Orally effective methylphenidate extended release powder and aqueous suspension product

• US 8,956,649 B2
• Filed: 06/09/2014
• Issued: 02/17/2015
• Est. Priority Date: 02/15/2011
• Status: Active Grant

• Current Assignee: Tris Pharma Incorporated
• Original Assignee: Tris Pharma Incorporated
• Inventors: Mehta, Ketan, Tu, Yu-Hsing, Perumal, Ashok
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Tcherkasskaya, Olga V
• Application Number:
  US14/299,421
• Publication Number:
  US 20140287038A1
• Time in Patent Office: 253 Days
• Field of Search: None
• US Class Current: 424/462
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 31/787 containing heterocyclic rings having nitrogen as a ring hetero atom
• CPC Class Codes: A61K 47/585 Ion exchange resins, e.g. polystyrene sulfonic acid resin
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1682 Processes
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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.

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)_0-∞

of about 114 ng-hr/mL to about 180 ng-hr/mL, C_max of about 11 ng/mL to about 17 ng/mL, T_max of about 4 hours to about 5.25 hours and T_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_0-∞

of about 143.65 ng-hr/mL, C_max of about 13.61 ng/mL, T_max of about 5 hours and T_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(C₂H₄O)₈₆(C₃H₆O)₂₇(C₂H₄O)₈₇H.

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.

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.

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)_0-∞

, of about 114 ng-hr/mL to about 180 ng-hr/mL and a C_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-α

-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-α

-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_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_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_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_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)_0-∞

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.

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-α

-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)_0-∞

of about 114 ng-hr/mL to about 180 ng-hr/mL in adults under fasted conditions,

a C_max of about 11 ng/mL to about 17 ng/mL in adults under fasted conditions, and

a reduced T_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_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.