Patent EA-005074-B1 (EA)
Title: Controlled release bead, a method of producing the same and multiple unit formulation comprising it
Inventor: GREN TORKEL
IPC: A61P13/10
Filed: 1999-11-11
Abstract: 1. A controlled release bead comprising: (i) a core unit of a substantially water-soluble or water-swellable inert material; (ii) a first layer on the core unit of a substantially water-insoluble polymer; (iii) a second layer covering the first layer and containing an active ingredient; and (iv) a third layer of polymer on the second layer effective for controlled release of the active ingredient, wherein said first layer is adapted to control water penetration into the core. 2. The bead according to claim 1, wherein the amount of polymer in said first layer is sufficient to substantially retard water penetration into the core. 3. The bead according to claim 1 or 2, wherein the thickness of said first layer is sufficient to affect the drug release rate from the bead. 4. The bead according to claim 1,2 or 3, wherein the amount of the first layer constitutes more than 2% (w/w), preferably more than 3% (w/w) of the final bead composition. 5. The bead according to any one of claims 1 to 4, wherein the amount of said second layer usually constitutes from about 0.05 to about 60 % (w/w), preferably from about 0.1 to about 30 % (w/w) of the final bead composition. 6. The bead according to any one of claims 1 to 5, wherein the amount of said third layer usually constitutes from about 1 to about 50 % (w/w), preferably from about 2 to about 25 % (w/w) of the final bead composition. 7. The bead according to any one of claims 1 to 6, wherein said third polymer layer is coated with a fourth layer of a water-soluble polymer or an additional functional coating. 8. The bead according to any one of claims 1 to 7, wherein said active ingredient is selected from compounds having the general formula: wherein R1 signifies hydrogen or methyl; R2, R3 and R4 independently signify hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen; and X represents a tertiary amino group-NR5, R6, wherein R5 and R6 signify non-aromatic hydrocarbyl groups, which may be the same or different, especially C1-6alkyl or adamantyl, and which together contain at least three, preferably at least four carbon atoms, and each of which may carry a hydroxy substituent, and wherein R5 and R6 may form a ring together with the amine nitrogen, preferably a non-aromatic ring having no heteroatom other than the amine nitrogen, their salts with physiologically acceptable acids and, when the compounds can be in the form of optical isomers, the racemic mixture and the individual enantiomers. 9. The bead according to claim 8, wherein said active ingredient is selected from tolterodine, the 5-hydroxymethyl metabolite of tolterodine, the (S)-enantiomer of tolterodine, the 5-hydroxymethyl metabolite of the (S)-enantiomer of tolterodine, the racemate of tolterodine, and prodrug forms and pharmacologically acceptable salts thereof. 10. The bead according to claim 9, wherein said active ingredient is tolterodine or a pharmacologically acceptable salt thereof. 11. The bead according to claim 10, wherein the fraction of active ingredient that is released in vitro is not more than about 30% after 1 hour, from about 40 to about 85% after 3 hours, and not less than about 80% after 7 hours. 12. The bead according to any one of claims 1 to 11, wherein the polymer material of said first layer comprises ethyl cellulose. 13. The bead according to any one of claims 1 to 12, wherein said second layer comprises hydroxypropylmethyl cellulose as binder. 14. The bead according to any one of claims 1 to 13, wherein the polymer material of said third layer comprises a combination of hydroxypropylmethyl cellulose and ethyl cellulose. 15. The bead according to any one of claims 1 to 14, wherein the core unit has a size of about 0.05 to about 2 mm. 16. A multiple unit formulation comprising a controlled release bead according to any one of claims 1 to 15. 17. The multiple unit formulation according to claim 16 which is a capsule. 18. A method of producing a controlled release bead, which method comprises the steps of: a) providing a core unit of a substantially water-soluble or water-swellable materia; b) applying a first layer of a substantially water-insoluble polymer to said core; c) applying onto said first layer, a second layer comprising an active ingredient and optionally a polymer binder; and d) applying onto said second layer, a third polymer layer effective for controlled release of the active ingredient; wherein the amount of material in said first is selected to provide a layer thickness that permits control of water penetration into the core. 19. A method for treating overactive bladder, which comprises administering a therapeutically effective amount of beads according to any one of claims 8 to 15. 20. The method according to claim 19, wherein the active ingredient is tolterodine or a pharmacologically acceptable salt thereof. 21. A method for treating nocturia, which comprises administering a therapeutically effective amount of beads according to any one of claims 8 to 15. 22. The method according to claim 21, wherein the active ingredient is tolterodine or a pharmacologically acceptable salt thereof. 23. A method for treating gastrointestinal disorders, which comprises administering a therapeutically effective amount of beads according to any one of claims 8 to 15.