Multiple mechanical microporation of skin or mucosa

• US 6,183,434 B1
• Filed: 06/14/1999
• Issued: 02/06/2001
• Est. Priority Date: 07/03/1996
• Status: Expired due to Term

• Current Assignee: MidCap Funding III, LLC, Nitto Denko Corporation
• Original Assignee: Altea Technologies Inc (Nitto Denko Corporation), Spectro Incorporated (Spectro Scientific, Inc.)
• Inventors: Eppstein, Jonathan A.
• Primary Examiner(s): Bockleman, Mark
• Application Number:
  US09/202,207
• Time in Patent Office: 603 Days
• Field of Search: 604/20-21, 604/501, 604/22, 606/186, 424/449, 600/362, 600/573, 600/578, 600/583
• US Class Current: 604/22
• CPC Class Codes: A61B 5/14514 using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
• CPC Class Codes: A61M 2037/0007 having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
• CPC Class Codes: A61M 2037/0023 Drug applicators using microneedles
• CPC Class Codes: A61M 2037/0038 having a channel at the side surface
• CPC Class Codes: A61M 2037/0053 Methods for producing microneedles
• CPC Class Codes: A61M 37/0015 by using microneedles
• CPC Class Codes: A61M 37/0092 using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis

Abstract

A method of enhancing the permeability of a biological membrane, including the skin or mucosa of an animal or the outer layer of a plant to a permeant is described utilizing microporation of selected depth and optionally one or more of sonic, electromagnetic, mechanical and thermal energy and a chemical enhancer. Microporation is accomplished to form a micropore of selected depth in the biological membrane and the porated site is contacted with the permeant. Additional permeation enhancement measures may be applied to the site to enhance both the flux rate of the permeant into the organism through the micropores as well as into targeted tissues within the organism.

Claims

1. A device for reducing the barrier properties of skin or mucosa to the delivery of a substance into the body or the withdrawal of an analyte from the body comprising:

(a) a base having a lower side and an upper side;

(b) a plurality of puncturing members extending from the lower side of the base, said puncturing members configured for puncturing said skin or mucosa to a depth sufficient to reduce the barrier properties thereof without significantly damaging underlying tissues;

(c) a plurality of holes extending from the lower side of the base to the upper side of the base, said holes configured for permitting a liquid to move therethrough by capillary action; and

(d) a network of channels configured in the upper side of said base to interconnect said holes.

2. The device of claim 1 wherein said device is fabricated by microlithography.

3. The device of claim 1 wherein said device is fabricated of a material selected from the group consisting of silicon, metal, and plastic.

4. The device of claim 1 wherein said puncturing member is in the shape of a pyramid or wedge.

5. The device of claim 4 wherein said pyramid or wedge comprises sharp edges having corner radii of less than 1 μ

m.

6. The device of claim 1 wherein said puncturing member is configured for puncturing said skin or mucosa to a depth of about 30-50 μ

m.

7. The device of claim 1 wherein said plurality of puncturing members occupy up to about 50% of the surface area of the lower surface of the base.

8. The device of claim 1 wherein said puncturing member has a dimension at a base thereof of about 10-50 μ

m.

9. The device of claim 1 wherein said each of said holes is positioned adjacent to a puncturing member.

10. The device of claim 1 wherein said network of channels further comprises a reservoir for holding liquid.

11. The device of claim 1 wherein said base is substantially planar.

12. The device of claim 1 further comprising a mechanism for producing vibrations, said vibrations for facilitating efficient and non-traumatic penetration of the puncturing members into the skin or mucosa.

13. The device of claim 12 wherein said mechanism for producing vibrations comprises a piezo-electric transducer.

14. The device of claim 12 wherein said mechanism for producing vibrations produces vibrations in the range of about 2000 Hz to about 100 MHz.

15. The device of claim 1 further comprising an external reservoir for holding a liquid drug composition to be delivered to the body.

16. The device of claim 15 further comprising a mechanism for limiting the rate of drug delivery, said mechanism positioned between the external reservoir and the puncturing members.

17. The device of claim 1 wherein said device is disposable.

18. A method for reducing the barrier function of skin or mucosa to the delivery of substances into a body or withdrawal of analytes out of the body, comprising:

(a) providing a device comprising;

a base having a lower side and an upper side;

a plurality of puncturing members extending from the lower side of the base, said puncturing members configured for puncturing said skin or mucosa to a depth sufficient to reduce the barrier properties thereof without significantly damaging underlying tissues;

a plurality of holes extending from the lower side of the base to the upper side of the base, said holes configured for permitting a liquid to move therethrough by capillary action; and

a network of channels configured in the upper side of said base to interconnect said holes;

(b) contacting said device with the skin or mucosa such that said plurality of puncturing members puncture the skin or mucosa to a depth sufficient to reduce the barrier properties thereof.

19. The method of claim 18 wherein said device is fabricated by microlithography.

20. The method of claim 18 wherein said device is fabricated of a material selected from the group consisting of silicon, metal, and plastic.

21. The method of claim 18 wherein said puncturing member is in the shape of a pyramid or wedge.

22. The method of claim 21 wherein said pyramid or wedge comprises sharp edges having corner radii of less than 1 μ

m.

23. The method of claim 18 wherein said puncturing member is configured for puncturing said skin or mucosa to a depth of about 30-50 μ

m.

24. The method of claim 18 wherein said plurality of puncturing members occupy up to about 50% of the surface area of the lower surface of the base.

25. The method of claim 18 wherein said puncturing member has a dimension at a base thereof of about 10-50 μ

m.

26. The method of claim 18 wherein said each of said holes is positioned adjacent to a puncturing member.

27. The method of claim 18 wherein said network of channels further comprises a reservoir for holding liquid.

28. The method of claim 18 wherein said base is substantially planar.

29. The method of claim 18 further comprising a mechanism for producing vibrations, said vibrations for facilitating efficient and non-traumatic penetration of the puncturing members into the skin or mucosa.

30. The method of claim 29 wherein said mechanism for producing vibrations comprises a piezo-electric transducer.

31. The method of claim 29 wherein said mechanism for producing vibrations produces vibrations in the range of about 2000 Hz to about 100 MHz.

32. The method of claim 18 further comprising an external reservoir for holding a liquid drug composition to be delivered to the body.

33. The method of claim 32 further comprising a mechanism for limiting the rate of drug delivery, said mechanism positioned between the external reservoir and the puncturing members.

34. The method of claim 18 wherein said device is disposable.

35. A method of transdermal or transmucosal monitoring of a selected analyte in a body comprising:

(a) providing a device comprising;

a base having a lower side and an upper side;

a plurality of puncturing members extending from the lower side of the base, said puncturing members configured for puncturing said skin or mucosa to a depth sufficient to reduce the barrier properties thereof without significantly damaging underlying tissues;

a plurality of holes extending from the lower side of the base to the upper side of the base, said holes configured for permitting a liquid to move therethrough by capillary action; and

a network of channels configured in the upper side of said base to interconnect said holes, said network of channels including a reservoir;

(b) contacting said device with the skin or mucosa such that said plurality of puncturing members puncture the skin or mucosa to a depth sufficient to reduce the barrier properties thereof resulting in seepage of interstitial fluid to the surface of said skin or mucosa such that interstitial fluid moves by capillary action through the holes, through the channels, to the reservoir;

(c) collecting the interstitial fluid from the reservoir; and

(d) analyzing the interstitial fluid with respect to the selected analyte.

36. The method of claim 35 further comprising applying suction to increase the rate of collection of interstitial fluid.

37. The method of claim 35 further comprising applying ultrasonic vibrations to the skin or mucosa to increase the rate of collection of the selected analyte.

38. The method of claim 37 wherein said ultrasonic vibrations are modulated in frequency, intensity, phase, or a combination thereof.

39. The method of claim 38 wherein said ultrasonic vibrations are in the range of about 2000 Hz to about 100 MHz.

40. The method of claim 35 wherein movement of interstitial fluid by capillary action is enhanced by applying ultrasonic vibrations.

41. The method of claim 35 wherein said selected analyte is glucose.

42. The method of claim 35 further comprising applying an anticoagulant to inhibit obstruction of the holes or channels.

43. A method of transdermally or transmucosally delivering a drug in liquid form to a body comprising:

(a) providing a device comprising;

a base having a lower side and an upper side;

a plurality of puncturing members extending from the lower side of the base, said puncturing members configured for puncturing said skin or mucosa to a depth sufficient to reduce the barrier properties thereof without significantly damaging underlying tissues;

a plurality of holes extending from the lower side of the base to the upper side of the base, said holes configured for permitting a liquid to move therethrough by capillary action; and

a network of channels configured in the upper side of said base to interconnect said holes, said network of channels including a reservoir;

(b) contacting said device with the skin or mucosa such that said plurality of puncturing members puncture the skin or mucosa to a depth sufficient to reduce the barrier properties thereof;

(c) supplying the drug to said reservoir such that said drug moves from the reservoir, through the channels and holes to the site of the punctures of the skin or mucosa and thus into the body.

44. The method of claim 43 further comprising applying pressure to increase the rate of delivery of the drug to the body.

45. The method of claim 43 further comprising applying ultrasonic vibrations to the skin or mucosa to increase the rate of delivery of the drug to the body.

46. The method of claim 45 wherein said ultrasonic vibrations are modulated in frequency, intensity, phase, or a combination thereof.

47. The method of claim 45 wherein said ultrasonic vibrations are in the range of about 2000 Hz to about 100 MHz.

48. The method of claim 43 wherein said drug in liquid form further comprises an anti-irritant, antiseptic, or analgesic to reduce trauma to the body due to the application of the device.