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Claims for Patent: 6,911,217

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Claims for Patent: 6,911,217

Title: Controlled release bead, a method of producing the same and multiple unit formulation comprising it
Abstract:A controlled release bead comprises: (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 the first layer is adapted to control water penetration into the core. A method of producing the controlled release bead is also disclosed.
Inventor(s): Gren; Torkel (Kalamazoo, MI), Ringberg; Anders (Stockholm, SE), Wikberg; Martin (Kullavik, SE), Wald; Randy J. (Portage, MI)
Assignee: Pharmacia AB (Stockholm, SE)
Application Number:09/763,281
Patent Claims: 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 that contains an active ingredient, comprising compounds of the general formula ##STR2## wherein R.sub.1 signifies hydrogen or methyl; R.sub.2, R.sub.3 and R.sub.4 independently signify hydrogen, methyl, methoxy, hydroxy, hydromethyl, carbamoyl, sulphamoyl or halogen; and X represents a tertiary amino group --NR.sub.5,R.sub.6, wherein R.sub.5 and R.sub.6 signify non-aromatic hydrocarbyl groups, which may be the same or different, especially C.sub.1-6 -alkyl 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 R.sub.5 and R.sub.6 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, and (iv) a third layer of polymer on the second layer effective for the controlled release of the active ingredient, wherein said first layer is adapted to control water penetration into the core, and wherein the controlled-release bead provides a mean fluctuation index of said serum level of the active moiety or moieties that is not higher than about 2.0, said fluctuation index, FI, being defined as FI=(Cmax-Cmin)/AUC.tau./.tau., wherein Cmax and Cmin are the maximum and minimum concentrations, respectively, of the active moiety or moieties, AUC.tau. is the area under the serum concentration profile, and .tau. is the length of the dosage interval.

2. The bead according to claim 1, wherein the amount of polymer in said first layer comprises from about 2.0% w/w to about 50% w/w of the bead and is sufficient to substantially retard water penetration into the core.

3. The bead according to claim 1 wherein the thickness of said first layer is from about 1.0 .mu.m to about 100 .mu.m and is sufficient to affect the drug release rate from the bead.

4. The bead according to claim 1, wherein the amount of the first layer constitutes more than 2% (w/w) of the final bead composition.

5. The bead according to claim 1, wherein the amount of said second layer constitutes from about 0.05 to about 60% (w/w).

6. The bead according to claim 1, wherein the amount of said third layer constitutes from about 1 to about 50% (w/w) of the final bead composition.

7. The bead according to claim 1, wherein said third polymer layer is coated with a fourth layer of a water-soluble polymer for an additional functional coating.

8. The bead according to claim 1, 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, its prodrug forms and pharmacologically acceptable salts thereof.

9. The bead according to claim 8, wherein said active ingredient is tolterodine or a pharmacologically acceptable salt thereof.

10. The bead according to claim 9, 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.

11. The bead according to claim 1, wherein the polymer material of said first layer comprises ethyl cellulose.

12. The bead according to claim 1, wherein said second layer comprises hydroxypropylmethyl cellulose as binder.

13. The bead according to claim 1, wherein the polymer material of said third layer comprises a combination of hydroxypropylmethyl cellulose and ethyl cellulose.

14. The bead according to claim 1, wherein the core unit has a size of about 0.05 to about 2 mm.

15. A multiple unit formulation comprising a controlled release bead according to claim 1.

16. The multiple unit formulation according to claim 15 which is a capsule.

17. A method of producing a controlled release bead according to claim 1, which method comprises the steps of: a) providing a core unit of a substantially water-soluble or water-swellable material; 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 the controlled release of the active ingredient; wherein the amount of material in said first layer is selected to provide a layer thickness that permits control of water penetration into the core.

18. A method for treating overactive bladder, which comprises administering a therapeutically effective amount of beads according to claim 1.

19. The method according to claim 18 wherein the active ingredient is tolterodine or a pharmacologically acceptable salt thereof.

20. A method for treating nocturia, which comprises administering a therapeutically effective amount of the beads according to claim 1.

21. The method according to claim 20, wherein the active ingredient is tolterodine or a pharmacologically acceptable salt thereof.

22. A method for treating gastrointestinal disorders, which comprises administering a therapeutically effective amount of beads according to claim 1.

23. A controlled release bead consisting essentially of: (i) a core unit of a substantially water-soluble or water-swelled inert material; (ii) a first layer on the core unit of a substantially water-insoluble polymer; (iii) a second layer covering the first layer that contains an active ingredient comprising compounds of the general formula: ##STR3## wherein R.sub.1 signifies hydrogen or methyl; R.sub.2, R.sub.3 and R.sub.4 independently signify hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen; and X represents a tertiary amino group --NR.sub.5,R.sub.6 wherein R.sub.5 and R.sub.6 signify non-aromatic hydrocarbyl groups, which may be the same or different, especially C.sub.1-6 -alkyl 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 R.sub.5 and R.sub.6 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; and (iv) a third layer of polymer on the second layer effective for the controlled release of the active ingredient.

24. A controlled release bead comprising: (i) a core unit of a substantially water-soluble or water-swelled inert material; (ii) a first layer of a substantially water-insoluble polymer on and in contact with the core unit; (iv) (iii) a second layer covering the first layer that contains an active ingredient comprising compounds of the general formula: ##STR4## wherein R.sub.1 signifies hydrogen or methyl; R.sub.2, R.sub.3 and R.sub.4 independently signify hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen; and X represents tertiary amino groups --NR.sub.5,R.sub.6, wherein R.sub.5 and R.sub.6 signify non-aromatic hydrocarbyl groups, which may be the same or different, especially C.sub.1-6 -alkyl 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 R.sub.5 and R.sub.6 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; and (iv) a third layer of polymer on the second layer effective for the controlled release of the active ingredient; wherein said first layer is adapted to control water penetration into the core.
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