# US 9,040,083 B2 · Orally effective methylphenidate extended release powder and aqueous suspension product

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- Number: US 9,040,083 B2
- Document ID: US9040083B2
- Status: Granted
- Kind: B2
- Application number: 14/554,123
- Filed: 2014-11-26
- Published: 2015-03-26
- Granted: 2015-05-26
- Earliest claimed: 2011-02-15
- Assignees: Tris Pharma, Inc.
- Applicants: Tris Pharma, Inc.
- Inventors: Ketan Mehta; Yu-Hsing Tu; Ashok Perumal
- Web page: https://patentgrep.com/patent/US9040083B2

## 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 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 Cmax 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 2)

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.

### Claim 4 (depends on 2)

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.

### Claim 5 (depends on 2)

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.

### Claim 6 (depends on 2)

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.

### Claim 7 (depends on 1)

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.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 1)

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.

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 1)

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.

### Claim 14 (depends on 1)

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.

### Claim 15 (depends on 1)

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.

### Claim 16 (depends on 1)

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.

### Claim 17 (depends on 1)

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.

### Claim 18 (depends on 1)

The powder according to claim 1, wherein the oral aqueous suspension provides a Tmax 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.

### Claim 19 (depends on 1)

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 Tmax 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.

### Claim 20 (depends on 19)

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 Tmax 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.

### Claim 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 Cmax 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 Tmax in adults subjects fed with a high-fat meal prior to administration compared to adult subjects in a fasted state prior to administration.

### Claim 22 (depends on 21)

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 Tmax 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.