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Claims for Patent: 8,956,649

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Claims for Patent: 8,956,649

Title:Orally effective methylphenidate extended release powder and aqueous suspension product
Abstract: An oral methylphenidate powder which is reconstitutable into a final oral aqueous sustained release formulation containing at least about 50%, or at least about 80% by weight water based on the total weight of the suspension, is provided. The powder is a blend containing a combination of an uncoated methylphenidate-ion exchange resin complex, a barrier coated methylphenidate-ion exchange resin complex-matrix, and a water soluble buffering agent such that upon formed into an aqueous liquid formulation, the formulation has a pH in the range of about 3.5 to about 5, or about 4 to about 4.5. Following administration of a single dose of the oral aqueous methylphenidate suspension, a therapeutically effective amount of methylphenidate is reached in less than one hour and the composition provides a twelve-hour extended release profile.
Inventor(s): Mehta; Ketan (Cranbury, NJ), Tu; Yu-Hsing (West Windsor, NJ), Perumal; Ashok (Monmouth Junction, NJ)
Assignee: Tris Pharma, Inc (Monmouth Junction, NJ)
Application Number:14/299,421
Patent Claims: 1. A methylphenidate aqueous extended release oral suspension, wherein said suspension has a single mean average plasma concentration peak and a therapeutically effective plasma profile for about 12 hours for d-methylphenidate, and has a pharmacokinetic profile in which the single mean plasma concentration peak for d-methylphenidate has an area under the curve (AUC).sub.0-.infin. of about 114 ng-hr/mL to about 180 ng-hr/mL, C.sub.max of about 11 ng/mL to about 17 ng/mL, T.sub.max of about 4 hours to about 5.25 hours and T.sub.1/2 of about 5 hours to about 7 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

2. The methylphenidate aqueous extended release oral suspension according to claim 1, which maintains at least about 95% of its initial potency over a period of at least about 4 months at room temperature.

3. The methylphenidate aqueous extended release oral suspension according to claim 1, wherein the pharmacokinetic profile of d-methylphenidate has an AUC.sub.0-.infin. of about 143.65 ng-hr/mL, C.sub.max of about 13.61 ng/mL, T.sub.max of about 5 hours and T.sub.1/2 of about 5.65 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

4. The methylphenidate aqueous extended release oral suspension according to claim 1, which comprises an immediate release methylphenidate component and a sustained release methylphenidate component, wherein said sustained release methylphenidate component comprises a water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate--ion exchange resin complex.

5. The methylphenidate aqueous extended release oral suspension according to claim 4, wherein the barrier coating is selected from the group consisting of (a) a cured water-permeable, high tensile strength, water insoluble, pH-independent barrier coating comprising a polyvinylacetate polymer and a plasticizer, (b) a barrier coating comprising an solvent-based ethylcellulose; and (c) a pH-independent acrylate based barrier coating comprising a methyl methyacrylate polymer or co-polymer.

6. The methylphenidate aqueous extended release oral suspension according to claim 5, wherein the barrier coating (a) comprises from about 70 to about 90% of polyvinylacetate, about 2.5 to about 15% of a plasticizer, and a stabilizer.

7. The methylphenidate aqueous extended release oral suspension according to claim 6, wherein the barrier coating further comprises from about 5 to about 10% of the stabilizer and from about 0.1 to about 1% surfactant.

8. The methylphenidate aqueous extended release oral suspension according to claim 5, wherein the plasticizer is triacetin.

9. The methylphenidate aqueous extended release oral suspension according to claim 7, wherein the surfactant is sodium lauryl sulfate or HO(C.sub.2H.sub.4O).sub.86(C.sub.3H.sub.6O).sub.27(C.sub.2H.sub.4O).sub.8- 7H.

10. The methylphenidate aqueous extended release oral suspension according to claim 5, wherein the methylphenidate--ion exchange resin complex is in a matrix formed by granulating said complex with at least one hydrophilic or hydrophobic polymeric matrix forming component.

11. The methylphenidate aqueous extended release oral suspension according to claim 10, wherein the coated methylphenidate ion exchange resin complex--matrix comprises a hydrophilic polymer in an amount of about 5 to about 20% by weight, based on the weight of the methylphenidate--ion exchange resin complex--matrix.

12. The methylphenidate aqueous extended release oral suspension according to claim 11, wherein the hydrophilic polymer is polyvinylpyrrolidone.

13. The methylphenidate aqueous extended release oral suspension according to claim 4, wherein the immediate release methylphenidate component is an uncoated methylphenidate--ion exchange resin complex, optionally in combination with a hydrophilic or hydrophobic polymeric matrix forming component.

14. The methylphenidate aqueous extended release oral suspension according to claim 1, wherein said methylphenidate is selected from the group consisting of racemic methylphenidate and dexmethylphenidate.

15. The methylphenidate aqueous extended release oral suspension according to claim 10, further comprising a buffering agent selected from the group consisting of one or more of a pharmaceutically acceptable acid consisting of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, and/or a pharmaceutically acceptable salt of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, and/or mixtures thereof.

16. A method of treating a patent having a disorder selected from Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder, postural orthostatic tachycardia syndrome, and narcolepsy, said method comprising delivering an effective amount of a methylphenidate aqueous suspension according to claim 1 to the patient.

17. A methylphenidate aqueous extended release oral suspension comprising an immediate release methylphenidate component and a sustained release methylphenidate component, wherein said suspension has a pH of 3.5 to 5, wherein said sustained release methylphenidate component comprises a water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate--ion exchange resin complex--matrix, and wherein said suspension has a pharmacokinetic profile in which the d-methylphenidate has an area under the curve (AUC).sub.0-.infin., of about 114 ng-hr/mL to about 180 ng-hr/mL and a C.sub.max of about 11 ng/mL to about 17 ng/mL following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

18. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein the pH is about 4.2.

19. The methylphenidate aqueous extended release oral suspension according to claim 18, wherein the suspension comprises at least about 80% of water based on the total weight of the suspension.

20. The methylphenidate aqueous extended release oral suspension according to claim 19, which has less than about 5% loss in potency over a period of about 1 month of storage at room temperature.

21. The methylphenidate aqueous extended release oral suspension according to claim 19, which has less than about 1% of threo-.alpha.-phenyl-2-piperidineacetic acid hydrochloride impurity after a period of about 1 month of storage at room temperature.

22. The methylphenidate aqueous extended release oral suspension according to claim 19, which has less than about 5% loss in potency over a period of about 4 months of storage at room temperature.

23. The methylphenidate aqueous extended release oral suspension according to claim 19, which has less than about 1% of threo-.alpha.-phenyl-2-piperidineacetic acid hydrochloride impurity after a period of about 4 months of storage at room temperature.

24. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein the T.sub.max is about 4 hours to about 5.25 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

25. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein said suspension provides a therapeutically effective plasma profile for methylphenidate for about 12 hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

26. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein said suspension provides a single mean average plasma concentration peak for methylphenidate following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

27. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein said suspension provides a therapeutically effective amount of methylphenidate within 45 minutes after administration following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

28. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults said suspension provides a reduced T.sub.max in subjects fed with a high-fat meal prior to administration compared to subjects in a fasted state prior to administration.

29. The methylphenidate aqueous extended release oral suspension according to claim 28, wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults said suspension provides a T.sub.max reduced by about 60 minutes in subjects fed with a high-fat meal prior to administration compared to subjects in a fasted state prior to administration.

30. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults said suspension provides a C.sub.max increased by about 28% in subjects fed with a high-fat meal prior to administration compared to subjects in a fasted state prior to administration.

31. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults said suspension provides an area under the curve (AUC).sub.0-.infin. increased by about 19% in subjects fed with a high-fat meal prior to administration compared to subjects in a fasted state prior to administration.

32. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein varrier coating is cured and comprises from about 70 to about 90% of polyvinylacetate, from about 2.5 to about 15% of a plasticizer, and a stabilizer.

33. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein the barrier coating comprises ethylcellulose.

34. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein the barrier coating comprises a methyl methyacrylate polymer or co-polymer.

35. The methylphenidate aqueous extended release oral suspension according to claim 17, further comprising a buffering agent selected from the group consisting of one or more of a pharmaceutically acceptable acid consisting of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, and/or a pharmaceutically acceptable salt of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid and/or mixtures thereof.

36. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein the suspension comprises at least about 60% of water based on the total weight of the suspension.

37. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein the suspension comprises at least about 70% of water based on the total weight of the suspension.

38. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein a liquid component of the aqueous suspension is from about 80% to about 100% of water.

39. The methylphenidate aqueous extended release oral suspension according to claim 17, wherein the AUC for d-methylphenidate at about three hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults under fasted conditions is about 20 ng-mL/hr.

40. The methylphenidate extended release oral suspension according to claim 1, wherein the AUC for d-methylphenidate at about three hours following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults under fasted conditions is about 20 ng-hr/mL.

41. A methylphenidate aqueous extended release oral suspension comprising an immediate release methylphenidate component and a sustained release methylphenidate component, wherein said suspension has a pH of about 4.2, wherein said sustained release methylphenidate component comprises a water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate--ion exchange resin complex, wherein said suspension comprises at least about 80% of water based on the total weight of the suspension, wherein said suspension has less than about 1% of threo-.alpha.-phenyl-2-piperidineacetic acid hydrochloride impurity after a period of about 1 month of storage at room temperature, and wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl said suspension has a pharmacokinetic profile in which the d-methylphenidate has an area under the curve (AUC).sub.0-.infin. of about 114 ng-hr/mL to about 180 ng-hr/mL in adults under fasted conditions, a C.sub.max of about 11 ng/mL to about 17 ng/mL in adults under fasted conditions, and a reduced T.sub.max in adults fed with a high-fat meal prior to administration compared to adult subjects in a fasted state prior to administration.

42. The methylphenidate aqueous extended release oral suspension according to claim 41 wherein following a single oral administration of an aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl said suspension has a pharmacokinetic profile in which the d-methylphenidate has a T.sub.max reduced by about 60 minutes in adults fed with a high-fat meal prior to administration compared to adult subjects in a fasted state prior to administration.

43. The methylphenidate aqueous extended release oral suspension according to claim 41, whether the methylphenidate--ion exchange resin complex is in a matrix with a water-insoluble polymer or co-polymer or a water-soluble polymer or co-polymer, wherein the barrier coating is over the methylphenidate--ion exchange resin complex--matrix.
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