Dosage forms for the delivery of drugs of abuse and related methods

• US 20070190142A1
• Filed: 01/22/2007
• Published: 08/16/2007
• Est. Priority Date: 01/21/2006
• Status: Abandoned Application

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: Abbott GmbH & Company KG (Abbott Laboratories)
• Inventors: Rosenberg, Jorg, Maegerlein, Markus, Lander, Ute, Woehrle, Gerd, BREITENBACH, Jorg
• Application Number:
  US11/625,705
• Publication Number:
  US 20070190142A1
• Time in Patent Office: Days
• US Class Current: 424/469
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• 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 9/2095 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: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 29/02 without antiinflammatory effect

Abstract

A dosage form and method for the delivery of drugs, particularly drugs of abuse, characterized by resistance to solvent extraction, tampering, crushing, or grinding, and providing an initial burst of release of drug followed by a prolonged period of controllable drug release.

Claims

1. An abuse-deterrent drug formulation comprising a melt-processed mixture of

a) at least one abuse-relevant drug,

b) at least one cellulose ether or cellulose ester, and

c) at least one alkyl alkacrylate polymer, alkacrylate polymer, or a combination thereof,

wherein the amount of the drug that is extracted in vitro from the formulation by 40% aqueous ethanol within one hour at 37°

C. is less than or equal to twice the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.; and

wherein the drug formulation is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.

2. The formulation of claim 1, wherein the cellulose ether is hydroxpropyl methylcellulose.

3. The formulation of claim 1, wherein the alkyl alkacrylate or the alkacrylate polymer has monomeric units of (C₁-C₂₂)alkyl ((C₁-C₁₀)alk)acrylate or (C₁-C₁₀)alkacrylate.

4. The formulation of claim 1, wherein the alkacrylate polymer is an acrylic polymer or a methacrylic polymer.

5. The formulation of claim 1, wherein the alkacrylate polymer is ionic acrylic polymer or ionic methacrylic polymer.

6. The formulation of claim 1, wherein the alkacrylate polymer is a cationic acrylic polymer or cationic methacrylic polymer.

7. The formulation of claim 1, wherein the alkacrylate polymer is a copolymer of the acrylic polymer and the methacrylic polymer esters containing quaternary ammonium groups.

8. The formulation of claim 1, wherein the abuse-relevant drug is selected from the group consisting of atropine, hyoscyamine, phenobarbital, and scopolamine salts, esters, prodrugs and mixtures thereof.

9. The formulation of claim 1, wherein the abuse-relevant drug is an analgesic.

10. The formulation of claim 1, wherein the abuse-relevant drug is an opioid.

11. The formulation as claimed in claim 10, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levophenacylmorphan, levorphanol, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbulphine, narceine, nicomorphine, norpipanone, opium, oxycodone, oxymorphone, papvretum, pentazocine, phenadoxone, phenazocine, phenomorphan, phenoperidine, piminodine, propiram, propoxyphene, sufentanil, tilidine, and tramadol, and salts, esters, prodrugs and mixtures thereof.

12. The formulation as claimed in one of claims 8-11, further comprising at least one further drug.

13. The formulation of claim 1, wherein the abuse-relevant drug is dispersed in the formulation in a state of a solid solution.

14. The formulation of claim 1, wherein between 11% and 47% of the abuse-relevant drug is released in vitro in 0.01 N hydrochloric acid within two hours at 37°

C.

15. The formulation of claim 1, wherein less than 20% of the abuse-relevant drug is released in vitro in 20% aqueous ethanol within one hour at 37°

C.

16. The formulation of claim 1, wherein the dosage form is monolithic

104. A method for treating pain in a human patient, comprising orally administering to the human patient a formulation from any one of the claim 1-103.

17. A monolithic, sustained release oral dosage formulation comprising a melt-processed mixture of:

a) an analgesically effective amount of at least one an abuse-relevant drug,

b) at least one cellulose ether or cellulose ester, and

c) at least one alkyl alkacrylate polymer, alkacrylate polymer, or a combination thereof,

wherein the amount of the drug that is extracted in vitro from the formulation by 40% aqueous ethanol within one hour at 37°

C. is less than or equal to twice the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.; and

wherein the drug formulation is adapted for sustained release so as to be useful for oral administration to a human 3, 2, or 1 times daily.

18. The formulation of claim 17, wherein the cellulose ether is hydroxpropyl methylcellulose.

19. The formulation of claim 17, wherein the alkacrylate polymer is an acrylic polymer or a methacrylic polymer.

20. The formulation of claim 17, wherein the alkacrylate polymer is an ionic acrylic polymer or an ionic methacrylic polymer.

21. The formulation of claim 17, wherein the alkacrylate polymer is a cationic acrylic polymer or a cationic methacrylic polymer.

22. The formulation of claim 17, wherein the alkacrylate polymer is a copolymer of the acrylic polymer and the methacrylic polymer esters containing quaternary ammonium groups.

23. The formulation of claim 17, wherein the abuse-relevant drug is an analgesic.

24. The formulation of claim 17, wherein the abuse-relevant drug is an opioid.

25. The formulation as claimed in one of claims 23-24 further comprising at least one further drug.

26. The formulation of claim 17, wherein the abuse-relevant drug is dispersed in the formulation in a state of a solid solution.

27. The formulation of claim 17, wherein between 11% and 47% of the abuse-relevant drug is released in vitro in 0.01 N hydrochloric acid within two hours at 37°

C.

28. The formulation of claim 17, wherein less than 20% of the abuse-relevant drug is released in vitro in 20% aqueous ethanol within one hour at 37°

C.

29. An oral sustained release dosage formulation of a drug characterized by at least two of the following features:

a) the drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37°

C. in vitro is less than or equal twice the amount of the drug that is extracted by 0.01 N hydrochloric acid in vitro within one hour at 37°

C.,

b) the formulation does not break under a force of 150 newtons, preferably 300 newtons, more preferably 450 newtons, yet more preferably 500 newtons as measured by “

Pharma Test PTB 501”

hardness tester, and

c) the formulation releases at least 15% of the one drug and not more than 45% of the one drug during the first hour in vitro dissolution testing and preferably also in vivo.

30. The oral sustained release dosage formulation of claim 29, wherein the formulation is not snortable via nasal administration.

31. The oral sustained release dosage formulation of claim 29, wherein the drug is an opioid, amphetamine or methamphetamine.

32. The oral sustained release dosage formulation of claim 29, wherein the formulation comprises an abuse-deterrent drug produced by a melt-processed mixture of

a) at least one abuse-relevant drug,

b) at least one cellulose ether or cellulose ester, and

c) at least one alkyl alkacrylate polymer, alkacrylate polymer, or a combination thereof,

wherein the amount of the drug that is extracted in vitro from the formulation by 40% aqueous ethanol within one hour at 37°

C. is less than or equal to twice the amount of the drug that is extracted by 0.01 N hydrochloric acid in vitro within one hour at 37°

C.; and

wherein the drug formulation is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.

33. The oral sustained release dosage formulation of claim 32, wherein the cellulose ether is hydroxpropyl methylcellulose.

34. The oral sustained release dosage formulation of claim 32, wherein the alkyl alkacrylate or the alkacrylate polymer has monomeric units of (C₁-C₂₂)alkyl ((C₁-C₁₀)alk)acrylate or (C₁-C₁₀)alkacrylate.

35. The oral sustained release dosage formulation of claim 32, wherein the alkacrylate polymer is an acrylic polymer or a methacrylic polymer.

36. The oral sustained release dosage formulation of claim 32, wherein the alkacrylate polymer is ionic acrylic polymer or ionic methacrylic polymer.

37. The oral sustained release dosage formulation of claim 32, wherein the alkacrylate polymer is a cationic acrylic polymer or cationic methacrylic polymer.

38. The oral sustained release dosage formulation of claim 32, wherein the alkacrylate polymer is a copolymer of the acrylic polymer and the methacrylic polymer esters containing quaternary ammonium groups.

39. The oral sustained release dosage formulation of claim 32, wherein the alkacrylate polymer is a copolymer or mixture of copolymers wherein the molar ratio of cationic groups to the neutral esters is in the range of about 1:

20 to 1;

35 on average.

40. A non-milled, melt-extruded drug formulation comprising a drug with abuse potential.

41. The formulation of claim 40, wherein the formulation is not snortable via nasal administration.

42. The formulation of claim 40, wherein the drug is an opioid, amphetamine or methamphetamine.

43. The formulation of claim 40, wherein the formulation is directly shaped from the melt-extrudate into a dosage form without (an intermediate) milling step.

44. The formulation of claim 40, wherein the formulation is directly shaped from the melt-extrudate into a dosage form without (an intermediate) multiparticulating step.

45. The formulation of claim 40, wherein the formulation is directly shaped from the melt-extrudate into a dosage form by the process of calendaring.

46. A monolithic, non-milled, non-multiparticulated, melt-extruded drug formulation comprising a drug with abuse potential having a diameter from about at least 5.1 mm to about 10 mm and a length from about 5.1 mm to about 30 mm.

47. The formulation of claim 46, wherein the formulation is directly shaped from the melt-extrudate into a dosage form without (an intermediate) milling step.

48. The formulation of claim 46, wherein the formulation is directly shaped from the melt-extrudate into a dosage form without (an intermediate) multiparticulating step.

49. The formulation of any of the claims 46-48 wherein the formulation is directly shaped from the melt-extrudate into a dosage form by the process of calendaring.

50. The formulation of claim 46, wherein the formulation comprises an abuse-deterrent drug produced by a melt-processed mixture of

a) at least one abuse-relevant drug,

b) at least one cellulose ether or cellulose ester, and

c) at least one alkyl alkacrylate polymer, alkacrylate polymer, or a combination thereof,

wherein the amount of the drug that is extracted in vitro from the formulation by 40% aqueous ethanol within one hour at 37°

C. is less than or equal to twice the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.; and

wherein the drug formulation is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.

51. The formulation of claim 50, wherein the alkacrylate polymer is a copolymer of the acrylic polymer and the methacrylic polymer esters containing quaternary ammonium groups.

52. An abuse-deterrent drug formulation formed by a process comprising melt extruding the formulation having at least one therapeutic drug and directly shaping the extrudate into a dosage form without (an intermediate) milling step or multiparticulating step.

53. The formulation of claim 52, wherein the therapeutic drug comprises an abuse-deterrent drug having:

a) at least one abuse-relevant drug,

b) at least one cellulose ether or cellulose ester, and

c) at least one alkyl alkacrylate polymer, alkacrylate polymer, or a combination thereof,

wherein the amount of the drug that is extracted in vitro from the formulation by 40% aqueous ethanol within one hour at 37°

C. is less than or equal to twice the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.; and

wherein the drug formulation is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.

54. A process for the manufacture of an abuse-resistant drug dosage formulation comprising melt extruding a formulation comprising at least one therapeutic drug further comprising directly shaping the extrudate into a dosage form without (an intermediate) milling step or multiparticulating step.

55. The process of claim 54, wherein the melt-extrudate comprises an abuse-deterrent drug having:

a) at least one abuse-relevant drug,

b) at least one cellulose ether or cellulose ester, and

c) at least one alkyl alkacrylate polymer, alkacrylate polymer, or a combination thereof,

wherein the amount of the drug that is extracted in vitro from the formulation by 40% aqueous ethanol within one hour at 37°

C. is less than or equal to twice the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.; and

wherein the drug formulation is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.

56. A monolithic, non-milled, melt-extruded drug formulation comprising a drug with abuse potential wherein the monolithic formulation has a substantially similar drug release profile to a crushed form of the monolithic formulation wherein the monolithic formulation is crushed at about 20,000 rpm to about 50,000 rpm in a coffee grinding machine for about 60 seconds.

57. The melt-extrudate drug formulation of claim 56, wherein the melt-extrudate comprises an abuse-deterrent drug having:

a) at least one abuse-relevant drug,

b) at least one cellulose ether or cellulose ester, and

c) at least one alkyl alkacrylate polymer, alkacrylate polymer, or a combination thereof,

wherein the amount of the drug that is extracted in vitro from the formulation by 40% aqueous ethanol within one hour at 37°

C. is less than or equal to twice the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.; and

wherein the drug formulation is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.

58. The melt-extrudate drug formulation of claim 57, wherein the drug formulation does not comprise more than 0.5% of a genotoxic compound after manufacturing and a minimum of 6 months of storage at 25°

C./60% relative humidity or 40°

C./75% relative humidity, or both.

59. The melt-extrudate drug formulation of claim 58, wherein the formulation comprises polyethylene oxide and an anti-oxidant.

60. The melt-extrudate drug formulation of claim 58, wherein the genotoxic compound is N-oxide of an opioid.

61. An abuse-deterrent drug formulation comprising a melt-processed mixture of

at least one abuse-relevant drug, and

at least one rate altering pharmaceutically acceptable polymer, copolymer, or a combination thereof,

wherein the amount of the drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37°

C. is less than or equal to twice the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.; and

wherein the drug formulation is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.

62. The abuse-deterrent drug formulation of claim 61, wherein the polymer is a cellulose ether or a cellulose ester polymer.

63. The abuse-deterrent drug formulation of claim 61, wherein the polymer is selected from a group consisting of homopolymers, copolymers, or combinations of monomers of N-vinyl lactams, nitrogen-containing monomers, oxygen-containing monomers, vinyl alcohol, ethylene glycol, alkylene oxides, ethylene oxide, propylene oxide, acrylamide, vinyl acetate, hydroxy acid.

64. The abuse-deterrent drug formulation of claim 61, wherein the polymer is hydrogen-peroxide polyvinylpyrrolidone polymer.

65. The abuse-deterrent drug formulation of claim 61, wherein the polymer, copolymer, or a combination thereof comprises at least one alkyl alkacrylate polymer, alkacrylate polymer, or a combination thereof.

66. The abuse-deterrent drug formulation of claim 62, wherein the cellulose ether has an alkyl degree of substitution of 1.3 to 2.0 and hydroxyalkyl molar substitution of up to 0.85.

67. The abuse-deterrent drug formulation of claim 66, wherein the alkyl substitution is methyl.

68. The abuse-deterrent drug formulation of claim 67, wherein the hydroxyalkyl substitution is hydroxpropyl.

69. The abuse-deterrent drug formulation of claim 62, wherein the cellulose ether is hydroxpropyl methylcellulose.

70. The abuse-deterrent drug formulation of claim 61, wherein the alkyl alkacrylate or the alkacrylate polymer has monomeric units of (C₁-C₂₂)alkyl ((C₁-C₁₀)alk)acrylate or (C₁-C₁₀)alkacrylate.

71. The abuse-deterrent drug formulation of claim 61, wherein the alkacrylate polymer is an acrylic polymer or a methacrylic polymer.

72. The abuse-deterrent drug formulation of claim 61, wherein the alkacrylate polymer is ionic acrylic polymer or ionic methacrylic polymer.

73. The abuse-deterrent drug formulation of claim 61, wherein the alkacrylate polymer is a cationic acrylic polymer or cationic methacrylic polymer.

74. The abuse-deterrent drug formulation of claim 61, wherein the alkacrylate polymer is a copolymer of the acrylic polymer and the methacrylic polymer esters containing quaternary ammonium groups.

75. The abuse-deterrent drug formulation of claim 61, wherein the alkacrylate polymer is a copolymer or mixture of copolymers wherein the molar ratio of cationic groups to the neutral esters is in the range of about 1:

20 to 1;

35 on average.

76. An abuse-deterrent drug formulation comprising a melt-processed mixture of

a) at least one abuse-relevant drug, wherein said drug is hydrocodone,

b) at least one cellulose ether or cellulose ester, and

c) at least one acrylic polymer, methacrylic polymer, or a combination thereof,

wherein the drug formulation is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily;

and

wherein about 90% of the hydrocodone is released in vitro at about 4-6 hours when adapted to be administered 3 times a day, at about 6-10 hours when adapted to be administered 2 times a day and about 16-22 hours when adapted to be administered 1 time a day.

77. The abuse-deterrent drug formulation of claim 76, wherein more than 30% of the hydrocodone is extracted from the formulation at about one hour at 37°

C. in 0.01 N hydrochloric acid.

78. The abuse-deterrent drug formulation of claim 76, wherein from about 12% to about 25% of the hydrocodone is extracted from the formulation at about one hour at 37°

C. in 0.01 N hydrochloric acid.

79. An abuse-deterrent drug formulation comprising a melt-processed mixture of

at least one opioid;

at least one rate altering pharmaceutically acceptable polymer, copolymer, or a combination thereof;

wherein the amount of the drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37°

C. is about 70% to about 110% of the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.; and

wherein the drug formulation is adapted so as to be useful for oral administration to a human 3, 2, or 1 times daily.

80. The abuse-deterrent drug formulation of claim 79, wherein the amount of the drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37°

C. is about 70% to about 100% of the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.

81. The abuse-deterrent drug formulation of claim 79, wherein the amount of the drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37°

C. is about 70% to about 90% of the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.

82. The abuse-deterrent drug formulation of claim 79, wherein the amount of the drug that is extracted from the formulation by 40% aqueous ethanol within one hour at 37°

C. is about 75% to about 90% of the amount of the drug that is extracted by 0.01 N hydrochloric acid within one hour at 37°

C.

83. The abuse-deterrent drug formulation of claim 79, wherein the abuse relevant drug further comprises a nonopioid analgesic.

84. The abuse-deterrent drug formulation of claim 79, wherein the non-opioid analgesic is acetaminophen or ibuprofen.

85. The abuse-deterrent drug formulation of claim 79, wherein the opioid is hydrocodone or oxycodone, or pharmaceutically acceptable salts or esters thereof.

86. The abuse-deterrent drug formulation of claim 79, wherein the opioid is hydrocodone and wherein when administered to the human patient, the formulation produces a plasma profile characterized by a Cmax for hydrocodone of between about 0.6 ng/mL/mg to about 1.4 ng/mL/mg after a single dose.

87. The abuse-deterrent drug formulation of claim 79, wherein the opioid is hydrocodone and wherein when administered to the human patient, the formulation produces a plasma profile characterized by a Cmax for hydrocodone of between about 0.4 ng/mL/mg to about 1.9 ng/mL/mg after a single dose.

88. The abuse-deterrent drug formulation of claim 79, wherein the opioid is hydrocodone and wherein when administered to the human patient, the formulation produces a plasma profile characterized by a Cmax for hydrocodone of form about 0.6 ng/mL/mg to about 1.0 ng/mL/mg after a single dose.

89. The abuse-deterrent drug formulation of claim 79, wherein the opioid is hydrocodone and wherein when administered to the human patient, the formulation produces a plasma profile characterized by a Cmin for hydrocodone of between about 0.4 ng/mL/mg, or optionally 0.6 ng/mL/mg, to about 1.4 ng/mL/mg after a single dose.

90. The abuse-deterrent drug formulation of claim 79, wherein the opioid is hydrocodone and wherein when administered to the human patient, the dosage form produces a minimum AUC for hydrocodone of about 7.0 ng*hr/mL/mg to a maximum AUC for hydrocodone of about 26.2 ng*hr/mL/mg.

91. The abuse-deterrent drug formulation of claim 79, wherein the opioid is hydrocodone and wherein when administered to the human patient, the dosage form produces a minimum AUC for hydrocodone of about 9.1 ng*hr/mL/mg to a maximum AUC for hydrocodone of about 19.9 ng*hr/mL/mg

92. The abuse-deterrent drug formulation of claim 79, wherein the in vitro rate of release of the formulation has a biphasic release profile, and wherein each phase of the in vitro rate of release is zero order or ascending.

93. The abuse-deterrent drug formulation of claim 79, wherein at least 30-45% of the opioid is released in vitro from the formulations in about 1 hour.

94. The abuse-deterrent drug formulation of claim 79, wherein at least 90% is of the opioid is released from the formulation in about 6 hours to about 10 hours.

95. The abuse-deterrent drug formulation of claim 79, wherein at least 90% is of the opioid is released from the formulation in about 15 hours to about 20 hours.

96. The abuse-deterrent drug formulation of claim 79, wherein at least 90% is of the opioid is released from the formulation in about 6 hours to about 9 hours.

97. The abuse-deterrent drug formulation of claim 79, wherein at least 95% is of the opioid is released from the formulation in about 6 hours to about 10 hours, and

wherein at least 95% is of the opioid is released from the formulation in about 7 hours to about 9 hours.

98. The abuse-deterrent drug formulation of claim 79, wherein at least 99% is of the opioid is released from the formulation in about 10 hours to about 11 hours.

99. The abuse-deterrent drug formulation of claim 79, wherein at least 99% is of the opioid is released from the formulation in less than about 12 hours.

100. The abuse-deterrent drug formulation of claim 79, wherein the AUC at one hour is from 0.22 to about 0.51 ng*h/ml/mg.

101. The abuse-deterrent drug formulation of claim 79, wherein the AUC at two hour is from 1.07 to about 1.76 ng*h/ml/mg.

102. The abuse-deterrent drug formulation of claim 79, wherein the AUC at three hour is from 2.06 to about 3.08 ng*h/ml/mg.

103. The abuse-deterrent drug formulation of claim 79, wherein the AUC at four hour is from 3.12 to about 4.44 ng*h/ml/mg.