Injectable capsaicin

• US 20050019436A1
• Filed: 12/18/2003
• Published: 01/27/2005
• Est. Priority Date: 12/18/2002
• Status: Abandoned Application

• Current Assignee: Sofinnova Venture Partners VII LP (Sofinnova Ventures, Inc.)
• Original Assignee: Algorx
• Inventors: Carter, Richard B., Burch, Ronald M., Lazar, Jeff
• Application Number:
  US10/742,621
• Publication Number:
  US 20050019436A1
• Time in Patent Office: Days
• US Class Current: 424/760
• 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 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 36/81 Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 231/02 from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
• CPC Class Codes: C07C 233/20 : having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton

Abstract

The present invention provides compositions and methods for relieving pain at a site in a human or animal in need thereof by administering at a discrete site in a human or animal in need thereof a dose of capsaicin in an amount effective to denervate a discrete site without eliciting an effect outside the discrete location, the dose of capsaicin ranging from 1 μg to 3000 μg.

Claims

1. A method for attenuating pain at a site in a human or animal in need thereof, comprising:

administering at a discrete painful site in a human or animal in need thereof a single injectable or implantable dose of a capsaicinoid in an amount effective to denervate said discrete site without eliciting an effect outside the discrete location and to attenuate pain emanating from said site, said effective dose being from about 1 μ

g to about 5000 μ

g of capsaicin or a therapeutically equivalent dose of a capsaicinoid other than capsaicin.

2. The method of claim 1, wherein said dose of capsaicin is from about 10 to about 3000 μ

g.

3. The method of claim 1, wherein said dose of capsaicin is from about 300 to about 1500 μ

g.

4. The method of claim 1, wherein said dose of capsaicin is from about 400 to about 1200 μ

g.

5. The method of claim 1, wherein said dose of capsaicinoid is administered in a pharmaceutically acceptable vehicle for injection or implantation.

6. The method of claim 4, wherein said pharmaceutically acceptable vehicle is an aqueous vehicle is selected from the group consisting of Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose, Lactated Ringers Injection and any combinations or mixtures thereof.

7. The method of claim 5, wherein said pharmaceutically acceptable vehicle comprises an agent selected form the group consisting of antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering, chelating agents and any combinations thereof.

8. The method of claim 5, wherein said pharmaceutically acceptable vehicle comprises about 20% PEG 300, about 10 mM histidine and about 5% sucrose in water for injection.

9. The method of claim 1, wherein said dose of capsaicinoid is injected or implanted into a site selected from the group consisting of subcutaneous, intramuscular, itrathecal, epidural, intraperitoneal, caudal, intradermal, or intracutaneous, intercostal at a single nerve, intra-articular, intrasynovial, intraspinal, intra-arterial, at a laparoscopic surgical site, and a body space.

10. The method of claim 7, wherein said intra-articular administration comprises administration into a joint selected from the group consisting of knee, elbow, hip, sternoclavicular, temporomandibular, carpal, tarsal, wrist, ankle, intervertebral disk, ligamentum flavum and any other joint subject to pain.

11. The method of claim 1, wherein said dose of capsaicinoid is administered in the form of injectable or implantable microparticles selected from the group consisting of microcapsules and microspheres.

12. The method of claim 1, further comprising administering a local anesthetic prior to or concurrently with said dose of capsaicinoid in an amount and location effective to attenuate an initial hyperalgesic effect of said administered dose of capsaicinoid.

13. The method of claim 12, wherein said local anesthetic is selected from the group consisting of dibucaine, bupivacaine, ropivacaine, etidocaine, tetracaine, procaine, chlorocaine, prilocaine, mepivacaine, lidocaine, xylocaine, 2-chloroprocaine, and acid addition salts or mixtures thereof.

14. The method of claim 13, wherein said local anesthetic is administered by direct injection into the site where said dose of capsaicinoid is administered.

15. The method of claim 13, wherein said local anesthetic is administered to said site as a regional nerve block.

16. The method of claim 1, further comprising administering phenol prior to or concurrently with said dose of capsaicinoid in an amount and location effective to attenuate an initial hyperalgesic effect of said administered dose of capsaicinoid.

17. The method of claim 1, wherein said administration of capsaicinoid at said discrete site provides attenuation of pain emanating from said site for at least about 48 hours.

18. The method of claim 1, wherein said dose comprises capsaicin.

19. The method of claim 1, wherein said dose comprises a capsaicinoid other than capsaicin.

20. The method of claim 19, wherein said capsaicinoid is selected from the group consisting of resiniferatoxin, N-vanillylnonanamides, N-vanillylsulfonamides, N-vanillylureas, N-vanillylcarbamates, N[(substituted phenyl)methyl]alkylamides, methylene substituted N[(substituted phenyl)methyl]alkanamides, N[(substituted phenyl) methyl]-cis-monosaturated alkenamides, N[(substituted phenyl)methyl]diunsaturated amides, 3-hydroxyacetanilide, hydroxyphenylacetamides, pseudocapsaicin, dihydrocapsaicin, nordihydrocapsaicin anandamide, piperine, zingerone, warburganal, polygodial, aframodial, cinnamodial, cinnamosmolide, cinnamolide, isovelleral, scalaradial, ancistrodial, β

-acaridial, merulidial, scutigeral, and any combinations thereof.

21. The method of claim 20, wherein said capsaicinoid is resiniferatoxin.

22. The method of claim 18, wherein said capsaicin consists essentially of trans-capsaicin.

23. The method of claim 1, wherein said capsaicinoid administration provides an effect selected from the group consisting of:

a) producing a selective, highly-localized destruction or incapacitation of C-fibers and/or A-delta fibers in a discrete, localized area responsible for the initiation of pain for the purpose of reducing or eliminating pain arising from a discrete locus, and b) minimizing potential adverse consequences of C-fiber and/or A-delta activation and or damage outside of the locus of pain.

24. The method of claim 1, wherein said pain is associated with median sternotomy, and the method further comprises administering to sternal edges of a human or animal undergoing a median sternotomy a single injectable or implantable dose-of capsaicinoid in an amount effective to denervate said sternal edges without eliciting an effect outside the sternal edge location, said dose of capsaicin ranging from about 1 μ

g to about 3000 μ

g.

25. The method of claim 1, wherein said pain is associated with chronic post-herniorrhapy, and the method further comprises administering to a site where hernia surgery was performed in a human or animal a single injectable or implantable dose of a capsaicin in an amount effective to denervate said site without eliciting an effect outside the site, said dose of capsaicin ranging from about 1 μ

g to about 3000 μ

g.

26. The method of claim 1, wherein said pain is associated with laparoscopic cholecystectomy, and the method further comprises administering to a site where said laparoscopic cholecystectomy was performed in a human or animal a single injectable or implantable dose of a capsaicin in an amount effective to denervate said site without eliciting an effect outside the site, said dose of capsaicin ranging from about 1 μ

g to about 3000 μ

g.

27. The method of claim 1, wherein said pain is associated with Morton'"'"'s Neuroma, and the method further comprises administering to a digital nerve in a human or animal in need thereof a single injectable or implantable dose of a capsaicin in an amount effective to denervate said digital nerve without eliciting an effect outside the digital nerve, said dose of capsaicin ranging from about 1 μ

g to about 3000 μ

g.

28. The method of claim 1, wherein said pain is associated with osteoarthritis of the knee, and the method further comprises administering intra-articularly to a knee of a human or animal a single injectable or implantable dose of a capsaicin in an amount effective to denervate said knee without eliciting an effect outside the knee, said dose of capsaicin ranging from about 1 μ

g to about 3000 μ

g.

29. The method of claim 1, wherein said pain is associated with tendonitis or bursitis of the shoulder, and the method further comprises administering to a subacromial bura of a human or animal a single injectable or implantable dose of a capsaicin in an amount effective to denervate said bursa without eliciting an effect outside the bursa, said dose of capsaicin ranging from about 1 μ

g to about 3000 μ

g.

30. The method of claim 1, wherein said pain is associated with epicondylitis, and the method further comprises administering into muscle and tissue distal to the lateral/medial epicondyle of a human or animal a single injectable or implantable dose of a capsaicin in an amount effective to denervate said muscle and tissue without eliciting an effect outside the muscle or tissue, said dose of capsaicin ranging from about 1 μ

g to about 3000 μ

g.

31. The method of claim 1, wherein said pain is associated with a bunionectomy, and the method further comprises administering into a wound opening resulting from a bunionectomy surgical procedure in a human or animal a single injectable or implantable dose of a capsaicin in an amount effective to denervate said wound opening without eliciting an effect outside the wound opening, said dose of capsaicin ranging from about 1 μ

g to about 3000 μ

g.

32. The method of claim 1, wherein said pain is associated with a condition selected from the group consisting of tendonitis, bursitis, osteoarthritis, and rheumatoid arthritis.

33. The method of claim 1, wherein said pain is associated with an orthopedic disorder of the foot selected from the group consisting of heel spurs, corns, bunions, Morton'"'"'s neuroma, hammertoes, ankle sprain, fractures of the ankle or metatarsals or sesamoid bone or toes, plantar fascitis and injuries to the achilles tendon.

34. The method of claim 1, wherein said pain is associated with an orthopedic disorder of the hand selected from the group consisting of arthritis, carpal tunnel syndrome, and ganglion cysts.

35. The method of claim 1, wherein said pain is associated with a disorder selected from the group consisting of lateral epicondylitis, medial epicondylitis, rotator cuff tendonitis, DeQuervian'"'"'s tenosynovitis, and trigger finger/trigger thumb.

36. The method of claim 1, wherein said pain is associated with a disorder selected from the group consisting of Paget'"'"'s disease, scoliosis, contusions, sprains, strains, lower back pain, and heel spur.

37. The method of claim 1, wherein said pain is associated with a bone fracture.

38. The method of claim 1, wherein said pain is associated an injury selected from the group consisting of a tear of the anterior cruciate ligament, a tear of the posterior cruciate ligament, a tear of the medial collateral ligament, a tear of the lateral collateral ligament;

a meniscal cartilage tear;

a cartilage defect of the knee; and

combinations of any of the foregoing.

39. The method of claim 1, wherein said pain is associated with an orthopedic disorder of the shoulder selected from the group consisting of bursitis, dislocation, separation, impingement and tear of the rotator cuff, tendonitis, adhesive capsulitis, shoulder fracture, and combinations of any of the foregoing.

40. The method of claim 1, wherein said dose of capsaicinoid is therapeutically equivalent to a dose of capsaicin in an amount from about 300 to about 1500 μ

g.

41. The method of claim 1, wherein said dose of capsaicinoid is therapeutically equivalent to a dose of capsaicin in an amount from about 400 to about 1200 μ

g.

42. The method of claim 1, wherein the capsaicinoid is a purified capsaicin.

43. The method of claim 1, wherein the capsaicinoid is at least about 97% trans-capsaicin.

44. The method of claim 1, wherein said pain at said site is associated with cancer pain.

45. The method of claim 1, wherein said pain at said site is associated with a muscle tear.

46. The method of claim 1, wherein said capsaicinoid comprises a mixture of capsaicinoids in a total amount equivalent to a capsaicin dose from about 1 μ

g to about 5000 μ

g of capsaicin.

47. The method of claim 1, wherein said pain at said site is associated with joint pain, and a single unit dose capsaicinoid injection or implantation attenuates pain at the site for at least about one month.

48. The method of claim 1, wherein said pain at said site is associated with joint pain, and a single unit dose capsaicinoid injection or implantation attenuates pain at the site for at least about three months.

49. The method of claim 1, wherein said pain at said site is associated with an arthritic condition, and a single unit dose capsaicinoid injection or implantation attenuates pain at the site for at least about three months.

50. The method of claim 1, wherein said pain at said site is post-surgical pain, and a single unit dose capsaicinoid injection or implantation attenuates pain at the site for at least about one week.

51. The method of claim 1, further comprising administering to said patient an analgesic to treat breakthrough pain.

52. A method of treating acute traumatic pain associated with an injury, comprising injecting a capsaicinoid in a physiologically compatible vehicle through the skin of a patient in proximity to an injury, said dose of capsaicinoid being sufficient to attenuate the dull, aching pain associated with C-fibers in proximity to the injury and such that the patient continues to have sensation in proximity to the injury and without affecting sharp protective pain associated with A-delta fibers in proximity to the site, the dose of capsaicinoid being therapeutically equivalent to a dose of capsaicin in an amount from about 300 to about 1500 μ

g and being effective to attenuate dull, aching pain in proximity to the injury for at least about 48 hours.

53. An injectable or implantable pharmaceutical composition for attenuating pain at a site in a human or animal in need thereof, consisting essentially of a capsaicinoid selected from the group consisting of from 1 μ

g to 5000 μ

g of capsaicin, a therapeutically equivalent amount of one or more other capsaicinoids, and combinations thereof;

in a pharmaceutically acceptable vehicle for injection or implantation.

58. The pharmaceutical composition of claim 53, wherein said pharmaceutically acceptable vehicle is an aqueous vehicle is selected from the group consisting of Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose, Lactated Ringers Injection and any combinations or mixtures thereof.

59. The pharmaceutical composition of claim 53, wherein said pharmaceutically acceptable vehicle comprises an agent selected form the group consisting of antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering, chelating agents and any combinations thereof.

60. The pharmaceutical composition of claim 53, wherein said pharmaceutically acceptable vehicle comprises effective concentrations of polyethylene glycol, histidine and sucrose, in water for injection.

61. The pharmaceutical composition of claim 60, wherein said pharmaceutically acceptable vehicle comprises about 20% PEG 300, about 10 mM histidine and about 5% sucrose in water for injection.

54. The pharmaceutical composition of claim 54, wherein said capsaicinoid comprises from about 300 μ

g to 1500 μ

g capsaicin.

55. The pharmaceutical composition of claim 54, wherein said capsaicinoid comprises from about 400 μ

g to 1200 μ

g capsaicin.

56. The pharmaceutical composition of claim 54, wherein said capsaicinoid comprises from about 300 μ

g to 1500 μ

g of trans-capsaicin.

57. The pharmaceutical composition of claim 54, wherein the capsaicinoid is at least about 97% trans-capsaicin.

62. An injectable or implantable pharmaceutical composition for attenuating pain at a site in a human or animal in need thereof, consisting essentially of from 1 μ

g to 5000 μ

g of trans-capsaicin and a pharmaceutically acceptable vehicle for injection or implantation.

63. The pharmaceutical composition of claim 62, wherein said pharmaceutically acceptable vehicle comprises effective concentrations of polyethylene glycol, histidine and sucrose, in water for injection.

64. The pharmaceutical composition of claim 62, wherein said pharmaceutically acceptable vehicle comprises about 20% PEG 300, about 10 mM histidine and about 5% sucrose in water for injection.

65. The composition of claim 62, wherein said trans-capsaicin is present in an amount from about 300 to about 1500 μ

g.

66. The composition of claim 62, wherein said trans-capsaicin is present in an amount from about 400 to about 1200 μ

g.