Interstitial fluid methods and devices for determination of an analyte in the body

• US 6,251,083 B1
• Filed: 09/07/1999
• Issued: 06/26/2001
• Est. Priority Date: 09/07/1999
• Status: Expired due to Term

• Current Assignee: Roche Diabetes Care Inc. (Roche Holding AG)
• Original Assignee: Amira Medical (Roche Holding AG)
• Inventors: Yum, Su I., Roe, Jeffrey N., Douglas, Joel S.
• Primary Examiner(s): Lacyk, John P.
• Assistant Examiner(s): MARMOR II, CHARLES ALAN
• Application Number:
  US09/391,002
• Time in Patent Office: 658 Days
• Field of Search: 600/309, 600/362, 600/365, 600/366, 600/367, 600/573, 600/584, 435/4
• US Class Current: 600/584
• CPC Class Codes: A61B 5/14514 using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement

Abstract

Devices and methods for utilizing dry chemistry dye indicator systems for body fluid analysis, such as glucose level provided by incorporating a porous membrane in a disposable patch. The devices also provide for microtitration of fluid samples in fixed volumetric openings containing indicator reagent. The devices provided are low cost due to efficient manufacturing methods provided.

Claims

1. A device for determining the presence or concentration of an analyte in the interstitial body fluid of a patient, the device comprising:

(a) a plurality of test areas, each test area independently comprising (i) a porous matrix material having an absorption side and a test side and (ii) an indicating reagent system positioned on or impregnated in the test side of the porous matrix material, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid;

(b) a substantially non-porous material separating each test area from adjacent test areas;

(c) an attachment means for attaching the device to the skin of a patient; and

(d) an extraction means for extracting interstitial body fluid through the skin of the patient;

wherein each test area is oriented so that the absorption side of the test area is positioned to contact the interstitial body fluid extracted through the skin of the patient.

2. The device according to claim 1 wherein the porous matrix material is selected from the group consisting of polyethersulfone, polysulfone, polyamide and cellulose.

3. The device according to claim 2 wherein the porous matrix material is polyethersulfone.

4. The device according to claim 3 wherein the porous matrix material has a microporous skin structure on one side and is isotropic through the remaining thickness of the material.

5. The device according to claim 2 wherein the porous matrix material is cellulose fiber.

6. The device according to claim 1 wherein the substantially non-porous material is selected from the group consisting of hot melt adhesives, silicone, fluorocarbon coatings, compressed polyethersulfone membrane, compressed cellulose fiber and combinations thereof.

7. The device according to claim 1 wherein the indicating reagent system comprises (i) an indicator or mixture of indicators capable of undergoing a color change in the presence of an oxidizing agent, and (ii) an oxidase enzyme or a peroxidase enzyme or a mixture thereof.

8. The device according to claim 7 wherein the oxidase enzyme is selected from the group consisting of glucose oxidase, cholesterol oxidase, uricase, alcohol oxidase, aldehyde oxidase and glycerophosphate oxidase.

9. The device according to claim 8 wherein the oxidase enzyme is glucose oxidase.

10. The device according to claim 7 wherein the indicator or mixture of indicators is selected from the group consisting of 2,2′

-azino-di(3-ethylbenzthiazoline)sulfonic acid;

pyrogallol red;

bromopyrogallol red;

acid green 25;

4-aminoantipyrene and 5-oxo-1-(p-sulfophenyl)-2-pyrazoline-3-carboxylic acid;

4-aminoantipyrene and N-(m-tolyl)diethanolamine;

4-aminoantipyrene and 4-methoxynaphthol;

3-methyl-2-benzothiazolinone hydrazone hydrochloride and 3,3-dimethylaminobenzoic acid;

3-methyl-2-benzothiazolinone hydrazone hydrochloride and 3,5-dichloro-2-hydroxybenzenesulfonic acid;

3-methyl-2-benzothiazolinone hydrazone hydrochloride and 8-anilino-1-naphthalenesulfonate;

3-methyl-2-benzothiazolinone hydrazone hydrochloride and N-(3-sulfopropyl)aniline;

3-methyl-6-(M sulfonate)-benzothiazolinone-2-hydrazone and 3,3-dimethylaminobenzoic acid;

3-methyl-6-(M sulfonate)-benzothiazolinone-2-hydrazone and 8-anilino-1-naphthalenesulfonate;

3-methyl-6-(M sulfonate)-benzothiazolinone-2-hydrazone and N-(3-sulfopropyl)aniline; and

3-methyl-6-(M sulfonate)-benzothiazolinone-2-hydrazone and N-ethyl-N-(3-sulfopropyl)aniline, where M is sodium, potassium or ammonium.

11. The device according to claim 10 wherein the indicator or mixture of indicators is 3-methyl-6-(M sulfonate)-benzothiazolinone-2-hydrazone, where M is sodium, potassium or ammonium, and N-ethyl-N-(3-sulfopropyl)aniline or N-(3-sulfopropyl)aniline or a mixture thereof.

12. The device according to claim 1 wherein the attachment means comprises an adhesive.

13. The device according to claim 1 wherein the extraction means comprises a skin permeation enhancer or a mixture of skin permeation enhancers;

ultrasound;

iontophoresis;

tape stripping;

microtines;

electroporation or a combination thereof.

14. The device according to claim 13 wherein the extraction means comprises a skin permeation enhancer or a mixture of skin permeation enhancers;

ultrasound;

or a combination thereof.

15. The device according to claim 14 wherein the skin permeation enhancer is a glucose permeation enhancer.

16. The device according to claim 14 wherein the skin permeation enhancer is selected from the group consisting of polyethylene glycol-3-lauramide, glycerol monooleate, glycerol monolinoleate, glycerol monolaurate, diethylene glycol monoethyl ether, dodecyl acetate, propylene glycol, methyl laurate, ethyl acetate, isopropyl myristrate, ethyl palmitate, isopropyl palmitate, glycerol monocaprylate, isopropyl oleate, ethyl oleate, lauryl pidolate, lauryl lactate, propylene glycol monolaurate, n-decyl methyl sulucide and mixtures thereof.

17. The device according to claim 1 wherein the each test area optionally further comprises an antioxidant or mixture of antioxidants.

18. The device according to claim 1 further comprising an absorbent layer comprising (i) a porous matrix material and (ii) an antioxidant or mixture of antioxidants, the absorbent layer being in contact with the absorption side of one or more of the test areas.

19. The device according to claim 17 or 18 wherein the antioxidant is selected from the group consisting of 2,3,4-trihydroxybenzoic acid, gallic acid, propyl gallate, ascorbic acid, isoascorbic acid, 3,4-dihydroxycinnamic acid, 3,4-dihydroxybenzaldehyde and 5,6-diaminouracil.

20. The device according to claim 19 wherein the antioxidant is ascorbic acid.

21. The method according to claim 20 wherein the spectrophotometric change or absence thereof is detected or measured by an instrument.

22. The method according to claim 20 wherein the spectrophotometric change or absence thereof is detected or measured visually.

23. The device according to claim 1, further comprising a reaction complete timer.

24. The device according to claim 1, wherein the plurality of test areas define a plurality of microtitration zones having a constant SV/TRV ratio, wherein SV=the sample volume and TRV=the test reagent volume remaining in the matrix.

25. The device according to claim 1, wherein the plurality of test areas and the non-porous material separating each test area are formed by embossments formed on the porous matrix material.

26. A method for testing the interstitial body fluid of a patient for the presence or concentration of an analyte comprising:

providing a device comprising (a) a plurality of test areas, each test area independently comprising (i) a porous matrix material having an absorption side and a test side and (ii) an indicating reagent system positioned on or impregnated in the test side of the porous matrix material, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid;

(b) a substantially non-porous material separating each test area from adjacent test areas;

(c) an attachment means for attaching the device to the skin of a patient; and

(d) an extraction means for extracting interstitial body fluid through the skin of the patient;

wherein each test area is oriented so that the absorption side of the test area is positioned to contact the interstitial body fluid extracted through the skin of the patient;

attaching the device to the skin of a patient;

extracting interstitial body fluid through the skin of the patient and onto the absorption side of the test areas;

detecting or measuring a spectrophotometric change or the absence thereof on the test side of the test areas.

27. The method according to claim 26 wherein the porous matrix material is selected from the group consisting of polyethersulfone, polysulfone, polyamide and cellulose.

28. The method according to claim 27 wherein the porous matrix material is polyethersulfone.

29. The method according to claim 28 wherein the porous matrix material has a microporous skin structure on one side and is isotropic through the remaining thickness of the material.

30. The method according to claim 27 wherein the porous matrix material is cellulose fiber.

31. The method according to claim 26 wherein the substantially non-porous material is selected from the group consisting of hot melt adhesives, silicone, fluorocarbon coatings, compressed polyethersulfone membrane, compressed cellulose fiber and combinations thereof.

32. The method according to claim 26 wherein the indicating reagent system comprises (i) an indicator or mixture of indicators capable of undergoing a color change in the presence of an oxidizing agent, and (ii) an oxidase enzyme or a peroxidase enzyme or a mixture thereof.

33. The method according to claim 32 wherein the oxidase enzyme is selected from the group consisting of glucose oxidase, cholesterol oxidase, uricase, alcohol oxidase, aldehyde oxidase and glycerophosphate oxidase.

34. The method according to claim 33 wherein the oxidase enzyme is glucose oxidase.

35. The method according to claim 32 wherein the indicator or mixture of indicators is selected from the group consisting of 2,2′

-azino-di(3-ethylbenzthiazoline)sulfonic acid;

pyrogallol red;

bromopyrogallol red;

acid green 25;

4-aminoantipyrene and 5-oxo-1-(p-sulfophenyl)-2-pyrazoline-3-carboxylic acid;

4-aminoantipyrene and N-(m-tolyl)diethanolamine;

4-aminoantipyrene and 4-methoxynaphthol;

3-methyl-2-benzothiazolinone hydrazone hydrochloride and 3,3-dimethylaminobenzoic acid;

3-methyl-2-benzothiazolinone hydrazone hydrochloride and 3,5-dichloro-2-hydroxybenzenesulfonic acid;

3-methyl-2-benzothiazolinone hydrazone hydrochloride and 8-anilino-1-naphthalenesulfonate;

3-methyl-2-benzothiazolinone hydrazone hydrochloride and N-(3-sulfopropyl)aniline;

3-methyl-6-(M sulfonate)-benzothiazolinone-2-hydrazone and 3,3-dimethylaminobenzoic acid;

3-methyl-6-(M sulfonate)-benzothiazolinone-2-hydrazone and 8-anilino-1-naphthalenesulfonate;

3-methyl-6-(M sulfonate)-benzothiazolinone-2-hydrazone and N-(3-sulfopropyl)aniline; and

3-methyl-6-(M sulfonate)-benzothiazolinone-2-hydrazone and N-ethyl-N-(3-sulfopropyl)aniline, where M is sodium, potassium or ammonium.

36. The method according to claim 35 wherein the indicator or mixture of indicators is 3-methyl-6-(M sulfonate)-benzothiazolinone-2-hydrazone, where M is sodium, potassium or ammonium, and N-ethyl-N-(3-sulfopropyl)aniline or N-(3-sulfopropyl)aniline or a mixture thereof.

37. The method according to claim 36 wherein the attachment means comprises an adhesive.

38. The method according to claim 36 wherein the extraction means comprises a skin permeation enhancer or a mixture of skin permeation enhancers;

ultrasound;

iontophoresis;

tape stripping;

microtines;

electroporation or a combination thereof.

39. The method according to claim 38 wherein the extraction means comprises a skin permeation enhancer or a mixture of skin permeation enhancers;

ultrasound;

or a combination thereof.

40. The method according to claim 39 wherein the skin permeation enhancer is a glucose permeation enhancer.

41. The method according to claim 39 wherein the skin permeation enhancer is selected from the group consisting of polyethylene glycol-3-lauramide, glycerol monooleate, glycerol monolinoleate, glycerol monolaurate, diethylene glycol monoethyl ether, dodecyl acetate, propylene glycol, methyl laurate, ethyl acetate, isopropyl myristrate, ethyl palmitate, isopropyl palmitate, glycerol monocaprylate, isopropyl oleate, ethyl oleate, lauryl pidolate, lauryl lactate, propylene glycol monolaurate, n-decyl methyl sulucide and mixtures thereof.

42. The method according to claim 36 wherein each test area further comprises an antioxidant or mixture of antioxidants.

43. The method according to claim 36 further comprising an absorbent layer comprising (i) a porous matrix material and (ii) an antioxidant or mixture of antioxidants, the absorbent layer being in contact with the absorption side of one or more of the test areas.

44. The method according to claim 42 or 43 wherein the antioxidant is selected from the group consisting of 2,3,4-trihydroxybenzoic acid, gallic acid, propyl gallate, ascorbic acid, isoascorbic acid, 3,4-dihydroxycinnamic acid, 3,4-dihydroxybenzaldehyde and 5,6-diaminouracil.

45. The device according to claim 44 wherein the antioxidant is ascorbic acid.

46. The method according to claim 26, further comprising providing the device with a reaction complete timer.

47. The method according to claim 26, further comprising defining a plurality of microtitration zones defined by the plurality of test areas, the plurality of microtitration zones having a constant SV/TRV ratio, where SV=the sample volume, any TRV=the test reagent volume remaining in the matrix.

48. The method according to claim 26, further comprising providing the plurality of test areas and non-porous material separating the test areas by embossing the porous matrix material.

49. A process for preparing a device for determining the presence or concentration of an analyte in the interstitial body fluid of a patient, the device comprising:

(a) a plurality of test areas, each test area independently comprising (i) a porous matrix material having an absorption side and a test side and (ii) an indicating reagent system positioned on or impregnated in the test side of the porous matrix material, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid;

(b) a substantially non-porous material separating each test area from adjacent test areas;

(c) an attachment means for attaching the device to the skin of a patient; and

(d) an extraction means for extracting interstitial body fluid through the skin of the patient;

wherein each test area is oriented so that the absorption side of the test area is positioned to contact the interstitial body fluid extracted through the skin of the patient;

the process comprising the steps of;

providing a porous matrix material having an absorption side and a test side;

applying an indicating reagent system to the test side of the porous matrix material, wherein the indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid;

compressing a pre-determined portion of the porous matrix material to form a substantially non-porous compressed area and a plurality of uncompressed test areas, each test area comprising the porous matrix material having the indicating reagent system positioned on or impregnated in the test side of the porous matrix material, the substantially non-porous compressed area being located between each test area;

applying or attaching an extraction means for extracting interstitial body fluid through the skin of a patient to the absorption side of the matrix material;

applying or attaching an attachment means for attaching the device to the skin of the patient to form the device.

50. The process of claim 49, wherein the process further comprises applying a substantially non-porous material between each test area.

51. A process for preparing a device for determining the presence or concentration of an analyte in the interstitial body fluid of a patient, the device comprising:

(a) a plurality of test areas, each test area independently comprising (i) a porous matrix material having an absorption side and a test side and (ii) an indicating reagent system positioned on or impregnated in the test side of the porous matrix material, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid;

(b) a substantially non-porous material separating each test area from adjacent test areas;

(c) an attachment means for attaching the device to the skin of a patient; and

(d) an extraction means for extracting interstitial body fluid through the skin of the patient;

wherein each test area is oriented so that the absorption side of the test area is positioned to contact the interstitial body fluid extracted through the skin of the patient;

the process comprising the steps of;

providing a porous matrix material having an absorption side and a test side;

compressing a pre-determined portion of the porous matrix material to form a substantially non-porous compressed area and a plurality of uncompressed test areas, the substantially non-porous compressed area being located between each test area;

applying an indicating reagent system to the test side of each test area, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid;

applying or attaching an extraction means for extracting interstitial body fluid through the skin of a patient to the absorption side of the matrix material;

applying or attaching an attachment means for attaching the device to the skin of the patient to form the device.

52. The process of claim 51, wherein the process further comprises applying a substantially non-porous material between each test area.

53. A kit for use by a patient to determine the presence or concentration of an analyte in the interstitial body fluid of the patient, the kit comprising:

(1) a device comprising;

(a) a plurality of test areas, each test area independently comprising (i) a porous matrix material having an absorption side and a test side and (ii) an indicating reagent system positioned on or impregnated in the test side of the porous matrix material, wherein each indicating reagent system is capable of indicating the presence or concentration of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid;

(b) a substantially non-porous material separating each test area from adjacent test areas;

(c) an attachment means for attaching the device to the skin of a patient; and

(d) an extraction means for extracting interstitial body fluid through the skin of the patient;

wherein each test area is oriented so that the absorption side of the test area is positioned to contact the interstitial body fluid extracted through the skin of the patient;

(2) an applicator for positioning and placing the device on the skin of the patient.

54. The kit according to claim 53 wherein the kit further comprises an applicator for applying at least one of an antiseptic agent and an anaesthetic agent to the skin of the patient.

55. The kit according to claim 53 wherein the kit further comprises a testing device capable converting a spectrophotometric change into an indication of the presence or concentration of an analyte in interstitial fluid.

56. A device for determining the presence or concentration of an analyte in the interstitial body fluid of a patient, the device comprising:

a substantially impermeable backing;

a semipermeable membrane secured to the backing to form at least one pocket;

a gel including an indicator reagent capable of indicating the presence of an analyte in interstitial body fluid by producing a spectrophotometric change upon contact with the interstitial body fluid;

an absorption side matrix in communication with the semipermeable membrane; and

an adhesive located on the absorption side of the matrix, the adhesive capable of securing a device to a patient.

57. The device of claim 56 further comprising a release liner covering the adhesive.

58. The device of claim 56 further comprising a skin compromising system attachable to the adhesive layer.

59. The device of claim 56 wherein the gel includes an osmotic agent.

60. The device of claim 59 wherein the osmotic agent is NaCl.

61. The device of claim 56 wherein the absorption side matrix is a non-woven fibrous layer.