# US 2014/0193494 A1 · Misuse preventative, controlled release formulation

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- Number: US 2014/0193494 A1
- Document ID: US20140193494A1
- Status: Published application
- Kind: A1
- Application number: 14/195,813
- Filed: 2014-03-03
- Published: 2014-07-10
- Earliest claimed: 2007-12-17
- Assignees: Paladin Labs Inc.; Paladin Labs Europe Limited; Paladin Labs (Barbados) Inc.
- Applicants: Paladin Labs Inc.; Paladin Labs Europe Limited; Paladin Labs (Barbados) Inc.
- Inventors: Miloud Rahmouni; Angela Ferrada; Fouzia Soulhi; Sonia Gervais; Vinayak Sant; Damon Smith; Frederic Duffayet; Shams Rustom; Ali El-Jammal; Jean-Michel Ndong; Bobby-Ernst Boursiquot; Ali Bichara
- Web page: https://patentgrep.com/patent/US20140193494A1

## CPC

- A61K 9/2081: {with microcapsules or coated microparticles according to A61K9/50}
- 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 9/20: Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers}
- A61K 9/205: {Polysaccharides, e.g. alginate, gums; Cyclodextrin}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- A61K 9/209: {containing drug in at least two layers or in the core and in at least one outer layer}
- A61K 9/28: Dragees; Coated pills or tablets {, e.g. with film or compression coating (A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209)}
- A61K 9/2813: {Inorganic compounds}
- A61K 9/282: {Organic compounds, e.g. fats}
- A61K 9/284: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone}
- A61K 9/2846: {Poly(meth)acrylates}
- A61K 9/286: {Polysaccharides, e.g. gums; Cyclodextrin}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/50: Microcapsules {having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals (A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167)}
- A61K 31/00: Medicinal preparations containing organic active ingredients
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

Disclosed is a misuse preventative, controlled release formulation comprising a core comprising a superabsorbent material (for example, polycarbophil), a controlled release coat surrounding the core, and a plurality of controlled release microparticles having a pharmaceutically active agent (for example, an opioid analgesic) disposed within the core, the coat, or both the core and the coat. When crushed, either intentionally or accidentally, and exposed to an aqueous medium, the superabsorbent material present in the coreswells to encapsulate the microparticles, which remain substantially intact thereby retarding the release of the pharmaceutically active agent from the formulation. Also disclosed is a method of using the misuse preventative, controlled release formulation to deliver a pharmaceutically active agent to a mammal, for example, a human, in need thereof.

## Claims

### Claim 1

A solid, compressed controlled release formulation, comprising:
(a) a core comprising a superabsorbent material comprising a cross-linked acrylic acid polymer characterized in that the cross-linked acrylic acid polymer absorbs at least 15 times its own weight of water, the superabsorbent material comprising from 30% to 70% (w/w) of the core;
(b) a controlled release coat surrounding the core; and
(c) a plurality of controlled release microparticles having a pharmaceutically active agent disposed therein, wherein the microparticles are disposed within the core, the coat, or both the core and the coat, the formulation having a hardness from about 200 N to about 400 N, and wherein the formulation
(i) when intact and exposed to an aqueous medium, the pharmaceutically active agent is released from the formulation over a prolonged period of time,
(ii) when crushed to break the controlled release coat and exposed to 2 mL of water, the superabsorbent material absorbs all of the water and creates a hard gel that traps the microparticles, whereupon the hard gel and the microparticles provide controlled release of the pharmaceutically active agent disposed within the microparticles, and
(iii) when broken and exposed to 900 mL of water in a U.S.P. Type I Apparatus with stirring at 100 rpm for 30 minutes at 37° C., less than about 50% by weight of the pharmaceutically active agent originally present in the formulation before it was broken is released into the water.

### Claim 2 (depends on 1)

The formulation of claim 1, wherein the microparticles are disposed within the core.

### Claim 3 (depends on 1)

The formulation of claim 1, wherein the microparticles are disposed within the coat.

### Claim 4 (depends on 1)

The formulation of claim 1, wherein the microparticles are disposed within both the core and the coat.

### Claim 5 (depends on 1)

The formulation of claim 1, wherein the core is monolithic.

### Claim 6 (depends on 1)

The formulation of claim 1, wherein the core comprises a first layer, a second layer and an optional third layer.

### Claim 7 (depends on 6)

The formulation of claim 6, wherein the first layer comprises the microparticles.

### Claim 8 (depends on 1)

The formulation of claim 1, wherein the pharmaceutically active agent is released over a period of at least 12 hours.

### Claim 9 (depends on 1)

The formulation of claim 1, wherein the pharmaceutically active agent is released over a period of at least 24 hours.

### Claim 10 (depends on 1)

The formulation of claim 1, wherein the superabsorbent material is present at about 30% to about 50% (w/w) of the core.

### Claim 11 (depends on 1)

The formulation of claim 1, wherein the core further comprises a granulating agent.

### Claim 12 (depends on 11)

The formulation of claim 11, wherein the granulating agent is selected from the group consisting of xanthan gum, polyethylene oxide, polyvinylpyrollidone, cellulose and sucrose derivatives, and mixtures thereof.

### Claim 13 (depends on 1)

The formulation of claim 1, wherein the coat comprises a controlled release agent.

### Claim 14 (depends on 13)

The formulation of claim 13, wherein the controlled release agent is selected from the group consisting of acetate succinate, a polyvinyl derivative, polyethylene oxide, polyacrylic acid, modified starch, cross-linked high amylose starch, hydroxypropyl starch, hydroxypropyl methylcellulose phthalate, cellulose, microcrystalline cellulose, carboxymethylethyl cellulose, cellulose acetate, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose phthalate, cellulose acetate, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate succinate, cellulose acetate butyrate, cellulose acetate trimellitate, poloxamer, povidone, alginic acid, sodium alginate, polyethylene glycol, polyethylene glycol alginate, gums, polymethacrylate, a copolymer of methacrylic acid and ethyl acrylate, a copolymer of polymethyl vinyl ether and malonic acid anhydride, a copolymer of polymethyl vinyl ether and malonic acid or the ethyl-, isopropyl-, n-butylesters thereof, zein, and mixtures of any of the foregoing.

### Claim 15 (depends on 13)

The formulation of claim 13, wherein the coat further comprises a viscosity-increasing agent.

### Claim 16 (depends on 15)

The formulation of claim 15, wherein the viscosity increasing agent is selected from the group consisting of xanthan gum, polyethylene oxide, polyvinylpyrollidone, cellulose and a sucrose derivative.

### Claim 17 (depends on 1)

The formulation of claim 1, wherein the microparticles comprise a controlled release agent.

### Claim 18 (depends on 17)

The formulation of claim 17, wherein the controlled release agent is selected from the group consisting of acetate succinate, polyvinyl derivatives, polyethylene oxide, polyacrylic acid, modified starch, cross-linked high amylose starch, hydroxypropyl starch, hydroxypropyl methylcellulose phthalate, cellulose, microcrystalline cellulose, carboxymethylethyl cellulose, cellulose acetate, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose phthalate, cellulose acetate, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate succinate, cellulose acetate butyrate, cellulose acetate trimellitate, poloxamer, povidone, alginic acid, sodium alginate, polyethylene glycol, polyethylene glycol alginate, gums, polymethacrylate, a copolymer of methacrylic acid and ethyl acrylate, a copolymer of polymethyl vinyl ether and malonic acid anhydride, a copolymer of polymethyl vinyl ether and malonic acid or the ethyl-, isopropyl-, n-butylesters thereof, zein, and mixtures of any of the foregoing.

### Claim 19 (depends on 1)

The formulation of claim 1, wherein the microparticles are coated with a controlled release coat.

### Claim 20 (depends on 19)

The formulation of claim 19, wherein the controlled release coat is selected from the group consisting of polymethacrylate, cellulose, a cellulose derivative, polyvinyl acetate, polyvinyl pyrollidone, and mixtures thereof.

### Claim 21 (depends on 20)

The formulation of claim 20, wherein the cellulose derivative is selected from the group consisting of ethyl cellulose and hydroxypropyl cellulose.

### Claim 22 (depends on 20)

The formulation of claim 20, wherein the polymethacrylate comprises a polymeric mixture of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate.

### Claim 23 (depends on 1)

The formulation of claim 1, wherein the microparticles have an average diameter in the range of from about 1 μm to about 1000 μm, from about 200 μm to about 900 μm, or from about 300 μm to about 800 μm.

### Claim 24 (depends on 23)

The formulation of claim 23, wherein the microparticles have an average diameter of about 700 μm.

### Claim 25 (depends on 23)

The formulation of claim 23, wherein the microparticles have an average diameter in the range of from about 1 μm to about 400 μm, from about 5 μm to about 300 μm, or from about 10 μm to about 200 μm.

### Claim 26 (depends on 25)

The formulation of claim 25, wherein the microparticles have an average diameter of about 100 μm.

### Claim 27 (depends on 1)

The formulation of claim 1, wherein, in element (iii), less than about 25% by weight of the pharmaceutically active agent originally present in the formulation before it was broken is released into the water.

### Claim 28 (depends on 1)

The formulation of claim 1, wherein, when the formulation is broken and exposed to 900 mL of an aqueous solution containing 60% (v/v) ethanol in a U.S.P. Type 1 Apparatus with stirring at 100 rpm for 30 minutes at 37° C., less than about 50% by weight of the pharmaceutically active agent originally present in the formulation before it was broken is released into the aqueous solution.

### Claim 29 (depends on 28)

The formulation of claim 28, wherein less than about 25% by weight of the pharmaceutically active agent originally present in the formulation before it was broken is released into the aqueous solution.

### Claim 30 (depends on 1)

The formulation of claim 1, wherein the formulation is in the form of a capsule, caplet, pill, or a compressed tablet.

### Claim 31 (depends on 1)

The formulation of claim 1, wherein the pharmaceutically active agent is a drug capable of abuse.

### Claim 32 (depends on 31)

The formulation of claim 31, wherein the drug is an opioid analgesic, hypnotic agent, anxiolytic, or a respiratory stimulant.

### Claim 33 (depends on 1)

The formulation of claim 1, wherein the cross-linked acrylic acid polymer is a copolymer.

### Claim 34 (depends on 1)

The formulation of claim 1, wherein the cross-linked acrylic acid polymer is selected from the group consisting of an acrylic acid polymer cross-linked with divinyl glycol, an acrylic acid polymer cross-linked with allyl ethers of pentaerythritol, and a mixture thereof.

### Claim 35 (depends on 1)

The formulation of claim 1, wherein the cross-linked acrylic acid polymer is polycarbophil.

### Claim 36 (depends on 1)

The formulation of claim 1, wherein the cross-linked acrylic acid polymer is polycarbophilic calcium.

### Claim 37 (depends on 1)

The formulation of claim 1, wherein the cross-linked acrylic acid polymer is a carbomer homopolymer type A.

### Claim 38 (depends on 1)

The formulation of claim 1, wherein the cross-linked acrylic acid polymer is a carbomer homopolymer type B.

### Claim 39 (depends on 1)

A method of providing controlled release of a pharmaceutically active agent, the method comprising orally administering to an individual in need of the pharmaceutically active agent the controlled release formulation of claim 1.