Hot melt TTS for administering rotigotine

• US 9,186,335 B2
• Filed: 07/29/2003
• Issued: 11/17/2015
• Est. Priority Date: 07/30/2002
• Status: Active Grant

• Current Assignee: Schwarz Pharma, UCB Pharma GmbH (UCB SA)
• Original Assignee: UCB Pharma GmbH (UCB SA)
• Inventors: Breitenbach, Armin, Wolff, Hans-Michael
• Primary Examiner(s): AHMED, HASAN SYED
• Application Number:
  US10/523,908
• Publication Number:
  US 20050260254A1
• Time in Patent Office: 4,494 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/381 having five-membered rings
• 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: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention relates to a transdermal therapeutic system (TTS) which contains a rotigotine-containing adhesive layer and is characterized by the fact that the adhesive layer contains a hot-meltable contact adhesive. The invention also relates to the use of rotigotine for producing the adhesive layer of a TTS in a hot melt method, and a method for producing such a TTS.

Claims

1. A transdermal therapeutic system comprising a drug-containing adhesive matrix, wherein the drug-containing adhesive matrix comprises:

a solidified melt comprising rotigotine free-base present in an amount of 1-40 weight % with a purity level above 98% and

a hot-melt adhesive present in an amount of 50-99 weight % ,

wherein the drug-containing adhesive matrix exhibits at 160°

C. a dynamic viscosity of not more than 100 Pa·

s and

wherein the drug-containing adhesive matrix is produced by metering the rotigotine free-base into a solvent-free melt at a temperature of between 70°

C. and 200°

C.

2. The transdermal therapeutic system of claim 1 wherein the rotigotine free-base is dispersed or partly or completely dissolved in said hot-melt adhesive.

3. The transdermal therapeutic system of claim 1 wherein the metering of the rotigotine free-base into the solvent-free melt is at a temperature of between 120°

C. and 160°

C.

4. The transdermal therapeutic system of claim 1 wherein the hot-melt adhesive consists of a mixture of an amine-resistant silicone adhesive and at least one suitable softener.

5. The transdermal therapeutic system of claim 4 wherein the softener is an organic wax.

6. The transdermal therapeutic system of claim 4 wherein the softener is ceresine or ozokerite.

7. The transdermal therapeutic system of claim 1 wherein the proportion of rotigotine free-base in the adhesive layer is 4 to 40 weight %.

8. The transdermal therapeutic system of claim 1 wherein the proportion of rotigotine free-base in the adhesive layer is 9 to 30 weight %.

9. The transdermal therapeutic system of claim 1 wherein the proportion of rotigotine free-base in the adhesive layer is 20 to 40 weight %.

10. The transdermal therapeutic system of claim 1 wherein the drug-containing adhesive matrix additionally contains an internal-phase component selected from the group consisting of

(a) hydrophilic and amphiphilic polymers;

(b) hydrophilic and amphiphilic copolymers;

(c) mixtures of (a) and/or (b) with pharmaceutically acceptable softeners;

(d) condensates from glycerin and fatty acids or polyols; and

(e) suitable mixtures of the components (a)-(d).

11. The transdermal therapeutic system of claim 10 wherein the internal-phase component is selected from the group consisting of polysaccharides, substituted polysaccharides, polyethylene oxides, polyvinyl acetates, polyvinyl pyrrolidones, copolymers from polyvinyl pyrrolidone and (poly)vinyl acetate, polyethylene glycol, polypropylene glycol, copolymers from ethylene and vinyl acetate, glycerin-fatty acid esters and mixtures of polyvinyl alcohol with glycerin.

12. (Withdrawn and Previously Presented) The transdermal therapeutic system of claim 1 wherein the adhesive matrix comprises:

(a) 50-99 weight % of said hot-melt adhesive;

(b) 4-40 weight % rotigotine in the base form;

(c) 0-40 weight % of an internal-phase component; and

(d) 0-10 weight % of other adjuvants.

13. The transdermal therapeutic system of claim 1 wherein the hot-melt adhesive is

(a1) an EVA adhesive,

(a2) an SxS adhesive, or

(a3) a mixture of

(i) 70-99 weight % of an amine-resistant silicone adhesive and

(ii) 1-30 weight % of a suitable softener.

14. The transdermal therapeutic system of claim 1 comprising:

a layer that comprises the rotigotine free-base, wherein the layer

(a) contains the rotigotine free-base in a percentile proportion of 20-40 weight %,

(b) has a rotigotine free-base content of at least 2.0 mg/cm², and

(c) optionally contains an organic wax and/or internal-phase component in an amount sufficient to retard the release of the rotigotine free-base.

15. The transdermal therapeutic system of claim 14 wherein rotigotine is transported through the skin at a steady-state flux rate of 100-500 μ

g per hour over a period of at least 5 days.

16. The transdermal therapeutic system of claim 14 wherein rotigotine is transported through the human skin at a flux rate of 100-500μ

g per hour over a period of at least 7 days.

17. The transdermal therapeutic system of claim 14 wherein the system induces in the patient an average plasma concentration of 0.4 to 2 ng/ml rotigotine for a period of at least 5 days.

18. A method for producing the transdermal therapeutic system of claim 1, the method comprising:

prior to lamination, components of the adhesive matrix are melted and homogenized, solvent-free, at temperatures of between 70°

C. and 200°

C.

19. The method of claim 18 wherein components of the adhesive matrix are melted and homogenized in an extruder.

20. The method of claim 18 wherein the hot-melting process takes place at temperatures between 120°

C. and 160°

C.

21. The method of claim 18 wherein the rotigotine free-base is introduced, in the adhesive matrix melt, in its solid state.

22. The method of claim 18 wherein the adhesive matrix, produced by the hot-melting process, contains the rotigotine free-base at a purity level of at least 98% as measured by HPLC at 220 nm and 272 nm.