Methods and compositions for treating pain

• US 20060111307A1
• Filed: 11/16/2005
• Published: 05/25/2006
• Est. Priority Date: 11/16/2004
• Status: Abandoned Application

• Current Assignee: Limerick Neurosciences, Inc.
• Original Assignee: Limerick Neurosciences, Inc.
• Inventors: Robbins, Wendye
• Application Number:
  US11/281,771
• Publication Number:
  US 20060111307A1
• Time in Patent Office: Days
• US Class Current: 514/27
• 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 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/7024 Esters of saccharides
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 23/02 Local anaesthetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system

Abstract

Methods and compositions are described for the modulation of central nervous system and/or fetal effects of substances. Methods and compositions are described for the modulation of efflux transporter activity to increase the efflux of drugs and other compounds out of a physiological compartment and into an external environment. In particular, the methods and compositions disclosed herein provide for the increase of efflux transporter activity at blood-brain, blood-CSF and placental-maternal barriers to increase the efflux of drugs and other compounds from physiological compartments, including central nervous system and fetal compartments.

Claims

1. A pharmaceutical composition comprising an analgesic agent, a blood brain barrier (BBB) transport protein activator and a pharmaceutically acceptable excipient, wherein the analgesic agent is present in an amount sufficient to produce an analgesic effect, and wherein the BBB transport protein activator is present in an amount sufficient to reduce a central nervous system (CNS) effect of the analgesic agent.

2. The composition of claim 1 wherein the BBB transport protein is an ABC transport protein.

3. The composition of claim 1 wherein the effect is selected from the group consisting of drowsiness, impaired concentration, sexual dysfunction, sleep disturbances, habituation, dependence, alteration of mood, respiratory depression, nausea, vomiting, dizziness memory impairment, neuronal dysfunction, neuronal death, visual disturbance, impaired mentation, tolerance, addiction, hallucinations, lethargy, myoclonic jerking, endocrinopathies, and combinations thereof.

4. The composition of claim 1 wherein a therapeutic effect of the therapeutic agent is increased at least about 10% compared to the therapeutic effect without the BBB transport protein activator, when the composition is administered to an animal.

5. The composition of claim 2 wherein the ABC transport protein is a P-gP.

6. The composition of claim 1 wherein the analgesic is selected from the group consisting of oxycodone, gabapentin, pregabalin, hydrocodone, fentanyl, hydromorphone, levorphenol, morphine, methadone, tramadol, topiramate, diacetyl morphine, codeine, olanzapine, hydrocortisone, prednisone, sufentanyl, alfentanyl, carbamazapine, lamotrigine, doxepin, and haloperidol.

7. The composition of claim 1 wherein the analgesic is selected from the group consisting of oxycodone and gabapentin.

8. The composition of claim 1 wherein the analgesic is oxycodone.

9. The composition of claim 1 wherein the analgesic is gabapentin.

10. The composition of claim 1 wherein the BBB transport protein activator is a polyphenol.

11. The composition of claim 10 wherein the BBB transport protein activator is a flavonoid.

12. The composition of claim 11 wherein the BBB transport protein activator is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

13. The composition of claim 12 wherein the BBB transport protein activator is quercetin.

14. The composition of claim 12 wherein the analgesic is selected from the group consisting of oxycodone, gabapentin, pregabalin, hydrocodone, fentanyl, hydromorphine, levorphenol, morphine, methadone, tramadol and topiramate.

15. The composition of claim 14 wherein the analgesic is selected from the group consisting of oxycodone and gabapentin.

16. The composition of claim 15 wherein the analgesic is oxycodone.

17. The composition of claim 15 wherein the analgesic is gabapentin.

18. The composition of claim 13 wherein the analgesic is selected from the group consisting of oxycodone and gabapentin.

19. The composition of claim 13 wherein the analgesic is oxycodone.

20. The composition of claim 19 wherein the oxycodone and the quercetin are present in a molar ratio of about 0.002:

1 to 0.1;

1.

21. The composition of claim 19 wherein the oxycodone is present at about 5-160 mg and the quercetin is present at about 10-500 mg.

22. The composition of claim 21 wherein the oxycodone is present at about 80 mg and the quercetin is present at about 500 mg.

23. The composition of claim 13 wherein the analgesic is gabapentin.

24. The composition of claim 23 wherein the gabapentin and the quercetin are present in a molar ratio of about 0.2:

1 to 6;

1

25. The composition of claim 23 wherein the gabapentin is present at about 100 to 800 mg and the quercetin is present at about 50-5000 mg.

26. The composition of claim 25 wherein the gabapentin is present at about 300 mg and the quercetin is present at about 150 mg.

27. The composition of claim 1 wherein the analgesic and the BBB transport protein activator are present in a molar ratio of about 0.001:

1 to about 10;

1.

28. The composition of claim 14 wherein the analgesic and the BBB transport protein activator are present in a molar ratio of about 0.001:

1 to about 10;

1.

29. The composition of claim 1 wherein the analgesic is present at about 0.001 to 500 mg and the BBB transport protein activator is present at about 10 to 1000 mg.

30. The composition of claim 1 wherein the central nervous system effect includes an effect selected from the group consisting of drowsiness, impaired concentration, sexual dysfunction, sleep disturbances, habituation, dependence, alteration of mood, respiratory depression, nausea, vomiting, dizziness memory impairment, neuronal dysfunction, neuronal death, visual disturbance, impaired mentation, tolerance, addiction, hallucinations, lethargy, myoclonic jerking, endocrinopathies, and combinations thereof.

31. The composition of claim 1 wherein the analgesic and the BBB transport protein activator are admixed.

32. A method of treating an animal for pain comprising administering to an animal in pain an effective amount of an analgesic agent and an amount of a BBB transport protein activator sufficient to reduce a central nervous system effect of the analgesic agent.

33. The method of claim 32 wherein the BBB transport protein activator is administered in an amount sufficient to substantially eliminate a central nervous system effect of the analgesic compound.

34. The method of claim 32 wherein the analgesic agent and the BBB transport protein activator are co-administered.

35. The method of claim 34 wherein the analgesic compound and the BBB transport protein activator are administered admixed in a single composition.

36. The method of claim 35 wherein the analgesic is present in the composition in an amount sufficient to produce an analgesic effect, and wherein the BBB transport protein activator is present in the composition in an amount sufficient to reduce a central nervous system effect of the analgesic.

37. The method of claim 35 wherein the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the BBB transport protein modulator is present in an amount sufficient to decrease a CNS effect of the therapeutic agent by an average of at least about 10%, compared to the side effect without the BBB transport protein modulator.

38. The method of claim 32 wherein the amount of analgesic agent is administered in an amount sufficient to produce an analgesic effect, and wherein said amount is different than the amount sufficient to produce an analgesic effect in the absence of administration of the BBB transport protein activator.

40. The method of claim 32 wherein the administration is oral administration.

41. The method of claim 32 wherein the administration is transdermal administration.

42. The method of claim 32 wherein the animal in pain suffers from chronic pain.

43. The method off claim 32 wherein the animal is a mammal.

44. The method of claim 32 wherein the animal is a human.

45. The method of claim 32 wherein the BBB transport protein activator is an activator of P-gP.

46. The method of claim 32 wherein the BBB transport protein activator comprises a polyphenol.

47. The method of claim 46 wherein the polyphenol is a flavonoid.

48. The method of claim 47 wherein the flavonoid is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

49. The method of claim 48 wherein the flavonoid is quercetin.

50. The method of claim 32 wherein the analgesic is selected from the group consisting of oxycodone, gabapentin, pregabalin, hydrocodone, fentanyl, hydromorphine, levorphenol, morphine, methadone, tramadol and topiramate.

51. The method of claim 50 wherein the analgesic is selected from the group consisting of oxycodone and gabapentin.

52. The method of claim 51 wherein the analgesic is oxycodone.

53. The method of claim 51 wherein the analgesic is gabapentin.

54. The method of claim 49 wherein the analgesic is selected from the group consisting of oxycodone, gabapentin, pregabalin, hydrocodone, fentanyl, hydromorphine, levorphenol, morphine, methadone, tramadol and topiramate.

55. The method of claim 54 wherein the analgesic is selected from the group consisting of oxycodone and gabapentin.

56. The method of claim 54 wherein the analgesic is oxycodone.

57. The method of claim 54 wherein the analgesic is gabapentin.

58. The method of claim 34 wherein the analgesic compound and the BBB transport protein activator are administered together about once per day to about 6 times per day.

59. The method of claim 58 wherein the administration continues for less than about 7 days.

60. The method of claim 58 wherein the administration continues for more than about 6 days.

61. The method of claim 32 further comprising administering to the animal in pain another therapeutic agent.

62. The method of claim 61 wherein the other therapeutic agent is selected from the group consisting of antinausea agents, amphetamines, antianxiolytics, and hypnotics.

63. The method of claim 32 wherein the molar ratio of the amount of analgesic agent administered and the amount of BBB transport protein modulator administered is about 0.001:

1 to about 10;

1.

39. The method of 38 wherein the amount of analgesic agent administered is lower than the amount sufficient to produce an analgesic effect in the absence of administration of the BBB transport protein activator.

64. A method of controlling chronic pain comprising co-administering to an animal suffering from chronic pain

(i) an effective amount of an analgesic agent;

and

(ii) an amount of a BBB transport protein modulator sufficient to prevent or delay the development of tolerance to the analgesic agent in the animal.

65. The method of claim 64 wherein the animal is a mammal

66. The method of claim 65 wherein the mammal is a human.

67. The method of claim 66 wherein the amount of the BBB transport protein modulator is sufficient to reduce the amount of analgesic necessary for pain relief.

68. The method of claim 66 wherein the analgesic agent is selected from the group consisting of oxycodone, gabapentin, pregabalin, hydrocodone, fentanyl, hydromorphine, levorphenol, morphine, methadone, tramadol and topiramate.

69. The method of claim 68 wherein the analgesic agent is oxycodone.

70. The method of claim 68 wherein the analgesic agent is gabapentin

71. The method of claim 64 wherein the BBB transport protein modulator is a polyphenol.

72. The method of claim 71 wherein the polyphenol is a flavonoid

73. The method of claim 72 wherein the flavonoid is selected from the group consisting of quercetin, isoquercetin, flavon, chrysin, apigenin, rhoifolin, diosmin, galangin, fisetin, morin, rutin, kaempferol, myricetin, taxifolin, naringenin, naringin, hesperetin, hesperidin, chalcone, phloretin, phlorizdin, genistein, biochanin A, catechin, and epicatechin.

74. The method of claim 73 wherein the flavonoid is quercetin.

75. The method of claim 64 wherein the analgesic agent and the BBB transport protein modulator are co-administered as admixed components of a single composition.