Modified release formulations containing drug-ion exchange resin complexes
View Patent ↗A coated drug-ion exchange resin complex comprising a core composed of a drug complexed with a pharmaceutically acceptable ion-exchange resin is provided. The drug-ion exchange resin complex is in admixture with a release retardant. The coating is a polyvinyl acetate polymer and a plasticizer. Methods of making and products containing this coated complex are described.
1. An orally ingestable, modified release, solid composition comprising particulates which provide at least an 8 hour release profile, said composition comprising:
(i) a particulate matrix comprising a particulate drug-ion exchange resin complex and a water insoluble polymer or copolymer, or a hydrophilic polymer, said particulate matrix capable of passing through a number 40 mesh screen,
said drug-ion exchange resin complex comprising a pharmaceutically acceptable drug bound to a pharmaceutically acceptable water insoluble ion exchange resin to form said drug-ion exchange resin complex, said ion exchange resin being irregularly shaped and selected from
(A) a copolymer comprising styrene and divinylbenzene and
(B) a copolymer comprising sytrene and divinylbenzene having quaternary ammonium functional groups,
wherein said water insoluble polymer or copolymer, or hydrophilic polymer, is present in an amount of about 3% to about 30% by weight, based on the weight of said drug-ion exchange resin complex defined in (i), and
(ii) a cured, high tensile strength, water permeable, water insoluble, non-ionic polymeric diffusion modified release barrier coating over said particulate drug-ion exchange resin complex—water insoluble polymer or copolymer, or hydrophilic polymer matrix defined in (i), said cured barrier coating applied as an aqueous dispersion and comprising
(a) about 75% w/w to about 90% w/w polyvinylacetate polymer
(b) a stabilizer, and
(c) about 2.5 to about 20% w/w of plasticizer effective to enhance the tensile strength of said cured barrier coating, whereby said cured coating provides a modified release profile to the drug in said drug-ion exchange resin complex in said matrix.
2. The composition according to claim 1 , wherein said water insoluble polymer or copolymer or the hydrophilic polymer matrix is present in an amount of about 5 to about 20% by weight, based on the weight of said drug-ion exchange resin complex defined in (i).
3. The composition according to claim 1 wherein said cured high tensile strength, water permeable, water insoluble non-ionic polymeric diffusion barrier coating has an elongation factor of between about 125% and about 400%.
4. The composition according to claim 1 , wherein said ion exchange resin is a sulfonated copolymer comprising styrene and divinylbenzene.
5. The composition according to claim 1 , wherein said ion exchange resin is a copolymer comprising styrene and divinylbenzene having quaternary ammonium functional groups.
6. The composition according to claim 1 , which further includes in said solid composition an uncoated orally ingestable drug, bound to a pharmaceutically acceptable, water insoluble ion exchange resin to form an uncoated particulate drug-ion exchange resin complex, said uncoated ion exchange resin being selected form a copolymer comprising styrene and divinylbenzene and a copolymer comprising styrene and divinylbenzene having quaternary ammonium functional groups and wherein said drug in said uncoated drug-ion exchange resin complex is either the same drug or a different drug as the drug included in the matrix in (ii) and said uncoated drug ion exchange resin complex being of a size capable of passing through a number 40 mesh screen.
7. The composition according to claim 6 , wherein said drug in said uncoated drug-ion exchange matrix is the same drug as the drug in said coated drug-ion exchange resin matrix defined in (ii).
8. The composition according to claim 1 , wherein said drug-ion exchange resin complex matrix includes a hydrophilic polymer.
9. The composition according to claim 8 , wherein said hydrophilic polymer comprises a polyvinylpyrrolidone.
10. The composition according to claim 1 , wherein said aqueous based coating dispersion comprises about 30% solids comprising polyvinylacetate, polyvinylpyrrolidone and an effective amount of a surfactant, said polyvinylacetate and polyvinylpyrrolidone being in a dry weight ratio about 10:1.
11. The composition according to claim 1 , wherein said particulate matrix comprises said particulate drug-ion exchange resin complex and a water insoluble polymer or copolymer.
12. The composition according to claim 11 , wherein said matrix comprises polyvinylacetate with a stabilizer comprising polyvinylpyrrolidone and an effective amount of a surfactant.
13. The composition according to claim 12 , wherein said particulate matrix is prepared by a process comprising mixing said particulate drug-ion exchange resin complex with an aqueous dispersion comprising polyvinylacetate, polyvinylpyrrolidone and a sodium lauryl sulfate surfactant to form a mass, drying said mass and milling through a 40 mesh screen, and wherein said polyvinylacetate is present in an amount of about 27% w/w of the solids of said aqueous dispersion, said polyvinylpyrrolidone is present in an amount of about 2.7% w/w of the solids, and said sodium lauryl sulfate is present in an amount of about 0.3% w/w of the solids in said aqueous dispersion which comprises 30% solids.
14. The composition according to claim 1 , wherein said water insoluble polymer or copolymer comprises an acrylate polymer or copolymer.
15. The composition according to claim 14 , wherein said water insoluble polymer or copolymer comprises a copolymer comprising ethyl acrylate and methyl methacrylate.
16. The composition according to claim 1 , wherein said plasticizer comprises about 5% to about 10% w/w of solids in said cured coating.
17. The composition according to claim 16 wherein said plasticizer comprises triacetin.
18. The composition according to claim 1 wherein said barrier coating further comprises a surfactant comprising sodium lauryl sulfate.
19. The composition according to claim 1 , wherein said cured, high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises about 5% to about 200% by weight of the matrix defined in (i).
20. The composition according to claim 19 , wherein said cured, high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises about 35% to about 50% by weight of the matrix defined in (i).
21. The composition according to claim 19 , wherein said cured, high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises about 30% to about 45% by weight of the matrix defined in (i).
22. The composition according to claim 1 , wherein said cured, high tensile strength, water permeable, water insoluble, non ionic polymeric diffusion barrier coating comprises 50% by weight of the matrix defined in (i).
23. The composition according to claim 1 , wherein said drug in said drug-ion exchange resin matrix defined in (ii) is selected form the group consisting of morphine, oxycodone, albuterol, dextromethorphan, codeine, tramadol, pseudoephedrine, phenylephrine, hydrocodone, venlafaxine, ibuprofen, oxybutynin, clonidine, dexchlorpheniramine, fexofenadine, diphenhydramine, oxymorphone, carbinoxamine, dicylomine, chlorpheniramine, amphetamine, naproxene, diclofenac, paroxetine, amoxicillin and pharmaceutically acceptable salts thereof.
24. The composition according to claim 1 , wherein said drug in said drug-ion exchange resin matrix defined in (i) is diphenhydramine.
25. The composition according to claim 1 , wherein said drug in said drug-ion exchange resin matrix in (i) is dextromethorphan.
26. The composition according to claim 1 , which comprises a finished unit dose in tablet form, wherein the particulates are compressed into the tablet.
27. An orally ingestable, modified release, powder composition comprising particulates which provide at least an 8 hour release profile, said composition comprising:
(i) a particulate matrix comprising a particulate drug-ion exchange resin complex and a water insoluble polymer or copolymer, or a hydrophilic polymer, said particulate matrix capable of passing through a number 40 mesh screen,
said drug-ion exchange resin complex comprising a pharmaceutically acceptable drug bound to a pharmaceutically acceptable water insoluble ion exchange resin to form a said drug-ion exchange resin complex, said ion exchange resin being irregularly shaped and selected from
(A) a copolymer comprising styrene and divinylbenzene and
(B) a copolymer comprising sytrene and divinylbenzene having quaternary ammonium functional groups,
wherein said water insoluble polymer or copolymer, or hydrophilic polymer, is present in an amount of about 3% to about 30% by weight, based on the weight of said drug-ion exchange resin complex defined in (i), and
(ii) a cured, high tensile strength, water permeable, water insoluble, non-ionic polymeric diffusion modified release barrier coating over said particulate drug-ion exchange resin complex—water insoluble polymer or copolymer, or hydrophilic polymer matrix defined in (i), said cured barrier coating applied as an aqueous dispersion and comprising
(a) about 75% w/w to about 90% w/w polyvinylacetate polymer
(b) a stabilizer, and
(c) at least an amount of plasticizer effective to enhance the tensile strength of said cured barrier coating, whereby said cured coating provides a modified release profile to the drug in said drug-ion exchange resin complex in said matrix.
28. The composition according to claim 27 , in which the powder is loaded into a capsule.
29. The composition according to claim 27 , wherein said plasticizer comprises about 5% to about 10% w/w of solids in said cured coating.