Tamper resistant dosage forms

• US 9,770,416 B2
• Filed: 01/24/2017
• Issued: 09/26/2017
• 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:
  US15/413,678
• Publication Number:
  US 20170128371A1
• Time in Patent Office: 245 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 pharmaceutical composition comprising:

at least one active agent comprising an opioid or a pharmaceutically acceptable salt thereof;

at least one high molecular weight polyethylene oxide (PEO), having an approximate molecular weight of from 1 million to 8 million;

optionally at least one low molecular weight PEO having an approximate molecular weight of less than 1,000,000;

wherein

(a) the active agent and high molecular weight PEO are combined in a solid oral extended release dosage form that is (i) compression shaped, (ii) air cured by heated air, without compression, for a curing time of about 15 minutes to about 8 hours at a curing temperature of about 60°

C. to about 90°

C., (iii) cooled, and (iv) hardened;

(b) the high molecular weight PEO is at least partially melted upon curing and comprises at least about 50% (by weight) of the dosage form;

(c) the active agent comprises at least about 1.3% (by weight) of the dosage form;

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

(e) the total weight of the dosage form is calculated by excluding the combined weight of said film coatings; and

(f) the dosage form is expanded upon curing, as measured by a decrease in density of at least about 1.5%, and the dosage form provides a hardness of at least about 439 N.

2. A pharmaceutical composition according to claim 1, wherein the high molecular weight PEO is selected from at least one PEO having an approximate molecular weight of 1 million, 2 million, 4 million, 5 million, 7 million, and 8 million.

3. A pharmaceutical composition according to claim 2, wherein the active agent (i) is selected from the group consisting of buprenorphine, oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, and pharmaceutically acceptable salts thereof.

4. A pharmaceutical composition according to claim 3, wherein the active agent comprises at least about 2.4% (by weight) of the dosage form.

5. A pharmaceutical composition according to claim 4, wherein the curing temperature is from about 70°

C. to about 85°

C. and the curing time is from about 15 minutes to about 5 hours.

6. A pharmaceutical composition according to claim 5, wherein the low molecular weight PEO is present, has an approximate molecular weight of from 100,000 to 900,000, and comprises at least about 10% (by weight) of the dosage form.

7. A pharmaceutical composition according to claim 5, wherein the low molecular weight PEO is present, has an approximate molecular weight of from 100,000 to 900,000, and comprises at least about 20% (by weight) of the dosage form.

8. A pharmaceutical composition according to claim 7, wherein the active agent is a tartrate salt of hydrocodone, the high molecular weight PEO is selected from 4 million and 7 million, and the high and low molecular weight PEO together comprise at least about 80% (by weight) of the dosage form.

9. A pharmaceutical composition according to claim 3, wherein the active agent comprises at least about 5% (by weight) of the dosage form.

10. A pharmaceutical composition according to claim 9, wherein the curing temperature is from about 70°

C. to about 85°

C. and the curing time is from about 15 minutes to about 5 hours.

11. A pharmaceutical composition according to claim 10, wherein the active agent is oxycodone hydrochloride, and the high molecular weight PEO is selected from 4 million and 7 million, and comprises at least about 65% (by weight) of the dosage form.

12. A pharmaceutical tablet comprising:

a dosage amount of least one active agent comprising an opioid or a pharmaceutically acceptable salt thereof;

at least one high molecular weight polyethylene oxide (PEO) having an approximate molecular weight of from 1 million to 8 million;

at least one additive comprising an anti-tacking agent, an antioxidant, an immediate release component, or a retardant;

at least one film coating; and

optionally at least one low molecular weight PEO having an approximate molecular weight of less than 1,000,000;

wherein

(a) the active agent and high molecular weight PEO are combined in a solid oral extended release tablet that is (i) shaped by direct compression, (ii) air cured by heated air, without compression, for a curing time of at least 15 minutes at a curing temperature of at least about 65°

C., (iii) cooled at a cooling temperature below about 50°

C., and (iv) hardened;

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

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

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

(e) the total weight of the dosage form is calculated by excluding the combined weight of said film coatings; and

(f) the dosage form is expanded upon curing, as measured by a decrease in density of at least about 1.5%, and the dosage form provides a hardness of at least about 439 N.

13. A pharmaceutical composition according to claim 12, wherein

at least one additive comprises an anti-tacking agent;

the compression shaped tablet is cured and cooled in a convection curing device provided with inlet air, exhaust air, and a bed of free flowing tablets; and

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

14. A pharmaceutical composition according to claim 13, wherein the convection curing device is a coating pan.

15. A pharmaceutical composition according to claim 14, wherein the curing temperature has a plateau-like profile.

16. A pharmaceutical composition according to claim 15, wherein each of the curing temperature and cooling temperature is the temperature of the exhaust air.

17. A pharmaceutical composition according to claim 16, wherein the cooling temperature is from about 30°

C. to about 34°

C.

18. A pharmaceutical composition according to claim 16, wherein the low molecular weight PEO is present, has an approximate molecular weight of from 100,000 to 900,000, and comprises at least about 20% (by weight) of the dosage form.

19. A pharmaceutical composition according to claim 16, 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.

20. A pharmaceutical composition according to claim 16, wherein at least one additive is magnesium stearate.

21. A pharmaceutical composition according to claim 16, 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 50% of the thickness of the non-flattened tablet; and

provides a dissolution of active agent, with ethanol, that deviates no more than about 15% 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 2 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.

22. A pharmaceutical composition according to claim 21, 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).

23. A pharmaceutical composition according to claim 22, wherein the deviation in dissolution upon flattening is no more than about 15% points and the deviation in dissolution upon storage is no more than about 5% points.

24. A pharmaceutical composition according to claim 23, wherein the deviation in dissolution upon storage is no more than about 3% points.

25. A pharmaceutical composition according to claim 23, wherein the stored dosage form comprises degradation products of the active agent in a total amount that is no greater than about 0.1% (by weight) of the dosage amount.

26. A pharmaceutical composition according to claim 23, wherein the high molecular weight PEO has an approximate molecular weight selected from 4 million and 7 million.

27. A pharmaceutical composition according to claim 23, wherein the tablets are stored for at least 6 months.

28. A pharmaceutical composition according to claim 27, wherein the stored dosage form comprises degradation products of the active agent in a total amount that is no greater than about 0.1% (by weight) of the dosage amount.

29. A pharmaceutical composition according to claim 28, wherein the active agent is a pharmaceutically acceptable salt of oxycodone and the tablet is suitable for twice-daily administration.

30. A pharmaceutical composition according to claim 28, wherein the active agent is a pharmaceutically acceptable salt of hydrocodone and the tablet is suitable for once-daily administration.