Matrix-type transdermal patch for steroid hormones

• US 6,440,454 B1
• Filed: 04/09/2001
• Issued: 08/27/2002
• Est. Priority Date: 06/22/1998
• Status: Expired due to Fees

• Current Assignee: Rottapharm Ltd. (Mylan N.V.)
• Original Assignee: ROTTAPHARM BV
• Inventors: Rovati, Lucio C., Santoro, Antonino
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Sheikh, Humera N.
• Application Number:
  US09/720,324
• Time in Patent Office: 505 Days
• Field of Search: 424/402, 424/443, 424/447, 424/449, 424/484, 424/448
• US Class Current: 424/449
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention refers to a transdermal patch for the release of Estradiol and at least one progestogen agent through the skin, comprising or consisting of an outer backing foil, a matrix and a protective liner wherein a) the Estradiol and the progestogen agent(s) are present in the matrix in an oversaturated solution, b) the matrix contains 1 to 5 wt% activated SiO2, and c) the matrix has a moisture content of less than 0.7 wt.-%. The patch can be used for hormonal replacement therapy.

Claims

1. A transdermal patch for the release of estradiol and at least one progestogen agent through the skin, comprising an outer backing foil, a matrix and a protective liner wherein:

(a) the estradiol and the progestogen agents (s) are present in the matrix in an supersaturated solution,

(b) the matrix contains 1 to 4 wt % activated SiO₂, and

(c) the matrix has a moisture content of less than 0.7% wt.-%.

2. A transdennal patch according to claim 1 wherein the matrix has moisture content of less than 0.5 wt.-%.

3. A transdennal patch according to claim 1 wherein the matrix contains 2.5 to 3.5 wt % SiO₂.

4. A transdermal patch according to claim 1 wherein the SiO₂ is activated by irradiation with an infrared souce.

5. A transdermal patch according to claim 1 which is free of penetration enhancers.

6. A transdermal patch according to claim 1 wherein the matrix comprises one, two or more pressure sensitive adhesive copolymers obtainable by radical copolymerization of:

2-ethylhexyl acrylate,

hydroxyethyl acrylate,

vinylacetate and

glycidyl methacrylate,

in Quantities of up to 0.5 wt.-%, based on the weight of the matrix.

7. A transdermal patch according to claim 6 wherein the monomers are used in the following amounts:

2-ethylhexyl acrylate is used in an amount of 44 to 80 wt.-%,

hydroxyethyl acrylate is used in an amount of 2.5 to 9.7 wt.-%,

vinylacetate is used in an amount of 8 to 48.2 wt.-%, and

glycidyl methacrylate is used in an amount of 0.01 to 0.3 wt.-% all percentages being based on the weight of the matrix.

8. A transdermal patch according to claim 1 wherein the matrix has a thickness of 20 to 100 μ

m.

9. A transdermal patch according to claim 1, wherein the matrix has an estradiol content of 1 to 3 wt.-%.

10. A transdermal patch according to claim 1, wherein the matrix has a progestogen agent content of 2 to 12 wt.-%.

11. A transdermal patch according to claim 1 wherein the matrix has a content of other compounds of up to 4 wt. %.

12. A transdermal patch according to claim 1 wherein the progestogen agent is norethindrone acetate.

13. A transdermal patch according to claim 1 wherein:

the backing foil comprises a material impermeable to the drugs and to the adhesive copolymer(s);

a side of the backing foil not facing the matrix is lacquered; and

the backing foil has a thickness of 10 to 50 μ

m.

14. A transdermal patch according to claim 1 wherein the patch comprises a removable protective liner,

made of at least one foil of paper, polyester, polyethylene, polyethylene terephtalate, polypropylene or polyvinylchloride or mixtures thereof,

having thickness of 50 to 200 μ

m; and

being provided with a cut-off tag and a stamped profile ring.

15. A transdermal patch according to claim 1, having a circular or oval shape or a square shape with round edges, and a release area of 5 to 60 cm².

16. A transdermal patch according to claim 1, wherein it is sealed in a sachet comprising a humidity impermeable foil which is made of sheets of aluminum, paper, polyethylene, polyvinylchloride or ionomer foil.

17. A transdermal patch according to claim 16, wherein the sachet contains a desiccant taken from the group comprising silica gel, sodium sulfate, calcium sulfate, calcium carbonate dihydrate or a mixture thereof.

18. A process for the production of a transdermal patch according to claim 1 which includes the steps of:

a) providing estradiol and at least one progestogen agent which are mixed with a copolymer solution,

b) adding silicon dioxide to the mixture,

c) applying the mixture to a backing layer to form a laminate,

d) applying the mixture at a temperature from 35 to 95°

C.,

e) irradiating the laminate with IR-rays, and

f) covering the laminate a protective liner.

19. A method of manufacture of a medicament for hormonal replacement therapy comprising the step of creating a transdermal patch in accordance with claim 1.

20. A transdermal patch according to claim 7 wherein:

2-ethylhexyl acrylate is in an amount of 48 to 75 wt.-%,

hydroxyethyl acrylate is in an amount of 4.0 to 5.0 wt.-%, and glycidyl methacrylate is in an amount of 0.1 to 0.2 wt.-%.

21. A transdermal patch in accordance to claim 7 wherein:

2-ethythexyl acrylate is in an amount of 50 to 68 wt.-%.

22. A transdermal patch according to claim 9 wherein the estradiol content is 1.5 to 2.5 wt.-%.

23. A transdermal patch according to claim 9 wherein the estradiol content is 1.8 to 2.4 wt.-%.

24. A transdermal patch according to claim 10 wherein the progestogen agent content is 4 to 11 wt.-%.

25. A transdermal patch according to claim 10 wherein the progestogen agent content is 5 to 9 wt.-%.

26. A transdermal patch according to claim 13 wherein:

the backing foil is made from one or more materials selected froze group consisting of polyester, polyurethane, polyethylene, polyethylene terephtalate, polypropylene and polyvinyl chloride materials;

the side of the backing foil comprises epoxy resins or polyaminoamido resins containing opacifying agents; and

the backing foil has a thickness of 12 to 30 μ

m.

27. A transdermal patch according to claim 14 wherein the patch comprises a removable protective liner that is coated with silicone or a fluropolymer on one or both sides, and has a thickness of 80 to 150 μ

m.

28. A transdermal patch according to claim 15 wherein the release area is 8 to 40 cm².

29. A transdermal patch according to claim 16 wherein the sachet comprises a multi-layered foil.