Multi-component biological transport systems
View Patent ↗Compositions and methods are provided that are useful for the delivery, including transdermal delivery, of biologically active agents, including nucleic acids and therapeutic proteins including insulin, larger therapeutic proteins such as botulinum toxin and other biologically active agents such as a therapeutic protein which does not therapeutically alter blood glucose levels, a therapeutic nucleic acid-based agent, a non-protein non-nucleic acid therapeutic agent such as an antifungal agent or alternately an agent for immunization. The compositions can be prepared with components useful for targeting the delivery of the compositions as well as imaging components.
1. A method of transdermally administering a biologically active protein which is not insulin to a subject in need thereof, said method comprising:
topically applying to the skin or epithelium of the subject an effective amount of a composition comprising the biologically active protein and a transport system for transdermal delivery of the biologically active protein,
wherein said transport system consists of a positively charged carrier consisting of a positively charged backbone selected from the group consisting of a polyalkyleneimine, a positively charged polypeptide and a peptoid;
said positively charged backbone having covalently attached thereto at least one positively charged efficiency group which is an amino acid sequence consisting of (gly) p -RKKRRQRRR-(gly) q (SEQ ID NO: 5) or GGGRKKRRQRRR (SEQ ID NO: 7), wherein the subscripts p and q are independently an integer from 0 to 20 ; and wherein the biologically active protein forms a non-covalent complex directly with the positively charged carrier of the transport system.
2. The method according to claim 1 , wherein the composition provides greater transdermal delivery of the biologically active protein relative to the biologically active protein in the absence of the carrier.
3. The method according to claim 2 , wherein the biologically active protein has therapeutic activity.
4. The method according to claim 3 , wherein the composition is a controlled release composition or sustained release composition.
5. The method according to claim 3 , wherein the biologically active protein is a botulinum toxin.
6. The method according to claim 5 , wherein the botulinum toxin is selected from botulinum toxin serotypes A, B, C, D, E, F and G.
7. The method according to claim 5 , wherein the botulinum toxin comprises a botulinum toxin derivative.
8. The method according to claim 5 , wherein the botulinum toxin comprises a recombinant botulinum toxin.
9. The method according to claim 5 , wherein the botulinum toxin is administered to provide an aesthetic and/or cosmetic benefit to the subject.
10. The method according to claim 5 , wherein the botulinum toxin and the positively-charged carrier are administered topically to a site on the face of the subject.
11. The method according to claim 5 , wherein the botulinum toxin and the positively-charged carrier are administered topically to a site on the subject other than the face.
12. The method according to claim 5 , wherein the botulinum toxin is botulinum toxin serotype A.
13. The method according to claim 5 , wherein the botulinum toxin is botulinum toxin serotype B.
14. The method according to claim 5 , wherein the botulinum toxin is botulinum toxin serotype C.
15. The method according to claim 5 , wherein the botulinum toxin is botulinum toxin serotype D.
16. The method according to claim 5 , wherein the botulinum toxin is botulinum toxin serotype E.
17. The method according to claim 5 , wherein the botulinum toxin is botulinum toxin serotype F.
18. The method according to claim 5 , wherein the botulinum toxin is botulinum toxin serotype G.
19. The method according to claim 1 , wherein the subscripts p and q are independently an integer in the range of 1 to 8.
20. The method according to claim 1 , wherein the subscripts p and q are independently an integer in the range of 2 to 5.
21. The method according to claim 1 , wherein the positively charged backbone is a linear polypeptide.
22. The method according to claim 1 , wherein the positively charged backbone is a linear polypeptide of repeating units.
23. The method according to claim 1 , wherein the positively charged backbone has covalently attached thereto a plurality of positively charged efficiency groups.
24. The method according to claim 23 , wherein the positively charged backbone is linear, and wherein the positively charged efficiency groups are covalently attached as sidechain groups to the positively charged backbone.
25. The method according to claim 1 , wherein the positively charged backbone has a plurality of positively charged efficiency groups attached thereto via the C-terminus or N-terminus of the amino acid sequences of said positively charged efficiency groups; wherein said amino acid sequence of said positively charged efficiency group is is (gly) p -RKKRRQRRR-(gly) q (SEQ ID NO: 5), wherein p and q are independently an integer from 0 to 20.
26. The method according to claim 1 , wherein the positively charged backbone comprises polyethyleneimine or polypropyleneimine.
27. The method according to claim 25 , wherein p and q are each independently an integer from 2 to 5.
28. The method according to claim 1 , wherein the at least one positively charged efficiency group covalently attached to the positively charged backbone is the amino acid sequence GGGRKKRRQRRR (SEQ ID NO:7).
29. The method according to claim 1 , wherein the at least one positively charged efficiency group is covalently attached to the positively charged backbone via the terminal glycine residue of the amino acid sequence of said positively charged efficiency group to free amines of the positively charged backbone.
30. The method according to claim 2 , wherein the positively charged backbone is polyethyleneimine.