Injectable drug delivery formulation

1. An injectable formulation comprising:

an active agent;

a non-aqueous, aprotic, biocompatible solvent system, wherein the solvent system comprises one or more solvents, and at least one of the solvents is non-miscible with water;

a plurality of polymers that each include a plurality of free hydroxyl groups; and

a plurality of crosslinking agents, wherein the crosslinking agent comprises X—(C 1 -C 16 )alkyl-X or X—(CH 2 CH 2 —O) n —CH 2 CH 2 —X where n is 0 to about 20, and each X is independently a chlorosilane group, a trialkoxysilane group, or —NCO, the crosslinking agents in solution with but not bonded to the plurality of polymers;

wherein the solvent system is chemically inert with respect to the crosslinking agents, and the formulation is substantially free of water.

2. The formulation of claim 1 , wherein the polymer having hydroxyl groups comprises one or more of: polysaccharides, PEG-PLA block copolymers having two or more free hydroxyl groups, polyglycerol, esterified polyglycerol having two or more free hydroxyl groups, polyvinylacetate (PVA) having two or more free hydroxyl groups, a star-shaped PLA, or a comb-shaped PLA.

3. The formulation of claim 1 , wherein the polymer having hydroxyl groups comprises a polysaccharide that have a degree of substitution by optionally substituted (C 2 -C 12 )alkanoate groups of about 0.25 to about 2.

4. The formulation of claim 1 , wherein the active agent comprises about 0.1 wt. % to about 30 wt. % of the formulation, the solvent system comprises about 10 wt. % to about 90 wt. % of the formulation, the polymers having hydroxyl groups comprise about 5 wt. % to about 50 wt. % of the formulation, and the crosslinking agents comprise about 1 wt. % to about 50 wt. % of the formulation.

5. The formulation of claim 1 , wherein the polymer having hydroxyl groups is soluble in the biocompatible solvent system and the active agent is substantially insoluble in the non-aqueous biocompatible solvent system.

6. The formulation of claim 1 , wherein the molar ratio of reactive groups on the crosslinking agents to free hydroxyl groups of the polymers having hydroxyl groups is about 0.1 to about 5.

7. The formulation of claim 1 , wherein the active agent comprises a peptide, a protein, a gene, a polynucleotide or an analog or complex thereof, a nucleotide, a nucleoside, or a small molecule drug.

8. The formulation of claim 1 , wherein the polymer has a viscosity of at least about 100 cP in the biocompatible solvent system at 37° C.

9. The formulation of claim 1 , wherein X comprises a chlorosilane group wherein the chlorosilane group is —Si(Me) 2 Cl or —Si(Et) 2 Cl; X comprises a trialkoxysilane group wherein the trialkoxysilane group is —Si(OMe) 3 or —Si(OEt) 3 ; or a combination thereof.

10. A method of delivering an active agent to a subject comprising:

injecting a formulation comprising:

an active agent;

a non-aqueous, aprotic, biocompatible solvent system, wherein the solvent system comprises one or more solvents and at least one of the solvents is non-miscible with water;

a plurality of polymers that each include a plurality of free hydroxyl groups; and

a plurality of crosslinking agents, wherein the crosslinking agent comprises X—(C 1 -C 16 )alkyl-X or X—(CH 2 CH 2 —O) n —CH 2 CH 2 —X where n is 0 to about 20, and each X is independently a chlorosilane group, a tri(C 1 -C 3 )alkoxysilane group, or —NCO, the crosslinking agents in solution with but not bonded to the plurality of polymers;

wherein the solvent system is chemically inert with respect to the crosslinking agents and the formulation is substantially free of water; and

the formulation forms a gel matrix within the subject and the gel matrix becomes crosslinked when the polysaccharides and crosslinking agents are contacted by fluids in the body of the subject; and

the matrix releases the active agent, over a period of weeks, to the body of the subject; thereby delivering the active agent to the subject.

11. The method of claim 10 , wherein the injecting comprises injecting the formulation into tissue of the subject.

12. The method of claim 10 , wherein the injecting comprises injecting ex vivo, allowing the resulting matrix to crosslink by contact with ambient humidity to form an implant, followed by inserting the resulting implant into the patient.

13. The method of claim 10 , wherein the active agent comprises about 0.1 wt. % to about 30 wt. % of the formulation, the solvent system comprises about 10 wt. % to about 90 wt. % of the formulation, the polymer comprise about 5 wt. % to about 50 wt. % of the formulation, and the crosslinking agents comprise about 1 wt. % to about 50 wt. % of the formulation.

14. The method of claim 10 , wherein the formulation is injected into the vitrius humor of the eye of the subject, the formulation is injected to a site under the skin of the subject, or the formulation is injected intramuscularly to the subject.

15. The method of claim 10 , wherein the active agent comprises a peptide, a protein, a gene, a polynucleotide or an analog or complex thereof, a nucleotide, a nucleoside, or a small molecule drug.

16. The method of claim 10 , wherein the method comprises the active agent in an effective amount to treat keratoconjunctivitis sicca (KCS) or dry eye syndrome, aphakia; pseudophakia; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcer; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupil disorders; refractive disorders and strabismus, acute macular neuroretinopathy; Behcet's disease; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections, such as fungal or viral-caused infections; macular degeneration, such as acute macular degeneration, non-exudative age related macular degeneration and exudative age related macular degeneration; edema, such as macular edema, cystoid macular edema and diabetic macular edema (DME); multifocal choroiditis; ocular trauma which affects a posterior ocular site or location; ocular tumors; retinal disorders, such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal arterial occlusive disease, retinal detachment, uveitic retinal disease; sympathetic opthalmia; Vogt Koyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocular condition caused by or influenced by an ocular laser treatment; posterior ocular conditions caused by or influenced by a photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa, or glaucoma.

17. The method of claim 10 , wherein less than about 15 wt. % of the initial mass of the active agent is delivered to the subject from the matrix within the first 10 post-injection days.

18. The method of claim 10 , wherein the active agent is delivered to the subject from the matrix at a rate of not more than about 10 wt. % of the initial mass of the active agent per week, after the first week post-injection.

19. The method of claim 10 , wherein the method delivers an effective amount of the active agent in a sustained release profile in an amount effective to treat a disease or condition recited in claim 16 .