Diffusion matrix for transdermal drug administration and transdermal drug delivery devices including same

• US 4,911,916 A
• Filed: 04/08/1988
• Issued: 03/27/1990
• Est. Priority Date: 12/22/1986
• Status: Expired due to Term

• Current Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Original Assignee: Cygnus Research Corporation
• Inventors: Cleary, Gary W.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Prater, P. L.
• Application Number:
  US07/179,561
• Time in Patent Office: 718 Days
• Field of Search: 424/449, 424/447, 424/448
• US Class Current: 424/449
• CPC Class Codes: A61K 9/7069 obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
• CPC Class Codes: A61K 9/7084 Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
• CPC Class Codes: A61K 9/7092 Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs

Abstract

A solid state, resilient laminated composite for administering a drug transdermally consisting of a top layer of a resilient elastomer; a middle diffusion matrix layer composed of a polyurethane macroporous foam framework in whose pores are embedded a viscoelastic blend of a medical grade polysiloxane adhesive, drug, and optionally a percutaneous absorption enhancer, and a basal surface layer of the medical grade polysiloxane adhesive.

Claims

1. A diffusion matrix for use as a reservoir for a drug in a transdermal drug delivery device comprising a viscoelastic body of:

(a) a reticulated macroporous polymeric foam framework;

(b) a viscoelastic drug-permeable hydrophobic polymer embedded in the pores of the foam; and

(c) a drug dispersed in and at least partly dissolved in the hydrophobic polymer that is capable of permeating through unbroken skin, the loading of drug in the polymer being in the range of about 1% to 20% by weight.

2. The diffusion matrix of claim 1 including:

an agent dispersed in and at least partly dissolved in the hydrophobic polymer that enhances the solubility of the drug in the polymer and/or is a percutaneous absorption enhancer that increases the permeability of the skin to the drug.

3. The diffusion matrix of claim 1 wherein the drug is estradiol, progesterone, piroxicam, fentanyl, a fentanyl analog, dihydroergotamine, salbutamol, nifedipine, spironolactone, demegestone, promegestrone, hydrochlorothiazide, nicotine, chlorpheniramene or triprolidine.

4. The diffusion matrix of claim 1 wherein the reticulated polymeric foam framework is made of a polyurethane or polyethylene.

5. The diffusion matrix of claim 1 wherein the weight ratio of (b) and (c) combined to (a) is in the range of about 1:

1 to 10;

1.

6. The diffusion matrix of claim 1 wherein the pore rating of the reticulated polymeric foam framework is about 10 to 40 pores per linear centimeter and the density of the reticulated polymeric foam framework in the range of about 0.01 and 0.5 g/cm³.

7. The diffusion matrix of claim 1 wherein the hydrophobic polymer is a pharmaceutically acceptable pressure sensitive adhesive.

8. The diffusion matrix of claim 7 wherein the hydrophobic polymer is a polysiloxane, a polyacrylate, a polyurethane, a plasticized ethylenevinyl acetate copolymer, a polyether blockamide copolymer or a tacky rubber.

9. The diffusion matrix of claim 7 wherein the hydrophobic polymer is a polydimethylsiloxane or a polymethylphenylsiloxane.

10. The diffusion matrix of claim 1 wherein the diffusion coefficient of the polymer to the drug is greater than about 10^-14 cm² /sec and the solubility of the drug in the hydrophobic polymer is greater than about 1 mg/ml.

11. The diffusion matrix of claim 1 wherein the diffusion coefficient of the polymer to the drug is in the range of 10^-8 to 10^-12 cm² /sec and the solubility of the drug in the hydrophobic polymer is in the range of 1 to 50 mg/ml.

12. The diffusion matrix of claim 2 wherein the agent is a fatty acid ester or fatty alcohol ether of a C₂ to C₄ alkanediol where each fatty acid or fatty alcohol portion of the ester or ether is of about 8 to 22 carbon atoms.

13. The diffusion matrix of claim 2 wherein the agent is a fatty acid monoester of fatty alcohol monoether of a C₂ to C₄ alkanediol.

14. The diffusion matrix of claim 2 wherein the drug is estradiol or fentanyl and the agent is propylene glycol monolaurate.

15. The diffusion matrix of claim 14 wherein the reticulated macroporous polymeric foam is made of a polyurethane having a pore rating of about 10 to 40 pores per linear centimeter and a density in the range of about 0.01 to 0.5 g/cm³, the hydrophobic polymer is a polydimethylsiloxane, the weight ratio of the polydimethylsiloxane, estradiol/fentanyl and propylene glycol monolaurate combined to the polyurethane is in the range of 1:

1 and 10;

1, and the loading of propylene glycol monolaurate in the polydimethylsiloxane is 2% to 20% by weight based on the weight of material embedded in the pores of the foam.

16. The diffusion matrix of claim 15 wherein the body is in the form of a thin film about 10 to 2500 microns thick.

17. A transdermal drug delivery device for administering a drug to a predetermined area of unbroken skin, said device being a resilient laminated composite comprising:

(a) the drug diffusion matrix of claim 1, and

(b) a layer of a pharmaceutically acceptable pressure sensitive adhesive, one face of which defines the basal surface of the body and contacts and adheres to the skin when the device is in use, said layer providing no rate controlling barrier to diffusion of components of the diffusion matrix from the diffusion matrix to the skin.

18. The device of claim 17 including:

a backing layer that forms the top surface of the composite.

19. The device of claim 18 including:

a release liner layer that covers said one face of the layer of pharmaceutically acceptable pressure sensitive adhesive and is adapted to be removed from the device prior to use to expose said one face of the layer of pharmaceutically acceptable pressure sensitive adhesive.

20. The device of claim 18 wherein the hydrophobic polymer and the pressure sensitive adhesive are the same material.

21. The device of claim 18 wherein the drug is estradiol, progesterone, piroxicam, fentanyl, a fentanyl analog, dihydroergotamine, salbutamol, nifedipine, spironolactone, hydrochlorothiazide, promegestrone, demegestone, nicotine, chlorpheniramine, or triprolidene.

22. A transdermal drug delivery device for administering a drug to a predetermined area of unbroken skin, said device being a resilient laminated composite comprising:

(a) the drug diffusion matrix of claim 2, and

(b) a layer of a pharmaceutically acceptable pressure sensitive adhesive, one face of which defines the basal surface of the body and contacts and adheres to the skin when the device is in use, said layer providing no rate controlling barrier to diffusion of components of the diffusion matrix from the diffusion matrix to the skin.

23. The device of claim 22 including:

an occlusive backing layer that forms the top surface of the device.

24. The device of claim 23 including:

a release liner layer that covers said one face of the layer of pharmaceutically acceptable pressure sensitive adhesive and is adapted to be removed from the device prior to use to expose said one face of the layer of pharmaceutically acceptable pressure sensitive adhesive.

25. The device of claim 23 wherein the hydrophobic polymer and the pressure sensitive adhesive are the same material.

26. The device of claim 25 wherein the drug is estradiol or fentanyl, the pore rating of the polymeric foam is 10 to 40 pores per linear centimeter, the density of the polymeric foam is 0.01 to 0.5 g/cm³, the weight ratio of the hydrophobic polymer, estradiol/fentanyl, and agent combined to the foam is 1:

1 to 10;

1, the hydrophobic polymer is a polysiloxane pressure sensitive adhesive, the hydrophobic polymer and the pressure sensitive adhesive of the pressure sensitive adhesive layer are the same material, the agent is a fatty acid ester or fatty alcohol ether of a C₂ to C₄ alkanediol where each fatty acid or fatty alcohol portion of the ether is of 8 to 22 carbon atoms and the loading of agent in the hydrophobic polymer is 2% to 20% based on the weight of the material embedded in the pores of the foam and the thickness of the diffusion matrix layer is about 10 to 2500 microns.

27. The device of claim 26 wherein the agent is a fatty acid monoester of propylene glycol.

28. The device of claim 26 wherein the agent is propylene glycol momolaurate.

29. The device of claim 28 wherein the pressure sensitive adhesive layer is preloaded with estradiol/fentanyl and propylene glycol momolaurate.

30. A transdermal drug delivery device for administering a drug to a predetermined area of unbroken skin comprising a laminated composite that includes a diffusion matrix layer that contains the drug and a layer of a viscoelastic pressure sensitive adhesive that defines the basal surface of the composite and contacts and adheres to the skin when the device is in use, wherein the diffusion matrix layer is in the form of a macroporous polymeric foam in whose pores are embedded a dispersion of the drug in the pressure sensitive adhesive and the diffusion matrix layer contains a sufficient amount of the pressure sensitive adhesive to provide a means for replenishing the pressure sensitive adhesive in the pressure sensitive adhesive layer by flow of pressure sensitive adhesive from the diffusion matrix to said basal surface, whereby the device may be replaced or repositioned on the skin without significant loss of adhesiveness.