ORALLY EFFECTIVE METHYLPHENIDATE EXTENDED RELEASE POWDER AND AQUEOUS SUSPENSION PRODUCT

• US 20130261152A1
• Filed: 05/30/2013
• Published: 10/03/2013
• 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
• Granted Patent: US 8,563,033 B1
• Time in Patent Office: Days
• US Class Current: 514/317
• 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 an immediate release methylphenidate component, a sustained release methylphenidate component, and water, said suspension having a pH of about 3.5 to about 5,

wherein said suspension provides a single mean average plasma concentration peak and a therapeutically effective plasma profile of about 12 hours for methylphenidate, and

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 liquid 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, wherein said suspension has a pH in the range of about 4 to about 4.5.

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 liquid suspension at a dose equivalent to 60 mg racemic methylphenidate HCl in adults.

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

5. 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.

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

7. 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 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.

8. The suspension according to claim 7, wherein the buffering agent is a mixture of sodium citrate and anhydrous citric acid.

9. A method of treating patients with a disorder for which methylphenidate is approved which comprises delivering to said patient a methylphenidate twelve-hour extended release suspension according to claim 1, wherein said suspension provides a therapeutically effective amount of methylphenidate as soon as about forty-five minutes in a human patient and a single average plasma concentration peak.

10. The method according to claim 9, wherein the suspension which has a pH from about 4 to about 4.5.

11. A methylphenidate aqueous extended release oral suspension comprising an immediate release methylphenidate component, a sustained release methylphenidate component, and water, said suspension having a pH of about 3.5 to about 5,

wherein said suspension provides a single mean average plasma concentration peak and a therapeutically effective plasma profile of about 12 hours for methylphenidate, and

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 liquid suspension at a dose equivalent to 72 mg racemic methylphenidate HCl in adults.

12. The methylphenidate aqueous extended release oral suspension according to claim 11 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 liquid suspension at a dose equivalent to 72 mg racemic methylphenidate HCl in adults.

13. The suspension according to claim 11, wherein said suspension contains at least about 80% water by weight based on the total weight of the suspension.

14. The suspension according to claim 11, 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 11, which comprises about 10 to about 30 parts by weight methylphenidate as provided in the immediate release component and to about 70 to about 90 parts by weight sustained release methylphenidate, based upon the total weight of methylphenidate in the suspension.

16. The suspension according to claim 11, 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.

17. The suspension according to claim 16, wherein the buffering agent is a mixture of sodium citrate and anhydrous citric acid.

18. A method of treating patients with a disorder for which methylphenidate is approved which comprises delivering to said patient a methylphenidate twelve-hour extended release suspension according to claim 11, wherein said suspension provides a therapeutically effective amount of methylphenidate as soon as about forty-five minutes in a human patient and a single average plasma concentration peak.

19. The method according to claim 18, wherein the suspension which has a pH from about 4 to about 4.5.