US 4,810,499 AGrant
Transdermal Drug Delivery System and Method
Issue Date:1989-03-07
•18 Claims
•2 Drawing Sheets
Abstract
A transdermal drug delivery system which system comprises an impervious backing sheet and 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. The liquid base material contains an effective, therapeutic amount of the drug for transdermal delivery, such as the contraceptive steroid, which drug is highly soluble in the liquid base material. In use, the liquid base material exuded from the macroporous membrane face forms a thermodynamically stable, thin film layer in intimate contact with the skin, while the drug is released from the base material and transdermally into the user.
Metadata
Assignee
- Biotek, Inc.
Inventor
- Elie S. Nuwayser
Application Information
Application Number:US 1529404
Filing Date:1988-02-05
Priority Date:1984-10-01
Art Unit:158
Classifications
IPC:
A61F 1302
Field of Search:
424448;449
Patent Drawings (2 sheets)
Description
Brief Description of the Drawings
FIG. 1 is a schematic, sectional, illustrative view of the drug delivery patch system of the invention;
FIG. 2 is a schematic, sectional, illustrative view of the patch delivery system of FIG. 1 as applied to the skin of a user; and
FIG. 3 (a and b) is a graphical representation of the comparison of in vitro release and plasma levels of levonorgestrel from microcapsules.
Description of the Embodiments
FIGS. 1 and 2 show a bandage-type, transdermal, sustained-release delivery system of the invention 10 wherein the device comprises an impervious backing sheet 12 and a macroporous face membrane 14. The backing sheet 12 and the macroporous membrane 14 form a generally flat reservoir 16 therebetween, the reservoir containing a viscous liquid base material 18 such as a viscous polyethylene glycol vehicle. Uniformly suspended or dissolved in the liquid viscous base is a drug 20, for example, levonorgestrel, in an amount to deliver about 30 micrograms per day of the levonorgestrel over a period of one to four weeks. Around the peripheral edge of the backing material is an adhesive layer 22 while a removable peel strip 24 against the face of the macroporous membrane 14 prevents the discharge of the viscous liquid base material prior to use. FIG. 2 shows the application of the bandage-type delivery system to the skin of a user 26 and illustrates that a thin liquid film 28 of the viscous liquid 18 in the reservoir 16 forms across the entire face of the macroporous membrane 14 to maintain intimate contact between the face of the macroporous membrane 14 in the skin 26 and to accelerate the transdermal delivery of the drug to the user 20.
To illustrate the effect of high solubility of the drug in the base liquid, a dosage form was prepared according to the invention, and contained 0.5 mg of levonorgestrel microparticles (microparticles prepared with levonorgestrel and poly L-lactide of about 200 microns in size and prepared as in the parent applicaion example). The microparticles had a drug loading of 30%, thus the dosage form contained 0.15 mg of levonorgestrel. The microparticles were suspended in 0.5 ml of base liquid vehicle, composed of polyethylene glycol 600. The solubility of levonorgestrel in the vehicle was found to be well in excess of 2 mg/ml. Therefore, on storage, the entire drug content of the microparticles leached into the vehicle. In this case, direct dissolution of the drug in the vehicle would give a dosage form equivalent to one based on a microparticle suspension.
List of References
Dasta, J. F. and Geraets, D. R., Topical Nitroglycerin: A New 'Twist to an Old Standby, Am. Pharm. NS22 (2), 29 (1982).
Feldman, R. J. and Maibach, H. I., J. Invest. Derm. 52, 89 (1969).
Schaefer, H., Stuttgen, G. and Schalla, W., Contraception via Topical Application? - A Review, Contraception, 20 (3), 225 (1979).
Scheuplein, R. J. and Blank, I. H., Permeability of the Skin, Physiol. Rev. 51, 702 (1971).
Vickers, C. F. H., Arch. Dermatol. 88, 20-23 (1963).
Claims
What is claimed is:
1. A transdermal drug delivery system, which system comprises: (a) an impervious backing sheet; (b) a macroporous liquid base retaining face membrane, which macroporous membrane has pores of sufficiently large size to avoid rate control of the drug to be transdermally delivered but to provide a thin film of a base material in use to the skin of the user; (c) the backing sheet and the macroporous membrane secured together to form an intermediate reservoir therebetween; (d) the resevoir having a composition therein comprising: (i) a dermatologically-acceptable, viscous liquid base material, which liquid base material comprises a hydrophilic material and 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 epidermic of the user in use; (ii) the liquid base material containing an effective, therapeutic amount of a water soluble drug for transdermal delivery, the active drug material for transdermal delivery having high solubility in the liquid base material; (e) a removable means to seal the face of the macroporous membrane prior to use; and (f) means to secure the membrane face to 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 liquid base material comprises a hydrophobic viscous material and the drug to be transdermally delivered comprises a hydrophobic drug.
4. 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.
5. 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.
6. The drug delivery system of claim 1 wherein the active drug comprises a contraceptive steroid hormone.
7. 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.
8. The drug delivery system of claim 7 wherein the liquid base material comprises a polyalkylene glycol and the drug comprises a glycol soluble steroid.
9. The 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 liquid base retaining face membrane having a pore size of from about 1 to 1000 microns and pores of sufficiently large 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 about the periphery of the macroporous face membrane to permit the macroporous face membrane to be placed in contact with the skin of the user after removal of the protective means; (f) the reservoir having a composition comprising: (i) dermatologically-acceptable, polyalkylene polyol liquid base material 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 force hydration of the stratum corneum layer with water from the lower layers of the epidermis of the user; (ii) the liquid base material containing an effective, therapeutic amount of a contraceptive steroid drug for transdermal delivery to the user, the steroid characterized by having a high solubility in the liquid base material; 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 thermodynamically stable, thin film on intimate contact with the skin of the user while the steroid hormone is released through the liquid base material directly into the skin of the user.
10. A method for the transdermal delivery of a drug to a user which method comprises: (a) preparing a composition which comprises: (i) a viscous, film-forming, hydrophilic liquid base material selected to occlude the skin of the user and to force hydration of the stratum corneum layer with water from the lower layers of thc epidermis of the user in use; and (ii) the liquid base material containing a highly soluble drug in an amount to provide an effective therapeutic amount of the drug to the user in a predertermined release pattern; and (b) applying a layer of the composition to the skin of the user.
11. The method of claim 10 wherein the liquid base material comprises a viscous hydrocarbon and the drug comprises a water insoluble drug.
12. The method of claim 10 wherein the liquid base material is a viscous hydrocarbon and the drug comprises a hydrocarbon soluble contraceptive steroid.
13. The method of claim 12 wherein the steroid comprises levonorgestrel, estradiol, and admixtures thereof.
14. The method of claim 10 which includes retaining the composition within a reservoir which includes a macroporous membrane and forming a thin layer of the liquid base material on the skin of the user by passing the liquid base material through the macroporous membrane.
15. The method of claim 10 wherein the liquid base material comprises a polyalkylene glycol and the drug is a glycol soluble steroid.
16. A method for the transdermal delivery of a drug from a reservoir containing the drug, which method comprises: (a) providing a transdermal delivery system which includes a reservoir and a macroporous face membrane, the reservoir containing a dermatologically-acceptable, viscous liquid base material selected to occlude the skin of the user and to force hydration of the stratum corneum layer of the user with water from the lower layers of the epidermis of the user, which liquid base material comprises a polyalkylene glycol containing an effective, therapeutic amount of a drug for transdermal delivery to the user, the reservoir having one face formed of a macroporous face membrane material; (b) placing the macroporous face membrane material adjacent to the skin of the user so as to permit the liquid base material to exude from the face membrane and to form a thin, thermodynamically stable thin film of the liquid base material on the skin of the user and in intimate contact with the thin film, and the liquid base material in the reservoir; and (c) introducing the drug from the liquid base material and through the thin liquid film into the skin.
17. The method of claim 9 wherein the liquid base material comprises a viscous polyethylene or polypropylene glycol and wherein the drug to be transdermally delivered comprises a glycol soluble steroid drug soluble in the liquid base material.
18. The method of claim 9 wherein the active drug comprises a contraceptive steroid hormone and wherein the contraceptive steroid hormone comprises norethindrone, norgestrel, estradiol, levonorgestrel, and mestranol and combinations thereof.