Orally effective methylphenidate extended release powder and aqueous suspension product

• US 9,040,083 B2
• Filed: 11/26/2014
• Issued: 05/26/2015
• 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:
  US14/554,123
• Publication Number:
  US 20150086641A1
• Time in Patent Office: 181 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 powder which when admixed with water forms an aqueous oral suspension, said powder comprising (i) an immediate release methylphenidate component, (ii) a sustained release water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex, and (iii) a buffering agent which adjusts the pH of the oral aqueous suspension comprising the powder to a pH of about 4.2,

wherein the oral aqueous suspension provides a pharmacokinetic profile in which 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 the oral aqueous suspension to adult subjects under fasted conditions at a dose equivalent to 60 mg racemic methylphenidate HCl.

2. The powder according to claim 1, wherein the suspension which comprises the powder further comprises at least about 80% of water based on the total weight of the suspension.

3. The powder according to claim 2, wherein the suspension has less than about 5% loss in potency over a period of about 1 month of storage at room temperature.

4. The powder according to claim 2, wherein the suspension has less than about 1% of an impurity which is threo-α

-phenyl-2-piperidineacetic acid hydrochloride after a period of about 1 month of storage at room temperature.

5. The powder according to claim 2, wherein the suspension has less than about 5% loss in potency over a period of about 4 months of storage at room temperature.

6. The powder according to claim 2, wherein the suspension has less than about 1% of an impurity which is threo-α

-phenyl-2-piperidineacetic acid hydrochloride after a period of about 4 months of storage at room temperature.

7. The powder according to claim 1, wherein the methylphenidate in the immediate release methylphenidate component of (i) comprises about 20% w/w of the total methylphenidate in said powder.

8. The powder according to claim 1, wherein the immediate release methylphenidate component comprises an uncoated methylphenidate-ion exchange resin complex.

9. The powder according to claim 1, wherein the immediate release methylphenidate component comprises a methylphenidate-ion exchange resin complex having a coating that provides immediate release.

10. The powder according to claim 1, wherein the barrier coating of the sustained release water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex comprises a polyvinylacetate polymer and a plasticizer.

11. The powder according to claim 10, wherein the barrier coating is cured.

12. The powder according to claim 1, wherein the barrier coating of the sustained release water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex comprises ethylcellulose.

13. The powder according to claim 1, wherein the barrier coating of the sustained release water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex comprises a methyl methyacrylate polymer or co-polymer.

14. The powder according to claim 1, which provides the aqueous oral suspension comprising at least about 70% of water based on the total weight of the suspension.

15. The powder according to claim 1, wherein the oral aqueous suspension has a therapeutically effective plasma profile for methylphenidate of about 12 hours following a single oral administration of the oral aqueous suspension to adult subjects under fasted conditions at a dose equivalent to 60 mg racemic methylphenidate HCl.

16. The powder according to claim 1, wherein the oral aqueous suspension provides a therapeutically effective amount of methylphenidate within 45 minutes after a single oral administration of the oral aqueous suspension to adult subjects under fasted conditions at a dose equivalent to 60 mg racemic methylphenidate HCl.

17. The powder according to claim 1, wherein the oral aqueous suspension provides a single average plasma concentration peak following a single oral administration of the oral aqueous suspension to adult subjects under fasting conditions at a dose equivalent to 60 mg racemic methylphenidate HCl.

18. The powder according to claim 1, wherein the oral aqueous suspension provides a T_max of about 4 hours to about 5.25 hours following a single oral administration of the oral aqueous suspension to adult subjects under fasted conditions at a dose equivalent to 60 mg racemic methylphenidate HCl.

19. The powder according to claim 1, wherein following a single oral administration of the oral aqueous suspension to adult subjects at a dose equivalent to 60 mg racemic methylphenidate HCl said suspension provides a reduced T_max for d-methylphenidate in adult subjects fed with a high-fat meal prior to administration compared to adult subjects in a fasted state prior to administration.

20. The powder according to claim 19, wherein following a single oral administration of the oral aqueous suspension at a dose equivalent to 60 mg racemic methylphenidate HCl, the oral aqueous suspension provides a T_max for d-methylphenidate reduced by about 60 minutes in adult subjects fed with a high-fat meal prior to administration compared to adult subjects in a fasted state prior to administration.

21. A powder which when admixed with water forms an aqueous oral suspension, said powder comprising (i) an immediate release methylphenidate component, (ii) a sustained release water-insoluble, water-permeable, pH-independent, barrier coated methylphenidate-ion exchange resin complex, and (iii) a buffering agent which adjusts the pH of the oral aqueous suspension comprising the powder to a pH of about 4.2,

wherein the oral aqueous suspension comprising the powder further comprises at least about 80% of water based on the total weight of the suspension,

wherein the oral aqueous 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 the aqueous oral suspension to adult subjects under fasted conditions, at a dose equivalent to 60 mg racemic methylphenidate HCl, the oral aqueous suspension has a pharmacokinetic profile in which 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, and

wherein following a single administration of the aqueous oral suspension to adult, the d-methylphenidate has a reduced T_max in adults subjects fed with a high-fat meal prior to administration compared to adult subjects in a fasted state prior to administration.

22. The powder according to claim 21, wherein following a single oral administration of an aqueous oral suspension at a dose equivalent to 60 mg racemic methylphenidate HCl the oral aqueous suspension has a pharmacokinetic profile in which the d-methylphenidate has a T_max reduced by about 60 minutes in adults subjects fed with a high-fat meal prior to administration compared to adult subjects in a fasted state prior to administration.