Orally Disintegrating Tablet Compositions Comprising Combinations of Non-Opioid and Opioid Analgesics

• US 20110003006A1
• Filed: 05/03/2010
• Published: 01/06/2011
• Est. Priority Date: 05/01/2009
• Status: Active Grant

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Adare Pharmaceuticals, Inc.
• Inventors: Gosselin, Michael, Lai, Jin-Wang, Clevenger, James, Venkatesh, Gopi
• Granted Patent: US 9,572,781 B2
• Time in Patent Office: Days
• US Class Current: 424/495
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4415 Pyridoxine, i.e. Vitamin B6 pyridoxal phosphate A61K31/675
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory 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 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention is directed to pharmaceutical compositions comprising a plurality of taste-masked non-opioid analgesic/opioid analgesic drug-containing microparticles, dosage forms comprising such pharmaceutical compositions (such as an orally disintegrating tablet), and methods of making the pharmaceutical compositions and dosage forms of the present invention. Dosage forms comprising the pharmaceutical compositions of the present invention are improved homogeneous blends of non-opioid and opioid analgesics which provide for more convenient and palatable administration of drug combinations, for example for treating pain.

Claims

1. A pharmaceutical composition comprising a plurality of non-opioid analgesic/opioid analgesic drug-containing microparticles, wherein the drug-containing microparticles comprise:

(a) a core comprising a non-opioid analgesic drug;

(b) a first coating disposed over the core, comprising an opioid analgesic drug; and

(c) a second coating disposed over the core, comprising a water-insoluble polymer.

2. The pharmaceutical composition of claim 1, wherein the weight ratio of non-opioid analgesic drug to opioid analgesic drug in the pharmaceutical composition is at least about 20:

1.

3. The pharmaceutical composition of claim 1, wherein the non-opioid analgesic drug-containing core comprises particles of the non-opioid analgesic drug.

7. The pharmaceutical composition of claim 1, wherein the second coating further comprises a plasticizer.

8. The pharmaceutical composition of claim 7, wherein the plasticizer is free of phthalates.

9. The pharmaceutical composition of claim 7, wherein the plasticizer is selected from the group consisting of glycerol, glycerol esters, acetylated mono- or diglycerides, glyceryl monostearate, glyceryl triacetate, glyceryl tributyrate, phthalates, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, citrates, acetylcitric acid tributyl ester, acetylcitric acid triethyl ester, tributyl citrate, acetyltributyl citrate, triethyl citrate, glyceroltributyrate, sebacates, diethyl sebacate, dibutyl sebacate, adipates, azelates, benzoates, chlorobutanol, polyethylene glycols, vegetable oils, fumarates, diethyl fumarate, malates, diethyl malate, oxalates, diethyl oxalate, succinates, dibutyl succinate, butyrates, cetyl alcohol esters, malonates, diethyl malonate, castor oil, and combinations thereof.

10. The pharmaceutical composition of claim 1, wherein the second coating substantially masks the taste of the non-opioid analgesic and/or the opioid analgesic.

12. The pharmaceutical composition of claim 10, wherein the second coating further comprises a gastrosoluble polymer or a gastrosoluble pore-former.

14. The pharmaceutical composition of claim 12, wherein the water-insoluble polymer is selected from the group consisting of water-insoluble cellulose ethers, ethylcellulose, water-insoluble cellulose esters, cellulose acetate, cellulose triacetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic acid-methylmethacrylate copolymers, and mixtures thereof;

and the gastrosoluble pore-former is selected from the group consisting of maltrin, aminoalkyl methacrylate copolymers, Eudragit®

E100 Eudragit®

EPO, polyvinylacetal diethylaminoacetate, AEA®

, terpolymers based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium phosphate, and mixtures thereof.

16. The pharmaceutical composition of claim 1, wherein the second coating further comprises a water-soluble polymer or an enteric polymer.

17. The pharmaceutical composition of claim 16, wherein the water-insoluble polymer is selected from the group consisting of water-insoluble cellulose ethers, ethylcellulose, water-insoluble cellulose esters, cellulose acetate, cellulose triacetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylic acid-methylmethacrylate copolymers, and mixtures thereof;

the water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; and

the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid/methylmethacrylate copolymers, shellac, and mixtures thereof.

18. The pharmaceutical composition of claim 1, wherein the second coating is disposed between the core and the first coating.

19. The pharmaceutical composition of claim 18, further comprising a third coating disposed over the first coating, wherein the third coating comprises a water-insoluble polymer which is the same as or different from the water-insoluble polymer of the second coating.

20. The pharmaceutical composition of claim 19, wherein the third coating substantially masks the taste of the opioid analgesic.

21. The pharmaceutical composition of claim 1, further comprising a third coating disposed between the core and the first coating, wherein the third coating comprises a water-insoluble polymer which is the same as or different from the water-insoluble polymer and a second coating.

22. The pharmaceutical composition of claim 21, wherein the third coating substantially masks the taste of the non-opioid analgesic.

23. The pharmaceutical composition of claim 22, wherein the third coating further comprises a gastrosoluble polymer or a gastrosoluble pore-former.

24. The pharmaceutical composition of claim 1, further comprising a flavorant coating disposed over the first coating, wherein the flavorant coating comprises a sweetener.

25. The pharmaceutical composition of claim 24, wherein the sweetener is selected from the group consisting of sucralose, lactitol, maltitol, sorbitol, and combinations thereof.

26. The pharmaceutical composition of claim 24, wherein the second coating is disposed between the core and the first coating.

27. The pharmaceutical composition of claim 26, wherein the second coating substantially modifies the release of the non-opioid analgesic.

28. The pharmaceutical composition of claim 1, wherein the second coating is disposed between the core and the first coating, and the second coating substantially modifies the release of the non-opioid analgesic.

29. The pharmaceutical composition of claim 28, further comprising a third coating disposed over the first coating, wherein the third coating comprises a water-insoluble polymer which is the same as or different from the water-insoluble polymer of the second coating, or the third coating comprises a flavorant coating comprising a sweetener;

and the third coating substantially masks the taste of the opioid analgesic.

30. The pharmaceutical composition of claim 1, wherein the non-opioid analgesic is a non-steroidal anti-inflammatory drug and the opioid analgesic is an opioid analgesic drug.

31. The pharmaceutical composition of claim 30, wherein the non-opioid analgesic is selected from the group consisting of acetaminophen, aspirin, ibuprofen, ketoprofen, meloxicam, diclofenac potassium, etodolac, sulindac, indomethacin, and celecoxib;

and the opioid analgesic is selected from the group consisting of hydrocodone, oxymorphone, buprenorphine, fentanyl, and hydromorphone.

32. The pharmaceutical composition of claim 31, wherein the non-opioid analgesic comprises acetaminophen, and the opioid analgesic comprises hydrocodone.

33. The pharmaceutical composition of claim 32, further comprising a flavorant coating comprising a sweetener disposed over the first coating, wherein the second coating is disposed between the core and the first coating.

34. The pharmaceutical composition of claim 33, wherein the second coating comprises ethylcellulose, and the third coating comprises sucralose and an optional binder.

35. The pharmaceutical composition of claim 1, further comprising a second population of non-opioid analgesic drug-containing particles, wherein the second population of non-opioid analgesic drug-containing particles comprise:

(i) a second core comprising the non-opioid analgesic drug; and

(ii) a fourth coating comprising a water-insoluble polymer disposed over the second core, wherein the water-insoluble polymer of the fourth coating is the same as or different from the water-insoluble polymer of the second coating.

40. A dosage form comprising the composition of claim 1 and one or more pharmaceutically acceptable excipients.

41. A dosage form comprising the composition of claim 30 and one or more pharmaceutically acceptable excipients.

43. The dosage form of any one of claims 40 or 41, wherein the dosage form further comprises rapidly dispersing granules comprising a disintegrant and a sugar alcohol and/or saccharide;

wherein the dosage form is an ODT.

45. The dosage form of claim 43, wherein the ODT substantially disintegrates within about 30 seconds when tested according to the USP <

701>

Disintegration Test.

46. The dosage form of claim 43, wherein the ODT releases at least about 75% of the total amount of the non-opioid analgesic and at least about 75% of the opioid analgesic in 30 minutes, when dissolution tested using USP Apparatus 1 (Baskets @ 100 rpm) or Apparatus 2 (Paddles @ 50 rpm), in 900 mL of a pH 1.2 buffer.

47. The dosage form of claim 43 in the form of an ODT, comprising 500 mg of acetaminophen and 5 mg of hydrocodone bitartrate, wherein the ODT has an acetaminophen C_max, of 80-125% of 6115 ng/mL, a hydrocodone bitartrate C_max, of 80-125% of 20.14 ng/mL, an acetaminophen AUC of 80-125% of 19920 ng·

hr/mL, and a hydrocodone bitartrate AUC of 80-125% of 141 ng·

hr/mL.

48. The dosage form of claim 43 in the form of an ODT, comprising 300 mg of acetaminophen and 10 mg of hydrocodone bitartrate, wherein the ODT has an acetaminophen C_max, of 80-125% of 3915 ng/mL, a hydrocodone bitartrate C_max, of 80-125% of 40.53 ng/mL, an acetaminophen AUC of 80-125% of 12794 ng·

hr/mL, and a hydrocodone bitartrate AUC of 80-125% of 280 ng·

hr/mL.

49. The dosage form of claim 43, wherein said the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, crosslinked carboxymethyl cellulose of sodium, low-substituted hydroxypropylcellulose and mixtures thereof and the sugar alcohol or saccharide is selected from the group consisting of mannitol, xylitol, maltol, maltitol, sorbitol, lactose, sucralose, maltose, and combinations thereof.

51. A method for preparing the pharmaceutical composition of claim 1, comprising:

(1) preparing cores comprising a non-opioid analgesic drug;

(2) coating the non-opioid analgesic drug-containing cores of step (1) with an opioid analgesic layer, thereby forming non-opioid analgesic/opioid analgesic drug-containing microparticles; and

(3) coating the non-opioid analgesic drug-containing cores of step (1) and/or the non-opioid analgesic/opioid analgesic drug-containing microparticles of step (2) with a second coating comprising a water-insoluble polymer.

66. A method of treating pain comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 31 to a patient in need thereof.

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