Compositions and methods for topical application and transdermal delivery of botulinum toxins
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 formulation for topical application and transdermal delivery of botulinum toxin 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, vehicle or medium; wherein the botulinum toxin is non-covalently associated with the positively charged polymeric backbone; and wherein the carrier comprising the positively charged polymeric backbone is the sole necessary agent for non-covalently associating with and transdermally delivering the botulinum toxin.
2. The formulation according to claim 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.
3. The formulation according to claim 1 , wherein the positively charged polymeric backbone is polylysine or polyethyleneimine (PEI).
4. The formulation according to claim 3 , wherein the efficiency groups are either protected oligo arginine or TAT domains.
5. The formulation according to claim 4 , further comprising a viscosity modifying agent.
6. The formulation according to claim 5 , wherein the viscosity modifying agent is hydroxypropylcellulose.
7. A kit for transdermal delivery of botulinum toxin, the kit comprising the formulation according to claim 4 and a device for delivering the formulation to the skin.
8. The formulation according to claim 4 , wherein the 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.
9. The formulation according to claim 8 , wherein at least one of the 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 0 to 20.
10. The formulation according to claim 8 , wherein at least one of the 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 0 to 20.
11. The formulation according to claim 8 , wherein at least one of the 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 0 to 20.
12. The formulation according to claim 8 , wherein the positively charged polymeric backbone comprises polylysine.
13. The formulation according to claim 12 , wherein the positively charged polylysine backbone has a molecular weight of about 21,000.
14. The formulation according to claim 12 , wherein the botulinum toxin is botulinum toxin A.
15. The formulation according to claim 8 , wherein the subscripts p and q are each independently an integer of from 2 to 5.
16. The formulation according to claim 4 , wherein the positively charged efficiency groups comprise at least about 0.05% by weight of the total carrier weight.
17. The formulation according to claim 4 , wherein the positively charged efficiency groups comprise from about 0.1% to about 30% by weight of the total carrier weight.
18. The formulation according to claim 8 , comprising botulinum toxin A, polylysine having covalently attached thereto one or more 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.
19. The formulation according to claim 1 or claim 17 , wherein the dermatologically or pharmaceutically acceptable excipient, vehicle 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.
20. The formulation according to claim 9 , wherein at least one of the efficiency groups has the 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.
21. The formulation according to claim 10 , wherein at least one of the efficiency groups has the 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.
22. The formulation according to claim 11 , wherein at least one of the efficiency groups has the 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.
23. The formulation according to claim 20 , wherein the positively charged polymeric backbone is polylysine.
24. The formulation according to claim 21 , wherein the positively charged polymeric backbone is polylysine.
25. The formulation according to claim 22 , wherein the positively charged polymeric backbone is polylysine.
26. The formulation according to claim 23 , wherein the botulinum toxin is serotype A.
27. The formulation according to claim 24 , wherein the botulinum toxin is serotype A.
28. The formulation according to claim 25 , wherein the botulinum toxin is serotype A.
29. The formulation according to claim 14 , wherein the botulinum toxin has a molecular weight of 150,000.
30. The formulation according to claim 26 , wherein the botulinum toxin has a molecular weight of 150,000.
31. The formulation according to claim 27 , wherein the botulinum toxin has a molecular weight of 150,000.
32. The formulation according to claim 28 , wherein the botulinum toxin has a molecular weight of 150,000.
33. The formulation according to claim 23 , wherein the polylysine has a molecular weight of about 21,000.
34. The formulation according to claim 24 , wherein the polylysine has a molecular weight of about 21,000.
35. The formulation according to claim 25 , wherein the polylysine has a molecular weight of about 21,000.
36. The formulation according to claim 12 , 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 formulation according to claim 23 , 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 formulation 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.
39. The formulation 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.
40. A method of treating hyperhidrosis comprising:
topically applying to an area of skin of a patent in need thereof, a therapeutically effective amount of the formulation according to any one of claims 1 , 2 , 8 , 9 , 10 , 11 , 14 , 23 , 29 or 36 , and optionally applying an occlusion agent afterward.
41. The method according to claim 40 , wherein the area of skin is selected from the axillae, forehead, back, chest, palms, dorsal portion of the hand, instep, or plantar portion of the foot.