Polyaflon and its administration to the eyelids

Abstract

To provide a novel composition capable of releasing a sufficient amount of therapeutic agent over a sustained period to achieve a therapeutic effect in the treatment of eye diseases or ophthalmic disorders. [Solution] A composition containing polyaflon used for topical administration to the upper and / or lower eyelids of a subject.

Description

Technical Field

[0001] The present invention relates to polyaphron which is easy to administer in the general area of galenic formulations. In particular, the present invention relates to a composition containing at least one polyaphron for topical administration, preferably eyelid administration.

Background Art

[0002] Introduction to Polyaphron Polyaphron is a dispersion. In the context of the present invention, "dispersion" means a system in which liquid globules or solid particles are dispersed in a continuous phase. In the present invention, the term "polyaphron" refers to liquid globules called immiscible "aphron" dispersed in a continuous phase. As long as the aphron remains immiscible in the continuous phase, the dispersed phase may be a hydrophilic phase or a hydrophobic phase. The continuous phase may be a fluid, a liquid or a gel.

[0003] More specifically, the dispersed phase of polyaphron may consist of composite aphrons dispersed in a continuous phase, said aphrons comprising - a core made of a material immiscible with the continuous phase, - an intermediate layer made of the same material as the continuous phase, - an outer layer containing a surfactant and having.

[0004] For example, in an oil-in-water polyaphron, the aphron may comprise a hydrophobic globule as an inner core, an intermediate layer consisting of an aqueous solution, and an outer layer containing a surfactant. In an oil-in-water polyaphron, the hydrophobic phase may represent up to 98% by weight of the total weight of the polyaphron, and the polyaphron contains a very small amount (typically in the range of 0.05 to 5% or 0.1 to 3% by weight relative to the total weight of the polyaphron) of surfactant considering the large amount of dispersed phase.

[0005] As another example, in a water-in-oil polyaflon, the aflon may comprise an inner core consisting of aqueous spheres, an intermediate layer made of a hydrophobic solution, and an outer layer containing a surfactant. In a water-in-oil polyaflon, the hydrophilic phase may account for up to 98% of the total weight of the polyaflon.

[0006] Notably, in contrast to emulsions characterized by a single interface, polyaflon can have a multilayer structure that contributes to its superior stability.

[0007] background Polyaflons were first described about 40 years ago. U.S. Patent No. 4,486,333 discloses a method for preparing polyaflons, particularly oil-in-water polyaflons, using kerosene, petroleum ether, carbon tetrachloride, or a carbon tetrachloride-cyclohexane mixture as the hydrophobic phase, and water or methanol as the hydrophilic phase.

[0008] Polyaflon compositions are known as oral drug delivery systems. For example, International Publication No. 2005 / 011628 discloses the delivery of lipophilic, poorly water-soluble drugs in an immediate dosage form using a polyaflon composition.

[0009] Polyaflon compositions can be used as topical drug delivery systems for carrying active ingredients. For example, U.S. Patent No. 4,999,198 discloses the delivery of scopolamine dissolved in peanut oil and mineral oil to another medium; International Publication No. 2008 / 110826 discloses the delivery of corticosteroids combined with vitamin E via topical application to the skin; and European Patent No. 1970049 discloses a topical composition for the use of a vitamin D-containing composition on the skin in the treatment of many skin diseases such as psoriasis or dermatitis.

[0010] Recently, polyaflon dispersions have been used for ocular administration. For example, International Publication No. 2012 / 123515 discloses methods for delivering different active ingredients such as antibiotics (cyclosporine, vancomycin), anti-inflammatory compounds (flurbiprofen, fluticasone), and prostaglandins (latanoprost). International Publication No. 2012 / 123515 also discloses eye drops for topical administration to the cornea of ​​humans / animals.

[0011] technical issues The applicant has noticed various problems when eye drops are administered topically to the patient's eye surface. Firstly, some patients are unable to administer eye drops themselves, leading to problems with topical administration. Secondly, when applying eye drops, patients may doubt whether at least one drop has reached the target (cornea and / or conjunctiva), and this problem is more prevalent in elderly and pediatric populations. As a result, problems with accurate medication administration arise. Furthermore, even when eye drops are properly delivered to the eye surface, patients may experience some discomfort or blurred vision. When eye drops are dropped onto the eye surface, a reflex blink usually occurs, and most of the eye drops are washed away within a few seconds. It has been observed that more than 95% of eye drops are washed away from the eye surface within two minutes of administration.

[0012] More importantly, direct administration of the composition to the ocular surface may cause irritation, particularly to the cornea and / or conjunctiva, due to the presence of irritating components in the formulation. Such consequences can be a real problem when the primary target of treatment is the eye.

[0013] Another important issue in eye treatment is the frequency of administration. Applying eye drops multiple times a day can be a burden for some patients and can dramatically reduce patient adherence to treatment.

[0014] Given these different problems with ophthalmic therapeutic compositions, the applicant conceived and implemented an easily administered polyaflon that can target the eye while avoiding direct administration of the composition to the cornea and also avoiding discomfort, blurred vision, and irritation.

[0015] Another challenge in eye treatment is achieving sustained release of the therapeutic agent into the eye, allowing it to be gradually delivered to the target area of ​​the eye. Administering large amounts of the active agent to the eye over a short period can lead to toxic concentrations, potentially causing harm to the target area of ​​the eye.

[0016] Therefore, there is growing interest in releasing sufficient amounts of therapeutic agent over a sustained period to achieve therapeutic effects without releasing excessive amounts that could cause local toxicity. Another advantage of extending the duration of delivery is that the frequency of administration can be reduced, resulting in improved treatment compliance.

[0017] Surprisingly, the applicant discovered that polyaflons could be an efficient medium for sustained and / or controlled release of the active pharmaceutical ingredient (API) into the target eye via eyelid application. This discovery led the applicant to conceive and implement polyaflons that can sustainably and / or controlledly release the API into the target eye over extended periods. [Overview of the project]

[0018] Accordingly, in a first aspect, the present invention relates to polyaflon itself or a composition containing polyaflon for topical administration to at least one eyelid of a subject. In one embodiment, the polyaflon contains an active ingredient.

[0019] In one embodiment, the present invention relates to a composition containing at least one polyaflon comprising the component, which is used for eyelid administration of the component to the eye of a target by topical administration of the polyaflon to at least one eyelid of the target. In one embodiment, the component is an active ingredient.

[0020] In a second aspect, the present invention relates to a method of transdermally delivering a polyfluoroalkane or a component thereof to an eye of a subject for treating an eye disease or disorder of interest. The method of the present invention is useful for delivering at least one component of the polyfluoroalkane to the ocular surface or anterior segment of the eye.

[0021] In a third aspect, the present invention relates to a process for manufacturing at least one polyfluoroalkane of the present invention.

[0022] In a fourth aspect, the present invention relates to an apparatus for administering the composition to the eyelids of a subject, wherein the composition is adhered to, impregnated with, or coated on the apparatus.

[0023] In a fifth aspect, the present invention relates to a kit comprising the apparatus and the composition for using the present invention.

[0024] In a sixth aspect, the present invention relates to a method of continuously and / or controllably releasing a component to the eye of a subject for treating an eye disease or disorder of interest.

Mode for Carrying Out the Invention

[0025] Polyfluoroalkane Thus, the present invention relates to a polyfluoroalkane comprising at least one hydrophilic phase, at least one hydrophobic phase, and at least one surfactant. More preferably, the polyfluoroalkane of the present invention - at least one hydrophilic phase, - at least one hydrophobic phase, - at least one surfactant selected from an ionic surfactant and / or a nonionic surfactant, - optionally, at least one additive selected from an antioxidant, an osmotic agent, a viscosity modifier, a pH adjuster, a buffer, a preservative, a solubilizer, a chelating agent, - optionally, at least one active ingredient and.

[0026] Hydrophilic phase According to one embodiment, the polyaflon of the present invention is a polyaflon in which the hydrophilic phase is an aqueous composition or water.

[0027] This aqueous composition may contain a water-miscible surfactant or polymer and water.

[0028] Hydrophobic phase According to one embodiment, the polyaflon of the present invention has a hydrophobic phase comprising: short-chain (C4-C6) fatty acid mono, di, and triesters of glycerin; medium-chain (C8-C12) fatty acid mono, di, and triesters of glycerin; long-chain (C14 or higher) saturated fatty acid mono, di, and triesters of glycerin; long-chain (C14 or higher) unsaturated fatty acid mono, di, and triesters of glycerin; vegetable oil, tonsil oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard oil, oat oil (oat Oils), olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, squalane, soybean oil, sunflower oil, walnut oil, wheat germ oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, fatty acid esters (e.g., ethyl oleate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate…), short-chain (C4~C6) fatty acid mono and diesters of propylene glycol, medium-chain (C8~C) propylene glycol 12) A polyaflon comprising at least one selected from the group consisting of fatty acid mono and diesters, long-chain (C14 or higher) saturated fatty acid mono and diesters of propylene glycol, long-chain (C14 or higher) unsaturated fatty acid mono and diesters of propylene glycol, fatty alcohols (e.g., myristyl alcohol, oleyl alcohol, etc.), branched fatty alcohols (e.g., octyldodecanol, etc.), silicone oil, mineral oil, petrolatum, vitamin E, vitamin E acetate, tocopherol, tocopherol acetate, saturated fatty acids, unsaturated fatty acids, and phospholipids.

[0029] Preferably, the hydrophobic phase of the polyaflon of the present invention is a pharmaceutically acceptable oil or a mixture of pharmaceutically acceptable oils or comprising them.

[0030] In one embodiment, the hydrophobic phase of the polyaflon of the present invention does not contain phospholipids.

[0031] In one embodiment, the hydrophobic phase of the polyaflon of the present invention includes MCT. In one embodiment, the hydrophobic phase of the polyaflon of the present invention consists of MCT.

[0032] In one embodiment, the hydrophobic phase of the polyaflon of the present invention contains mineral oil. In one embodiment, the hydrophobic phase of the polyaflon of the present invention consists of mineral oil.

[0033] In one embodiment, the hydrophobic phase of the polyaflon of the present invention contains triacetin.

[0034] surfactant Nonionic surfactants In one embodiment, the polyaflon of the present invention comprises at least one nonionic surfactant. Advantageously, this at least one nonionic surfactant may be alkyl polyglycol ether, alkyl polyglycol ester, ethoxylated alcohol, polyoxyethylene sorbitan fatty acid ester, castor oil derivative, polyoxyethylene fatty acid ester, polyoxyethylene glycol hydrogenated castor oil, polyoxyethylene glycol castor oil, sorbitan fatty acid ester (e.g., sorbitan monolaurate, sorbitan monooleate), ethylene oxide and propylene oxide block copolymer (e.g., poloxamer 188, poloxamer 407), poloxamer, tyloxapole, polysorbate, sucrose alkyl ester, sucrose alkyl ether, or short-chain glycerin (C4-C6) The following groups are selected: fatty acid mono and diesters, medium-chain (C8-C12) fatty acid mono and diesters of glycerin, long-chain (C14 or higher) saturated fatty acid mono and diesters of glycerin, long-chain (C14 or higher) unsaturated fatty acid mono and diesters of glycerin, short-chain (C4-C6) fatty acid monoesters of propylene glycol, medium-chain (C8-C12) fatty acid monoesters of propylene glycol, long-chain (C14 or higher) saturated fatty acid monoesters of propylene glycol, long-chain (C14 or higher) unsaturated fatty acid monoesters of propylene glycol, polyoxylglycerides, polyoxyethylene alkyl esters, polyoxylethylene ethers, vitamin E succinate polyethylene glycol, and alkyl polyglycosides.

[0035] Ionic surfactants In one embodiment, the polyaflon contains at least one ionic surfactant. This ionic surfactant may be a cationic surfactant or an anionic surfactant.

[0036] Advantageously, at least one ionic surfactant is a cationic surfactant selected from the group consisting of C10-C24 primary alkylamines, tertiary aliphatic amines, quaternary ammonium compounds, cationic lipids (e.g., phosphatidylcholine), amino alcohols, biguanide salts, cationic polymers, and mixtures of two or more thereof. In preferred embodiments, at least one cationic surfactant is preferably a quaternary ammonium compound selected from the group consisting of benzalkonium halide, lauralkonium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium 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 of these, and the halide is preferably a chloride or bromide.

[0037] In one embodiment, at least one ionic surfactant is an anionic surfactant selected from the group consisting of phospholipids, lecithin, perfluorooctanoates, perfluorooctanesulfonates, alkyl sulfates, sodium lauryl ether sulfate, alkylbenzene sulfonates, soaps, fatty acid salts, or mixtures thereof.

[0038] Amount of surfactant The polyaflon of the present invention contains at least one surfactant. Advantageously, the amount of surfactant in the polyaflon of the present invention is in the range of 0.005 to 5%, preferably 0.05 to 5%, relative to the total weight of the polyaflon. Generally, in conventional emulsions, the surfactant:oil ratio is in the range of 1 / 10 to 2 / 1. In the polyaflon of the present invention, the surfactant:oil ratio is in the range of 1 / 50 to 1 / 40, and therefore the amount of surfactant in the polyaflon of the present invention is significantly less than in conventional emulsions. This difference provides a clear advantage for the polyaflon of the present invention over emulsions in that surfactant-related side effects are limited.

[0039] additives In one embodiment, the polyaflon contains additives selected from the group consisting of antioxidants, osmotic agents, viscosity modifiers, pH adjusters or buffers, preservatives, solubilizers, and chelating agents. The amount of additives may be calculated by those skilled in the art in accordance with pharmacopoeia and biological standards.

[0040] Antioxidants In one embodiment, the polyaflon contains an antioxidant selected from the group consisting of vitamin E, sodium bisulfite, sodium metasulfite, anhydrous sodium thiosulfate, citrate monohydrate, ascorbyl palmitate and ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, and propyl gallate. These antioxidants can be used individually or in combination. The amount of antioxidant may be calculated by a person skilled in the art in accordance with pharmacopoeia and biological standards.

[0041] Penetrating agent In one embodiment, the polyaflon contains at least one penetrating agent selected from the group consisting of glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol, and xylitol. The amount of the penetrating agent is determined in accordance with pharmacopoeia standards and biological standards.

[0042] Viscosity modifier - viscosity of the polyaflon of the present invention In one embodiment, the polyaflon comprises at least one viscosity modifier selected from the group consisting of carbomer, polycarbophil, cellulose derivatives (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc.), povidone, copovidone, natural gums (e.g., gellan gum, guar gum, xanthan gum, agar, xyloglucan, etc.), poloxamer, etc. These viscosity modifiers can be used alone or in combination in amounts that meet the requirements of pharmacopoeias (European and United States Pharmacopoeia) and biological standards.

[0043] In one embodiment, the polyaflon of the present invention has a very low shear rate (0.1s). -1 It exhibits a viscosity higher than 1 Pa·s at (less than) a shear rate. In one embodiment, the polyaflon of the present invention exhibits a viscosity higher than 1 Pa·s at zero shear rate.

[0044] The viscosity of this polyaflon is measured at atmospheric pressure (1 atm) and 25-35°C using a rheometer known to those skilled in the art (e.g., a rotary rheometer, Kinexus, Malvain, UK).

[0045] In one embodiment, the polyaflon exhibits shear-thickening behavior and thixotropic properties that make it easier and more convenient to apply to at least one eyelid of the subject.

[0046] pH adjuster or buffer In one embodiment, the polyaflon contains at least one pH adjuster or buffer selected from hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium bicarbonate, etc. The amount of pH adjuster is a function of the final pH value within the range of 3.5 to 7.5. Furthermore, the amount of pH adjuster used conforms to pharmacopoeia standards and biological standards.

[0047] Preservatives In one embodiment, the polyaflon contains, alone or in combination with, at least one preservative selected from benzalkonium chloride, benzyl alcohol, mercury salts, thiomersal, chlorhexidine, boric acid, and / or their salts. The amount of preservative used is in accordance with pharmacopoeia standards and biological standards.

[0048] Solubilizer In one embodiment, the polyaflon contains at least one solubilizing agent selected from ethanol, polyethylene glycol, glycerin, propylene glycol, N-methylpyrrolidone, glycoflol, and dimethyl isosorbide. The amount of solubilizing agent used is in accordance with pharmacopoeia standards and biological standards.

[0049] Chelating agents In one embodiment, the polyaflon contains at least one chelating agent selected from edetic acid and its salts, ethylene glycoltetraacetic acid and its salts, citric acid, metaphosphate, pyrophosphate, polyphosphate, malic acid, tartaric acid, phytic acid and their salts, more preferably at least one selected from the group consisting of edetic acid, citric acid, metaphosphate, polyphosphate and their salts, particularly preferably a salt of edetic acid. In addition, the amount of chelating agent used is in accordance with pharmacopoeia standards and biological standards.

[0050] Oil-in-water polyaflons and manufacturing processes In one embodiment, the polyaflon is an oil-in-water polyaflon in which the continuous phase contains or consists of water or a hydrophilic phase, and the dispersed phase contains or consists of aflon having a hydrophobic internal core. In this embodiment, the amount of the continuous phase may be in the range of 2% to 50%, preferably 2% to 20%, of the total weight of the polyaflon (aqueous composition), and the amount of aflon may be in the range of 50% to 98% w / w, preferably 70% to 98% w / w, and more preferably 80% to 98% w / w, of the total weight of the polyaflon. In one embodiment, the oil-in-water polyaflon contains aflon having an average diameter in the range of 0.1 to 100 μm.

[0051] In one embodiment, the oil-in-water polyaflon of the present invention is produced by a process of stirring an aqueous solution and then dropping a hydrophobic phase. Preferably, this aqueous solution is stirred at room temperature using a magnetic stirrer or propeller at 200 rpm to 1000 rpm, and the hydrophobic phase is added at a specific rate that allows for the formation of the aflon autocatalyst.

[0052] Water-in-oil polyaflons and their manufacturing processes In one embodiment, the polyaflon is a water-in-oil polyaflon comprising or consisting of aflon having a hydrophobic continuous phase and a hydrophilic internal core dispersed phase. In this embodiment, the amount of the continuous phase may be in the range of 2% to 50%, preferably 2% to 20%, of the total weight of the polyaflon (hydrophobic phase), and the amount of aflon may be in the range of 50% to 98% w / w, preferably 70% to 98% w / w, and more preferably 80% to 98% w / w, of the total weight of the polyaflon. In one embodiment, the water-in-oil polyaflon comprises aflon having an average diameter in the range of 0.1 to 100 μm.

[0053] In one embodiment, the water-in-oil polyaflon of the present invention is produced by a process of stirring an oily phase and then dropping an aqueous solution. Preferably, the aqueous solution is stirred at room temperature using a magnetic stirrer or propeller at 200 rpm to 1000 rpm, and the oily phase is added at a specific rate that allows for the formation of the aflon autocatalyst.

[0054] Polyaflon without active ingredients In one embodiment, the polyaflon contains no active ingredients, that is, it contains no drugs at all.

[0055] In this embodiment, the polyaflon may be considered a pharmaceutically acceptable medium.

[0056] In this embodiment, the polyaflon is particularly useful for treating dry eye conditions such as dry eye syndrome or chronic dry eye disease (CDED), both of which are clinically known as keratoconjunctivitis sicca (KCS).

[0057] Polyaflon containing active ingredients In one embodiment, the polyaflon contains an active ingredient. In one embodiment, the active ingredient is a therapeutic molecule.

[0058] In one embodiment, the active ingredient is selected from the following (single or in combination). - Antiallergic drugs such as sodium cromoglycate, antazoline, chlorpheniramine, cetirizine, olopatadine, epinastine, ketotifen, azelastine, emedastine, levocabastine, terfenadine, and loratadine. - Anti-inflammatory drugs such as cortisone, hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, dexamethasone palmitate, fluoroquinolones, prednisone, methylprednisone, prednisolone acetate, fluorometholone, triamcinolone, betamethasone, loteprednol, flumethasone, beclomethasone, difluprednate, triamcinolone acetonide and their derivatives, - Salicylates, indomethacin, ibuprofen, diclofenac, flurbiprofen, oxicam, piroxicam, and COX2 inhibitors, such as nonsteroidal anti-inflammatory drugs like rofecoxib, nimeslide, and nepafenac. - Timolol containing timolol maleate and its salts, levobunolol hydrochloride and betaxolol hydrochloride, betaxolol, atenolol, befundol, metipranolol, forskolin, carteolol and other beta-adrenergic blockers, - Cytokines, interleukins and latanoprost, as well as prostaglandins such as bimatoprost, tafluprost or travoprost (including anti-prostaglandins and prostaglandin precursors), - Cyclosporine, sirolimus, tacrolimus, - Antioxidants such as lutein, vitamins, especially vitamin A, coenzyme Q10, polyunsaturated fatty acids and their derivatives, - Carbonic anhydrase inhibitors such as brinzolamide, dorzolamide, acetazolamide, metazolamide, and diclofenamide. - Antiviral drugs such as idoxuridine, trifluorothymidine, acyclovir, valacyclovir, ganciclovir, cidofovir, and interferon. - Antibiotics such as aminoglycosides, carbasephalosporins, carbapenems, cephalosporins, glycopeptides, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, kanamycin, rifampicin, tobramycin, gentamicin, ciprofloxacin, aminosides, erythromycin, ceftazidime, vancomycin, imipenem, macrolides, azithromycin, clarithromycin, fluoroquinolones, etc. - Antibiotics such as sulfonamides, sulfadiazine, sulfacetamide, sulfamethizol, sulfisoxazole, nitrofurazone, and sodium propionate. - and / or their derivatives and / or their prodrugs and / or their precursors and / or their acceptable salts.

[0059] In one embodiment, the active ingredient is selected from latanoprost, tafluprost, timolol, dorzolamide, olopatadine, epinastine, azithromycin, clarithromycin, cyclosporine A and sirolimus, dexamethasone, and dexamethasone palmitate.

[0060] In one embodiment, the active ingredient is olopatadine. In one embodiment, the active ingredient is epinastine. In one embodiment, the active ingredient is clarithromycin. In one embodiment, the active ingredient is cyclosporine A. In one embodiment, the active ingredient is dexamethasone palmitate.

[0061] In one embodiment, the polyaflon stabilizes and / or preserves the active ingredient.

[0062] sterile In one embodiment, the polyaflon may be sterilized.

[0063] Non-exclusive examples of sterilization methods include heating, such as autoclaving, sieving or filtration, irradiation, and gas sterilization.

[0064] form In one embodiment, the polyaflon of the present invention may be a liquid, fluid, gel, powder, ointment, cream, patch, film formulation, or any delivery formulation suitable for eyelid administration.

[0065] Preferably, the polyaflon has a viscosity suitable for topical administration to the eyelid skin and is administered to the subject by instillation or administration in the form of a gel, cream, ointment, or patch, or any form suitable for use in the eye by eyelid administration.

[0066] packaging In one embodiment, the polyaflon is packaged in unit doses, and in another embodiment, the polyaflon is packaged in a suitable multi-dose container.

[0067] method Eyelid application kit In one embodiment, the present invention relates to a method for topically applying polyaflon to at least one eyelid, upper eyelid and / or lower eyelid of a subject.

[0068] In one embodiment, the polyaflon is applied locally to the skin around the target eye. In another embodiment, the polyaflon is applied to the target eyelid. In yet another embodiment, the polyaflon is applied to the target upper eyelid. In yet another embodiment, the polyaflon is applied to the target lower eyelid.

[0069] In another embodiment, the polyaflon is applied using, for example, a spreading device such as a brush or applicator.

[0070] The present invention also relates to a container containing the polyaflon of the present invention and a kit equipped with the above-mentioned spreading device.

[0071] Transdermal delivery In another aspect, the present invention relates to a method for transdermally delivering polyaflon or its components to a target eye in order to treat a target eye disease or ophthalmological condition.

[0072] In one embodiment, the method of the present invention is useful for delivering the polyaflon or its components to the ocular surface or anterior segment of the eye.

[0073] In one embodiment, the method of the present invention is useful for treating the eye.

[0074] In one embodiment, the polyaflon contains, as an additive, a penetration enhancer, i.e., a compound that promotes the transdermal penetration of the polyaflon or its components into the ocular surface or anterior segment of the eye.

[0075] Sustained and / or controlled release of components In another aspect, the present invention relates to a method for causing a component to be released continuously and / or controlledly into the eye of a target in order to treat a target eye disease or ophthalmological condition.

[0076] In one embodiment, sustained and / or controlled release is achieved by applying a polyaflon of the present invention containing the component to at least one eyelid, upper eyelid and / or lower eyelid of the subject.

[0077] In one embodiment, the method of the present invention is efficient for achieving sustained and / or controlled-release administration of therapeutic agents.

[0078] In one embodiment, the component is sustained and / or released under controlled conditions for a period ranging from 1 hour to 2 weeks, preferably 6 hours to 1 week, and preferably 12 hours to 5 days. In a specific embodiment, the component is sustained and / or released under controlled conditions for a period ranging from 1 to 3 days.

[0079] In one embodiment, the sustained and / or controlled release kinetics may be determined by the formulation of the polyaflon. In a specific embodiment, the release kinetics are determined by the properties of the hydrophilic phase of the polyaflon. In a specific embodiment, the release kinetics are determined by the properties of the hydrophobic phase of the polyaflon. In a specific embodiment, the release kinetics are determined by the properties of the surfactant or mixture of surfactants contained in the polyaflon. In a specific embodiment, the release kinetics are determined by the concentration of the surfactant or mixture of surfactants contained in the polyaflon.

[0080] In one embodiment, the sustained and / or controlled release rate may be determined by the viscosity of the polyaflon. In a specific embodiment, as the viscosity of the polyaflon increases, the release rate decreases.

[0081] In one embodiment, the sustained and / or controlled release rate may be determined by the average sphere size of the polyaflon. In a specific embodiment, the release rate decreases as the average sphere size of the polyaflon decreases.

[0082] In one embodiment, the sustained and / or controlled release rate may be determined by the volume of polyaflon applied to the target eye.

[0083] In one embodiment, the sustained and / or controlled release rate can be tailored to the precise needs of the subject. In a specific embodiment, the release rate can be tailored to the precise needs of the subject by selecting a surfactant or mixture of surfactants to be included in the polyaflon. In a specific embodiment, the release rate can be tailored to the precise needs of the subject by selecting an appropriate concentration of the surfactant or mixture of surfactants to be included in the polyaflon. In a specific embodiment, the release rate can be tailored to the precise needs of the subject by changing the viscosity and / or average sphere size of the polyaflon.

[0084] In one embodiment, the method of the present invention is useful for sustained and / or controlled release of the component onto the ocular surface or anterior segment of the eye.

[0085] In one embodiment, the method of the present invention is useful for treating the eye.

[0086] Eye disease or eye condition In the sense of the present invention, eye diseases or ophthalmic conditions include, for example, dry eye conditions such as dry eye syndrome or chronic dry eye disease, e.g., keratoconjunctivitis sicca (KCS), atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC), glaucoma, inflammatory conditions of the eye such as keratitis, corneal epithelial erosion, uveitis (including anterior uveitis), endophthalmitis, allergies and dry eye syndrome eye infections, eye infections, eye allergies, corneal or conjunctival lesions, cancerous proliferation, diabetic macular edema, age-related macular degeneration, corneal loss of sensation, and pupillary dilation (mydriase).

[0087] In one embodiment, the eye disease may be blepharitis, glaucoma, meibomian gland diseases such as meibomian gland dysfunction (MGD), dry eye conditions such as dry eye syndrome or chronic dry eye disease, diabetic keratopathy or neurotrophic keratopathy.

[0088] In one embodiment, the eye disease may be related to a demodectic mange infection. In one embodiment, the eye disease is glaucoma. In one embodiment, the eye disease is anterior uveitis.

[0089] In another embodiment, the polyaflon of the present invention is for use in the treatment of eye diseases or ophthalmic disorders.

[0090] In another embodiment, the polyaflon of the present invention is for use in the manufacture of pharmaceuticals or drugs for the treatment of eye diseases or ophthalmic disorders.

[0091] In another embodiment, the present invention relates to a method for treating an eye disease or ophthalmic condition, comprising administering a therapeutically active amount of a therapeutic agent to a patient in need by topical application of a polyaflon containing the therapeutic agent. In one embodiment, the method includes the step of topically administering a composition containing polyaflon to the upper and / or lower eyelids of the target. In one embodiment, the topical application is an eyelid application.

[0092] In one embodiment, the polyaflon is administered once a day for four weeks.

[0093] In one embodiment, administration via the eyelid through polyaflon reduces the toxicity and / or side effects of the treatment in patients.

[0094] definition In this invention, the following terms have the meanings set forth below.

[0095] "Aflon" refers to a composite sphere consisting of a core made of a phase that is immiscible with the continuous phase, an outer layer containing a surfactant that encloses an intermediate layer made of the same material as the continuous phase.

[0096] The term "continuous phase" refers to a phase that encompasses the dispersed phase.

[0097] The term "dispersed phase" refers to small spheres dispersed in a continuous phase.

[0098] The term "eyelid" includes the upper eyelid, which begins at the eyebrow and extends to the lower limit defined by the base of the eyelashes, and the lower eyelid, which begins below the orbit and extends to the limit defined by the base of the eyelashes.

[0099] "MCT" stands for medium-chain triglyceride.

[0100] "Therapeutic molecules" refer to any molecule that has a specific purpose of treating a pathological condition or disease.

[0101] "ND" means "Undecided".

[0102] "Eyelid administration" refers to topical application to the outer surface of at least one eyelid of the subject.

[0103] "Polyaflon" refers to small liquid spheres called aflon dispersed in a continuous phase. [Brief explanation of the drawing]

[0104] [Figure 1] This graph shows the results of in vitro efficacy tests of polyaflon #28 filled with clarithromycin, oily solution #29, and ointment #30 (Example 6). [Figure 2] This graph shows the results of in vitro penetration tests of polyaflon #31-#33 filled with dexamethasone (Example 7). [Figure 3] This graph shows the results of in vitro skin penetration tests of polyaflon #21-#23 filled with olopatadine HCl (Example 8). [Figure 4] This is a histogram showing the results of in vivo efficacy tests of polyaflon #34 and solution #39 filled with clarithromycin (Example 10). [Figure 5] This is a histogram showing the results of in vivo efficacy tests of clarithromycin-filled polyaflon #34 and ointment #40 (Example 11). [Figure 6] This histogram shows the results of in vivo efficacy tests of clarithromycin-filled polyaflon #34 and emulsion #41 (Example 12). [Examples]

[0105] The present invention is further illustrated by the following embodiments.

[0106] Example 1: Oil-in-water polyaflon without the active pharmaceutical ingredient according to the present invention [Table 1]

[0107] Example 2: Oil-in-water polyaflon containing cyclosporine A according to the present invention [Table 2]

[0108] Example 3: Oil-in-water polyaflon containing dexamethasone palmitate according to the present invention [Table 3]

[0109] Example 4: A water-in-oil polyaflon containing fluorescein sodium as a hydrophilic marker or olopatadine HCl as the active pharmaceutical ingredient according to the present invention. [Table 4]

[0110] Example 5: Water-in-oil polyaflon containing epinastine as the active pharmaceutical ingredient according to the present invention [Table 5]

[0111] The particle size distribution of each polyaflon was measured using a state-of-the-art laser diffraction instrument (Helos Sympatec, Germany). This particle size distribution was determined on a volume basis (Dv). The viscosity of each polyaflon was measured using a state-of-the-art rheometer (Kinexus, Malvain, UK).

[0112] According to the physical properties of the compositions shown in Table 6, a correlation is observed between the particle size distribution and the viscosity of the system. That is, as the viscosity of the composition increases, the particle size distribution decreases. These characteristics may be determined by either the qualitative or quantitative composition of the polyaflon. [Table 6]

[0113] Example 6: In vitro evaluation of the penetration of oil-in-water polyaflons containing clarithromycin The transdermal penetration of clarithromycin was evaluated using a Franz Cell instrument equipped with a Strat-M membrane purchased from Millipore (Morsheim, France). The Strat-M membrane is a synthetic membrane used for in vitro studies that simulate skin penetration.

[0114] The emission of clarithromycin from polyaflon (composition #28) was compared with that from an oily solution (composition #29) and an ointment (composition #30). Clarithromycin concentrations in the receptor compartment over 72 hours were measured by ultra-high-performance liquid chromatography (UPLC).

[0115] The following formulations were evaluated. [Table 7]

[0116] As disclosed in Figure 1, application of ointment #30 did not result in transdermal penetration, but clarithromycin was released from polyaflon #28. Therefore, this experiment clearly demonstrates that polyaflon is superior to ointment in terms of therapeutic drug skin penetration.

[0117] Clarithromycin evaporates from the oily solution #29 through the membrane, but such compositions are not suitable for topical application to the eyelids because their viscosity (25-33 mPa.s) is not high enough to keep the oily solution on the eyelids. The oily solution would run along the eyelids and / or into the eye. In contrast, the viscosity (greater than 1 Pa.s) of polyaflon #28 is high enough to keep on the eyelids and is therefore suitable for eyelid administration.

[0118] Furthermore, as also shown in Figure 1, polyaflon #28 can release clarithromycin remarkably efficiently for over 72 hours, while oily solution #29 releases clarithromycin immediately. This demonstrates that sustained and controlled release of therapeutic agents through the skin can be achieved by using polyaflon.

[0119] Example 7: In vitro evaluation of the penetration of oil-in-water polyaflons containing dexamethasone. The transdermal penetration of dexamethasone was evaluated using a Franz Cell instrument equipped with a Strat-M membrane purchased from Millipore (Morsheim, France). The Strat-M membrane is a synthetic membrane used for in vitro studies that simulate skin penetration.

[0120] The particle size distribution of each polyaflon was measured using a state-of-the-art laser diffraction instrument (Helos Sympatec, Germany). This particle size distribution was determined by volume (Dv). The viscosity of each polyaflon was measured using a state-of-the-art rheometer (Kinexus, Malvain, UK).

[0121] The emission of dexamethasone from polyaflons with different compositions (compositions #31-33) was compared. Dexamethasone concentrations in the receptor compartment were measured by ultra-high-performance liquid chromatography (UPLC) over a 48-hour period.

[0122] The following formulations were evaluated. [Table 8]

[0123] According to the physical properties of the compositions shown in Table 9, a correlation is observed between the particle size distribution and the viscosity of the system. That is, as the viscosity of the composition increases, the particle size distribution decreases. These characteristics may be determined by either the qualitative or quantitative composition of the polyaflon. [Table 9]

[0124] The results disclosed in Figure 2 clearly demonstrate that polyaflons can sustainably release dexamethasone through the skin for more than 48 hours. Furthermore, they demonstrate that the composition of the polyaflons influences the dexamethasone release profile.

[0125] Surprisingly, the release rate is determined by the properties of the surfactant. This release is faster when using Polyaflon #31, which is a mixture of PEG-40 stearate and sorbitan oleate, than when using compositions #32 and #33, which use poloxamer as the surfactant.

[0126] Surprisingly, the release rate also correlates with the viscosity and particle size distribution of the composition. Comparing compositions #32 and #33, as the relative concentration of the surfactant increases, the particle size distribution decreases and the viscosity increases. Therefore, the release rate is slower when using polyaflon #32, which has smaller particle sizes and higher viscosity, than when using polyaflon #33, which has larger particle sizes and lower viscosity.

[0127] Therefore, the release rate from polyaflon can be controlled by changing the qualitative and / or quantitative formulation of the polyaflon, for example, by affecting the properties and / or concentration of the surfactant.

[0128] Example 8: In vitro evaluation of the penetration of water-in-oil polyaflons containing olopatadine HCl The transdermal penetration of olopatadine HCl was evaluated using a Franz Cell instrument equipped with a Strat-M membrane purchased from Millipore (Morsheim, France). The Strat-M membrane is a synthetic membrane used for in vitro studies that simulate skin penetration.

[0129] The emission of olopatadine HCl from polyaflons (compositions #21-23) with different compositions disclosed in Table 4 of Example 4 was compared. The olopatadine HCl concentration in the receptor compartment over 48 hours was measured by ultra-high-performance liquid chromatography (UPLC).

[0130] As shown in Figure 3, sustained and controlled release can also be obtained by releasing olopatadine HCl via polyaflon.

[0131] Surprisingly, the addition of hydrophilic cosolvents that act as penetration enhancers (e.g., glycerin, PEG400) promotes penetration through the Strat-M membrane in vitro.

[0132] Example 9: Method for producing Polyaflon #34-38 Polyaflon #34-38 containing clarithromycin (Examples 10-13 below) was used for in vivo evaluation.

[0133] Polyaflon #34 shown in Table 10 below was prepared according to the following process: To an aqueous phase (8.995 g) containing polysorbate 80SR (1 g) stirred at 200 rpm, an oily phase MCT (39 g) containing CKC (0.005 g), propylene glycol monocaprylate (50 g), and clarithromycin (1 g) was added dropwise. The rate of addition of the oily phase was slow at the start of the process (approximately one drop every 7 seconds), but was quickly accelerated after 20% of the oily phase was added so that the total time to prepare this polyaflon was approximately 20 minutes.

[0134] Polyaflon #35-38 shown in Table 10 below were prepared following the same manufacturing process. [Table 10]

[0135] For comparison, emulsions and ointments #39-42 containing clarithromycin, as shown in Table 11 below, were prepared. [Table 11]

[0136] Example 10: In vivo experiment - Application of polyaflon #34 to the eyelids compared with ophthalmic solution #39 to the cornea. Obstruction of the meibomian glands is called meibomian gland dysfunction (MGD), which is often a cause of dry eye and can also be a contributing factor to blepharitis.

[0137] Polyaflon #34 (1% w / w clarithromycin) was topically applied once daily to the eyelids of subjects showing meibomian gland obstruction for 4 weeks. For comparison, solution #39 (1% w / w clarithromycin) was instilled into the corneas of subjects three times daily for 4 weeks. Each formulation was evaluated in 6 eyes (n=6). The results are shown in Figure 4.

[0138] Polyaflon #34 (1% w / w clarithromycin) reduced the number of occluded glands at the same rate as solution #39 (1% w / w clarithromycin) administered as eye drops to the cornea after 4 weeks of treatment.

[0139] Furthermore, it was clinically observed that the toxicity of polyaflon #34 applied topically to the eyelids was lower than that of solution #39 applied directly to the cornea. While the solution applied to the cornea caused irritation and necrosis of the corneal epithelium, no signs of corneal toxicity were reported with the application of polyaflon #34 to the eyelids.

[0140] Example 11: In vivo experiment - Eyelid application of Polyaflon #34 compared to application of ointment #40. Polyaflon #34 (1% w / w clarithromycin) was applied topically once daily to the eyelids of subjects showing meibomian gland obstruction for 4 weeks. For comparison, ointment #40 (3% w / w clarithromycin) was applied topically once daily to the eyelids of the same subjects for 4 weeks. Each formulation was evaluated in 6 eyes (n=6). The results are shown in Figure 5.

[0141] Polyaflon #34 reduced the number of occluded glands at the same rate as ointment #40 after 4 weeks of treatment. However, this reduction in the number of occluded cells must be balanced against the fact that ointment #40 is more than three times more concentrated than polyaflon #34. Therefore, when using polyaflon #34, it is necessary to reduce the amount of clarithromycin in the polyaflon to produce the same efficacy as ointment #40.

[0142] Despite the aforementioned ointment being more than three times more concentrated with clarithromycin than the aforementioned polyaflon, the toxicity profile of polyaflon #34 is similar to that of ointment #40. No corneal toxicity was observed when polyaflon #34 was used.

[0143] Therefore, applying polyaflon #34 to the eyelids allows for the use of clarithromycin in smaller doses and exhibits a better safety profile.

[0144] Example 12: In vivo experiment - Eyelid application of Polyaflon #34 compared to corneal application of emulsion #41. Polyaflon #34 (1% w / w clarithromycin) was topically applied once daily to the eyelids of subjects showing meibomian gland obstruction for 4 weeks. For comparison, emulsion #41 (1% w / w clarithromycin) was topically applied three times daily to the eyelids of the same subjects for 4 weeks. Each formulation was evaluated in 6 eyes (n=6). The results are shown in Figure 6.

[0145] Polyaflon #34 reduced the number of occluded glands to a much greater extent than emulsion #41 after one week of treatment.

[0146] Furthermore, Polyaflon #34 shows an improved safety profile compared to emulsion #41 when applied to the cornea. In fact, no signs of corneal toxicity were reported after application of Polyaflon #34 to the eyelids, while serious toxicity (i.e., corneal epithelial necrosis) was reported after application of emulsion #41.

[0147] Example 13: Stability measurement of clarithromycin by quantitative analysis in polyaflon #37 and oil-in-water emulsion #42 Polyaflon #37 (0.5% w / w clarithromycin) and oil-in-water emulsion #42 (0.5% w / w clarithromycin) were heated at 40°C and 60°C for one week. The amount of clarithromycin was measured at the end of the experiment and compared to the initial amount. The results are shown as a percentage of the initial amount of clarithromycin and are presented in Table 12. [Table 12]

[0148] At 40°C, 99% of the active ingredient is recovered in polyaflon #37 after a week of experimentation, but only 90% is recovered in oil-in-water emulsion #42. At 60°C, only 72% of the active ingredient is recovered in oil-in-water emulsion #42, but polyaflon #37 still contains 96% of the active ingredient.

[0149] Therefore, compared to oil-in-water emulsion #42, the stability of clarithromycin can be improved by using polyaflon #37.

Claims

1. A composition for use in topical administration to the upper and / or lower eyelids of the target, The composition is a gel or cream containing polyaflon, The polyaflon comprises small spheres with an average size in the range of 0.1 to 100 μm. The composition wherein the amount of nonionic surfactant in the polyaflon is in the range of 0.05 to 5% by weight relative to the total weight of the polyaflon.

2. The composition for use according to claim 1, wherein the nonionic surfactant is selected from the group consisting of at least alkyl polyglycol ethers, alkyl polyglycol esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene glycol hydrogenated castor oil, polyoxyethylene glycol castor oil, sorbitan fatty acid esters, poloxamer, tyroxapole, sucrose alkyl esters, short-chain fatty acid esters of glycerin, medium-chain fatty acid esters of glycerin, long-chain saturated fatty acid esters of glycerin, long-chain unsaturated fatty acid esters of glycerin, polyoxylglycerides, and alkyl polyglycosides.

3. The composition for use according to claim 1, wherein the polyaflon comprises small spheres having a particle size distribution D90 of 51.5 μm or less.

4. The composition for use according to claim 1, wherein the polyaflon comprises small spheres having a particle size distribution D10 of 1.5 μm or more.

5. The composition for use according to claim 1, wherein the polyaflon is an oil-in-water type polyaflon, the amount of the hydrophilic phase is in the range of 2% to 50% by weight relative to the total weight of the polyaflon, and the amount of the hydrophobic phase is in the range of 50% to 98% by weight relative to the total weight of the polyaflon.

6. The composition for use according to claim 1, wherein the polyaflon is a water-in-oil polyaflon, the amount of the hydrophobic phase is in the range of 2% to 50% by weight relative to the total weight of the polyaflon, and the amount of the hydrophilic phase is in the range of 50% to 98% by weight relative to the total weight of the polyaflon.

7. The composition for use according to claim 1, further comprising at least one active ingredient.

8. At least one hydrophilic phase, At least one hydrophobic phase, Optionally, at least one additive selected from antioxidants, osmotic agents, viscosity modifiers, pH adjusters, buffers, preservatives, solubilizers, and chelating agents. A composition for use according to claim 1, comprising:

9. The composition for use according to claim 8, wherein the hydrophilic phase is selected from the group consisting of aqueous compositions and water.

10. The composition for use according to claim 8, wherein the hydrophobic phase is selected from the group consisting of monoesters, diesters and triesters of medium-chain fatty acids of glycerin, triacetin, monoesters and diesters of medium-chain fatty acids, mineral oil and petrolatum.

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