Compositions and methods for enhancing drug delivery across and into epithelial tissues

• US 6,759,387 B2
• Filed: 07/30/2002
• Issued: 07/06/2004
• Est. Priority Date: 08/24/1999
• Status: Expired due to Fees

• Current Assignee: Kai Pharmaceuticals, Inc. (Amgen Inc.)
• Original Assignee: Cellgate, Inc. (Tbg Diagnostics Limited)
• Inventors: Wender, Paul A., McGrane, P. Leo, Rothbard, Jonathan B., Kirschberg, Thorsten A., Sista, Lalitha V. S.
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US10/209,421
• Publication Number:
  US 20030083256A1
• Time in Patent Office: 707 Days
• Field of Search: 424/1.69, 424/9.322, 424/9.323, 424/9.34, 424/9.341, 424/9.1, 424/9.411, 424/433, 424/434, 424/435, 424/436, 424/437, 424/428, 424/449, 514/2, 514/3, 514/11, 514/12, 514/13, 514/14, 514/15, 514/16, 514/17, 514/634, 514/635, 514/636, 514/159, 514/169, 514/291, 514/456, 514/252.13, 514/252.14, 514/252.19, 514/254.07, 514/166, 514/263, 514/383, 514/423, 514/457, 514/458, 514/25, 514/152, 514/198, 514/199, 514/200, 514/262, 514/269, 514/399, 520/300, 520/302, 520/303, 520/315, 520/317, 520/321, 520/324, 520/325, 520/326, 520/327, 520/328, 520/329, 520/330, 544/366, 564/225, 564/230, 564/236, 564/243, 540/461, 548/266.5, 548/342.5
• US Class Current: 514/1.2
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/557 the modifying agent being biotin
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 47/665 the pre-targeting system, clearing therapy or rescue therapy involving biotin-(strept) avidin systems
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/146 the peptide being a polyamino acid, e.g. poly-lysine
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids
• CPC Class Codes: C07K 7/64 : Cyclic peptides containing only normal peptide links

Abstract

This invention provides compositions and methods for enhancing delivery of drugs and other agents across epithelial tissues, including the skin, gastrointestinal tract, pulmonary epithelium, and the like. The compositions and methods are also useful for delivery across endothelial tissues, including the blood brain barrier. The compositions and methods employ a delivery enhancing transporter that has sufficient guanidino or amidino sidechain moieties to enhance delivery of a compound conjugated to the reagent across one or more layers of the tissue, compared to the non-conjugated compound. The delivery-enhancing polymers include, for example, poly-arginine molecules that are preferably between about 6 and 25 residues in length (SEQ ID NO:50).

Claims

1. A method of treating a skin disorder by enhancing delivery of an immunosuppressive conjugate into and across one or more layers of the skin of an animal, the method comprising,

contacting the skin of the animal with an immunosuppressive conjugate formed from an ascomycin and a delivery-enhancing transporter,

wherein the delivery-enhancing transporter comprises sufficient guanidino or amidino moieties to increase delivery of the conjugate into and across skin compared to delivery of the ascomycin in the absence of the delivery-enhancing transporter.

2. The method of claim 1, wherein the skin disorder is selected from the group consisting of psoriasis, eczema, atopic dermatitis, contact dermatitis, allergic dermatitis, and alopecia areata.

3. The method of claim 1, wherein the ascomycin is selected from the group consisting of FK506 and rapamycin.

4. The method of claim 1, wherein the delivery-enhancing transporter comprises a non-peptide backbone.

5. The method of claim 1, wherein the delivery-enhancing transporter comprises from 5 to 25 guanidino or amidino moieties.

6. The method of claim 5, wherein the delivery-enhancing transporter comprises between 7 and 15 guanidino moieties.

7. The method of claim 1, wherein the delivery-enhancing transporter comprises at least 6 contiguous guanidino and/or amidino moieties.

8. 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.

9. The method of claim 1, wherein the delivery-enhancing transporter comprises 5 to 25 arginine residues or analogs thereof.

10. The method of claim 9, wherein the delivery-enhancing transporter comprises 8 arginine residues.

11. The method of claim 9, wherein at least one arginine is a D-arginine.

12. The method of claim 11, wherein all of the arginines are D-arginines.

13. The method of claim 8, wherein at least 70 percent of the amino acids that comprise the delivery-enhancing transporter are arginines or arginine analogs.

14. The method of claim 8, wherein the delivery-enhancing transporter comprises at least 5 contiguous arginines or arginine analogs.

15. The method of claim 1, wherein delivery of the compound into and across the skin is at least two-fold greater than that of the compound conjugated to a basic HIV tat peptide consisting of residues 49-57.

16. The method of claim 1, wherein the ascomycin is attached to the delivery enhancing transporter by a linker.

17. A method of treating a fungal infection of the skin by enhancing delivery of an anti-fungal conjugate into and across one or more layers of the skin of an animal, the method comprising,

contacting the skin of the animal with the conjugate;

wherein the conjugate comprises an anti-fungal agent and a delivery-enhancing transporter, and

wherein the delivery-enhancing transporter comprises sufficient guanidino or amidino moieties to increase delivery of the conjugate into and across skin compared to delivery of the anti-fungal agent in the absence of the delivery-enhancing transporter.

18. The method of claim 17, wherein the fungal infection is selected from the group consisting of tinea corporis, tinea pedis, onychomycosis, candidiasis, and tinea versicolor.

19. The method of claim 17, wherein the delivery-enhancing transporter comprises a non-peptide backbone.

20. The method of claim 17, 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 17, wherein the delivery-enhancing transporter comprises at least 6 contiguous guanidino and/or amidino moieties.

23. The method of claim 17, 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 17, wherein the delivery-enhancing transporter comprises 5 to 25 arginine residues or analogs thereof.

25. The method of claim 24, wherein the delivery-enhancing transporter comprises 8 arginine residues.

26. The method of claim 24, wherein at least one arginine is a D-arginine.

27. The method of claim 26, wherein all of the arginines are D-arginines.

28. 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.

29. The method of claim 17, wherein the delivery-enhancing transporter comprises at least 5 contiguous arginines or arginine analogs.

30. The method of claim 17, wherein delivery of the compound into and across the skin is at least two-fold greater than that of the compound conjugated to a basic HIV tat peptide consisting of residues 49-57.

31. The method of claim 17, wherein the antifungal agent is attached to the delivery enhancing transporter by a linker.