Tamper resistant dosage forms

• US 9,775,811 B2
• Filed: 01/24/2017
• Issued: 10/03/2017
• 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 Pharmaceuticals L.P. (Purdue Pharma L.P.), Purdue Pharma L.P.
• Inventors: McKenna, William H., Mannion, Richard O., O'Donnell, Edward P., Huang, Haiyong H.
• Primary Examiner(s): Fubara, Blessing M
• Application Number:
  US15/413,554
• Publication Number:
  US 20170128374A1
• Time in Patent Office: 252 Days
• 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. A method of producing a plurality of extended release pharmaceutical dosage forms comprising the steps of:

mixing an active agent comprising oxycodone or a pharmaceutically acceptable salt thereof and at least one high molecular weight polyethylene oxide (PEO), having an approximate molecular weight of from 1 million to 8 million, to provide a PEO composition;

compressing the PEO composition to provide a plurality of shaped matrix compositions;

curing the shaped matrix compositions by exposure to heated air at a curing temperature that is at least about 60°

C. for a curing time of at least about 10 minutes, to provide a plurality of cured matrix compositions;

cooling the cured matrix compositions;

combining any of the matrix compositions with at least one additive, before or after curing; and

optionally providing the cured matrix compositions with at least one film coating, after curing and cooling;

wherein

(a) the molecular weight of each PEO is based on rheological measurements;

(b) the high molecular weight PEO comprises at least about 30% (by weight) of each dosage form;

(c) the total weight of each dosage form is calculated by excluding the combined weight of any film coatings;

(d) the active agent comprises at least about 2.4% (by weight) of each dosage form; and

(e) each cured matrix composition comprises a solid oral pharmaceutical dosage form that provides an extended release of at least one active agent.

2. A method according to claim 1, wherein the curing temperature does not exceed about 90°

C.

3. A method according to claim 2, wherein the curing time does not exceed about 10 hours.

4. A method according to claim 3, wherein the film coating is present.

5. A method according to claim 3, wherein the additive comprises at least one of an anti-tacking agent, an antioxidant, an immediate release component, and a retardant.

6. A method according to claim 5, wherein the additive comprises at least one of butylated hydroxytoluene (BHT), magnesium stearate, talc, silica, fumed silica, colloidal silica dioxide, calcium stearate, carnauba wax, stearic acid, stearyl alcohol, mineral oil, paraffin, micro crystalline cellulose, glycerin, propylene glycol, polyethylene glycol, lactose, povidone, triacetin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and copolymers comprising methyl methacrylate.

7. A method according to claim 5, wherein the additive comprises at least one of magnesium stearate, talc, silica, fumed silica, colloidal silica dioxide, calcium stearate, carnauba wax, stearic acid, stearyl alcohol, mineral oil, paraffin, micro crystalline cellulose, glycerin, propylene glycol, polyethylene glycol, lactose, povidone, triacetin, and hydroxypropyl cellulose.

8. A method according to claim 5, wherein the high molecular weight PEO has a molecular weight that is selected from at least one of 1 million, 2 million, 4 million, 5 million, 7 million, and 8 million.

9. A method according to claim 8, wherein the active agent is oxycodone hydrochloride in a dosage amount selected from 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg;

and the high molecular weight PEO comprises at least about 50% (by weight) of each dosage form.

10. A method according to claim 9, wherein the high molecular weight PEO has a molecular weight that is selected from at least one of 4 million and 7 million;

the film coating is present; and

at least one additive is an anti-tacking agent.

11. A method of producing a plurality of solid oral extended release pharmaceutical tablets comprising the steps of:

mixing an active agent comprising oxycodone or a pharmaceutically acceptable salt thereof, and at least one high molecular weight polyethylene oxide (PEO), having an approximate molecular weight of from 1 million to 8 million, to provide a PEO composition;

compressing the PEO composition to provide a plurality of tablet shaped matrix compositions;

curing the shaped matrix compositions by exposure to heated air at a curing temperature that is at least about 60°

C. for a curing time of at least about 10 minutes, to provide a plurality of cured matrix compositions;

cooling the cured matrix compositions;

combining the matrix compositions with at least one additive, before or after curing; and

optionally providing the cured matrix compositions with at least one film coating, after curing and cooling;

wherein

(a) the molecular weight of each PEO is based on rheological measurements;

(b) the high molecular weight PEO comprises at least about 50% (by weight) of each tablet;

(c) the active agent comprises more than about 5% (by weight) of each tablet;

(d) the total weight of each tablet is calculated by excluding the combined weight of said film coating; and

(e) each cured matrix composition comprises a solid oral pharmaceutical tablet that provides an extended release of at least one active agent.

12. A method according to claim 11, wherein

at least one additive comprises an anti-tacking agent;

the curing and cooling steps are conducted in a convection curing device comprising a bed of free flowing tablets;

the heated air comprises inlet air and exhaust air entering and leaving the convection curing device;

the curing temperature does not exceed about 90°

C.;

the curing time does not exceed about 10 hours;

the cooling temperature is below about 50°

C.; and

each of the curing temperature and the cooling temperature is one of (a) the temperature of the inlet air, (b) the temperature of the exhaust air; and

(c) the temperature inside the convection curing device.

13. A method according to claim 12, wherein the combining step comprises at least one of blending, compressing, layering, spraying, and coating.

14. A method according to claim 12, wherein each of the curing temperature and the cooling temperature is the temperature of the exhaust air.

15. A method according to claim 14, wherein the high molecular weight PEO has an approximate molecular weight that is selected from at least one of 1 million, 2 million, 4 million, 5 million, 7 million, and 8 million.

16. A method according to claim 14, wherein the high molecular weight PEO has an approximate molecular weight that is selected from 1 million, 2 million, 4 million, and 7 million.

17. A method according to claim 16, wherein the low molecular weight PEO comprises at least about 20% (by weight) of each tablet.

18. A method according to claim 16, further comprising the step of combining the matrix composition with a low molecular weight PEO having an approximate molecular weight of from 100,000 to 900,000, wherein the low molecular weight PEO comprises at least about 10% (by weight) of each tablet.

19. A method according to claim 18, wherein the low molecular weight PEO has an approximate molecular weight selected from 100,000and 900,000.

20. A method according to claim 14, wherein the high molecular weight PEO has an approximate molecular weight selected from 4 million and 7 million.

21. A method according to claim 20, wherein

the step of compressing the PEO composition comprises tableting by direct compression;

the convection curing device comprises a coating pan;

the curing temperature optionally has a plateau-like profile;

the film coating is present and is combined with the matrix composition, in the coating pan; and

the coating pan has a rotation speed selected for each of the curing, cooling, and film coating steps.

22. A method according to claim 21, wherein the active agent is oxycodone hydrochloride in a dosage amount selected from 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg.

23. A method according to claim 22, wherein the high molecular weight PEO comprises at least about 72% (by weight) of each tablet.

24. A method according to claim 22, wherein the high molecular weight PEO comprises at least about 79% (by weight) of each tablet.

25. A method according to claim 22, wherein at least one of the additive and the film coating comprises at least one of butylated hydroxytoluene (BHT), magnesium stearate, talc, silica, fumed silica, colloidal silica dioxide, calcium stearate, carnauba wax, stearic acid, stearyl alcohol, mineral oil, paraffin, micro crystalline cellulose, glycerin, propylene glycol, polyethylene glycol, lactose, povidone, triacetin, and hydroxypropyl cellulose.

26. A method according to claim 22, wherein the high molecular weight PEO comprises at least about 65% (by weight) of each tablet.

27. A method according to claim 26, wherein the curing temperature has a plateau-like profile.

28. A method according to claim 26, wherein the cured and cooled tablets have a hardness of at least about 439 N;

and the tablets expand upon curing, as measured by a decrease in tablet density of at least about 1.5%.

29. A method according to claim 26, wherein the tablet, when subjected to about 15,000 pounds of applied pressure from a hydraulic press, provides a flattened tablet that

is flattened without breaking apart;

has a thickness that is no more than about 60% of the thickness the non-flattened tablet; and

provides a dissolution of active agent, with ethanol, that deviates no more than about 20% points from the dissolution of a non-flattened reference tablet, without ethanol;

wherein dissolution is measured (i) as a percent amount of active agent released at selected time points up to and including at least a 1 hour period;

(ii) using a USP Apparatus 1 (basket) at 37°

C. and 100 rpm, in 900 ml simulated gastric fluid without enzymes (SGF) for the non-flattened tablet, and further comprising 40% ethanol for the flattened tablet.

30. A method according to claim 26, wherein the tablet,

when measured (a) without an antioxidant additive and (b) as the average of at least 10 of 100 tablet samples stored at 40°

C. and 75% relative humidity for at least 3 months;

provides a dissolution of the active agent that deviates no more than about 10% points from the dissolution of a reference tablet before storage;

wherein dissolution is measured (i) as a percent amount of active agent released at selected time points up to and including at least a 12 hour period;

(ii) using a USP Apparatus 1 (basket) at 37°

C. and 100 rpm, in 900 ml simulated gastric fluid without enzymes (SGF).