Method for producing a transdermal therapeutic system which contains a D2 agonist
View Patent ↗A substantially solvent-free matrix layer containing (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol is produced by adding an active substance to an adhesive solution, coating the resultant active substance-containing adhesive solution onto a suitable sheet, and removing the solvents in a drying process to give said substantially solvent-free matrix layer.
1. A method for producing a matrix layer suitable for transdermal administration of a therapeutic effective amount of (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol free base, the method comprising:
(a) mixing a solution comprising (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol free base and organic solvent with soluble polyvinylpyrrolidone and amine-resistant silicone adhesive to form a mass;
(b) coating the mass onto a sheet; and
(c) removing solvent in a drying process.
2. The method of claim 1 , wherein the (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol free base is prepared by converting (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol hydrochloride into said free base.
3. The method of claim 2 , wherein said (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol hydrochloride is dissolved or suspended in said organic solvent.
4. The method of claim 2 , wherein an alkaline substance capable of converting said (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol hydrochloride into the free base is added to the organic solvent prior to or following addition thereto of the adhesive and prior to or following addition thereto of the (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol hydrochloride.
5. The method of claim 4 , wherein said alkaline substance comprises an alkali metal hydroxide or an alkali metal silicate.
6. The method of claim 4 , wherein said alkaline substance comprises at least one member selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium trisilicate, potassium trisilicate, sodium metasilicate and potassium metasilicate.
7. The method of claim 6 , wherein following reaction of (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol hydrochloride with the alkaline substance, the resulting adhesive solution containing (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol free base is filtered to remove at least one by-product selected from the group consisting of sodium chloride, potassium chloride and polymeric silicon dioxide.
8. The method of claim 1 , further comprising admixing with said solution at least one permeation enhancer selected from the group consisting of fatty alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerol, fatty acid esters of glycerol, N-methyl-pyrrolidone, terpenes, limonene, a-pinene, a-terpineol, carvone, carveol, limonene oxide, pinene oxide and 1,8-eucalyptol.
9. The method of claim 1 , wherein the matrix layer has a solubility for (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol free base of ≥5% (w/w).
10. The method of claim 1 , wherein (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol free base is contained in the matrix in a concentration of from 5% to 25% (w/w).
11. The method of claim 1 , wherein the soluble polyvinylpyrrolidone is admixed to provide a concentration of 1.5-5% (w/w) soluble polyvinylpyrrolidone in the matrix layer.
12. The method of claim 1 , wherein the organic solvent comprises ethanol.
13. The method of claim 4 , wherein following reaction of (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol hydrochloride with the alkaline substance, the resulting adhesive solution containing (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol free base is filtered to remove at least one by-product.
14. The method of claim 1 , wherein the resulting matrix layer is a non-aqueous matrix layer.
15. The method of claim 1 , wherein the matrix layer is a single-phase matrix.
16. The method of claim 11 , wherein the soluble polyvinylpyrrolidone is admixed in an amount to provide a concentration of 1.5-3% (w/w) soluble polyvinylpyrrolidone in the matrix layer.
17. The method of claim 1 , further comprising preparing a plaster having an area of 2 to 40 cm 2 from the matrix layer, said plaster containing 1 to 10 mg of the (−)-5,6,7,8-tetrahydro-6-[propyl-1[2-(2-thienyl)ethyl]amino]-1-naphthalenol free base.
18. The method of claim 17 , wherein the plaster has an area of approximately 20 cm 2 .
19. The method of claim 1 , wherein a backing layer is applied to the matrix layer on the side thereof opposing said sheet, and wherein said sheet forms a removable protective layer.