Microporation of tissue for delivery of bioactive agents

• US 6,527,716 B1
• Filed: 08/12/1999
• Issued: 03/04/2003
• Est. Priority Date: 12/30/1997
• Status: Expired due to Term

• Current Assignee: Nitto Denko Corporation
• Original Assignee: Altia Technology (Altia Group)
• Inventors: Eppstein, Jonathan A.
• Primary Examiner(s): Smith; Ruth S.
• Application Number:
  US09/331,124
• Time in Patent Office: 1,300 Days
• Field of Search: 600/309,365,573,473,476,310,316 604/19,20,500,501,290,291 606/27,131
• US Class Current: 600/309
• CPC Class Codes: A61B 1/313 for introducing through surgical openings, e.g. laparoscopes
• CPC Class Codes: A61B 18/04 by heating by applying electromagnetic radiation A61B18/18; hyperthermia using electric or magnetic fields, radiation or ultrasound A61N
• CPC Class Codes: A61B 18/203 applying laser energy to the outside of the body
• CPC Class Codes: A61B 2017/00026 Conductivity or impedance, e.g. of tissue
• CPC Class Codes: A61B 2017/00172 Pulse trains, bursts, intermittent continuous operation
• 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: A61M 37/0092 using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
• CPC Class Codes: A61N 1/325 for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body electrodes for external use A61N1/0428

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 20 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 method of delivering a permeant into an organism comprising steps of:

porating a biological membrane of an organism at a selected area to form at least one micropore 1-1000 μ

m in diameter in said biological membrane, comprising the step of ablating the biological membrane by placing a heat conducting element in substantial physical contact with the selected area to deliver sufficient energy by conduction to said selected area of said biological membrane 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 biological membrane in said selected area;

applying an electromagnetic field to the selected area; and

contacting the selected area with a permeant having a formulation and under conditions whereby the electromagnetic field actively induces the flux of the permeant into the organism through the at least one micropore formed in the biological membrane.

2. The method of claim 1, and further comprising the step of applying one or more enhancers, including one or more of sonic energy and mechanically generated pressure gradients to the selected area.

3. The method of claim 1, wherein the step of applying an electromagnetic field comprises applying an iontophoretic field to the selected area, wherein the formulation of the permeant has an electrical charge property such that the iontophoretic field induces movement of the permeant into the organism through the at least one micropore.

4. The method of claim 1, wherein the step of applying an electromagnetic field comprises applying a magnetic field to the selected area, wherein the formulation of the permeant has a magnetic property such that the magnetic field induces movement of the permeant into the organism through the at least one micropore.

5. A method of detecting presence of an analyte in an organism comprising steps of:

porating a biological membrane at a selected area of the organism to form at least one micropore 1-1000 μ

m in diameter in said biological membrane, comprising the step of ablating the biological membrane by placing a heat conducting element in substantial physical contact with the selected area to deliver sufficient energy by conduction to said selected area of said biological membrane 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 biological membrane in said selected area;

contacting the selected area with a probe compound under conditions whereby the probe compound is taken up in the organism and interacts with an analyte in the organism; and

interrogating non-invasively the selected area to obtain information regarding the levels of the analyte in the organism.

6. The method of claim 5, wherein the step of contacting comprises contacting the selected area with a microparticle carrier incorporating the probe compound.

7. The method of claim 6, wherein the microparticle comprises a porous microsphere and the probe compound is a glucose specific fluorophore compound which alters its fluorescence response in the presence of glucose.

8. The method of claim 5, wherein the step of interrogating comprises steps of:

irradiating the selected area with electromagnetic radiation; and

detecting radiation emanating from the selected area in response to the electromagnetic radiation, whereby at least one characteristic of the radiation detected from the selected area is a measure of the analyte in the organism.

9. The method of claim 8,wherein the step of detecting at least one characteristic comprises detecting one or more of amplitude, wavelength, or fluorescent lifetime of the radiation.

10. The method of claim 8, wherein the step of irradiating comprises irradiating the selected area with infrared radiation.

11. A method of delivering a nucleic acid into an organism comprising steps of:

porating a biological membrane at a selected area of the organism to form at least one micropore 1-1000 μ

m in diameter in said biological membrane comprising the step of ablating the biological membrane by placing a heat conducting element in substantial physical contact with the selected area to deliver sufficient energy by conduction to said selected area of said biological membrane 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 biological membrane in said selected area;

applying an electromagnetic field to the selected area; and

contacting the selected area with a nucleic acid under conditions whereby the electromagnetic field actively induces the flux of the nucleic acid into the organism through the at least one micropore formed in the biological membrane.

12. The method of claim 11, wherein the nucleic acid is DNA.

13. The method of claim 11, wherein the nucleic acid is RNA.

14. A method for delivering a permeant into an organism comprising steps of:

porating a biological membrane at a selected area of the organism to form at least one micropore 1-1000 μ

m in diameter in said biological membrane, comprising the step of ablating the biological membrane by placing a heat conducting element in substantial physical contact with the selected area to deliver sufficient energy by conduction to said selected area of said biological membrane 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 biological membrane in said selected area;

applying an electromagnetic field to the selected area; and

contacting the selected area with a permeant having a formulation and under conditions whereby the electromagnetic field actively induces the flux of the permeant into the organism through the at least one micropore formed in the biological membrane,

wherein the permeant is selected from the group consisting of insulin, interferon and heparin.

15. A method of delivering a permeant associated with a carrier into an organism comprising steps of:

porating a biological membrane at a selected area of the organism to form at least one micropore 1-1000 μ

m in diameter in said biological membrane comprising the step of ablating the biological membrane by placing a heat conducting element in substantial physical contact with the selected area to deliver sufficient energy by conduction to said selected area of said biological membrane 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 biological membrane in said selected area;

applying an electromagnetic field to the selected area; and

contacting the selected area with the carrier under conditions whereby the electromagnetic field actively induces the flux of the permeant associated with the carrier into the organism through the at least one micropore formed in the biological membrane.

16. The method of claim 15, wherein the carrier comprises liposomes.

17. The method of claim 15, wherein the carrier comprises lipid complexes.

18. The method of claim 15, wherein the carrier is formulated to have a charge.

19. The method of claim 15, wherein the carrier comprises microparticles.

20. The method of claim 15, wherein the carrier comprises polyethylene glycol compounds.

21. An apparatus for stimulating an immune response in an organism wherein a permeant is delivered into the organism comprising:

a heat source, which, when put in substantial physical contact with a selected area of a biological membrane of the organism, is capable of porating the biological membrane at the selected area to form at least one micropore 1-1000 μ

m in diameter and at a depth coincident with increased concentration of langerhans cells, by delivering sufficient energy to the selected area such that the temperature of tissue-bound water and other vaporizable substances in the selected area is elevated above the vaporization point of the water and other vaporizable substances, thereby removing the biological membrane in the selected area, and wherein the apparatus enables the permeant, when the permeant is put in contact with the selected area, to be taken up through the micropore into the organism.