Compositions and methods for topical diagnostic and therapeutic transport
View Patent ↗Compositions and methods are provided that are useful for the delivery, including transdermal delivery, of biologically active agents, such as non-protein non-nucleotide therapeutics and protein-based therapeutics excluding insulin, botulinum toxins, antibody fragments, and VEGF. The compositions and methods are particularly useful for topical delivery of antifungal agents and antigenic agents suitable for immunization. Alternately, the compositions can be prepared with components useful for targeting the delivery of the compositions as well as imaging components.
1. A composition comprising
a biologically active protein which is not insulin and
a positively charged carrier comprising a positively charged polymeric backbone having attached thereto amino acid sequences selected from the group consisting of -(gly) n1 -(arg) n2 , (gly) p -RGRDDRRQRRR-(gly) q (SEQ ID NO. 2), (gly) p -YGRKKRRQRRR-(gly) q (SEQ ID NO. 3), (gly) p -RKKRRQRRR-(gly) q (SEQ ID NO. 4), and Antennapedia protein transduction domain (PTD),
wherein the subscript n1 is an integer of from 0 to about 20, and the subscript n2 is independently an odd integer of from about 5 to about 25,
wherein the subscripts p and q are each independently an integer of from 0 to 20;
wherein the positively charged polymeric backbone is a polypeptide that promotes transdermal delivery of the biologically active protein;
wherein said positively charged carrier is present in an effective amount for transdermal delivery of said biologically active protein,
wherein the biologically active protein is not modified by covalent attachment to a negatively charged backbone; and
wherein the positively charged carrier and the biologically active protein directly contact to form a non-covalent complex.
2. The composition according to claim 1 in which the biologically active protein does not comprise botulinum toxins, vascular endothelial growth factor (VEGF), or antibody fragments.
3. The composition according to claim 2 in which the biologically active protein does not therapeutically alter blood glucose levels.
4. The composition according to claim 2 in which the biologically active protein excludes botulinum toxins.
5. The composition according to claim 2 in which the biologically active protein excludes VEGF.
6. The composition according to claim 2 in which the biologically active protein excludes antibody fragments.
7. The composition 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 positively charged carrier.
8. The composition according to claim 7 in which the biologically active protein has therapeutic activity.
9. The composition according to claim 8 in which the biologically active protein has a molecular weight of less than 20,000 kD.
10. The composition according to claim 1 in which the positively charged polymeric backbone comprises a positively charged polypeptide having a molecular weight of from about 10,000 to about 1,500,000.
11. The composition according to claim 10 in which the positively charged polymeric backbone comprises a positively charged polypeptide having a molecular weight of from about 25,000 to about 1,200,000.
12. The composition according to claim 11 in which the positively charged polymeric backbone comprises a positively charged polypeptide having a molecular weight of from about 100,000 to about 1,000,000.
13. The composition according to claim 1 in which the positively charged polymeric backbone comprises a positively charged polylysine.
14. The composition according to claim 13 in which the positively charged polymeric backbone comprises a positively charged polylysine having a molecular weight of from about 10,000 to about 1,500,000.
15. The composition according to claim 13 in which the positively charged polymeric backbone comprises a positively charged polylysine having a molecular weight of from about 25,000 to about 1,200,000.
16. The composition according to claim 13 in which the positively charged polymeric backbone comprises a positively charged polylysine having a molecular weight of from about 100,000 to about 1,000,000.
17. The composition according to claim 1 in which the amino acid sequences have the formula -(gly) n1 -(arg) n2 .
18. The composition according to claim 17 in which the subscript n1 is an integer of from about 1 to about 8.
19. The composition according to claim 17 in which the subscript n1 is an integer of from about 2 to about 5.
20. The composition according to claim 17 in which the subscript n2 is an odd number of from about 7 to about 17.
21. The composition according to claim 17 in which the subscript n2 is an odd number of from about 7 to about 13.
22. The composition according to claim 1 in which the amino acid sequences are HIV-TAT fragments that have the formula (gly) p -RGRDDRRQRRR-(gly) q (SEQ ID NO. 2), (gly) p -YGRKKRRQRRR-(gly) q (SEQ ID NO. 3), or (gly) p -RKKRRQRRR-(gly) q (SEQ ID NO. 4), wherein the subscripts p and q are independently an integer of from 0 to 20.
23. The composition according to claim 1 in which the amino acid sequences are Antennapedia PTD fragments.
24. A kit for administration of a composition to a subject wherein said kit comprises
a composition comprising a biologically active protein which is not insulin and a positively charged carrier, the positively charged carrier comprising a positively charged polymeric backbone having attached thereto amino acid sequences selected from the group consisting of -(gly) n1 -(arg) n2 , (gly) p -RGRDDRRQRRR-(gly) q (SEQ ID NO. 2), (gly) p -YGRKKRRQRRR-(gly) q (SEQ ID NO. 3), (gly) p -RKKRRQRRR-(gly) q (SEQ ID NO. 4), and Antennapedia protein transduction domain (PTD),
wherein the subscript n1 is an integer of from 0 to about 20, and the subscript n2 is independently an odd integer of from about 5 to about 25,
wherein the subscripts p and q are each independently an integer of from 0 to 20;
wherein the positively charged polymeric backbone is a polypeptide that promotes transdermal delivery of the biologically active protein;
wherein said positively charged carrier is present in an effective amount for transdermal delivery of said biologically active protein,
wherein the biologically active protein is not modified by covalent attachment to a negatively charged backbone; and
wherein the positively charged carrier and the biologically active protein directly contact to form a non-covalent complex, and
a device for delivering said composition.
25. The kit according to claim 24 wherein the biologically active protein does not comprise botulinum toxins, VEGF, or antibody fragments.
26. The kit according to claim 25 in which the composition is contained in a device for administering the biologically active protein to a subject via the skin or epithelium.
27. The kit according to claim 26 in which the device is a skin patch.
28. A kit for administration of a biologically active protein to a subject, wherein said kit comprises
a biologically active protein which is not insulin,
a positively charged polymeric carrier, and
a device for delivering the biologically active protein and the positively charged polymeric carrier to skin or epithelium,
wherein the biologically active protein is not modified by covalent attachment to a negatively charged backbone; and
wherein the positively charged polymeric carrier and the biologically active protein directly contact to form a non-covalent complex,
wherein said positively charged polymeric carrier comprises a polypeptide that promotes transdermal delivery of the biologically active protein;
wherein said positively charged polymeric carrier has amino acid sequences attached thereto, said amino acid sequences selected from the group consisting of -(gly) n1 -(arg) n2 , (gly) p -RGRDDRRQRRR-(gly) q (SEQ ID NO. 2), (gly) p -YGRKKRRQRRR-(gly) q (SEQ ID NO. 3), (gly) p -RKKRRQRRR-(gly) q (SEQ ID NO. 4), and Antennapedia protein transduction domain (PTD);
wherein the subscripts p and q are each independently an integer of from 0 to 20, and
wherein the subscript n1 is an integer of from 0 to about 20, and the subscript n2 is independently an odd integer of from about 5 to about 25.
29. The kit according to claim 28 in which the device is a skin patch.
30. A composition comprising
an antigen suitable for immunization which is not insulin and
a positively charged carrier comprising a positively charged polymeric backbone having amino acid sequences attached thereto,
wherein the positively charged polymeric backbone is a polypeptide that promotes transdermal delivery of the antigen suitable for immunization;
wherein the amino acid sequences are selected from the group consisting of -(gly) n1 -(arg) n2 , (gly) p -RGRDDRRQRRR-(gly) q (SEQ ID NO. 2), (gly) p -YGRKKRRQRRR-(gly) q (SEQ ID NO. 3), (gly) p -RKKRRQRRR-(gly) q (SEQ ID NO. 4), and Antennapedia protein transduction domain (PTD);
wherein the subscript n1 is an integer of from 0 to about 20, and the subscript n2 is independently an odd integer of from about 5 to about 25,
wherein the subscripts p and q are each independently an integer of from 0 to 20,
wherein said positively charged carrier is present in an effective amount for transdermal delivery of said antigen suitable for immunization,
wherein the antigen suitable for immunization is not modified by covalent attachment to a negatively charged backbone; and
wherein the positively charged carrier and the antigen suitable for immunization directly contact to form a non-covalent complex.
31. The composition according to claim 30 in which the positively charged polymeric backbone comprises a positively charged polypeptide having a molecular weight of from about 10,000 to about 1,500,000.
32. The composition according to claim 30 in which the positively charged polymeric backbone comprises a positively charged polypeptide having a molecular weight of from about 25,000 to about 1,200,000.
33. The composition according to claim 30 in which the positively charged polymeric backbone comprises a positively charged polypeptide having a molecular weight of from about 100,000 to about 1,000,000.
34. The composition according to claim 30 in which the positively charged polymeric backbone comprises a positively charged polylysine.
35. The composition according to claim 34 in which the positively charged polymeric backbone comprises a positively charged polylysine having a molecular weight of from about 10,000 to about 1,500,000.
36. The composition according to claim 34 in which the positively charged polymeric backbone comprises a positively charged polylysine having a molecular weight of from about 25,000 to about 1,200,000.
37. The composition according to claim 34 in which the positively charged polymeric backbone comprises a positively charged polylysine having a molecular weight of from about 100,000 to about 1,000,000.
38. The composition according to claim 30 in which the amino acid sequences have the formula -(gly) n1 -(arg) n2 , wherein n1 is an integer from 0 to 20 and n2 is independently an odd integer from about 5 to about 25.
39. The composition according to claim 38 in which the subscript n1 is an integer of from about 1 to about 8.
40. The composition according to claim 38 in which the subscript n1 is an integer of from about 2 to about 5.
41. The composition according to claim 38 in which the subscript n2 is an odd number of from about 7 to about 17.
42. The composition according to claim 38 in which the subscript n2 is an odd number of from about 7 to about 13.
43. The composition according to claim 30 in which the amino acid sequences are HIV-TAT fragments that have the formula (gly) p -RGRDDRRQRRR-(gly) q (SEQ ID NO. 2), (gly) p -YGRKKRRQRRR-(gly) q (SEQ ID NO. 3), or (gly) p -RKKRRQRRR-(gly) q (SEQ ID NO. 4), wherein the subscripts p and q are independently an integer of from 0 to 20.
44. The composition according to claim 30 in which the amino acid sequences are Antennapedia PTD fragments.
45. The composition according to claim 30 in which the polypeptide is selected from polylysines, polyarginines, polyornithines, and polyhomoarginines.
46. The composition according to claim 45 in which the polypeptide is a polylysine.
47. The composition according to claim 30 containing from about 1×10 −10 to about 49.9 weight % of the antigen suitable for immunization and from about 1×10 −9 to about 50 weight % of the positively charged carrier.
48. The composition according to claim 30 , wherein said composition is a controlled release composition.
49. The composition according to claim 30 in which the antigen suitable for immunization does not comprise botulinum toxins, VEGF, or antibody fragments.
50. The composition according to claim 30 in which the antigen suitable for immunization is suitable for childhood immunizations.
51. A kit for administration of an antigen suitable for immunization to a subject, wherein said kit comprises
an antigen suitable for immunization which is not insulin;
a positively charged carrier, and
a device for delivering the antigen suitable for immunization and the positively charged carrier to the skin or epithelium,
wherein the antigen suitable for immunization is not modified by covalent attachment to a negatively charged backbone; and
wherein the positively charged carrier and the antigen suitable for immunization directly contact to form a non-covalent complex,
wherein said positively charged carrier comprises a positively charged polymeric backbone having amino acid sequences attached thereto,
wherein the positively charged polymeric backbone is a polypeptide having a molecular weight from about 10,000 to about 1,500,000; and
wherein the amino acid sequences are selected from the group consisting of -(gly) n1 -(arg) n2 , (gly) p -RGRDDRRQRRR-(gly) q (SEQ ID NO. 2), (gly) p -YGRKKRRQRRR-(gly) q (SEQ ID NO. 3), (gly) p -RKKRRQRRR-(gly) q (SEQ ID NO. 4), and Antennapedia protein transduction domain (PTD);
wherein the subscripts p and q are each independently an integer of from 0 to 20, and
wherein the subscript n1 is an integer of from 0 to about 20, and the subscript n2 is independently an odd integer of from about 5 to about 25.
52. A kit for administration of an antigen suitable for immunization to a subject comprising a device for delivering the antigen suitable for immunization to the skin or epithelium and a composition according to claim 30 .
53. The kit according to claim 51 further comprising a custom applicator.
54. The kit according to claim 51 in which the antigen suitable for immunization is contained in a device for administering the antigen suitable for immunization to a subject via the skin or epithelium.
55. The kit according to claim 51 in which the device is applied topically.
56. The kit according to claim 51 in which the device is a skin patch.