Ophthalmic Oil-in-Water Type Emulsion with Stable Positive Zeta Potential

• US 20070248645A1
• Filed: 10/10/2005
• Published: 10/25/2007
• Est. Priority Date: 11/09/2004
• Status: Active Grant

• Current Assignee: Santen SAS (Santen Pharmaceutical Company Limited)
• Original Assignee: Novagali Pharma S.A. (Santen Pharmaceutical Company Limited)
• Inventors: Lambert, Gregory, Philips, Betty, Garrigue, Jean-Sebastien, Bague, Severine, Rabinovich-Guilatt, Laura
• Granted Patent: US 8,372,434 B2
• Time in Patent Office: Days
• US Class Current: 424/427
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• 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 27/14 Decongestants or antiallergics
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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

An ophthalmic oil-in-water type emulsion, which includes colloid particles having an oily core surrounded by an interfacial film, the emulsion including at least one cationic agent, at least one no ionic surfactant, the emulsion having a positive zeta potential and meeting zeta potential stability Test A requirements. Process for making the emulsions. Delivery device selected from the group including lenses, ocular patch, implant, insert, the device containing an emulsion according to the invention.

Claims

1-27. -27. (canceled)

28. An ophthalmic oil-in-water submicron type emulsion, which comprises colloid particles having an oily core surrounded by an interfacial film, said emulsion comprising:

0.001% to 0.1% by weight of at least one cationic agent selected from the group consisting of tertiary-aliphatic amines, quaternary ammonium compounds, cationic lipids, amino alcohols, biguanide salts, cationic polymers and a mixture of two or more thereof,

less than 1% by weight of at least one non ionic surfactant selected from the group consisting of tyloxapol, polysorbates, polyoxyethylene castor oil derivatives, sorbitan esters, polyoxyl stearates and a mixture of two or more thereof,

said emulsion having appositive zeta potential, and being stable,

provided that the emulsion does not contain phospholipids.

29. An ophthalmic emulsion according to claim 28, which is stable for at least 15 hours under thermal stress conditions.

30. An ophthalmic emulsion according to claim 28, which is stable for at least 48 hours under thermal stress conditions.

31. An ophthalmic emulsion according to claim 28, which is stable for at least 7 days under thermal stress conditions.

32. An ophthalmic emulsion according to claim 28, which is stable for at least 14 days under thermal stress conditions.

33. An ophthalmic emulsion according to claim 28, wherein the concentration of the cationic agent is comprised between 0.002 and 0.05% w/w and still more preferably between 0.003 and 0.03% w/w.

34. An ophthalmic emulsion according to claim 28, wherein the concentration of oil is not higher than 7% (w/w), preferably about 0.5 to 5% w/w, and even more preferably about 1% to 3% w/w.

35. An ophthalmic emulsion according to claim 28, wherein the weight ratio cationic agent/oil is comprised between 0.0025 and 0.06, preferably between 0.005 and 0.04.

36. An ophthalmic emulsion according to claim 28, wherein the concentration of the non-ionic agent is comprised preferably between 0.01 to 0.6% w/w.

37. An ophthalmic oil-in-water emulsion according to claim 28, wherein the cationic agent is selected in the group consisting of C10-C24 primary alkylamines, teriary-aliphatic amines, quaternary ammonium compounds, cationic lipids, amino alcohols, biguanide salts, cationic polymers and a mixture of two or more thereof.

38. An ophthalmic oil-in-water emulsion according to claim 37, wherein the biguanide salt is selected from the group comprising chlorhexidine and salts thereof, polyaminopropyl biguanide, phenformin, alkylbiguanide or a mixture of two or more thereof.

39. An ophthalmic oil-in-water emulsion according to claim 37, wherein the quaternary ammonium compound is selected from the group comprising benzalkonium halide, laurelkonium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, centrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallyl methenamine halide, myristalkonium halide, stearalkonium halide or a mixture of two or more thereof, halide being preferably chloride or bromide.

40. An ophthalmic emulsion according to claim 39, wherein said cationic agent is selected from the group comprising benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethenium chloride, hexacdecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide or a mixture of two or more thereof.

41. An ophthalmic emulsion according to claim 28, wherein the cationic agent is selected from chitosan, 1,2-dioleyl-3-trimethylammonium-propane, 1,2-dioleoyl-sn-glycero-phosphatidylethanolamine, cationic glycosphingo-lipids or cationic cholesterol derivatives, or mixtures of two or more thereof.

42. An ophthalmic emulsion according to claim 28, wherein the non-ionic surfactant is a mixture of two or more non-ionic surfactants selected from the group consisting of poloxamers, tyloxapol, polysorbates, polyoxyethylene castor oil derivatives, sorbitan esters, polyoxyl stearates and a mixture.

43. An ophthalmic emulsion according to claim 28, comprising benzalkonium chloride as cationic agent and tyloxapol as non-ionic surfactant.

44. An ophthalmic emulsion according to claim 28, wherein the emulsion contains benzalkonium chloride as cationic agent and a combination of tyloxapol and poloxamer as non-ionic surfactants.

45. An ophthalmic emulsion according to claim 28, wherein said colloidal particles have an average particle size of equal or less than 1 μ

m, advantageously equal or less than 300 μ

m, more advantageously in the range of 100 to 250 μ

m.

46. An ophthalmic emulsion according to claim 28, comprising a pharmaceutically active substance.

47. An ophthalmic emulsion according to claim 46, wherein the active substance is selected from the group comprising antibiotics (such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chlorampenicol, kanamycin, rifampicin, tobramycin, gentamycin, ciprofloxacin, aminosides, erythromycin and penicillin, quinolone, ceftazidime, vancomycine imipeneme);

antifungals such as ampohotericin B and miconazole;

antibacterials such as sulfonamides, sulfadiazine, sulfacetamide, sufamethizole and sufixoazole, nitrofurazone and sodium propionate;

antivirals, such as idoxuridine, trifluorotymidine, acyclovir, ganciclovir, cidofovir and interferon;

antibacterial agents such as nitrofurazone and sodium propionate;

non-antibiotic, anti-infection, antibacterial or anti-microbial drugs such as iodine based preparation triclosan, chlorhexidine;

antiallergenics such as sodium cromoglycate, antazoline, methapyriline, chlorpheniramine, cetririzine, pyrilamine and prophenpyridamine;

antiproliferative agents such as thalidomide;

synthetic gluocorticoids and mineralcerticoids and more generally hormone forms derivating from the cholesterol metabolism (progesterone, estrogens, androgenic hormones such as testosterone, DHEA and their derivatives)/anti-inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluorocinolene, medrysone, prednisolone acetate, luoromethalone, triamcinolone and triamcinolene acetonide and their derivatives;

non-steroidal anti-inflammatories such as salicylate, indomethacin, ibuprofen, diclofenac, flurbiprofen and piroxicam and COX2 inhibitors such as rofecoxib, diclofenac, nimesulide, nepafenac;

antineoplastics such as carmustine, cisplatin, mitomycin and fluororacil;

immunological drugs such as vaccines and immune stimulants;

insulin, calcitonin, parathyroid hormone and peptide and vaseppressin hypothalamus releasing factor;

beta adrenergic blockers such as timolol maleate, levobunolol HCl and betaxolol HCl, timolol-base, betaxolol, atenolol, epinephrine, dipivalyl, oxonolol, acetazolamide-base and methazolamide;

cytokines, interleukins, and growth factors (growth factors such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, ciliary neurotrophic growth factor, glial derived neurotrophic factor, NGF, EPO, P1GF);

antibodies or antibodies fragments, oligoaptamers, aptamers and gene fragments (oligonucleotides, plasmids, ribozymes, small interference RNA, nucleic acid fragments, peptides, antisense sequences);

immunosuppressants such as cyclosporine, sirolimus and tacrolimus, immunomodulators such as endoxan, tamoxifene;

antithroinbolytic and vasodilator agents such as rtPA, urokinase, plasmin, nitric oxide donors;

antioxidants such as lutein, vitamins and/or their derivatives; and

/or optically acceptable salts thereof.

48. An ophthalmic emulsion according to claim 45, wherein the active substance is an immunosuppressive agent selected in the group consisting of cyclosporine, sirolimus and tacrolimus.

49. An ophthalmic emulsion according to claim 48, wherein the active substance is cyclosporin A.

51. Ophthalmic formulation comprising a submicron emulsion according to claim 28, in combination with an ophthalmic acceptable carrier, said formulation being in the form of eye drops, eye ointment, or ophthalmic gel.

52. Ophthalmic formulation according to claim 51, comprising a pharmaceutically effective amount of an active ingredient in or within the ophthalmic acceptable carrier.

53. Delivery device selected from the group comprising lenses, ocular patch, implant, insert, said device containing an emulsion according to claim 28.

50. Process of preparation of a submicron ophthalmic oil-in-water type emulsion, which comprises colloid particles having an oily-core surrounded by an interfacial film, said emulsion comprising at least one cationic agent, at least one non ionic surfactant said emulsion having a positive zeta potential and meeting zeta potential stability Test A requirements, said process comprising the steps of shear mixing followed by high pressure homogenization of the coarse emulsions obtained through mixing of the aqueous and the oily phase.