Methods for treating pain by topical application and transdermal delivery of botulinum toxin
View Patent ↗Improved formulations for transdermal delivery of botulinum toxin are disclosed. The formulations include, for example, botulinum toxin non-covalently associated with a positively charged backbone having branching or efficiency groups. The formulations also include a partitioning agent, oligo-bridge, or polyanion bridge, and may optionally contain a viscosity modifying agent. The formulations are designed for topical application onto the skin of a patient and may be used to treat wrinkles, hyperhidrosis, and other health-related problems. Kits for administration are also described.
1. A method of treating pain in a patient in need thereof, said method comprising:
topically administering to an affected area of the patient in need of treatment, a pharmaceutically acceptable composition comprising:
botulinum toxin,
a carrier comprising a positively charged polymeric backbone with positively charged efficiency groups covalently attached thereto;
a poloxamer; and
a dermatologically or pharmaceutically acceptable excipient, diluent, or medium;
wherein the botulinum toxin is non-covalently associated with the positively charged polymeric backbone; and wherein the carrier comprising the positively charged backbone is the sole necessary agent for non-covalently associating with the botulinum toxin and delivering the botulinum toxin to the affected area so as to treat the s pain in said patient.
2. The method according to claim 1 , wherein the pain is selected from one or more of neurologic pain, migraine headache pain, non-migraine headache pain, or muscle-spasm pain.
3. The method according to claim 2 , wherein the pain is neurologic pain.
4. The method according to claim 2 , wherein the pain is migraine headache pain.
5. The method according to claim 2 , wherein the pain is non-migraine headache pain.
6. The method according to claim 2 , wherein the pain is muscle-spasm pain.
7. The method according to claim 1 , wherein the composition is topically administered a patient's skin.
8. The method according to claim 1 or claim 2 , wherein the positively charged polymeric backbone is polylysine or polyethyleneimine (PEI).
9. The method according to claim 8 , wherein the positively charged polymeric backbone has a molecular weight of less than 21,000.
10. The method according to claim 8 , wherein the positively charged efficiency groups are either protected oligoarginine or TAT domains.
11. The method according to claim 10 , wherein the composition further comprises a viscosity modifying agent or a gelling agent.
12. The method according to claim 11 , wherein the viscosity modifying agent or gelling agent is polyethylene glycol (PEG) or hydroxypropylcellulose (HPC).
13. The method according to claim 10 , wherein the positively charged efficiency groups are amino acid sequences selected from the group consisting of (gly)p-RGRDDRRQRRR-(gly)q (SEQ ID NO: 2), (gly)p-YGRKKRRQRRR-(gly)q (SEQ ID NO: 3), and (gly)p-RKKRRQRRR-(gly)q (SEQ ID NO: 4), wherein the subscripts p and q are each independently an integer of from 0 to 20.
14. The method according to claim 13 , wherein the positively charged efficiency groups include the amino acid sequence (gly)p-RGRDDRRQRRR-(gly)q (SEQ ID NO: 2), wherein the subscripts p and q are each independently an integer of from 0 to 20.
15. The method according to claim 13 , wherein the positively charged efficiency groups include the amino acid sequence (gly)p-YGRKKRRQRRR-(gly)q (SEQ ID NO: 3), wherein the subscripts p and q are each independently an integer of from 0 to 20.
16. The method according to claim 13 , wherein the positively charged efficiency groups include the amino acid sequence (gly)p-RKKRRQRRR-(gly)q (SEQ ID NO: 4), wherein the subscripts p and q are each independently an integer of from 0 to 20.
17. The method according to claim 13 , wherein the subscripts p and q are each independently an integer of from 0 to 8.
18. The method according to claim 13 , wherein the subscripts p and q are each independently an integer of from 2 to 5.
19. The method according to claim 8 , wherein the positively charged polymeric backbone is polylysine and the positively charged efficiency groups include amino acid sequence (gly)p-RGRDDRRQRRR-(gly)q (SEQ ID NO: 2), wherein the subscripts p and q are each independently an integer of from 2 to 5.
20. The method according to claim 8 , wherein the positively charged polymeric backbone is polylysine and the positively charged efficiency groups include amino acid sequence (gly)p-YGRKKRRQRRR-(gly)q (SEQ ID NO: 3), wherein the subscripts p and q are each independently an integer of from 2 to 5.
21. The method according to claim 8 , wherein the positively charged polymeric backbone is polylysine and the positively charged efficiency groups include amino acid sequence (gly)p-RKKRRQRRR-(gly)q (SEQ ID NO: 4), wherein the subscripts p and q are each independently an integer of from 2 to 5.
22. The method according to 1, wherein the botulinum toxin is a serotype selected from the group consisting of serotype A, B, C, D, E, F, G and mixtures thereof.
23. The method according to claim 22 , wherein the botulinum toxin is of serotype A.
24. The method according to claim 19 , wherein the botulinum toxin is of serotype A.
25. The method according to claim 20 , wherein the botulinum toxin is of serotype A.
26. The method according to claim 21 , wherein the botulinum toxin is of serotype A.
27. The method according to claim 23 , wherein the botulinum toxin has a molecular weight of 150,000.
28. The method according to claim 24 , wherein the botulinum toxin has a molecular weight of 150,000.
29. The method according to claim 25 , wherein the botulinum toxin has a molecular weight of 150,000.
30. The method according to claim 26 , wherein the botulinum toxin has a molecular weight of 150,000.
31. The method according to claim 19 , wherein the polylysine has a molecular weight of about 21,000.
32. The method according to claim 20 , wherein the polylysine has a molecular weight of about 21,000.
33. The method according to claim 21 , wherein the polylysine has a molecular weight of about 21,000.
34. The method according to claim 11 , wherein the positively charged backbone is polylysine and the amino acid sequence is attached to the polylysine via either the C-terminus or the N-terminus of the amino acid sequence.
35. The method according to claim 19 , wherein the amino acid sequence is attached to the polylysine via either the C-terminus or the N-terminus of the amino acid sequence.
36. The method according to claim 24 , wherein the amino acid sequence is attached to the polylysine via either the C-terminus or the N-terminus of the amino acid sequence.
37. The method according to claim 25 , wherein the amino acid sequence is attached to the polylysine via either the C-terminus or the N-terminus of the amino acid sequence.
38. The method according to claim 26 , wherein the amino acid sequence is attached to the polylysine via either the C-terminus or the N-terminus of the amino acid sequence.
39. The method according to claim 10 , wherein the positively charged efficiency groups comprise at least about 0.05% by weight of the total carrier weight in the composition.
40. The method according to claim 39 , wherein the positively charged efficiency groups comprise from about 0.1% to about 30%% by weight of the total carrier weight in the composition.
41. The method according to claim 13 , wherein the composition comprises botulinum toxin of serotype A, polylysine having covalently attached thereto positively charged efficiency groups having the amino acid sequence (gly)p-RKKRRQRRR-(gly)q (SEQ ID NO. 4), wherein the subscripts p and q are each independently an integer of from 0 to 20, and poloxamer.
42. The method according to claim 41 , wherein the positively charged efficiency groups comprise from about 0.1% to about 30%% by weight of the total carrier weight in the composition.
43. The method according to claim 41 , wherein the polylysine has a molecular weight of about 21,000.
44. The method according to claim 41 , wherein the botulinum toxin of serotype A has a molecular weight of 150,000.
45. The method according to claim 1 , wherein the dermatologically or pharmaceutically acceptable excipient, diluent, or medium is an aqueous diluent comprising a saline solution of 15% poloxamer, and wherein the carrier and the botulinum toxin are present in the saline solution in a ratio corresponding to 0.5 μg carrier to 100 U of toxin.