Claims
- 1. A method of targeting a compound to a gastrointestinal epithelium of an animal, the method comprising administering to the gastrointestinal epithelium a conjugate comprising the compound and a delivery-enhancing transporter,
wherein:
i. the compound is attached to the delivery-enhancing transporter through a linker; and ii. the delivery-enhancing transporter comprises fewer than 50 subunits and comprises at least 5 guanidino or amidino moieties, thereby increasing delivery of the conjugate into the gastrointestinal epithelium compared to delivery of the compound in the absence of the delivery-enhancing transporter.
- 2. The method of claim 1, wherein delivery of the conjugate into the gastrointestinal epithelium is increased at least two-fold compared to delivery of the compound in the absence of the delivery-enhancing transporter.
- 3. The method of claim 1, wherein delivery of the conjugate into the gastrointestinal epithelium is increased at least ten-fold compared to delivery of the compound in the absence of the delivery-enhancing transporter.
- 4. The method of claim 1, wherein the linker is a releasable linker.
- 5. The method of claim 1, wherein the subunits are amino acids.
- 6. The method of claim 1, wherein the conjugate has a structure selected from the group consisting of structures 3, 4, or 5, as follows:
- 7. The method of claim 6, wherein X is selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO2NH—, —SONH—, phosphate, phosphonate phosphinate, and CR7R8, wherein R7 and R8 are each independently selected from the group consisting of H and alkyl.
- 8. The method of claim 6, wherein the conjugate comprises structure 3, Y is N, and R2 is methyl, ethyl, propyl, butyl, allyl, benzyl or phenyl.
- 9. The method of claim 6, wherein R2 is benzyl; k, m, and n are each 1, and X is —OC(O)—.
- 10. The method of claim 6, wherein the conjugate comprises structure 4; R4 is S; R5 is NHR6; and R6 is hydrogen, methyl, allyl, butyl or phenyl.
- 11. The method of claim 6 wherein the conjugate comprises structure 4; R5 is NHR6; R6 is hydrogen, methyl, allyl, butyl or phenyl; and k and m are each 1.
- 12. The method of claim 1, wherein the conjugate comprises structure 6 as follows:
- 13. The method of claim 12, wherein X is selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO2NH—, —SONH—, phosphate, phosphonate phosphinate, and CR7R8, wherein R7 and R8 are each independently selected from the group consisting of H and alkyl.
- 14. The method of claim 12, wherein R4 is S; R5 is NHR6; and R6 is hydrogen, methyl, allyl, butyl or phenyl.
- 15. The method of claim 1, wherein the conjugate comprises at least two delivery-enhancing transporters.
- 16. The method of claim 1, wherein the conjugate is administered buccally.
- 17. The method of claim 1, wherein the conjugate is administered as a suppository.
- 18. The method of claim 1, wherein the delivery-enhancing transporter comprises a non-peptide backbone.
- 19. The method of claim 1, wherein the delivery-enhancing transporter is not attached to an amino acid sequence to which the delivery enhancing transporter molecule is attached in a naturally occurring protein.
- 20. The method of claim 1, wherein the delivery-enhancing transporter comprises from 5 to 25 guanidino or amidino moieties.
- 21. The method of claim 20, wherein the delivery-enhancing transporter comprises between 7 and 15 guanidino moieties.
- 22. The method of claim 20, wherein the delivery-enhancing transporter comprises at least 6 contiguous guanidino and/or amidino moieties.
- 23. The method of claim 1, wherein the delivery-enhancing transporter consists essentially of 5 to 50 amino acids, at least 50 percent of which amino acids are arginines or analogs thereof.
- 24. The method of claim 23, wherein the delivery-enhancing transporter comprises 5 to 25 arginine residues or analogs thereof.
- 25. The method of claim 24, wherein at least one arginine is a D-arginine.
- 26. The method of claim 25, wherein all of the arginines are D-arginines.
- 27. The method of claim 23, wherein at least 70 percent of the amino acids that comprise the delivery-enhancing transporter are arginines or arginine analogs.
- 28. The method of claim 23, wherein the delivery-enhancing transporter is seven contiguous D-arginines.
- 29. The method of claim 1, wherein the compound is a therapeutic for the disease selected from the group consisting of inflammatory bowel disease, colon cancer, ulcerative colitis, gastrointestinal ulcers, constipation and imbalance of salt and water absorption.
- 30. The method of claim 1, wherein the compound is selected from the group consisting of immunosuppressives, ascomycins, corticosteroids, laxatives, antibiotics and anti-neoplastic agents.
- 31. The method of claim 1, wherein the compound is targeted to the iliem and/or colon.
- 32. A method for enhancing delivery of a compound into and across one or more layers of an animal ocular epithelial tissue, the method comprising:
administering to the ocular epithelial tissue a conjugate comprising the compound and a delivery-enhancing transporter, wherein:
i. the compound is attached to the delivery-enhancing transporter through a linker, and ii. the delivery-enhancing transporter comprises fewer than 50 subunits and comprises at least 5 guanidino or amidino moieties, thereby increasing delivery of the conjugate into the gastrointestinal epithelium compared to delivery of the compound in the absence of the delivery-enhancing transporter.
- 33. The method of claim 32, wherein delivery of the conjugate into the gastrointestinal epithelium is increased at least two-fold compared to delivery of the compound in the absence of the delivery-enhancing transporter.
- 34. The method of claim 32, wherein delivery of the conjugate into the gastrointestinal epithelium is increased at least ten-fold compared to delivery of the compound in the absence of the delivery-enhancing transporter.
- 35. The method of claim 32, wherein the linker is a releasable linker.
- 36. The method of claim 32, wherein the subunits are amino acids.
- 37. The method of claim 32, wherein the conjugate has a structure selected from the group consisting of structures 3, 4, or 5, as follows:
- 38. The method of claim 37, wherein X is selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO2NH—, —SONH—, phosphate, phosphonate phosphinate, and CR7R8, wherein R7 and R8 are each independently selected from the group consisting of H and alkyl.
- 39. The method of claim 37, wherein the conjugate comprises structure 3, Y is N, and R2 is methyl, ethyl, propyl, butyl, allyl, benzyl or phenyl.
- 40. The method of claim 37, wherein R2 is benzyl; k, m, and n are each 1, and X is —OC(O)—.
- 41. The method of claim 37, wherein the conjugate comprises structure 4; R4 is S; R5 is NHR6; and R6 is hydrogen, methyl, allyl, butyl or phenyl.
- 42. The method of claim 37, wherein the conjugate comprises structure 4; R5 is NHR6; R6 is hydrogen, methyl, allyl, butyl or phenyl; and k and m are each 1.
- 43. The method of claim 32, wherein the conjugate comprises structure 6 as follows:
- 44. The method of claim 43, wherein X is selected from the group consisting of —C(O)O—, —C(O)NH—, —OC(O)NH—, —S—S—, —C(S)O—, —C(S)NH—, —NHC(O)NH—, —SO2NH—, —SONH—, phosphate, phosphonate phosphinate, and CR7R8, wherein R7 and R8 are each independently selected from the group consisting of H and alkyl.
- 45. The method of claim 43, wherein R4 is S; R5 is NHR6; and R6 is hydrogen, methyl, allyl, butyl or phenyl.
- 46. The method of claim 32, wherein the conjugate comprises at least two delivery-enhancing transporters.
- 47. The method of claim 32, wherein the conjugate is administered as an eye drop.
- 48. The method of claim 32, wherein the conjugate is administered as an injection
- 49. The method of claim 32, wherein the delivery-enhancing transporter comprises a non-peptide backbone.
- 50. The method of claim 32, wherein the delivery-enhancing transporter is not attached to an amino acid sequence to which the delivery enhancing transporter molecule is attached in a naturally occurring protein.
- 51. The method of claim 32, wherein the delivery-enhancing transporter comprises from 5 to 25 guanidino or amidino moieties.
- 52. The method of claim 51, wherein the delivery-enhancing transporter comprises between 7 and 15 guanidino moieties.
- 53. The method of claim 51, wherein the delivery-enhancing transporter comprises at least 6 contiguous guanidino and/or amidino moieties.
- 54. The method of claim 32, wherein the delivery-enhancing transporter consists essentially of 5 to 50 amino acids, at least 50 percent of which amino acids are arginines or analogs thereof.
- 55. The method of claim 54, wherein the delivery-enhancing transporter comprises 5 to 25 arginine residues or analogs thereof.
- 56. The method of claim 55, wherein at least one arginine is a D-arginine.
- 57. The method of claim 56, wherein all of the arginines are D-arginines.
- 58. The method of claim 54, wherein at least 70 percent of the amino acids that comprise the delivery-enhancing transporter are arginines or arginine analogs.
- 59. The method of claim 54, wherein the delivery-enhancing transporter is seven contiguous D-arginines.
- 60. The method of claim 32, wherein the compound is a therapeutic for the disease selected from the group consisting of conjunctivitis, bacterial infections, viral infections, dry eye, and glaucoma.
- 61. The method of claim 32, wherein the compound is selected from the group consisting of antibacterial compounds, antiviral compounds, cyclosporin, ascomycins, and corticosteroids.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of U.S. patent application Ser. No. 09/648,400, which claims priority to U.S. Provisional Patent Application No. 60/150,510, filed Aug. 24, 1999. Both of these applications are incorporated herein by reference for all purposes
Provisional Applications (1)
|
Number |
Date |
Country |
|
60150510 |
Aug 1999 |
US |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
09648400 |
Aug 2000 |
US |
Child |
09792480 |
Feb 2001 |
US |