Device for transdermal administration of active medicinal agents

• US 5,071,657 A
• Filed: 08/31/1990
• Issued: 12/10/1991
• Est. Priority Date: 09/12/1983
• Status: Expired due to Fees

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Zimmermann, Ingfried, Oloff, Horst, Tack, Johannes-Wilhelm, Windt, Fred
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US07/575,739
• Time in Patent Office: 466 Days
• Field of Search: 424/486, 424/78, 424/DIG. 7, 514/944, 514/945, 604/304, 536/98
• US Class Current: 424/486
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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: Y10S 424/07 Microporous membranes

Abstract

A device for transdermal administration of active medicinal agents is based on the active medicinal agent dissolved to an extent of at least 50% in a nonflowable, physiologically acceptable gel, which latter is distributed in a microdisperse mode in a crosslinked silicone elastomer.

Claims

1. An agent useful for transdermal administration of a pharmacologically active agent, comprising:

(a) a matrix of a pharmacologically acceptable crosslinked, silicone elastomer, comprising;

(i) 1-10% by weight of a polydimethylhydrogensiloxane having an average molecular weight of 300-2000;

(ii) 1-10% by weight of a 2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane; and

(iii) 10-100 ppm of platinum catalyst in a vinyl group-terminated polydimethylsiloxane having an average molecular weight of 3000-20,000;

(b) a non-flowable, physiologically acceptable gel microdispersed in said matrix, wherein said gel is based on a combination of a gel-forming thickener, water, and a solvent which is a polyhydric alcohol or a polyvalent ether; and

(c) an active agent dissolved in the microdispersed gel phase in a concentration of at least 50 wt. % based on the gel phase, wherein said matrix is in the form of a sheet having a thickness of 0.5 to 5 mm.

2. An agent of claim 1, wherein the active medicinal agent is a steroid hormone, an ergot compound, a β

-receptor blocker, a prostaglandin, a prostacyclin, a cardioactive glycoside, or a pharmacologically active peptide.

3. An agent of claim 2, wherein the active medicinal agent is a steroid hormone.

4. An agent of claim 3, wherein the agent is an estradiol, norethisterone acetate, levonorgestrel, chlormadinone acetate, cyproterone acetate, desogestrel, gestodene, a testosterone, methandrostenolone or nandrolone.

5. An agent of claim 1 wherein said combination upon which the gel is based further comprises water.

6. An agent of claim 1, wherein the crosslinked silicone elastomer is an addition-crosslinked silicone RTV elastomer.

7. An agent of claim 1, wherein the crosslinked silicone elastomer has a network chain length of 20-500.

8. An agent of claim 7, wherein the crosslinked silicone elastomer has a network chain length of 50-250.

9. An agent of claim 1 wherein the solvent is ethylene glycol, propylene glycol, glycerol, ethylene gylcol monomethyl ether, ethylene glycol dimethyl ether, dimethylisosorbide, diethylene glycol, a diethylene glycol ether or a polyethylene glycol.

10. An agent of claim 1 wherein the thickener is agar-agar, gelatin, gum arabic, a pectin, cellulose, a ether, a polyacrylic compound, a vinyl polymer or a polyether.

11. An agent of claim 1 wherein the thickener is a Carbopol or carboxymethylcellulose.

12. An agent of claim 1 wherein the content of the gel component containing the active agent is 25-75 wt %.

13. An agent of claim 1 wherein the particle size of the gel is 5-500 μ

m.

14. A process for the preparation of an agent useful for transdermal administration of active medicinal agents according to claim 1, comprising suspending the active agent-containing gel in the components required for formation of the crosslinked silicone elastomer, and vulcanizing the thus-obtained suspension.

15. In a method of transdermally administering a pharmacologically active compound in an agent suitable for transdermal administration, the improvement wherein the agent is one of claim 1.

16. An agent of claim 1, wherein the active medicinal agent exhibits a water solubility of about 5% or lower.

17. An agent of claim 2, wherein the gel comprises a gel-forming thickener and an organic solvent having an HLB value from about 2-20.

18. An agent of claim 17, wherein the particle size of the gel is 5-500 μ

m.

19. An agent useful for transdermal administration of a pharmacologically active agent, comprising a solid, self-supporting matrix material having dispersed therein a gel with an active agent dissolved therein, wherein:

said matrix comprises a pharmacologically acceptable, cross-linked, vulcanized silicone elastomer;

said gel is physiologically acceptable and is microdispersed within said matrix at particle sizes of from 5-500 μ

m;

said active agent is present in the gel phase at a concentration of at least 50 wt. % based on the gel phase; and

said matrix material is in the form of a molded sheet having a thickness of 0.5 to 5 mm.

20. An agent of claim 19, wherein the gel is based on a combination of gel-forming thickener, water, and a solvent which is a polyhydric alcohol or a polyvalent ether.

21. An agent as in claim 19, which does not contain a backing layer.

22. An agent of claim 19, wherein the crosslinked silicone elastomer is prepared from a bicomponent system, comprising 1-10% by weight polydimethylhydrogensiloxane having an average molecular weight of 300-2000, 1-10% by weight of 2,4,6,8-tetramethyl-2,4,6,8-tetravinylchlorotetrasiloxane, and 10-100 ppm of platinum catalyst and vinyl group-terminated polydimethylsiloxane having an average molecular weight of 3000-20,000;

wherein the thickener is agar, gelatin, gum arabic, a pectin, carboxymethyl-cellulose, a cellulose ether, a polyacrylic compound, a vinyl polymer, or a polyether;

wherein the solvent is ethylene glycol, propylene glycol, glycerol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, dimethyl isosorbide, diethylene glycol, diethylene glycol ethers, or polyethylene glycols; and

wherein the active agent is estradiol, norethisterone acetate, levonorgestrel, chloromadinone, cyproterone acetate, desogestrel, gestodene, testosterones, methandrostenolone, or nondrolone.

23. An agent of claim 19, wherein the silicone elastomer is vulcanized at 40°

-100 C.