TREATMENT OF PAIN WITH GAP JUNCTION MODULATION COMPOUNDS

• US 20110223204A1
• Filed: 06/04/2009
• Published: 09/15/2011
• Est. Priority Date: 06/04/2008
• Status: Abandoned Application

• Current Assignee: Bradford J. Duft, Colin Richard Green
• Original Assignee: Bradford J. Duft, Colin Richard Green
• Inventors: Green, Colin Richard, Duft, Bradford J
• Application Number:
  US12/996,359
• Publication Number:
  US 20110223204A1
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.

Abstract

The present invention relates to delivery, including transdermal delivery, of a therapeutically effective amount of a compound useful for modulating gap junction formation and function, including an oligonucleotide for reducing gap junction formation and function, and methods and compositions for treating a subject suffering from pain associated with a disease, disorder or condition and associated with pain, including but not limited to muscle pain, ligament pain, tendon pain, joint pain and post-operative pain.

Claims

1. A method for reducing pain in a supporting body structure of a subject, comprising topically administering to said subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a connexin 43 gap junction modulation agent in a pharmaceutically acceptable transdermal delivery form, whereby pain is reduced.

2. A method according to claim 1, wherein the supporting body structure is a joint.

3. A method according to claim 1, wherein the supporting body structure is selected from the group consisting of muscles, bones, tendons, ligaments and cartilage.

4. A method according to claim 1, wherein the subject is suffering from arthritis.

5. A method according to claim 1 or 2, wherein the subject is suffering from osteoarthritis.

6. A method according to claim 1, wherein the subject is suffering from rheumatoid arthritis.

7. A method according to claim 1, wherein the subject is suffering from cervical arthritis.

8. A method according to claim 1, wherein the subject is suffering from ankylosing spondylitis.

9. A method according to claim 1, wherein the subject is suffering from acute pain.

10. A method according to claim 9, wherein the subject is suffering from back pain, knee pain, hip pain, shoulder pain, hand pain or finger pain.

11. A method according to claim 1, wherein the subject is suffering from chronic pain.

12. A method according to claim 11, wherein the subject is suffering from back pain, knee pain, hip pain, shoulder pain, hand pain or finger pain.

13. A method according to claim 1, wherein the subject is suffering from postoperative pain.

14. A method according to claim 1, wherein the transdermal dosage form is selected from the group consisting of a topical gel, lotion, ointment, or spray.

15. A method according to claim 1, wherein said transdermal delivery form comprises a transdermal penetration agent comprising an oil.

16. A method according to claim 15, wherein the oil is an ethoxylated oil having between 10 and 19 ethoxylations/molecule.

17. A method according to claim 15, wherein said ethoxylated oil contains 16 ethoxylations/molecule.

18. A method according to claim 15, wherein said oil comprises an oil selected from the group consisting of macadamia nut oil, meadowfoam oil, castor oil, jojoba oil, corn oil, sun flower oil, sesame oil and emu oil.

19. A method according to claim 16, wherein said ethoxylated oil comprises an ethoxylated oil selected from the group consisting of macadamia nut oil, meadowfoam oil, castor oil, jojoba oil, corn oil, sun flower oil, sesame oil and emu oil.

20. A method according to claim 15, wherein said oil is an emu oil.

21. A method according to claim 16, wherein said oil ethoxylated is an ethoxylated emu oil.

22. A method according to claim 1, wherein said connexin 43 gap junction modulation agent is 10,000 daltons or greater.

23. A method according to claim 1, wherein said connexin 43 gap junction modulation agent is less than 10,000 daltons.

24. A method according to claim 1, wherein said connexin 43 gap junction modulation agent is an oligonucleotide.

25. A method according to claim 24, wherein said oligonucleotide is selected from the group consisting of an antisense oligonucleotide, a ribozyme, a RNAi oligonucleotide and a siRNA oligonucleotide.

26. A method according to claim 1, wherein said connexin 43 gap junction modulation agent is a connexin 43 antisense oligonucleotide.

27. A method according to claim 26, wherein said antisense oligonucleotide is selected from GTA ATT GCG GCA AGA AGA ATT GTT TCT GTC (SEQ ID NO:

1);

GTA ATT GCG GCA GGA GGA ATT GTT TCT GTC (SEQ ID NO;

2); and

, GGC AAG AGA CAC CAA AGA CAC TAC CAG CAT (SEQ ID NO;

3).

28. A method according to claim 26, wherein said antisense oligonucleotide has from about 15 to about 35 nucleotides and is sufficiently complementary to connexin 43 mRNA to form a duplex having a melting point greater than 20°

C. under physiological conditions.

29. A method according to claim 26, wherein the antisense oligonucleotide has from about 15 to about 35 nucleotides and has at least about 70 percent homology to an antisense sequence of connexin 43 mRNA.

30. A method according to claim 1, wherein said connexin 43 gap junction modulation agent is an RNAi or siRNA polynucleotide.

31. A method according to claim 1, wherein said connexin 43 gap junction modulation agent is a peptide or peptidomimetic.

32. A method according to claim 31, wherein said peptide or peptidomimetic binds to a connexin 43 hemichannel.

33. A method according to claim 31, wherein said peptide or peptidomimetic binds to a connexin 43 ZO-1 protein binding site.

34. A method according to claim 1, further comprising a second pharmaceutical compound, wherein said second pharmaceutical compound is a non-steroidal anti inflammatory drug.

35. A method according to claim 1, wherein said connexin 43 gap junction modulation agent is a connexin 43 phosphorylation agent.

36. A method according to claim 1, wherein the amount of said connexin 43 gap junction modulation agent by weight or volume is from about 0.01% to about 50.0%.

37. A method according to claim 1, wherein said connexin 43 gap junction modulation agent has an approximate average molecular weight of less than about 10,000 daltons and the therapeutically effective amount by weight or volume is about 0.01% to about 50.0%.

38. A method according to claim 1, wherein the therapeutically effective amount of said connexin 43 gap junction modulation agent is about 0.01% to about 10.0%.

39. A method according to claim 1, wherein the therapeutically effective amount of said connexin 43 gap junction modulation agent by weight or volume is about 0.01% to about 5.0%.

40. A method according to claim 1, wherein said composition is administered to an area of skin proximal to a site of tissue or joint pain in the subject.

41. A pharmaceutical composition for reducing pain in a subject, comprising a pain-reducing amount of an anti-connexin 43 compound and a pharmaceutically acceptable vehicle comprising a transdermal delivery agent.

43. A pharmaceutical composition according to claim 41, wherein said composition comprises a transdermal penetration enhancer.

44. A pharmaceutical composition according to claim 41, wherein said anti-connexin 43 compound is an oligonucleotide and said transdermal penetration agent promotes the delivery of oligonucleotides through the skin.

42. A pharmaceutical composition for reducing pain in a supporting body structure of a subject, comprising a formulation having a pain-reducing amount of an anti-connexin 43 compound in a transdermal dosage form.

45. A method for reducing pain in a supporting body structure of a subject, which comprises applying to the subject in need thereof a transdermal delivery device comprising an anti-connexin 43 compound to an area of skin proximal to a site of tissue or joint pain in said subject.

46. A method according to claim 45, wherein the anti-connexin 43 compound is an oligonucleotide and the transdermal delivery device promotes delivery of oligonucleotides through the skin.

47. A method according to claim 46, wherein said transdermal delivery device is a transdermal microprojection delivery device.

48. A method according to claim 47 wherein said microprojection device has a biocompatible coating being formed from a coating formulation having the anti-connexin 43 compound disposed thereon.

49. A method according to claim 46 wherein said transdermal delivery device forms at least one micropore in a tissue membrane whereby delivery of said anti-connexin 43 compound through the skin is promoted.

50. An article of manufacture comprising a packaging material and a transdermal delivery composition contained within said packaging material, wherein said transdermal delivery composition comprises a pain relief effective amount of an anti-connexin 43 compound and a transdermal penetration effective amount of an ethoxylated oil;

and wherein said packaging material comprises a label that indicates that said composition may be used for reducing pain in a supporting structure.

51. An article of manufacture according to claim 50 wherein said ethoxylated oil is selected from the group comprising of ethoxylated macadamia nut oil, ethoxylated meadowfoam oil, ethoxylated castor oil, ethoxylated jojoba oil, ethoxylated corn oil, ethoxylated sunflower oil, ethoxylated sesame oil, and ethoxylated emu oil.

52. An article according to claim 50 wherein said anti-connexin 43 compound is an oligonucleotide.

53. An article of manufacture comprising a packaging material and a transdermal delivery composition contained within said packaging material, wherein said transdermal delivery composition comprises a pain relief effective amount of an anti-connexin 43 compound and a transdermal penetration effective amount of an oil;

and wherein said packaging material comprises a label that indicates that said composition may be used for reducing pain in a supporting structure.

54. An article of manufacture according to claim 53 wherein said oil is selected from the group comprising of macadamia nut oil, meadowfoam oil, castor oil, jojoba oil, corn oil, sunflower oil, sesame oil, and emu oil.

55. An article according to claim 53 wherein said anti-connexin 43 compound is an oligonucleotide.

56. A method for reducing pain in a supporting body structure or musculoskeletal system of a subject, comprising administering to said subject in need thereof a therapeutically effective amount of a connexin 43 gap junction modulation agent-containing transdermal, injectable, instillation, or depot dosage form, whereby pain is reduced.