Transdermal pharmaceutical preparation with a progesterone A-specific ligand (PRASL) as active ingredient

• US 20060134188A1
• Filed: 12/19/2005
• Published: 06/22/2006
• Est. Priority Date: 12/20/2004
• Status: Abandoned Application

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Bracht, Stefan, Podhaisky, Hans-Peter
• Application Number:
  US11/311,752
• Publication Number:
  US 20060134188A1
• Time in Patent Office: Days
• US Class Current: 424/449
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61K 9/7061 Polyacrylates
• 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

Abstract

A transdermal patch for hormone therapy and fertility control has a backing layer, an effective-ingredient-containing adhesive layer adhering to the backing layer and a removable protective film. The adhesive layer includes a progestagenic effective ingredient and an estrogen in an adhesive matrix based on a silicone polymer, a polyisobutylene polymer (PIB), a polyacrylate polymer or a styrene block copolymer with butadiene or isoprene (SBS or SIS). The transdermal patch contains from 0.1 to 10%, based on a total weight of the adhesive matrix, of a progestagenic effective ingredient of formula I:
wherein R₁ and R₂ each represent, independently of each other, H or F;
R₃ represents CH₃ or CF₃ and
Ar is a group of formula II or III: or a pharmaceutically suitable derivative thereof.

Claims

1. A transdermal patch comprising a backing layer, at least one effective-ingredient-containing adhesive layer adhering to the backing layer and a removable protective film, wherein said at least one effective-ingredient-containing adhesive layer comprises an effective ingredient and an adhesive matrix based on a silicone polymer, a polyisobutylene polymer, a polyacrylate polymer or a styrene block copolymer with butadiene or isoprene;

wherein said effective ingredient is contained in a concentration of from 0.1 to 10%, based on a total weight of the adhesive matrix; and

wherein said effective ingredient is a compound of formula I;

wherein R₁ and R₂ each represent, independently of each other, H or F;

R₃ represents CH₃ or CF₃ and

Ar is a group of formula II or III;

or a pharmaceutically suitable derivative thereof (progesterone A-specific ligand, PRASL).

2. The transdermal patch as defined in claim 1, wherein said concentration of said effective ingredient is from 0.1 to 5%, based on a total weight of the adhesive matrix.

3. The transdermal patch as defined in claim 1, wherein said concentration of said effective ingredient is from 0.1 to 2%, based on a total weight of the adhesive matrix.

4. The transdermal patch as defined in claim 1, wherein the effective ingredient has a solubility of 0.1 to 5% in said at least one effective-ingredient-containing adhesive layer.

5. The transdermal patch as defined in claim 1, wherein the effective ingredient has a solubility of 0.5 to 2% in said at least one effective-ingredient-containing adhesive layer.

6. The transdermal patch as defined in claim 1, wherein less than 50% of the effective ingredient is embedded in the adhesive matrix in undissolved form.

7. The transdermal patch as defined in claim 6, wherein the effective ingredient embedded in the adhesive matrix in undissolved form is in the form of microparticles and microdroplets dispersed in the adhesive matrix.

8. The transdermal patch as defined in claim 6, wherein the effective ingredient embedded in the adhesive matrix in undissolved form is in the form of nanoparticles and nanodroplets dispersed in the adhesive matrix.

9. The transdermal patch as defined in claim 6, wherein the effective ingredient embedded in the adhesive matrix in undissolved form is in an amorphous state.

10. The transdermal patch as defined in claim 1, wherein the at least one effective-ingredient-containing adhesive layer comprises a crystallization inhibitor and said crystallization inhibitor is selected from the group consisting of N-vinyl lactam polymers, polymers of vinyl pyrrolidone and copolymers of vinyl pyrrolidone and vinyl acetate.

11. The transdermal patch as defined in claim 1, wherein said adhesive martrix comprises a crystallization inhibitor and said crystallization inhibitor is selected from the group consisting of polyvidone, N-vinyl-1-aza-cycloheptan-2-one homopolymers and N-vinylpiperdin-2-one homopolymers.

12. The transdermal patch as defined in claim 1, wherein said adhesive matrix contains a copovidone as a crystallization inhibitor and said copovidone contains 6 parts vinyl pyrrolidone and 4 parts vinyl acetate.

13. The transdermal patch as defined in claim 1, wherein said at least one effective-ingredient-containing adhesive layer contains a silicone-based adhesive, and said silicone-based adhesive comprises a polymer and resin with a large portion of the polymer in comparison to the resin.

14. The transdermal patch as defined in claim 1, wherein said at least one effective-ingredient-containing adhesive layer contains a silicone-based adhesive, and wherein said silicone-based adhesive is amine-compatible and comprises a polymer and resin with a mass ratio of the polymer to the resin of greater than or equal to a value in a range between 40% and 60%.

15. The transdermal patch as defined in claim 1, wherein said at least one effective-ingredient-containing adhesive layer contains a polyisobutylene-based adhesive.

16. The transdermal patch as defined in claim 1, further comprising an estrogen selected from the group consisting of 17β

-estradiol, ethinyl estradiol, estradiol valerate, estradiol cypionate, estradiol lactate and estradiol benzoate.

17. The transdermal patch as defined in claim 1, wherein more than 30% of a total amount of said effective ingredient contained therein is released during a seven day application cycle.

18. The transdermal patch as defined in claim 1, wherein more than 50% of a total amount of said effective ingredient contained therein is released during a seven day application cycle.

19. A method of making a transdermal patch,

wherein said transdermal patch comprises a backing layer, at least one effective-ingredient-containing adhesive layer adhering to the backing layer and a removable protective film, wherein said at least one effective-ingredient-containing adhesive layer comprises an effective ingredient and an adhesive matrix based on a silicone polymer, a polyisobutylene polymer, a polyacrylate polymer or a styrene block copolymer with butadiene or isoprene;

wherein said effective ingredient is contained in a concentration of from 0.1 to 10%, based on a total weight of the adhesive matrix; and

wherein said effective ingredient is a compound of formula I;

wherein R₁ and R₂ each represent, independently of each other, H or F;

R₃ represents CH₃ or CF₃ and

Ar is a group of formula II or III;

or a pharmaceutically suitable derivative thereof (progesterone A-specific ligand, PRASL); and

wherein said method comprises the steps of;

a) taking up the effective ingredient in a combination of solvents having a comparatively low solubility for the effective ingredient and a solvent having a comparatively high solubility for the effective ingredient to form an effective-ingredient-containing mixture;

b) mixing the effective-ingredient-containing mixture with the adhesive matrix to form a resulting batch; and

c) removing the solvent having the comparatively high solubility for the effective ingredient from the resulting batch.

20. The method as defined in claim 19, wherein the solvent with the comparatively low solubility for the effective ingredient is 1,4-dioxane and the solvent with the comparatively high solubility for the effective ingredient is heptane.