COMBINATION THERAPY FOR BIPOLAR DISORDER

• US 20090311347A1
• Filed: 04/10/2009
• Published: 12/17/2009
• Est. Priority Date: 04/11/2008
• Status: Active Grant

• Current Assignee: Comgenrx, Inc.
• Original Assignee: Comgenrx, Inc.
• Inventors: Oronsky, Bryan T., Oronsky, Neil C.
• Granted Patent: US 8,138,169 B2
• Time in Patent Office: Days
• US Class Current: 424/722
• 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 31/485 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: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

Treatment regimens for mood disorders that include administration of buprenorphine, alone or in combination with additional pharmacological agents are described. Specifically, treatment regimens that alleviate racing thoughts associated with bipolar disorder, and pharmaceutical compositions and kits for use therein are described. Dosing regimens, compositions, and kits including buprenorphine for treating mania associated with opioid withdrawal are also described.

Claims

1. A method for treating mania associated with opioid withdrawal in a subject, comprising administering a first dose of a kappa opioid and at least one additional dose of the kappa opioid to the subject according to a predetermined dosage regimen, the at least one additional dose being less than the first dose, wherein the first dose is administered in the morning and the at least one additional dose is administered in the evening or late evening.

2. The method of claim 1, wherein the kappa opioid comprises a kappa-receptor antagonist.

3. The method of claim 2, wherein the kappa-receptor antagonist comprises 5′

-guanidinonaltrindole, buprenorphine, norbinaltorphimine, JDTic, or combinations thereof.

4. The method of claim 3, wherein the kappa-receptor antagonist comprises buprenorphine.

5. The method of claim 1, wherein the kappa opioid comprises a kappa-receptor agonist.

6. The method of claim 5, wherein the kappa-receptor agonist is selected from the group consisting of butorphanol, BRL-52537, cyclazocine, enadoline, GR-89696, HZ-2, ICI-204,448, ketazocine, LPK-26 (2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrrolinyl))ethyl]acetamide), nalbuphine, pentazocine, salvinorin A, spiradoline, tifluadom, U-50488, U-62066, U-69593, and combinations thereof.

7. The method of claim 1, further comprising administering a second active agent.

8. The method of claim 7, wherein the second active agent is selected from the group consisting of antipsychotic agents, atypical antipsychotic agents, antiepileptic agents, cannabinoids, lithium, naloxone, P-450 CYP3A4 inhibitors, P-450 CYP2D6 inhibitors, CB1 agonists, CB2 agonists, CB2 antagonists, salts, and acids thereof, and combinations thereof.

9. The method of claim 8, wherein the second active agent comprises an atypical antipsychotic.

10. The method of claim 9, wherein the atypical antipsychotic is selected from the group consisting of aripriprazole, arisulpride, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, and combinations thereof.

11. The method of claim 10, wherein the atypical antipsychotic comprises ziprasidone.

12. The method of claim 7, wherein the predetermined dosing regimen comprises administering the second active agent in the morning.

13. The method of claim 12, wherein the second active agent comprises a P-450 CYP3A4 inhibitor, a P-450 CYP2D6 inhibitor, or combinations thereof.

14. The method of claim 7, wherein the predetermined dosing regimen comprises administering the second active agent in the evening.

15. The method of claim 7, wherein the predetermined dosing regimen comprises administering multiple doses of the second active agent.

16. The method of claim 15, wherein the multiple doses of the second active agent are administered so that the highest dose is administered in evening and the lowest dose is administered in the morning.

17. The method of claim 4, wherein the at least one additional administered dose is a subtherapeutic dose of buprenorphine.

18. The method of claim 17, wherein the subtherapeutic dose of buprenorphine is about 2.0 mg.

19. The method of claim 4, wherein the first administered dose is about 8.0 mg, about 16 mg, about 24 mg, or about 32 mg of buprenorphine.

20. The method of claim 1, wherein predetermined dosing regimen comprises administering two or more additional doses of the kappa opioid in a gradually decreasing fashion.

21. The method of claim 20, wherein the kappa opioid comprises buprenorphine.

22. The method of claim 1, further comprising treating a comorbid condition.

23. The method of claim 22, wherein the comorbid condition is a sleep disorder.

24. The method of claim 23, wherein the sleep disorder is selected from the group consisting of hypoventilation-obesity syndrome (Picwickian syndrome), idiopathic hypersomnia, narcolepsy, night terrors, parasomnias, primary snoring, sleep apnea, nocturnal sleep-related eating disorder, spousal arousal syndrome, upper airway resistance syndrome, and combinations thereof.

25. The method of claim 23, wherein the sleep disorder is due to alcoholism, allergic rhinitis, altered light-dark cycles, amphetamine use, antidepressant use, anxiety, asthma, benzodiazepine withdrawal, chronic fatigue syndrome, chronic obstructive pulmonary disease (COPD), chronic pain, cocaine use, compulsive hyperphagia, anorexia, bulimia, anorexia-bulimia, starvation, restricted caloric intake, dementia, disturbances in circadian rhythm, dyspnea, edema, eneuresis, fibromyalgia, food intolerance, gastroesophageal reflux, hyperammonemia, hypersensitivity to stimulants, incontinence, infection, inflammatory bowel syndrome, irritable bowel syndrome, modafinil (Provigil®

tablet) use, neuromuscular disorders, nocturia, nocturnal myoclonus, orthopnea, paroxysmal nocturnal dyspnea, pica, Prinzmetal'"'"'s angina, pruritis, racing thoughts, restless leg syndrome, seizure disorder, sinusitis, sleepwalking, or combinations thereof.

26. The method of claim 1, wherein the first dose and the at least one additional dose of the kappa opioid is provided in the same dosage form.

27. The method of claim 1, wherein the first dose and the at least one additional dose of the kappa opioid is provided in different dosage forms.

28. The method of claim 1, wherein the kappa opioid is provided in a dosage form adapted for oral, sublingual, buccal, parenteral, intravenous, intramuscular, subcutaneous, topical, inhalation, or needle-free administration, or combinations thereof.

29. The method of claim 28, wherein the dosage form comprises a solid, semi-solid, or liquid formulation.

58. The method of claim 1, wherein the bipolar condition subtype is cyclothymia.

59. The method of claim 1, wherein the bipolar condition subtype is acute mania, drug-induced mania, or drug-induced hypomania.

60. The method of claim 1, further comprising administering an opioid antagonist.

61. The method of claim 60, wherein the opioid antagonist comprises naloxone.

62. The method of claim 61, wherein the buprenorphine and naloxone are administered together in a unit dose.

63. The method of claim 62, wherein about 2.0 mg of buprenorphine is administered in the unit dose.

64. The method of claim 62, wherein about 8.0 mg of buprenorphine is administered in the unit dose.

65. The method of claim 1, further comprising administering a second active agent to the subject.

66. The method of claim 65, wherein the second active agent is selected from the group consisting of antipsychotic agents, atypical antipsychotic agents, antiepileptic agents, lithium, and salts and acids thereof.

67. The method of claim 66, wherein the second active agent comprises an atypical antipsychotic agent selected from the group consisting of aripriprazole, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, arisulpride, and combinations thereof.

68. The method of claim 66, wherein the second active agent comprises an antiepileptic agent selected from the group consisting of divalproex, lamotrigine, oxacarbazine, valproic acid, lithium, and combinations thereof.

93. The kit of claim 68, wherein the plurality of buprenorphine dosage forms further comprise an opioid antagonist.

94. The kit of claim 93, wherein the opioid antagonist comprises naloxone.

129. The kit of claim 68, further comprising a light-emitting diode.

30. A composition comprising buprenorphine and a second active agent in a single dosage form, wherein the second active agent comprises an antipsychotic agent, an atypical antipsychotic agent, an antiepileptic agent, lithium, naloxone, a P-450 CYP3A4 inhibitor, a P-450 CYP2D6 inhibitor, salts and acids thereof, and combinations thereof.

31. The composition of claim 30, wherein the single dosage form is selected from the group consisting of powders, granules, capsules, films, transdermal patches, buccal patches, sublingual formulations, gums, chewables, oral strips, rapid dissolve tablets, coated tablets, solutions, ointments, creams, and gels.

32. The composition of claim 30, wherein the single dosage form is configured for oral, sublingual, buccal, parenteral, intravenous, intramuscular, subcutaneous, topical, inhalation, or needle-free administration, or combinations thereof.

33. The composition of claim 30, wherein the single dosage form comprises a sublingual formulation within a rapid dissolve tablet.

34. The composition of claim 30, wherein the single dosage form comprises a sublingual formulation surrounded by a buccal patch.

35. The composition of claim 30, wherein the single dosage form comprises a sublingual formulation surrounded by a mouth strip.

36. The composition of claim 30, wherein the second active agent comprises an atypical antipsychotic.

37. The composition of claim 36, wherein the atypical antipsychotic is selected from the group consisting of aripriprazole, arisuipride, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, and combinations thereof.

38. The composition of claim 37, wherein the atypical antipsychotic comprises ziprasidone.

39. The composition of claim 30 comprising about 2.0 mg, about 8.0 mg, about 16 mg, about 24 mg, or about 32 mg of buprenorphine.

40. A kit for treating mania associated with opioid withdrawal comprising a plurality of buprenorphine dosage forms and instructions for administering the dosage forms according to a predetermined dosage regimen, wherein the predetermined dosing regimen comprises administering a first buprenorphine dose and at least one additional buprenorphine dose that is less than the first dose, and wherein the first dose is administered in the morning and the at least one additional dose is administered in the evening or late evening.

41. The kit of claim 40 wherein the plurality of buprenorphine dosage forms comprise about 0.5 mg, about 1.0 mg, about 2.0 mg, about 8.0 mg, about 16 mg, about 24 mg, or about 32 mg of buprenorphine, or combinations thereof.

42. The kit of claim 40, wherein the plurality of buprenorphine dosage forms further comprise an opioid antagonist.

43. The kit of claim 42, wherein the opioid antagonist comprises naloxone.

44. The kit of claim 40, further comprising a housing configured to organize the dosage forms according to the predetermined dosing regimen.

45. The kit of claim 44, wherein the housing is configured to organize the plurality of dosage forms into morning dosage forms and evening dosage forms.

46. The kit of claim 44, wherein the housing is configured to organize the plurality of buprenorphine dosage forms according to a rapidly or a gradually decreasing dosing regimen.

47. The kit of claim 40, further comprising a second dosage form including a second active agent.

48. The kit of claim 47, wherein the second active agent is selected from the group consisting of aripriprazole, arisulpride, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, and combinations thereof.

49. The kit of claim 40, further comprising an additional agent to treat a comorbid condition.

50. The kit of claim 49, wherein the additional agent comprises an antihistamine.

51. The kit of claim 50, wherein the comorbid condition is a sleep disorder.

52. A method for treating a bipolar condition and subtypes thereof in a subject, the subject experiencing at least one episode of racing thoughts, comprising administering buprenorphine to the subject to alleviate the racing thoughts.

53. The method of claim 52, wherein the bipolar condition is bipolar I disorder.

54. The method of claim 52, wherein the bipolar condition is bipolar II disorder.

55. The method of claim 52, wherein the bipolar condition is mixed bipolar disorder.

56. The method of claim 55, wherein the subject affected with the mixed bipolar disorder rapidly cycles between manic or hypomanic phases and depressive phases.

57. The method of claim 56, wherein the at least one episode of racing thoughts occurs during the depressive phase.

69. The method of claim 52, further comprising administering a supplemental agent to the subject to treat a comorbid condition, a side-effect of the second active agent, a symptom associated with the bipolar condition, or combinations thereof.

70. The method of claim 69, wherein the supplemental agent is administered to treat a comorbid condition.

71. The method of claim 70, wherein the comorbid condition is diabetes mellitus.

72. The method of claim 71, wherein the supplemental agent comprises metformin.

73. The method of claim 70, wherein the comorbid condition is fibromyalgia.

74. The method of claim 73, wherein the supplemental agent is selected from the group consisting of carisoprodol, colchicine, cyclobenzaprine, duloxetine, gabapentin, guafenisin, interferon, methocarbamol, pregabalin, probenecid, sulfinpyrazone, and vitamin B12.

75. The method of claim 69, wherein the supplemental agent is administered to treat a side-effect of the second active agent.

76. The method of claim 75, wherein the side-effect is an extrapyrimidal symptom.

77. The method of claim 76, wherein the extrapyrimidal symptom is akisthesia.

78. The method of claim 77, wherein the supplemental agent comprises an antihistamine.

79. The method of claim 78, wherein the antihistamine is selected from the group consisting of certrizine, diphenydramine, fenofexadine, and loratidine.

80. The method of claim 76, wherein the supplemental agent comprises an anticholinergic agent.

81. The method of claim of claim 69, wherein the supplemental agent is administered to treat a symptom associated with the bipolar condition or subtype thereof.

82. The method of claim 81, wherein the symptom is selected from the group consisting of grandiosity, hypersexuality, hypervolubility, impulsivity, insomnia, and combinations thereof.

83. The method of claim 52, further comprising administering light therapy to the subject.

84. The method of claim 52, wherein about 2.0 mg of buprenorphine is administered to the subject.

85. The method of claim 52, wherein about 8.0 mg of buprenorphine is administered to the subject.

86. A kit for treating a bipolar condition and subtypes thereof comprising:

a plurality of buprenorphine dosage forms;

at least one second dosage form comprising a second active agent;

a housing; and

instructions for taking the dosage forms for racing thoughts associated with the depressed phase of the bipolar condition or subtype thereof, and according to a predetermined dosing regimen,

wherein the housing is configured to organize the dosage forms according to the predetermined dosing regimen.

87. The kit of claim 86, wherein the bipolar condition is bipolar I disorder.

88. The kit of claim 86, wherein the bipolar condition is bipolar II disorder.

89. The kit of claim 86, wherein the bipolar condition is a mixed bipolar disorder having a plurality of manic or hypomanic phases and a plurality of depressive phases.

90. The kit of claim 89, wherein the mixed bipolar disorder rapidly cycles between the manic or hypomanic phases and depressive phases.

91. The kit of claim 86, wherein the bipolar condition subtype is cyclothymia.

92. The kit of claim 86, wherein the bipolar condition subtype is acute mania, drug-induced mania, or drug-induced hypomania.

95. The kit of claim 86, wherein the second active agent is selected from the group consisting of antipsychotic agents, atypical antipsychotic agents, antiepileptic agents, lithium, and salts and acids thereof.

96. The kit of claim 95, wherein the second active agent comprises an atypical antipsychotic agent selected from the group consisting of aripriprazole, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, arisulpride, and combinations thereof.

97. The kit of claim 95, wherein the second active agent comprises an antiepileptic agent selected from the group consisting of divalproex, lamotrigine, oxacarbazine, valproic acid, lithium, and combinations thereof.

98. The kit of claim 86, comprising a plurality of second dosage forms.

99. The kit of claim 98, wherein the plurality of second dosage forms comprises the same second active agent or different second active agents.

100. The kit of claim 98, wherein the plurality of second dosage forms comprises the second active agent in the same dose or different doses.

101. The kit of claim 86, further comprising a supplemental dosage form comprising a supplemental agent for treating a comorbid condition, a side-effect of the second active agent, or a symptom associated with the bipolar condition, or combinations thereof.

102. The kit of claim 101, wherein the supplemental agent treats a comorbid condition.

103. The kit of claim 102, wherein the comorbid condition is diabetes mellitus.

104. The kit of claim 102, wherein the supplemental agent comprises metformin and the second active agent comprises an atypical antipsychotic agent or an antiepileptic agent.

105. The kit of claim 102, wherein the atypical antipsychotic agent comprises aripiprazole or ziprasidone.

106. The kit of claim 104, wherein the antiepileptic agent comprises lamotrigine, oxcarbazepine, or valproic acid.

107. The kit of claim 102, wherein the comorbid condition is obesity.

108. The kit of claim 107, wherein the supplemental agent comprises metformin or topiramate.

109. The kit of claim 102, wherein the comorbid condition is fibromyalgia.

110. The kit of claim 109, wherein the supplemental agent is selected from the group consisting of carisoprodol, colchicine, cyclobenzaprine, duloxetine, gabapentin, guafenisin, interferon, methocarbamol, pregabalin, probenecid, sulfinpyrazone, and vitamin B12.

111. The kit of claim 101, wherein the supplemental agent treats a side-effect of the second active agent.

112. The kit of claim 111, wherein the side-effect is an extrapyrimidal symptom.

113. The kit of claim 112, wherein the extrapyrimidal symptom is akisthesia.

114. The kit of claim 112, wherein the supplemental agent comprises an antihistamine.

115. The kit of claim 114, wherein the antihistamine is selected from the group consisting of certrizine, diphenydramine, fenofexadine, and loratidine.

116. The method of claim 112, wherein the supplemental agent comprises an anticholinergic agent.

117. The kit of claim 101, wherein the supplemental agent treats a symptom associated with the bipolar condition or subtype thereof.

118. The kit of claim 117, wherein the symptom is selected from the group consisting of grandiosity, hypersexuality, hypervolubility, impulsivity, insomnia, and combinations thereof.

119. The kit of claim 101, wherein the plurality of buprenorphine dosage forms, at least one second dosage form, and supplemental dosage form are configured for oral, sublingual, buccal, topical, or injectable modes of administration, or a combination thereof.

120. The kit of claim 101, wherein the plurality of buprenorphine dosage forms, at least one second dosage form, and supplemental dosage form are configured as solid dosage forms, semi-solid dosage forms, liquid dosage forms, or a combination thereof.

121. The kit of claim 101, comprising the plurality of buprenorphine dosage forms, at least one second dosage form, and supplemental dosage form in the same dosage form.

122. The kit of claim 101, comprising the plurality of buprenorphine dosage forms, at least one second dosage form, and supplemental dosage form in different dosage forms.

123. The kit of claim 98, wherein the housing is configured to organize the plurality of buprenorphine dosage forms and second dosage forms by the day of the week taken.

124. The kit of claim 98, wherein the housing is configured to organize the buprenorphine dosage forms and second dosage forms into morning dosage forms and evening dosage forms.

125. The kit of claim 98, wherein the housing is configured to organize the buprenorphine dosage forms and second dosage forms according to a rapid or a gradual titration regimen to a maintenance dose.

126. The kit of claim 101, wherein the housing is configured to organize the plurality of buprenorphine dosage forms, second dosage forms, and supplemental dosage forms by the day of the week taken.

127. The kit of claim 101, wherein the housing is configured to organize the buprenorphine dosage forms, second dosage forms, and supplemental dosage forms into morning dosage forms and evening dosage forms.

128. The kit of claim 101, wherein the housing is configured to organize the buprenorphine dosage forms, second dosage forms, and supplemental dosage forms according to a rapid or a gradual titration regimen to a maintenance dose.