Conveniently implantable sustained release drug compositions

• US 20060073182A1
• Filed: 09/27/2005
• Published: 04/06/2006
• Est. Priority Date: 10/01/2004
• Status: Active Grant

• Current Assignee: Ramscor, Inc.
• Original Assignee: Ramscor, Inc.
• Inventors: Wood, Louis L., Wong, Vernon G.
• Granted Patent: US 7,906,136 B2
• 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 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• 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 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/12 for cataracts
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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 comprising a biocompatible, biodegradable 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 tocopherol isomers and tocotrienal isomers and their esters;

benzyl alcohol;

benzyl benzoate;

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-C₁₀ straight and branched chain aliphatic alcohols; and

liquid and semisolid polycarbonate oligomers.

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-tublerculosis agents, anti-virals, 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 inhibitos, epidermal growth fator 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 (Botox, Allergan), and psychotherapeutic agents.

10. 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.

11. The pharmaceutical formulation of claim 10, 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.

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 dexamethasone and triamcinolone acetonide.

13. The pharmaceutical formulation of claim 8, wherein the active agent is one or more non-steroidal anti-inflammables selected from the group consisting of naproxin, diclofenac, celecoxib, rofecoxib, sulendac, diflunisal, piroxicam, indomethacin, etodolac, meloxicam, ibuprofin, ketoprofin, r-flurbiprofen, mefenamic, nabumetone, tolmetin, aspirin, and methyl and ethyl esters of aspirin.

14. 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 (e.g., brodimoprim, tetroxoprim, trimethoprim), nitrofurans (e.g., furaltadone, furazolium chloride, nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin), quinolones and analogs (e.g., cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin, miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin), sulfonamides (e.g., acetyl sulfamethoxypyrazine, benzylsulfamide, chloramine-b, chloramine-t, dichloramine t, n²-formylsulfisomidine, n⁴-β

-d-glucosylsulfanilamide, mafenide, 4′

-(methylsulfamoyl)sulfanilanilide, noprylsulfamide, phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine, succinylsulfathiazole, sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfamerazine, sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide, 4-sulfanilamidosalicylic acid, n⁴-sulfanilylsulfanilamide, sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine, sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine, sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea, sulfatolamide, sulfisomidine, sulfisoxazole) sulfones (e.g., acedapsone, acediasulfone, acetosulfone sodium, dapsone, diathymosulfone, glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid, p-sulfanilylbenzylamine, sulfoxone sodium, thiazolsulfone), and others (e.g., clofoctol, hexedine, methenamine, methenamine anhydromethylene-citrate, methenamine hippurate, methenamine mandelate, methenamine sulfosalicylate, nitroxoline, taurolidine, and xibomol).

15. A method of treating inflammatory conditions comprising delivering to a patient in need thereof the pharmaceutical formulation of claim 11.

16. The method of claim 15, wherein said formulation further comprises ciprofloxin.

17. A method of treating a malady of the eye by implanting the pharmaceutical formulation of claim 1 to a patient in need thereof, wherein said malady is selected from the group consisting of 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 ophthalmopathy, chronic focal immunalogic corneal graft reaction, neovascular glaucoma, pars plana vitrectomy (for proliferative diabetic retinopathy), pars plana vitrectomy for proliferatve vitreoretinopathy, sympathetic ophthalmia, intermediate uveitis, chronic uveitis, intraocular infection such as endophthalmitis, and Irvine-Gass syndrome.

21. A method for the management of skin wrinkles or bladder, prostatic and pelvic floor disorders comprising a step of implanting by injection a pharmaceutical formulation comprising a biodegradable, biocompatible excipient selected from the group in claim 7 and botulinum toxins into a strategic position in the skin or bladder, prostate or pelvic floor region to provide controlled and sustained release of a therapeutically effective but non-toxic level of the botulinum toxins within the effected areas.

22. A method for the management of uterine fibroids comprising a step of implanting by injection a pharmaceutical formulation comprising a biodegradable, biocompatible excipient selected from the group listed in claim 7 and suitable therapeutic agent such as pirfenidone, human interferin-alpha, GnRH antagonists, Redoxifene, estrogen-recptor modulators, into strategic positions inside the fibroids to provide controlled and sustained release of therapeutically effective but non-toxic levels of the therapeutic agents within the fibroids.

2. A pharmaceutical formulation for implantation into a patient for the sustained release of an active agent comprising a biocompatible, biodegradable 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.

18. The pharmaceutical formulation of claim 2, wherein said formulation is a solid form containing from 1% to about 60% of an LSBB.

19. The pharmaceutical formulation of claim 2, wherein said formulation is a gel form containing from 20% to about 80% of an LSBB.

20. The pharmaceutical formulation of claim 2, wherein said formulation is an injectable liquid or gel form containing from 30% to about 99.9% of an LSBB.

3. A pharmaceutical formulation for implantation into a patient for the sustained release of an active agent comprising a biocompatible, biodegradable 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 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.

23. A pharmaceutical formulation for the sustained release of an active agent comprising a biocompatible, biodegradable 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 tocotrienal isomers and their esters;

benzyl alcohol;

benzyl benzoate;

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-C₁₀ straight and branched chain aliphatic alcohols;

dimethyl sulfone; and

liquid and semisolid polycarbonate oligomers.