Microporation of human skin for drug delivery and monitoring applications

• US 6,142,939 A
• Filed: 12/09/1998
• Issued: 11/07/2000
• Est. Priority Date: 11/15/1993
• Status: Expired due to Term

• Current Assignee: Nitto Denko Corporation
• Original Assignee: Altea Technologies Inc (Nitto Denko Corporation), Spectro Incorporated (Spectro Scientific, Inc.)
• Inventors: Hatch, Michael R., Yang, Difei, Eppstein, Jonathan A.
• Primary Examiner(s): Smith, Ruth S.
• Application Number:
  US09/208,166
• Time in Patent Office: 699 Days
• Field of Search: 600/309, 600/310, 600/316, 600/365, 600/573, 600/476, 601/2, 601/3, 607/96, 607/100, 607/104, 604/22, 604/20, 604/49, 604/289, 604/290, 606/9, 606/131
• US Class Current: 600/309
• CPC Class Codes: A61B 10/0045 Devices for taking samples of body liquids devices for taking blood samples A61B5/15
• CPC Class Codes: A61B 17/3203 Fluid jet cutting instruments
• CPC Class Codes: A61B 18/20 using laser
• CPC Class Codes: A61B 18/203 applying laser energy to the outside of the body
• CPC Class Codes: A61B 2017/00172 Pulse trains, bursts, intermittent continuous operation
• CPC Class Codes: A61B 2017/00761 Removing layer of skin tissue, e.g. wrinkles, scars or cancerous tissue
• CPC Class Codes: A61B 2017/00765 Decreasing the barrier function of skin tissue by radiated energy, e.g. using ultrasound, using laser for skin perforation
• CPC Class Codes: A61B 2018/00452 Skin
• CPC Class Codes: A61B 2018/0047 Upper parts of the skin, e.g. skin peeling or treatment of wrinkles
• CPC Class Codes: A61B 2562/0295 Strip shaped analyte sensors for apparatus classified in A61B5/145 or A61B5/157
• CPC Class Codes: A61B 5/14514 using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
• CPC Class Codes: A61B 5/1486 using enzyme electrodes, e.g. with immobilised oxidase
• CPC Class Codes: A61B 5/681 Wristwatch-type devices
• CPC Class Codes: A61K 41/0047 Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
• CPC Class Codes: A61K 49/22 Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
• 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 37/0092 using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis

Abstract

A method of enhancing the permeability of the skin to an analyte for diagnostic purposes or to a drug for therapeutic purposes is described utilizing microporation and optionally sonic energy and a chemical enhancer. If selected, the sonic energy may be modulated by means of frequency modulation, amplitude modulation, phase modulation, and/or combinations thereof. Microporation is accomplished by (a) ablating the stratum corneum by localized rapid heating of water such that such water is vaporized, thus eroding the cells; (b) puncturing the stratum corneum with a micro-lancet calibrated to form a micropore of up to about 1000 μm in diameter; (c) ablating the stratum corneum by focusing a tightly focused beam of sonic energy onto the stratum corneum; (d) hydraulically puncturing the stratum corneum with a high pressure jet of fluid to form a micropore of up to about 1000 μm in diameter, or (e) puncturing the stratum corneum with short pulses of electricity to form a micropore of up to about 1000 μm in diameter. A dye with an absorption maximum matched to the wavelength of a pulsed light source can be absorbed into the stratum corneum to concentrate the energy of the pulsed light source and aid in ablation of the stratum corneum. Alternatively, a hot wire can be caused to contact the stratum corneum.

Claims

1. An apparatus for forming micropores in a selected area of the stratum corneum for enhancing the permeability of the skin, the apparatus comprising a heat conducting element to be placed in substantial physical contact with the selected area to deliver sufficient energy by conduction to said selected area such that the temperature of tissue-bound water and other vaporizable substances in said selected area is elevated above the vaporization point of said water and other vaporizable substances thereby removing the stratum corneum and forming at least one micropore 1-1000 μ

m across in said selected area of said stratum corneum.

2. The apparatus of claim 1, wherein the heat conducting element comprises an effective amount of an energy-absorbing compound that exhibits absorption over a predetermined frequency range of electromagnetic energy, and further comprising a pulsed light source capable of emitting electromagnetic energy in the predetermined frequency range, wherein the pulsed light source is focused onto said energy-absorbing compound such that said energy-absorbing compound is heated sufficiently to conductively transfer heat to said stratum corneum.

3. The apparatus of claim 2, wherein the heat conducting element comprises a film treated with said energy-absorbing compound.

4. The apparatus of claim 2, wherein the heat conducting element comprises a solid support comprising on one side an adhesive that is treated with said energy-absorbing compound.

5. The apparatus of claim 2, and further comprising a chemical enhancer combined with said energy-absorbing compound.

6. The apparatus of claim 2, and further comprising a controller coupled to the pulsed light source that controls said pulsed light source to emit pulses at a wavelength that is not significantly absorbed by the stratum corneum.

7. The apparatus of claim 6, wherein the controller controls the duration of a pulse on-time and the duration of a pulse off-time of a cycle of the pulsed light source so as to reduce the sensation to the individual.

8. The apparatus of claim 6, wherein the controller controls the duration of the pulse on-time to be less than 50 milliseconds and the duration of the pulse off-time to be greater than 10 milliseconds.

9. The apparatus of claim 2, wherein the pulsed light source comprises a laser diode emitting in the range of about 630 to 1550 nm.

10. The apparatus of claim 2, wherein the pulsed light source comprises a laser diode pumped optical parametric oscillator emitting in the range of about 700 to 3000 nm.

11. The apparatus of claim 2, wherein the pulsed light source is a member selected from the group consisting of arc lamps, incandescent lamps, and light emitting diodes.

12. The apparatus of claim 2, and further comprising means for sensing when the barrier properties of the stratum corneum have been surmounted.

13. The apparatus of claim 12, wherein the means for sensing comprises a sensor that receives reflected light from said selected area and a controller coupled to the sensor and to the pulsed light source that measures a quality of said reflected light and terminates output of the pulse light source based upon the quality of the reflected light.

14. The apparatus of claim 1, and further comprising a cooling device suitable for being disposed around said selected area to cool said selected area of stratum corneum and adjacent skin tissues to a selected cooled condition.

15. The apparatus of claim 14, wherein the cooling device comprises a Peltier device.

16. The apparatus of claim 1, wherein the heat conducting element comprises a solid probe.

17. The apparatus of claim 16, and further comprising a heat source coupled to the solid probe, wherein the heat source is an ohmic heating element.

18. The apparatus of claim 16, and further comprising means for modulating the temperature of said selected area of the stratum corneum with the solid probe.

19. The apparatus of claim 18, wherein the means for modulating heats the selected area of the stratum corneum to greater than 123°

C. for less than 50 milliseconds for an on-time of a cycle and returns the temperature of the selected area of the stratum corneum to approximately ambient temperature for more than 10 milliseconds for an off-time of a cycle.

20. The apparatus of claim 18, wherein the means for modulating comprises a mechanical element capable of alternately applying and withdrawing the solid probe in contact with the surface of the stratum corneum.

21. The apparatus of claim 16, and further comprising a controller coupled to the solid probe and to the skin, the controller determining the depth of said micropore by monitoring electrical impedance between said solid probe and the biological organism through said selected area of stratum corneum and adjacent skin tissues, and wherein the controller controls a mechanical element to withdraw said solid thermal probe from contact with the stratum corneum when a predetermined change in impedance associated with contacting an epidermal layer underlying the stratum corneum is detected.

22. The apparatus of claim 16, wherein the solid probe comprises a current loop having a high resistance point.

23. The apparatus of claim 22, and further comprising a current source coupled to the current loop and a controller coupled to the current source, wherein the controller modulates the current supplied by the current source to the current loop.

24. The apparatus of claim 16, wherein the solid probe comprises a wire.

25. The apparatus of claim 24, and further comprising an excitation coil arranged such that the wire is positioned within the excitation coil and a controller coupled to the excitation coil, the controller controlling an alternating magnetic field of the excitation coil such that energizing the excitation coil with alternating current produces eddy currents sufficient to heat the solid thermal probe by internal ohmic losses.

26. The apparatus of claim 1, and further comprising means for applying sonic energy to said selected area at a frequency in the range of 5 kHz to 100 MHZ to further enhance the permeability of the skin.

27. The apparatus of claim 26, wherein said means for applying sonic energy further comprises means for modulating the sonic energy by frequency modulation, amplitude modulation, phase modulation, or combinations thereof.

28. The apparatus of claim 1, and further comprising means for applying a pressure gradient to said selected area of stratum corneum for enhancing exudation of biological fluid.

29. The apparatus of claim 28, wherein the means for applying a pressure gradient comprises a suction device for applying a vacuum to said selected area of the stratum corneum.

30. The apparatus of claim 1, and further comprising means for collecting biological fluid from said selected area of the stratum corneum.

31. The apparatus of claim 30, and further comprising means for quantitating an analyte in the biological fluid.

32. The apparatus of claim 31, wherein the means for quantitating comprises a glucose assay strip.

33. The apparatus of claim 1, and further comprising means for delivering a composition comprising an effective amount of a permeant through the at least one micropore.