Eva-based transdermal matrix system for the administration of an estrogen and/or a progestogen

• US 5,605,702 A
• Filed: 03/28/1995
• Issued: 02/25/1997
• Est. Priority Date: 03/28/1994
• Status: Expired due to Fees

• Current Assignee: Laboratoires D'Hygiene Et De Dietetique
• Original Assignee: Laboratoires D'Hygiene Et De Dietetique
• Inventors: Sawaya, Antoine, Teillaud, Eric, Math, Marie-Christine
• Primary Examiner(s): Phelan, D. Gabrielle
• Application Number:
  US08/413,208
• Time in Patent Office: 700 Days
• Field of Search: 424/448, 424/449, 514/946
• US Class Current: 424/448
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system

Abstract

The present invention relates to a new self-adhesive transdermal matrix system for the administration of a hormone by percutaneous route, said system which comprises a support and self-adhesive matrix, having a matrix comprising:

(a) 40 to 60 parts by weight of an ethylene/vinyl acetate copolymer,

(b) 5 to 20 parts by weight of a cellulosic material,

(c) 35 to 55 parts by weight of at least one compound selected from the group consisting of: crotamiton, N-substituted 2-pyrrolidones of the formula I, ##STR1## in which the R group represents a (C₁ -C₁₅)-alkyl, cyclohexyl or 2-hydroxyethyl group, and higher C₁₂ -C₂₀ aliphatic alcohols, and

(d) 0,01 to 7 parts by weight of a hormone selected from the group consisting of estrogen components, progestogen components and mixtures thereof.

It also relates to a method for preparing this transdermal matrix system.

Claims

1. A self-adhesive transdermal matrix system for the administration by percutaneous route of a hormone, said system, which comprises a support and self-adhesive matrix, having a matrix consisting essentially of:

(a) 40 to 60 parts by weight of an ethylene/vinyl acetate copolymer,

(b) 5 to 20 parts by weight of a cellulose compound,

(c) 35 to 55 parts by weight of at least one compound selected from the group consisting of;

crotamiton,

N-substituted 2-pyrrolidones of the formula I, ##STR3## in which the R group represents a (C₁ -C₁₅)-alkyl, cyclohexyl or 2 - hydroxyethyl group, and higher C₁₂ -C₂₀ aliphatic alcohols, and

(d) 0.01 to 7 parts by weight of a hormone selected from the group consisting of estrogen compounds, progestogen compounds and mixtures thereof.

2. A system according to claim 1 wherein the higher aliphatic alcohol is 2-octyl-1-dodecanol.

3. A system according to claim 1 wherein the compound of the formula I is an N-alkyl-2-pyrrolidone, in which the alkyl group contains from 1 to 15 carbon atoms.

4. A system according to claim 1 wherein the ethylene/vinyl acetate copolymer has a vinyl acetate content of between 30 and 75% by weight with respect to the weight of said copolymer.

5. A system according to claim 1 wherein the hormone is an estrogen compound.

6. A system according to claim 1 wherein the hormone is a progestogen compound.

7. A system according to claim 1, wherein the hormone is a mixture consisting of an estrogen compound.

8. A system according to claim 1, wherein the matrix comprises, per total 100 parts by weight:

(a) 46 parts by weight of EVA,

(b) 10 parts by weight of ethylcellulose,

(c1) 31.5 parts by weight of 2-octyl-1-dodecanol,

(c2) 10.5 parts by weight of N-dodecyl-2-pyrrolidone, and

(d) 2 parts by weight of 17-β

-estradiol.

9. A system according to claim 1, wherein the matrix comprises, per total 100 parts by weight:

(a) 45 parts by weight of EVA,

(b) 10 parts by weight of ethylcellulose,

(c1) 30.75 parts by weight of 2-octyl-1-dodecanol,

(c2) 10.25 parts by weight of N-dodecyl-2-pyrrolidone, and

(d) 4 parts by weight of norethisterone acetate.

10. A system according to claim 1 wherein the matrix comprises, per total 100 parts by weight:

(a) 42 parts by weight of EVA,

(b) 15 parts by weight of ethylcellulose,

(c1) 28 parts by weight of 2-octyl-1-dodecanol,

(c2) 10 parts by weight of N-dodecyl-2-pyrrolidone,

(d1) 2 parts by weight of 17-β

-estradiol, and

(d2) 3 parts by weight of norethisterone acetate.

11. A method for preparing a transdermal matrix system according to claim 1, said method comprising the steps of:

(α

) mixing the EVA and the cellulose compound by stirring at a temperature higher than 110°

C. to form a homogeneous mixture;

(β

) incorporating into the resulting homogeneous mixture, the hormone selected from the group consisting of estrogen compounds, progestogen compounds and mixtures thereof, under continued stirring at a temperature higher than 110°

C., and homogenizing to form a further homogeneous mixture;

(γ

) coating the further homogeneous mixture onto a temporary anti-adherent support, at a temperature of between 100° and

140°

C., in order to obtain a deposit of 50 to 300 g/m₂ on said support to form a matrix; and

(δ

) transferring the matrix thus obtained onto a final support.

12. A method for preparing a transdermal matrix system according to claim 1, said method comprising the steps of:

(α

) successively incorporating while stirring a compound selected from the group consisting of a higher aliphatic alcohol, crotamiton and an N-substituted 2-pyrrolidone of the formula I;

the hormone selected from the group consisting of estrogen compounds, progestogen compounds and mixtures thereof;

the EVA material;

the cellulosic material and the chosen solvent to form a mixture;

(β

) stirring the mixture thus obtained at a temperature lower than the boiling point temperature of the solvent to form a homogeneous mixture;

(γ

) coating the homogeneous mixture onto a temporary anti-adherent support, at a temperature of between 50° and

70°

C., to form a coating of 50 to 300 g/m² on said support;

(δ

) heating the coating thus obtained to evaporate the solvent at a temperature of between 40° and

80°

C. in accordance with the boiling point temperature of the solvent to form a dry matrix;

(ε

) transferring the dry matrix thus obtained to a final support.

13. A system according to claim 3 wherein the compound of formula I is N-dodecyl-2-pyrrolidone.

14. A system according to claim 5, wherein the hormone is 17-β

-estradiol.

15. A system according to claim 6, wherein the hormone is norethisterone acetate.

16. A method for preparing a transdermal matrix system according to claim 11, wherein step (β

) further comprises the step of adding at least one compound selected from the group consisting of crotamiton and an aliphatic alcohol.

17. A method for preparing a transdermal matrix system according to claim 11, comprising the further step of incorporating into the resulting homogeneous mixture of step (β

) the N-substituted 2-pyrrolidone(s) of formula 1, while stirring at a temperature below 110°

C., and homogenizing.

18. A method for preparing a transdermal matrix system according to claim 8, said method comprising the steps of:

(α

) mixing the EVA and the cellulose compound by stirring at a temperature higher than 110°

C. to form a homogeneous mixture;

(β

) incorporating into the resulting homogeneous mixture, the hormone selected from the group consisting of estrogen compounds, progestogen compounds and mixtures thereof, under continued stirring at a temperature higher than 110°

C., and homogenizing to form a further homogeneous mixture;

(γ

) coating the further homogeneous mixture onto a temporary anti-adherent support, at a temperature of between 100° and

140°

C., in order to obtain a deposit of 50 to 300 g/m₂ on said support to form a matrix; and

(δ

) transferring the matrix thus obtained onto a final support.

19. A method for preparing a transdermal matrix system according to claim 18, wherein step (β

) further comprises the step of adding at least one compound selected from the group consisting of crotamiton and an aliphatic alcohol.

20. A method for preparing a transdermal matrix system according to claim 18, comprising the further step of incorporating into the resulting homogeneous mixture of step (β

) the N-substituted 2-pyrrolidone(s) of formula 1, while stirring at a temperature below 110°

C., and homogenizing.

21. A method for preparing a transdermal matrix system according to claim 9, said method comprising the steps of:

(α

) mixing the EVA and the cellulose compound by stirring at a temperature higher than 110°

C. to form a homogeneous mixture;

(β

) incorporating into the resulting homogeneous mixture, the hormone selected from the group consisting of estrogen compounds, progestogen compounds and mixtures thereof, under continued stirring at a temperature higher than 110°

C., and homogenizing to form a further homogeneous mixture;

(γ

) coating the further homogeneous mixture onto a temporary anti-adherent support, at a temperature of between 100° and

140°

C., in order to obtain a deposit of 50 to 300 g/m₂ on said support to form a matrix; and

(δ

) transferring the matrix thus obtained onto a final support.

22. A method for preparing a transdermal matrix system according to claim 21, wherein step (β

) further comprises the step of adding at least one compound selected from the group consisting of crotamiton and an aliphatic alcohol.

23. A method for preparing a transdermal matrix system according to claim 21, comprising the further step of incorporating into the resulting homogeneous mixture of step (β

) the N-substituted 2-pyrrolidone(s) of formula 1, while stirring at a temperature below 110°

C., and homogenizing.

24. A method for preparing a transdermal matrix system according to claim 10, said method comprising the steps of:

(α

) mixing the EVA and the cellulose compound by stirring at a temperature higher than 110°

C. to form a homogeneous mixture;

(β

) incorporating into the resulting homogeneous mixture, the hormone selected from the group consisting of estrogen compounds, progestogen compounds and mixtures thereof, under continued stirring at a temperature higher than 110°

C., and homogenizing to form a further homogeneous mixture;

(γ

) coating the further homogeneous mixture onto a temporary anti-adherent support, at a temperature of between 100° and

140°

C., in order to obtain a deposit of 50 to 300 g/m₂ on said support to form a matrix; and

(δ

) transferring the matrix thus obtained onto a final support.

25. A method for preparing a transdermal matrix system according to claim 24, wherein step (β

) further comprises the step of adding at least one compound selected from the group consisting of crotamiton and an aliphatic alcohol.

26. A method for preparing a transdermal matrix system according to claim 24, comprising the further step of incorporating into the resulting homogeneous mixture of step (β

) the N-substituted 2-pyrrolidone(s) of formula 1, while stirring at a temperature below 110°

C., and homogenizing.

27. A method for preparing a transdermal matrix system according to claim 8, said method comprising the steps of:

(α

) successively incorporating while stirring a compound selected from the group consisting of a higher aliphatic alcohol, crotamiton and an N-substituted 2-pyrrolidone of the formula I;

the hormone selected from the group consisting of estrogen compounds, progestogen compounds and mixtures thereof;

the EVA material;

the cellulose compound and the chosen solvent to form a mixture;

(β

) stirring the mixture at a temperature lower than the boiling point temperature of the solvent, to form a homogeneous mixture;

(γ

) coating the homogeneous mixture onto a temporary anti-adherent support, at a temperature of between 50° and

70°

C., so as to form a coating of 50 to 300 g/m² on said support;

(δ

) heating the coating to evaporate the solvent at a temperature of between 40° and

80°

C. in accordance with the boiling point temperature of the solvent to form a dry matrix;

(ε

) transferring the dry matrix to a final support.

28. A method for preparing a transdermal matrix system according to claim 9, said method comprising the steps of:

(α

) successively incorporating while stirring a compound selected from the group consisting of a higher aliphatic alcohol, crotamiton and an N-substituted 2-pyrrolidone of the formula I;

the hormone selected from the group consisting of estrogen compounds, progestogen compounds and mixtures thereof;

the EVA material;

the cellulose compound and the chosen solvent to form a mixture;

(β

) stirring the mixture at a temperature lower than the boiling point temperature of the solvent, to form a homogeneous mixture;

(γ

) coating the homogeneous mixture onto a temporary anti-adherent support, at a temperature of between 50° and

70°

C., so as to form a coating of 50 to 300 g/m² on said support;

(δ

) heating the coating to evaporate the solvent at a temperature of between 40° and

80°

C. in accordance with the boiling point temperature of the solvent to form a dry matrix;

(ε

) transferring the dry matrix to a final support.

29. A method for preparing a transdermal matrix system according to claim 10, said method comprising the steps of:

(α

) successively incorporating while stirring a compound selected from the group consisting of a higher aliphatic alcohol, crotamiton and an N-substituted 2-pyrrolidone of the formula I;

the hormone selected from the group consisting of estrogen compounds, progestogen compounds and mixtures thereof;

the EVA material;

the cellulose compound and the chosen solvent to form a mixture;

(β

) stirring the mixture at a temperature lower than the boiling point temperature of the solvent, to form a homogeneous mixture;

(γ

) coating the homogeneous mixture onto a temporary anti-adherent support, at a temperature of between 50° and

70°

C., so as to form a coating of 50 to 300 g/m² on said support;

(δ

) heating the coating to evaporate the solvent at a temperature of between 40° and

80°

C. in accordance with the boiling point temperature of the solvent to form a dry matrix;

(ε

) transferring the dry matrix to a final support.