Conveniently implantable sustained release drug compositions

• US 20080038316A1
• Filed: 07/18/2007
• Published: 02/14/2008
• Est. Priority Date: 10/01/2004
• Status: Abandoned Application

• Current Assignee: Ramscor, Inc.
• Original Assignee: Ramscor, Inc.
• Inventors: Wong, Vernon, Wood, Louis
• Application Number:
  US11/826,833
• Publication Number:
  US 20080038316A1
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 47/06 Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants

Abstract

This invention provides for biocompatible and biodegradable syringeable liquid, implantable solid, and injectable gel pharmaceutical formulations useful for the treatment of systemic and local disease states.

Claims

1. A pharmaceutical formulation for the sustained release of an active agent consisting essentially of a biocompatible, biodegradable, non-polymeric excipient and an active agent or pharmaceutically acceptable salt thereof, wherein said formulation is capable of being implanted by injection.

4. The pharmaceutical formulation of claim 1, wherein about 2% to about 60% of the active agent is released over a period ranging from about 1 day to at least about 365 days.

5. The pharmaceutical formulation of claim 1, comprising an active agent at a concentration from about 5% to about 50% of the implant and biodegradable, biocompatible excipient at a concentration of at least about 5% of the implant.

6. The pharmaceutical formulation of claim 1, comprising an active agent at a concentration from about 0.5% to about 95% of the implant and the corresponding concentration of the excipient ranges from about 5% to about 99.5%.

7. The pharmaceutical formulation of claim 1, wherein said biocompatible, biodegradable excipient is selected from the group consisting of benzyl benzoate;

esters of benzoic acid with straight, branched, or cyclic chain aliphatic alcohols having one to twenty carbon atoms wherein one of the hydrogen atoms on the aliphatic chain is replaced with a hydroxyl group (e.g., such alcohols as methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol, n-pentanol, i-pentanol, neo-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octonol, n-nonanol, n-decanol, and the like);

d, 1 and d1 isomers of α

, β

, δ

, ε

, η

tocopherols and similar isomers of the tocotrienols and the esters of these tocopherols and tocotrienols with;

straight and branched chain C₂ to C₂₀ aliphatic acids, or their esters of C₃ to C₂₀ straight chain dicarboxylic acids, including maleic, malic, fumaric, succinic, or their esters with lactic, glycolic, benzoic, nicotinic, pyruvic acids, succinic-PEG ester;

the mono, di, and tri esters of O-acetylcitric acid or O-propionylcitric acid or O-butyrylcitric acid with C₁ to C₁₀ straight and branched chain aliphatic alcohols;

the mono, di, and tri esters of citric acid with C₁ to C₁₀ straight and branched chain aliphatic alcohols;

dibenzoate esters of poly(oxyethylene) diols having low water solubility;

poly(oxypropylene)diols having low water solubility;

liquid and semisolid polycarbonate oligomers, and dimethyl sulfone.

8. The pharmaceutical formulation of claim 1, wherein said active agent is selected from the group consisting of analgesics, anesthetics, narcotics, angiostatic steroids, anti-inflammatory steroids, angiogenesis inhibitors, nonsteroidal anti-inflammatories, anti-infective agents, anti-fungals, anti-malarials, anti-tuberculosis agents, antivirals, alpha androgenergic agonists, beta adrenergic blocking agents, carbonic anhydrase inhibitors, mast cell stabilizers, miotics, prostaglandins, antihistamines, antimicrotubule agents, antineoplastic agents, antipoptotics, aldose reductase inhibitors, antihypertensives, antioxidants, growth hormone antagonists, vitrectomy agents, adenosine receptor antagonists, adenosine deaminase inhibitor, glycosylation antagonists, anti aging peptides, topoisemerase inhibitors, anti-metabolites, alkylating agents, antiandrigens, anti-oestogens, oncogene activation inhibitors, telomerase inhibitors, antibodies or portions thereof, antisense oligonucleotides, fusion proteins, luteinizing hormone releasing hormones agonists, gonadotropin releasing hormone agonists, tyrosine kinase inhibitors, epidermal growth factor inhibitors, ribonucleotide reductase inhibitors, cytotoxins, IL2 therapeutics, neurotensin antagonists, peripheral sigma ligands, endothelin ETA/receptor antagonists, antihyperglycemics, anti-glaucoma agents, anti-chromatin modifying enzymes, obesity management agents, anemia therapeutics, emesis therapeutics, neutropaenia therapeutics, tumor-induced hypercalcaemia therapeutics, blood anticoagulants, immunosuppressive agents, tissue repair agents, insulins, glucagon-like-peptides, botulinum toxins, and psychotherapeutic agents.

11. The pharmaceutical formulation of claim 8, wherein the active agent is one or more steroidal anti-inflammatory agents selected from the group consisting of 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, dexamethasone 21-acetate, dexamethasone 21-phosphate di-Na salt, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, and triamcinolone hexacetonide.

12. The pharmaceutical formulation of claim 11, wherein the active agent is one or more steroidal anti-inflammatory agents selected from the group consisting of cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone acetonide.

13. The pharmaceutical formulation of claim 12, wherein the active agent is one or more steroidal anti-inflammatory agents selected from the group consisting of dexamethasone and triamcinolone acetonide.

14. The pharmaceutical formulation of claim 8, wherein the active agent is one or more non-steroidal anti-inflammatory agents selected from the group consisting of naproxin;

diclofenac;

celecoxib;

sulindac;

diflunisal;

piroxicam;

indomethacin;

etodolac;

meloxicam;

ibuprofen;

ketoprofen;

r-flurbiprofen;

mefenamic;

nabumetone;

tolmetin, and sodium salts of each of the foregoing;

ketorolac bromethamine;

ketorolac tromethamine;

ketorolac acid;

choline magnesium trisalicylate;

rofecoxib;

valdecoxib;

lumiracoxib;

etoricoxib;

aspirin;

salicylic acid and its sodium salt;

salicylate esters of alpha, beta, gamma-tocopherols and tocotrienols (and all their d, 1, and racemic isomers);

methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, esters of acetylsalicylic acid;

tenoxicam;

aceclofenac;

nimesulide;

nepafenac;

amfenac;

bromfenac;

flufenamate; and

phenylbutazone.

15. The pharmaceutical formulation of claim 8, wherein the active agent is one or more anti-infectives selected from the group consisting of 2,4-diaminopyrimidines, nitrofurans, quinolones and quinolone analogs, sulfonamides, sulfones, clofoctol, hexedine, methenamine, methenamine anhydromethylene-citrate, methenamine hippurate, methenamine mandelate, methenamine sulfosalicylate, nitroxoline, taurolidine, xibomol, moxifloxacin, and vancomycin.

16. A method of treating inflammatory conditions comprising delivering to a patient in need thereof the pharmaceutical formulation of claim 12.

17. The method of claim 16, wherein said pharmaceutical formulation further comprises a quinolone or quinalone analog antibiotic.

18. The method of claim 17, wherein said pharmaceutical formulation further comprises an antioxidant.

19. A method of treating a malady of the eye by implanting the pharmaceutical formulation of claim 1, wherein said malady is selected from the group consisting of allergic and infectious conjunctivitis, uveitis of the anterior and posterior segments, infectious endophthalmitis of the anterior segment and posterior segment, dry-eye syndrome, post-surgical inflammation and infection of the anterior and posterior segments, angle-closure glaucoma, open-angle glaucoma, post-surgical glaucoma procedures, exopthalmos, scleritis, episcleritis, Grave'"'"'s disease, pseudotumor of the orbit, lymphoma of the orbit, tumors of the orbit, orbital cellulitis, blepharitis, intraocular tumors, retinoblastoma, malignant melanoma, retinal fibrosis, vitreous substitute and vitreous replacement, iris neovascularization from cataract surgery, macular edema in central retinal vein occlusion, cellular transplantation (as in retinal pigment cell transplantation), cystiod macular edema, psaudophakic cystoid macular edema, diabetic macular edema, pre-phthisical ocular hypotomy, proliferative vitreoretinopathy, proliferative diabetic retinopathy, exudative age-related macular degeneration, extensive exudative retinal detachment (Coat'"'"'s disease), diabetic retinal edema, diffuse diabetic macular edema, ischemic opthalmopathy, chronic focal immunologic and chemical corneal graft reaction, neovascular glaucoma, pars plana vitrectomy (for proliferative diabetic retinopathy), pars plana vitrectomy for proliferative vitreoretinopathy, sympathetic ophthalmia, intermediate uveitis, chronic uveitis, intraocular infection such as endophthalmitis, and Irvine-Gass syndrome;

conditions of inflammatory and immunological in nature, sequalae of surgical complications, and acquired and hereditary ocular conditions such as Tay-Sach'"'"'s disease, Niemann-Pick'"'"'s disease, cystinosis, corneal dystrophies and multiple myeloma.

24. The pharmaceutical formulation of claim 7, wherein said liquid to semisolid polycarbonate oligomers is selected from the group consisting of those polycarbonate oligomers prepared by the polymerization of trimethylene carbonate [poly(1,3-propanediol carbonate)], the ester exchange polymerization of diethylene carbonate with aliphatic diols or polyoxyalkane diols [poly(di-1,2-propylene glycol carbonate), and poly(tri-1,2-propylene glycol carbonate)].

28. The pharmaceutical formulation of claim 1, wherein said active agent is an oxymethylene polymer or trimer.

29. The pharmaceutical formulation of claim 28, wherein said oxymethylene polymer or trimer is selected from the group consisting of Paraformaldehyde, Trioxane, Oxymethylene polymers of acetaldehyde, Paraldehyde, and Oxymethylene polymers of gluteraldehyde.

30. The pharmaceutical formulation of claim 8, wherein said antioxidant is selected from the group consisting of ascorbic acids and salts, ascorbyl palmitate, ascorbyl dipalmitate, ascorbyl stearate, ascorbyl-2,6-dibutyrate, d-tocopherol (α

, β

, γ

, δ

isomers), d1-tocopherol (α

, β

, γ

, δ

isomers), the acetate, hemisuccinate, nicotinate and succinate-PEG ester derivatives of the above tocopherol isomers, glutathione, β

-carotine, carnitine, carnitine acetate, trans reveratrol, retinoic acid, retinyl palmitate, melatonin, timolol, luteolin, kaempferol, thyroxine, pyrroloquinolone, retinyl palmitate, probucol, erythorbic acid, sodium erythorbate, α

-lipoic acid, isocitrate, lutein/zeaxanthin/meso-zeaxanthin, eugenol, isoeugenol, (−

)-epicatechin, (−

)-epigallocatechin gallate, benzyl alcohol, benzyl benzoate, 2,6-di-tertbutyl-4-methoxy phenol, butylated hydroxytoluene, butylated hydroxyanisole, quercetin, catechin, rutin, coenzyme Q, fisetin, methyl gallate, and superoxide dismutase.

31. The pharmaceutical formulation of claim 30, further comprising a steroid or quinolone anti-infective.

32. The pharmaceutical formulation of claim 31, wherein said quinolone anti-infective is selected from the group consisting of cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine, gatifloxacin, grepafloxacin, lomefloxacin, miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, and trovafloxacin.

33. The pharmaceutical formulation of claim 31, wherein said steroid is selected from the group consisting of triamcinolone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone acetate, triamcinolone disodium phosphate, triamcinolone hemisuccinate, triamcinolone benetonide, dexamethasone, dexamethasone acetate, dexamethasone disodium phosphate, dexamethasone 3,3-dimethylbutyrate, cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, tetrahydrocortisol, fludrocortisones, fludrocortisone acetate, fludrocortisone phosphate, anacortive, anacortive acetate, mometasone furoate, fluocinolone, dexamethasone diethyl aminoacetate, dexamethasone isonicotinate, dexamethasone palmitate, prednisone, prednisolone, prednisolone acetate, prednisolone sodium phosphate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, paramethasone, etrahydrocortexolone, betamethasone, betamethasone acetate, betamethasone disodium phosphate, betamethasone benzoate, betamethasone valerate, betamethasone dipropionate, betamethasone adamantoate, beclomethasone, beclomethasone dipropionate, diflorasone, and diflorasone diacetate.

34. The pharmaceutical formulation of claim 1, wherein said excipient or active agent is an omega-3 fatty acid or an ester thereof.

2. A pharmaceutical formulation for implantation into a patient for the sustained release of an active agent consisting essentially of a biocompatible, biodegradable, non-polymeric excipient and an active agent or pharmaceutically acceptable salt thereof, wherein said formulation exhibits an in vitro or in vivo dissolution profile wherein about 2% to about 100% of the active agent is released over a period ranging from about 1 day to about 105 days.

20. The pharmaceutical formulation of claim 2, wherein said formulation is a solid form containing from 1% to about 60% of a limited solubility, biocompatible, biodegradable nonpolymeric excipient.

21. The pharmaceutical formulation of claim 2, wherein said formulation is a gel form containing from 20% to about 80% of a limited solubility, biocompatible, biodegradable nonpolymeric excipient.

22. The pharmaceutical formulation of claim 2, wherein said formulation is an injectable liquid or gel form containing from 30% to about 99.9% of a limited solubility, biocompatible, biodegradable nonpolymeric excipient.

3. A pharmaceutical formulation for implantation into a patient for the sustained release of an active agent comprising a biocompatible, biodegradable, non-polymeric excipient and an active agent or pharmaceutically acceptable salt thereof, wherein said formulation exhibits an in vitro or in vivo dissolution profile wherein about 2% to about 100% of the active agent is released over a period ranging from about 1 day to about 365 days.

9. A method for treating joint inflammation comprising the step of:

implanting, by injection, a pharmaceutical formulation comprising a biodegradable, biocompatible, nonpolymeric excipient and a steroidal or non-steroidal anti-inflammatory into a strategic position in the inflamed joint to provide controlled and sustained release of a therapeutically effective but nontoxic level of the anti-inflammatory to the affected areas.

10. The method of claim 9 wherein said pharmaceutical formulation further comprises an antioxidant.

23. A pharmaceutical formulation for the sustained release of an active agent consisting essentially of a biocompatible, biodegradable, nonpolymeric excipient and an active agent or pharmaceutically acceptable salt thereof, wherein said formulation is capable of being implanted by injection, and wherein said biocompatible, biodegradable excipient is selected from the group consisting of tocopherol isomers and tocotrienol isomers and their esters;

benzyl benzoate;

esters of benzoic acid with straight, branched, or cyclic chain aliphatic alcohols having one to twenty carbon atoms wherein one of the hydrogen atoms on the aliphatic chain is replaced with a hydroxyl group;

dibenzoate esters of poly(oxyethylene) diols having low water solubility;

dimethyl sulfone poly(oxypropylene) diols having low water solubility;

the mono, di, and triesters of O-acetylcitric acid with C₁ to C₁₀ straight and branched chain aliphatic alcohols;

mono, di, and triesters of citric acid with C₁ to C₁₀ straight and branched chain aliphatic alcohols;

dimethyl sulfone;

omega-3 fatty acids and their esters of C₁ to C₈ straight and branched chain aliphatic alcohols; and

liquid and semisolid polycarbonate oligomers.

25. A liquid, solid or gel formulation conveniently implantable in a brain tumor for the sustained release of active agents, comprising one or more of the excipients selected from group (a) and one or more of the pharmaceutical agents selected from group (b) or group (c), or both group (b) and group (c):

(a) benzyl benzoate;

esters of benzoic acid with straight, branched, or cyclic chain aliphatic alcohols having one to twenty carbon atoms wherein one of the hydrogen atoms on the aliphatic chain is replaced with a hydroxyl group (e.g., such alcohols as methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol, n-pentanol, i-pentanol, neo-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octonol, n-nonanol, n-decanol, and the like), d.1 and d1 isomers of α

, β

, δ

, ε

, η

tocopherols and similar isomers of the tocotrienols and the esters of these tocopherols and tocotrienols with straight and branched chain C₁ to C₁₀ aliphatic acids, C₃ to C₂₀ straight chain dicarboxylic acids, maleic, malic, fumaric, lactic, glycolic, benzoic, nicotinic, pyruvic acids, succinic-PEG ester, the mono, di, and tri esters of O-acetylcitric acid or O-propionylcitric acid or O-butyrylcitric acid with C₁ to C₁₀ straight and branched chain aliphatic alcohols;

the mono, di, and tri esters of citric acid with C₁ to C₁₀ straight and branched chain aliphatic alcohols, dibenzoate esters of poly(oxyethylene) diols having low water solubility, poly(oxypropylene)diols having low water solubility, liquid and semisolid polycarbonate oligomers, and dimethyl sulfone, diethylene glycol dibenzoate, triethylene glycol dibenzoate, dibenzoate esters of poly(oxyethylene) diols of up to about 400 mwt, propylene glycol dibenzoate, dipropylene glycol dibenzoate, tripropylene glycol dibenzoate, dibenzoate esters of poly(oxypropylene) diols of up to about 3000 mwt;

poly(oxypropylene) diols of up to about 3000 mwt, dimethyl sulfone, liquid to semisolid polycarbonate oligomers, polymers and copolymers of glycolic and lactic acids, poly(lactic acid) and poly(glycolic acid);

(b) tetrahydrocortisol;

4,9(11)-pregnadien-17α

,21-diol-3,20-dione;

4,9(11)-pregnadien-17α

,21-diol-3,20-dione-21-acetate;

11-epicortisol;

17α

-hydroxyprogesterone;

tetrahydrocortexolone;

cortisone;

cortisone acetate;

hydrocortisone;

hydrocortisone acetate;

fludrocortisones;

fludrocortisone acetate;

fludrocortisone phosphate;

prednisone;

prednisolone;

prednisolone sodium phosphate;

methylprednisolone, methylprednisolone acetate;

methylprednisolone sodium succinate;

triamcinolone;

triamcinolone-16,21-diacetate;

triamcinolone acetonide;

triamcinolone acetonide-21-acetate;

triamcinolone acetonide-21-disodium phosphate;

triamcinolone acetonide-21-hemisuccinate;

triamcinolone benetonide;

triamcinolone hexacetonide;

fluocinolone;

fluocinolone acetate;

fluocinolone acetonide;

dexamethasone;

dexamethasone-21-acetate;

dexamethasone-21-(3,3-dimethylbutyrate);

dexamethasone-21-phosphate disodium salt;

dexamethasone-21-diethylaminoacetate;

dexamethasone-21-isonicotinate;

dexamethasone-21-dipropionate;

dexamethasone-21-palmitate;

betamethasone;

betamethasone-21-acetate;

betamethasone-21-adamantoate;

betamethasone-17-benzoate;

betamethasone-17,21-dipropionate;

betamethasone-17-valerate;

betamethasone-21-phosphate disodium salt;

beclomethasone;

beclomethasone dipropionate;

diflorasone;

diflorasone diacetate;

mometasone furoate;

acetazolamide;

naproxen;

naproxin sodium salt;

diclofenac;

diclofenac sodium salt;

celecoxib;

rofecoxib;

valdecoxib;

etoricocib;

lumiracoxib;

sulindac;

sulindac sodium salt;

diflunisal;

diflunisal sodium salt;

piroxicam;

indomethacin;

indomethacin sodium salt;

etodolac;

etodolac sodium salt;

meloxicam;

ibuprofen;

ibuprofen sodium salt;

ketoprofen;

ketoprofen sodium salt;

r-flurbiprofen;

mefenamic;

mefenamic sodium salt;

nabumetone;

tolmetin;

tolmetin sodium salt;

ketorolac bromethamine;

ketorolac tromethamine;

ketorolac acid;

choline magnesium trisalicylate;

aspirin;

salicylic acid;

salicylic acid sodium salt;

salicylate esters of alpha, beta, gamma-tocopherols (and all their d, 1, and racimic isomers);

tenoxicam;

aceclofenac;

nimesulide;

nepafenac;

amfenac;

bromfenac;

flufenamate;

phenylbutazone;

CV 247;

pegaptanib octasodium;

ranibizumab;

2-methoxyestradiol;

shark cartilage extract;

NX-278-L ant-VEGF aptamer;

squalamine;

2′

-O-methoxyethyl) antisense C-raf oncogene inhibitor;

vitronectin and osteopontin antagonist;

combretstatin A-4 phosphate;

Fab fragment alpha-V/beta-1 integrin antagonist;

alpha-v/beta-3 integrin antagonist;

matrix metalloprotienase inhibitor;

matrix metalloprotienase inhibitor;

urokinase plasminogen activator fragment;

vascular endothelial growth factor antagonist;

kdr tyrosine kinase inhibitor;

cytochalasin E;

kallikrinin-binding protein;

combretastatin analog;

pigment-epithelium derived growth factor;

pigment-epithelium derived growth factor;

plasminogen kringle;

rapamycin;

cytokine synthesis inhibitor/p38 mitogen-activated protein kinaseinhibitor;

vascular endothelial growth factor antagonist;

vascular endothelial growth factor antagonist;

vascular endothelial growth factor antagonist;

vascular endothelial growth factor antagonist;

FGF1 receptor antagonist/tyrosine kinase inhibitor (Pfizer/Sugen);

endostatin, vascular endothelial growth factor antagonist;

bradykinin B1 receptor antagonist;

bactericidal/permeability-increasing protein;

protein kinase C inhibitor;

ruboxistaurinn mesylate;

polysulphonic acid derivatives;

growth factor antagonists;

Tunica internal endothelial cell kinase;

acetylcysteine;

mannitol;

antineoplaston;

human corticotropin-releasing factor;

VN40101M;

everolimus;

GW572016;

thalidomide;

temozolomide;

tariquidar;

doxorubicin;

dalteparin;

tarceva;

CC-5013;

hCRF;

bevacizumab;

melphalan;

thiotepa;

depsipeptide;

erlotinib;

tamoxifen;

bortezomib;

lenalidomide;

vorinostat;

temsirolimus;

modifinil;

enzastuarin;

motexafin gadolinium;

F-18-OMFD-PET;

pemetrexed disodium;

ZD6474;

valproic acid;

vincristine;

irinotecan;

PEG-interferon alpha-2b;

procarbazine;

lonafarnib;

arsenic trioxide;

GP9;

carboplatin;

cyclophosphamide;

1311-TM-601;

lapatinib;

O6-benzylguanine;

TP-38 toxin;

cilengitide;

poly-ICLC;

FR901228;

TransMid™

;

talabostat;

ixabepilone;

AEE788;

sirolimus;

alanosine;

sorafenib;

efaproxiral;

carmustine;

¹³¹Iodine monoclonal antibody TNT-1/B;

intratumoral TransMid™

;

topatecan;

lomustine;

³²Phosphorus;

18F-fluorodeoxyglucose;

vinblastine;

BMS-247550;

CC-8490;

IL 13-PE38QQR;

imatib mesylate;

hydroxyurea;

G207;

radiolabeled monoclonal antibody;

2-deoxyglucose;

talampanel;

retinoic acid;

gefitinib;

tipifarnib;

CPT-11;

rituximab;

efaproxiral;

PS-341;

capecitabine;

G-CFS;

vinorelbine;

DCVax®

-Brain;

paclitaxel;

patipilone;

iressa;

methotrexate;

ABT-751;

oxaliplatin;

MS-275;

trastuzumab;

pertuzumab;

PS-341;

17AAG;

lenalidomide;

campath-1H;

somatostatin analog;

resveratrol;

CEP-7055;

CEP-5214;

PTC-299;

inhibitors of hepatocyte growth factor;

statins;

receptor tyrosine kinase inhibitors;

aspirin (acetylsalicylic acid), and peroxisome proliferator-activated receptor (PPAR-alpha) activators (fenofibrate and clofibrate);

(c) Anti-neovascularization steroids selected from the group consisting of;

21-nor-5β

-pregnan-3α

,17α

,20-triol-3-acetate;

21-nor-5α

-pregnan-3α

,17α

,20-triol-3-phosphate;

21-nor-5β

-pregn-17(20)en-3α

,16-diol;

21-nor-5β

-pregnan-3α

,17β

,20-triol;

20-acetamide-21-nor-5β

-pregnan-3α

,17α

-diol-3-acetate;

3β

acetamido-5β

-pregnan-11β

,17α

,21-triol-20-one-21-acetate;

21-nor-5α

-pregnan-3α

,17β

,20-triol;

21α

-methyl-5β

-pregnan-3α

,11β

,17α

,21-tetrol-20-one-21-methyl ether;

20-azido-21-nor-5β

-pregnan-3α

,17α

-diol;

20(carbethoxymethyl)thio-21-nor-5β

-pregnan-3α

,17α

-diol;

20-(4-fluorophenyl)thio-21-nor-5β

-pregnan-3α

,17α

-diol;

16α

-(2-hydroxyethyl)-17β

-methyl-5β

-androstan-3α

,17α

diol;

20-cyano-21-nor-5β

-pregnan-3α

,17α

-diol;

17α

-methyl-5β

-androstan-3α

,17β

-diol;

21-nor-5β

-pregn-17(20)en-3α

-ol;

21-or -5β

-pregn-17(20)en-3α

-ol-3-acetate;

21-nor-5-pregn-17(20)-en-3α

-ol-16-acetic acid 3-acetate;

3β

-azido-5β

-pregnan-11β

,17α

,21-triol-20-one-21-acetate; and

5β

-pregnan-11β

,17α

,21-triol-20-one;

4-androsten-3-one-17β

-carboxylic acid;

17α

-ethynyl-5(10)-estren-17β

-ol-3-one; and

17α

-ethynyl-1,3,5(10)-estratrien-3,17β

-diol.

26. The formulation of claim 25, wherein said liquid to semisolid polycarbonate oligomers is selected from the group consisting of those polycarbonate oligomers prepared by the polymerization of trimethylene carbonate [poly(1,3-propanediol carbonate)], the ester exchange polymerization of diethylene carbonate with aliphatic diols or polyoxyalkane diols [poly(di-1,2-propylene glycol carbonate), and poly(tri-1,2-propylene glycol carbonate)].

27. The formulation of claim 25, wherein said statin is selected from the group consisting of atorvastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, lovastatin, and cerivastatin.