CONVENIENTLY IMPLANTABLE SUSTAINED RELEASE DRUG COMPOSITIONS

• US 20150273066A1
• Filed: 04/20/2015
• Published: 10/01/2015
• Est. Priority Date: 10/01/2004
• Status: Abandoned Application

• Current Assignee: Ramscor, Inc.
• Original Assignee: Ramscor, Inc.
• Inventors: Wong, Vernon G., Wood, Louis L.
• Application Number:
  US14/691,057
• Publication Number:
  US 20150273066A1
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 method of delivering the sustained release of an active agent to the eye of a subject comprising:

injecting into the eye of a subject in need of such treatment a therapeutically effective amount of at least one pharmaceutically active agent, or acceptable salt thereof, in a liquid pharmaceutical composition consisting essentially of at least one excipient selected from the group consisting of 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, wherein the amount of the excipient is sufficient to evenly dissolve or disperse the entire amount of the active agent in the composition;

wherein upon initial injection into the eye the composition maintains its integrity as a single bolus; and

wherein said excipient releases the active agent from the composition for a continuous and sustained period of at least about five days.

2. The method of claim 1, wherein at least one active agent is an anti-infective 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, ciprofloxacin, vancomycin, and a combination of any of these.

3. The method of claim 2, wherein the active agent is ciprofloxacin.

4. The method of claim 1, wherein at least one active agent is a steroidal anti-inflammatory agent 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, triamcinolone hexacetonide, and a combination of any of these.

5. The method of claim 1, wherein at least one active agent is a non-steroidal anti-inflammatory agent selected from the group consisting of naproxen, diclofenac, celecoxib, sulindac, diflunisal, piroxicam, indomethacin, etodolac, meloxicam, ibuprofen, ketoprofen, r-flurbiprofen, mefenamic, nabumetone, tolmetin, ketorolac bromethamine, ketorolac tromethamine, ketorolac acid, choline magnesium trisalicylate, rofecoxib, valdecoxib, lumiracoxib, etoricoxib, aspirin, salicylic acid, salicylate esters of alpha, beta, gamma-tocopherols and tocotrienols, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, and t-butyl, esters of acetylsalicylic acid, tenoxicam, aceclofenac, nimesulide, nepafenac, amfenac, bromfenac, flufenamate, phenylbutazone, pharmaceutically acceptable salts of any of these, and a combination of any of these.

6. The method of claim 4 or 5, wherein said pharmaceutical composition further includes a quinolone, quinolone analog or quinolone derivative antibiotic.

7. The method of claim 1, wherein said pharmaceutical composition further includes an antioxidant.

8. The method of claim 7, wherein said antioxidant is selected from the group consisting of ascorbic acids and salts, ascorbyl palmitate, ascorbyl dipalmitate, ascorbyl stearate, ascorbyl-2,6-dibutyrate, alpha d-tocopherol, beta d-tocopherol, gamma d-tocopherol, delta d-tocopherol, alpha dl-tocopherol, beta dl-tocopherol, gamma dl-tocopherol, delta dl-tocopherol, the acetate, hemisuccinate, nicotinate and succinate-PEG ester derivatives of tocopherol isomers, glutathione, beta-carotine, carnitine, carnitine acetate, trans reveratrol, retinoic acid, retinyl palmitate, melatonin, timolol, luteolin, kaempferol, thyroxine, pyrroloquinolone, retinyl palmitate, probucol, erythorbic acid, sodium erythorbate, alpha-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.

9. The method of claim 1, wherein at least one active agent is cyclosporine A.

10. The method of claim 1, wherein the subject is suffering a malady of the eye 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, exophthalmos, 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, cystoid macular edema, pseudophakic cystoid macular edema, diabetic macular edema, diffuse diabetic macular edema, pre-phthisical ocular hypotomy, proliferative vitreoretinopathy, proliferative diabetic retinopathy, macular degeneration, extensive exudative retinal detachment, diabetic retinal edema, retinitis pigmentosa, ischemic ophthalmopathy, chronic focal immunologic and chemical corneal graft reaction, neovascular glaucoma, pars plana vitrectomy, sympathetic ophthalmia, intermediate uveitis, chronic uveitis, intraocular infection, endophthalmitis, Irvine-Gass syndrome, conditions of inflammatory and immunological nature, sequelae of surgical complications, acquired and hereditary ocular conditions, Tay-Sach'"'"'s disease, Niemann-Pick'"'"'s disease, cystinosis, corneal dystrophies, and multiple myeloma.