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Claims for Patent: 7,781,448

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Claims for Patent: 7,781,448

Title:Once daily dosage forms of trospium
Abstract:A pharmaceutical composition of a pharmaceutically acceptable trospium salt, with upon administration to a human patient generates an average steady state blood levels of trospium with a minimum (C.sub.min) and maximum (C.sub.max) blood levels of about 0.5-2.5 ng/ml and about 2.0-6.0 ng/ml, respectively.
Inventor(s): Kidane; Argaw (Montgomery Village, MD), Flanner; Henry H. (Montgomery Village, MD), Bhatt; Padmanabh (Rockville, MD), Raoufinia; Arash (McLean, VA)
Assignee: Supernus Pharmaceuticals, Inc. (Rockville, MD)
Application Number:11/889,962
Patent Claims: 1. An oral pharmaceutical composition suitable for once-a-day administration of trospium, comprising a first trospium containing component comprising at least one component selected from the group consisting of an extended release (XR) component and a delayed release (DR) component and a second trospium containing component comprising at least one component selected from the group consisting of an extended release (XR) component, a delayed release (DR) component, and an immediate release component, wherein the first and second trospium containing components are different from each other, and wherein said composition at once-a-day administration provides steady state blood levels of trospium of a minimum of about 0.5 ng/ml and a maximum of about 6.0 ng/ml; comprises from 25 to 80 mg of trospium chloride and at least one polymer selected from the enteric polymers, release controlling polymers, or combinations thereof, and wherein at least a portion of which releases trospium in the lower gastrointestinal (GI) tract.

2. The composition of claim 1, wherein once-a-day administration results in minimizing the occurrence of the adverse side effects and in steady state blood levels of trospium which are comparable to steady state blood levels of trospium achieved with twice daily administration of 20 mg of immediate release trospium chloride tablets.

3. The composition of claim 2, wherein said adverse side effects are selected from the group consisting of dry mouth, headache, constipation, dyspepsia, abdominal pain, and a combination thereof.

4. The composition of claim 1, wherein said XR component comprises at least one release controlling polymer selected from the group consisting of copolymers of acrylic and methacrylic acid esters, ethylcellulose aqueous dispersions, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyethylene glycols and combinations thereof.

5. The composition of claim 1, wherein said DR component comprises at least one enteric polymer selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride, ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, zein, shellac, copal collophorium, carboxymethyl ethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters and combinations thereof.

6. The composition of claim 1, wherein the IR component contains not more than about 20 mg of trospium chloride.

7. The composition of claim 6, wherein said composition is a combination of an IR trospium component and a DR trospium component.

8. The composition of claim 6, wherein said composition is a combination of an IR trospium component and an XR trospium component.

9. The composition of claim 6, wherein said composition is a combination of an IR trospium component, an XR trospium component, and a DR trospium component.

10. The composition of claim 1, which is a combination of an XR trospium component and a DR trospium component.

11. The composition of claim 10, wherein the DR component comprises trospium chloride and an enteric polymer, and the XR component comprises trospium chloride and a release controlling polymer.

12. The composition of claim 1, wherein each one of XR component and DR component is in the form of pellets.

13. The composition of claim 12, wherein said DR component is composed of DR pellets consisting essentially of a) trospium chloride, b) a sugar core c) hydroxypropyl methylcellulose, d) a coating of the enteric polymer that delays release of the trospium chloride from the pellet for a period of time after administration, e) triethyl citrate, f) a protective overcoating, and g) talc; and said XR component is composed of XR pellets consisting essentially of a) trospium chloride, b) a sugar core, c) hydroxypropyl methylcellulose, d) a surface coating that controls a release profile of the trospium chloride from the pellet after administration, e) a protective overcoating, and f) talc.

14. The composition of claim 13, wherein the XR component contains about 30 mg trospium chloride, and the DR component contains about 30 mg trospium chloride.

15. The composition of claim 1, wherein each component is in the form of a layer.

16. The composition of claim 1, wherein said DR component releases trospium at a pH of about 7.0.

17. The composition of claim 1, wherein said DR component releases trospium in the lower intestine.

18. The composition of claim 1, wherein said DR component releases trospium in the colon.

19. The composition of claim 1 in an oral dosage form selected from the group consisting of a granule, tablet, pellet, beadlet, powder, sachet, capsule, gel, dispersion, solution and suspension.

20. The composition of claim 19, wherein said tablet is a rapidly dispersible tablet.

21. The composition of claim 19, wherein said tablet, pellet or beadlet is a layered tablet, pellet or beadlet comprising at least two trospium-containing layers, wherein each layer comprises at least one component selected from an XR component, a DR component or an immediate release (IR) component.

22. The composition of claim 1 in an amount effective for the treatment of a bladder dysfunction in a mammal, wherein said bladder dysfunction is selected from the group consisting of urinary frequency, urgency, nocturia, urge-incontinence due to detrusor instability, urge syndrome, detrusor hyperreflexia, and combinations thereof.

23. An oral pharmaceutical composition of trospium chloride for once-a-day administration comprising a combination of a DR component and an XR component, wherein said DR component is composed of enteric coated pellets consisting essentially of: a) trospium chloride, b) a sugar core, c) hydroxypropyl methylcellulose, d) a coating of the enteric polymer that delays release of the trospium chloride from the pellet for a period of time after administration, e) triethyl citrate, f) a protective overcoating, and g) talc; and said XR component is composed of extended release pellets consisting essentially of: a) trospium chloride, b) a sugar core, c) hydroxypropyl methylcellulose, d) a surface coating that controls a release profile of the trospium chloride from the pellet after administration, e) a protective overcoating, and f) talc, wherein at least a portion of the trospium chloride is released from said compostion in the lower GI tract, and once-a-day administration of said pharmaceutical composition provides steady state blood levels of trospium achieved with twice daily administration of 20 mq of immediate release (IR) trospium chloride tablets.

24. An oral pharmaceutical composition of trospium chloride for once-a-day administration comprising a mixture of enteric coated pellets and extended release pellets in a ratio of 1:1, the enteric coated pellets consisting essentially of trospium chloride, sugar spheres, hydroxypropyl methylcellulose, methacrylic acid copolymer, triethyl citrate, and talc and wherein the extended release pellets consist essentially of trospium chloride, sugar spheres, hyroxypropyl methylcellulose, ethyl cellulose, and talc, wherein at least a portion of the trospium chloride is released from said composition in the lower GI tract, and once-a-day administration of said pharmaceutical composition provides steady state blood levels of trospium that are comparable to steady state blood levels of trospium achieved with twice daily administration of 20 mg immediate release (IR) trospium chloride tablets.

25. The composition of one of claim 23 or 24 containing 60 mg of trospium chloride.

26. The composition of claim 25, wherein the 60 mg of trospium chloride is equally divided between the enteric coated pellets and extended release pellets.

27. A method of preparation of a once-a-day pharmaceutical composition of trospium comprising first and second trospium components that are different from each other, the method comprising the steps of: a) preparing a first component comprising at least one trospium-containing component selected from an extended release (XR) component and a delayed release (DR) component, said first component comprising at least one polymer selected from enteric polymers, release controlling polymers, or combinations thereof, and preparing a second component comprising at least one trospium-containing component selected from an extended release (XR) component and a delayed release (DR) component, wherein the first and second components are different from each other and wherein at least one of the XR components or DR components delivers trospium to the lower gastrointestinal (GI) tract; b) preparing an optional immediate release (IR) component; c) combining components of step a) and optionally b) into the composition such that it comprises from 25 to 80 mg of trospium chloride and at once-a-day administration provides steady state blood levels of trospium of a minimum of about 0.5 ng/ml and a maximum of about 6.0 ng/ml.

28. The method of claim 27, wherein the composition at once-a-day administration results in steady state blood levels of trospium which are comparable to steady state blood levels of trospium achieved with twice daily administration of 20 mg of immediate release trospium chloride tablets, and in minimizing the occurrence of the adverse side effects.

29. The method of claim 27, additionally comprising a step of formulating said composition into a solid, oral dosage form.

30. The method of claim 29, wherein said dosage form is selected from the group consisting of a granule, tablet, pellet, powder, sachet, capsule, gel, dispersion, solution and suspension.

31. The method of claim 27, wherein said XR component comprises at least one release controlling polymer selected from copolymers of acrylic and methacrylic acid esters, ethylcellulose aqueous dispersions, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyethylene glycols and combinations thereof.

32. The method of claim 27, wherein said DR component comprises at least one enteric polymer selected from cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride, ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, zein, shellac, copal collophorium, carboxymethyl ethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters and combinations thereof.

33. The method of claim 27, wherein said XR component or DR component is prepared by granulating the trospium chloride with the pharmaceutically acceptable carrier thereby producing trospium chloride containing pellets and then coating the pellets with the at least one release controlling polymer or with at least one enteric polymer, respectively, and the IR component is prepared by granulating the trospium chloride with the pharmaceutically acceptable carrier thereby producing trospium chloride containing pellets.

34. The method of claim 33, wherein the IR component contains not more than about 20 mg of trospium chloride.

35. The method of claim 33, wherein at least one XR component and at least one DR component are combined into the composition.

36. The method of claim 33, wherein at least one XR component or DR component is combined into the composition with the IR component.

37. The method of claim 33, wherein at least one XR component with at least one DR component and the IR component are combined into the composition.

38. The method of claim 27, wherein said XR component or DR component is prepared by applying a layer of trospium chloride to a core comprising a pharmaceutically acceptable carrier, and coating the trospium chloride-coated core with the release controlling or enteric polymer, respectively.

39. The method of claim 38, wherein the pharmaceutically acceptable carrier comprises a sugar sphere.

40. The method of claim 38, wherein at least one XR component and at least one DR component are combined into the composition.

41. The method of claim 27, wherein the optional IR component is prepared by applying a layer of trospium chloride to a core comprising a pharmaceutically acceptable carrier and contains not more than about 20 mg of trospium chloride.

42. The method of claim 41, wherein at least one of the XR component or DR component is combined into the composition with the IR component.

43. The method of claim 41, wherein at least one XR component with at least one DR component and the IR component are combined into the composition.

44. The method of claim 27, wherein the optional IR component is formed by further applying a layer of trospium chloride over at least one XR or DR component and contains not more than about 20 mg of trospium chloride.
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