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

• US 7,229,961 B2
• Filed: 02/25/2002
• Issued: 06/12/2007
• 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:
  US10/083,960
• Publication Number:
  US 20030022831A1
• Time in Patent Office: 1,933 Days
• Field of Search: None
• US Class Current: 514/1.2
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• 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 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• 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: A61K 9/0048 Eye, e.g. artificial tears
• 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 into and across ocular tissues 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:86).

Claims

1. A method for enhancing delivery of a compound into and across an animal ocular tissue, the method comprising:

administering to the ocular 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 ocular tissue 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 ocular tissue 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 ocular tissue 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 ocular tissue is one or more layers of epithelial or endothelial tissue.

5. The method of claim 1, wherein the ocular tissue is the retina.

6. The method of claim 1, wherein the ocular tissue is the optic nerve.

7. The method of claim 1, wherein the linker is a releasable linker.

8. The method of claim 7, wherein the linker is stable in a saline solution at pH 7 but is cleaved when transported into a cell.

9. The method of claim 1, wherein the subunits are amino acids.

10. The method of claim 1, wherein the conjugate has a structure selected from the group consisting of structures 3, 4, and 5, as follows:

11. The method of claim 10, 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.

12. The method of claim 10, wherein the conjugate comprises structure 3, Y is NH, and R² is methyl, ethyl, propyl, butyl, allyl, benzyl or phenyl.

13. The method of claim 10, wherein R is benzyl;

k, m, and n are each 1, and X is —

OC(O)—

.

14. The method of claim 10, wherein the conjugate comprises structure 4;

R⁴ is S;

R⁵ is NHR⁶; and

R⁶ is hydrogen, methyl, allyl, butyl or phenyl.

15. The method of claim 10, wherein the conjugate comprises structure 4;

R⁵ is NHR⁶;

R⁶ is hydrogen, methyl, allyl, butyl or phenyl; and

k and m are each 1.

16. The method of claim 1, wherein the conjugate comprises structure 6 as follows:

17. The method of claim 16, 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.

18. The method of claim 16, wherein R⁴ is S;

R⁵ is NHR⁶; and

R⁶ is hydrogen, methyl, allyl, butyl or phenyl.

19. The method of claim 1, wherein the conjugate comprises at least two delivery-enhancing transporters.

20. The method of claim 1, wherein the conjugate is administered as an eye drop.

21. The method of claim 1, wherein the conjugate is administered as an injection.

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

23. 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.

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

25. The method of claim 24, wherein the delivery-enhancing transporter comprises between 7 and 15 guanidino moieties.

26. The method of claim 24, wherein the delivery-enhancing transporter comprises at least 6 contiguous guanidino and/or amidino moieties.

27. 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.

28. The method of claim 27, wherein the delivery-enhancing transporter comprises 5 to 25 arginine residues or analogs thereof.

29. The method of claim 28, wherein at least one arginine is a D-arginine.

30. The method of claim 29, wherein all of the arginines are D-arginines.

31. The method of claim 27, wherein at least 70 percent of the amino acids that comprise the delivery-enhancing transporter are arginines or arginine analogs.

32. The method of claim 27, wherein the delivery-enhancing transporter is seven contiguous D-arginines.

33. The method of claim 1, wherein the compound is a therapeutic for a disease selected from the group consisting of bacterial infections, viral infections, fungal infections, glaucoma, anterior, intermediate, and posterior uveitis, optic neuritis, Leber'"'"'s neuroretinitis, retinitis, pseudotumor/myositis, orbital myositis, hemangioma/lymphangioma, toxocariasis, Behcet'"'"'s panuveitis, inflammatory choriosretinopathies, vasculitis, dry eye syndrome (Sjogren'"'"'s syndrome), corneal edema, accommodative esotropia, cycloplegia, mydriasis, reverse mydriasis, and macular degeneracy.

34. The method of claim 1, wherein the compound is selected from the group consisting of anti-bacterial compounds, anti-viral compounds, anti-fungal compounds, anti-protozoan compounds, anti-histamines, compounds that dilate the pupil, anesthetic compounds, steroidal antiinflammatory agents, antiinflammatory analgesics, chemotherapeutic agents, hormones, anticataract agents, neovascularization inhibitors, immunosuppressants, protease inhibitors, aldose reductase inhibitors, corticoid steroids, immunosuppressives, cholinergic agents, anticholinesterase agents, ,muscarinic antagonists, sympathomimetic agents, α

and β

adrenergic antagonists, and anti-angiogenic factors.

35. The method of claim 34, wherein the compound is selected from the group consisting of acyclovir and cyclosporins.

36. The method of claim 1, wherein the compound is transported across the blood-brain barrier.