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 hyperhidrosis 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 hyperhidrosis in said patient.
2. The method according to claim 1 , wherein the hyperhidrosis is selected from one or more of axillary hyperhidrosis and forehead hyperhidrosis.
3. The method according to claim 1 , wherein the positively charged polymeric backbone is polylysine and 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.
4. The method according to claim 1 , 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.
5. The method according to claim 1 , 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.
6. The method according to claim 1 , 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.
7. The method according to claim 4 , wherein the botulinum toxin is of serotype A.
8. The method according to claim 5 , wherein the botulinum toxin is of serotype A.
9. The method according to claim 6 , wherein the botulinum toxin is of serotype A.
10. The method according to claim 7 , wherein the botulinum toxin has a molecular weight of 150,000.
11. The method according to claim 8 , wherein the botulinum toxin has a molecular weight of 150,000.
12. The method according to claim 9 , wherein the botulinum toxin has a molecular weight of 150,000.
13. The method according to claim 7 , wherein the amino acid sequence is attached to the polylysine via either the C-terminus or the N-terminus of the amino acid sequence.
14. The method according to claim 8 , wherein the amino acid sequence is attached to the polylysine via either the C-terminus or the N-terminus of the amino acid sequence.
15. The method according to claim 9 , wherein the amino acid sequence is attached to the polylysine via either the C-terminus or the N-terminus of the amino acid sequence.
16. The method according to claim 3 , wherein the composition comprises botulinum toxin of serotype, and 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.
17. The method according to claim 16 , wherein the positively charged efficiency groups comprise from about 0.1% to about 30% by weight of the total carrier weight in the composition.
18. The method according to claim 16 , wherein the polylysine has a molecular weight of about 21,000.
19. The method according to claim 16 , wherein the botulinum toxin of serotype A has a molecular weight of 150,000.
20. 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.