US11367516B2 (en) | 2018-10-31 | 2022-06-21 | Medtronic Minimed, Inc. | Automated detection of a physical behavior event and corresponding adjustment of a medication dispensing system |
US20200289373A1 (en) | 2018-10-31 | 2020-09-17 | Medtronic Minimed, Inc. | Automated detection of a physical behavior event and corresponding adjustment of a physiological characteristic sensor device |
US11367517B2 (en) | 2018-10-31 | 2022-06-21 | Medtronic Minimed, Inc. | Gesture-based detection of a physical behavior event based on gesture sensor data and supplemental information from at least one external source |
US11363986B2 (en) | 2018-10-31 | 2022-06-21 | Medtronic Minimed, Inc. | Automated detection of a physical behavior event and corresponding adjustment of a medication dispensing system |
US11382541B2 (en) | 2018-11-16 | 2022-07-12 | Medtronic Minimed, Inc. | Miniaturized analyte sensor |
US11540750B2 (en) | 2018-12-19 | 2023-01-03 | Medtronic Minimed, Inc | Systems and methods for physiological characteristic monitoring |
AU2019414451A1 (en) * | 2018-12-28 | 2021-06-17 | Dexcom, Inc. | Analyte sensor break-in mitigation |
US11439752B2 (en) | 2019-02-01 | 2022-09-13 | Medtronic Minimed, Inc. | Methods and devices for occlusion detection using actuator sensors |
US11389587B2 (en) | 2019-02-06 | 2022-07-19 | Medtronic Minimed, Inc. | Patient monitoring systems and related presentation methods |
US11191899B2 (en) | 2019-02-12 | 2021-12-07 | Medtronic Minimed, Inc. | Infusion systems and related personalized bolusing methods |
US11464908B2 (en) | 2019-02-18 | 2022-10-11 | Tandem Diabetes Care, Inc. | Methods and apparatus for monitoring infusion sites for ambulatory infusion pumps |
EP3946513A4 (en) * | 2019-03-25 | 2022-11-30 | Biolinq Incorporated | Devices and methods for the incorporation of a microneedle array analyte-selective sensor |
AU2020244743A1 (en) | 2019-03-25 | 2021-10-14 | Biolinq Incorporated | Devices and methods for the incorporation of a microneedle array analyte-selective sensor |
US11311215B2 (en) | 2019-04-04 | 2022-04-26 | Medtronic Minimed, Inc. | Measurement of device materials using non-Faradaic electrochemical impedance spectroscopy |
US11224361B2 (en) | 2019-04-23 | 2022-01-18 | Medtronic Minimed, Inc. | Flexible physiological characteristic sensor assembly |
US11317867B2 (en) | 2019-04-23 | 2022-05-03 | Medtronic Minimed, Inc. | Flexible physiological characteristic sensor assembly |
US10939488B2 (en) | 2019-05-20 | 2021-03-02 | Medtronic Minimed, Inc. | Method and system for controlling communication between devices of a wireless body area network for an medical device system |
US11844925B2 (en) | 2019-06-06 | 2023-12-19 | Medtronic Minimed, Inc. | Fluid infusion systems |
USD1002852S1 (en) | 2019-06-06 | 2023-10-24 | Abbott Diabetes Care Inc. | Analyte sensor device |
US11448611B2 (en) | 2019-07-03 | 2022-09-20 | Medtronic Minimed, Inc. | Structurally reinforced sensor and method for manufacturing the same |
US11617828B2 (en) | 2019-07-17 | 2023-04-04 | Medtronic Minimed, Inc. | Reservoir connection interface with detectable signature |
WO2021012075A1 (en) * | 2019-07-19 | 2021-01-28 | Medtrum Technologies Inc. | Integrated drug infusion device |
US11718865B2 (en) | 2019-07-26 | 2023-08-08 | Medtronic Minimed, Inc. | Methods to improve oxygen delivery to implantable sensors |
US11523757B2 (en) | 2019-08-01 | 2022-12-13 | Medtronic Minimed, Inc. | Micro-pillar working electrodes design to reduce backflow of hydrogen peroxide in glucose sensor |
US11617522B2 (en) | 2019-08-06 | 2023-04-04 | Medtronic Minimed, Inc. | Sensor inserter with disposal lockout state |
US11883208B2 (en) | 2019-08-06 | 2024-01-30 | Medtronic Minimed, Inc. | Machine learning-based system for estimating glucose values based on blood glucose measurements and contextual activity data |
US11724045B2 (en) | 2019-08-21 | 2023-08-15 | Medtronic Minimed, Inc. | Connection of a stopper and piston in a fluid delivery device |
KR102113011B1 (en) * | 2019-08-29 | 2020-05-20 | 최형찬 | Epi check point |
US11571515B2 (en) | 2019-08-29 | 2023-02-07 | Medtronic Minimed, Inc. | Controlling medical device operation and features based on detected patient sleeping status |
US11565044B2 (en) | 2019-09-12 | 2023-01-31 | Medtronic Minimed, Inc. | Manufacturing controls for sensor calibration using fabrication measurements |
US11654235B2 (en) | 2019-09-12 | 2023-05-23 | Medtronic Minimed, Inc. | Sensor calibration using fabrication measurements |
US11801344B2 (en) | 2019-09-13 | 2023-10-31 | Insulet Corporation | Blood glucose rate of change modulation of meal and correction insulin bolus quantity |
US11241537B2 (en) | 2019-09-20 | 2022-02-08 | Medtronic Minimed, Inc. | Contextual personalized closed-loop adjustment methods and systems |
US11213623B2 (en) | 2019-09-20 | 2022-01-04 | Medtronic Minimed, Inc. | Infusion systems and related personalized bolusing methods |
US11935637B2 (en) | 2019-09-27 | 2024-03-19 | Insulet Corporation | Onboarding and total daily insulin adaptivity |
US11511099B2 (en) | 2019-10-08 | 2022-11-29 | Medtronic Minimed, Inc. | Apparatus for detecting mating of a cap with a fluid delivery device and method |
US11638545B2 (en) | 2019-10-16 | 2023-05-02 | Medtronic Minimed, Inc. | Reducing sensor foreign body response via high surface area metal structures |
US11496083B2 (en) | 2019-11-15 | 2022-11-08 | Medtronic Minimed, Inc. | Devices and methods for controlling electromechanical actuators |
US11944784B2 (en) | 2019-11-18 | 2024-04-02 | Medtronic Minimed, Inc. | Combined analyte sensor and infusion set |
US11324881B2 (en) | 2019-11-21 | 2022-05-10 | Medtronic Minimed, Inc. | Systems for wearable infusion port and associated pump |
US11559624B2 (en) | 2019-11-21 | 2023-01-24 | Medtronic Minimed, Inc. | Systems for wearable infusion port and associated pump |
US20210170103A1 (en) | 2019-12-09 | 2021-06-10 | Medtronic Minimed, Inc. | Methods and systems for real-time sensor measurement simulation |
US11938301B2 (en) | 2019-12-13 | 2024-03-26 | Medtronic Minimed, Inc. | Controlling medication delivery system operation and features based on automatically detected muscular movements |
WO2021119549A1 (en) | 2019-12-13 | 2021-06-17 | Medtronic Minimed, Inc. | Method and system for training a mathematical model of a user based on data received from a discrete insulin therapy system |
US11786655B2 (en) | 2019-12-13 | 2023-10-17 | Medtronic Minimed, Inc. | Context-sensitive predictive operation of a medication delivery system in response to gesture-indicated activity changes |
US11488700B2 (en) | 2019-12-13 | 2022-11-01 | Medtronic Minimed, Inc. | Medical device configuration procedure guidance responsive to detected gestures |
US11375955B2 (en) | 2019-12-18 | 2022-07-05 | Medtronic Minimed, Inc. | Systems for skin patch gravity resistance |
US11690573B2 (en) | 2019-12-18 | 2023-07-04 | Medtronic Minimed, Inc. | Systems for skin patch gravity resistance |
US11833329B2 (en) | 2019-12-20 | 2023-12-05 | Insulet Corporation | Techniques for improved automatic drug delivery performance using delivery tendencies from past delivery history and use patterns |
US11821022B2 (en) | 2019-12-23 | 2023-11-21 | Medtronic Minimed, Inc. | Ethylene oxide absorption layer for analyte sensing and method |
US11244753B2 (en) | 2020-01-30 | 2022-02-08 | Medtronic Minimed, Inc. | Activity monitoring systems and methods |
US11551802B2 (en) | 2020-02-11 | 2023-01-10 | Insulet Corporation | Early meal detection and calorie intake detection |
US11547800B2 (en) | 2020-02-12 | 2023-01-10 | Insulet Corporation | User parameter dependent cost function for personalized reduction of hypoglycemia and/or hyperglycemia in a closed loop artificial pancreas system |
US11324889B2 (en) | 2020-02-14 | 2022-05-10 | Insulet Corporation | Compensation for missing readings from a glucose monitor in an automated insulin delivery system |
US11833327B2 (en) | 2020-03-06 | 2023-12-05 | Medtronic Minimed, Inc. | Analyte sensor configuration and calibration based on data collected from a previously used analyte sensor |
USD958167S1 (en) | 2020-03-23 | 2022-07-19 | Companion Medical, Inc. | Display screen with graphical user interface |
USD958817S1 (en) | 2020-03-31 | 2022-07-26 | Medtronic Minimed, Inc. | Display screen with graphical user interface |
US11607493B2 (en) | 2020-04-06 | 2023-03-21 | Insulet Corporation | Initial total daily insulin setting for user onboarding |
US11596359B2 (en) | 2020-04-09 | 2023-03-07 | Medtronic Minimed, Inc. | Methods and systems for mitigating sensor error propagation |
US11583631B2 (en) | 2020-04-23 | 2023-02-21 | Medtronic Minimed, Inc. | Intuitive user interface features and related functionality for a therapy delivery system |
US11690955B2 (en) | 2020-04-23 | 2023-07-04 | Medtronic Minimed, Inc. | Continuous analyte sensor quality measures and related therapy actions for an automated therapy delivery system |
US11272884B2 (en) | 2020-06-04 | 2022-03-15 | Medtronic Minimed, Inc. | Liner for adhesive skin patch |
US11650248B2 (en) | 2020-07-28 | 2023-05-16 | Medtronic Minimed, Inc. | Electrical current measurement system |
US11445807B2 (en) | 2020-07-31 | 2022-09-20 | Medtronic Minimed, Inc. | Pump clip with tube clamp for a fluid infusion device |
US11684716B2 (en) | 2020-07-31 | 2023-06-27 | Insulet Corporation | Techniques to reduce risk of occlusions in drug delivery systems |
US11839743B2 (en) | 2020-10-07 | 2023-12-12 | Medtronic Minimed, Inc. | Graphic user interface for automated infusate delivery |
US11737783B2 (en) | 2020-10-16 | 2023-08-29 | Medtronic Minimed, Inc. | Disposable medical device introduction system |
US11844930B2 (en) | 2020-10-29 | 2023-12-19 | Medtronic Minimed, Inc. | User-mountable electronic device with accelerometer-based activation feature |
US11806503B2 (en) | 2020-10-29 | 2023-11-07 | Medtronic Minimed, Inc. | Removable wearable device and related attachment methods |
US11534086B2 (en) | 2020-10-30 | 2022-12-27 | Medtronic Minimed, Inc. | Low-profile wearable medical device |
US11951281B2 (en) | 2020-11-11 | 2024-04-09 | Medtronic Minimed, Inc. | Fluid conduit insertion devices |
USD999913S1 (en) | 2020-12-21 | 2023-09-26 | Abbott Diabetes Care Inc | Analyte sensor inserter |
US11904140B2 (en) | 2021-03-10 | 2024-02-20 | Insulet Corporation | Adaptable asymmetric medicament cost component in a control system for medicament delivery |
CN113331831B (en) * | 2021-04-22 | 2022-12-16 | 深圳市奥极健康科技有限公司 | Sensor for continuous blood glucose monitoring |
US11904146B2 (en) | 2021-06-08 | 2024-02-20 | Medtronic Minimed, Inc. | Medicine injection devices, systems, and methods for medicine administration and tracking |
US11792714B2 (en) | 2021-06-16 | 2023-10-17 | Medtronic Minimed, Inc. | Medicine administration in dynamic networks |
US11587742B1 (en) | 2021-09-02 | 2023-02-21 | Medtronic Minimed, Inc. | Ingress-tolerant input devices |
US11817285B2 (en) | 2021-09-02 | 2023-11-14 | Medtronic Minimed, Inc. | Ingress-tolerant input devices comprising sliders |
WO2023049900A1 (en) | 2021-09-27 | 2023-03-30 | Insulet Corporation | Techniques enabling adaptation of parameters in aid systems by user input |
US11439754B1 (en) | 2021-12-01 | 2022-09-13 | Insulet Corporation | Optimizing embedded formulations for drug delivery |
US11896447B2 (en) | 2022-03-14 | 2024-02-13 | Medtronic Minimed, Inc. | Safeguards against separation from portable medicine delivery devices |
Family Cites Families (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2408323A (en) * | 1943-06-10 | 1946-09-24 | Margaret L Lockhart | Hypodermic syringe |
US2576951A (en) * | 1950-09-29 | 1951-12-04 | Compule Corp | Hypodermic syringe assemblies, including plural-compartment admixing ampoules for segregated storage of ingredients of liquid mediginal solutions and parts thereof |
US3837339A (en) * | 1972-02-03 | 1974-09-24 | Whittaker Corp | Blood glucose level monitoring-alarm system and method therefor |
US4340458A (en) * | 1980-06-02 | 1982-07-20 | Joslin Diabetes Center, Inc. | Glucose sensor |
DE3278334D1 (en) * | 1981-10-23 | 1988-05-19 | Genetics Int Inc | Sensor for components of a liquid mixture |
EP0098592A3 (en) * | 1982-07-06 | 1985-08-21 | Fujisawa Pharmaceutical Co., Ltd. | Portable artificial pancreas |
US4515584A (en) * | 1982-07-06 | 1985-05-07 | Fujisawa Pharmaceutical Co., Ltd. | Artificial pancreas |
US4697622A (en) * | 1984-06-01 | 1987-10-06 | Parker Hannifin Corporation | Passive filling device |
US4684365A (en) * | 1985-01-24 | 1987-08-04 | Eaton Corporation | Disposable refill unit for implanted medication infusion device |
US4627445A (en) * | 1985-04-08 | 1986-12-09 | Garid, Inc. | Glucose medical monitoring system |
US4687423A (en) * | 1985-06-07 | 1987-08-18 | Ivac Corporation | Electrochemically-driven pulsatile drug dispenser |
GB8612861D0 (en) * | 1986-05-27 | 1986-07-02 | Cambridge Life Sciences | Immobilised enzyme biosensors |
US4902278A (en) * | 1987-02-18 | 1990-02-20 | Ivac Corporation | Fluid delivery micropump |
DE3806955A1 (en) * | 1987-03-03 | 1988-09-15 | Res Ass Bio Tech Chem | Glucose-sensitive FET sensor, and method for its fabrication |
GB8710472D0 (en) * | 1987-05-01 | 1987-06-03 | Cambridge Life Sciences | Amperometric method |
GB8724446D0 (en) * | 1987-10-19 | 1987-11-25 | Cambridge Life Sciences | Immobilised enzyme electrodes |
US5547467A (en) * | 1988-01-21 | 1996-08-20 | Massachusettes Institute Of Technology | Method for rapid temporal control of molecular transport across tissue |
US5070886A (en) * | 1988-01-22 | 1991-12-10 | Safety Diagnostice, Inc. | Blood collection and testing means |
GB8817997D0 (en) * | 1988-07-28 | 1988-09-01 | Cambridge Life Sciences | Enzyme electrodes & improvements in manufacture thereof |
JPH0297933A (en) * | 1988-10-05 | 1990-04-10 | Fujiretsukusu Kk | Photographing frame of large-sized camera for industrial photograph |
AT393213B (en) * | 1989-02-08 | 1991-09-10 | Avl Verbrennungskraft Messtech | DEVICE FOR DETERMINING AT LEAST ONE MEDICAL MEASURING SIZE |
US4953552A (en) * | 1989-04-21 | 1990-09-04 | Demarzo Arthur P | Blood glucose monitoring system |
US5298022A (en) * | 1989-05-29 | 1994-03-29 | Amplifon Spa | Wearable artificial pancreas |
IT1231916B (en) * | 1989-05-29 | 1992-01-15 | Ampliscientifica S R L | WEARABLE ARTIFICIAL PANCREAS |
US5286362A (en) * | 1990-02-03 | 1994-02-15 | Boehringer Mannheim Gmbh | Method and sensor electrode system for the electrochemical determination of an analyte or an oxidoreductase as well as the use of suitable compounds therefor |
US5165407A (en) * | 1990-04-19 | 1992-11-24 | The University Of Kansas | Implantable glucose sensor |
US5079421A (en) * | 1990-04-19 | 1992-01-07 | Inomet, Inc. | Invasive FTIR blood constituent testing |
US5527288A (en) * | 1990-12-13 | 1996-06-18 | Elan Medical Technologies Limited | Intradermal drug delivery device and method for intradermal delivery of drugs |
NL9002764A (en) * | 1990-12-14 | 1992-07-01 | Tno | ELECTRODE, FITTED WITH A POLYMER COATING WITH A REDOX ENZYM BOND TO IT. |
US5562613A (en) * | 1991-07-02 | 1996-10-08 | Intermed, Inc. | Subcutaneous drug delivery device |
AT396598B (en) * | 1991-07-15 | 1993-10-25 | Andritz Patentverwaltung | SUCTION ROLLER |
US5322063A (en) * | 1991-10-04 | 1994-06-21 | Eli Lilly And Company | Hydrophilic polyurethane membranes for electrochemical glucose sensors |
US5524338A (en) * | 1991-10-22 | 1996-06-11 | Pi Medical Corporation | Method of making implantable microelectrode |
DE4139122C1 (en) * | 1991-11-28 | 1993-04-08 | Fenzlein, Paul-Gerhard, 8500 Nuernberg, De | |
US5227042A (en) * | 1992-05-15 | 1993-07-13 | The United States Of America As Represented By The United States Department Of Energy | Catalyzed enzyme electrodes |
GB9215973D0 (en) * | 1992-07-28 | 1992-09-09 | Univ Manchester | Sensor devices |
IL102930A (en) * | 1992-08-25 | 1997-03-18 | Yissum Res Dev Co | Electrobiochemical analytical method and electrodes |
KR960004971B1 (en) * | 1993-01-15 | 1996-04-18 | 경북대학교센서기술연구소 | Biosensor with ion-sensitive field-effect transistor |
US5545143A (en) * | 1993-01-21 | 1996-08-13 | T. S. I. Medical | Device for subcutaneous medication delivery |
US5399245A (en) * | 1993-09-03 | 1995-03-21 | North Carolina State University | Methods of indirect electrochemistry using ionomer coated electrodes |
US5582184A (en) * | 1993-10-13 | 1996-12-10 | Integ Incorporated | Interstitial fluid collection and constituent measurement |
US5497772A (en) * | 1993-11-19 | 1996-03-12 | Alfred E. Mann Foundation For Scientific Research | Glucose monitoring system |
US5390671A (en) * | 1994-03-15 | 1995-02-21 | Minimed Inc. | Transcutaneous sensor insertion set |
US5391250A (en) * | 1994-03-15 | 1995-02-21 | Minimed Inc. | Method of fabricating thin film sensors |
US5568806A (en) * | 1995-02-16 | 1996-10-29 | Minimed Inc. | Transcutaneous sensor insertion set |
US5586553A (en) * | 1995-02-16 | 1996-12-24 | Minimed Inc. | Transcutaneous sensor insertion set |
-
1994
- 1994-11-04 IE IE940865A patent/IE72524B1/en not_active IP Right Cessation
- 1994-11-21 TW TW083110809A patent/TW290442B/zh active
-
1995
- 1995-10-27 NZ NZ295458A patent/NZ295458A/en unknown
- 1995-10-27 WO PCT/IE1995/000055 patent/WO1996014026A1/en active IP Right Grant
- 1995-10-27 AU AU38800/95A patent/AU693279B2/en not_active Ceased
- 1995-10-27 CA CA002204370A patent/CA2204370A1/en not_active Abandoned
- 1995-10-27 AT AT95938003T patent/ATE205686T1/en active
- 1995-10-27 DE DE69522821T patent/DE69522821T2/en not_active Expired - Fee Related
- 1995-10-27 EP EP95938003A patent/EP0789540B1/en not_active Expired - Lifetime
- 1995-10-27 JP JP8515182A patent/JPH10508518A/en not_active Withdrawn
- 1995-11-02 US US08/556,744 patent/US5807375A/en not_active Expired - Fee Related
- 1995-11-03 ZA ZA959309A patent/ZA959309B/en unknown
-
1996
- 1996-12-18 US US08/769,212 patent/US5820622A/en not_active Expired - Fee Related
- 1996-12-19 US US08/769,996 patent/US5800420A/en not_active Expired - Fee Related
-
1998
- 1998-04-29 AU AU63702/98A patent/AU713246B2/en not_active Ceased
Also Published As
Publication number | Publication date |
---|---|
US5800420A (en) | 1998-09-01 |
EP0789540A1 (en) | 1997-08-20 |
JPH10508518A (en) | 1998-08-25 |
TW290442B (en) | 1996-11-11 |
AU3880095A (en) | 1996-05-31 |
WO1996014026A1 (en) | 1996-05-17 |
US5807375A (en) | 1998-09-15 |
ZA959309B (en) | 1996-05-29 |
AU713246B2 (en) | 1999-11-25 |
EP0789540B1 (en) | 2001-09-19 |
AU693279B2 (en) | 1998-06-25 |
DE69522821D1 (en) | 2001-10-25 |
ATE205686T1 (en) | 2001-10-15 |
US5820622A (en) | 1998-10-13 |
IE940865A1 (en) | 1996-05-15 |
AU6370298A (en) | 1998-11-12 |
DE69522821T2 (en) | 2002-04-11 |
IE72524B1 (en) | 1997-04-23 |
NZ295458A (en) | 1999-04-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5820622A (en) | Analyte-controlled liquid delivery device and analyte monitor | |
EP0393054B1 (en) | A process and system and measuring cell assembly for glucose determination | |
Soeldner | Treatment of diabetes mellitus by devices | |
JP5624322B2 (en) | Liquid supply with in-vivo electrochemical analyte sensing | |
US7544185B2 (en) | Needle device comprising a plurality of needles | |
CA2165810C (en) | Infusion pump and glucose sensor assembly | |
Johnson et al. | In vivo evaluation of an electroenzymatic glucose sensor implanted in subcutaneous tissue | |
US6368274B1 (en) | Reusable analyte sensor site and method of using the same | |
US6553244B2 (en) | Analyte monitoring device alarm augmentation system | |
US20100268043A1 (en) | Device and Method for Preventing Diabetic Complications | |
US20030125613A1 (en) | Implantable sensor flush sleeve | |
EP1333751A2 (en) | Glucose sensor system | |
JP2011507556A5 (en) | ||
EP1866011A1 (en) | Device and method for delivery of a physiologically active substance depending on a measured physiological parameter | |
CN113546294A (en) | Self-service detection and treatment device for micro-needle | |
Pfeiffer | Artificial pancreas: state of the art |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Discontinued |