Formulations of Tie-2 activators and methods of use thereof

1. A pharmaceutical composition comprising, in a unit dosage form: a Tie-2 activator; and a micelle, wherein the micelle comprises a mucoadhesive component, wherein the Tie-2 activator is a compound of the formula:

wherein:

Aryl 1 is an aryl group which is substituted or unsubstituted; Aryl 2 is an aryl group which is substituted or unsubstituted; X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO 2 R g , or NHCOR g , any of which is substituted or unsubstituted, or

wherein:

L 2 is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L 2 is bound forms an amide linkage, a carbamate linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R a , R b , R c , and R d forms a ring that is substituted or unsubstituted;

R a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R b , R c , and R d forms a ring that is substituted or unsubstituted;

R b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R a , R c , and R d forms a ring that is substituted or unsubstituted;

R c is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R d forms a ring that is substituted or unsubstituted;

R d is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R c forms a ring that is substituted or unsubstituted; and

R g is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or a pharmaceutically-acceptable salt, tautomer, or zwitterion thereof.

2. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a solution.

3. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a drop.

4. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a gel.

5. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for topical administration.

6. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for administration to an eye.

7. The pharmaceutical composition of claim 1 , wherein the micelle is less than 200 nm in size.

8. The pharmaceutical composition of claim 1 , wherein the micelle further comprises a degradable hydrophobic polymer and a degradable synthetic hydrophilic polymer.

9. The pharmaceutical composition of claim 8 , wherein the micelle comprises the degradable hydrophobic polymer, the degradable hydrophilic polymer, and the mucoadhesive component at a ratio from about 0.5:94.5:5 to about 5:65:30, respectively.

10. The pharmaceutical composition of claim 8 , wherein the degradable hydrophobic polymer is a polylactide, polyglycolide, poly(lactide-co-glycolide), poly(ε-caprolactone), poly-3-hydroxybutyrate, poly(dioxanone), poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(valerolactone), poly(tartaric acid), poly(malonic acid), poly(anhydrides), poly(orthoesters), polyphosphazenes and acryloyloxy dimethyl-γ-butyrolactone (DBA), or a combination thereof.

11. The pharmaceutical composition of claim 8 , wherein the degradable synthetic hydrophilic polymer is selected from the group consisting of methacrylic acid, acrylic acid, hydroxyethyl methacrylate, hydroxypropylmethacrylamide, hydroxyethyl acrylate, poly(ethylene glycol) methacrylate, poly(N-isopropylacrylamide) (PNIPAM), poly(vinyl alcohol) (PVA), poly(2-oxazoline), polyethylene glycol, polyvinylpyrollidone, and copolymers thereof.

12. The pharmaceutical composition of claim 1 , wherein the mucoadhesive component is selected from the group consisting of a boronic acid or derivative thereof, a thiol-containing compound, an acrylate, chitosan, cellulose, thiolated chitosan, thiolated hyaluronic acid, thiolated poly(acrylic) acid, and mixtures thereof.

13. The pharmaceutical composition of claim 1 , wherein the mucoadhesive component is a boronic acid.

14. The pharmaceutical composition of claim 1 , wherein the mucoadhesive component is a boronic ester.

15. The pharmaceutical composition of claim 1 , wherein the mucoadhesive component is a phenylboronic acid moiety.

16. The pharmaceutical composition of claim 1 , wherein the micelle is a biocompatible mucoadhesive block copolymer micelle.

17. The pharmaceutical composition of claim 1 , wherein the micelle is a poly(L-lactide)-b-poly(methacrylic acid-co-phenylboronic acid) copolymer micelle.

18. The pharmaceutical composition of claim 1 , wherein the micelle comprises the Tie-2 activator at about 5-50% the weight of the micelle.

19. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises a shear-responsive ophthalmic hydrogel.

20. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises a thermoresponsive polymer scaffold.

21. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises an in situ gelling agent.

22. The pharmaceutical composition of claim 1 , wherein the micelle comprises a portion that is poly(oligoethylene glycol methacrylate).

23. The pharmaceutical composition of claim 1 , wherein the micelle comprises a portion that is polylactide.

24. The pharmaceutical composition of claim 1 , wherein the micelle comprises a portion that is polymethacrylic acid.

25. The pharmaceutical composition of claim 1 , wherein the micelle comprises: a portion that is polylactide; a portion that is polymethacrylic acid; and a monomer that comprises a phenylboronic acid unit, wherein the pharmaceutical composition comprises a population of molecules of the polymer, wherein the molecules in the population of the polymer have an average molecular weight of about 10 kDa.

26. The pharmaceutical composition of claim 1 , wherein the Tie-2 activator is an inhibitor of HPTPβ.