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1. (WO2019043172) TRANSDERMAL DELIVERY SYSTEM INCLUDING AN EMULSIFIER
注意: このテキストは、OCR 処理によってテキスト化されたものです。法的な用途には PDF 版をご利用ください。

CLAIMS

1. Transdermal therapeutic system for the transdermal administration of an active agent

comprising an active agent-containing layer structure, the active agent-containing layer structure comprising

A) a backing layer, and

B) a biphasic matrix layer, the biphasic matrix layer having

a) a continuous, outer phase having a composition comprising 70 to 100 % by weight of at least one polymer,

b) a discontinuous, inner phase having a composition comprising the active agent and a dissolver for the active agent in amount sufficient so that the active agent forms a solution with the dissolver in the inner phase,

wherein the discontinuous, inner phase forms dispersed deposits in the continuous, outer phase,

and

c) an emulsifier in an amount of 0.1 to 20 % by weight based on the biphasic matrix layer,

wherein the emulsifier is selected from a group consisting of emulsifiers which, when blended at about 500 to 1500 rpm with an equal weight amount of the composition of the continuous, outer phase for about 1 hour in a test tube, provide a mixture with the composition of the continuous, outer phase showing less than 20 % of phase separation after storage for about 24 hours at about 20 °C, determined by comparing the height of the separated phase in the test tube and the height of the total content in the test tube.

2. Transdermal therapeutic system in accordance with claim 1, wherein the biphasic matrix layer contains 0.1 to less than 20 %, or 0.5 to 10%, or 0.5 to 5% by weight of the emulsifier.

3. Transdermal therapeutic system in accordance with any one of claims 1 or 2, wherein the emulsifier is selected from the group consisting of an emulsifier based on polysiloxane, an emulsifier based on polyisobutylene, an emulsifier based on ethoxylated castor oil, an emulsifier based on poloxamer, and mixtures thereof.

4. Transdermal therapeutic system in accordance with any one of claims 1 to 3, wherein the emulsifier is based on polysiloxane.

5. Transdermal therapeutic system in accordance with claim 1 to 4, wherein the emulsifier comprises at least one polydimethylsiloxane copolymerized or crosspolymerized with at least polyethylene glycol.

6. Transdermal therapeutic system in accordance with claim 5, wherein the polyethylene glycol has an average number of ethylene oxide repeating units of 10 to 20.

7. Transdermal therapeutic system in accordance with any one of claims 1 to 6, wherein the emulsifier is based on polysiloxanes selected from the group consisting of PEG- 12 dimethicone crosspolymer, PEG- 10 dimethicone, PEG- 12 dimethicone, PEG/PPG- 18/1 8 dimethicone, PEG/ PPG- 19/ 19 dimethicone, bis-isobutyl PEG/PPG- 18/18 dimethicone copolymer, and mixtures thereof.

8. Transdermal therapeutic system in accordance with any one of claims 1 to 3, wherein the emulsifier is based on polyisobutylene, preferably comprising at least one polyisobutylene linked to a succinic acid derivative.

9. Transdermal therapeutic system in accordance with any one of claims 1 to 3, wherein the emulsifier is based on ethoxylated castor oil selected from the group consisting of polyoxyl 35 hydrogenated castor oil, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, and mixtures thereof.

10. Transdermal therapeutic system in accordance with any one of claims 1 to 3, wherein the emulsifier is based on poloxamer, wherein preferably the two polyethyle oxide blocks of the poloxamer have an ethylene oxide repeating units number of 12 and the propylene oxide block of the poloxamer has a propylene oxide repeating units number of 20.

1 1. Transdermal therapeutic system in accordance with any one o claims 1 to 10, wherein the at least one polymer in the continuous, outer phase is polysiloxane or polyisobutylene.

12. Transdermal therapeutic system in accordance with any one of claims 1 to 1 1 , wherein the at least one polymer in the continuous, outer phase is a pressure-sensitive adhesive polymer.

13. Transdermal therapeutic system in accordance with any one of claims 1 to 12, wherein the active agent is contained in an amount of from 1 to 30 % by weight based on the biphasic matrix layer, and/or wherein the active agent is contained in an amount of from 0.1 to 5 mg em2 based on the biphasic matri layer.

14. Transdermal therapeutic system in accordance with any one of claims 1 to 13, wherein the active agent is selected from the group consisting of buprenorphine and diclofenac.

15. Transdermal therapeutic system in accordance with any one of claims 1 to 14, wherein the biphasic matrix layer has an area weight of more than 60 g/m2.

16. Transdermal therapeutic system in accordance with any one of claims 1 to 15, wherein the dissolver for the active agent is selected from the group consisting of carboxylic acids, long-chain alcohols with more than four carbon atoms, fatty alcohols, polyoxyethylene ethers of fatty alcohols, long-chain esters with more than four carbon atoms, fatty acid esters or mixtures thereof.

17. Transdermal therapeutic system in accordance with claim 16, wherein the active agent is in solution in a carboxylic acid to form an active agent-carboxylic acid mixture in the

discontinuous, inner phase of the biphasic matrix layer.

18. Transdermal therapeutic system in accordance with any one of claims 1 to 17, wherein the biphasic matrix layer further comprises a viscosity-increasing substance, preferably in an amount of from about 0.1% to about 8% by weight o the biphasic matrix layer.

19. Transdermal therapeutic system in accordance with any one of claims 1 to 18, wherein the dissolver for the active agent is a carboxylic acid and the carboxylic acid is contained in an amount of from 2 to 20 %, preferably from 5 to 15%, in particular from 6 to 12%, by weight based on the biphasic matrix layer.

20. Transdermal therapeutic system in accordance with any one of claims 1 to 19, wherein the active agent-containing layer structure is an active agent-containing self-adhesive layer structure, and wherein preferably the biphasic matrix layer is the skin contact layer.

21. Transdermal therapeutic system in accordance with any one of claims 1 to 20, wherein the active agent is buprenorphine, for use in a method of treating pain, preferably for use in a method of treating pain wherein the transdermal therapeutic system is applied for 7 days on the skin of a patient.

22. Transdermal therapeutic system in accordance with any one of claims 1 to 20, wherein the active agent is diclofenac, for use in a method of treating patients suffering from

pain/inflammation such as osteoarthritis, shoulder periarthritis, muscle pain, low back pain, rheumatism, bruises, pulled muscles, lumbago, arthrosis, sweat gland abscess, or Multiple system atrophy.

23. Transdermal therapeutic system in accordance with any one of claims 1 to 20, wherein a therapeutically effective amount of diclofenac is provided for about 24 hours by said transdermal therapeutic system during an administration period on the skin o a human patient of about 24 hours.

24. Use of an emulsifier to reduce the maximum size of the dispersed deposits in a biphasic coating mixture during the process of preparing a transdermal therapeutic system in accordance with any one of claims 1 to 23.

25. Use of an emulsifier to reduce the maximum size of the dispersed deposits in the biphasic matrix layer of a transdermal therapeutic system in accordance with any one of claims 1 to 23.

26. Use of an emulsifier based on polysiloxane in a transdermal therapeutic system with an active agent-containing biphasic matrix layer having a discontinuous, inner phase and a continuous, outer phase for controlling the maximum sphere size of the discontinuous, inner phase of the biphasic matrix layer.

27. Use of an emulsifier selected from the group consisting of an emulsifier based on polyisobutylene, an emulsifier based on ethoxylated castor oil, and an emulsifier based on poloxamer in a transdermal therapeutic system with an active agent-containing biphasic matrix layer having a discontinuous, inner phase and a continuous, outer phase for controlling the maximum sphere size of the discontinuous, inner phase of the biphasic matrix layer

28. Method of stabilizing a biphasic coating mixture that comprises a discontinuous, inner phase having a composition comprising an active agent and a dissolver for the active agent in amount sufficient so that the active agent forms a solution with the dissolver in the inner phase, the inner phase forming dispersed deposits in a continuous, outer phase comprising a polymer, by mixing the biphasic coating mixture with an emulsifier that is selected from a group consisting of emulsifiers which, when blended at about 500 to 1500 rpm with an equal weight amount of the composition of the continuous, outer phase for about 1 hour in a test tube, provide a mixture with the composition of the continuous, outer phase showing less than 20 % of phase separation after storage for about 24 hours at about 20 °C, determined by comparing the height of the separated phase in the test tube and the height of the total content in the test tube.

29. Method of manufacture of a biphasic matrix layer comprising the steps of:

(1 ) preparing a stabilized biphasic coating mixture in accordance with claim 28,

(2) coating the stabilized biphasic coating mixture on a film in an amount to provide a

desired area weight,

(3) evaporating the solvents to provide a biphasic matrix layer with the desired area weight.

30. Method of manufacture of a transdermal therapeutic system in accordance with any one of claim 1 to 23, comprising the steps of:

(1 ) providing a stabilized biphasic coating mixture comprising

a. a polymer,

b. an active agent,

c. a dissolver for the active agent

d. an em ul si tier,

e. a solvent,

f. optionally a viscosity-increasing substance,

(2) coating the stabilized biphasic coating mixture on a film in an amount to provide the desired area weight,

(3) evaporating the solvents to provide a biphasic matrix layer with the desired area weight,

(4) laminating the biphasic matrix layer to a backing layer to provide an active agent- containing layer structure,

(5) optionally laminating the active agent-containing layer structure to an additional skin contact layer,

(6) optionally punching the individual systems from the buprenorphine-containing self- adhesive layer structure with the desired area of release, and

(7) optionally adhering to the individual systems an active-free self-adhesive layer structure comprising also a backing layer and an active agent- free pressure-sensitive adhesive layer and which is larger than the individual systems of buprenorphine-containing self- adhesive layer structure.