Orally effective methylphenidate extended release powder and aqueous suspension product

• US 8,465,765 B2
• Filed: 09/12/2012
• Issued: 06/18/2013
• 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:
  US13/611,183
• Publication Number:
  US 20130004571A1
• Time in Patent Office: 279 Days
• Field of Search: None
• US Class Current: 424/452
• 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 comprising (1) an immediate release methylphenidate component, (2) a sustained release methylphenidate component comprising a water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex, and (3) water,

wherein said suspension has a pH of about 3.5 to about 5 and said suspension provides a single mean average plasma concentration peak for methylphenidate and a therapeutically effective plasma profile for methylphenidate for about 12 hours.

2. The methylphenidate aqueous extended release oral suspension according to claim 1, wherein said suspension has a pH in the range of about 4 to about 4.5.

3. The suspension according to claim 1, 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.

4. The suspension according to claim 3, wherein the acrylate based barrier coating comprises a poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonoethyl methacrylate chloride) polymer system.

5. The suspension according to claim 1, 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.

6. The suspension according to claim 1, wherein the suspension 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.

7. The methylphenidate aqueous extended release oral suspension according to claim 6 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.

8. The suspension according to claim 1 wherein the suspension has a pharmacokinetic profile in which the single mean plasma concentration peak for methylphenidate has an area under the curve (AUC)_0-∞

of about 137.2 to about 214.4 ng-hr/mL, a C_max of about 13.6 to about 21.3 ng/mL, and T_max of about 3 to about 5 hours, following a single oral administration of an aqueous suspension at a dose equivalent to 72 mg racemic methylphenidate HCl in adults.

9. The methylphenidate aqueous extended release oral suspension according to claim 8 wherein said suspension has a pharmacokinetic profile in which methylphenidate has an AUC_0-∞

of about 171.5 ng-hr/mL, a C_max of about 17.0 ng/mL, and a T_max of about 3.77 hours following a single oral administration of an aqueous suspension at a dose equivalent to 72 mg racemic methylphenidate HCl in adults.

10. The suspension according to claim 1, wherein the methylphenidate ion exchange resin complex is in a matrix with about 5 to about 20% by weight of a hydrophilic or hydrophobic polymeric matrix forming component, based on the weight of the uncoated methylphenidate-ion exchange resin complex-matrix.

11. The suspension according to claim 10, wherein the polymeric matrix forming component is a hydrophilic polymer comprising polyvinylpyrrolidone.

12. The suspension according to claim 10, wherein the polymeric matrix forming component is a hydrophobic polymer comprising polyvinylacetate.

13. The suspension according to claim 1, wherein said suspension contains at least about 80% of water by weight based on the total weight of the suspension.

14. The suspension according to claim 1, wherein said methylphenidate in the immediate release and/or sustained release component is independently selected from the group consisting of racemic methylphenidate and dexmethylphenidate.

15. The suspension according to claim 1, wherein the barrier coat comprises about 20% to about 45% by weight of the coated methylphenidate-ion exchange resin complex-matrix.

16. The suspension according to claim 1, wherein the suspension contains about 10 to about 30 parts by weight of methylphenidate as provided in the immediate release component and to about 70 to about 90 parts by weight of sustained release methylphenidate, based upon the total weight of methylphenidate in the suspension.

17. The suspension according to claim 1, further comprising a buffering agent selected from the group consisting of one or more of a pharmaceutically acceptable acid selected from the group consisting of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, a pharmaceutically acceptable salt of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, or a mixture of said pharmaceutically acceptable acid or salt, and mixtures thereof.

18. The suspension according to claim 17, wherein the buffering agent is a mixture of sodium citrate and anhydrous citric acid.

19. A method for treating a patient having a condition susceptible to treatment with methylphenidate, the method comprising administering to the patient a methylphenidate aqueous extended release oral suspension of claim 1, wherein said suspension provides a therapeutically effective amount of methylphenidate within 45 minutes after administering of said suspension and a single average plasma concentration peak.

20. The method according to claim 19, wherein the suspension which has a pH from about 4 to about 4.5.

28. The methylphenidate aqueous extended release oral suspension according to claim 1 which has a stable shelf-life under ambient conditions over a period of at least about four months at room temperature.

29. The methylphenidate aqueous extended release oral suspension according to claim 28, which has less than about 5% loss in potency over a period of at least about 4 months of storage at room temperature.

30. The methylphenidate aqueous extended release oral suspension according to claim 29, which has less than about 3% loss in potency over a period of at least about 4 months of storage at room temperature.

21. A methylphenidate extended release powder blend, said extended release powder blend comprising:

(i) an immediate release methylphenidate component;

(ii) a sustained release water-insoluble, water-permeable, pH-independent, diffusion barrier coating over a methylphenidate-ion exchange resin complex-matrix;

(iii) a water soluble buffering agent which adjusts the pH of an aqueous suspension formed by admixing said extended release powder blend with water to a pH in the range of about 3.5 to about 5; and

(iv) optional pharmaceutical excipients, wherein said powder blend provides a therapeutically effective profile of d-methylphenidate for about 12 hours and a single mean plasma concentration peak for d-methylphenidate.

22. The powder blend according to claim 21, wherein the barrier coating is selected from the group consisting of:

(a) a cured water-permeable, high tensile strength, water insoluble, barrier coating comprising a polyvinylacetate polymer and a plasticizer;

(b) a barrier coating comprising a solvent-based ethylcellulose; and

(c) a poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammoniumethylmethacrylate chloride) polymer.

23. The powder blend according to claim 21, wherein said methylphenidate extended release powder blend further comprises water-soluble diluent granules which contain the buffering agent.

24. The powder blend according to claim 23, wherein the diluent granules further comprise one or more of a surfactant, a sweetener, and a preservative.

25. The powder blend according to claim 24, wherein the surfactant in the diluent granules comprises a poloxamer.

26. The powder blend according to claim 21, wherein said buffering agent is selected from the group consisting of one or more of a pharmaceutically acceptable acid selected from the group consisting of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, a pharmaceutically acceptable salt of citric acid, ascorbic acid, acetic acid, tartartic acid, phosphoric acid, or a mixture of said pharmaceutically acceptable acid or salt.

27. A tablet or capsule comprising the powder blend according to claim 21.