Transdermal therapeutic system for extended dosing of pramipexole in treating neurological disorders

Patent metadata

Field	Value
Publication number	US-9682068-B2
Application number	US-201414893020-A
Country	US
Kind code	B2
Filing date	May 19, 2014
Priority date	May 20, 2013
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

This disclosure relates to a transdermal therapeutic system (TTS) containing pramipexole or related compounds and methods of making the system as well as its use in administering such compounds as a single dose over an extended period, for example, one week. The system comprises an acrylic-based or silicone-based matrix layer containing pramipexole at concentrations of at least about 5 wt. % of the matrix, which is resistant to crystallizing and discoloration of the active ingredient even when stored over long periods.

First claim

What is claimed is:

1. A transdermal therapeutic system (TTS) for the administration of one or more active ingredients selected from the group consisting of pramipexole, pharmaceutically acceptable pramipexole salts, and pharmaceutically acceptable pramipexole derivatives, the system comprising:
(i) a substantially active-ingredient-impermeable backing layer,
(ii) at least one matrix layer which contains at least about 5% to 10% w/w active ingredient(s), and
(iii) a substantially impermeable protective release liner layer which releasably contacts the matrix layer or other adhesive layer;

wherein 1) the matrix layer comprises an adhesive selected from acrylate-based adhesive and silicone-based adhesive, 2) the transdermal therapeutic system provides a therapeutically effective administration of the active ingredient(s), at a flux rate ranging from 1 μg/cm 2 /hr to 4.6 μg/cm 2 /hr between the 96 th and 168 th hour after treatment is initiated, and 3) the matrix layer is color-stable and lacks crystal growth of the active ingredient, over an extended storage period of at least one of 30 or more days, 90 or more days, and 180 or more days.

2. The transdermal therapeutic system of claim 1 , wherein the active-ingredient-containing matrix layer contains from about 5.5% to about 7% w/w active ingredient(s) and provides a therapeutically effective flux profile ranging from about 1 μg/cm 2 /hr to 4.6 μg/cm 2 /hr between the 96 th hour and 168 th hour after treatment is initiated.

3. The transdermal therapeutic system of claim 1 , wherein the active-ingredient-containing matrix layer provides a therapeutically effective flux profile ranging from about 1.2 μg/cm 2 /hr to 4.6 μg/cm 2 /hr 168 hours after treatment is initiated.

4. The transdermal therapeutic system of claim 1 , wherein the active ingredient comprises pramipexole free base.

5. The transdermal therapeutic system of claim 1 , wherein the active ingredient comprises one or more salts of pramipexole comprising reaction products of pramipexole or a pramipexole derivative and an acid.

6. The transdermal therapeutic system of claim 1 , wherein the matrix layer is self-adhesive.

7. The transdermal therapeutic system of claim 1 , wherein the matrix layer comprises an acrylate-based adhesive comprising polyacrylate lacking a carboxylic acid functional group.

8. The transdermal therapeutic system of claim 7 , wherein the matrix layer comprises a polymer material free of solubilizers and/or crystal growth inhibitors.

9. The transdermal therapeutic system of claim 7 , wherein the matrix layer comprises 0 wt. % to about 20 wt. % of a solubilizer and/or crystal growth inhibitor.

10. The transdermal therapeutic system of claim 7 , wherein the matrix layer comprises from about 2.5 wt. % to about 17.5 wt. % of a solubilizer and/or crystal growth inhibitor.

11. The transdermal therapeutic system of claim 7 , wherein the matrix layer comprises about 10 wt. % of a solubilizer and/or crystal growth inhibitor.

12. The transdermal therapeutic system of claim 9 , wherein the solubilizer and/or crystal growth inhibitor is selected from the group consisting of optionally saturated and/or unsaturated fatty alcohols each containing from 8 to 18 carbon atoms; tea tree oil; saturated and/or unsaturated cyclic ketones; alkyl methyl sulfoxides; saturated and/or unsaturated fatty acids each containing from 8 to 18 carbon atoms; esters and salts thereof; natural vitamin E; synthetic vitamin E and/or vitamin E derivatives; sorbitan fatty acid esters and/or ethoxylated sorbitan fatty acid esters; azones (laurocapram); 1-alkylpyrrolidone; polyvinylpyrrolidone; block copolymers of polyethylene glycol and dimethylsiloxane with a cationic group at one end; polysiloxanes; polyoxyethylene-10-stearyl ether; mixture of polyoxyethylene-10-stearyl ether and glyceryl dilaurate; dodecyl-2-(N,N-dimethylamino)-propanol tetradecanoate and/or dodecyl-2-(N,N-dimethylamino)-propionate; N-acetylprolinate esters with >8 carbon atoms; non-ionic surfactants, for example lauryl ethers and/or esters of polyoxyethylene; dimethyl(arylimino)sulfuran; mixture of oleic acid analogues and propylene glycol; mixture of octyl salicylate, isopropyl myristate, isopropyl palmitate, octylmethoxy cinnamate and laurocapram or a mixture of individual components; phospholipids; highly dispersed silicon dioxide; polyoxyethylene-7-glycerol monococoate; 2-octyldodecanol or a mixture of various individual components.

13. The transdermal therapeutic system of claim 9 , wherein the solubilizer and/or crystal growth inhibitor is polyvinylpyrrolidone.

14. The transdermal therapeutic system of claim 1 , wherein the active ingredient matrix layer contains from about 5.5% to about 7% w/w active ingredient(s).

15. A method for preparing a transdermal therapeutic system according to claim 1 which comprises:
i) providing an active-ingredient containing matrix layer by:
1) forming a mixture comprising a) active ingredient pramipexole free base, b) a solvent selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and tert-butanol, acetone, pentane, hexane, heptane, ethyl acetate, isopropanol, toluene, xylene, 2,4-pentanedione, and water, and c) an optional solubilizer and/or crystal growth inhibitor;
2) dissolving the mixture to provide a dissolved mixture;
3) combining the dissolved mixture with a matrix forming ingredient to form a pramipexole-containing matrix precursor mixture; and
4) optionally degassing the matrix precursor mixture to provide a degassed matrix precursor mixture;

ii) coating one side of a release liner film with the matrix precursor mixture or optionally degassed matrix precursor mixture; and
iii) laminating a backing film to the coated side of the release liner film.

16. The method of claim 15 , wherein the solvent comprises ethanol, the dissolving step comprises sonication, the optional solubilizer and/or crystal growth inhibitor comprises polyvinylpyrrolidone, and the matrix forming ingredient comprises an adhesive selected from acrylate-based adhesive and silicone-based adhesive.

17. The method of claim 16 , wherein the adhesive comprises polyacrylate lacking a carboxylic acid functional group.

18. The method of claim 15 , wherein the optional solubilizer and/or crystal growth inhibitor comprises polyvinylpyrrolidone.

19. The method of claim 15 , wherein the adhesive comprises silicone-based adhesive, silicone oil, and colloidal silicon dioxide.

20. A method for administering pramipexole to a human subject in need thereof, which method comprises:
i) providing a transdermal dosage form according to claim 1 ; and
ii) applying the dosage form onto an area of skin of the subject in an amount sufficient to provide a therapeutic concentration of pramipexole in the bloodstream or the subject.

21. The method according to claim 20 , wherein the human subject is in need of pramipexole to treat a neurological disorder.

22. The method according to claim 21 , wherein the human subject is in need of pramipexole to treat a condition selected from the group consisting of Parkinson's Disease, Restless Legs Syndrome, Tourette's Syndrome, Chronic Tic Disorder, Essential Tremor, and Attention Deficit Hyperactivity Disorder.

23. The method according to claim 20 , which comprises applying up to about 10 grams of the dosage form daily to a skin surface area of about 50 to about 500 cm 2 .

24. The method according to claim 20 , whe

Assignees

• Mylan Inc

Inventors

• Deshmukh Abhijit Mukund
• Dixit Akhilesh
• Kumar Prasanna
• Bindra Vikram

Classifications

• A61K9/7061

  Polyacrylates · CPC title

• A61F13/025

  having a special distribution arrangement of the adhesive · CPC title

• A61K9/7069

  obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide · CPC title

• A61K31/428 Primary

  condensed with carbocyclic rings · CPC title

• A61F13/0283

  for making adhesive or cohesive tape or fabrics therefor, e.g. coating or mechanical treatments · CPC title