Compositions and methods for topical application and transdermal delivery of botulinum toxins
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 wrinkles, comprising:
applying to an area of skin of a patient in need of treating wrinkles a formulation comprising:
a 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 backbone; and wherein the carrier comprising the positively charged backbone is the sole necessary agent for non-covalently associating with the botulinum toxin, and, optionally, applying an occlusion agent afterwards.
2. The method according to claim 1 , wherein the area of the skin is selected from the group consisting of the face, forehead, neck, hands and feet.
3. The method according to claim 1 , wherein the positively charged polymeric backbone has a molecular weight of less than 21,000.
4. The method according to claim 1 , wherein the positively charged polymeric backbone is polylysine or polyethyleneimine (PEI).
5. The method according to claim 4 , wherein the positively charged efficiency groups are either protected oligoarginine or TAT domains.
6. The method according to claim 5 , wherein the formulation further comprises hydroxypropylcellulose (HPC) or polyethylene glycol (PEG).
7. The method according to claim 5 , wherein the positively charged efficiency groups include an the amino acid sequence 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.
8. The method according to claim 7 , 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.
9. The method according to claim 7 , 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.
10. The method according to claim 7 , 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.
11. The method according to claim 7 , wherein the subscripts p and q are each independently an integer of from 0 to 8.
12. The method according to claim 7 , wherein the subscripts p and q are each independently an integer of from 2 to 5.
13. The method according to claim 7 , wherein the positively charged efficiency groups has 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 2 to 5.
14. The method according to claim 7 , wherein the positively charged efficiency groups has 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 2 to 5.
15. The method according to claim 7 , wherein the positively charged efficiency groups has 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 2 to 5.
16. The method according to 1 , wherein the botulinum toxin is of a serotype selected from the group consisting of serotypes A, B, C, D, E, F, G and mixtures thereof.
17. The method according to 16 , wherein the botulinum toxin is of serotype A.
18. The method according to claim 7 , wherein the positively charged polymeric backbone is polylysine.
19. The method according to claim 13 , wherein the positively charged polymeric backbone is polylysine.
20. The method according to claim 14 , wherein the positively charged polymeric backbone is polylysine.
21. The method according to claim 15 , wherein the positively charged polymeric backbone is polylysine.
22. The method according to claim 18 , wherein the botulinum toxin is of serotype A.
23. The method according to claim 19 , wherein the botulinum toxin is of serotype A.
24. The method according to claim 20 , wherein the botulinum toxin is of serotype A.
25. The method according to claim 21 , wherein the botulinum toxin is of serotype A.
26. The method according to claim 22 , wherein the botulinum toxin has a molecular weight of 150,000.
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 18 , wherein the polylysine has a molecular weight of about 21,000.
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 18 , wherein 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 20 , 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 21 , wherein the amino acid sequence is attached to the polylysine via either the C-terminus or the N-terminus of the amino acid sequence.