# US 2013/0251802 A1 · Tamper resistant dosage forms

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2013/0251802 A1
- Document ID: US20130251802A1
- Status: Published application
- Kind: A1
- Application number: 13/901,218
- Filed: 2013-05-23
- Published: 2013-09-26
- Earliest claimed: 2006-08-25
- Assignees: Purdue Pharma L.P.
- Applicants: Purdue Pharma L.P.
- Inventors: William H. McKenna; Richard O. Mannion; Edward P. O'Donnell; Haiyong H. Huang
- Web page: https://patentgrep.com/patent/US20130251802A1

## CPC

- 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)}
- A61J 3/005: {Coating of tablets or the like (coating of sweetmeats or confectionery A23G3/20; coating of granules in general B01J2/006)}
- A61J 3/06: into the form of pills, lozenges or dragees
- A61J 3/10: into the form of compressed tablets (tablet presses B30B11/00)
- A61K 9/0002: {Galenical forms characterised by the drug release technique; Application systems commanded by energy}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/1641: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- 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 9/2054: {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 9/2095: {Tabletting processes}
- A61K 9/284: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone}
- A61K 9/2853: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2893: {Tablet coating processes (mechanical aspects A61J3/06)}
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 29/02: without antiinflammatory effect
- B29B 7/02: non-continuous, with mechanical mixing or kneading devices, i.e. batch type
- B29B 7/88: Adding charges {, i.e. additives}
- B29C 35/045: {using gas or flames}
- B29C 35/16: Cooling {(cooling extruded material B29C48/911; cooling preforms for blow moulding B29C49/6427; cooling blown articles B29C49/66; cooling tyres during post cure inflation B29D30/0643)}
- B29C 37/0025: {Applying surface layers, e.g. coatings, decorative layers, printed layers, to articles during shaping, e.g. in-mould printing (moulding on preformed layers as inserts B29C70/68; applying fluent material to surfaces in general B05)}
- B29C 43/003: {characterised by the choice of material}
- B29C 43/02: of articles of definite length, i.e. discrete articles {(B29C35/0227 takes precedence)}
- B29C 43/52: Heating or cooling
- B29C 71/00: After-treatment of articles without altering their shape; Apparatus therefor (B29C44/56, B29C73/00 take precedence; surface shaping B29C59/00 {; for joined or sealed parts B29C66/03; after-treatment specially adapted for vulcanising tyres B29D30/0633})
- B29C 71/009: {using gases without chemical reaction (C08J7/12 takes precedence; in combination with blow-moulding B29C49/46; surface treatment using plasma B29C59/14, ionised gas B29C59/16)}
- A61K 9/2072: {characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms (A61K9/0004, A61K9/0056, A61K9/0065 take precedence)}
- B29C 2035/046: {dried air}
- B29C 2035/1658: {using gas}
- B29K 2071/02: {Polyalkylene oxides, e.g. PEO, i.e. polyethylene oxide, or derivatives thereof}
- B29K 2105/0035: {Medical or pharmaceutical agents}
- B29K 2105/251: {Particles, powder or granules (expandable particles B29K2105/046)}
- B29K 2995/0088: Molecular weight
- B29L 2031/753: {Medical equipment; Accessories therefor (bloodbags, medical bags B29L2031/7148; artificial eyes B29L2011/0008)}
- 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)
- A61J: CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B29B: PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
- B29C: SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING (making preforms B29B11/00; making laminated products by combining previously unconnected layers which become one product whose layers will remain together B32B37/00 - B32B41/00)
- B29K: INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR {MOULDS, } REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
- B29L: INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES

## Abstract

The present invention relates to pharmaceutical dosage forms, for example to a tamper resistant dosage form including an opioid analgesic, and processes of manufacture, uses, and methods of treatment thereof.

## Claims

### Claim at position 1

1-169. (canceled)

### Claim 170

A solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation, the extended release matrix formulation comprising a composition comprising at least:
(1) at least one active agent selected from opioid analgesics; and
(2) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000;
(3) at least one polyethylene oxide having, based on rheological measurements, an approximate molecular weight of less than 1,000,000; and
wherein the composition comprises at least about 80% (by wt) of polyethylene oxide and at least about 50% (by wt) of polyethylene oxide having, based on rheological measurements, a molecular weight of at least 1,000,000.

### Claim 171 (depends on 170)

The solid oral extended release pharmaceutical dosage form of claim 170, wherein the density of the extended release matrix formulation is equal to or less than about 1.20 g/cm3 or equal to or less than about 1.19 g/cm3.

### Claim 172 (depends on 170)

The solid oral extended release pharmaceutical dosage form of claim 170, wherein the extended release matrix formulation after having been stored at 25° C. and 60% relative humidity (RH) or at 40° C. and 75 % relative humidity (RH), for at least 1 month provides a dissolution rate, when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C., characterized by the percent amount of active agent released at 1, 4 and 12 hours of dissolution that deviates no more than about 15% points from the corresponding in-vitro dissolution rate of a reference formulation prior to storage.

### Claim 173 (depends on 170)

The solid oral extended release pharmaceutical dosage form of claim 170, wherein the extended release matrix formulation after having been stored at 25° C. and 60% relative humidity (RH) or at 40° C. and 75% relative humidity (RH), for at least 1 month contains an amount of the at least one active agent in % (by wt) relative to the label claim of the active agent for the extended release matrix formulation that deviates no more than about 10 % points from the corresponding amount of active agent in % (by wt) relative to the label claim of the active agent for the extended release matrix formulation of a reference formulation prior to storage.

### Claim 174 (depends on 170)

The solid oral extended release pharmaceutical dosage form of claim 170, wherein the dosage form provides a dissolution rate, which when measured in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37° C., is between 12.5 and 55% (by wt) active released after 1 hour, between 25 and 65% (by wt) active released after 2 hours, between 45 and 85% (by wt) active released after 4 hours and between 55 and 95% (by wt) active released after 6 hour.

### Claim 175 (depends on 170)

The solid oral extended release pharmaceutical dosage form of claim 170, wherein the active agent is oxycodone hydrochloride and wherein the dosage form when tested in a comparative clinical study is bioequivalent to the commercial product OxyContin™.

### Claim 176 (depends on 170)

The solid oral extended release pharmaceutical dosage form of claim 170, wherein the active agent is oxycodone hydrochloride and wherein a dosage form comprising 10 mg of oxycodone hydrochloride when tested in a comparative clinical study is bioequivalent to a reference tablet containing 10 mg of oxycodone hydrochloride in a matrix formulation containing:
a) Oxycodone hydrochloride: 10.0 mg/tablet;
b) Lactose (spray-dried): 69.25 mg/tablet;
c) Povidone: 5.0 mg/tablet;
d) Eudragit® RS 30D (solids): 10.0 mg/tablet;
e) Triacetin®: 2.0 mg/tablet;
f) Stearyl alcohol: 25.0 mg/tablet;
g) Talc: 2.5 mg/tablet; and
h) Magnesium Stearate: 1.25 mg/tablet;
and wherein the reference tablet is prepared by the following steps:
1. Eudragit® RS 30D and Triacetin® are combined while passing through a 60 mesh screen, and mixed under low shear for approximately 5 minutes or until a uniform dispersion is observed;
2. Oxycodone HCl, lactose, and povidone are placed into a fluid bed granulator/dryer (FBD) bowl, and the suspension sprayed onto the powder in the fluid bed;
3. After spraying, the granulation is passed through a #12 screen if necessary to reduce lumps;
4. the dry granulation is placed in a mixer;
5. in the meantime, the required amount of stearyl alcohol is melted at a temperature of approximately 70° C.;
6. the melted stearyl alcohol is incorporated into the granulation while mixing;
7. the waxed granulation is transferred to a fluid bed granulator/dryer or trays and allowed to cool to room temperature or below;
8. the cooled granulation is then passed through a #12 screen;
9. the waxed granulation is placed in a mixer/blender and lubricated with the required amounts of talc and magnesium stearate for approximately 3 minutes; and
10. the granulate is compressed into 125 mg tablets on a suitable tableting machine.

### Claim 177 (depends on 172)

The extended release dosage form of claim 172, wherein the composition comprises at least about 80% (by wt) polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000.

### Claim 178 (depends on 176)

The extended release dosage form of claim 176, wherein the composition comprises at least about 80% (by wt) polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000.

### Claim 179 (depends on 170)

The extended release dosage forth of claim 170, wherein the active agent is an opioid analgesic.

### Claim 180 (depends on 179)

The extended release dosage form of claim 179, wherein the opioid analgesic is selected from the group of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.

### Claim 181 (depends on 179)

The extended release dosage form of claim 179, wherein the opioid analgesic is selected from the group of codeine, morphine, oxycodone, hydrocodone, hydromorphone, or oxymorphone or pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing.

### Claim 182 (depends on 179)

The extended release dosage form of claim 179, wherein the opioid analgesic is oxycodone hydrochloride and the dosage form comprises from about 5 mg to about 500 mg of oxycodone hydrochloride.

### Claim 183 (depends on 182)

The extended release dosage form of claim 182, wherein the dosage form comprises 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 60 mg, 80 mg, 90 mg, 120 mg or 160 mg of oxycodone hydrochloride.

### Claim 184 (depends on 179)

The extended release dosage form of claim 179, wherein the opioid analgesic is oxycodone hydrochloride having a 14-hydroxycodeinone level of less than about 25 ppm, of less than about 15 ppm, less than about 10 ppm, or less than about 5 ppm.

### Claim 185 (depends on 179)

The extended release dosage form of claim 179, wherein the opioid analgesic is oxymorphone hydrochloride and the dosage form comprises from about 1 mg to about 500 mg of oxymorphone hydrochloride or 5 mg, 7.5 mg, 10 mg, 15 mg, 20 tug, 30 mg, 40 mg, 45 mg, 60 mg, 80 mg, 90 mg, 120 mg, or 160 mg of oxymorphone hydrochloride.

### Claim 186 (depends on 179)

The extended release dosage form of claim 179, wherein the opioid analgesic is hydromorphone hydrochloride and the dosage form comprises from about 1 tug to about 100 mg of hydromorphone hydrochloride or 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg, or 64 mg of hydromorphone hydrochloride.

### Claim 187 (depends on 170)

The extended release dosage form of claim 170, which is in the form of a tablet formed by direct compression of the composition and cured by at least subjecting said tablet to a temperature of at least about 60° C. or at least about 62° C. for a time period of at least about 1 minute, at least about 5 minutes, or at least about 15 minutes.

### Claim 188 (depends on 170)

The extended release dosage form of claim 170, which is in the form of a tablet and which is over coated with a polyethylene oxide powder layer to form a tablet that has a core tablet and a layer of polyethylene oxide surrounding the core tablet.

### Claim 189 (depends on 176)

The extended release dosage form of claim 176, which is in the form of a tablet and which is over coated with a polyethylene oxide powder layer to form a tablet that has a core tablet and a layer of polyethylene oxide surrounding the core tablet.

### Claim 190 (depends on 170)

The extended release dosage form of claim 170, which is in the form of a stacked bi or multi layered tablet, wherein one of the layers contains an extended release formulation and one of the other layers contains an immediate release formulation.

### Claim 191 (depends on 190)

The extended release dosage form of claim 190, wherein the extended release formulation and the immediate release formulation contain the same or different active agents.

### Claim 192 (depends on 190)

The extended release dosage form of claim 190, wherein the extended release formulation comprises an opioid analgesic and the immediate release formulation comprises a non opioid analgesic.

### Claim 193 (depends on 170)

A method of treatment wherein a dosage form according to claim 170 is administered for the treatment of pain to a patient in need thereof, wherein the dosage form comprises an opioid analgesic.

### Claim 194 (depends on 170)

A pharmaceutical tablet in accordance with claim 170 having a cracking force of at least 110 N, at least 120 N, at least 130 N, or at least 140 N, when subjected to an indentation test.

### Claim 195 (depends on 170)

A pharmaceutical tablet in accordance with claim 170 having a penetration depth to crack distance of at least 1.0 mm, at least 1.2 mm, at least 1.4 mm, or at least 1.6 mm, when subjected to an indentation test.

### Claim 196 (depends on 170)

A pharmaceutical tablet in accordance with claim 170 capable of resisting a work of at least 0.06 J without cracking.

### Claim 197 (depends on 170)

A pharmaceutical tablet in accordance with claim 170 having (a) a cracking force of at least 110 N, at least 120 N, at least 130 N, or at least 140 N, when subjected to an indentation test; (b) a penetration depth to crack distance of at least 1.0 mm, at least 1.2 mm, more at least 1.4 mm, or at least 1.6 mm, when subjected to an indentation test; and (c) capable of resisting a work of at least 0.06 J without cracking.

### Claim 198 (depends on 176)

A pharmaceutical tablet in accordance with claim 176 having (a) a cracking force of at least 110 N, at least 120 N, at least 130 N, or at least 140 N, when subjected to an indentation test; (b) a penetration depth to crack distance of at least 1.0 mm, at least 1.2 mm, more at least 1.4 mm, or at least 1.6 mm, when subjected to an indentation test; and (c) capable of resisting a work of at least 0.06 J without cracking.

### Claim 199 (depends on 194)

The pharmaceutical tablet in accordance with claim 194 having a density of less than 1.20 g/cm3 or less than 1.19 g/cm3.