Orally effective methylphenidate extended release powder and aqueous suspension product

• US 8,778,390 B2
• Filed: 09/03/2013
• Issued: 07/15/2014
• 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): Krass, Frederick
• Assistant Examiner(s): Tcherkasskaya, Olga V
• Application Number:
  US14/016,384
• Publication Number:
  US 20140004160A1
• Time in Patent Office: 315 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 an immediate release methylphenidate component, a sustained release methylphenidate component, and water,

wherein said suspension is stable at room temperature for at least one month and provides a single mean average plasma concentration peak and a therapeutically effective plasma profile for 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 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 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.

3. The suspension according to claim 1, wherein the sustained release methylphenidate component comprises a water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex, wherein the complex comprises methylphenidate bound to an ion exchange resin, and wherein the barrier coating is over the methylphenidate-ion exchange resin complex.

4. The suspension according to claim 3, 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 ethylcellulose applied as a non-aqueous solution; and

(c) a pH-independent acrylate based barrier coating comprising a methyl methyacrylate polymer or co-polymer.

5. The suspension according to claim 4, wherein the cured diffusion barrier coating (a) comprises about 70 to about 90% of polyvinylacetate by weight, about 2.5 to about 15% of a plasticizer by weight, and a stabilizer, based on the weight of the cured diffusion barrier coating.

6. The suspension according to claim 5, wherein the cured barrier coating further comprises about 5 to about 10% of the stabilizer by weight, and about 0.1 to about 1% of a surfactant by weight, based on the weight of the cured diffusion barrier coating.

7. The suspension according to claim 6, wherein the plasticizer is triacetin and the surfactant is sodium lauryl sulfate.

8. The suspension according to claim 4, wherein in the water-insoluble, water-permeable, pH-independent, barrier coated complex, 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.

9. The suspension according to claim 8, wherein the matrix forming component comprises a hydrophilic polymer present in an amount of about 5 to about 20% by weight, based on the weight of the methylphenidate-ion exchange resin complex-matrix.

10. The suspension according to claim 9, wherein the hydrophilic polymer is polyvinylpyrrolidone.

11. The suspension according to claim 8, wherein the matrix forming component comprises a hydrophobic polymer or co-polymer present 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 suspension according to claim 8, wherein the cured barrier coat is present in an amount which comprises about 20% to about 45% weight gain to the methylphenidate-ion exchange resin complex-matrix.

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

14. The suspension according to claim 3, wherein the immediate release methylphenidate component is a methylphenidate-ion exchange resin complex, wherein the complex comprises methylphenidate bound to an ion exchange resin, wherein the complex is uncoated.

15. The suspension according to claim 14 which comprises 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 methylphenidate as provided in the sustained release component, based upon the total weight of methylphenidate in the suspension.

16. 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.

17. 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.

18. 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.

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

20. The suspension according to claim 3, wherein the suspension has less than about 5% loss in potency over a period of at least about 4 months at room temperature.

21. The suspension according to claim 3, wherein the suspension is stable at room temperature for at least four months.

22. A method of treating patients which comprises delivering to said patients a methylphenidate twelve-hour extended release suspension according to claim 1.

23. A methylphenidate aqueous extended release oral suspension comprising an immediate release methylphenidate component, a sustained release methylphenidate component comprising a water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex, water, and a buffering agent,

wherein said suspension is stable at room temperature for at least one month and 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.

24. The methylphenidate aqueous extended release oral suspension according to claim 23 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.

25. The suspension according to claim 23, wherein said suspension contains at least about 80% of water by weight based on the total weight of the suspension.

26. The suspension according to claim 23, wherein said methylphenidate in the immediate release and/or sustained release component is independently selected from the group consisting of racemic methylphenidate and dexmethylphenidate.

27. The suspension according to claim 23, which comprises 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 methylphenidate as provided in the sustained release component, based upon the total weight of methylphenidate in the suspension.

28. The suspension according to claim 23, wherein the 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, and mixtures thereof.

29. The suspension according to claim 28, wherein the buffering agent is a mixture of sodium citrate and anhydrous citric acid.

30. A method of treating patients which comprises delivering to said patients a methylphenidate twelve-hour extended release suspension according to claim 23.