# US 8,465,765 B2 · Orally effective methylphenidate extended release powder and aqueous suspension product

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- Number: US 8,465,765 B2
- Document ID: US8465765B2
- Status: Granted
- Kind: B2
- Application number: 13/611,183
- Filed: 2012-09-12
- Published: 2013-01-03
- Granted: 2013-06-18
- Earliest claimed: 2011-02-15
- Assignees: Tris Pharma, Inc.
- Applicants: Ketan Mehta; Yu-Hsing Tu; Ashok Perumal
- Inventors: Ketan Mehta; Yu-Hsing Tu; Ashok Perumal
- Web page: https://patentgrep.com/patent/US8465765B2

## CPC

- A61K 31/4458: only substituted in position 2, e.g. methylphenidate
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- 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)}
- 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)}
- A61K 9/146: {with organic macromolecular compounds}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/1682: {Processes}
- 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)}
- A61K 9/5015: {Organic compounds, e.g. fats, sugars}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 31/787: containing heterocyclic rings having nitrogen as a ring hetero atom
- A61K 47/585: {Ion exchange resins, e.g. polystyrene sulfonic acid resin}
- A61K 49/0021: {the fluorescent group being a small organic molecule}
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/24: Antidepressants
- A61P 25/26: Psychostimulants, e.g. nicotine, cocaine
- 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
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 3)

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.

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 1)

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, Cmax of about 11 ng/mL to about 17 ng/mL, Tmax of about 4 hours to about 5.25 hours and T1/2 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.

### Claim 7 (depends on 6)

The methylphenidate aqueous extended release oral suspension according to claim 6 wherein the pharmacokinetic profile of d-methylphenidate has an AUC0-∞ of about 143.65 ng-hr/mL, Cmax of about 13.61 ng/mL, Tmax of about 5 hours and T1/2 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.

### Claim 8 (depends on 1)

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 Cmax of about 13.6 to about 21.3 ng/mL, and Tmax 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.

### Claim 9 (depends on 8)

The methylphenidate aqueous extended release oral suspension according to claim 8 wherein said suspension has a pharmacokinetic profile in which methylphenidate has an AUC0-∞ of about 171.5 ng-hr/mL, a Cmax of about 17.0 ng/mL, and a Tmax 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.

### Claim 10 (depends on 1)

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.

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 10)

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

### Claim 13 (depends on 1)

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.

### Claim 14 (depends on 1)

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.

### Claim 15 (depends on 1)

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.

### Claim 16 (depends on 1)

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.

### Claim 17 (depends on 1)

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.

### Claim 18 (depends on 17)

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

### Claim 19 (depends on 1)

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.

### Claim 20 (depends on 19)

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

### Claim 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.

### Claim 22 (depends on 21)

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.

### Claim 23 (depends on 21)

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.

### Claim 24 (depends on 23)

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

### Claim 25 (depends on 24)

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

### Claim 26 (depends on 21)

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.

### Claim 27 (depends on 21)

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

### Claim 28 (depends on 1)

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.

### Claim 29 (depends on 28)

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.

### Claim 30 (depends on 29)

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.