CA2193884C - Device and method for sampling of substances using alternating polarity - Google Patents
Device and method for sampling of substances using alternating polarity Download PDFInfo
- Publication number
- CA2193884C CA2193884C CA002193884A CA2193884A CA2193884C CA 2193884 C CA2193884 C CA 2193884C CA 002193884 A CA002193884 A CA 002193884A CA 2193884 A CA2193884 A CA 2193884A CA 2193884 C CA2193884 C CA 2193884C
- Authority
- CA
- Canada
- Prior art keywords
- substance
- sampling
- polarity
- chamber
- sampling chamber
- 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.)
- Expired - Lifetime
Links
Classifications
-
- 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
- A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
- A61B5/683—Means for maintaining contact with the body
- A61B5/6832—Means for maintaining contact with the body using adhesives
- A61B5/6833—Adhesive patches
-
- 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
- A61B5/14532—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 for measuring glucose, e.g. by tissue impedance measurement
Abstract
A method for sampling of a substance from a subject is provided, which comprises placing one or more sampling chambers on a collection sire on a tissue surfa ce on the subject; conducting electric current through the tissue to extract a substan ce from the subject in a first direction in one or more sampling chambers that function alternatively as both an anode and cathode during the course of the method; reversing the polarity to cause direct current to flow in second direction opposite the first direction; and analyzing the sampling chamber or chambers for the concentration of a substance or a substance metabolite. There is also provided a device for sampling of a substance from an organism on continuously or intermittently using alternating polarit y method based on the application of low intensity electric fields of alternating polarity across the skin (iontophoresis) to enhance the transport of a substance (such as glucos e, lactic acid, pyruvic acid, and the like) from body tissues to a sampling chamber. T he device comprises an electrical power supply; a transdermal system that contains one ro more sampling chambers that function as both anode and cathode during the course of sampling; a means to alternate or reverse the polarity during the iontophoretic sampling; and means for analyzing forthe concentration of a substance or a substance metabolite.
Description
VVO 96/00109 PCTlUS95l07579 p~VICE AND METHOA FOR SAMPLING OF
SUBSTANCES USING A.T_.TFR_rTATING POLARITY
Field of the Invention This invention relates to a device and method 7.0 for sampling of substances across-tissue using electrical energy of alternating polarity.
~ackaround of the Invention Iontophoresis is employed for therapeutic 1.5 topical treatment of humans or other organisms. Glikfeld et al., U.S. Patent No. 5,279,543, describes the use of iontopho~esis to non-invasively sample a substance through skin into a receptor chamber on the skin surface.
The Glikfeld device consists of two chambers, each 20 containing an electrically conductive medium, which medium is in electrical contact with the skin. A
positive electrode (anode) is disposed in one chamber, and a negative electrode (cathode) is disposed in the other. The two chambers are separated by an electrically 25 insulating material. In use, a constant or pulsed current is generated by a power source between the electrodes through the skin. The direction of current flow never changes during sampling. Glikfeld does not correlate the collected substance levels with blood 30 substance levels and does not address any problems associated with long term transdermal monitoring of a substance.
' The Lattin and Spevak U.S. Patent No.
4,406,658, Tapper U.S. Patent Nos. 4,301,794, 4,340,047 35 and 5,224,927, Masaki U.S. Patent No. 4,786,278, Masaki WO 96100109 2 ~ 9 3 g g q. PC'T/U595/U7579 _2_ U.S. Patent No. 4,792,702 and Maeaki European Patent No.
230,153 describe the iontophoretic delivery of a substance across tissue. In addition, these publications describe operation methods in which the polarity of the applied electrical energy is reversed during delivery.
None of these publications addresses Extraction of substances from tissue or any of the problems associated with such extraction. -The Tapper '794 and '047 patents address the irritation caused by iontophoretic delivery of ionized molecules through skin. In the Tapper apparatus, all delivery occurs at a single-electrode. Tapper determined that the irritation can be eliminated if the polarity of the applied current is reversed for equal periods.--A
complete and equal polarity reversal eliminates the molecule delivery, however. Tapper compromises by providing for a shorter period for the reverse direction and a longer period for the forward (substance delivery) direction.
The Tapper '927 patent discloses an apparatus that iontophoretically delivers a substance into the patient's skin from two source reservoirs, each attached to an electrode. The electrodes are connected to an AC
power source having a frequency in the range of 0.0027-10 Hz. Use of an AC power source minimizes the build-up of irritating chemicals at positive and negative electrodes (e. g., HC1 and H202, respectively). Providing a source reaeruoir at both electrodes permits delivery from one of the reservoirs in each phase-of the AC
signal, thereby eliminating -the drawback of using a single source reservoir-noted in the earlier-Tapper patents.
Some alternating polarity methods for drug delivery, such as in the Tapper '927 patent focus on prevention of pH changes. For many electrode systems, DfO 96100109 2 1 ~ ,~ ~ 8 ~ PCfIUS95I07579 water hydrolysis upon the application of current causes the pH to-dramatically decrease at the anode and increase at the cathode. This can cause skin irritation.
Furthermore, -the-pH changes in the drug donor electrodes can reduce the amount of ionized-drug relative to non-ionized rirug in the donor depending on the pKa of the drug. These patents propose-switching between the anode and cathode to prevent these pH changes, reducing irritation and possibly increasing drug flux, especially I0 of ionizable drugs.
The Lattin and Spevak '658 patent allows for delivery from both electrodes, thus doubling the potential delivery area. For drug delivery applications, more area means more deliverable drug per application of a single device. However, for iontophoretic sampling applications, there is no advantage to doubling the area because total delivery is not an important factor. The amount that is sampled per area is more important because it is the substance concentration that is to be measured, not the total substance amount.
The Masaki patents disclose a device and a switch which can iontophorese both anions and cations by switching the polarity of the two electrodes during the treatment cycle. In the Masaki '702 patent, the cations and anions come from a single source-reservoir attached to one electrode. The other two patents do not disclose where the cation and anion sources are located. In any event, these patents teach nothing about iontophoretic sampling from skin into a reservoir.
Sibalis U.S. Patent No. 5,013,293 describes an "electrophoretic" drug delivery system in which a drug is delivered from a reser~roir into the patient's skin under the action of current applied to two electrodes, one of which is attached to the reservoir.--The polarity of the current may be alternated periodically to control the wo 9e~ooio9 21 g 3 ~ 8 4 PCTIUS95/07579 amount of drug delivered. Sibalis does not disclose the use of iontophoresis for removing a substance from a patient's tissue.
LaPrade U.S. patent 5,006,108 discloses , alternating polarity for the delivery of drugs in which the surface area of both electrodes teach alternating , between being the anode and cathode) is available to deliver the drug. The LaPrade disclosure does not suggest that:- (1J a single-electrode may be used as a collector during iontophoretic extraction, with that electrode alternating between being an anode and a cathode; (2) two electrodes may act alternatively as anode and cathode during ioritophoretic extraction, or (3) iontophoresis can be used generally for removing substances from tissue.
Some alternating polarity patents for drug delivery such as the above LaPrade and Lattin patents, focus on increasing drug dosage with the same size patch.
The principle is that the available surface area for delivery is larger for alternating polarity because each electrode can be both an anode and a cathode, rather than one electrode being the "active" electrode and the other electrode-taking up space, but not helping drug delivery, as the 'indifferent" electrode. This results in more drug delivery, but would not aid in extraction where substance flux, not "total" substance delivered, is the critical factor.
Teijin LTD, Japanese patent publication 4224770, discloses an apparatus with electrodes for attachment to skin which has hydrous medium for electrically contacting the electrodes, containing medically active agent to be absorbed through the skin, and-current polarity switching means. Apparently, this patent is designed to reduce pH deviation.
~V096/00109 ~ ~ ~ ~ ~ PCTIU595107579 Teijin LTD, Japanese patent publication 3045272, discloses a compact iontophoresis device which comprises electrodes containing medicine and applied with high frequency AC for percutaneous administration and with the objective of reducing skin irritation.
Summary of the znvention In the area of in vivo extraction of substances from tissue, correlation between measured concentrations of extracted substances must be correlated with levels of the substance within the patient's tissue and/or blood stream. For example, studies have shown a need for a virtual continuous glucose monitor, which could potentially signal a diabetic of dangerously low or high blood sugar levels. The greater the flux of the extracted substance-from the tissue into the substance collector, the greater the accuracy with which the measured flux can be correlated with the concentration of the substance within the tissue and/or blood stream.
What is needed, therefore, is a way to decrease the difference between the measured concentration of the extracted substance and the concentration of the substance within the tissue and/or blood.
Standard iontophoretic electrodes generally involve either water hydrolysis, which can cause undesirable pH changes, or a silver/silver chloride reaction in which silver chloride is converted to silver at the cathode, and silver is converted to silver chloride at the anode. For either of these systems, long term application of current can be a problem due to the eventual depletion of the reactants. What is needed, therefore, is a iontophoretic sampling system and method ~ that avoids this problem.
This invention is directed to a device and method for sampling of a substance using electrical energy applied in alternating polarity. Alternating the polarity allows the reactions, such as silver/silver chloride reaction or the water hydrolysis reaction, to cycle back and forth, potentially lengthening the time , that a particular electrode-could be used. In the non-invasive sampling method of the invention the pertinent parameter is the extraction of the desired substance per unit surface area (flux), not the total extraction.
The invention includes a method for sampling of a substance from a subject, which comprises (a) placing one or more sampling chambers on a collection site on a tissue surface of a subject;
(b) conducting electrical current through the tissue in a first polarity to extract a substance from the subject into one or more sampling chambers;
(c) reversing the polarity of the electrical current during the course of the method (i.e., changing an anode to a cathode and a cathode to an anode); and (d) analyzing the sampling chamber or chambers for the concentration of the substance or a substance metabolite.
The invention also includes a sampling device comprising-(a) an electrical power supply means;
(b) a transdermal system that contains one or more sampling chambers for receiving a sample that function as both anode and cathode during the course of iontophoretic sampling;
(c) means for reversing the polarity of the power source during the iontophoretic sampling; and (d) means for analyzing the sampling chamber or chambers for the concentration of the substance or a substance metabolite.
'~'V0 96/00109 PCT113S95f07579 The invention also includes a substance monitor comprising:
first and second substance sampling chambers each containing substance collection medium selected from the group consisting of water, saline solutions, buffer solutions, and polyols; -a power supply means having a positive connector and a negative connector;
conductors and a switch electrically connecting the first and second -sampling chambers-to the power supply means positive connector and the power supply means negative connector, the switch having a first position in which the first sampling chamber is electrically connected to the positive connector and the second sampling chamber is electrically connected to the negative connector and a second position in which the second sampling chamber is electrically connected to the positive connector and the first sampling chamber is electrically connected to the negative connector.
The reversal of polarity during the sampling method of the invention hae advantages over a prior standard iontophoresis method (non-alternating direct or intermittent current application) including: (1) there is unexpected enhancement of the correlation between blood and iontophoretically extracted samples under the alternating polarity method of the invention as compared to a non-alternating polarity protocol, (2) there is a particularly unexpected normalized flux rate increase over the use of direct current, and (3) the alternating polarity method of the invention enables continuous or intermittent application of current for Ag/AgCl or other electrodes without depletion of the AgCl plating or pH
variations which occur for non-alternating systems.
The ionization state of the substance of the drug delivery materials of the prior art were dictated by WO 96/00109 ~ ~ ~ ~ P~'/pS95107579 _8_ the pH of the donor solutions. However, in the alternating polarity sampling method of-the invention, the ionization state of the extracted substance does not rely on the pH of the donor chamber; rather, the ionization state of the extracted species going from the body to the top of the skin is dictated by the pH of the body, which is relatively constant.
The alternating polarity sampling method and device of the invention preferably uses low frequencies of about 0.1 Hz (one switch .every 10_seconds) to about 1 switch every hour. This is in contrast to the drug delivery of the prior art, such as Tapper '794 and Masaki '351 which disclose that in a desire to reduce skin irritation, rapid, high frequency pulsing, of either the same or alternating polarity, reduces skin irritation caused by iontophoresis.
These advantages are surprising considering the non-invasive nature of-the method and device which produces these advantages when transporting substances that are beneath the akin to a collection reservoir-on top of the skin while no part of the device penetrates into or beneath the skin.
Detailed Description of the Drawincrs Figure 1A is a block diagram of a substance monitoring device according to the invention.
Figure 1B shows an-iontophoretic monitoring device-useful for practicing this invention in place on a patient.
Figure 1C is an exploded drawing of-the electrode/collection reservoir assembly illustrating the various layers thereof.
Figure 1D is a cross-section of one of an electrode/reservair assembly Figure 1C.
\N0 96/00109 ~ ~ ~ ~ ~ ~ PCTIUS95107579 Figure 2 is a graph of the results of a blood oral glucose tolerance glucose monitoring experiment on subject A, right arm, using a standard protocol.
Figure 3 is'a graph of the results of a blood oral glucose.tolerance glucose monitoring experiment on subject A, left arm, using an alternating protocol.
Figure 4-is a graph of the results of a blood oral glucose-tolerance glucose monitoring experiment on subject B, right arm, using a standard protocol.
Figure 5 is a graph ofthe results of a blood oral glucose-tolerance glucose monitoring experiment on subject B, left arm, using an alternating protocol.
Figure 6 is a graph of the results of a blood glucose monitoring experiment using several cycles of 15. direct current and a cycle of alternating polarity.
Figure 7 is the results of a blood glucose monitoring experiment with the subject A of Figure 3, under fasted conditions.
Figure 8 is a graph of the results of a blood 2D glucose monitoring experiment with the subject A of Figures 3, left arm, compensating for drift at the cathode.
Figure 9 is a graph of the results of a blood glucose monitoring experiment with the subject A of 25 Figure 3 compensating for time lag and drift at the cathode.
Figure 10 is a graph of the results of a blood glucose monitoring experiment with the subject A of Figure-3 compensating for drift at the anode.
30 Figure 11 is a graph of the results of a blood glucose monitoring experiment with the subject A of Figure 3 compensating,for time lag and drift at the anode.
Figure 12 is.a graph of the results of a blood 35 glucose monitoring experiment withthe subject B of W096/00109 ~ ~ ~ ~ (~ PCTIUS95107579 Figure 5, left arm, compensating for time lag and drift at the cathode. -Figure 13 is a graph of the results of a blood glucose monitoring experiment with the subject B of Figure 5, left-=arm, compensating for time lag and drift at the anode. - -Figure 14, subject D, right arm, demonstrates that the standard DC protocol did not show this oscillation.
Figure 15, Subject D, left arm, showed sharp oscillation in the iontophoretically extracted glucose at the cathode as the physical-site of extraction was switched from one extraction site on the forearm to the other during the alternating polarity protocol.
Figure 16, subject B, left arm, shows that the oscillatory behavior is smoothed out by alternating the polarity every 7.5 minutearather than every 15 minutes.
Figure 17, subject B, right arm, shows the oscillatory behavior, similar to that observed in Example 4, for the 15-minute alternating polarity protocol.
Figure 18, subject A, right arm, demonstrates the dramatic enhancement in flux at the cathode for a direct current protocol using pH 8.2 sodium bicarbonate buffered saline solution compared to Figure 2 for the same Subject B using 0.45% sodium chloride solution.
Figure 19, subject A, left arm, demonstrates the dramatic enhancement of flux at the cathode for the alternating polarity protocol using pH 8.2 sodium bicarbonate buffered saline solution compared to Figure 3 for the same Subject B using 0.45%sodium chloride solution.
Detailed Descr~ot~on of the Invents~n Unless defined otherwise all technical and scientific terms used herein have the same meaning as ifO 96/00109 1 ~ ~ ~ ~ ~ PCTII3S95I07579 commonly understood-by one of ordinary skill in art to which this invention is directed. Although any methods and materials similar or equivalent to those described herein can be used--in the practice or testing of this invention, the preferred-methods and materials are now described.
All patents and publications cited herein are incorporated herein by reference for-the purpose of disclosing and describing information_izi-connection with which the patents and publications are cited.
By "conducting electrical current through the tissue to extract the substance into one or more sampling chambers/collection reservoirs" is meant applying electrical energy of sufficient strength and duration to the tissue surface of a subject in order to transport a substance or a metabolite from beneath the skin at a collection site on the surface of the tissue into a defined collection area. This includes the method known as iontophoresis. "IOntophoresis" as used herein means a method of treatment to drive uncharged non-ionic materials and positive or negative ions out of an organism through tissue. In conventional iontophoresis two electrodes are placed in contact with the tissue.
One or both of the electrodes is in a sampling chamber/
collection reservoir to collect the substance extracted and a voltage is applied between the two electrodes. The sampling chamber/collection reservoir is provided at the tissue surface to serve as a collector of material transported.
As used herein "sampling" or "monitoring" means the extraction-of a substance from an organism through the tissue. The tissue or skin can be natural or artificial tissue and can be of plant or animal nature, such as natural or artificial akin, blood vessel tissue, intestinal tissue, mucosal epithelial tissue, and the '~ PGTIHJS95107579 like. The term "artificial" as used herein means an aggregation of cells of monolayerthickness or greater which are grown or cultured 't~ v'v or,jn vi and-which function as a tissue of an organism butare not actually derived, or excised, from a pre-existing source or host.
The subject/patient or host organism can include warm-blo~ded animals and is, particularly, a mammal, such as rats, mice, pigs, dogs, cats, cattle, sheep, horses, and especially a human being. When the tissue is human skin, the tissue surface is the stratum corneum surface, mucosal tissue as in the oral, nasal, or vaginal cavity or the like.
There is a need to sample and quantify or qualify bioactive substances, such as glucose or a -glucose metabolite, in a body, such as in the blood, for example, to monitor the presence of a endogenous biochemical for the purpose of diabetes diagnosis and treatment, forensic evaluation, or to follow, and preferably optimize the blood level of an administered drug during a dhemotherapeutic regimen. This preferably needs to be~done without the invasive withdrawal of blood by a needle into a collection reservoir/container. In some applications, e.g. diabetes treatment, for maximum benefit, sampling and quantification also should be performed substantially continuously and the measured substance values need to correlate actual blood substance levels.
Substances that can be sampled from an organism include anything found in the system of an animal, including a wide variety of body materials intended for diagnosis', such as natural and therapeutically introduced metabolites, hormones, amino acids, peptides and proteins, electrolytes,- metal ions, suspected drugs of abuse, enzymes, tranquilizers, anesthetics, muscle relaxants, sedatives, an~ipsychotic agents, WO 96/00109 ~ . ~ t~Y~ YC17U595IU7579 antidepressants, antianxiety agents, small drug molecules, and the like. Non-limiting representative examples of such materials include glucose, lactic acid, pyruvic acid, alcohols, fatty acids, glycols, thyroxine, estrogen, testosterone, theobromine, sucrose, galactose, uric acid, alpha amylase, choline, L-lysine, sodium, potassium, copper, iron, magnesium, calcium, zinc, potassium, citrate, morphine, morphine sulfate, heroin, insulin, steroids, neomycin, nitrofurazone, beta-_10 methasone, clonidine and clonidine HC1, acetic acid, alkaloids, acetaminophen, and amino acids. More than one substance can be sampled at one time. In one embodiment, the invention includes a continuous monitoring of the levels of glucose or glucose metabolite from the body.
According to one embodiment, the invention is useful in continuous monitoring of levels of a substance (glucose or a substance (glucose) metabolite, e.g., lactic acid, from the body. The method can also be used for measurement of blood substance (glucose) levels in either a semi-continuous or a single measurement method.
The method can be practiced by a device that provides electrodes or other means for applying electric current to the tissue at the collection site; one or more collection reservoirs or sampling chambers to receive the substance (glucose); and a substance concentration measurement system. A continuous glucose monitoring ____.__, _.. _- method and apparatus according to this embodiment is described in a patent application entitled "Continuous Transdermal Glucose Monitoring Method and Apparatus"
filed concurrently with this application and assigned to the assignee of this application, and published as PCT WO 96/00110 on January 4, 1996 having Canadian Serial Number 2,193,885. A preferred embodiment of the ~5 method and apparatus are described in more detail below.
WO 96!00109 ~ ~ PCTYUS95/07579 The method and device of the invention are useful in providing non-invasivemonitoring-of the levels of a substance, such as glucose or a glucose metabolite, from the body. For example, the method-and--device can be used forthe measurement of-blood glucose levels in a diabetic subject in either a semi-continuous or a single measurement method. The method can be practiced with a device of the invention based on the application of low intensity electric fields-of alternating polarity across the tissue/skin (iontophoresis) to enhance the transport of molecules, such as glucose, lactic acid, pyruvic acid, and the like, from body tissues to one or more collection reservoirs/sampling chambers.
According to the method of the invention, a collection-reservoir is placed at a collection site on a tissue surface of the patient, for example, on the stratum corneum of the patient's skin or on the mucosal epithelium. Electrical energy is applied to the tissue at the collection site to move the substance from the tissue into the collection reservoir. The collection reservoir is analyzed periodically to measure the substance level concentration therein, and this measured concentration value is preferably correlated with the patient's blood substance level. The steps are repeated to monitor the patient's blood substance level, preferably substantially continuously, and to track changes in the patient's blood substance level.
In a preferred embodiment of the method, two electrodes provide the electrical energy to the tissue at the collection site or sites. Two collection-reservoirs are provided, one at or near each electrode. -The applied electrical-current is preferably in the range of about 0.01 to about 2 mA/cm2. In applying the electrical energy, the polarity of the electrodes is alternated, ,e.g., at a rate in the range of about 0.1 Hz (one switch R'O 96/00109 PCT/US95107579 every 10 seconds) to-about~l switch every hour, so that each electrode is alternately a cathode or an anode. The substance in question (e.g., glucose) is collected in both reservoirs, but is most preferably measured in the reservoir acting as the cathode_ In other words, the reservoir in which glucose-concentration is monitored alternates as the polarity of the electrodes alternates.
The actual frequency of the polarity switch may need to be optimized for-the substance being extracted and measured.
The reversal of polarity during sampling has advantages, including: (1) an unexpected enhancement of the corre-lation between blood and/or tissue concentrations and iontophoretically extracted samples under the alternating polarity method of the invention as compared to a non-alternating polarity protocol, (2) a particularly unexpected increase in the normalized flux rate, and (3) the avoidance of depletion of the AgCl plating on AgCl electrodes or pH variations which occur for non-alternating systems.
The polarity switching can be manual or automatic. The polarity switching can be of any frequency, especially at frequencies between about 1 cycle per 20 seconds to about 1 cycle per 4 hours, preferably between about 1 cycle per 20 seconds to about 1 cycle per 2 hours, or more preferably between about 1 cycle per minute to about 1 cycle per 2 hours, or between about 1 cycle per 10 minutes to about 1 cycle per hour, and especially is about 1 cycle per half hour. By cycle is meant one interval of current in each direction. The application of electrical energy in a given cycle may cease during analysis of the collection medium.
In the preferred method, part or all of the collection medium is extracted from the collection reservoir-and analyzed for concentration of the substance . E r-i t i-!;~'i.':,'~
x" "u;~,',!,. ~,.1 :..
2193884 IPEA/US zYJAN 1996 s~ que~tTOn one ~fe~erred aralysi~ method zs ha.sh ~r~.~su~~
liquid chromatography (HPLC), although other analysis methods may be used, such as pulsed amperometric detection. To provide useful information regarding concentration levels of S the substance in the patient's blood and/or tissue, the substance concentrations detected in the collection medium must be correlated with the tissue and/or blood levels.
Concentration in the collection medium is computed in flux terms, such as nmoles/cm2~hr. This information must be translated into corresponding values (expressed, e.g., in terms of mg/dl for-blood substance concentrations).
For example, correlation between blood glucose concentration and measure glucose flux may be expressed in terms of four variables: the time lag between blood glucose concentration values and measured glucose flux values; linear drift over time of the measured glucose flux values; and the slope and intercept (i.e., the low-end blood glucose value below which no glucose flux is detected) of a line relating time lag and drift-corrected glucose flux data to blood glucose conceritration. Correlation between measured glucose flux and actual blood glucose concentration is accomplished through a calibration procedure which relates blood glucose data and glucose flux data. Time lag is defined as the constant time shift between blood glucose and glucose flux curves that achieves a best fit in curve shape along the time axis within predefined tolerances. The amount of time shift may be determined manually or automatically with the aid of a computer or other processor using known curve shape comparison algorithms. Timeshift is illustrated in Figs. 8 & 9 and Figs. 10-& 1i:
Drift is defined as the linear change with time of the measured glucose flux for a given blood glucose qMENDED SHEE1 CVO 96/00109 PC'flUS95107579 -1~- 2 7 93884 concentration. Drift is computed by shifting the plotted glucose flux curve with respect to the blood glucose concentration curve along the glucose flux axis by a constant multiple of the time variable to achieve a best fit. The value of the constant multiple may be computed in many different ways. For example, experimental data taken from a given subject at given times under "baseline" conditions (i.e., the patient is fasting and the blood-glucose leuel is therefore constant) may be subtracted from measured-glucose flux data point by point during the oral glucose tolerance test at the same times for the same patient.
As another example, a linear fit (obtained, e.g., from a-least squares linear regression) of the baseline data for a given patient may be subtracted from experimental data obtained during the oral glucose tolerance test. Measured glucose flux values can also be corrected without first obtaining baseline values. One approach is to estimate the value of drift time constant, adjust for drift based-on the estimate, and determine the correlation between drift-corrected measured values and measured blood glucose values. The estimated drift time constant can then be increased or decreased, and the correlation recalculated, until an acceptable tolerance between measure glucose flux values and blood glucose values is achieved.
The drift time constant may also be computed by measuring a different physiological parameter, such as the electrical resistance of the patient's skin (which 3D may change with time in the same manner as the glucose flux value drift) or a parameter that remains relatively constant over time, such as the pH of the patient's blood.
Finally, the slope and intercept of the relationship between the time arid drift corrected values R'O 96100109 PCTIUS95/07579 -18- 2 i 93884 is computed using a linear best fit of the data. These steps may be performed by hand or by a suitably programmed processor or computer. -Other correlation-variables and correlating relationships may be determined for other sample substances.
The-sampled substance-may be present in non-systemic amounts in the stratum corneum prior to application of the monitoring method and device. A time delay may therefore-be provided between the start of the sampling and the time of analysis.
The method of this- invention may be performed substantially continuously for an indefinite period of time. The method of the_invention may also include the step of treating the patient in response to the determined (i.e., correlated) systemic concentration of the substance in the patient.
The collection reservoir/sampling chamber of the device of the invention can be in the form of (1) a single chamber with an electrode, which alternates polarity, with an indifferent counterelectrode which also alternates polarity, with the electrode in the sampling chamber acting as anode, cathode or both during the course of sampling, (2) two chambers in which the anode and cathode chambers are on alternate sites as the polarity alternates or (3) two or more chambers in which the polarity alternates during the treatment allowing for signal averaging between cathode and anode.
The collection reservoir/sampling chamber for receiving the sample of the target substance from the subject can be in the form of adhesive patch enclosing the electrode means. A wide variety of adhesives for patches are known in the iontophoresis art.
Figure 7:A shows in-block diagram form a monitor according to this invention. The monitor includes a 2~~388~ ~'~~i~~J 95/Q7579 collection reservoir IDS eontaihing a 'collection medium R pair of electrodes 102 and 104 connected to a power supply 106 having positive and r~egative connectors -107 axed 108, -respectively, via conductors 109 and 110-and a switch 112 provide current for transport of. the sampled substance from a tissue surface into reservoir 100.-The switch 11Z may be controlled manually or,by an automatic controllQr 113. An analyzer 114-associated with the monitor-measures the substance concen-tration in collection reservoir-100andcomputes a substance..flux. A calibrator 116 correlates the computed substance flux-crith the patient's systemic concentration. Figures iB-1D are drawings of a preferred device for- practicing the method of this invention. As shown in Figure 1B, two integral electrode/reservoir assemblies 10 are-attached to collection sites 12-on a tissue surface 14 of a patient. The electrode/reservoir assemblies 10 are connected to a power supply 20.
Figure 1-C is an exploded view of the electrode/reservoir-assembly 10_ Element 1 is a release liner which is a protective layer for the adhesive of the skin contacting surface of the patch; element 2 is a sample port which can be a tube through which samples are removed; element 3 is the top layer; which can be a polymeric layer, which forms the upper=housing for the collection reservoir/sample chamber and makes it possible to view the condition of the electrode as the treatment progresses; element 4 is a foam 7.ayer coated on one side with an adhesive top layer, which prevents contact of the electrode with the skin and serves as ahe walls of the collection reservoir/sample chamber; element 5 or 6 is-an electrode which serves as either the cathode (i.e., electron donor) or the anode (i.e., electron receiver) depending on the polarity of the electrodes; element 7 is a transfer adhesive layer which holds the electrode.5.and the sample port 2 in place; and element 8 is a protective layer positioned between the electrode 5 and 4MEtdDED SNEE1 ENO 96100109 ~' ~ 3 ~ ~ ~CTIUS95~07579 the sample port 2 in place; and element 8 is a protective layer positioned between the electrode 5 and the skin to prevent the electrode from contacting the skin.
As illustrated, layers-4 and 7 each comprise part of the housing of the collection reservoir and allow for the collection reservoir to be open to the skin.
The release Liner 1 is a protective layer for the adhesive of the skin contacting surface of the patch.
This liner can be any suitable flexible material conventional known in the art. It should be strong enough notto be torn away by normal movement but easily removed by the application of some manual effort.
The sample port 2 can be a tube through which samples are removed.
The top layer 3 can be any flexible material conventionally_known in the art, such as a polymeric layer, which forms the upper wallof the housing of the collection reservoirJsample chamber and is preferably transparent, which makes it possible to view the condition of the electrode as the treatment progresses.
Any transparent polymeric material conventionally used as the top layer in tranadermal patches can be used.
Preferably, the top layer is made of polyester or preferably polyethylene.
The foam layer 4 is any medical grade foam coated on one side with an adhesive (foam tape) which prevents contact of the electrode with the skin and serves as the walls of the sample chamber. Any foam tape which is conventionally used in transdermal patches which is compatible with the tissue and material to be sampled can be used, preferably the faam tape is a closed-cell polyolefin foam coated on one side with an acrylate adhesive, such as 3M #9773.
-.._ _ , ~. ., ,: "~
't ii 1:~t44.~",', C: ' l i i. ...,:
WO 96/UU109 t _'y) t ~ YC:IIUJyJ/U'/~'/Y
w The electrode 5 can be made of Ag/AgCl or any other electrode material. It is attached to the power source via electrical wires/leads.
The transfer adhesive layer 7 which is a transfer adhesive layer which holds the electrode and the sample port in place. The adhesive can be any adhesive conventionally known in the art which can hold the layers together with the electrodes between. For example, the transfer adhesive can be 3M Product # 1524, medical transfer tape.
The protective layer 8 is positioned between the electrode 5 and the skin to prevent the electrode from contacting the skin. The protective layer is a polyurethane film coated on one side with an adhesive layer which keeps it in contact with the electrodes. Any conventional adhesive which is compatible with the skin can be used. For example, the protective layer is an Acutek'Ytape (Flexcon-Deraflex4NRU 100 clear H566 spec 50K-9 (nylon reinforced cast polyurethane film coated with an acrylic adhesive).
Figure 1D is a cross-section of one of an electrode/reservoir assembly 10 in place at the collection site 12. A collection reservoir/sampling chamber 16 is preferably filled with an electrically conductive medium/fluid. Any fluid which is capable of conducting electric current between the electrodes can be used. Suitable fluids include water, aqueous saline solutions and preferably aqueous buff eyed saline solutions having a pH.in the range of from about 4 to about 9. A preferred fluid is an aqueous sodium bicarbonate buffered sodium chloride solution having a pH
of from about pH 7 to about pH 9. Obviously, the fluid is one that is inert to the material desired to be sampled (i.e., glucose) and compatible with skin. The '~ Trade-mark nv~ ~J! U~~ j'~' 9 collection medium prom des an electrical circuit connection between electrode 5 and the tissue surface.
Instead of the collection reservoir described above, a collection matrix may be provided, as in known in the art. Also, electrodes in direct contact with the skin may be used in place of the electrodes immersed in conducted fluid as described above.
Preferably, power supply 20 comprises a means for reversing the polarity of the power source during the l0 sampling, such as a manual or automatic programmable switch. One suitable power supply is the Iomed Phoresor2~' iontophoretic power supply.
One of skill in the art can recognize that there is variation between subjects or even for a given subject and for use of different iontophoretic device designs, surface area, current density, and the like as to background (non-systemic) substance concentrations, ' time lag and drift. .These can be determined by standard methods and the correlation of the data adjusted for background substance concentrations, time lag and drift far an individual and/or device.
. In one embodiment the invention includes a . substance monitor comprising:
first and second substance sampling chambers each containing substance collection medium selected from the group consisting of water, saline solutions, buffer solutions, and polyols;
a power supply means having a positive connector and a negative connector;
conductors and a switch electrically connecting the first and second sampling chambers to the power supply means' positive connector and the power supply means' negative connector, the switch having a first position in which the first sampling chamber is electrically connected to the positive connector and the Trade-mark second sampling chamber is electrically connected to the negative connector and a second position in which the second sampling chamber is electrically connected to the positive connector and the firsL.sampling chamber is electrically connected to the negative connector.
Preferably, the monitor is one in which the first and second sampling chambers each further comprises an electrode in electrical communication with the collection medium and with the power supply through a conductor and the switch.
The method of the invention is preferably one wherein the tissue surface is a stratum corneum surface of the patient's skin, the analysis step comprising the step of delaying the time between. the applying step and the analyzing step to allow for depletion of non-systemic substance (glucose) in the stratum corneum.
The delaying step can comprise delaying performance of the analyzing step for about one hour after commencing the applying step.
The method of the invention preferably is one in which the collection reservoir contains a collection medium, the analyzing step comprising the step of extracting at least a portion of the collection medium form the collection reservoir.
The method of the invention can further comprise the step of providing correlation data between collection reservoir substance (glucose) levels and patient's blood substance (glucose) levels.
The method of the invention can also include the correlating step comprising calculating substance (glucose) flux from the collection site into the collection reservoir.
The method of the invention preferably comprises the method wherein the steps of placing the collection-reservoir on a tissue surface, applying the R'U 9G~~U1U9 ~ 1 ~ ~ ~ ~ ~ PCTIUS95107579 electrical energy to the tissue, analyzing the collection reservoir for-collected substance concentration, and correlating the analyzed substance-concentration with systemic level are perfoimied substantially continuously for'about 2 hours to about 72 hours-, preferably from about 16 hours to about 24 hours.-EXAMPLES
The following examples are provided to illustrate the invention but should not be regarded as limiting it in any way.
Exam lx~ a 1 -Blood glucose monitoring-experiments were performed in which a comparison was made between a standard iontophoretic-protocol consisting of direct current (DC) between an anode site and a cathode site versus an iontophoretic protocol of this invention in which the electrodes act as both the anode and the cathode (alternating polarity, AP) during the course of extraction. Two iontophoretic extractions were performed simultaneously on human subjects, one-using the standard (DC) protocol on the right arm and the other using the protocol of this invention-(AP) on the left arm.
In these experiments, two adhesive sampling patches, each with Ag or AgCl electrodes inserted into the aqueous sampling chamber of the patches, were applied to each forearm. The iontophoretic patches had a collection surface area of 2_8S cm2 her patch and a collection-reservoir volume 0.4 mL per patch. The chambers were filled with 0.45% sodium chloride in water, U.S.P.
For the direct current or DC protocol (the standard protocol), a current of 0.32 mAjcm2 was applied for about 15-minutes, followed by a 5-minute interval in WO 96/00109 ' 1 ~ '.~ PC'1'IUS95/U7579 which the saline was removed for analysis and then replaced with fresh saline. During the 5-minute rest period, blood glucose was measured by a standard finger prick (One Touch Basic' LifeScan, Milpitas, CA) method for comparison to extracted glucose. The 15-minute iontophoresis and S-minute rest/sampling procedure was repeated over a period of 3 to 5 hours. The extract samples were analyzed by HPLC.
The method of this invention (alternating l0 polarity, AP) was identical to the standard protocol, except that the polarity of the power supply was switched during each 5-minute rest period. In this way, the cathode chamber of one S-minute period became the anode chamber of the next 5-minute period, and vise versa.
During the method, an oral glucose tolerance test was conducted on the non-diabetic subjects who had fasted prior to the experiment for 12 hours overnight.
One hour into the test, 75 g of glucose was administered orally. Blood glucose levels typically increased from 80 to 150 mg/dL. The results of the test are set forth in Figures 2-5.
These figures, are graphs comparing the results of the standard protocol and the alternating polarity method of the invention performed simultaneously on the same subject. Figures 2 and 4 show the standard (DC) method, which was performed on the right arms of subjects A and B, respectively, and Figures 3 and 5 show the alternating polarity method of the invention, which was performed on the left arms of subjects A and B, respectively. In each figure, blood glucose concentration in mg/dL is given versus time in minutes.
The "x" is for blood glucose, solid triangle is for iontophoretic glucose at the anode, and the solid sa_uare is for iontophoretic glucose at the cathode.
* Trade-mark R'O 96100109 ~ ; ~ ~ ~ ~ ~ PCTIU595107579 As can be seen by comparing the Figures 2 and 4 with Figures 3 and 5s respectively, the alternating polarity method of the invention gave better correlation, particularly for the anode response.
The above results demonstrate the improvement in sampling profiles from alternating polarity, or the use one or more sampling electrodes that-act, -alternatively, as anode and cathode during a-cycling period during the course of the extraction, as compared to the direct current (DC) standard mode of iontophoresis. -A continuous iontophoretic extraction was conducted on subject C. Iontophoreais was administered and glucose was monitored as deacYibed in Example 1 above, with the following modification. The 15-minute extraction, 5-minute rest period sampling procedure was applied DC for 8 sampling periods. On the 9th sample period, the current was switched to an alternating polarity protocol of a switch every 15-minutes. The results are set forth in Figure 6. There was a sharp and dramatic increase in flux as the protocol was switched from direct current to alternating polarity.
Example 3 The following are results of teats in which the data from the alternating polarity protocol is corrected for time lag and/or drift as discussed below.
A continuous iontophoretic extraction was conducted on subject A as in Figure 2, but in a protocol in which the subject had fasted 12 hours overnight prior to the start of the experiment and during the experiment (no oral glucose tolerance test). Iontophoresis was administered using the alternating polarity method of aJ0 96/00109 2 1 ~ j ~ ~ ~ PCTYUS95107579 this invention and glucose -was monitored as described in Example 1 above. The results are--shown in Figure 7.
Figure 7 demonstrates that there was a drift in the anode and cathode fluxes for subject A using alternating polarity.
Figure 8 is a graph of-the results of a M ood glucose monitoring as shown in Figure-3 of subject A, but with the flux values for the cathode in Figure 7 subtracted from the flux values for the cathode in Figure 3.
Figure 9 is a graph of the results of a blood glucose monitoring as shown in Figure 3 of subject A, but with the cathode flux adjusted for a 20 minute time lag and the drift as in Figure 8.
Figure 10 is a graph of the results of a blood glucose monitoring as shown in Figure 3 of subject A, but with the flux values for the anode in Figure 7 subtracted from the'flux values for the anode in Figure 3.
Figure 11 is a graph of the results of a blood glucose monitoring as shown in Figure 3 of subject A, but with the anode flux adjusted for a 40 minute time lag and the drift as in Figure 1D.
Figure 12 is a graph of the results of a blood glucose monitoring as shown in Figure 5 of subject .B, but with the cathode flux adjusted for a 20 minute time lag and an empirically fitted linear drift.
Figure 13 is a graph of the results of a blood glucose monitoring as shown in Figure 5 of subject B, but with the anode flux adjusted for a 4D minute time lag and an empirically fitted linear drift.
Example 4 Two iontophoretic extractions were performed simultaneously on subject D, one using the standard (DC) protocol on the right arm and the other using the WO 96100109 ~ ~ ~ ~ PCT/US95I07579 protocol- of this invention-SAP)-pn the left arm.
Iontophoresis was administered and glucose vial monitored as described in Example 1 above. The results of the test are setforth in Figures L4 and 15_ .
In Figure 15, Subject D showed sharp oscillation in the iontophoretically extracted glucose at the cathode as the physical-site of extraction was switched frpm one extraction site on the forearm to the other during the alternating polarity protocol.
Figure 14 demonstrates that the standard DC
protocol did not show this oscillation.
In total, 12 normal subjects were tested as in Examples 1 and 4. The results are summarized in Table 1 below.
Table 1 -Direct Current Alternating Polarity Cathode Anode Cathode Anode Good tracking 0 S* 7 4 Oscillation 0 0 5 6 Long Lag (>60 min) 5 1 0 2 No response 7 6 0 0 Good = tracking with drift = r2 >_ 0.5, lag < 40 min Long lag = r ~ 0.5, lag >_ 60 min Oscillation = qualitative tracking with oscillation(r2 >
0.5, lag <_ 40 m~n) No response = r < 0.5 -*Anode tracking, but low magnitude of flux Example 5 A continuous iontophoretic extraction was conducted on one arm of subject B, as in Figures 4 and 5, except with a polarity switch every 7.5 minutes instead of every 15 minutes. Iontophoresis was administered and glucose was monitored as described in Example 1 above, with the following modification. Halfway through the 15-1N0 96/00109 PCTlUS95107579 -29- 2 ~ X3884 minute extraction period, the polarity was switched while the saline solution remained in the sample chambers. The sample was removed at the end of the 15-minute cycle. In this way, each electrode acts as the cathode for 7.5 minutes and the anode for 7.5 minutes. This method was performed simultaneously on the other arm with the 15-minute alternating polarity protocol as described in Example 1 to the same subject B. The results are set forth in Figures 16 and 17.
Figure 17 shows the oscillatory behavior, similar to that observed in Example 4, for the 15-minute alternating polarity protocol.
Figure 16 shows that the oscillatory behavior is smoothed out by alternating the polarity every 7.5 minutes rather than every 15 minutes. The 7.5-minute protocol administered to each site an equal period of anode and cathode extraction. The correlation of extracted and blood glucose was thereby improved. This demonstrates that one or more electrodes can act as anode, cathode, or both during the course of the experiment.
Example 6 Two iontophoretic extractions using a modified buffer solution were performed simultaneously on same subject A as in Figure 2 and 3, one extraction using the standard (DC) protocol on the right arm and the other using the protocol of this invention (AP) on the left arm. Iontophoresis was administered and glucose was monitored as described in Example-1 above, with the following modification. Sodium bicarbonate buffer solution, 5% U.S.P, pH 7 - 9, mixed in a 1:9 ratio with 0.45% sodium chloride U.S.P. was used as the receiver solution instead of 0.45% sodium chloride. The results are set forth in Figures 18 and 19.
R'O 96/00109 PCTlUS95107579 -30- - 2 i 93884 Figure 18 demonstr tes the dramatic enhancement in fluac at the cathode for--a direct current protocol using pH 8.2 sodium bicarbonate buffered saline solution compared to Figure 2 for the same Subject B using-0.45%
sodium chloride solution. -Figure 19 demonstrates the dramatic enhancement of flux at the cathode forthe alternating polarity protocol-using pH 8.2 sodium bicarbonate buffered saline solution compared to Figure 3 for the same Subject B
using 0.45% sodium chloride--solution. -Further, a comparison of Figures 18 and 19 indicates that there was enhanced anode extraction for the sodium bicarbonate solution in the alternating polarity method compared to the direct current method.
\.
SUBSTANCES USING A.T_.TFR_rTATING POLARITY
Field of the Invention This invention relates to a device and method 7.0 for sampling of substances across-tissue using electrical energy of alternating polarity.
~ackaround of the Invention Iontophoresis is employed for therapeutic 1.5 topical treatment of humans or other organisms. Glikfeld et al., U.S. Patent No. 5,279,543, describes the use of iontopho~esis to non-invasively sample a substance through skin into a receptor chamber on the skin surface.
The Glikfeld device consists of two chambers, each 20 containing an electrically conductive medium, which medium is in electrical contact with the skin. A
positive electrode (anode) is disposed in one chamber, and a negative electrode (cathode) is disposed in the other. The two chambers are separated by an electrically 25 insulating material. In use, a constant or pulsed current is generated by a power source between the electrodes through the skin. The direction of current flow never changes during sampling. Glikfeld does not correlate the collected substance levels with blood 30 substance levels and does not address any problems associated with long term transdermal monitoring of a substance.
' The Lattin and Spevak U.S. Patent No.
4,406,658, Tapper U.S. Patent Nos. 4,301,794, 4,340,047 35 and 5,224,927, Masaki U.S. Patent No. 4,786,278, Masaki WO 96100109 2 ~ 9 3 g g q. PC'T/U595/U7579 _2_ U.S. Patent No. 4,792,702 and Maeaki European Patent No.
230,153 describe the iontophoretic delivery of a substance across tissue. In addition, these publications describe operation methods in which the polarity of the applied electrical energy is reversed during delivery.
None of these publications addresses Extraction of substances from tissue or any of the problems associated with such extraction. -The Tapper '794 and '047 patents address the irritation caused by iontophoretic delivery of ionized molecules through skin. In the Tapper apparatus, all delivery occurs at a single-electrode. Tapper determined that the irritation can be eliminated if the polarity of the applied current is reversed for equal periods.--A
complete and equal polarity reversal eliminates the molecule delivery, however. Tapper compromises by providing for a shorter period for the reverse direction and a longer period for the forward (substance delivery) direction.
The Tapper '927 patent discloses an apparatus that iontophoretically delivers a substance into the patient's skin from two source reservoirs, each attached to an electrode. The electrodes are connected to an AC
power source having a frequency in the range of 0.0027-10 Hz. Use of an AC power source minimizes the build-up of irritating chemicals at positive and negative electrodes (e. g., HC1 and H202, respectively). Providing a source reaeruoir at both electrodes permits delivery from one of the reservoirs in each phase-of the AC
signal, thereby eliminating -the drawback of using a single source reservoir-noted in the earlier-Tapper patents.
Some alternating polarity methods for drug delivery, such as in the Tapper '927 patent focus on prevention of pH changes. For many electrode systems, DfO 96100109 2 1 ~ ,~ ~ 8 ~ PCfIUS95I07579 water hydrolysis upon the application of current causes the pH to-dramatically decrease at the anode and increase at the cathode. This can cause skin irritation.
Furthermore, -the-pH changes in the drug donor electrodes can reduce the amount of ionized-drug relative to non-ionized rirug in the donor depending on the pKa of the drug. These patents propose-switching between the anode and cathode to prevent these pH changes, reducing irritation and possibly increasing drug flux, especially I0 of ionizable drugs.
The Lattin and Spevak '658 patent allows for delivery from both electrodes, thus doubling the potential delivery area. For drug delivery applications, more area means more deliverable drug per application of a single device. However, for iontophoretic sampling applications, there is no advantage to doubling the area because total delivery is not an important factor. The amount that is sampled per area is more important because it is the substance concentration that is to be measured, not the total substance amount.
The Masaki patents disclose a device and a switch which can iontophorese both anions and cations by switching the polarity of the two electrodes during the treatment cycle. In the Masaki '702 patent, the cations and anions come from a single source-reservoir attached to one electrode. The other two patents do not disclose where the cation and anion sources are located. In any event, these patents teach nothing about iontophoretic sampling from skin into a reservoir.
Sibalis U.S. Patent No. 5,013,293 describes an "electrophoretic" drug delivery system in which a drug is delivered from a reser~roir into the patient's skin under the action of current applied to two electrodes, one of which is attached to the reservoir.--The polarity of the current may be alternated periodically to control the wo 9e~ooio9 21 g 3 ~ 8 4 PCTIUS95/07579 amount of drug delivered. Sibalis does not disclose the use of iontophoresis for removing a substance from a patient's tissue.
LaPrade U.S. patent 5,006,108 discloses , alternating polarity for the delivery of drugs in which the surface area of both electrodes teach alternating , between being the anode and cathode) is available to deliver the drug. The LaPrade disclosure does not suggest that:- (1J a single-electrode may be used as a collector during iontophoretic extraction, with that electrode alternating between being an anode and a cathode; (2) two electrodes may act alternatively as anode and cathode during ioritophoretic extraction, or (3) iontophoresis can be used generally for removing substances from tissue.
Some alternating polarity patents for drug delivery such as the above LaPrade and Lattin patents, focus on increasing drug dosage with the same size patch.
The principle is that the available surface area for delivery is larger for alternating polarity because each electrode can be both an anode and a cathode, rather than one electrode being the "active" electrode and the other electrode-taking up space, but not helping drug delivery, as the 'indifferent" electrode. This results in more drug delivery, but would not aid in extraction where substance flux, not "total" substance delivered, is the critical factor.
Teijin LTD, Japanese patent publication 4224770, discloses an apparatus with electrodes for attachment to skin which has hydrous medium for electrically contacting the electrodes, containing medically active agent to be absorbed through the skin, and-current polarity switching means. Apparently, this patent is designed to reduce pH deviation.
~V096/00109 ~ ~ ~ ~ ~ PCTIU595107579 Teijin LTD, Japanese patent publication 3045272, discloses a compact iontophoresis device which comprises electrodes containing medicine and applied with high frequency AC for percutaneous administration and with the objective of reducing skin irritation.
Summary of the znvention In the area of in vivo extraction of substances from tissue, correlation between measured concentrations of extracted substances must be correlated with levels of the substance within the patient's tissue and/or blood stream. For example, studies have shown a need for a virtual continuous glucose monitor, which could potentially signal a diabetic of dangerously low or high blood sugar levels. The greater the flux of the extracted substance-from the tissue into the substance collector, the greater the accuracy with which the measured flux can be correlated with the concentration of the substance within the tissue and/or blood stream.
What is needed, therefore, is a way to decrease the difference between the measured concentration of the extracted substance and the concentration of the substance within the tissue and/or blood.
Standard iontophoretic electrodes generally involve either water hydrolysis, which can cause undesirable pH changes, or a silver/silver chloride reaction in which silver chloride is converted to silver at the cathode, and silver is converted to silver chloride at the anode. For either of these systems, long term application of current can be a problem due to the eventual depletion of the reactants. What is needed, therefore, is a iontophoretic sampling system and method ~ that avoids this problem.
This invention is directed to a device and method for sampling of a substance using electrical energy applied in alternating polarity. Alternating the polarity allows the reactions, such as silver/silver chloride reaction or the water hydrolysis reaction, to cycle back and forth, potentially lengthening the time , that a particular electrode-could be used. In the non-invasive sampling method of the invention the pertinent parameter is the extraction of the desired substance per unit surface area (flux), not the total extraction.
The invention includes a method for sampling of a substance from a subject, which comprises (a) placing one or more sampling chambers on a collection site on a tissue surface of a subject;
(b) conducting electrical current through the tissue in a first polarity to extract a substance from the subject into one or more sampling chambers;
(c) reversing the polarity of the electrical current during the course of the method (i.e., changing an anode to a cathode and a cathode to an anode); and (d) analyzing the sampling chamber or chambers for the concentration of the substance or a substance metabolite.
The invention also includes a sampling device comprising-(a) an electrical power supply means;
(b) a transdermal system that contains one or more sampling chambers for receiving a sample that function as both anode and cathode during the course of iontophoretic sampling;
(c) means for reversing the polarity of the power source during the iontophoretic sampling; and (d) means for analyzing the sampling chamber or chambers for the concentration of the substance or a substance metabolite.
'~'V0 96/00109 PCT113S95f07579 The invention also includes a substance monitor comprising:
first and second substance sampling chambers each containing substance collection medium selected from the group consisting of water, saline solutions, buffer solutions, and polyols; -a power supply means having a positive connector and a negative connector;
conductors and a switch electrically connecting the first and second -sampling chambers-to the power supply means positive connector and the power supply means negative connector, the switch having a first position in which the first sampling chamber is electrically connected to the positive connector and the second sampling chamber is electrically connected to the negative connector and a second position in which the second sampling chamber is electrically connected to the positive connector and the first sampling chamber is electrically connected to the negative connector.
The reversal of polarity during the sampling method of the invention hae advantages over a prior standard iontophoresis method (non-alternating direct or intermittent current application) including: (1) there is unexpected enhancement of the correlation between blood and iontophoretically extracted samples under the alternating polarity method of the invention as compared to a non-alternating polarity protocol, (2) there is a particularly unexpected normalized flux rate increase over the use of direct current, and (3) the alternating polarity method of the invention enables continuous or intermittent application of current for Ag/AgCl or other electrodes without depletion of the AgCl plating or pH
variations which occur for non-alternating systems.
The ionization state of the substance of the drug delivery materials of the prior art were dictated by WO 96/00109 ~ ~ ~ ~ P~'/pS95107579 _8_ the pH of the donor solutions. However, in the alternating polarity sampling method of-the invention, the ionization state of the extracted substance does not rely on the pH of the donor chamber; rather, the ionization state of the extracted species going from the body to the top of the skin is dictated by the pH of the body, which is relatively constant.
The alternating polarity sampling method and device of the invention preferably uses low frequencies of about 0.1 Hz (one switch .every 10_seconds) to about 1 switch every hour. This is in contrast to the drug delivery of the prior art, such as Tapper '794 and Masaki '351 which disclose that in a desire to reduce skin irritation, rapid, high frequency pulsing, of either the same or alternating polarity, reduces skin irritation caused by iontophoresis.
These advantages are surprising considering the non-invasive nature of-the method and device which produces these advantages when transporting substances that are beneath the akin to a collection reservoir-on top of the skin while no part of the device penetrates into or beneath the skin.
Detailed Description of the Drawincrs Figure 1A is a block diagram of a substance monitoring device according to the invention.
Figure 1B shows an-iontophoretic monitoring device-useful for practicing this invention in place on a patient.
Figure 1C is an exploded drawing of-the electrode/collection reservoir assembly illustrating the various layers thereof.
Figure 1D is a cross-section of one of an electrode/reservair assembly Figure 1C.
\N0 96/00109 ~ ~ ~ ~ ~ ~ PCTIUS95107579 Figure 2 is a graph of the results of a blood oral glucose tolerance glucose monitoring experiment on subject A, right arm, using a standard protocol.
Figure 3 is'a graph of the results of a blood oral glucose.tolerance glucose monitoring experiment on subject A, left arm, using an alternating protocol.
Figure 4-is a graph of the results of a blood oral glucose-tolerance glucose monitoring experiment on subject B, right arm, using a standard protocol.
Figure 5 is a graph ofthe results of a blood oral glucose-tolerance glucose monitoring experiment on subject B, left arm, using an alternating protocol.
Figure 6 is a graph of the results of a blood glucose monitoring experiment using several cycles of 15. direct current and a cycle of alternating polarity.
Figure 7 is the results of a blood glucose monitoring experiment with the subject A of Figure 3, under fasted conditions.
Figure 8 is a graph of the results of a blood 2D glucose monitoring experiment with the subject A of Figures 3, left arm, compensating for drift at the cathode.
Figure 9 is a graph of the results of a blood glucose monitoring experiment with the subject A of 25 Figure 3 compensating for time lag and drift at the cathode.
Figure 10 is a graph of the results of a blood glucose monitoring experiment with the subject A of Figure-3 compensating for drift at the anode.
30 Figure 11 is a graph of the results of a blood glucose monitoring experiment with the subject A of Figure 3 compensating,for time lag and drift at the anode.
Figure 12 is.a graph of the results of a blood 35 glucose monitoring experiment withthe subject B of W096/00109 ~ ~ ~ ~ (~ PCTIUS95107579 Figure 5, left arm, compensating for time lag and drift at the cathode. -Figure 13 is a graph of the results of a blood glucose monitoring experiment with the subject B of Figure 5, left-=arm, compensating for time lag and drift at the anode. - -Figure 14, subject D, right arm, demonstrates that the standard DC protocol did not show this oscillation.
Figure 15, Subject D, left arm, showed sharp oscillation in the iontophoretically extracted glucose at the cathode as the physical-site of extraction was switched from one extraction site on the forearm to the other during the alternating polarity protocol.
Figure 16, subject B, left arm, shows that the oscillatory behavior is smoothed out by alternating the polarity every 7.5 minutearather than every 15 minutes.
Figure 17, subject B, right arm, shows the oscillatory behavior, similar to that observed in Example 4, for the 15-minute alternating polarity protocol.
Figure 18, subject A, right arm, demonstrates the dramatic enhancement in flux at the cathode for a direct current protocol using pH 8.2 sodium bicarbonate buffered saline solution compared to Figure 2 for the same Subject B using 0.45% sodium chloride solution.
Figure 19, subject A, left arm, demonstrates the dramatic enhancement of flux at the cathode for the alternating polarity protocol using pH 8.2 sodium bicarbonate buffered saline solution compared to Figure 3 for the same Subject B using 0.45%sodium chloride solution.
Detailed Descr~ot~on of the Invents~n Unless defined otherwise all technical and scientific terms used herein have the same meaning as ifO 96/00109 1 ~ ~ ~ ~ ~ PCTII3S95I07579 commonly understood-by one of ordinary skill in art to which this invention is directed. Although any methods and materials similar or equivalent to those described herein can be used--in the practice or testing of this invention, the preferred-methods and materials are now described.
All patents and publications cited herein are incorporated herein by reference for-the purpose of disclosing and describing information_izi-connection with which the patents and publications are cited.
By "conducting electrical current through the tissue to extract the substance into one or more sampling chambers/collection reservoirs" is meant applying electrical energy of sufficient strength and duration to the tissue surface of a subject in order to transport a substance or a metabolite from beneath the skin at a collection site on the surface of the tissue into a defined collection area. This includes the method known as iontophoresis. "IOntophoresis" as used herein means a method of treatment to drive uncharged non-ionic materials and positive or negative ions out of an organism through tissue. In conventional iontophoresis two electrodes are placed in contact with the tissue.
One or both of the electrodes is in a sampling chamber/
collection reservoir to collect the substance extracted and a voltage is applied between the two electrodes. The sampling chamber/collection reservoir is provided at the tissue surface to serve as a collector of material transported.
As used herein "sampling" or "monitoring" means the extraction-of a substance from an organism through the tissue. The tissue or skin can be natural or artificial tissue and can be of plant or animal nature, such as natural or artificial akin, blood vessel tissue, intestinal tissue, mucosal epithelial tissue, and the '~ PGTIHJS95107579 like. The term "artificial" as used herein means an aggregation of cells of monolayerthickness or greater which are grown or cultured 't~ v'v or,jn vi and-which function as a tissue of an organism butare not actually derived, or excised, from a pre-existing source or host.
The subject/patient or host organism can include warm-blo~ded animals and is, particularly, a mammal, such as rats, mice, pigs, dogs, cats, cattle, sheep, horses, and especially a human being. When the tissue is human skin, the tissue surface is the stratum corneum surface, mucosal tissue as in the oral, nasal, or vaginal cavity or the like.
There is a need to sample and quantify or qualify bioactive substances, such as glucose or a -glucose metabolite, in a body, such as in the blood, for example, to monitor the presence of a endogenous biochemical for the purpose of diabetes diagnosis and treatment, forensic evaluation, or to follow, and preferably optimize the blood level of an administered drug during a dhemotherapeutic regimen. This preferably needs to be~done without the invasive withdrawal of blood by a needle into a collection reservoir/container. In some applications, e.g. diabetes treatment, for maximum benefit, sampling and quantification also should be performed substantially continuously and the measured substance values need to correlate actual blood substance levels.
Substances that can be sampled from an organism include anything found in the system of an animal, including a wide variety of body materials intended for diagnosis', such as natural and therapeutically introduced metabolites, hormones, amino acids, peptides and proteins, electrolytes,- metal ions, suspected drugs of abuse, enzymes, tranquilizers, anesthetics, muscle relaxants, sedatives, an~ipsychotic agents, WO 96/00109 ~ . ~ t~Y~ YC17U595IU7579 antidepressants, antianxiety agents, small drug molecules, and the like. Non-limiting representative examples of such materials include glucose, lactic acid, pyruvic acid, alcohols, fatty acids, glycols, thyroxine, estrogen, testosterone, theobromine, sucrose, galactose, uric acid, alpha amylase, choline, L-lysine, sodium, potassium, copper, iron, magnesium, calcium, zinc, potassium, citrate, morphine, morphine sulfate, heroin, insulin, steroids, neomycin, nitrofurazone, beta-_10 methasone, clonidine and clonidine HC1, acetic acid, alkaloids, acetaminophen, and amino acids. More than one substance can be sampled at one time. In one embodiment, the invention includes a continuous monitoring of the levels of glucose or glucose metabolite from the body.
According to one embodiment, the invention is useful in continuous monitoring of levels of a substance (glucose or a substance (glucose) metabolite, e.g., lactic acid, from the body. The method can also be used for measurement of blood substance (glucose) levels in either a semi-continuous or a single measurement method.
The method can be practiced by a device that provides electrodes or other means for applying electric current to the tissue at the collection site; one or more collection reservoirs or sampling chambers to receive the substance (glucose); and a substance concentration measurement system. A continuous glucose monitoring ____.__, _.. _- method and apparatus according to this embodiment is described in a patent application entitled "Continuous Transdermal Glucose Monitoring Method and Apparatus"
filed concurrently with this application and assigned to the assignee of this application, and published as PCT WO 96/00110 on January 4, 1996 having Canadian Serial Number 2,193,885. A preferred embodiment of the ~5 method and apparatus are described in more detail below.
WO 96!00109 ~ ~ PCTYUS95/07579 The method and device of the invention are useful in providing non-invasivemonitoring-of the levels of a substance, such as glucose or a glucose metabolite, from the body. For example, the method-and--device can be used forthe measurement of-blood glucose levels in a diabetic subject in either a semi-continuous or a single measurement method. The method can be practiced with a device of the invention based on the application of low intensity electric fields-of alternating polarity across the tissue/skin (iontophoresis) to enhance the transport of molecules, such as glucose, lactic acid, pyruvic acid, and the like, from body tissues to one or more collection reservoirs/sampling chambers.
According to the method of the invention, a collection-reservoir is placed at a collection site on a tissue surface of the patient, for example, on the stratum corneum of the patient's skin or on the mucosal epithelium. Electrical energy is applied to the tissue at the collection site to move the substance from the tissue into the collection reservoir. The collection reservoir is analyzed periodically to measure the substance level concentration therein, and this measured concentration value is preferably correlated with the patient's blood substance level. The steps are repeated to monitor the patient's blood substance level, preferably substantially continuously, and to track changes in the patient's blood substance level.
In a preferred embodiment of the method, two electrodes provide the electrical energy to the tissue at the collection site or sites. Two collection-reservoirs are provided, one at or near each electrode. -The applied electrical-current is preferably in the range of about 0.01 to about 2 mA/cm2. In applying the electrical energy, the polarity of the electrodes is alternated, ,e.g., at a rate in the range of about 0.1 Hz (one switch R'O 96/00109 PCT/US95107579 every 10 seconds) to-about~l switch every hour, so that each electrode is alternately a cathode or an anode. The substance in question (e.g., glucose) is collected in both reservoirs, but is most preferably measured in the reservoir acting as the cathode_ In other words, the reservoir in which glucose-concentration is monitored alternates as the polarity of the electrodes alternates.
The actual frequency of the polarity switch may need to be optimized for-the substance being extracted and measured.
The reversal of polarity during sampling has advantages, including: (1) an unexpected enhancement of the corre-lation between blood and/or tissue concentrations and iontophoretically extracted samples under the alternating polarity method of the invention as compared to a non-alternating polarity protocol, (2) a particularly unexpected increase in the normalized flux rate, and (3) the avoidance of depletion of the AgCl plating on AgCl electrodes or pH variations which occur for non-alternating systems.
The polarity switching can be manual or automatic. The polarity switching can be of any frequency, especially at frequencies between about 1 cycle per 20 seconds to about 1 cycle per 4 hours, preferably between about 1 cycle per 20 seconds to about 1 cycle per 2 hours, or more preferably between about 1 cycle per minute to about 1 cycle per 2 hours, or between about 1 cycle per 10 minutes to about 1 cycle per hour, and especially is about 1 cycle per half hour. By cycle is meant one interval of current in each direction. The application of electrical energy in a given cycle may cease during analysis of the collection medium.
In the preferred method, part or all of the collection medium is extracted from the collection reservoir-and analyzed for concentration of the substance . E r-i t i-!;~'i.':,'~
x" "u;~,',!,. ~,.1 :..
2193884 IPEA/US zYJAN 1996 s~ que~tTOn one ~fe~erred aralysi~ method zs ha.sh ~r~.~su~~
liquid chromatography (HPLC), although other analysis methods may be used, such as pulsed amperometric detection. To provide useful information regarding concentration levels of S the substance in the patient's blood and/or tissue, the substance concentrations detected in the collection medium must be correlated with the tissue and/or blood levels.
Concentration in the collection medium is computed in flux terms, such as nmoles/cm2~hr. This information must be translated into corresponding values (expressed, e.g., in terms of mg/dl for-blood substance concentrations).
For example, correlation between blood glucose concentration and measure glucose flux may be expressed in terms of four variables: the time lag between blood glucose concentration values and measured glucose flux values; linear drift over time of the measured glucose flux values; and the slope and intercept (i.e., the low-end blood glucose value below which no glucose flux is detected) of a line relating time lag and drift-corrected glucose flux data to blood glucose conceritration. Correlation between measured glucose flux and actual blood glucose concentration is accomplished through a calibration procedure which relates blood glucose data and glucose flux data. Time lag is defined as the constant time shift between blood glucose and glucose flux curves that achieves a best fit in curve shape along the time axis within predefined tolerances. The amount of time shift may be determined manually or automatically with the aid of a computer or other processor using known curve shape comparison algorithms. Timeshift is illustrated in Figs. 8 & 9 and Figs. 10-& 1i:
Drift is defined as the linear change with time of the measured glucose flux for a given blood glucose qMENDED SHEE1 CVO 96/00109 PC'flUS95107579 -1~- 2 7 93884 concentration. Drift is computed by shifting the plotted glucose flux curve with respect to the blood glucose concentration curve along the glucose flux axis by a constant multiple of the time variable to achieve a best fit. The value of the constant multiple may be computed in many different ways. For example, experimental data taken from a given subject at given times under "baseline" conditions (i.e., the patient is fasting and the blood-glucose leuel is therefore constant) may be subtracted from measured-glucose flux data point by point during the oral glucose tolerance test at the same times for the same patient.
As another example, a linear fit (obtained, e.g., from a-least squares linear regression) of the baseline data for a given patient may be subtracted from experimental data obtained during the oral glucose tolerance test. Measured glucose flux values can also be corrected without first obtaining baseline values. One approach is to estimate the value of drift time constant, adjust for drift based-on the estimate, and determine the correlation between drift-corrected measured values and measured blood glucose values. The estimated drift time constant can then be increased or decreased, and the correlation recalculated, until an acceptable tolerance between measure glucose flux values and blood glucose values is achieved.
The drift time constant may also be computed by measuring a different physiological parameter, such as the electrical resistance of the patient's skin (which 3D may change with time in the same manner as the glucose flux value drift) or a parameter that remains relatively constant over time, such as the pH of the patient's blood.
Finally, the slope and intercept of the relationship between the time arid drift corrected values R'O 96100109 PCTIUS95/07579 -18- 2 i 93884 is computed using a linear best fit of the data. These steps may be performed by hand or by a suitably programmed processor or computer. -Other correlation-variables and correlating relationships may be determined for other sample substances.
The-sampled substance-may be present in non-systemic amounts in the stratum corneum prior to application of the monitoring method and device. A time delay may therefore-be provided between the start of the sampling and the time of analysis.
The method of this- invention may be performed substantially continuously for an indefinite period of time. The method of the_invention may also include the step of treating the patient in response to the determined (i.e., correlated) systemic concentration of the substance in the patient.
The collection reservoir/sampling chamber of the device of the invention can be in the form of (1) a single chamber with an electrode, which alternates polarity, with an indifferent counterelectrode which also alternates polarity, with the electrode in the sampling chamber acting as anode, cathode or both during the course of sampling, (2) two chambers in which the anode and cathode chambers are on alternate sites as the polarity alternates or (3) two or more chambers in which the polarity alternates during the treatment allowing for signal averaging between cathode and anode.
The collection reservoir/sampling chamber for receiving the sample of the target substance from the subject can be in the form of adhesive patch enclosing the electrode means. A wide variety of adhesives for patches are known in the iontophoresis art.
Figure 7:A shows in-block diagram form a monitor according to this invention. The monitor includes a 2~~388~ ~'~~i~~J 95/Q7579 collection reservoir IDS eontaihing a 'collection medium R pair of electrodes 102 and 104 connected to a power supply 106 having positive and r~egative connectors -107 axed 108, -respectively, via conductors 109 and 110-and a switch 112 provide current for transport of. the sampled substance from a tissue surface into reservoir 100.-The switch 11Z may be controlled manually or,by an automatic controllQr 113. An analyzer 114-associated with the monitor-measures the substance concen-tration in collection reservoir-100andcomputes a substance..flux. A calibrator 116 correlates the computed substance flux-crith the patient's systemic concentration. Figures iB-1D are drawings of a preferred device for- practicing the method of this invention. As shown in Figure 1B, two integral electrode/reservoir assemblies 10 are-attached to collection sites 12-on a tissue surface 14 of a patient. The electrode/reservoir assemblies 10 are connected to a power supply 20.
Figure 1-C is an exploded view of the electrode/reservoir-assembly 10_ Element 1 is a release liner which is a protective layer for the adhesive of the skin contacting surface of the patch; element 2 is a sample port which can be a tube through which samples are removed; element 3 is the top layer; which can be a polymeric layer, which forms the upper=housing for the collection reservoir/sample chamber and makes it possible to view the condition of the electrode as the treatment progresses; element 4 is a foam 7.ayer coated on one side with an adhesive top layer, which prevents contact of the electrode with the skin and serves as ahe walls of the collection reservoir/sample chamber; element 5 or 6 is-an electrode which serves as either the cathode (i.e., electron donor) or the anode (i.e., electron receiver) depending on the polarity of the electrodes; element 7 is a transfer adhesive layer which holds the electrode.5.and the sample port 2 in place; and element 8 is a protective layer positioned between the electrode 5 and 4MEtdDED SNEE1 ENO 96100109 ~' ~ 3 ~ ~ ~CTIUS95~07579 the sample port 2 in place; and element 8 is a protective layer positioned between the electrode 5 and the skin to prevent the electrode from contacting the skin.
As illustrated, layers-4 and 7 each comprise part of the housing of the collection reservoir and allow for the collection reservoir to be open to the skin.
The release Liner 1 is a protective layer for the adhesive of the skin contacting surface of the patch.
This liner can be any suitable flexible material conventional known in the art. It should be strong enough notto be torn away by normal movement but easily removed by the application of some manual effort.
The sample port 2 can be a tube through which samples are removed.
The top layer 3 can be any flexible material conventionally_known in the art, such as a polymeric layer, which forms the upper wallof the housing of the collection reservoirJsample chamber and is preferably transparent, which makes it possible to view the condition of the electrode as the treatment progresses.
Any transparent polymeric material conventionally used as the top layer in tranadermal patches can be used.
Preferably, the top layer is made of polyester or preferably polyethylene.
The foam layer 4 is any medical grade foam coated on one side with an adhesive (foam tape) which prevents contact of the electrode with the skin and serves as the walls of the sample chamber. Any foam tape which is conventionally used in transdermal patches which is compatible with the tissue and material to be sampled can be used, preferably the faam tape is a closed-cell polyolefin foam coated on one side with an acrylate adhesive, such as 3M #9773.
-.._ _ , ~. ., ,: "~
't ii 1:~t44.~",', C: ' l i i. ...,:
WO 96/UU109 t _'y) t ~ YC:IIUJyJ/U'/~'/Y
w The electrode 5 can be made of Ag/AgCl or any other electrode material. It is attached to the power source via electrical wires/leads.
The transfer adhesive layer 7 which is a transfer adhesive layer which holds the electrode and the sample port in place. The adhesive can be any adhesive conventionally known in the art which can hold the layers together with the electrodes between. For example, the transfer adhesive can be 3M Product # 1524, medical transfer tape.
The protective layer 8 is positioned between the electrode 5 and the skin to prevent the electrode from contacting the skin. The protective layer is a polyurethane film coated on one side with an adhesive layer which keeps it in contact with the electrodes. Any conventional adhesive which is compatible with the skin can be used. For example, the protective layer is an Acutek'Ytape (Flexcon-Deraflex4NRU 100 clear H566 spec 50K-9 (nylon reinforced cast polyurethane film coated with an acrylic adhesive).
Figure 1D is a cross-section of one of an electrode/reservoir assembly 10 in place at the collection site 12. A collection reservoir/sampling chamber 16 is preferably filled with an electrically conductive medium/fluid. Any fluid which is capable of conducting electric current between the electrodes can be used. Suitable fluids include water, aqueous saline solutions and preferably aqueous buff eyed saline solutions having a pH.in the range of from about 4 to about 9. A preferred fluid is an aqueous sodium bicarbonate buffered sodium chloride solution having a pH
of from about pH 7 to about pH 9. Obviously, the fluid is one that is inert to the material desired to be sampled (i.e., glucose) and compatible with skin. The '~ Trade-mark nv~ ~J! U~~ j'~' 9 collection medium prom des an electrical circuit connection between electrode 5 and the tissue surface.
Instead of the collection reservoir described above, a collection matrix may be provided, as in known in the art. Also, electrodes in direct contact with the skin may be used in place of the electrodes immersed in conducted fluid as described above.
Preferably, power supply 20 comprises a means for reversing the polarity of the power source during the l0 sampling, such as a manual or automatic programmable switch. One suitable power supply is the Iomed Phoresor2~' iontophoretic power supply.
One of skill in the art can recognize that there is variation between subjects or even for a given subject and for use of different iontophoretic device designs, surface area, current density, and the like as to background (non-systemic) substance concentrations, ' time lag and drift. .These can be determined by standard methods and the correlation of the data adjusted for background substance concentrations, time lag and drift far an individual and/or device.
. In one embodiment the invention includes a . substance monitor comprising:
first and second substance sampling chambers each containing substance collection medium selected from the group consisting of water, saline solutions, buffer solutions, and polyols;
a power supply means having a positive connector and a negative connector;
conductors and a switch electrically connecting the first and second sampling chambers to the power supply means' positive connector and the power supply means' negative connector, the switch having a first position in which the first sampling chamber is electrically connected to the positive connector and the Trade-mark second sampling chamber is electrically connected to the negative connector and a second position in which the second sampling chamber is electrically connected to the positive connector and the firsL.sampling chamber is electrically connected to the negative connector.
Preferably, the monitor is one in which the first and second sampling chambers each further comprises an electrode in electrical communication with the collection medium and with the power supply through a conductor and the switch.
The method of the invention is preferably one wherein the tissue surface is a stratum corneum surface of the patient's skin, the analysis step comprising the step of delaying the time between. the applying step and the analyzing step to allow for depletion of non-systemic substance (glucose) in the stratum corneum.
The delaying step can comprise delaying performance of the analyzing step for about one hour after commencing the applying step.
The method of the invention preferably is one in which the collection reservoir contains a collection medium, the analyzing step comprising the step of extracting at least a portion of the collection medium form the collection reservoir.
The method of the invention can further comprise the step of providing correlation data between collection reservoir substance (glucose) levels and patient's blood substance (glucose) levels.
The method of the invention can also include the correlating step comprising calculating substance (glucose) flux from the collection site into the collection reservoir.
The method of the invention preferably comprises the method wherein the steps of placing the collection-reservoir on a tissue surface, applying the R'U 9G~~U1U9 ~ 1 ~ ~ ~ ~ ~ PCTIUS95107579 electrical energy to the tissue, analyzing the collection reservoir for-collected substance concentration, and correlating the analyzed substance-concentration with systemic level are perfoimied substantially continuously for'about 2 hours to about 72 hours-, preferably from about 16 hours to about 24 hours.-EXAMPLES
The following examples are provided to illustrate the invention but should not be regarded as limiting it in any way.
Exam lx~ a 1 -Blood glucose monitoring-experiments were performed in which a comparison was made between a standard iontophoretic-protocol consisting of direct current (DC) between an anode site and a cathode site versus an iontophoretic protocol of this invention in which the electrodes act as both the anode and the cathode (alternating polarity, AP) during the course of extraction. Two iontophoretic extractions were performed simultaneously on human subjects, one-using the standard (DC) protocol on the right arm and the other using the protocol of this invention-(AP) on the left arm.
In these experiments, two adhesive sampling patches, each with Ag or AgCl electrodes inserted into the aqueous sampling chamber of the patches, were applied to each forearm. The iontophoretic patches had a collection surface area of 2_8S cm2 her patch and a collection-reservoir volume 0.4 mL per patch. The chambers were filled with 0.45% sodium chloride in water, U.S.P.
For the direct current or DC protocol (the standard protocol), a current of 0.32 mAjcm2 was applied for about 15-minutes, followed by a 5-minute interval in WO 96/00109 ' 1 ~ '.~ PC'1'IUS95/U7579 which the saline was removed for analysis and then replaced with fresh saline. During the 5-minute rest period, blood glucose was measured by a standard finger prick (One Touch Basic' LifeScan, Milpitas, CA) method for comparison to extracted glucose. The 15-minute iontophoresis and S-minute rest/sampling procedure was repeated over a period of 3 to 5 hours. The extract samples were analyzed by HPLC.
The method of this invention (alternating l0 polarity, AP) was identical to the standard protocol, except that the polarity of the power supply was switched during each 5-minute rest period. In this way, the cathode chamber of one S-minute period became the anode chamber of the next 5-minute period, and vise versa.
During the method, an oral glucose tolerance test was conducted on the non-diabetic subjects who had fasted prior to the experiment for 12 hours overnight.
One hour into the test, 75 g of glucose was administered orally. Blood glucose levels typically increased from 80 to 150 mg/dL. The results of the test are set forth in Figures 2-5.
These figures, are graphs comparing the results of the standard protocol and the alternating polarity method of the invention performed simultaneously on the same subject. Figures 2 and 4 show the standard (DC) method, which was performed on the right arms of subjects A and B, respectively, and Figures 3 and 5 show the alternating polarity method of the invention, which was performed on the left arms of subjects A and B, respectively. In each figure, blood glucose concentration in mg/dL is given versus time in minutes.
The "x" is for blood glucose, solid triangle is for iontophoretic glucose at the anode, and the solid sa_uare is for iontophoretic glucose at the cathode.
* Trade-mark R'O 96100109 ~ ; ~ ~ ~ ~ ~ PCTIU595107579 As can be seen by comparing the Figures 2 and 4 with Figures 3 and 5s respectively, the alternating polarity method of the invention gave better correlation, particularly for the anode response.
The above results demonstrate the improvement in sampling profiles from alternating polarity, or the use one or more sampling electrodes that-act, -alternatively, as anode and cathode during a-cycling period during the course of the extraction, as compared to the direct current (DC) standard mode of iontophoresis. -A continuous iontophoretic extraction was conducted on subject C. Iontophoreais was administered and glucose was monitored as deacYibed in Example 1 above, with the following modification. The 15-minute extraction, 5-minute rest period sampling procedure was applied DC for 8 sampling periods. On the 9th sample period, the current was switched to an alternating polarity protocol of a switch every 15-minutes. The results are set forth in Figure 6. There was a sharp and dramatic increase in flux as the protocol was switched from direct current to alternating polarity.
Example 3 The following are results of teats in which the data from the alternating polarity protocol is corrected for time lag and/or drift as discussed below.
A continuous iontophoretic extraction was conducted on subject A as in Figure 2, but in a protocol in which the subject had fasted 12 hours overnight prior to the start of the experiment and during the experiment (no oral glucose tolerance test). Iontophoresis was administered using the alternating polarity method of aJ0 96/00109 2 1 ~ j ~ ~ ~ PCTYUS95107579 this invention and glucose -was monitored as described in Example 1 above. The results are--shown in Figure 7.
Figure 7 demonstrates that there was a drift in the anode and cathode fluxes for subject A using alternating polarity.
Figure 8 is a graph of-the results of a M ood glucose monitoring as shown in Figure-3 of subject A, but with the flux values for the cathode in Figure 7 subtracted from the flux values for the cathode in Figure 3.
Figure 9 is a graph of the results of a blood glucose monitoring as shown in Figure 3 of subject A, but with the cathode flux adjusted for a 20 minute time lag and the drift as in Figure 8.
Figure 10 is a graph of the results of a blood glucose monitoring as shown in Figure 3 of subject A, but with the flux values for the anode in Figure 7 subtracted from the'flux values for the anode in Figure 3.
Figure 11 is a graph of the results of a blood glucose monitoring as shown in Figure 3 of subject A, but with the anode flux adjusted for a 40 minute time lag and the drift as in Figure 1D.
Figure 12 is a graph of the results of a blood glucose monitoring as shown in Figure 5 of subject .B, but with the cathode flux adjusted for a 20 minute time lag and an empirically fitted linear drift.
Figure 13 is a graph of the results of a blood glucose monitoring as shown in Figure 5 of subject B, but with the anode flux adjusted for a 4D minute time lag and an empirically fitted linear drift.
Example 4 Two iontophoretic extractions were performed simultaneously on subject D, one using the standard (DC) protocol on the right arm and the other using the WO 96100109 ~ ~ ~ ~ PCT/US95I07579 protocol- of this invention-SAP)-pn the left arm.
Iontophoresis was administered and glucose vial monitored as described in Example 1 above. The results of the test are setforth in Figures L4 and 15_ .
In Figure 15, Subject D showed sharp oscillation in the iontophoretically extracted glucose at the cathode as the physical-site of extraction was switched frpm one extraction site on the forearm to the other during the alternating polarity protocol.
Figure 14 demonstrates that the standard DC
protocol did not show this oscillation.
In total, 12 normal subjects were tested as in Examples 1 and 4. The results are summarized in Table 1 below.
Table 1 -Direct Current Alternating Polarity Cathode Anode Cathode Anode Good tracking 0 S* 7 4 Oscillation 0 0 5 6 Long Lag (>60 min) 5 1 0 2 No response 7 6 0 0 Good = tracking with drift = r2 >_ 0.5, lag < 40 min Long lag = r ~ 0.5, lag >_ 60 min Oscillation = qualitative tracking with oscillation(r2 >
0.5, lag <_ 40 m~n) No response = r < 0.5 -*Anode tracking, but low magnitude of flux Example 5 A continuous iontophoretic extraction was conducted on one arm of subject B, as in Figures 4 and 5, except with a polarity switch every 7.5 minutes instead of every 15 minutes. Iontophoresis was administered and glucose was monitored as described in Example 1 above, with the following modification. Halfway through the 15-1N0 96/00109 PCTlUS95107579 -29- 2 ~ X3884 minute extraction period, the polarity was switched while the saline solution remained in the sample chambers. The sample was removed at the end of the 15-minute cycle. In this way, each electrode acts as the cathode for 7.5 minutes and the anode for 7.5 minutes. This method was performed simultaneously on the other arm with the 15-minute alternating polarity protocol as described in Example 1 to the same subject B. The results are set forth in Figures 16 and 17.
Figure 17 shows the oscillatory behavior, similar to that observed in Example 4, for the 15-minute alternating polarity protocol.
Figure 16 shows that the oscillatory behavior is smoothed out by alternating the polarity every 7.5 minutes rather than every 15 minutes. The 7.5-minute protocol administered to each site an equal period of anode and cathode extraction. The correlation of extracted and blood glucose was thereby improved. This demonstrates that one or more electrodes can act as anode, cathode, or both during the course of the experiment.
Example 6 Two iontophoretic extractions using a modified buffer solution were performed simultaneously on same subject A as in Figure 2 and 3, one extraction using the standard (DC) protocol on the right arm and the other using the protocol of this invention (AP) on the left arm. Iontophoresis was administered and glucose was monitored as described in Example-1 above, with the following modification. Sodium bicarbonate buffer solution, 5% U.S.P, pH 7 - 9, mixed in a 1:9 ratio with 0.45% sodium chloride U.S.P. was used as the receiver solution instead of 0.45% sodium chloride. The results are set forth in Figures 18 and 19.
R'O 96/00109 PCTlUS95107579 -30- - 2 i 93884 Figure 18 demonstr tes the dramatic enhancement in fluac at the cathode for--a direct current protocol using pH 8.2 sodium bicarbonate buffered saline solution compared to Figure 2 for the same Subject B using-0.45%
sodium chloride solution. -Figure 19 demonstrates the dramatic enhancement of flux at the cathode forthe alternating polarity protocol-using pH 8.2 sodium bicarbonate buffered saline solution compared to Figure 3 for the same Subject B
using 0.45% sodium chloride--solution. -Further, a comparison of Figures 18 and 19 indicates that there was enhanced anode extraction for the sodium bicarbonate solution in the alternating polarity method compared to the direct current method.
\.
Claims (51)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS
FOLLOWS:
1. A method for sampling of a substance from a subject, which comprises (a) placing a sampling chamber on a collection site on a tissue surface on the subject;
(b) conducting electrical current through the tissue in a first polarity to the collection site to extract a substance from the subject into the sampling chamber;
(c) reversing polarity to apply electrical current in a second polarity; and (d) analyzing the sampling chamber for concentration of the substance or a substance metabolite.
(b) conducting electrical current through the tissue in a first polarity to the collection site to extract a substance from the subject into the sampling chamber;
(c) reversing polarity to apply electrical current in a second polarity; and (d) analyzing the sampling chamber for concentration of the substance or a substance metabolite.
2. The method of claim 1 wherein the polarity reversing step comprises the step of using a switch to reverse polarity.
3. The method of claim 1 wherein the step of reversing polarity is performed at a frequency of from about 1 cycle per 20 seconds to about 1 cycle per 4 hours.
4. The method of claim 1 wherein the sampling chamber comprises an an Ag/AgCl electrode, the conducting step comprising conducting current through the electrode.
5. The method of claim 1 wherein the alternating polarity current is applied continuously.
6. The method of claim 1 wherein the alternating polarity current is applied intermittently.
7. The method of claim 1 wherein the tissue surface is a stratum corneum surface.
8. The method of claim 1 wherein the step of placing a sampling chamber on a collection site on a tissue surface comprises the step of placing a sampling chamber on a collection site on a stratum corneum surface.
9. The method of claim 1 further comprising the step of placing electrodes on a tissue surface before the step of conducting electrical current.
10. The method of claim 9 wherein the electrodes are placed at the collection site.
11. The method of claim 9 wherein the electrodes are placed adjacent to the collection site.
12. The method of claim 9 wherein the step of placing electrodes comprises the step of placing on the tissue surface electrodes which are integral with the sampling chamber.
13. The method of claim 1 wherein the sampling chamber contains a collection medium, the step of conducting electrical current to the collection site comprising the step of applying electrical energy to the collection medium.
14. The method of claim 1 wherein the step of conducting electrical current comprises iontophoresis.
15. The method of claim 1 wherein the step of conducting electrical current comprises applying a current density in the range of 0.01 to 2 mA/cm2.
16. The method of claim 1 wherein the step of conducting electrical current comprises the step of ceasing the application of electrical energy during the analyzing step.
17. The method of claim 1 wherein the analyzing step comprises the step of using pulsed amperometric detection.
18. The method of claim 1 wherein the analyzing step comprises the step of using high performance liquid chromatography (HPLC).
19. The method of claim 18 wherein the analyzing step comprises delaying performance of the analyzing step for about one hour after commencing the applying step.
20. The method of claim 1 wherein the sampling chamber contains a collection medium, the analyzing step comprising the step of extracting at least a portion of the collection medium from the sampling chamber.
21. The method of claim 1 further comprising correlating the concentration determined in step (d) with blood substance level.
22. The method of claim 21 further comprising the step of providing correlation data between sampling chamber substance level and patient blood substance level.
23. The method of claim 22 wherein the correlating step comprises calculating substance flux from the collection site into the sampling chamber.
24. The method of claim 23 wherein the correlating step, also comprises compensating for time lag between blood substance level values and substance flux.
25. The method of claim 24 wherein the correlating step also comprises compensating for substance flux value drift.
26. The method of claim 1 wherein the steps are performed substantially continuously for about 2 hours to about 72 hours.
27. The method of claim 1 further comprising the step of treating a patient in response to the substance level determined.
28. The method of claim 3 wherein the frequency of polarity switching is from about 1 cycle per 20 seconds to about 1 cycle per 2 hours.
29. The method of claim 28 wherein the frequency of polarity switching is from about 1 cycle per minute to about 1 cycle per 2 hours.
30. The method of claim 29 wherein the frequency of polarity switching is from about 1 cycle per 10 minutes to about 1 cycle per hour.
31. The method of claim 30 wherein the frequency of polarity switching is about 1 cycle per half hour.
32. An iontophoresis sampling device comprising (a) an electrical power supply;
(b) a transdermal system that contains a sampling chamber for receiving a sample, the sampling chamber functioning as both an anode and a cathode during iontophoretic sampling;
(c) means for reversing polarity of the power supply during iontophoretic sampling; and (d) means for analyzing concentration of a substance or a substance metabolite received in the sampling chamber.
(b) a transdermal system that contains a sampling chamber for receiving a sample, the sampling chamber functioning as both an anode and a cathode during iontophoretic sampling;
(c) means for reversing polarity of the power supply during iontophoretic sampling; and (d) means for analyzing concentration of a substance or a substance metabolite received in the sampling chamber.
33. The device of claim 32 wherein the means for reversing polarity comprises means for reversing polarity of the power supply at a frequency of from about 1 cycle per 20 seconds to about 1 cycle per 4 hours.
34. The device of claim 32 wherein the sampling chamber comprises an Ag/AgCl electrode.
35. The device of claim 32 wherein the current is applied continuously.
36. The device of claim 32 wherein the current is applied intermittently.
37. The device of claim 32 wherein the frequency of polarity switching is from about 1 cycle per 20 seconds to about 1 cycle per 2 hours.
38. The device of claim 32 wherein the frequency of polarity switching is from about 1 cycle per minute to about 1 cycle per 2 hours.
39. The device of claim 32 wherein the frequency of polarity switching is from about 1 cycle per 10 minutes to about 1 cycle per hour.
40. The device of claim 32 wherein the frequency of polarity switching is about 1 cycle per half hour.
41. A substance monitor comprising:
first and second substance sampling chambers each containing substance collection medium selected from the group consisting of water, saline solutions, buffer solutions, and polyols;
a power supply having a positive connector and a negative connector;
conductors and a switch electrically connecting the first and second sampling chambers to the power supply positive connector and the power supply negative connector, the switch having a first position in which the first sampling chamber is electrically connected to the positive connector and the second sampling chamber is electrically connected to the negative connector and a second position in which the second sampling chamber is electrically connected to the positive connector and the first sampling chamber is electrically connected to the negative connector.
first and second substance sampling chambers each containing substance collection medium selected from the group consisting of water, saline solutions, buffer solutions, and polyols;
a power supply having a positive connector and a negative connector;
conductors and a switch electrically connecting the first and second sampling chambers to the power supply positive connector and the power supply negative connector, the switch having a first position in which the first sampling chamber is electrically connected to the positive connector and the second sampling chamber is electrically connected to the negative connector and a second position in which the second sampling chamber is electrically connected to the positive connector and the first sampling chamber is electrically connected to the negative connector.
42. The monitor of claim 41 wherein the first and second sampling chambers each further comprise an electrode in electrical communication with the collection medium and with the power supply through a conductor and the switch.
43. The monitor of claim 41 further comprising a collection medium substance concentration analyzer and calibration means for correlating collection medium substance concentration with blood substance concentration.
44. The method of claim 1 wherein the sampling chamber comprises a first electrode, the method further comprising the steps of placing the first electrode in electrical communication with the tissue surface and placing a second electrode in electrical communication with the tissue surface, the conducting step comprising conducting current through the first and second electrodes, the step of reversing polarity comprising the step of reversing polarity between the first and second electrodes.
45. The method of claim 1 wherein the sampling chamber is a first sampling chamber and the collection site is a first collection site, the method further comprising the step of placing a second sampling chamber on a second collection site, each chamber comprising an electrode, the analyzing step comprising analyzing the first chamber while conducting current in the first polarity and analyzing the second chamber while conducting current in the second polarity.
46. The method of claim 1 further comprising the step of placing a second chamber on a tissue surface, the sampling chamber and the second chamber each comprising an electrode.
47. The method of claim 46 further comprising the steps of extracting a substance from the subject into the second chamber and analyzing the second chamber for concentration of the substance or a substance metabolite.
48. The device of claim 32 wherein the sampling chamber comprises a first electrode in communication with the power source, the device further comprising a second electrode in communication with the power source, the means for reversing polarity comprising means for reversing polarity between the first and second electrodes.
49. The device of claim 32 wherein the sampling chamber is a first sampling chamber and the collection site is a first collection site, the device further comprising a second sampling chamber that functions as both anode and cathode during the course of iontophoretic sampling, each chamber comprising an electrode, the means for analyzing comprising means for analyzing-the first chamber while conducting current in a first polarity and, analyzing the second chamber while conducting current in a second polarity.
50. The device of claim 32 further comprising a second chamber, the sampling chamber and the second chamber each comprising an electrode.
51. The method of claim 1 further comprising the step of repeating at least steps (b)-(c) at a predetermined frequency.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/265,844 | 1994-06-24 | ||
US08/265,844 US5771890A (en) | 1994-06-24 | 1994-06-24 | Device and method for sampling of substances using alternating polarity |
PCT/US1995/007579 WO1996000109A1 (en) | 1994-06-24 | 1995-06-23 | Device and method for sampling of substances using alternating polarity |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2193884A1 CA2193884A1 (en) | 1996-01-04 |
CA2193884C true CA2193884C (en) | 2002-08-20 |
Family
ID=23012093
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002193884A Expired - Lifetime CA2193884C (en) | 1994-06-24 | 1995-06-23 | Device and method for sampling of substances using alternating polarity |
Country Status (11)
Country | Link |
---|---|
US (4) | US5771890A (en) |
EP (1) | EP0766577B1 (en) |
JP (1) | JP3350053B2 (en) |
AT (1) | ATE255936T1 (en) |
AU (1) | AU2902695A (en) |
CA (1) | CA2193884C (en) |
DE (1) | DE69532282T2 (en) |
DK (1) | DK0766577T3 (en) |
ES (1) | ES2211909T3 (en) |
PT (1) | PT766577E (en) |
WO (1) | WO1996000109A1 (en) |
Families Citing this family (369)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5771890A (en) | 1994-06-24 | 1998-06-30 | Cygnus, Inc. | Device and method for sampling of substances using alternating polarity |
US20040062759A1 (en) * | 1995-07-12 | 2004-04-01 | Cygnus, Inc. | Hydrogel formulations for use in electroosmotic extraction and detection of glucose |
US5735273A (en) | 1995-09-12 | 1998-04-07 | Cygnus, Inc. | Chemical signal-impermeable mask |
US6108570A (en) * | 1995-10-10 | 2000-08-22 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Non-invasive device and method for quantitative determination of oxidants and/or antioxidants in the skin |
WO1997024059A1 (en) | 1995-12-28 | 1997-07-10 | Cygnus, Inc. | Continuous monitoring of physiological analyte |
US8825152B2 (en) | 1996-01-08 | 2014-09-02 | Impulse Dynamics, N.V. | Modulation of intracellular calcium concentration using non-excitatory electrical signals applied to the tissue |
US8321013B2 (en) | 1996-01-08 | 2012-11-27 | Impulse Dynamics, N.V. | Electrical muscle controller and pacing with hemodynamic enhancement |
US7167748B2 (en) | 1996-01-08 | 2007-01-23 | Impulse Dynamics Nv | Electrical muscle controller |
US9289618B1 (en) | 1996-01-08 | 2016-03-22 | Impulse Dynamics Nv | Electrical muscle controller |
JP4175662B2 (en) | 1996-01-08 | 2008-11-05 | インパルス ダイナミクス エヌ.ヴイ. | Electric muscle control device |
US9713723B2 (en) | 1996-01-11 | 2017-07-25 | Impulse Dynamics Nv | Signal delivery through the right ventricular septum |
US5954685A (en) * | 1996-05-24 | 1999-09-21 | Cygnus, Inc. | Electrochemical sensor with dual purpose electrode |
US6001067A (en) | 1997-03-04 | 1999-12-14 | Shults; Mark C. | Device and method for determining analyte levels |
US6862465B2 (en) | 1997-03-04 | 2005-03-01 | Dexcom, Inc. | Device and method for determining analyte levels |
US8527026B2 (en) | 1997-03-04 | 2013-09-03 | Dexcom, Inc. | Device and method for determining analyte levels |
US6139718A (en) | 1997-03-25 | 2000-10-31 | Cygnus, Inc. | Electrode with improved signal to noise ratio |
US5954643A (en) * | 1997-06-09 | 1999-09-21 | Minimid Inc. | Insertion set for a transcutaneous sensor |
US6558351B1 (en) * | 1999-06-03 | 2003-05-06 | Medtronic Minimed, Inc. | Closed loop system for controlling insulin infusion |
US7267665B2 (en) * | 1999-06-03 | 2007-09-11 | Medtronic Minimed, Inc. | Closed loop system for controlling insulin infusion |
US8287483B2 (en) | 1998-01-08 | 2012-10-16 | Echo Therapeutics, Inc. | Method and apparatus for enhancement of transdermal transport |
US7066884B2 (en) * | 1998-01-08 | 2006-06-27 | Sontra Medical, Inc. | System, method, and device for non-invasive body fluid sampling and analysis |
US20060015058A1 (en) * | 1998-01-08 | 2006-01-19 | Kellogg Scott C | Agents and methods for enhancement of transdermal transport |
CA2265119C (en) | 1998-03-13 | 2002-12-03 | Cygnus, Inc. | Biosensor, iontophoretic sampling system, and methods of use thereof |
DE19814084B4 (en) * | 1998-03-30 | 2005-12-22 | Lts Lohmann Therapie-Systeme Ag | D2 agonist-containing transdermal therapeutic system for the treatment of Parkinson's syndrome and process for its preparation |
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 |
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 |
US8346337B2 (en) | 1998-04-30 | 2013-01-01 | 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 |
US8688188B2 (en) | 1998-04-30 | 2014-04-01 | 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 |
US9066695B2 (en) | 1998-04-30 | 2015-06-30 | 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 |
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 |
US8480580B2 (en) | 1998-04-30 | 2013-07-09 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods of use |
US6023639A (en) * | 1998-05-01 | 2000-02-08 | Hakky; Said | Non-invasive bodily fluid withdrawal and monitoring system |
JP2002514452A (en) | 1998-05-13 | 2002-05-21 | シグナス, インコーポレイテッド | Signal processing for measurement of physiological analytes |
PT1077634E (en) | 1998-05-13 | 2003-12-31 | Cygnus Therapeutic Systems | MONITORING OF PHYSIOLOGICAL SUBSTANCES TO BE ANALYZED |
DK1053043T3 (en) | 1998-05-13 | 2002-11-18 | Cygnus Therapeutic Systems | Collection units for transdermal sampling systems |
US6272364B1 (en) | 1998-05-13 | 2001-08-07 | Cygnus, Inc. | Method and device for predicting physiological values |
JPH11347014A (en) * | 1998-06-05 | 1999-12-21 | Hisamitsu Pharmaceut Co Inc | Iontophoresis device structure and method for detecting biological component |
US6532386B2 (en) | 1998-08-31 | 2003-03-11 | Johnson & Johnson Consumer Companies, Inc. | Electrotransort device comprising blades |
CA2342801A1 (en) | 1998-09-04 | 2000-03-16 | Powderject Research Limited | Monitoring methods using particle delivery methods |
US6602678B2 (en) | 1998-09-04 | 2003-08-05 | Powderject Research Limited | Non- or minimally invasive monitoring methods |
US6918874B1 (en) * | 1998-09-10 | 2005-07-19 | Spectrx, Inc. | Attribute compensation for analyte detection and/or continuous monitoring |
CA2344254A1 (en) | 1998-09-17 | 2000-03-23 | Cygnus, Inc. | Press device for a gel/sensor assembly |
US6180416B1 (en) | 1998-09-30 | 2001-01-30 | Cygnus, Inc. | Method and device for predicting physiological values |
JP3537136B2 (en) * | 1998-09-30 | 2004-06-14 | シグナス, インコーポレイテッド | Method and apparatus for predicting physiological values |
US6391643B1 (en) | 1998-10-28 | 2002-05-21 | Cygnus, Inc. | Kit and method for quality control testing of an iontophoretic sampling system |
US20040171980A1 (en) | 1998-12-18 | 2004-09-02 | Sontra Medical, Inc. | Method and apparatus for enhancement of transdermal transport |
US6561978B1 (en) | 1999-02-12 | 2003-05-13 | Cygnus, Inc. | Devices and methods for frequent measurement of an analyte present in a biological system |
US8666495B2 (en) | 1999-03-05 | 2014-03-04 | Metacure Limited | Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar |
US9101765B2 (en) | 1999-03-05 | 2015-08-11 | Metacure Limited | Non-immediate effects of therapy |
US8700161B2 (en) | 1999-03-05 | 2014-04-15 | Metacure Limited | Blood glucose level control |
US8019421B2 (en) | 1999-03-05 | 2011-09-13 | Metacure Limited | Blood glucose level control |
US6959211B2 (en) | 1999-03-10 | 2005-10-25 | Optiscan Biomedical Corp. | Device for capturing thermal spectra from tissue |
EP1171195B1 (en) | 1999-04-16 | 2005-03-16 | Johnson & Johnson Consumer Companies, Inc. | Electrotransport delivery system comprising internal sensors |
EP1064046A1 (en) | 1999-04-22 | 2001-01-03 | Cygnus, Inc. | Methods and devices for removing interfering species |
US6669663B1 (en) * | 1999-04-30 | 2003-12-30 | Medtronic, Inc. | Closed loop medicament pump |
US6312612B1 (en) | 1999-06-09 | 2001-11-06 | The Procter & Gamble Company | Apparatus and method for manufacturing an intracutaneous microneedle array |
US6256533B1 (en) | 1999-06-09 | 2001-07-03 | The Procter & Gamble Company | Apparatus and method for using an intracutaneous microneedle array |
US6379324B1 (en) | 1999-06-09 | 2002-04-30 | The Procter & Gamble Company | Intracutaneous microneedle array apparatus |
US20050037374A1 (en) * | 1999-11-08 | 2005-02-17 | Melker Richard J. | Combined nanotechnology and sensor technologies for simultaneous diagnosis and treatment |
US20020177232A1 (en) * | 2001-05-23 | 2002-11-28 | Melker Richard J. | Method and apparatus for detecting illicit substances |
NZ518740A (en) * | 1999-11-08 | 2004-04-30 | Univ Florida | Marker detection method and apparatus to monitor drug compliance |
DE60022540T2 (en) * | 1999-11-15 | 2006-06-14 | Velcro Ind | FASTENING ELEMENT FOR THE SKIN |
WO2001060448A1 (en) * | 2000-02-18 | 2001-08-23 | University Of Utah Research Foundation | Methods for extracting substances using alternating current |
US6512950B2 (en) | 2000-02-18 | 2003-01-28 | University Of Utah Research Foundation | Methods for delivering agents using alternating current |
US7890295B2 (en) * | 2000-02-23 | 2011-02-15 | Medtronic Minimed, Inc. | Real time self-adjusting calibration algorithm |
US6895263B2 (en) * | 2000-02-23 | 2005-05-17 | Medtronic Minimed, Inc. | Real time self-adjusting calibration algorithm |
WO2001088534A2 (en) * | 2000-05-16 | 2001-11-22 | Cygnus, Inc. | Methods for improving performance and reliability of biosensors |
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 |
EP1309271B1 (en) * | 2000-08-18 | 2008-04-16 | Animas Technologies LLC | Device for prediction of hypoglycemic events |
US6633772B2 (en) | 2000-08-18 | 2003-10-14 | Cygnus, Inc. | Formulation and manipulation of databases of analyte and associated values |
DE10041478A1 (en) * | 2000-08-24 | 2002-03-14 | Sanol Arznei Schwarz Gmbh | New pharmaceutical composition |
US20020026111A1 (en) * | 2000-08-28 | 2002-02-28 | Neil Ackerman | Methods of monitoring glucose levels in a subject and uses thereof |
US7108681B2 (en) * | 2000-10-16 | 2006-09-19 | Corium International, Inc. | Microstructures for delivering a composition cutaneously to 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 |
US6522903B1 (en) * | 2000-10-19 | 2003-02-18 | Medoptix, Inc. | Glucose measurement utilizing non-invasive assessment methods |
US6553255B1 (en) | 2000-10-27 | 2003-04-22 | Aciont Inc. | Use of background electrolytes to minimize flux variability during iontophoresis |
US7104963B2 (en) | 2002-01-22 | 2006-09-12 | University Of Florida Research Foundation, Inc. | Method and apparatus for monitoring intravenous (IV) drug concentration using exhaled breath |
US6981947B2 (en) | 2002-01-22 | 2006-01-03 | University Of Florida Research Foundation, Inc. | Method and apparatus for monitoring respiratory gases during anesthesia |
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 |
US6591133B1 (en) * | 2000-11-27 | 2003-07-08 | Microlin Llc | Apparatus and methods for fluid delivery using electroactive needles and implantable electrochemical delivery devices |
US6560471B1 (en) | 2001-01-02 | 2003-05-06 | Therasense, Inc. | Analyte monitoring device and methods of use |
US7137975B2 (en) * | 2001-02-13 | 2006-11-21 | Aciont, Inc. | Method for increasing the battery life of an alternating current iontophoresis device using a barrier-modifying agent |
US6663820B2 (en) | 2001-03-14 | 2003-12-16 | The Procter & Gamble Company | Method of manufacturing microneedle structures using soft lithography and photolithography |
WO2002078512A2 (en) | 2001-04-02 | 2002-10-10 | Therasense, Inc. | Blood glucose tracking apparatus and methods |
US6748250B1 (en) * | 2001-04-27 | 2004-06-08 | Medoptix, Inc. | Method and system of monitoring a patient |
US20090137888A9 (en) * | 2001-04-27 | 2009-05-28 | Berman Herbert L | System for monitoring of patients |
US20030027793A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal treatment of parkinson's disease |
US20030026830A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal therapeutic system for parkinson's disease inducing high plasma levels of rotigotine |
US6591124B2 (en) | 2001-05-11 | 2003-07-08 | The Procter & Gamble Company | Portable interstitial fluid monitoring system |
US6503209B2 (en) | 2001-05-18 | 2003-01-07 | Said I. Hakky | Non-invasive focused energy blood withdrawal and analysis system |
US7052854B2 (en) * | 2001-05-23 | 2006-05-30 | University Of Florida Research Foundation, Inc. | Application of nanotechnology and sensor technologies for ex-vivo diagnostics |
EP1393069A1 (en) * | 2001-05-24 | 2004-03-03 | The University Of Florida | Method and apparatus for detecting environmental smoke exposure |
US7981056B2 (en) | 2002-04-19 | 2011-07-19 | Pelikan Technologies, Inc. | Methods and apparatus for lancet actuation |
DE60238119D1 (en) | 2001-06-12 | 2010-12-09 | Pelikan Technologies Inc | ELECTRIC ACTUATOR ELEMENT FOR A LANZETTE |
US9795747B2 (en) | 2010-06-02 | 2017-10-24 | Sanofi-Aventis Deutschland Gmbh | Methods and apparatus for lancet actuation |
US8337419B2 (en) | 2002-04-19 | 2012-12-25 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
US7025774B2 (en) * | 2001-06-12 | 2006-04-11 | Pelikan Technologies, Inc. | Tissue penetration device |
US7749174B2 (en) | 2001-06-12 | 2010-07-06 | Pelikan Technologies, Inc. | Method and apparatus for lancet launching device intergrated onto a blood-sampling cartridge |
US7316700B2 (en) | 2001-06-12 | 2008-01-08 | Pelikan Technologies, Inc. | Self optimizing lancing device with adaptation means to temporal variations in cutaneous properties |
US9226699B2 (en) | 2002-04-19 | 2016-01-05 | Sanofi-Aventis Deutschland Gmbh | Body fluid sampling module with a continuous compression tissue interface surface |
US9427532B2 (en) | 2001-06-12 | 2016-08-30 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
US7011630B2 (en) * | 2001-06-22 | 2006-03-14 | Animas Technologies, Llc | Methods for computing rolling analyte measurement values, microprocessors comprising programming to control performance of the methods, and analyte monitoring devices employing the methods |
EP1270041A1 (en) | 2001-06-22 | 2003-01-02 | Universite De Geneve | Device for non-invasively determining the relative levels of two substances present in a biological system |
WO2003003915A2 (en) * | 2001-07-06 | 2003-01-16 | Optiscan Biomedical | Site selection for determining analyte concentration in living tissue |
US20030208113A1 (en) * | 2001-07-18 | 2003-11-06 | Mault James R | Closed loop glycemic index system |
US6631282B2 (en) | 2001-08-09 | 2003-10-07 | Optiscan Biomedical Corporation | Device for isolating regions of living tissue |
US6678542B2 (en) * | 2001-08-16 | 2004-01-13 | Optiscan Biomedical Corp. | Calibrator configured for use with noninvasive analyte-concentration monitor and employing traditional measurements |
US6827702B2 (en) | 2001-09-07 | 2004-12-07 | Medtronic Minimed, Inc. | Safety limits for closed-loop infusion pump control |
US20040087992A1 (en) * | 2002-08-09 | 2004-05-06 | Vladimir Gartstein | Microstructures for delivering a composition cutaneously to skin using rotatable structures |
US20030108976A1 (en) | 2001-10-09 | 2003-06-12 | Braig James R. | Method and apparatus for improving clinical accuracy of analyte measurements |
US6898465B2 (en) * | 2001-10-17 | 2005-05-24 | The Ludlow Company Ip | Differential gel body for a medical stimulation electrode |
FR2831790B1 (en) * | 2001-11-06 | 2004-07-16 | Oreal | MEASUREMENT AND / OR ANALYSIS DEVICE OF AT LEAST ONE PARAMETER OF AN EXTERNAL PORTION OF THE HUMAN BODY |
WO2003045233A1 (en) * | 2001-11-21 | 2003-06-05 | Optiscan Biomedical Corporation | Method and apparatus for improving the accuracy of alternative site analyte concentration measurements |
AU2002346486A1 (en) | 2001-11-21 | 2003-06-10 | James R. Braig | Method for adjusting a blood analyte measurement |
WO2003045234A2 (en) | 2001-11-21 | 2003-06-05 | Optiscan Biomedical Corporation | Method and apparatus for adjusting signal variation of an electronically controlled infrared transmissive window |
US20070167853A1 (en) * | 2002-01-22 | 2007-07-19 | Melker Richard J | System and method for monitoring health using exhaled breath |
US7004928B2 (en) | 2002-02-08 | 2006-02-28 | Rosedale Medical, Inc. | Autonomous, ambulatory analyte monitor or drug delivery device |
US9247901B2 (en) | 2003-08-22 | 2016-02-02 | Dexcom, Inc. | Systems and methods for replacing signal artifacts in a glucose sensor data stream |
US8010174B2 (en) | 2003-08-22 | 2011-08-30 | Dexcom, Inc. | Systems and methods for replacing signal artifacts in a glucose sensor data stream |
US8260393B2 (en) | 2003-07-25 | 2012-09-04 | Dexcom, Inc. | Systems and methods for replacing signal data artifacts in a glucose sensor data stream |
DE60337038D1 (en) | 2002-03-22 | 2011-06-16 | Animas Technologies Llc | Performance improvement of an analyte monitoring device |
US6823202B2 (en) * | 2002-04-01 | 2004-11-23 | Iomed, Inc. | Iontophoretic power supply |
TR200200942A2 (en) * | 2002-04-08 | 2004-02-23 | Tuncer De��M �. | Urea meter / urea clock: detection of urea in human blood by reverse iontophoresis, without taking blood or biological samples. |
US8360992B2 (en) | 2002-04-19 | 2013-01-29 | Sanofi-Aventis Deutschland Gmbh | 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 |
US7175642B2 (en) | 2002-04-19 | 2007-02-13 | Pelikan Technologies, Inc. | Methods and apparatus for lancet actuation |
US8702624B2 (en) | 2006-09-29 | 2014-04-22 | Sanofi-Aventis Deutschland Gmbh | Analyte measurement device with a single shot actuator |
US9795334B2 (en) | 2002-04-19 | 2017-10-24 | Sanofi-Aventis Deutschland Gmbh | 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 |
US9248267B2 (en) | 2002-04-19 | 2016-02-02 | Sanofi-Aventis Deustchland Gmbh | Tissue penetration device |
US7674232B2 (en) | 2002-04-19 | 2010-03-09 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US9314194B2 (en) | 2002-04-19 | 2016-04-19 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
US7909778B2 (en) | 2002-04-19 | 2011-03-22 | 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 |
US8372016B2 (en) | 2002-04-19 | 2013-02-12 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for body fluid sampling and analyte sensing |
US7713214B2 (en) | 2002-04-19 | 2010-05-11 | Pelikan Technologies, Inc. | Method and apparatus for a multi-use body fluid sampling device with optical analyte sensing |
US8579831B2 (en) | 2002-04-19 | 2013-11-12 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for penetrating tissue |
US7901362B2 (en) | 2002-04-19 | 2011-03-08 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US7229458B2 (en) | 2002-04-19 | 2007-06-12 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
US8221334B2 (en) | 2002-04-19 | 2012-07-17 | 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 |
US7547287B2 (en) | 2002-04-19 | 2009-06-16 | Pelikan Technologies, Inc. | Method and apparatus for penetrating tissue |
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 |
US7491178B2 (en) | 2002-04-19 | 2009-02-17 | 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 |
US6801804B2 (en) | 2002-05-03 | 2004-10-05 | Aciont, Inc. | Device and method for monitoring and controlling electrical resistance at a tissue site undergoing iontophoresis |
US20040048779A1 (en) * | 2002-05-06 | 2004-03-11 | Erwin Schollmayer | Use of rotigotine for treating the restless leg syndrome |
DE10234673B4 (en) * | 2002-07-30 | 2007-08-16 | Schwarz Pharma Ag | Hot-melt TTS for the administration of rotigotine and process for its preparation, and use of rotigotine in the manufacture of a hot-melt TTS |
US8211462B2 (en) * | 2002-07-30 | 2012-07-03 | Ucb Pharma Gmbh | Hot-melt TTS for administering rotigotine |
US8246980B2 (en) * | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system |
US8246979B2 (en) | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system for the administration of rotigotine |
US7150975B2 (en) * | 2002-08-19 | 2006-12-19 | Animas Technologies, Llc | Hydrogel composition for measuring glucose flux |
WO2004032963A2 (en) * | 2002-10-04 | 2004-04-22 | Photokinetix Inc. | Photokinetic delivery of biologically active substances using pulsed incoherent light |
US7993108B2 (en) | 2002-10-09 | 2011-08-09 | Abbott Diabetes Care Inc. | Variable volume, shape memory actuated insulin dispensing pump |
US7727181B2 (en) | 2002-10-09 | 2010-06-01 | Abbott Diabetes Care Inc. | Fluid delivery device with autocalibration |
EP2386758A1 (en) | 2002-10-09 | 2011-11-16 | Abbott Diabetes Care Inc. | A method of pumping a predetermined dose of a medical fluid |
US20060160134A1 (en) * | 2002-10-21 | 2006-07-20 | Melker Richard J | Novel application of biosensors for diagnosis and treatment of disease |
US7248912B2 (en) * | 2002-10-31 | 2007-07-24 | The Regents Of The University Of California | Tissue implantable sensors for measurement of blood solutes |
ATE295726T1 (en) * | 2002-12-02 | 2005-06-15 | Sanol Arznei Schwarz Gmbh | ADMINISTRATION OF ROTIGOTINE FOR THE TREATMENT OF PARKINSON'S DISEASE BY IONTOPHORESIS |
US8574895B2 (en) | 2002-12-30 | 2013-11-05 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus using optical techniques to measure analyte levels |
DE10261696A1 (en) | 2002-12-30 | 2004-07-15 | Schwarz Pharma Ag | Device for the transdermal administration of rotigotine base |
US7811231B2 (en) | 2002-12-31 | 2010-10-12 | Abbott Diabetes Care Inc. | Continuous glucose monitoring system and methods of use |
US20040132168A1 (en) | 2003-01-06 | 2004-07-08 | Peter Rule | Sample element for reagentless whole blood glucose meter |
US7578954B2 (en) * | 2003-02-24 | 2009-08-25 | Corium International, Inc. | Method for manufacturing microstructures having multiple microelements with through-holes |
US20060254912A1 (en) * | 2003-03-04 | 2006-11-16 | Amos Nussinovitch | System and method for treating biological tissue usiing curret electrical field |
CN1787850B (en) | 2003-03-10 | 2015-12-16 | 脉冲动力公司 | For transmitting the signal of telecommunication to revise the apparatus and method of gene expression in heart tissue |
US9931503B2 (en) | 2003-03-10 | 2018-04-03 | Impulse Dynamics Nv | Protein activity modification |
US11439815B2 (en) | 2003-03-10 | 2022-09-13 | Impulse Dynamics Nv | Protein activity modification |
US7052652B2 (en) | 2003-03-24 | 2006-05-30 | Rosedale Medical, Inc. | Analyte concentration detection devices and methods |
JP4381705B2 (en) * | 2003-03-26 | 2009-12-09 | シスメックス株式会社 | Transcutaneous analyte extraction system and analysis system, and transcutaneous analyte extraction method and analysis method |
US7415299B2 (en) * | 2003-04-18 | 2008-08-19 | The Regents Of The University Of California | Monitoring method and/or apparatus |
US7679407B2 (en) | 2003-04-28 | 2010-03-16 | Abbott Diabetes Care Inc. | Method and apparatus for providing peak detection circuitry for data communication systems |
JP2004343275A (en) * | 2003-05-14 | 2004-12-02 | Murata Mach Ltd | Image processing system and scanner |
US8262614B2 (en) | 2003-05-30 | 2012-09-11 | Pelikan Technologies, Inc. | Method and apparatus for fluid injection |
US7850621B2 (en) | 2003-06-06 | 2010-12-14 | Pelikan Technologies, Inc. | Method and apparatus for body fluid sampling and analyte sensing |
US7258673B2 (en) * | 2003-06-06 | 2007-08-21 | Lifescan, Inc | Devices, systems and methods for extracting bodily fluid and monitoring an analyte therein |
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 |
US8792985B2 (en) | 2003-07-21 | 2014-07-29 | Metacure Limited | Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar |
US7519408B2 (en) * | 2003-11-19 | 2009-04-14 | Dexcom, Inc. | Integrated receiver for continuous analyte sensor |
US20080119703A1 (en) | 2006-10-04 | 2008-05-22 | Mark Brister | Analyte sensor |
US20190357827A1 (en) | 2003-08-01 | 2019-11-28 | Dexcom, Inc. | Analyte sensor |
US8160669B2 (en) | 2003-08-01 | 2012-04-17 | Dexcom, Inc. | Transcutaneous analyte sensor |
US9135402B2 (en) * | 2007-12-17 | 2015-09-15 | Dexcom, Inc. | Systems and methods for processing sensor data |
US8275437B2 (en) | 2003-08-01 | 2012-09-25 | Dexcom, Inc. | Transcutaneous analyte sensor |
US7591801B2 (en) | 2004-02-26 | 2009-09-22 | Dexcom, Inc. | Integrated delivery device for continuous glucose sensor |
US7774145B2 (en) | 2003-08-01 | 2010-08-10 | Dexcom, Inc. | Transcutaneous analyte sensor |
US20100168542A1 (en) * | 2003-08-01 | 2010-07-01 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US8845536B2 (en) | 2003-08-01 | 2014-09-30 | Dexcom, Inc. | Transcutaneous analyte sensor |
US6931327B2 (en) | 2003-08-01 | 2005-08-16 | Dexcom, Inc. | System and methods for processing analyte sensor data |
US7189341B2 (en) * | 2003-08-15 | 2007-03-13 | Animas Technologies, Llc | Electrochemical sensor ink compositions, electrodes, and uses thereof |
KR20110041579A (en) | 2003-08-15 | 2011-04-21 | 애니머스 테크놀로지스 엘엘씨 | Microprocessors, devices, and methods for use in monitoring of physiological analytes |
US20140121989A1 (en) | 2003-08-22 | 2014-05-01 | Dexcom, Inc. | Systems and methods for processing analyte sensor data |
US7920906B2 (en) | 2005-03-10 | 2011-04-05 | Dexcom, Inc. | System and methods for processing analyte sensor data for sensor calibration |
WO2005033659A2 (en) | 2003-09-29 | 2005-04-14 | Pelikan Technologies, Inc. | 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 |
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 |
US9247900B2 (en) | 2004-07-13 | 2016-02-02 | Dexcom, Inc. | Analyte sensor |
US11633133B2 (en) | 2003-12-05 | 2023-04-25 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
WO2005057168A2 (en) | 2003-12-05 | 2005-06-23 | Dexcom, Inc. | Calibration techniques for a continuous analyte sensor |
US8423114B2 (en) | 2006-10-04 | 2013-04-16 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
WO2005057175A2 (en) | 2003-12-09 | 2005-06-23 | Dexcom, Inc. | Signal processing for continuous analyte sensor |
US8017145B2 (en) * | 2003-12-22 | 2011-09-13 | Conopco, Inc. | Exfoliating personal care wipe article containing an array of projections |
EP1547592A1 (en) * | 2003-12-23 | 2005-06-29 | Schwarz Pharma Ag | Intranasal formulation of rotigotine |
US8668656B2 (en) | 2003-12-31 | 2014-03-11 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for improving fluidic flow and sample capture |
US7822454B1 (en) | 2005-01-03 | 2010-10-26 | Pelikan Technologies, Inc. | Fluid sampling device with improved analyte detecting member configuration |
US20050191757A1 (en) * | 2004-01-20 | 2005-09-01 | Melker Richard J. | Method and apparatus for detecting humans and human remains |
ATE520340T1 (en) * | 2004-02-03 | 2011-09-15 | Sysmex Corp | ANALYZER, CARTRIDGE, CARTRIDGE KIT |
US8165651B2 (en) | 2004-02-09 | 2012-04-24 | Abbott Diabetes Care Inc. | Analyte sensor, and associated system and method employing a catalytic agent |
US7699964B2 (en) * | 2004-02-09 | 2010-04-20 | Abbott Diabetes Care Inc. | Membrane suitable for use in an analyte sensor, analyte sensor, and associated method |
WO2005089103A2 (en) | 2004-02-17 | 2005-09-29 | Therasense, Inc. | Method and system for providing data communication in continuous glucose monitoring and management system |
US8808228B2 (en) | 2004-02-26 | 2014-08-19 | Dexcom, Inc. | Integrated medicament delivery device for use with continuous analyte sensor |
US8548583B2 (en) | 2004-03-10 | 2013-10-01 | Impulse Dynamics Nv | Protein activity modification |
US11779768B2 (en) | 2004-03-10 | 2023-10-10 | Impulse Dynamics Nv | Protein activity modification |
US8352031B2 (en) | 2004-03-10 | 2013-01-08 | Impulse Dynamics Nv | Protein activity modification |
WO2005094526A2 (en) | 2004-03-24 | 2005-10-13 | Corium International, Inc. | Transdermal delivery device |
WO2006011062A2 (en) | 2004-05-20 | 2006-02-02 | Albatros Technologies Gmbh & Co. Kg | Printable hydrogel for biosensors |
US9775553B2 (en) | 2004-06-03 | 2017-10-03 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for a fluid sampling device |
EP1765194A4 (en) | 2004-06-03 | 2010-09-29 | Pelikan Technologies Inc | Method and apparatus for a fluid sampling device |
GB2414675B (en) * | 2004-06-05 | 2006-09-06 | Dewan Fazlul Hoque Chowdhury | Transdermal drug delivery device |
US8565848B2 (en) | 2004-07-13 | 2013-10-22 | Dexcom, Inc. | Transcutaneous analyte sensor |
US8452368B2 (en) | 2004-07-13 | 2013-05-28 | Dexcom, Inc. | Transcutaneous analyte sensor |
US20060020192A1 (en) | 2004-07-13 | 2006-01-26 | Dexcom, Inc. | Transcutaneous analyte sensor |
US8886272B2 (en) | 2004-07-13 | 2014-11-11 | Dexcom, Inc. | Analyte sensor |
US7410614B2 (en) * | 2004-07-26 | 2008-08-12 | Kabushiki Kaisha Toshiba | Optical waveguide type iontophoresis sensor chip and method for packaging sensor chip |
US7943294B2 (en) | 2004-07-30 | 2011-05-17 | Hologic, Inc. | Methods for detecting oncofetal fibronectin |
US20060062734A1 (en) * | 2004-09-20 | 2006-03-23 | Melker Richard J | Methods and systems for preventing diversion of prescription drugs |
EP1819283A4 (en) * | 2004-10-28 | 2011-08-10 | Sontra Medical Corp | System and method for analyte sampling and analysis with hydrogel |
US8224414B2 (en) * | 2004-10-28 | 2012-07-17 | Echo Therapeutics, Inc. | System and method for analyte sampling and analysis with hydrogel |
US8652831B2 (en) | 2004-12-30 | 2014-02-18 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for analyte measurement test time |
US20060166629A1 (en) * | 2005-01-24 | 2006-07-27 | Therasense, Inc. | Method and apparatus for providing EMC Class-B compliant RF transmitter for data monitoring an detection systems |
US10130801B1 (en) | 2005-02-07 | 2018-11-20 | Ipventure, Inc. | Electronic transdermal chemical delivery |
WO2006097934A2 (en) | 2005-03-18 | 2006-09-21 | Metacure Limited | Pancreas lead |
CN101180093B (en) | 2005-03-21 | 2012-07-18 | 雅培糖尿病护理公司 | Method and system for providing integrated medication infusion and analyte monitoring system |
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 |
US20060257883A1 (en) * | 2005-05-10 | 2006-11-16 | Bjoraker David G | Detection and measurement of hematological parameters characterizing cellular blood components |
US7768408B2 (en) | 2005-05-17 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and system for providing data management in data monitoring system |
US7620437B2 (en) * | 2005-06-03 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and apparatus for providing rechargeable power in data monitoring and management systems |
US20060281187A1 (en) | 2005-06-13 | 2006-12-14 | Rosedale Medical, Inc. | Analyte detection devices and methods with hematocrit/volume correction and feedback control |
US20070025869A1 (en) * | 2005-07-15 | 2007-02-01 | Gordon John H | Fluid Delivery Device |
KR100692783B1 (en) * | 2005-07-19 | 2007-03-12 | 케이엠에이치 주식회사 | Patch for extracting glucose |
US7756561B2 (en) | 2005-09-30 | 2010-07-13 | Abbott Diabetes Care Inc. | Method and apparatus for providing rechargeable power in data monitoring and management systems |
US8801631B2 (en) | 2005-09-30 | 2014-08-12 | Intuity Medical, Inc. | Devices and methods for facilitating fluid transport |
US7572360B2 (en) * | 2005-09-30 | 2009-08-11 | Fatigue Solutions Corp. | Electrochemical fatigue sensor systems and methods |
EP3461406A1 (en) | 2005-09-30 | 2019-04-03 | Intuity Medical, Inc. | Multi-site body fluid sampling and analysis cartridge |
US7583190B2 (en) | 2005-10-31 | 2009-09-01 | Abbott Diabetes Care Inc. | Method and apparatus for providing data communication in data monitoring and management systems |
US20090054747A1 (en) * | 2005-10-31 | 2009-02-26 | Abbott Diabetes Care, Inc. | Method and system for providing analyte sensor tester isolation |
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 |
US7432069B2 (en) * | 2005-12-05 | 2008-10-07 | Sontra Medical Corporation | Biocompatible chemically crosslinked hydrogels for glucose sensing |
US20070169533A1 (en) | 2005-12-30 | 2007-07-26 | Medtronic Minimed, Inc. | Methods and systems for detecting the hydration of sensors |
US20070173712A1 (en) | 2005-12-30 | 2007-07-26 | Medtronic Minimed, Inc. | Method of and system for stabilization of sensors |
US8114268B2 (en) * | 2005-12-30 | 2012-02-14 | Medtronic Minimed, Inc. | Method and system for remedying sensor malfunctions detected by electrochemical impedance spectroscopy |
US7985330B2 (en) * | 2005-12-30 | 2011-07-26 | Medtronic Minimed, Inc. | Method and system for detecting age, hydration, and functional states of sensors using electrochemical impedance spectroscopy |
US8114269B2 (en) | 2005-12-30 | 2012-02-14 | Medtronic Minimed, Inc. | System and method for determining the point of hydration and proper time to apply potential to a glucose sensor |
US7736310B2 (en) | 2006-01-30 | 2010-06-15 | Abbott Diabetes Care Inc. | On-body medical device securement |
US8344966B2 (en) | 2006-01-31 | 2013-01-01 | Abbott Diabetes Care Inc. | Method and system for providing a fault tolerant display unit in an electronic device |
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 |
US7620438B2 (en) | 2006-03-31 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and system for powering an electronic device |
US8226891B2 (en) | 2006-03-31 | 2012-07-24 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods therefor |
US20090054749A1 (en) * | 2006-05-31 | 2009-02-26 | Abbott Diabetes Care, Inc. | Method and System for Providing Data Transmission in a Data Management System |
US20080071158A1 (en) | 2006-06-07 | 2008-03-20 | Abbott Diabetes Care, Inc. | Analyte monitoring system and method |
US20070299617A1 (en) * | 2006-06-27 | 2007-12-27 | Willis John P | Biofouling self-compensating biosensor |
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 |
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 |
US7914460B2 (en) * | 2006-08-15 | 2011-03-29 | University Of Florida Research Foundation, Inc. | Condensate glucose analyzer |
US20080119710A1 (en) * | 2006-10-31 | 2008-05-22 | Abbott Diabetes Care, Inc. | Medical devices and methods of using the same |
US8579853B2 (en) | 2006-10-31 | 2013-11-12 | Abbott Diabetes Care Inc. | Infusion devices and methods |
EP2103324B1 (en) * | 2006-11-14 | 2013-07-03 | Kagoshima University | Drug injecting device |
US20080147186A1 (en) * | 2006-12-14 | 2008-06-19 | Joshi Ashok V | Electrochemical Implant For Delivering Beneficial Agents |
US20080161666A1 (en) * | 2006-12-29 | 2008-07-03 | Abbott Diabetes Care, Inc. | Analyte devices and methods |
US7946985B2 (en) * | 2006-12-29 | 2011-05-24 | Medtronic Minimed, Inc. | Method and system for providing sensor redundancy |
CA2676221C (en) | 2007-01-22 | 2016-12-20 | Corium International, Inc. | Applicators for microneedles |
US8930203B2 (en) | 2007-02-18 | 2015-01-06 | Abbott Diabetes Care Inc. | Multi-function analyte test device and methods therefor |
US8732188B2 (en) | 2007-02-18 | 2014-05-20 | Abbott Diabetes Care Inc. | Method and system for providing contextual based medication dosage determination |
US8123686B2 (en) | 2007-03-01 | 2012-02-28 | Abbott Diabetes Care Inc. | Method and apparatus for providing rolling data in communication systems |
RU2444980C2 (en) * | 2007-03-07 | 2012-03-20 | Эко Терапьютикс, Инк. | Transdermal system of analite monitoring and methods of analite detection |
US20080228056A1 (en) * | 2007-03-13 | 2008-09-18 | Michael Blomquist | Basal rate testing using frequent blood glucose input |
EP2146689B1 (en) | 2007-04-16 | 2020-08-12 | Corium, Inc. | Solvent-cast microneedle arrays containing active |
US8911749B2 (en) | 2007-04-16 | 2014-12-16 | Corium International, Inc. | Vaccine delivery via microneedle arrays |
US20080269714A1 (en) | 2007-04-25 | 2008-10-30 | Medtronic Minimed, Inc. | Closed loop/semi-closed loop therapy modification system |
US20080269723A1 (en) * | 2007-04-25 | 2008-10-30 | Medtronic Minimed, Inc. | Closed loop/semi-closed loop therapy modification system |
MX2009011581A (en) | 2007-04-27 | 2010-02-17 | Echo Therapeutics Inc | Skin permeation device for analyte sensing or transdermal drug delivery. |
EP1987815A1 (en) * | 2007-05-04 | 2008-11-05 | Schwarz Pharma Ag | Oronasopharyngeally deliverable pharmaceutical compositions of dopamine agonists for the prevention and/or treatment of restless limb disorders |
US7928850B2 (en) | 2007-05-08 | 2011-04-19 | 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 |
US8461985B2 (en) | 2007-05-08 | 2013-06-11 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US20080281179A1 (en) * | 2007-05-08 | 2008-11-13 | 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 |
US7751907B2 (en) | 2007-05-24 | 2010-07-06 | Smiths Medical Asd, Inc. | Expert system for insulin pump therapy |
US8221345B2 (en) | 2007-05-30 | 2012-07-17 | Smiths Medical Asd, Inc. | Insulin pump based expert system |
US8197844B2 (en) | 2007-06-08 | 2012-06-12 | Activatek, Inc. | Active electrode for transdermal medicament administration |
US20080306444A1 (en) | 2007-06-08 | 2008-12-11 | 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 |
EP2227132B1 (en) | 2007-10-09 | 2023-03-08 | DexCom, Inc. | Integrated insulin delivery system with continuous glucose sensor |
JP5178132B2 (en) * | 2007-10-11 | 2013-04-10 | キヤノン株式会社 | Image processing system and image processing method |
JP2009136526A (en) * | 2007-12-07 | 2009-06-25 | Omron Corp | Analysis chip |
US8290559B2 (en) | 2007-12-17 | 2012-10-16 | Dexcom, Inc. | Systems and methods for processing sensor data |
US20090177147A1 (en) | 2008-01-07 | 2009-07-09 | Michael Blomquist | Insulin pump with insulin therapy coaching |
US8862223B2 (en) | 2008-01-18 | 2014-10-14 | Activatek, Inc. | Active transdermal medicament patch and circuit board for same |
CA2715628A1 (en) | 2008-02-21 | 2009-08-27 | Dexcom, Inc. | Systems and methods for processing, transmitting and displaying sensor data |
US20090259118A1 (en) * | 2008-03-31 | 2009-10-15 | Abbott Diabetes Care Inc. | Shallow Implantable Analyte Sensor with Rapid Physiological Response |
EP2106784B1 (en) * | 2008-04-03 | 2015-04-22 | Rohm and Haas Company | Hair styling composition |
EP2265324B1 (en) | 2008-04-11 | 2015-01-28 | Sanofi-Aventis Deutschland GmbH | Integrated analyte measurement system |
JP5816080B2 (en) | 2008-05-30 | 2015-11-17 | インテュイティ メディカル インコーポレイテッド | Body fluid collection device and collection site interface |
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 |
US9636051B2 (en) | 2008-06-06 | 2017-05-02 | Intuity Medical, Inc. | Detection meter and mode of operation |
ES2907152T3 (en) | 2008-06-06 | 2022-04-22 | Intuity Medical Inc | Blood glucose meter and method of operation |
GB0811874D0 (en) * | 2008-06-30 | 2008-07-30 | Nemaura Pharma Ltd | Patches for reverse iontophoresis |
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 |
US8560082B2 (en) | 2009-01-30 | 2013-10-15 | Abbott Diabetes Care Inc. | Computerized determination of insulin pump therapy parameters using real time and retrospective data processing |
US20100198196A1 (en) * | 2009-01-30 | 2010-08-05 | Abbott Diabetes Care, Inc. | Therapy Delivery Device Programming Tool |
GB2467377A (en) | 2009-02-02 | 2010-08-04 | Nemaura Pharma Ltd | Transdermal patch with extensor means actuated to expel drug towards the skin of a patient |
ES2634667T3 (en) * | 2009-04-24 | 2017-09-28 | Corium International, Inc. | Methods for manufacturing microprojection assemblies |
WO2010127050A1 (en) | 2009-04-28 | 2010-11-04 | Abbott Diabetes Care Inc. | Error detection in critical repeating data in a wireless sensor system |
US8467972B2 (en) | 2009-04-28 | 2013-06-18 | Abbott Diabetes Care Inc. | Closed loop blood glucose control algorithm analysis |
EP2425209A4 (en) | 2009-04-29 | 2013-01-09 | Abbott Diabetes Care Inc | Method and system for providing real time analyte sensor calibration with retrospective backfill |
WO2010138856A1 (en) | 2009-05-29 | 2010-12-02 | Abbott Diabetes Care Inc. | Medical device antenna systems having external antenna configurations |
WO2011011739A2 (en) | 2009-07-23 | 2011-01-27 | Abbott Diabetes Care Inc. | Real time management of data relating to physiological control of glucose levels |
EP3284494A1 (en) | 2009-07-30 | 2018-02-21 | Tandem Diabetes Care, Inc. | Portable infusion pump system |
US9314195B2 (en) | 2009-08-31 | 2016-04-19 | Abbott Diabetes Care Inc. | Analyte signal processing device and methods |
EP2473099A4 (en) | 2009-08-31 | 2015-01-14 | Abbott Diabetes Care Inc | Analyte monitoring system and methods for managing power and noise |
WO2011041469A1 (en) | 2009-09-29 | 2011-04-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing notification function in analyte monitoring systems |
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 |
US8882701B2 (en) | 2009-12-04 | 2014-11-11 | Smiths Medical Asd, Inc. | Advanced step therapy delivery for an ambulatory infusion pump and system |
US20100178307A1 (en) * | 2010-01-13 | 2010-07-15 | Jianye Wen | Transdermal anti-dementia active agent formulations and methods for using the same |
WO2011092710A2 (en) | 2010-02-01 | 2011-08-04 | Metacure Limited | Gastrointestinal electrical therapy |
US8965476B2 (en) | 2010-04-16 | 2015-02-24 | Sanofi-Aventis Deutschland Gmbh | Tissue penetration device |
JP6327852B2 (en) | 2010-05-04 | 2018-05-23 | コリウム インターナショナル, インコーポレイテッド | Methods and devices for transdermal delivery of parathyroid hormone using microprojection arrays |
EP2584964B1 (en) | 2010-06-25 | 2021-08-04 | Intuity Medical, Inc. | Analyte monitoring devices |
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 |
DK3575796T3 (en) | 2011-04-15 | 2021-01-18 | Dexcom Inc | ADVANCED ANALYZE SENSOR CALIBRATION AND ERROR DETECTION |
US9782114B2 (en) | 2011-08-03 | 2017-10-10 | Intuity Medical, Inc. | Devices and methods for body fluid sampling and analysis |
US20130046279A1 (en) * | 2011-08-16 | 2013-02-21 | Paul J. Niklewski | User interface feature for drug delivery system |
US9092559B2 (en) | 2011-08-16 | 2015-07-28 | Ethicon Endo-Surgery, Inc. | Drug delivery system with open architectural framework |
WO2013070794A2 (en) | 2011-11-07 | 2013-05-16 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods |
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 |
US9180242B2 (en) | 2012-05-17 | 2015-11-10 | Tandem Diabetes Care, Inc. | Methods and devices for multiple fluid transfer |
US9238100B2 (en) | 2012-06-07 | 2016-01-19 | Tandem Diabetes Care, Inc. | Device and method for training users of ambulatory medical devices |
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 |
JP6865524B2 (en) | 2012-12-21 | 2021-04-28 | コリウム, インコーポレイテッド | Microarrays and usages for delivering therapeutic agents |
US10245422B2 (en) | 2013-03-12 | 2019-04-02 | Corium International, Inc. | Microprojection applicators and methods of use |
US10357606B2 (en) | 2013-03-13 | 2019-07-23 | Tandem Diabetes Care, Inc. | System and method for integration of insulin pumps and continuous glucose monitoring |
US9173998B2 (en) | 2013-03-14 | 2015-11-03 | Tandem Diabetes Care, Inc. | System and method for detecting occlusions in an infusion pump |
EP2968116A1 (en) | 2013-03-15 | 2016-01-20 | Corium International, Inc. | Microarray with polymer-free microstructures, methods of making, and methods of use |
EP2968751B1 (en) | 2013-03-15 | 2022-11-30 | Corium, Inc. | Multiple impact microprojection applicators |
CA2903583C (en) | 2013-03-15 | 2021-12-28 | Corium International, Inc. | Microarray for delivery of therapeutic agent, methods of use, and methods of making |
US10016561B2 (en) | 2013-03-15 | 2018-07-10 | Tandem Diabetes Care, Inc. | Clinical variable determination |
CN105246458B (en) | 2013-03-15 | 2020-09-15 | 考里安公司 | Microarrays for therapeutic agent delivery and methods of use thereof |
WO2014205412A1 (en) | 2013-06-21 | 2014-12-24 | Intuity Medical, Inc. | Analyte monitoring system with audible feedback |
US11229382B2 (en) | 2013-12-31 | 2022-01-25 | Abbott Diabetes Care Inc. | Self-powered analyte sensor and devices using the same |
US9669160B2 (en) | 2014-07-30 | 2017-06-06 | Tandem Diabetes Care, Inc. | Temporary suspension for closed-loop medicament therapy |
WO2016036866A1 (en) | 2014-09-04 | 2016-03-10 | Corium International, Inc. | Microstructure array, methods of making, and methods of use |
WO2017004067A1 (en) | 2015-06-29 | 2017-01-05 | Corium International, Inc. | Microarray for delivery of therapeutic agent, methods of use, and methods of making |
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 |
JP6778058B2 (en) * | 2016-08-31 | 2020-10-28 | シスメックス株式会社 | Sensor assembly, test substance monitoring system and test substance monitoring method |
FI127811B (en) * | 2016-11-21 | 2019-03-15 | Helsingin Yliopisto | Device for sampling one or more analytes |
US11331022B2 (en) | 2017-10-24 | 2022-05-17 | Dexcom, Inc. | Pre-connected analyte sensors |
AU2018354120A1 (en) | 2017-10-24 | 2020-04-23 | Dexcom, Inc. | Pre-connected analyte sensors |
FI129463B (en) | 2019-03-19 | 2022-02-28 | Glucomodicum Oy | Device for sampling one or more analytes |
Family Cites Families (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3289671A (en) * | 1963-09-11 | 1966-12-06 | Troutman Edwin Glenn | Iontophoresis method |
JPS4934910B1 (en) * | 1969-11-20 | 1974-09-18 | ||
US3794910A (en) * | 1971-07-26 | 1974-02-26 | Sherwood Medical Ind Inc | Iontophoresis and conductivity analysis circuit |
US4325367A (en) * | 1977-06-13 | 1982-04-20 | Robert Tapper | Iontophoretic treatment apparatus |
US4301794A (en) * | 1978-10-18 | 1981-11-24 | Robert Tapper | Method for iontophoretic treatment |
US4340047A (en) * | 1978-10-18 | 1982-07-20 | Robert Tapper | Iontophoretic treatment apparatus |
US4256978A (en) * | 1978-12-26 | 1981-03-17 | Honeywell Inc. | Alternating polarity power supply control apparatus |
US4633879A (en) * | 1979-11-16 | 1987-01-06 | Lec Tec Corporation | Electrode with disposable interface member |
US4406658A (en) * | 1981-03-06 | 1983-09-27 | Medtronic, Inc. | Iontophoretic device with reversible polarity |
US4477971A (en) * | 1981-11-06 | 1984-10-23 | Motion Control, Inc. | Iontophoretic electrode structure |
US4640689A (en) * | 1983-08-18 | 1987-02-03 | Drug Delivery Systems Inc. | Transdermal drug applicator and electrodes therefor |
USH71H (en) * | 1984-08-03 | 1986-06-03 | Medtronic, Inc. | Apparatus and method for indication of iontophoretic drug dispenser operability |
US4702732A (en) * | 1984-12-24 | 1987-10-27 | Trustees Of Boston University | Electrodes, electrode assemblies, methods, and systems for tissue stimulation and transdermal delivery of pharmacologically active ligands |
JPS62139672A (en) * | 1985-12-14 | 1987-06-23 | 林原 健 | Remedy device for positive and negative iontophoresis |
JPS62159661A (en) * | 1985-12-31 | 1987-07-15 | 林原 健 | Low frequency remedy device for introducing both positive and negative ions |
US4752285B1 (en) * | 1986-03-19 | 1995-08-22 | Univ Utah Res Found | Methods and apparatus for iontophoresis application of medicaments |
US4722761A (en) * | 1986-03-28 | 1988-02-02 | Baxter Travenol Laboratories, Inc. | Method of making a medical electrode |
IE60941B1 (en) * | 1986-07-10 | 1994-09-07 | Elan Transdermal Ltd | Transdermal drug delivery device |
US4725263A (en) * | 1986-07-31 | 1988-02-16 | Medtronic, Inc. | Programmable constant current source transdermal drug delivery system |
JPS63145669A (en) * | 1986-10-11 | 1988-06-17 | 林原 健 | Switch for positive and negative iontophorese |
US4822334A (en) * | 1986-12-04 | 1989-04-18 | Robert Tapper | Electrical dosimetry control system |
US4731049A (en) * | 1987-01-30 | 1988-03-15 | Ionics, Incorporated | Cell for electrically controlled transdermal drug delivery |
US5013293A (en) * | 1987-05-28 | 1991-05-07 | Drug Delivery Systems Inc. | Pulsating transdermal drug delivery system |
US4821733A (en) * | 1987-08-18 | 1989-04-18 | Dermal Systems International | Transdermal detection system |
JPS6456060A (en) * | 1987-08-27 | 1989-03-02 | Hayashibara Takeshi | Low frequency medical treatment device |
US5362307A (en) * | 1989-01-24 | 1994-11-08 | The Regents Of The University Of California | Method for the iontophoretic non-invasive-determination of the in vivo concentration level of an inorganic or organic substance |
WO1989006989A1 (en) * | 1988-01-29 | 1989-08-10 | The Regents Of The University Of California | Iontophoretic non-invasive sampling or delivery device |
US5076273A (en) * | 1988-09-08 | 1991-12-31 | Sudor Partners | Method and apparatus for determination of chemical species in body fluid |
US5006108A (en) * | 1988-11-16 | 1991-04-09 | Noven Pharmaceuticals, Inc. | Apparatus for iontophoretic drug delivery |
US5139023A (en) * | 1989-06-02 | 1992-08-18 | Theratech Inc. | Apparatus and method for noninvasive blood glucose monitoring |
US5140985A (en) * | 1989-12-11 | 1992-08-25 | Schroeder Jon M | Noninvasive blood glucose measuring device |
US5036861A (en) * | 1990-01-11 | 1991-08-06 | Sembrowich Walter L | Method and apparatus for non-invasively monitoring plasma glucose levels |
US5158537A (en) * | 1990-10-29 | 1992-10-27 | Alza Corporation | Iontophoretic delivery device and method of hydrating same |
US5224927A (en) * | 1990-11-01 | 1993-07-06 | Robert Tapper | Iontophoretic treatment system |
US5156591A (en) * | 1990-12-13 | 1992-10-20 | S. I. Scientific Innovations Ltd. | Skin electrode construction and transdermal drug delivery device utilizing same |
US5771890A (en) * | 1994-06-24 | 1998-06-30 | Cygnus, Inc. | Device and method for sampling of substances using alternating polarity |
US5989409A (en) | 1995-09-11 | 1999-11-23 | Cygnus, Inc. | Method for glucose sensing |
US5735273A (en) | 1995-09-12 | 1998-04-07 | Cygnus, Inc. | Chemical signal-impermeable mask |
US5954685A (en) | 1996-05-24 | 1999-09-21 | Cygnus, Inc. | Electrochemical sensor with dual purpose electrode |
US6139718A (en) | 1997-03-25 | 2000-10-31 | Cygnus, Inc. | Electrode with improved signal to noise ratio |
JP2002514452A (en) | 1998-05-13 | 2002-05-21 | シグナス, インコーポレイテッド | Signal processing for measurement of physiological analytes |
PT1077634E (en) | 1998-05-13 | 2003-12-31 | Cygnus Therapeutic Systems | MONITORING OF PHYSIOLOGICAL SUBSTANCES TO BE ANALYZED |
USD437603S1 (en) | 1998-09-17 | 2001-02-13 | Cygnus, Inc. | Device for the application of mechanical force to a gel/sensor assembly |
US6180416B1 (en) | 1998-09-30 | 2001-01-30 | Cygnus, Inc. | Method and device for predicting physiological values |
USD438807S1 (en) | 1998-10-28 | 2001-03-13 | Cygnus, Inc. | Cover for quality control testing of an iontophoretic sampling system |
-
1994
- 1994-06-24 US US08/265,844 patent/US5771890A/en not_active Expired - Lifetime
-
1995
- 1995-06-23 AU AU29026/95A patent/AU2902695A/en not_active Abandoned
- 1995-06-23 DE DE69532282T patent/DE69532282T2/en not_active Expired - Lifetime
- 1995-06-23 AT AT95924591T patent/ATE255936T1/en not_active IP Right Cessation
- 1995-06-23 PT PT95924591T patent/PT766577E/en unknown
- 1995-06-23 ES ES95924591T patent/ES2211909T3/en not_active Expired - Lifetime
- 1995-06-23 CA CA002193884A patent/CA2193884C/en not_active Expired - Lifetime
- 1995-06-23 EP EP95924591A patent/EP0766577B1/en not_active Expired - Lifetime
- 1995-06-23 DK DK95924591T patent/DK0766577T3/en active
- 1995-06-23 JP JP50322796A patent/JP3350053B2/en not_active Expired - Lifetime
- 1995-06-23 WO PCT/US1995/007579 patent/WO1996000109A1/en active IP Right Grant
-
1997
- 1997-11-10 US US08/968,700 patent/US6023629A/en not_active Expired - Lifetime
-
1999
- 1999-11-01 US US09/430,914 patent/US6298254B2/en not_active Expired - Lifetime
-
2001
- 2001-06-28 US US09/893,916 patent/US6687522B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JPH10505761A (en) | 1998-06-09 |
US6023629A (en) | 2000-02-08 |
JP3350053B2 (en) | 2002-11-25 |
US20020002328A1 (en) | 2002-01-03 |
AU2902695A (en) | 1996-01-19 |
WO1996000109A1 (en) | 1996-01-04 |
DE69532282D1 (en) | 2004-01-22 |
PT766577E (en) | 2004-03-31 |
US20010020124A1 (en) | 2001-09-06 |
US5771890A (en) | 1998-06-30 |
ATE255936T1 (en) | 2003-12-15 |
CA2193884A1 (en) | 1996-01-04 |
DK0766577T3 (en) | 2004-03-22 |
ES2211909T3 (en) | 2004-07-16 |
EP0766577A1 (en) | 1997-04-09 |
EP0766577B1 (en) | 2003-12-10 |
US6298254B2 (en) | 2001-10-02 |
US6687522B2 (en) | 2004-02-03 |
DE69532282T2 (en) | 2004-12-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2193884C (en) | Device and method for sampling of substances using alternating polarity | |
EP0766578B1 (en) | Iontophoretic sampling device | |
US5279543A (en) | Device for iontophoretic non-invasive sampling or delivery of substances | |
US8046043B2 (en) | Extraction device, analyzer, extraction method, and analysis method | |
JP3155523B2 (en) | Biosensor, ion permeation sampling system and method of using the same | |
US20010044617A1 (en) | Methods for extracting substances using alternating current | |
US20030040682A1 (en) | Sensor controlled analysis and therapeutic delivery system | |
WO2008037316A2 (en) | Device and method for determining a value of a physiological parameter of a body fluid | |
Leboulanger et al. | Reverse iontophoresis as a noninvasive tool for lithium monitoring and pharmacokinetic profiling | |
JP2004294242A (en) | Percutaneous anatyte extracting system, analyte analyzing system, percutaneous analyte extracting method and analyte analyzing method | |
EP1270041A1 (en) | Device for non-invasively determining the relative levels of two substances present in a biological system | |
AU639888C (en) | Iontophoretic non-invasive sampling or delivery device |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKEX | Expiry |
Effective date: 20150623 |