TAMPER RESISTANT DOSAGE FORMS

• US 20130251798A1
• Filed: 05/23/2013
• Published: 09/26/2013
• Est. Priority Date: 08/25/2006
• Status: Active Grant

• Current Assignee: Purdue Pharmaceuticals L.P. (Purdue Pharma L.P.), Purdue Pharma L.P.
• Original Assignee: Purdue Pharma L.P.
• Inventors: McKenna, William H., Mannion, Richard O., O'Donnell, Edward P., Huang, Haiyong H.
• Granted Patent: US 8,894,988 B2
• Time in Patent Office: Days
• US Class Current: 424/472
• CPC Class Codes: A61J 3/005 Coating of tablets or the like coating of sweetmeats or confectionery A23G3/20; coating of granules in general B01J2/006
• CPC Class Codes: A61J 3/06 into the form of pills, lozenges or dragees
• CPC Class Codes: A61J 3/10 into the form of compressed tablets tablet presses B30B11/00
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/284 : obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
• CPC Class Codes: 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)
• CPC Class Codes: A61K 9/2866 : Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2893 : Tablet coating processes mechanical aspects A61J3/06
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• CPC Class Codes: B29B 7/02 : non-continuous, with mechanical mixing or kneading devices, i.e. batch type
• CPC Class Codes: B29B 7/88 : Adding charges , i.e. additives
• CPC Class Codes: B29C 2035/046 : dried air
• CPC Class Codes: B29C 2035/1658 : using gas
• CPC Class Codes: B29C 35/045 : using gas or flames
• CPC Class Codes: 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
• CPC Class Codes: 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
• CPC Class Codes: B29C 43/003 : characterised by the choice of material
• CPC Class Codes: B29C 43/02 : of articles of definite length, i.e. discrete articles B29C35/0227 takes precedence
• CPC Class Codes: B29C 43/52 : Heating or cooling
• CPC Class Codes: 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
• CPC Class Codes: 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
• CPC Class Codes: B29K 2071/02 : Polyalkylene oxides, e.g. PEO, i.e. polyethylene oxide, or derivatives thereof
• CPC Class Codes: B29K 2105/0035 : Medical or pharmaceutical agents
• CPC Class Codes: B29K 2105/251 : Particles, powder or granules expandable particles B29K2105/046
• CPC Class Codes: B29K 2995/0088 : Molecular weight
• CPC Class Codes: B29L 2031/753 : Medical equipment; Accessories therefor bloodbags, medical bags B29L2031/7148; artificial eyes B29L2011/0008

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

1-169. -169. (canceled)

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 polyethylene oxide having, based on rheological measurements, an approximate molecular weight of at least 1,000,000; and

(2) at least one active agent; and

wherein the extended release matrix formulation is cured at a temperature of at least about 60°

C. for a time period of at least about 1 minute and has a cracking force of at least about 110 N when subjected to an indentation test.

171. The solid oral extended release pharmaceutical dosage form of claim 170, wherein the extended release matrix formulation when subjected to an indentation test has a penetration depth to crack distance of at least about 1.0 mm.

172. The solid oral extended release pharmaceutical dosage form of claim 170, wherein the extended release matrix formulation has a cracking force of at least about 120 N, at least about 130 N, or at least about 140 N and/or a penetration depth to crack distance of at least about 1.2 mm, at least about 1.4 mm, at least about 1.5 mm, or at least about 1.6 mm.

173. The solid oral extended release pharmaceutical dosage form of claim 170, wherein the extended release matrix formulation resists a work of at least about 0.06 J without cracking

174. 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) 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.

175. The solid oral extended release pharmaceutical dosage form of claim 174, wherein the extended release matrix formulation has been stored at 40°

C. and 75% relative humidity (RH).

176. 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) 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.

177. The solid oral extended release pharmaceutical dosage form of claim 176, wherein the extended release matrix formulation has been stored at 40°

C. and 75% relative humidity (RH).

178. 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 hours.

179. 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™

.

180. 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.

181. The extended release dosage form of claim 170, wherein the composition comprises at least about 80% (by wt) of polyethylene oxide.

182. The extended release dosage form of claim 181, 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.

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

184. The extended release dosage form of claim 183, wherein the opioid analgesic is selected from the group consisting 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, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, hydrates, and solvates thereof, or mixtures of any of the foregoing.

185. The extended release dosage form of claim 183, wherein the opioid analgesic is selected from the group consisting of codeine, morphine, oxycodone, hydrocodone, hydromorphone, and oxymorphone or pharmaceutically acceptable salts, hydrates and solvates thereof, or mixtures of any of the foregoing.

186. The extended release dosage form of claim 183, wherein the opioid analgesic is oxycodone hydrochloride and the dosage form comprises from about 5 mg to about 500 mg of oxycodone hydrochloride.

187. The extended release dosage form of claim 186, 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.

188. The extended release dosage form of claim 183, 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.

189. The extended release dosage form of claim 183, wherein the opioid analgesic is oxymorphone hydrochloride and the dosage form comprises from about 1 mg to about 500 mg of oxymorphone hydrochloride.

190. The extended release dosage form of claim 189, 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 oxymorphone hydrochloride.

191. The extended release dosage form of claim 183, wherein the opioid analgesic is hydromorphone hydrochloride and the dosage form comprises from about 1 mg to about 100 mg of hydromorphone hydrochloride.

192. The extended release dosage form of claim 191, wherein the dosage form comprises 2 mg, 4 mg, 8 mg, 12 mg, 16 mg, 24 mg, 32 mg, 48 mg or 64 mg of hydromorphone hydrochloride.

193. 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.

194. 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.

195. 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.

196. The extended release dosage form of claim 195, wherein the extended release formulation and the immediate release formulation contain the same or different active agents.

197. The extended release dosage form of claim 195, wherein the extended release formulation comprises an opioid analgesic and the immediate release formulation comprises a non opioid analgesic.

198. 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.

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