Misuse preventative, controlled release formulation

• US 8,486,449 B2
• Filed: 12/16/2009
• Issued: 07/16/2013
• Est. Priority Date: 12/16/2008
• Status: Active Grant

• Current Assignee: 9254-0145 Quebec, Inc., ENDO Ventures Unlimited Company (Endo International PLC)
• Original Assignee: Paladin Labs Europe Ltd. (Endo International PLC), Paladin Labs Inc. (Endo International PLC)
• Inventors: Rahmouni, Miloud, Gervais, Sonia, Sant, Vinayak, Smith, Damon, Duffayet, Frederic, Rustom, Shams, El-Jammal, Ali, Ndong, Jean-Michel, Bichara, Ali
• Primary Examiner(s): AHMED, HASAN SYED
• Application Number:
  US12/639,664
• Publication Number:
  US 20100239662A1
• Time in Patent Office: 1,308 Days
• Field of Search: None
• US Class Current: 424/464
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• 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 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• 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 9/28 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 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

Disclosed is a misuse preventative, controlled release composition in the form of a multilayered oral dosage form. A first layer contains a plurality of controlled release microparticles having a pharmaceutically active agent (for example, an opioid analgesic) disposed therein. The second layer, which can be adjacent the first layer comprises a pharmaceutically active agent that can be the same or different from the pharmaceutically active agent in the microparticles in the first layer. The composition further comprises a superabsorbent material (for example, polycarbophil) disposed within the first layer, the second layer, or both the first layer and the second layer. When intact, the pharmaceutically active agent is released from the second layer faster than the pharmaceutically active agent in the first layer. When crushed, either intentionally or accidentally, and exposed to an aqueous medium, the superabsorbent material present swells to encapsulate the microparticles, which remain substantially intact thereby retarding the release of the pharmaceutically active agent from the composition. Also disclosed is a method of using the misuse preventative, controlled release composition to deliver at least one pharmaceutically active agent to a mammal, for example, a human, in need thereof.

Claims

1. A solid, compressed controlled release composition for oral administration of at least one pharmaceutically active agent, comprising:

(a) a first layer comprising a first population of controlled release microparticles having a pharmaceutically active agent disposed therein;

(b) a second layer comprising a pharmaceutically active agent disposed therein, wherein the second layer is adjacent the first layer;

(c) a superabsorbent material selected from the group consisting of an acrylic acid polymer cross-linked with divinyl glycol, an acrylic acid polymer cross-linked with allyl ethers of pentaerythritol, and a mixture thereof disposed within the first layer, the second layer, or both the first layer and the second layer, wherein the superabsorbent material comprises from about 10% to about 50% w/w of the layer containing the superabsorbent material;

(d) a controlled release agent disposed within the first layer, the second layer, or both the first layer and the second layer; and

(e) the composition having a hardness from about 200 N to about 400 N, and wherein the composition,

(i) when intact and exposed to an aqueous medium, the pharmaceutically active agent disposed in the second layer is initially released at a faster rate than the pharmaceutically active agent disposed in the first layer,

(ii) when crushed and exposed to a volume of an aqueous medium that weighs 30 times the weight of the superabsorbent material in the composition, the composition absorbs all of the aqueous medium and swells to create a hard gel that traps the microparticles, whereupon the hard gel, the controlled release agent and microparticles provide controlled release of at least the pharmaceutically active agent disposed within the microparticles, and

(iii) when broken and exposed to 900 mL of water in a U.S.P. Type I Apparatus with stirring at 100 rpm for 30 minutes at 37°

C., less than about 50% by weight of the pharmaceutically active agent originally present in the formulation before it was broken is released into the water.

2. The composition of claim 1, wherein the superabsorbent material is disposed within the first layer.

3. The composition of claim 1, wherein the superabsorbent material is disposed within the second layer.

4. The composition of claim 1, wherein the pharmaceutically active agent disposed in the second layer is present in a second population of controlled release microparticles.

5. The composition of claim 1, wherein the pharmaceutically active agent present in the first layer and the pharmaceutically active agent present in the second layer are the same.

6. The composition of claim 1, wherein the pharmaceutically active agent present in first layer and the pharmaceutically active agent present in the second layer are different.

7. The composition of claim 1, wherein the pharmaceutically active agent present in the first layer is released over a period of at least 6 hours.

8. The composition of claim 7, wherein the pharmaceutically active agent present in the first layer is released over a period of at least 12 hours.

9. The composition of claim 8, wherein the pharmaceutically active agent present in the first layer is released over a period of at least 24 hours.

10. The composition of claim 1, wherein the controlled release agent is selected from the group consisting of acetate succinate, a polyvinyl derivative, polyethylene oxide, polyacrylic acid, modified starch, cross-linked high amylose starch, hydroxypropyl starch, hydroxypropyl methylcellulose phthalate, cellulose, microcrystalline cellulose, carboxymethylethyl cellulose, cellulose acetate, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose phthalate, cellulose acetate, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate succinate, cellulose acetate butyrate, cellulose acetate trimellitate, poloxamer, povidone, alginic acid, sodium alginate, polyethylene glycol, polyethylene glycol alginate, gums, polymethacrylate, a copolymer of methacrylic acid and ethyl acrylate, a copolymer of polymethyl vinyl ether and malonic acid anhydride, a copolymer of polymethyl vinyl ether and malonic acid or the ethyl-, isopropyl-, n-butylesters thereof, zein, and mixtures of any of the foregoing.

11. The composition of claim 1, wherein the first layer, the second layer or both the first and second layers further comprise a diluent, a lubricant, a glidant, or a mixture thereof.

12. The composition of claim 1, wherein the second layer further comprises a disintegrant.

13. The composition of claim 1, wherein the composition further comprises a coating that encapsulates the first layer and the second layer.

14. The composition of claim 13, wherein the coating is a controlled release coating.

15. The composition of claim 14, wherein the controlled release coating comprises a controlled release agent.

16. The composition of claim 15, wherein the controlled release agent is selected from the group consisting of acetate succinate, a polyvinyl derivative, polyethylene oxide, polyacrylic acid, modified starch, cross-linked high amylose starch, hydroxypropyl starch, hydroxypropyl methylcellulose phthalate, cellulose, microcrystalline cellulose, carboxymethylethyl cellulose, cellulose acetate, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose phthalate, cellulose acetate, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate succinate, cellulose acetate butyrate, cellulose acetate trimellitate, poloxamer, povidone, alginic acid, sodium alginate, polyethylene glycol, polyethylene glycol alginate, gums, polymethacrylate, a copolymer of methacrylic acid and ethyl acrylate, a copolymer of polymethyl vinyl ether and malonic acid anhydride, a copolymer of polymethyl vinyl ether and malonic acid or the ethyl-, isopropyl-, n-butylesters thereof, zein, and mixtures of any of the foregoing.

17. The composition of claim 1, wherein the controlled release microparticles are coated with a controlled release film.

18. The composition of claim 17, wherein the controlled release film is selected from the group consisting of polymethacrylate, cellulose, a cellulose derivative, polyvinyl acetate, polyvinyl pyrollidone, and mixtures thereof.

19. The composition of claim 18, wherein the cellulose derivative is selected from the group consisting of microcrystalline cellulose, carboxymethylethyl cellulose, cellulose acetate, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose phthalate, cellulose acetate, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate succinate, cellulose acetate butyrate, and cellulose acetate trimellitate.

20. The composition of claim 18, wherein the polymethacrylate comprises a polymeric mixture of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate.

21. The composition of claim 1, wherein the microparticles have an average diameter in the range of from about 1 μ

m to about 1000 μ

m.

22. The composition of claim 21, wherein the microparticles have an average diameter in the range of from about 300 μ

m to about 800 μ

m.

23. The composition of claim 22, wherein the microparticles have an average diameter of about 700 μ

m.

24. The composition of claim 21, wherein the microparticles have an average diameter in the range of from about 1 μ

m to about 400 μ

m.

25. The composition of claim 24, wherein the microparticles have an average diameter in the range of from about 10 μ

m to about 200 μ

m.

26. The composition of claim 25, wherein the microparticles have an average diameter of about 100 μ

m.

27. The composition of claim 1, wherein, in element (iii), less than about 25% by weight of the pharmaceutically active agent originally present in the composition before it was broken is released into the water.

28. The composition of claim 1, wherein, when the composition is broken and exposed to 900 mL of an aqueous solution containing 60% (v/v) ethanol in a U.S.P. Type 1 Apparatus with stirring at 100 rpm for 30 minutes at 37°

C., less than about 50% by weight of a pharmaceutically active agent originally present in the composition before it was broken is released into the aqueous solution.

29. The composition of claim 28, wherein less than about 25% by weight of the pharmaceutically active agent originally present in the composition before it was broken is released into the aqueous solution.

30. The composition of claim 1, wherein the composition is in the form of a capsule, caplet, pill, or a compressed tablet.

31. The composition of claim 1, wherein at least one of the pharmaceutically active agents present in the first layer or in the second layer is a drug capable of abuse.

32. The composition of claim 31, wherein the drug is an opioid analgesic, hypnotic agent, an anxiolytic or a respiratory stimulant.

33. A method of providing controlled release of a pharmaceutically active agent, the method comprising orally administering to an individual in need of the pharmaceutically active agent the composition of claim 1.

34. The formulation of claim 1, wherein the superabsorbent material is polycarbophil.

35. The formulation of claim 1, wherein the superabsorbent material is polycarbophilic calcium.

36. The formulation of claim 1, wherein the superabsorbent material is a carbomer homopolymer type A.

37. The formulation of claim 1, wherein the superabsorbent material is a carbomer homopolymer type B.