Transdermal drug delivery system

• US 4,687,481 A
• Filed: 03/03/1986
• Issued: 08/18/1987
• Est. Priority Date: 10/01/1984
• Status: Expired due to Term

• Current Assignee: BioTex Incorporated
• Original Assignee: BioTex Incorporated
• Inventors: Nuwayser, Elie S.
• Primary Examiner(s): Silverberg, Sam
• Application Number:
  US06/835,154
• Time in Patent Office: 533 Days
• Field of Search: 604/897, 604/896, 424/28
• US Class Current: 424/449
• 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

Abstract

A transdermal drug delivery system useful for the controlled, for example zero order release of one or more drugs to a selected skin area of a user, which system comprises an impervious backing sheet and a face membrane, the backing sheet and membrane secured together to form an intermediate reservoir. The face membrane is a macroporous membrane which has pores of sufficient size to avoid any rate control of the drug to be transdermally delivered to the user. The reservoir contains a viscous liquid base material selected to exude from the membrane to form a film and to occlude the skin of the user to force hydration of the stratum corneum with water from the lower layers of the epidermis of the user and a plurality of solid microparticles generally uniformly dispersed and suspended in the liquid base material. The microparticles containing an effective therapeutic amount of the drug for transdermal delivery, such as the contraceptive steroid. In use the liquid base material exuded from the macroporous membrane face forms a thermodynamically stable thin film layer in an intimate contact with the skin, while the drug is released from the microparticles into the base material and transdermally into the user.

Claims

1. A transdermal drug delivery system, which system comprises:

(a) an impervious backing sheet;

(b) a macroporous, nondrug rate-controlling, liquid-base-retaining face member, which macroporous membrane has pores of sufficiently large size, to avoid rate control of the drug to be transdermally delivered, and of sufficiently small size, to provide a controlled amount of a thin film of a base material to the skin of the user;

(c) the backing sheet and the macroporous membrane secured together to form an intermediate reservoir therebetween; and

(d) the reservoir having a composition therein comprising;

(i) a dermatologically acceptable viscous liquid base material, which liquid base material is selected to exude in a controlled amount through the pores of the face membrane, to form a thin film on the skin of the user and to occlude the skin of the user and to force hydration of the stratum corneum layer with water from the lower layers of the epidermis of the user in use; and

(ii) a plurality of solid, drug-rate-controlling microparticles generally uniformly dispersed and suspended in the liquid base material in the reservoir in an amount to provide for the desired time period of delivery of the drug to be transdermally delivered, the microparticles having a particle size of less than about 1000 microns and containing an effective therapeutic amount of a drug for transdermal delivery, the active drug material for transdermal delivery and the liquid base material being compatible to form a compatible transport relationship,

whereby, on application to the skin of a user of the transdermal drug delivery system, the liquid base material exuded from the macroporous membrane forms a stable thin film on intimate contact with the skin of the user, while the drug is released at a controlled release rate from the suspended microparticles into the liquid base material and directly into the skin of the user.

2. The drug delivery system of claim 1 wherein the macroporous face membrane has a pore size of about 1 to 1000 microns.

3. The drug delivery system of claim 1 wherein the viscous liquid base material comprises a hydrophilic material and the drug to be delivered comprises a water soluble drug.

4. The drug delivery system of claim 1 wherein the liquid base material comprises a hydrophobic viscous material and the drug to be transdermally delivered comprises a hydrophobic drug.

5. The drug delivery system of claim 1 wherein the liquid base material comprises a glycerol water-containing liquid base material and wherein the drug to be transdermally delivered comprises a water soluble drug.

6. The drug delivery system of claim 1 wherein the liquid base material comprises a viscous hydrocarbon-type material and wherein the drug to be transdermally delivered comprises a hydrophobic drug soluble in the viscous hydrocarbon liquid base material.

7. The drug delivery system of claim 1 wherein the active drug comprises a contraceptive steroid hormone.

8. The drug delivery system of claim 7 wherein the contraceptive steroid hormone is selected from the group consisting of norethindrone, norgestrel, estradiol, levonorgestrel, and mestranol and combinations thereof.

9. The drug delivery system of claim 8 wherein the liquid base material comprises a viscous long chain hydrocarbon material.

10. The drug delivery system of claim 1 which includes a removable means to seal the face of the macroporous membrane prior to use;

and means to secure the face membrane to the skin of a user.

11. The drug delivery system of claim 1 wherein the microparticle comprises a microparticle having a particle size of about 200 microns or less and wherein the active ingredient comprises a levonorgestrel or estradiol wherein the active drug is admixed with a lactide or glycolide polymer and wherein the microparticle has a wall thickness composed of a lactide or glycolide polymer.

12. The drug delivery system of claim 1 wherein the microparticles comprise a solid admixture of the drug and a biodegradable polymer and a thin outer layer of a biodegradable polymer.

14. The drug delivery system of claim 1 wherein the amount of the drug in the microparticles varies from about 0.1 to 30 weight percent of the microparticles.

15. The drug delivery system of claim 1 wherein the viscous liquid base material comprises a jelly-like hydrocarbon having a melting point of about 38°

C. to 60°

C.

16. The drug delivery system of claim 1 wherein the amount of microparticles dispersed in the liquid base material comprises from about 5 to 70 weight percent of the composition.

17. The drug delivery system of claim 1 wherein the drug comprises a contraceptive steroid to be transdermally delivered at a rate of about 5 to 150 micrograms per day.

18. The drug delivery system of claim 1 wherein the microparticles provide a zero-order release pattern to the transdermal delivery of the drug.

13. A transdermal drug delivery system for the delivery of a contraceptive steroid drug to the skin of a user, which system comprises:

(a) an impervious backing sheet;

(b) a macroporous face membrane having a pore size of from about 1 to 1000 microns, the pores of sufficient size to avoid rate control of the contraceptive hormone to be transdermally delivered by the drug delivery system;

(c) the backing sheet and the macroporous membrane sheet secured together to form an intermediate reservoir therebetween;

(d) means to seal the face of the macroporous face membrane prior to use, said means being easily removable by the user prior to use;

(e) adhesive securing means to permit the macroporous face membrane to be placed in contact with the skin of the user after removal of the protective means; and

(f) the reservoir having a composition therein comprising;

(i) a dermatologically acceptable hydrophobic viscous hydrocarbon liquid base material to occlude the skin of the user and force hydration of the stratum corneum layer with water from the lower layers of the epidermis of the user; and

(ii) a plurality of drug-rate-controlling solid microparticles having a particle size of less than about 300 microns, the microparticles generally uniformly dispersed and suspended in the liquid base material in an amount of about 5 to 70 weight percent of the composition, and having a wall coating of about 0.1 to 20 microns and adapted and designed to provide for zero order release, the microparticles containing an effective therapeutic amount of a contraceptive steroid drug for transdermal delivery to the user, the steroid characterized by having a low water solubility and being generally hydrophobic,

whereby, on application to the skin of a user of the liquid drug delivery system, the liquid base material exuded from the macroporous face membrane forms a stable thin film in intimate contact with the skin of the user, while the steroid hormone is released from the solid microparticles in a desired rate pattern through the liquid base material and directly transdermally into the skin of the user.