|Publication number||WO1995002357 A1|
|Publication date||26 Jan 1995|
|Filing date||14 Jun 1994|
|Priority date||16 Jul 1993|
|Also published as||CA2167393A1, EP0708615A1, EP0708615A4|
|Publication number||PCT/1994/6684, PCT/US/1994/006684, PCT/US/1994/06684, PCT/US/94/006684, PCT/US/94/06684, PCT/US1994/006684, PCT/US1994/06684, PCT/US1994006684, PCT/US199406684, PCT/US94/006684, PCT/US94/06684, PCT/US94006684, PCT/US9406684, WO 1995/002357 A1, WO 1995002357 A1, WO 1995002357A1, WO 9502357 A1, WO 9502357A1, WO-A1-1995002357, WO-A1-9502357, WO1995/002357A1, WO1995002357 A1, WO1995002357A1, WO9502357 A1, WO9502357A1|
|Inventors||Nooshin T. Azimi|
|Applicant||Cygnus Therapeutic Systems|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (3), Non-Patent Citations (1), Referenced by (70), Classifications (4), Legal Events (9)|
|External Links: Patentscope, Espacenet|
NONINVASIVE GLUCOSE MONITOR
Background of the Invention
This invention relates generally to methods and apparatus for glucose collection and concentration measurement. In particular, the invention is directed to a method and apparatus for monitoring blood glucose levels noninvasively through a patient's skin.
People suffering from diabetes mellitus must monitor blood glucose levels over the course of the day. The most common prior art method of measuring blood glucose levels is by actually drawing a portion of the subject's blood and performing a chemical analysis on the sample. Continually drawing blood creates safety risks for the patient, however. The prior art has described "noninvasive" methods for measuring blood glucose levels. These supposedly noninvasive methods actually involve the application of chemicals, electricity, heat, or negative pressure to draw out body fluids other than blood that may nonetheless contain levels of glucose that correlate with blood glucose levels. For example, U.S. Patent No. 5,161,532 describes a glucose sensor that uses a pump to draw interstitial fluid out through the patient's skin into a sensor. The '532 patent states that any glucose in the interstitial fluid reacts with a chemical within the sensor to produce an electrical signal that is detected by a pair of electrodes.
U.S. Patent No. 5,036,861 describes a glucose monitor that collects the patient's sweat through a skin patch attached to the patient's wrist. Iontophoresis is used to transdermally introduce a gel into the patient's skin. The gel contains a cholinergic agent for stimulating the secretion mechanism of the eccrine sweat gland and agents that minimize or prevent loss of glucose from the sweat as it travels from the sweat gland to the skin patch. As in the '532 patent, the device described in the '861 patent measures the glucose level in the collected sweat using electrodes.
U.S. Patent No. 5,139,023 describes yet another "noninvasive" apparatus and method for monitoring blood glucose. The monitor includes a glucose receiving medium such as water enclosed in a housing that holds the receiving medium against the patient's epithelial membrane. The glucose receiving medium includes a permeation enhancing chemical such as a natural bile salt that enhances glucose permeability from interstitial fluid across the epithelial membrane into the monitor. An attempt to collect glucose according to the '023 method and apparatus but without any permeation enhancing agent failed to show that any glucose was collected.
Finally, published European Patent Application EP 0 304 304 discloses a transdermal glucose detection system in which the detector contains a porous carrier saturated with detector chemicals. The detector adhesively attaches to the patient's skin. A membrane serves as a barrier to prevent migration of the detector chemicals out of the detector while permitting glucose to migrate into the detector. Interaction between glucose and the detector chemicals causes a perceivable color change over a six to twelve hour period. The device only detects the presence of glucose; it does not measure the actual amount of glucose in the detector. Summary of the Invention
This invention provides a truly noninvasive glucose monitoring apparatus and method that does not rely upon heat, electricity or chemicals to collect glucose from interstitial fluid across the patient's skin. Moreover, the method and apparatus of this invention monitor blood glucose in real time, that is to say, in a time period short enough to enable a diabetic to take appropriate action to correct blood glucose levels.
In a preferred embodiment, a collection device comprising a reservoir containing a glucose collection medium such as water is placed against the stratum corneum of the patient's skin for a predetermined period of time. At least a portion of the glucose collection medium is removed from the reservoir at the end of the predetermined time and analyzed for glucose concentration.
Brief Description of the Drawings
Figure 1 is a side cross-sectional view of a glucose collection device according to the preferred embodiment of this invention.
Figure 2 is a bottom elevational view of the preferred glucose collection device.
Figure 3 is a cross-sectional view of a sensor for use with a glucose analysis method for use with this invention.
Figure 4 is a schematic representation of a glucose monitoring system according to this invention.
Detailed Description of the Preferred Embodiment
This invention presents a simple and noninvasive method for monitoring blood glucose levels. It is well-known that glucose can be found in a patient's interstitial fluid and in a patient's sweat. Heretofore, however, it had been thought that glucose could not cross the patient's skin in a detectable amount in real time without the use of a permeability enhancer. See, e.g., U.S. Patent No. 5,139,023 at col. 7, line 3. It had also been thought that even when sweat or interstitial fluid is actively extracted from the patient, active pharmacological agents are needed to preserve the presence of glucose in the extracted sample. See, e.g., U.S. Patent No. 5,036,861, col. 3, lines 1-10.
This invention is a method and apparatus for detecting blood glucose in a truly noninvasive manner without actively extracting interstitial fluid from the patient and without the use of sweat inducers, glucose preservers or permeability enhancers. In a preferred embodiment, glucose is collected through the stratum corneum of the patient's skin by a reservoir containing a glucose collection medium. After the passage of a predetermined time period, the glucose collection medium is analyzed to measure the quantity of glucose present. A preferred collection device for practicing this invention is shown in Figures 1 and 2. The device 10 comprises a reservoir 12 bordered by a cover 14, adhesive layer 16, and the stratum corneum of the patient's skin 18. As shown in part in Figure 2, the device is formed by attaching the plastic cover 14 to a double-sided adhesive 16 in which an oval or other-shaped hole has been formed. In the preferred embodiment, cover 14 is formed from cellophane plastic and adhesive layer 16 is Avery double-sided adhesive, part no. MED 3044.
The preferred glucose collection medium is distilled deionized water. According to the preferred method, the distilled deionized water is injected into reservoir 12 through a hypodermic needle and syringe 20. Despite suggestions to the contrary in the prior art, glucose will migrate from the patient's interstitial fluid through the skin 18 and into the water within reservoir 12. After the water has rested against the patient's skin for a predetermined period of time, the water is withdrawn for analysis. This glucose collection device and method can collect glucose from the patient without the use of chemicals or mechanical extraction.
Alternatively, a hydrogel may be used as a collection medium. Suitable hydrogels are described in U.S. Patent No. 5,139,023.
Water (or other collection medium) from the reservoir may be extracted at periodic intervals (preferably in the range of 5 to 10 minutes) and analyzed to determine its glucose content. A preferred glucose analysis method is described by LaCourse et al. in "Optimization of Waveforms for Pulsed Amperometric Detection of Carbohydrates Based on Pulsed Voltammetry, " 65 Analytical Chemistry 50-55 (1 January 1993) , although other analysis methods may be used. The preferred pulse amperometric voltammetry (PAD) analysis method combines high performance liquid chromatography with electrochemical detection using bi-directional voltage waveforms. Specifically, water extracted from the reservoir is diffused onto a chromatography column. The column is washed with a high pressure solvent such as a NaOH solution. A stepped voltage waveform is applied across two electrodes in the solution, one of which is a gold rotating disk electrode. The voltage waveform has three parts: a detection potential in the range of -200 to +400 mV for greater than 40 ms detection period, an oxidation potential in the range of 300 to 800 mV for greater than approximately 60 ms, and a reduction potential in the range of -800 to +100 mV for greater than approximately 60 ms. A plot of electrode current at the gold electrode versus applied voltage yields a curve with signature peaks at specific voltage values for certain solutes such as glucose. The peak amplitude or peak area are measures of the concentration of that solute. An alternative glucose concentration analysis method is shown schematically in Figures 3 and 4. The glucose measurement technique of this embodiment is similar to the enzymatic technique described in U.S. Patent No. 5,165,407 and does not require the glucose collection medium to be extracted from the collection device.
A glucose sensor 30 is shown in detail in Figure 3. A sensor body 32 is received within a stainless steel hollow tubular needle 34. The sensor body includes a Teflon-coated platinum-iridium wire 36
(90% Pt/10% Ir) having a total O.D. of about 0.2 mm and a cavity 38 formed therein. Cavity 38 is approximately 1.0 mm in length and is located about 3.0 mm from the distal tip of the wire 36. A glucose oxidase layer 40 is immobilized within the cavity 38, and comprises a cellulose acetate polymer layer attached to the surface of the Pt-Ir wire, with glucose oxidase crosslinked through glutaraldehyde onto the cellulose acetate to form an indicating electrode. The procedure is described in more detail in U.S. Patent No. 5,165,407. The entirety of the indicating electrode is covered by a membrane 42 of polyurethane, also as described in U.S. Patent No. 5,165,407, to control the diffusion rate of glucose onto the indicating electrode. Needle 34 has an aperture 44 adjacent its sharpened distal end 46 to expose layer 40. A silicone rubber plug 48 closes one end of the needle and a bead of epoxy 50 closes the other end, as shown. A plastic sheet 52 surrounding the proximal end of the needle serves as a holder. Figure 4 is a schematic representation of a glucose collection and measurement system using this alternative glucose analysis method. The sensor 30 described above with reference to Figure 3 is inserted into a glucose collection device attached to the patient's skin 18 as described with reference to Figures 1 and 2 above so that the sensor's aperture 44 is exposed to the glucose collection medium 12. A conductor 60 leads from the indicating electrode of sensor 30 to a glucose measurement instrument 62. A second conductor 64 leads from a reference electrode 66 attached to the patient's skin 18. Instrument 62 applies a voltage across conductors 60 and 64; the current measured across the electrodes is related to the concentration of glucose in the collection medium in a manner known in the art.
The invention may be further explained through the following examples. The examples are not intended as a limitation to any claimed embodiment.
Glucose was collected from an adult human using an apparatus substantially similar to the apparatus shown in Figures 1 and 2. The device was attached to the stratum corneum of the skin on the patient's forearm, and the device's reservoir was initially filled with a sample consisting of 0.5 ml. of distilled deionized water via a hypodermic needle and syringe. The sample was withdrawn from the reservoir after five minutes and was replaced with a fresh sample of distilled deionized water at five minute intervals for a total of 30 minutes. The final sample remained in the reservoir for 30 minutes before being withdrawn and analyzed.
The withdrawn samples were analyzed using pulsed amperometric voltammetry. The results are shown in Table I, with the glucose concentrations expressed in micromoles.
Sample 1 2 3 4 5
0-5 min 3.13μM 2.86 M 6.lOμM 9.24μM 1.66/iM
5-10 min 1.74 " 1.42 " 3.80 " 4.07 " 1.05 "
10-15 min 1.08 " 0.85 " 2.53 " 2.90 " 0.83 "
15-20 min 1.44 " 0.88 " 1.67 " 2.24 " 0.56 "
20-25 min 1.13 " 0.46 " 1.48 " 2.57 " 0.70 "
25-30 min 0.77 " 0.56 " 1.15 " 3.07 " 1.09 "
30-60 min 1.91 " 1.46 " 3.35 " 13.5 " 1.20 "
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US5056521 *||29 Jun 1989||15 Oct 1991||Health Craft International, Inc.||Method for monitoring glucose level|
|US5076273 *||13 Nov 1990||31 Dec 1991||Sudor Partners||Method and apparatus for determination of chemical species in body fluid|
|US5139023 *||2 Jun 1989||18 Aug 1992||Theratech Inc.||Apparatus and method for noninvasive blood glucose monitoring|
|1||*||See also references of EP0708615A4|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|WO1998004190A3 *||30 Jul 1997||25 Jun 1998||Dtr Dermal Therapy Inc||Method and apparatus for non-invasive determination of glucose in body fluids|
|WO2010052849A1||27 Oct 2009||14 May 2010||パナソニック株式会社||Measurement device, insulin infusion device, measurement method, method for controlling insulin infusion device, and program|
|EP2255724A1||20 May 2010||1 Dec 2010||Sysmex Corporation||Method for analyzing analyte in tissue fluid, analyzer for analyzing analyte in tissue fluid, cartridge for analyzing analyte in tissue fluid, and kit for analyzing analyte in tissue fluid|
|EP2329771A3 *||13 Jul 2005||22 Jun 2011||DexCom, Inc.||Transcutaneous analyte sensor|
|EP2998731A1 *||6 Nov 2014||23 Mar 2016||i-Sens, Inc.||Apparatus and method for measuring concentration of an analyte in whole blood samples|
|EP3043174A1||27 Oct 2009||13 Jul 2016||Panasonic Healthcare Holdings Co., Ltd.||Measurement device|
|US5890489 *||30 Jul 1996||6 Apr 1999||Dermal Therapy (Barbados) Inc.||Method for non-invasive determination of glucose in body fluids|
|US5954685 *||24 May 1996||21 Sep 1999||Cygnus, Inc.||Electrochemical sensor with dual purpose electrode|
|US6144869 *||11 May 1999||7 Nov 2000||Cygnus, Inc.||Monitoring of physiological analytes|
|US6180416||30 Sep 1998||30 Jan 2001||Cygnus, Inc.||Method and device for predicting physiological values|
|US6233471||11 May 1999||15 May 2001||Cygnus, Inc.||Signal processing for measurement of physiological analysis|
|US6251083||7 Sep 1999||26 Jun 2001||Amira Medical||Interstitial fluid methods and devices for determination of an analyte in the body|
|US6272364||11 May 1999||7 Aug 2001||Cygnus, Inc.||Method and device for predicting physiological values|
|US6284126||28 Aug 2000||4 Sep 2001||Cygnus, Inc.||Electrode with improved signal to noise ratio|
|US6326160||27 Sep 1999||4 Dec 2001||Cygnus, Inc.||Microprocessors for use in a device for predicting physiological values|
|US6341232||16 Mar 2001||22 Jan 2002||Cygnus, Inc.||Methods of producing collection assemblies, laminates, and autosensor assemblies for use in transdermal sampling systems|
|US6356776||16 Aug 2000||12 Mar 2002||Cygnus, Inc.||Device for monitoring of physiological analytes|
|US6391643||27 Oct 1999||21 May 2002||Cygnus, Inc.||Kit and method for quality control testing of an iontophoretic sampling system|
|US6393318||11 May 1999||21 May 2002||Cygnus, Inc.||Collection assemblies, laminates, and autosensor assemblies for use in transdermal sampling systems|
|US6438414||30 Nov 2001||20 Aug 2002||Cygnus, Inc.||Collection assemblies, laminates, and autosensor assemblies for use in transdermal sampling systems|
|US6546269||5 Jan 2001||8 Apr 2003||Cygnus, Inc.||Method and device for predicting physiological values|
|US6561978||11 Feb 2000||13 May 2003||Cygnus, Inc.||Devices and methods for frequent measurement of an analyte present in a biological system|
|US6587705||10 Mar 1999||1 Jul 2003||Lynn Kim||Biosensor, iontophoretic sampling system, and methods of use thereof|
|US6594514||20 Dec 2001||15 Jul 2003||Cygnus, Inc.||Device for monitoring of physiological analytes|
|US6595919||27 Feb 2001||22 Jul 2003||Cygnus, Inc.||Device for signal processing for measurement of physiological analytes|
|US6615078||21 Apr 2000||2 Sep 2003||Cygnus, Inc.||Methods and devices for removing interfering species|
|US6653091||23 Jul 2001||25 Nov 2003||Cyngnus, Inc.||Method and device for predicting physiological values|
|US6736777||29 Jan 2003||18 May 2004||Cygnus, Inc.||Biosensor, iontophoretic sampling system, and methods of use thereof|
|US6816742||13 Feb 2004||9 Nov 2004||Cygnus, Inc.||Biosensor and methods of use thereof|
|US6850790||14 May 2003||1 Feb 2005||Cygnus, Inc.||Monitoring of physiological analytes|
|US6902905||14 May 2003||7 Jun 2005||Cygnus, Inc.||Glucose measuring assembly with a hydrogel|
|US6999810||8 Sep 2004||14 Feb 2006||Animas Technologies Llc||Biosensor and methods of use thereof|
|US7150975||18 Aug 2003||19 Dec 2006||Animas Technologies, Llc||Hydrogel composition for measuring glucose flux|
|US7163511||29 Jan 2003||16 Jan 2007||Animas Technologies, Llc||Devices and methods for frequent measurement of an analyte present in a biological system|
|US7174199||5 Nov 2004||6 Feb 2007||Animas Technologies, Llc||Monitoring a physiological analytes|
|US7183068||17 Feb 2005||27 Feb 2007||Animas Technologies, Llc||Methods of manufacturing glucose measuring assemblies with hydrogels|
|US7295867||12 Feb 2003||13 Nov 2007||Animas Corporation||Signal processing for measurement of physiological analytes|
|US7405055||24 Jul 2003||29 Jul 2008||Animas Technologies Llc||Method and device for predicting physiological values|
|US7497940||1 Sep 2004||3 Mar 2009||Koji Sode||Glucose sensor and glucose level measuring apparatus|
|US7699775||13 Oct 2004||20 Apr 2010||Animas Technologies, Llc||Methods for estimating analyte-related signals, microprocessors comprising programming to control performance of the methods, and analyte monitoring devices employing the methods|
|US7873399||30 Jan 2007||18 Jan 2011||Animas Corporation||Monitoring of physiological analytes|
|US7935499||30 Jun 2008||3 May 2011||Animas Corporation||Method and device for predicting physiological values|
|US8277636||17 Feb 2009||2 Oct 2012||Koji Sode||Glucose sensor and glucose level measuring apparatus|
|US8597570||27 Oct 2009||3 Dec 2013||Panasonic Corporation||Measurement device, insulin infusion device, measurement method, method for controlling insulin infusion device, and program|
|US8690775||11 Apr 2008||8 Apr 2014||Dexcom, Inc.||Transcutaneous analyte sensor|
|US8747316||28 Jan 2011||10 Jun 2014||Sysmex Corporation||In vivo component measurement method, data processing method for in vivo component measurement, in vivo component measurement apparatus and collection member|
|US8858434||10 Mar 2005||14 Oct 2014||Dexcom, Inc.||Transcutaneous analyte sensor|
|US8870810||13 Sep 2012||28 Oct 2014||Echo Therapeutics, Inc.||Method and apparatus for enhancement of transdermal transport|
|US8886272||22 Feb 2006||11 Nov 2014||Dexcom, Inc.||Analyte sensor|
|US8989833||10 Mar 2005||24 Mar 2015||Dexcom, Inc.||Transcutaneous analyte sensor|
|US9044199||10 Mar 2005||2 Jun 2015||Dexcom, Inc.||Transcutaneous analyte sensor|
|US9060742||19 Mar 2010||23 Jun 2015||Dexcom, Inc.||Transcutaneous analyte sensor|
|US9078626||31 Mar 2011||14 Jul 2015||Dexcom, Inc.||Transcutaneous analyte sensor|
|US9247900||4 Jun 2013||2 Feb 2016||Dexcom, Inc.||Analyte sensor|
|US9247901||2 Aug 2006||2 Feb 2016||Dexcom, Inc.||Systems and methods for replacing signal artifacts in a glucose sensor data stream|
|US9414777||10 Mar 2005||16 Aug 2016||Dexcom, Inc.||Transcutaneous analyte sensor|
|US9420968||4 Apr 2012||23 Aug 2016||Dexcom, Inc.||Systems and methods for replacing signal artifacts in a glucose sensor data stream|
|US9504413||15 Apr 2013||29 Nov 2016||Dexcom, Inc.||Dual electrode system for a continuous analyte sensor|
|US9510782||4 Apr 2012||6 Dec 2016||Dexcom, Inc.||Systems and methods for replacing signal artifacts in a glucose sensor data stream|
|US9572527||22 Jan 2013||21 Feb 2017||Echo Therapeutics, Inc.||Skin permeation device for analyte sensing or transdermal drug delivery|
|US9579053||26 Mar 2010||28 Feb 2017||Dexcom, Inc.||Dual electrode system for a continuous analyte sensor|
|US9585607||4 Apr 2012||7 Mar 2017||Dexcom, Inc.||Systems and methods for replacing signal artifacts in a glucose sensor data stream|
|US9603557||13 May 2013||28 Mar 2017||Dexcom, Inc.||Transcutaneous analyte sensor|
|US9610031||13 Apr 2011||4 Apr 2017||Dexcom, Inc.||Transcutaneous analyte sensor|
|US9622690||17 Oct 2013||18 Apr 2017||Panasonic Healthcare Holdings Co., Ltd.||Measurement device|
|US9668677||26 Oct 2015||6 Jun 2017||Dexcom, Inc.||Analyte sensor|
|US9801572||18 Jun 2015||31 Oct 2017||Dexcom, Inc.||Transcutaneous analyte sensor|
|US9814414||30 Mar 2010||14 Nov 2017||Dexcom, Inc.||Transcutaneous analyte sensor|
|US9833176||12 Jul 2012||5 Dec 2017||Dexcom, Inc.||Transcutaneous analyte sensor|
|USRE38681 *||2 Dec 2002||4 Jan 2005||Cygnus, Inc.||Electrode with improved signal to noise ratio|
|International Classification||G01N33/66, A61B5/00|
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