Methods and compositions for deterring abuse of orally administered pharmaceutical products

• US 20060177380A1
• Filed: 05/24/2005
• Published: 08/10/2006
• Est. Priority Date: 11/24/2004
• Status: Abandoned Application

• Current Assignee: Acura Pharmaceuticals Incorporated (Abuse Deterrent Pharma LLC)
• Original Assignee: Acura Pharmaceuticals Incorporated (Abuse Deterrent Pharma LLC)
• Inventors: Emigh, James F., Spivey, Ron J., Reddick, Andrew D.
• Application Number:
  US11/136,636
• Publication Number:
  US 20060177380A1
• Time in Patent Office: Days
• US Class Current: 424/10.100
• 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 31/455 Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• 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 9/0043 Nose
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• 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 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• 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 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/485 Inorganic compounds
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

This invention relates to an abuse deterrent formulation of an oral dosage form of a therapeutically effective amount of any active drug substance that can be subject to abuse combined with a gel forming polymer, a nasal mucosal irritating surfactant and a flushing agent. Such a dosage form is intended to deter abuse of the active drug substance via injection, nasal inhalation or consumption of quantities of the dosage unit exceeding the usual therapeutically effective dose.

Claims

1. A therapeutic pharmaceutical composition comprising

(a) an opioid analgesic;

(b) a gel forming polymer;

(c) a nasal tissue irritant; and

(d) a flushing agent in sufficient amount to cause flushing if greater than a prescribed amount of the analgesic of the therapeutic composition is ingested.

2. The therapeutic pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in unit dose form.

3. The therapeutic pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in a suppository, capsule, caplet, pill, gel, soft gelatin capsule, or compressed tablet form.

4. The therapeutic pharmaceutical composition of claim 1, wherein the analgesic comprises an opioid analgesic present in an amount of about 5 mg to about 200 mg on a solid weight basis.

5. The therapeutic pharmaceutical composition of claim 1, wherein the analgesic comprises hydrocodone or a therapeutically acceptable salt thereof.

6. The therapeutic pharmaceutical composition of claim 1, wherein the analgesic comprises oxycodone or a therapeutically acceptable salt thereof.

7. The therapeutic pharmaceutical composition of claim 1, wherein the analgesic comprises morphine or a therapeutically acceptable salt thereof.

8. The therapeutic pharmaceutical composition of claim 1, wherein the analgesic is selected from the group consisting of alfentanil, amphetamines, buprenorphine, butorphanol, carfentanil, codeine, dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine, diphenoxylate, diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone, β

-hydroxy-3-methylfentanyl, levo-α

-acetylmethadol, levorphanol, lofentanil, meperidine, methadone, methylphenidate, morphine, nalbuphine, nalmefene, o-methylnaltrexone, naloxone, naltrexone, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tilidine and tramodol, or therapeutically acceptable salts thereof.

9. The therapeutic composition of claim 1, wherein the gel forming polymer comprises one or more of polyethylene oxide having average molecular weight ranging form about 300,000 to about 5,000,000, polyvinyl alcohol having a molecular weight of about 20,000 to 200,000, hydroxypropyl methyl cellulose having a molecular weight of about 10,000 to 1,500,000, and a carbomer having a molecular weight ranging of about 700,000 to 4,000,000,000.

10. The therapeutic composition of claim 1, wherein the gel forming polymer comprises one or more of polyethylene oxide having a viscosity in the range from about 8,800 to about 17,600 cps., polyvinyl alcohol having a viscosity in the range from about 4 to about 65 cps., hydroxypropyl methyl cellulose having a viscosity in the range from about 3600 to about 5600 cps., and a carbomer having a viscosity in the range from about 4000 to about 39,400 cps.

11. The therapeutic composition of claim 1, wherein the gel forming polymer comprises polyvinyl alcohol.

12. The therapeutic composition of claim 1, wherein the gel forming polymer comprises hydroxypropyl methyl cellulose.

13. The therapeutic composition of claim 1, wherein the gel forming polymer comprises polyethylene oxide.

14. The therapeutic composition of claim 1, wherein the nasal tissue irritating amount of a surfactant includes 1 to 5 percent by weight of one or more of poloxamer, sorbitan monoesters, glyceryl monooleates and sodium lauryl sulfate.

15. The therapeutic composition of claim 1, wherein the nasal tissue irritating amount of a surfactant includes 1 to 5 percent by weight sodium lauryl sulfate.

16. The therapeutic composition of claim 1, wherein the flushing agent comprises niacin at about 2 to 40 percent by weight on a solid basis.

17. The therapeutic composition of claim 1, when the flushing agent comprises niacin.

33. The therapeutic composition of claim 1, wherein the flushing agent comprises niacin at about 2 to 40 percent by weight on a solid basis.

43. The therapeutic pharmaceutical composition of claim 1, wherein the nasal tissue irritant comprises a surfactant.

45. The therapeutic pharmaceutical composition of claim 1, further comprising a tissue staining dye.

46. The therapeutic pharmaceutical composition of claim 45, wherein the tissue staining dye is sequestered.

47. The therapeutic pharmaceutical composition of claim 1, further comprising a stool softener.

48. The therapeutic pharmaceutical composition of claim 47, wherein the stool softener comprises docusate sodium.

18. A method of making a therapeutic composition suitable for deterring drug abuse comprising

(a) providing a drug, a gel-forming polymer having a viscosity, a nasal tissue irritant and flushing agent;

(b) controlling the molecular weight or viscosity of the gel forming polymer;

(c) controlling the amount of nasal tissue irritant such that nasal tissue irritation occurs if inhaled;

(d) controlling the amount of flushing agent such that flushing ensues only if more than a prescribed amount of the drug is consumed; and

(e) combining the analgesic, gel forming polymer, nasal tissue irritant and flushing agent to form a therapeutic composition;

wherein the composition deters abuse of the analgesic by forming a viscous gel upon contact with a solvent;

inducing nasal irritation if inhaled, and inducing flushing if more than a prescribed amount of the analgesic is consumed.

19. The method of claim 18, further comprising the step of processing the composition into a unit dose form.

20. The method of claim 18, further comprising the step of processing the composition into a suppository, capsule, caplet, pill, or a direct compressed tablet form.

21. The method of claim 18, wherein the drug comprises an opioid analgesic.

22. The method of claim 18, wherein the drug is selected from the group consisting of alfentanil, amphetamines, buprenorphine, butorphanol, carfentanil, codeine, dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine, diphenoxylate, diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone, β

-hydroxy-3-methylfentanyl, levo-α

-acetylmethadol, levorphanol, lofentanil, meperidine, methadone, methylphenidate, morphine, nalbuphine, nalmefene, o-methylnaltrexone, naloxone, naltrexone, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tilidine and tramodol, or therapeutically acceptable salts thereof.

23. The method of claim 18, wherein the drug comprises hydrocodone or a therapeutically acceptable salt thereof.

24. The method of claim 18, wherein the drug comprises oxycodone or a therapeutically acceptable salt thereof.

25. The method of claim 18, wherein the drug comprises morphine or a therapeutically acceptable salt thereof.

26. The method of claim 18, wherein the gel forming polymer comprises one or more of polyethylene oxide having average molecular weight ranging form about 300,000 to about 5,000,000, polyvinyl alcohol having a molecular weight of about 20,000 to 200,000, hydroxypropyl methyl cellulose having a molecular weight of about 10,000 to 1,500,000, and a carbomer having a molecular weight ranging of about 700,000 to 4,000,000,000.

27. The method of claim 18, wherein the gel forming polymer comprises one or more of polyethylene oxide having a viscosity in the range from about 8,800 to about 17,600 cps., polyvinyl alcohol having a viscosity in the range from about 4 to about 65 cps., hydroxypropyl methyl cellulose having a viscosity in the range from about 3600 to about 5600 cps., and a carbomer having a viscosity in the range from about 4000 to about 39,400 cps.

28. The method of claim 18, wherein the step of controlling the amount of nasal tissue irritant comprises the step of adding 1 to 5 percent by weight of one or more of poloxamer, sorbitan monoesters, glyceryl monooleates and sodium lauryl sulfate.

29. The method of claim 18, wherein the gel forming polymer comprises polyvinyl alcohol.

30. The method of claim 18, wherein the gel forming polymer comprises hydroxypropyl methyl cellulose.

31. The method of claim 18, wherein the gel forming polymer comprises polyethylene oxide.

32. The method of claim 18, wherein the step of controlling the amount of nasal tissue irritant comprises the step of adding 1 to 5 percent by weight sodium lauryl sulfate.

34. A therapeutic pharmaceutical composition in unit dose form comprising

(a) an opioid analgesic;

(b) a gel forming polymer comprising one or more of polyethylene oxide having average molecular weight ranging form about 300,000 to about 5,000,000, polyvinyl alcohol having a molecular weight of about 20,000 to 200,000, hydroxypropyl methyl cellulose having a molecular weight of about 10,000 to 1,500,000, and a carbomer having a molecular weight ranging of about 700,000 to 4,000,000,000;

(c) 1 to 5 percent by weight sodium lauryl sulfate; and

(d) less than about 0.01 to 0.5 gm of niacin.

35. The therapeutic pharmaceutical composition in unit dose form of claim 34, wherein the analgesic is selected from the group consisting of alfentanil, amphetamines, buprenorphine, butorphanol, carfentanil, codeine, dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine, diphenoxylate, diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone, β

-hydroxy-3-methylfentanyl, levo-α

-acetylmethadol, levorphanol, lofentanil, meperidine, methadone, methylphenidate, morphine, nalbuphine, nalmefene, o-methylnaltrexone, naloxone, naltrexone, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tilidine and tramodol, or therapeutically acceptable salts thereof.

36. The therapeutic pharmaceutical composition of claim 34, wherein the analgesic comprises hydrocodone or a therapeutically acceptable salt thereof.

37. The therapeutic pharmaceutical composition of claim 34, wherein the analgesic comprises oxycodone or a therapeutically acceptable salt thereof.

38. The therapeutic pharmaceutical composition of claim 34, wherein the analgesic comprises morphine or a therapeutically acceptable salt thereof.

39. A therapeutic pharmaceutical composition comprising

(a) an analgesic;

(b) a gel forming polymer;

(c) a mucosal tissue irritant; and

(d) a flushing agent in sufficient amount to cause flushing if greater than a prescribed amount of the analgesic of the therapeutic composition is ingested.

40. The therapeutic pharmaceutical composition of claim 39, wherein the analgesic comprises hydrocodone or a therapeutically acceptable salt thereof.

41. The therapeutic pharmaceutical composition of claim 39, wherein the analgesic comprises oxycodone or a therapeutically acceptable salt thereof.

42. The therapeutic pharmaceutical composition of claim 39, wherein the analgesic comprises morphine or a therapeutically acceptable salt thereof.

44. The therapeutic pharmaceutical composition of claim 39, wherein the mucosal tissue irritant comprises a surfactant.

49. The therapeutic pharmaceutical composition of claim 39, where the flushing agent comprises niacin.

50. A therapeutic pharmaceutical composition comprising

(a) an analgesic;

(c) an emetic in sufficient amount to cause emesis if greater than a prescribed amount of the analgesic of the therapeutic composition is ingested; and

(d) a flushing agent in sufficient amount to cause flushing if greater than a prescribed amount of the analgesic of the therapeutic composition is ingested.

51. A method of inhibiting the abuse of an analgesic comprising the step of providing to a subject who is susceptible to abusing an analgesic the composition of claim 50.

52. A method of reducing the conversion of methamphetamine precursor compounds to methamphetamine comprising the step of mixing the methamphetamine precursor compounds with a gel forming polymer having a viscosity in a solvent, wherein upon contact with the solvent the viscosity of the gel forming polymer is sufficient to prevent at least a portion of the methamphetamine precursor compounds from solubilizing and subsequently converting to methamphetamine.

53. A therapeutic pharmaceutical composition comprising

(a) a drug susceptible to abuse;

and

(b) a flushing agent in sufficient amount to cause flushing if greater than a prescribed amount of the drug of the therapeutic composition is ingested.

55. The therapeutic pharmaceutical composition of claim 53, wherein the flushing agent comprises niacin.

54. A therapeutic pharmaceutical composition comprising

(a) an opioid analgesic;

and

(b) a flushing agent in sufficient amount to cause flushing if greater than a prescribed amount of the analgesic of the therapeutic composition is ingested.

56. The therapeutic pharmaceutical composition of claim 54, wherein the amount of niacin comprises about 15 mg to about 150 mg. of niacin.

57. The therapeutic pharmaceutical composition of claim 54, wherein the amount of niacin comprises about 30 mg. of niacin.

58. A therapeutic pharmaceutical composition comprising

(a) an opioid analgesic;

(b) a gel forming polymer;

(c) a nasal tissue irritant; and

(d) a flushing agent in sufficient amount to cause flushing only when greater than a prescribed amount of the analgesic of the therapeutic composition is ingested.

59. A therapeutic pharmaceutical composition comprising

(a) a drug susceptible to abuse;

and

(b) a flushing agent in a sub-therapeutic amount.

62. The therapeutic pharmaceutical composition of claim 59, wherein the composition comprises an immediate release composition.

63. The therapeutic pharmaceutical composition of claim 59, wherein the composition comprises a controlled release composition.

64. The therapeutic pharmaceutical composition of claim 63, wherein the controlled release composition comprises a sustained release composition.

60. A therapeutic pharmaceutical composition comprising

(a) a drug susceptible to abuse;

(b) a second drug in a sub-therapeutic amount; and

(c) one or more abuse deterrent components selected from the group of abuse deterrents comprising

1.) a gel forming polymer;

2.) a nasal tissue irritant; and

3.) a flushing agent.

61. The therapeutic pharmaceutical composition of claim 60, wherein the second drug comprises one or more of niacin, atropine sulfate, homatropine methylbromide, sildenafil citrate, nifedipine, zinc sulfate, dioctyl sodium sulfosuccinate and capsaicin.