Tamper resistant dosage forms

• US 9,775,810 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:
  US15/413,530
• Publication Number:
  US 20170128373A1
• 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 solid oral extended release pharmaceutical dosage forms, comprising the steps of:

mixing at least one active agent and at least one polyethylene oxide (PEO) having an approximate molecular weight of from 1 million to 15 million, to provide a first PEO composition;

providing a second PEO composition comprising at least one low molecular weight PEO having an approximate molecular weight of less than 1 million;

compressing the first 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 the softening temperature of the high molecular weight PEO for a curing time of at least about 5 minutes, to provide a plurality of cured matrix compositions;

cooling the cured matrix compositions;

combining the first and second PEO compositions, before or after curing, to provide a plurality of combined matrix compositions; and

optionally 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 total of high and low molecular weight PEO comprises at least about 50% (by weight) of each dosage form;

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

(d) 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 is at least about 60°

C. and the curing time is at least about 10 minutes.

3. A method according to claim 2, 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.

4. A method according to claim 2, wherein the high molecular weight PEO has an approximate molecular weight of from 1 million to 8 million.

5. A method according to claim 4, wherein the low molecular weight PEO comprises at least about 10% (by weight) of each dosage form.

6. A method according to claim 5, wherein the high molecular weight PEO comprises at least about 50% (by weight) of each dosage form.

8. A method according to claim 4, wherein the low molecular weight PEO comprises at least about 20% (by weight) of each dosage form.

9. A method according to claim 8, wherein 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 total of high and low molecular weight PEO comprises at least about 80% (by weight) of each dosage form.

7. A method according to claimed 6, wherein the low molecular weight PEO has an approximate molecular weight of 100,000 to 900,000;

the curing temperature is from about 65°

C to about 90°

C and the curing time is about 10 to about 10 hours.

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

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

providing a second PEO composition comprising at least one low molecular weight PEO having an approximate molecular weight of less than 1,000,000;

compressing the first 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 first and second PEO compositions, before or after curing, to provide a plurality of combined matrix compositions;

optionally 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 tablet and the low molecular weight PEO comprises at least about 10% (by weight) of each tablet;

(c) the total weight of each tablet is calculated by excluding the combined weight of any final coatings; and

(d) 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 or film coating is present, and 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.

13. 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.

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

15. A method according to claim 13, wherein each of the curing temperature and the cooling temperature is the temperature of the exhaust air.

16. A method according to claim 15, 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.

17. A method according to claim 15, wherein at least one additive or film coating is present, and 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.

18. A method according to claim 15, wherein the high molecular weight PEO has an approximate molecular weight that is selected from 1 million, 2 million, 4 million, and 7 million;

the low molecular weight PEO has an approximate molecular weight of from 100,000 to 900,000; and

the total of high and low molecular weight PEO comprises at least about 50% (by weight) of each tablet.

19. A method according to claim 18, wherein the low molecular weight PEO has an approximate molecular weight of approximately 900,000.

20. A method according to claim 18, wherein the high molecular weight PEO has an approximate molecular weight selected from 4 million and 7 million.

21. A method according to claim 18, wherein at least one film coating is present.

22. A method according to claim 18, wherein the high molecular weight PEO comprises at least about 50% (by weight) of each tablet.

23. A method according to claim 18, wherein the total of high and low molecular weight PEO comprises at least about 80% (by weight) of each tablet.

24. A method according to claim 18, wherein the anti-tacking agent comprises magnesium stearate.

25. A method according to claim 18, wherein at least one additive comprises an antioxidant.

26. A method according to claim 25, wherein the antioxidant comprises butylated hydroxytoluene (BHT).

27. A method according to claim 26, wherein the total of high and low molecular weight PEO comprises at least about 90% (by weight) of each tablet.

28. A method according to claim 18, wherein the active agent (i) is selected from the group consisting of buprenorphine, oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, and pharmaceutically acceptable salts thereof, and (ii) is at least about 5% (by weight) of each tablet.

29. A method according to claim 28, wherein the total of high and low molecular weight PEO comprises at least about 80% (by weight) of each tablet.

30. A method according to claim 28, wherein at least one film coating is present;

the high molecular weight PEO is selected from 4 million and 7 million;

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%.