Polyaphrons and palpebral administration thereof

Abstract

The present invention relates to a composition for use in topical administration on the upper and / or lower eyelids of a subject, comprising polyapron.

Description

Technology Field

[0001] The present invention relates to a polyaphron that is easy to apply within the general scope of herbal formulations. In particular, the present invention relates to a composition containing at least one polyaphron for topical administration, preferably for eyelid administration. Background Technology

[0002] Explanation of Polyapron

[0003] Polyaphron is a dispersion. In the sense 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 "Aphron" dispersed in a continuous phase, wherein the Aphron is not miscible. The dispersion phase may be a hydrophilic phase or a hydrophobic phase, provided that the Aphron remains unmiscible in the continuous phase. The continuous phase may be a fluid, a liquid, or a gel.

[0004] More precisely, the dispersed polyapron may consist of a composite aphron dispersed in the continuous phase, and said aphron

[0005] - A core composed of a continuous phase and a non-miscible material;

[0006] - An intermediate layer composed of the same material as the continuous phase;

[0007] - Outer layer containing a surfactant

[0008] has

[0009] For example, in an oil-in-water polyapron, the apron may comprise an inner core which is a hydrophobic sphere, an intermediate layer consisting of an aqueous solution, and an outer layer containing a surfactant. In an oil-in-water polyapron, the hydrophobic phase may represent up to 98% by weight relative to the total weight of the polyapron, and the polyapron contains a very small amount of surfactant (typically in the range of 0.05 to 5% or 0.1 to 3% by weight relative to the total weight of the polyapron) compared to a large amount of dispersed phase.

[0010] As another example, in a water-in-oil polyapron, the apron may comprise an inner core which is an aqueous sphere, an intermediate layer consisting of a hydrophobic solution, and an outer layer containing a surfactant. In a water-in-oil polyapron, the hydrophilic phase may represent up to 98% by weight relative to the total weight of the polyapron.

[0011] It is noteworthy that, unlike emulsions characterized by a single interface, polyafron has a multi-layer structural architecture and can have excellent stability.

[0012] background

[0013] Polyaprons were first described 40 years ago. US 4,486,333 describes a method for preparing polyaprons, specifically oil-in-water polyaprons using kerosene, petroleum ether, carbon tetrachloride, a carbon tetrachloride-cyclohexane mixture as the hydrophobic phase and water or methanol as the hydrophilic phase.

[0014] Polyaphron compositions are known as oral drug delivery systems. For example, WO 2005 / 011628 describes the delivery of a lipophilic and poorly soluble drug in an immediate administration form as a polyaphron composition.

[0015] Polyaphron compositions can be used as topical drug delivery systems for transporting active ingredients. For example, US 4,999,198 describes the delivery of scopolamine dissolved in peanuts and mineral oil into another medium; WO 2008 / 110826 describes a corticosteroid combined with vitamin E by application to the skin via topical application; and EP 1 970 049 describes a topical composition for skin use of a composition containing vitamin D in the treatment of a number of skin conditions such as psoriasis or dermatitis.

[0016] Recently, polyapron dispersions are being used for ophthalmic purposes. For example, WO 2012 / 123515 describes a method for delivering different active ingredients such as antibiotics (cyclosporine, vancomycin), anti-inflammatory compounds (flurbiprofen, fluticasone), and prostaglandins (latanoprost). WO 2012 / 123515 describes eye drops administered topically to the cornea of ​​humans / animals.

[0017] technical issues

[0018] The inventors have observed that various problems arise when eye drops are administered topically directly to the surface of a patient's eye. First, some patients are unable to administer the eye drops themselves, which creates problems with local administration. Additionally, when the eye drops are dispersed, patients wonder whether at least one drop has reached the target (cornea and / or conjunctiva); this problem increases with age and in children. Consequently, issues regarding the correct dosage arise. Furthermore, even if the eye drops are properly delivered to the surface of the eye, patients may experience some degree of discomfort or blurred vision. Instilling eye drops onto the surface of the eye usually triggers the eyelid reflex, causing most of the drops to be washed away within a few seconds. It is estimated that more than 95% of the eye drops are washed away from the surface of the eye within 2 minutes of administration.

[0019] More importantly, direct application of the composition to the surface of the eye may cause irritation, particularly corneal and / or conjunctival irritation, due to the presence of irritating components in the formulation. This can be a practical issue when the primary target of treatment is the eye.

[0020] Another major issue in eye treatment is the frequency of administration. Applying eye drops multiple times a day can be a significant burden for some patients and may severely impair their tolerance to the treatment.

[0021] These different issues regarding eye treatment compositions led the inventors to devise an easy-to-apply polyapron that targets the eye and cornea while avoiding direct application of the composition, and also prevents discomfort, blurred vision, and irritation.

[0022] Another issue regarding eye treatment is achieving extended release of the therapeutic agent into the eye in order to gradually deliver the agent to the targeted area of ​​the eye. Administering a large amount of the active agent into the eye over a short period can cause toxic concentration and, consequently, harm to the targeted area of ​​the eye.

[0023] Therefore, releasing a specific amount of therapeutic agent over a sustained period is of interest, wherein the specific amount is sufficient to achieve therapeutic efficacy and should not release an excessive amount of therapeutic agent that could cause local toxicity. Another advantage of an extended delivery period is that the frequency of administration is reduced and, consequently, the indication may be improved.

[0024] Surprisingly, the inventors realized that polyaprons could be effective vehicles for sustained and / or controlled release of drugs into a subject's eye through palpebral application. This discovery led the inventors to devise a polyapron capable of sustained and / or controlled release of drugs onto a subject's eye.

[0025] In a first aspect, the present invention relates to a composition for topical administration onto at least one eyelid of a subject or a composition comprising a polyapron. In one embodiment, the polyapron comprises an active ingredient.

[0026] In one embodiment, the present invention relates to a composition containing at least one polyapron, said component, for use in eyelid administration of said component to the eye of a subject by locally administering said polyapron onto at least one eyelid of the subject. In one embodiment, said component is an active component.

[0027] In a second aspect, the present invention relates to a method for transdermally delivering polyapron or a component thereof onto the eye of a subject to treat an eye disease or eye condition of said subject. The method of the present invention is useful for delivering at least one component of polyapron to the surface of the eye or to the anterior segment of the eyeball.

[0028] In a third aspect, the present invention relates to a method for manufacturing at least one polyapron of the present invention.

[0029] In a fourth aspect, the present invention relates to an apparatus for applying a composition for use on the eyelids of an object, said composition being deposited, impregnated, or coated onto the apparatus.

[0030] In a fifth aspect, the present invention relates to a kit comprising a device and a composition for use in the present invention.

[0031] In a sixth aspect, the present invention relates to a method of continuously and / or regulatedly releasing a component onto the eye of a subject to treat an eye disease or eye condition of the subject. Brief explanation of the drawing

[0032] Fig. 1 silver Clarithromycin-loaded polyapron #28 , oily solution #29 and ointment #30 This is a graph showing the results of an in vitro efficacy test (Example 6). Fig. 2 dexamethasone-loaded polyapron #31 inside #33 This is a graph showing the results of an in vitro efficacy test (Example 7). Fig. 3 olopatatin HCl-loaded polyapron #21 inside #23 This is a graph showing the results of an in vitro skin penetration test (Example 8). Fig. 4 is clarithromycin-loaded polyapron #34 solution #39 This is a histogram showing the results of an in vivo efficacy test of (Example 10). Fig. 5 Is Clarithromycin loaded Polyaphron #34 and ointment #40 This is a histogram showing the results of an in vivo efficacy test of (Example 11). Fig. 6 Clarithromycin-loaded polyapron #34 and emulsion #41 This is a histogram showing the results of an in vivo efficacy test of (Example 12). Specific details for implementing the invention

[0033] Polyaphron

[0034] Accordingly, the present invention relates to a polyapron comprising at least one hydrophilic phase, at least one hydrophobic phase, and at least one surfactant. More preferably, the polyapron of the present invention is

[0035] - At least one hydrophilic phase;

[0036] - At least one hydrophobic phase;

[0037] - At least one surfactant selected from ionic surfactants and / or non-ionic surfactants;

[0038] - At least one additive optionally selected from antioxidants, osmotic agents, viscosity modifiers, pH modifiers, buffers, preservatives, solubilizers, and chelating agents;

[0039] - At least one active ingredient

[0040] Includes

[0041] hydrophilic phase

[0042] According to one embodiment, the polyapron of the present invention is a polyapron in which the hydrophilic phase is an aqueous composition or water.

[0043] The aqueous composition may include a water-miscible surfactant or polymer and water.

[0044] hydrophobic phase

[0045] According to one embodiment, the polyapron of the present invention comprises, wherein the hydrophobic phase is a short-chain (C4 to C6) fatty acid mono-, di-, and triester of glycerol, a medium-chain (C8 to C12) fatty acid mono-, di-, and triester of glycerol, a long-chain (C14 or higher) saturated fatty acid mono-, di-, and triester of glycerol, a long-chain (C14 or higher) unsaturated fatty acid mono-, di-, and triester of glycerol, vegetable oil, almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, laurel oil, fish oil, grapeseed oil, mustard seed oil, oat oil, 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, etc.), short-chain (C4 to C6) fatty acid mono- and diesters of propylene glycol, medium-chain (C8 to C12) fatty acid mono- and diesters of propylene glycol, 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, petroleum jelly, vitamin E, vitamin E acetate, tocopherol, tocopherol acetate, saturated fatty acids, unsaturated It is a polyapron that includes at least one of the groups selected from fatty acids and phospholipids.

[0046] Preferably, the hydrophobic phase of the polyapron of the present invention is or comprises a pharmaceutically acceptable oil or a mixture of pharmaceutically acceptable oils.

[0047] In one embodiment, the hydrophobic phase of the polyapron of the present invention is free of phospholipids.

[0048] In one embodiment, the hydrophobic phase of the polyafron of the present invention comprises MCT. In one embodiment, the hydrophobic phase of the polyafron of the present invention is composed of MCT.

[0049] In one embodiment, the hydrophobic phase of the polyafron of the present invention comprises mineral oil. In one embodiment, the hydrophobic phase of the polyafron of the present invention is composed of mineral oil.

[0050] In one embodiment, the hydrophobic phase of the polyapron of the present invention comprises triacetin.

[0051] surfactants

[0052] Non-ionic surfactants

[0053] In one embodiment, the polyapron of the present invention comprises at least one non-ionic surfactant. Advantageously, at least one non-ionic surfactant is an alkyl polyglycol ether, an alkyl polyglycol ester, an ethoxylated alcohol, a polyoxyethylene sorbitan fatty acid ester, a castor oil derivative, a polyoxyethylene fatty acid ester, a polyoxyethylene glycol hydrogenated castor oil, a polyoxyethylene glycol castor oil, a sorbitan fatty acid ester (e.g., sorbitan monolaurate, sorbitan monooleate), a block copolymer of ethylene oxide and propylene oxide (e.g., Poloxamer 188, Poloxamer 407), a poloxamer, tiloxapol, a polysorbate, a sucrose alkyl ester, a sucrose alkyl ether, a short-chain (C4 to C6) fatty acid mono- and diester of glycerol, a medium-chain (C8 to C12) fatty acid mono- and diester of glycerol, a long-chain (C14 or higher) saturated fatty acid mono- and diester of glycerol, It is selected from the group consisting of long-chain (C14 or higher) unsaturated fatty acid mono- and diesters of glycerol, short-chain (C4 to C6) fatty acid monosters of propylene glycol, medium-chain (C8 to C12) fatty acid monosters of propylene glycol, long-chain (C14 or higher) saturated fatty acid monosters of propylene glycol, long-chain (C14 or higher) unsaturated fatty acid monosters of propylene glycol, polyoxyglycerides, polyoxyethylene alkyl esters, polyoxyethylene ethers, vitamin E polyethylene glycol succinate, and alkyl polyglycosides.

[0054] ionic surfactants

[0055] In one embodiment, the polyapron comprises at least one ionic surfactant. The ionic surfactant may be a cationic surfactant or an anionic surfactant.

[0056] Advantageously, at least one surfactant It is a cationic surfactant selected from the group 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 of these. In a preferred embodiment, at least one cationic agent is a quaternary ammonium compound preferably selected from the group consisting of benzalkonium halide, lauralkonium halide, cetrimid, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetetyldimonium 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.

[0057] In one embodiment, at least one ionic surfactant is an anionic surfactant selected from the group consisting of phospholipids, lecithin, perfluorooctanoate, perfluorooctanesulfonate, alkyl sulfate salts, sodium lauryl ether sulfate, alkyl benzene sulfonate, soap or fatty acid salts or mixtures thereof.

[0058] Amount of surfactant

[0059] The polyapron of the present invention comprises at least one surfactant. Advantageously, the amount of surfactant in the polyapron of the present invention is in the range of 0.005 to 5% by weight relative to the total weight of the polyapron, preferably 0.05 to 5%. Generally, in conventional emulsions, the surfactant-to-oil ratio is 1 / 10 to 2 / 1. In the polyapron of the present invention, the surfactant-to-oil ratio in the polyapron is in the range of 1 / 50 to 1 / 40; thus, the amount of surfactant is less in the polyapron of the present invention than in conventional emulsions. This difference provides the polyapron of the present invention with a distinct advantage over emulsions in terms of limited surfactant-related side effects.

[0060] additives

[0061] In one embodiment, the polyapron comprises an additive selected from the group of antioxidants, osmotic agents, viscosity modifiers, pH modifiers or buffers, preservatives, solubilizers, and chelating agents. The amount of the additive can be calculated by a skilled person according to pharmacopeia and biological criteria.

[0062] Antioxidants

[0063] In one embodiment, the polyapron of the present invention comprises an antioxidant selected from the group consisting of vitamin E, sodium bisulfite, sodium metasulfite, sodium thiosulfate anhydride, citric acid monohydrate, ascorbyl palmitate and ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, and propyl gallate. These antioxidants may be used alone or in combination. The amount of the antioxidant may be calculated by a person skilled in the art according to pharmacopoeias and biological standards.

[0064] Osmotic agents

[0065] In one embodiment, the polyapron comprises at least one osmotic agent selected from the group consisting of glycerol, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol, xylitol, etc. Additionally, the amount of the osmotic agent is determined according to pharmacopoeias and biological standards.

[0066] Viscosity modifier - Viscosity of the polyapron of the present invention

[0067] In one embodiment, the polyapron comprises at least one viscosity modifier selected from the group consisting of carbomers, polycarbophils, cellulose derivatives (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc.), povidone, copovidone, natural gums (e.g., gelatin gum, guar gum, xanthan gum, agar, xyloglucan, etc.), poloxamers, etc. These viscosity modifiers may be used alone or in combination in amounts that meet the requirements of pharmacopoeias (European and American) and biological standards.

[0068] In one embodiment, the polyapron of the present invention has a very low shear rate (0.1 s -1 It exhibits a viscosity greater than 1 Pa.s at a shear rate of less than 1. In one embodiment, the polyapron of the present invention exhibits a viscosity greater than 1 Pa.s at a shear rate of 0.

[0069] The viscosity of polyapron is measured using a rheometer known to those skilled in the art (e.g., Rotational rheometer Kinexus, Malvern UK) at 25 to 35 °C and 1 atm.

[0070] In one embodiment, the polyapron exhibits shear thinning behavior and thixotropic properties, allowing it to be applied more easily and conveniently to at least one eyelid of a target.

[0071] pH adjuster or buffer

[0072] In one embodiment, the polyapron comprises at least one pH adjuster or buffer selected from hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, boron, sodium carbonate, sodium bicarbonate, etc. The amount of the pH adjuster is a function of a final pH value of 3.5 to 7.5. Additionally, the amount of the pH adjuster is used in accordance with pharmacopoeias and biological standards.

[0073] preservatives

[0074] In one embodiment, the polyapron comprises at least one preservative selected from benzalkonium chloride, benzyl alcohol, mercury salt, thiomersal, chlorhexidine, boric acid and / or salts thereof, e.g., or combinations thereof. Additionally, the amount of preservative used is in accordance with pharmacopoeia and biological standards.

[0075] solubilizer

[0076] In one embodiment, the polyapron comprises at least one solubilizing agent selected from ethanol, polyethylene glycol, glycerol, propylene glycol, N-methylpyrrolidone, glycofurol, and dimethyl isosorbide. Additionally, the amount of solubilizing agent is used in accordance with pharmacopoeia and biological standards.

[0077] Chelating agent

[0078] In one embodiment, the polyapron comprises edetic acid and its salt, ethylene glycol tetraacetic acid and its salt, citric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric acid, malic acid, tartaric acid, phytic acid, and their salts; more preferably at least one type selected from edetic acid, citric acid, metaphosphoric acid, polyphosphoric acid, and their salts; and particularly preferably at least one chelating agent selected from the salt of edetic acid. Additionally, the amount of the chelating agent is used in accordance with pharmacopoeial and biological standards.

[0079] Oil-in-water polyapron and manufacturing process

[0080] In one embodiment, the polyapron is an oil-in-water polyapron in which the continuous phase comprises or is composed of water or a hydrophilic phase, and the dispersed phase comprises or is composed of an apron 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 aqueous composition in terms of weight relative to the total weight of the polyapron; and the amount of the apron may be in the range of 50% to 98% w / w, preferably 70% to 98% w / w, more preferably 80% to 98% w / w, in terms of weight relative to the total weight of the polyapron. In one embodiment, the oil-in-water polyapron comprises an apron having an average diameter in the range of 0.1 to 100 μm.

[0081] In one embodiment, the oil-in-water polyapron of the present invention is prepared according to a process of stirring an aqueous solution and then adding a hydrophobic phase dropwise. Preferably, the aqueous solution is stirred at room temperature using magnetic stirring or a propeller at 200 rpm to 1000 rpm, and the hydrophobic phase is added at a specific rate at which autocatalytic formation of the apron occurs.

[0082] Water-in-oil Polyapron and Manufacturing Process

[0083] In one embodiment, the polyapron is a water-in-oil polyapron comprising or composed of an apron having a hydrophilic inner core, wherein the continuous phase is a hydrophobic phase and the dispersed phase is a hydrophilic inner 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 hydrophobic phase in terms of weight relative to the total weight of the polyapron; and the amount of the apron may be in the range of 50% to 98% w / w, preferably 70% to 98% w / w, more preferably 80% to 98% w / w in terms of weight relative to the total weight of the polyapron. In one embodiment, the water-in-oil polyapron comprises an apron having a diameter in the range of 0.1 to 100 μm.

[0084] In one embodiment, the water-in-oil polyapron of the present invention is prepared according to a process of stirring an oil phase and then adding an aqueous solution dropwise. Preferably, the aqueous solution is stirred at room temperature using magnetic stirring or a propeller at 200 rpm to 1000 rpm, and the oil phase is added at a specific rate at which autocatalytic formation of the apron occurs.

[0085] Polyaphron without active ingredients

[0086] In one embodiment, the polyapron does not contain any active ingredient, for example, a drug.

[0087] In this embodiment, polyapron can be considered as a pharmaceutically acceptable vehicle.

[0088] In this embodiment, polyapron is particularly useful for the treatment of dry eye conditions, such as dry eye syndrome or chronic dry eye syndrome (CDED), which is also clinically known as keratoconjunctivitis sicca (KCS).

[0089] Polyapron containing active ingredients

[0090] In one embodiment, the polyapron comprises an active ingredient. In one embodiment, the active ingredient is a therapeutic molecule of interest.

[0091] In one embodiment, the active ingredient is

[0092] - Anti-allergic agents, e.g., sodium cromoglycate, antazoline, chlorpheniramine, cetirizine, olopatadine, epinastine, ketotifen, azelastine, emedastine, levocavastin, terfenadine, and loratadine;

[0093] - anti-inflammatory drugs, e.g., cortisone, hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, dexamethasone palmitate, fluoroquinolones, prednisone, methylprednisolone, prednisolone acetate, fluorometholone, triamcinolone, betamethasone, loteprednol, flumethasone, beclomethasone, difluprednate and triamcinolone acetonide and derivatives thereof;

[0094] - Non-steroidal anti-inflammatory drugs , e.g., salicylates, indomethacin, ibuprofen, diclofenac, flurbiprofen, oxycam, piroxicam, and COX2 inhibitors, e.g., rofecoxib, nimesulide, nefafenac;

[0095] - Beta-adrenergic blockers , for example, timolol and timolol maleate and their salts, levovunolol hydrochloride and betaxolol hydrochloride, betaxolol, atenolol, bepunolol, metipranollol, forskolin, carteolol;

[0096] - Cytokines, interleukins, prostaglandins (also antiprostaglandins, and prostaglandin precursors), e.g., latanoprost, bimatoprost, tafluprost, or travoprost;

[0097] - Cyclosporine, sirolimus, tacrolimus ;

[0098] - Antioxidants , for example, lutein, vitamins, especially vitamin A, coenzyme Q10, polyunsaturated fatty acids and derivatives thereof;

[0099] - carbonic anhydrase inhibitor , for example, brinzolamide, dorzolamide, acetazolamide, metazolamide, dichlorfenamide;

[0100] - antiviral drugs , for example, idoxuridine, trifluorothymidine, acyclovir, valacyclovir, ganciclovir, cidofovir, and interferon;

[0101] - antibiotics, for example, aminoglycosides, carbacepem, carbapenem, cephalosporins, glycopeptides, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, chlortetracyclines, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, kanamycin, rifampicin, tobramycin, gentamicin, ciprofloxacin, aminosides, erythromycin, ceftazidim, vancomycin, imipenem; macrolides, azithromycin, clarithromycin, fluoroquinolones;

[0102] - antibacterial agents , e.g., sulfonamides, sulfadiazines, sulfacetamide, sulfamethisole, sulfisoxazole, nitrofuraszone, and sodium propionate;

[0103] - and / or derivatives thereof; and / or prodrugs thereof; and / or precursors thereof; and / or acceptable salts thereof; alone or in combination thereof

[0104] It is selected from among them.

[0105] In one embodiment, the active ingredient is selected from latanoprost, tafluprost, timolol, dorzolamide, olopatadine, epinastine, azithromycin, clarithromycin, cyclosporine A, sirolimus, dexamethasone, and dexamethasone palmitate.

[0106] 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.

[0107] In one embodiment, the polyapron stabilizes and / or protects the active ingredient.

[0108] Sterilization

[0109] In one embodiment, polyapron can be sterilized.

[0110] Non-limiting examples of sterilization methods include, for example, autoclaving, filtering or filtration, irradiation, and gas sterilization.

[0111] form

[0112] In one embodiment, the polyapron of the present invention may be a liquid, fluid, gel, powder, ointment, patch, film formulation, or any delivery formulation suitable for eyelid administration.

[0113] Preferably, polyaphron has a viscosity suitable for topical administration on the skin of the eyelids and is dispersed or administered to a subject in any form suitable for ophthalmic use as a gel or cream, or ointment, or patch, or as an eyelid administration.

[0114] Package

[0115] In one embodiment, the polyapron is packaged in a single volume; in another embodiment, the polyapron is packaged in a suitable multi-volume container.

[0116] method

[0117] Application to the eyelids - Kit

[0118] In one embodiment, the present invention relates to a method for locally applying polyapron to the upper eyelid and / or lower eyelid of a subject.

[0119] In one embodiment, polyapron is applied topically by spreading it on the skin around the eyes of the subject. In one embodiment, polyapron is applied by spreading it on the eyelids of the subject. In one embodiment, polyapron is applied by spreading it on the upper eyelids of the subject. In one embodiment, polyapron is applied by spreading it on the lower eyelids of the subject.

[0120] In another embodiment, polyaphron is applied using a spreading device, such as a brush or a spatula.

[0121] The present invention also relates to a kit comprising a container containing the polyapron of the present invention and a spreading device as described above.

[0122] Transdermal delivery

[0123] In another aspect, the present invention relates to a method for transdermally delivering polyapron or a component thereof onto the eye of a subject to treat an eye disease or eye condition of the subject.

[0124] In one embodiment, the method of the present invention is useful for delivering polyapron or a component thereof to the surface of the eye or the anterior part of the eyeball.

[0125] In one embodiment, the method of the present invention is useful for eye care.

[0126] In one embodiment, the polyapron comprises, as an additive, a penetration enhancer, that is, a compound that promotes the transdermal permeability of the polyapron or its components to the surface of the eye or the anterior part of the eyeball.

[0127] Continuous and / or controlled release of the component

[0128] In another aspect, the present invention relates to a method of continuously and / or regulatedly releasing a component onto the eye of a subject to treat an eye disease or eye condition of the subject.

[0129] In one embodiment, sustained and / or controlled release is obtained by applying the polyapron of the present invention containing the component onto at least one eyelid, upper eyelid and / or lower eyelid of a subject.

[0130] In one embodiment, the method of the present invention effectively achieves sustained and / or controlled administration of a therapeutic agent.

[0131] In one embodiment, the component is released in a sustained and / or controlled manner. It is released in a sustained and / or controlled manner for a period of 1 hour to 2 weeks, preferably 6 hours to 1 week, preferably 12 hours to 5 days. In a specific embodiment, the component is released in a sustained and / or controlled manner for 1 to 3 days.

[0132] In one embodiment, the sustained and / or controlled release kinetics may vary depending on the polyapron formulation. In a specific embodiment, the release rate depends on the properties of the hydrophilic phase of the polyapron. In a specific embodiment, the release rate depends on the properties of the hydrophobic phase of the polyapron. In a specific embodiment, the release rate depends on the properties of the surfactant or mixture of surfactants included in the polyapron. In a specific embodiment, the release rate depends on the concentration of the surfactant or mixture of surfactants included in the polyapron.

[0133] In one embodiment, the sustained and / or controlled release kinetics may vary depending on the viscosity of the polyapron. In a specific embodiment, the release rate decreases as the viscosity of the polyapron increases.

[0134] In one embodiment, the sustained and / or controlled release kinetics may vary depending on the average sphere size of the polyapron. In a specific embodiment, the release rate decreases as the average sphere size of the polyapron decreases.

[0135] In an embodiment, the sustained and / or controlled emission kinetics may vary depending on the volume of polyapron applied to the eye of the subject.

[0136] In one embodiment, sustained and / or controlled release kinetics may be adjusted according to the exact needs of the target. In a specific embodiment, release kinetics may be adjusted according to the exact needs of the target by selecting a surfactant or a mixture of surfactants to be included in the polyapron. In a specific embodiment, release kinetics may be adjusted according to the exact needs of the target by selecting an appropriate concentration of the surfactant or a mixture of surfactants to be included in the polyapron. In a specific embodiment, release kinetics may be adjusted according to the exact needs of the target by changing the viscosity and / or average sphere size of the polyapron.

[0137] In one embodiment, the method of the present invention is useful for sustained and / or controlled release of a component to the surface of the eye or the anterior part of the eyeball.

[0138] In one embodiment, the method of the present invention is useful for eye care.

[0139] Eye disease or eye condition

[0140] In the sense of the present invention, eye diseases or eye conditions are dry eye conditions, e.g., dry eye syndrome or chronic dry eye syndrome, e.g., keratoconjunctivitis dryis (KCS), atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC), glaucoma, inflammatory eye conditions, e.g., keratitis, corneal epithelium erosion, uveitis including anterior uveitis, intraocular inflammation, allergies and dry eye syndromes, ocular infections, ocular allergies, corneal or conjunctival lesions, cancerous growth, diabetic macular edema, age-related macular degeneration, corneal paralysis, pupil dilation.

[0141] In one embodiment, the eye condition may be blepharitis, glaucoma, meibomian gland disorder, e.g., meibomian gland dysfunction (MGD), and dry eye condition, e.g., dry eye or chronic dry eye, diabetic corneal condition, or neurotrophic corneal condition.

[0142] In one embodiment, the condition may be related to a demodex mite infection. In one embodiment, the condition is glaucoma. In one embodiment, the condition is anterior uveitis.

[0143] In another aspect, the polyapron of the present invention is intended for use in the treatment of eye diseases or eye conditions.

[0144] In another aspect, the polyapron of the present invention is intended for use in the manufacture of medicines or drugs for the treatment of eye diseases or eye conditions.

[0145] In another aspect, the present invention relates to a method for treating an eye disease or eye condition, wherein a therapeutically active amount of a therapeutic agent is administered to a patient in need through the topical application of a polyapron containing said therapeutic agent. In one embodiment, the method comprises the step of topically administering a composition containing a polyapron to the upper and / or lower eyelids of a subject. In one embodiment, the topical application is an eyelid application.

[0146] In one embodiment, polyaphron is administered once a day for 4 weeks.

[0147] In one embodiment, eyelid administration with polyapron reduces toxicity and / or side effects of patient treatment.

[0148] definition

[0149] In the present invention, the following terms have the following meanings:

[0150] - AphronIt refers to a composite sphere that consists of an outer layer containing a surfactant surrounding an intermediate layer composed of the same material as a continuous phase, and which itself surrounds a core composed of an immiscible phase and a continuous phase.

[0151] - Consecutive Award It refers to the phase surrounding the dispersed phase.

[0152] - "Dispersion" It refers to small spheres dispersed in a continuous phase.

[0153] - "eyelid" It includes the upper eyelid starting from the eyebrow to the lower limit identified at the tip of the eyelashes, and the lower eyelid starting from the area below the eye to the lower limit identified at the tip of the eyelashes.

[0154] - "MCT" means medium-chain triglycerides.

[0155] - Therapeutic molecules of interest means any molecule having specific particles for treating pathology or disease.

[0156] - "ND" means "not measured".

[0157] - Eyelid administration This means applying locally to the outer surface of at least one eyelid of the subject.

[0158] - Polyaphron It refers to liquid spheres called aphrons dispersed in the continuous phase.

[0159] Examples

[0160] The present invention is further explained by the following examples.

[0161] Example 1: Drug-free oil-in-water polyapron of the present invention

[0162] Composition # 1 2 3 4 5 6 MCT 90 90 90 90 90 45 triacetin 45 Poloxamer 188 0.1 1.0 Poloxamer 407 0.1 1.0 Polyoxyl-40 Stearate 1.0 0.1 Sorbitan oleate 0.9 water Qs 100 Qs 100 Qs 100 Qs 100 Qs 100 Qs 100

[0163] Composition of polyapron #1 to #6 (amounts expressed in % w / w).

[0164] Example 2: Oil-in-water polyapron of the present invention comprising cyclosporine A

[0165] Composition # 7 8 9 10 11 12 13 14 15 Cyclosporine A 1 1 1 1 1 1 1 1 1 MCT 88.1 88.1 88.1 88.1 88.1 89 88.1 77.2 88.1 Polyoxyethylene (4) lauryl ether 0.9 Sorbitan oleate 0.9 0.9 0.9 0.9 0.9 1.8 0.9 Poloxamer 188 0.1 Polyoxyl-40 Stearate 0.1 1 Sucrose 0.1 Sucrose palmitate 0.1 Sucrose stearate 0.1 Alkyl polyglycosides 0.1 Polysorbate 80 0.2 Vitamin E TPGS 0.1 water qs 100 qs 100 qs 100 qs 100 qs 100 qs 100 qs 100 qs 100 qs 100

[0166] Composition of polyapron #7 to #15 (amounts expressed in % w / w).

[0167] Example 3: Oil-in-water polyapron of the present invention comprising dexamethasone palmitate

[0168] Composition # 16 17 18 Dexamethasone palmitate 0.8 0.8 0.8 MCT 88.3 89.2 89.2 Sorbitan oleate 0.9 Poloxamer 407 1 0.1 Polyoxyl-40 Stearate 0.1 water qs 100 qs 100 qs 100

[0169] Composition of polyapron #16 to #18 (amounts expressed in % w / w).

[0170] Example 4: The water-in-oil polyapron of the present invention comprising fluorescein sodium as a hydrophilic marker or olopatadine HCl as a drug

[0171] Composition # 19 20 21 22 23 sodium fluorescein 0.0005 0.05 Olopatadine HCl 0.5 0.5 0.5 light mineral oil 19 19 17.9 17.9 17.9 Sorbitan oleate 1 1 2 2 2 Sucrose Tristearate 0.1 0.1 0.1 Glycerol 5.0 PEG 400 5.0 water qs 100 qs 100 Qs 100 Qs 100 Qs 100

[0172] Composition of polyapron #19 to #23 (amounts expressed in % w / w).

[0173] Example 5: Water-in-oil polyapron of the present invention comprising epinastine as a drug

[0174] Composition # 24 25 26 27 Epinastine HCl 0.5 0.5 0.5 0.5 light mineral oil 17.9 17.9 16.9 17.9 Sorbitan oleate 2 2 2 2 Sucrose Tristearate 0.1 0.1 0.1 0.1 isopropyl myristate 1 Glycerol 5 Diethylene glycol monoethyl ether 2.5 PEG 400 5 2.5 5 water Qs 100 Qs 100 Qs 100 Qs 100

[0175] Composition of polyapron #24 to #27 (amounts expressed in % w / w).

[0176] The spheroid size distribution of each polyapron was measured using state-of-the-art laser diffraction equipment (Helos Sympatec, Germany). The particle size distribution was measured in bulk (Dv). The viscosity of each polyapron was measured using a state-of-the-art rheometer (Kinexus, Malvern, UK).

[0177] Based on the physical properties of the compositions shown in Table 6, the correlation between the sphere size distribution and the viscosity of the system is indicated: the sphere size distribution is smaller when the composition is more viscous. This characteristic may vary depending on the qualitative or quantitative composition of polyapron.

[0178] Composition # 24 25 26 27 Microsphere size distribution ( ㎛ ) D(v,10) ( ㎛ ) 1.8 2.9 2.5 1.8 D(v,50) ( ㎛ ) 7.2 16.7 12.3 7.7 D(v,90) ( ㎛ ) 37.9 48.8 38.3 33.6 Viscosity (Pa.s) Initial viscosity θ 0 (Pa.s) 4549 3398 5662 6744

[0179] Physical properties of Polyapron #24 to #27

[0180] Example 6: In vitro evaluation of the permeability of oil-in-water polyapron containing clarithromycin

[0181] The transdermal permeability of clarithromycin was evaluated using Franz-cell equipment equipped with a Strat-M membrane purchased from Millipore. The Strat-M membrane is a synthetic membrane used in in vitro tests to stimulate skin permeability.

[0182] The diffusion of clarithromycin from polyapron (Composition #28) was compared with the diffusion from an oily solution (Composition #29) and an ointment (Composition #30). The concentration of clarithromycin in the aqueous compartment was measured by high-performance liquid chromatography (UPLC) for 72 hours.

[0183] The following formulations were evaluated:

[0184] Composition # 28 29 30 Clarithromycin 1 1 1 Capmul PG8 50 56 MCT 39 43 light mineral oil 25 heavy mineral oil 25 vaseline 49 CKC 0.005 Polysorbate 80 1 water Qs 100

[0185] Composition of polyapron #28 to #30 (amounts expressed in % w / w).

[0186] As shown in Figure 1, the application of ointment #30 did not cause transdermal penetration, but clarithromycin diffused from polyapron #28. Therefore, this experiment clearly demonstrates that polyapron is superior to ointment in terms of the skin penetration of therapeutic agents.

[0187] Clarithromycin diffuses from oily solution #29 through the membrane, but because its viscosity (25-33 mPa.s) is not high enough to keep the oily solution on the eyelid, this composition is not suitable for topical application on the eyelid. The oily solution will flow along the eyelid and / or into the eye. Conversely, the viscosity (> 1 Pa.s) of polyapron #28 is high enough to keep it on the eyelid, making it suitable for ocular administration.

[0188] In addition, as shown in Figure 1, polyaphron #28 can release clarithromycin remarkably effectively for more than 72 hours, whereas oily solution #29 releases clarithromycin immediately. This demonstrates that the use of polyaphron can cause sustained and controlled release of the therapeutic agent through the skin.

[0189] Example 7: In vitro evaluation of the permeability of oil-in-water polyapron containing dexamethasone

[0190] The transdermal permeability of dexamethasone was evaluated using a Franz-Cell instrument equipped with a Strat-M membrane purchased from Millipore. The Strat-M membrane is a synthetic membrane used in in vitro tests to stimulate skin permeability.

[0191] The spheroid size distribution of each polyapron was measured using state-of-the-art laser diffraction equipment (Helos Sympatec, Germany). The particle size distribution was measured in bulk (Dv). The viscosity of each polyapron was measured using a state-of-the-art rheometer (Kinexus, Malvern, UK).

[0192] The diffusion of dexamethasone from polyaprons with different compositions (compositions #31-33) was compared. The concentration of dexamethasone in the aqueous compartment was measured by high-performance liquid chromatography (UPLC) for 48 hours.

[0193] The following formulations were evaluated:

[0194] Composition # 31 32 33 Dexamethasone 0.024 0.024 0.024 MCT 89 90 90 Sorbitan oleate 0.9 Poloxamer 407 1 0.1 PEG-40 Stearate 0.1 water Qs 100 Qs 100 Qs 100

[0195] Composition of polyapron #31 to #33 (amounts are expressed in % w / w).

[0196] Based on the physical properties of the compositions shown in Table 9, the correlation between the sphere size distribution and the viscosity of the system is indicated: the sphere size distribution is smaller when the composition is more viscous. This characteristic may vary depending on the qualitative or quantitative composition of polyapron.

[0197] Composition # 31 32 33 Microsphere size distribution ( ㎛ ) D(v,10) ( ㎛ ) 4.7 1.5 14.9 D(v,50) ( ㎛ ) 20.3 3.8 32.7 D(v,90) ( ㎛㎛ 29.3 8.7 51.5 Viscosity (Pa.s) Initial viscosity θ 0 (Pa.s) 22 300 5

[0198] Physical properties of polyapron #31 to #33.

[0199] The results shown in Figure 2 clearly demonstrate that polyaphron can sustainably release dexamethasone through the skin for more than 48 hours. In addition, this demonstrates that the composition of polyaphron influences the release profile of dexamethasone.

[0200] Surprisingly, release kinetics depend on the properties of the surfactant. The release of polyafrone #31, where the surfactant is a mixture or PEG-40 stearate and sorbitan oleate, is faster than that of compositions #32 and #33, where the surfactant is poloxamer.

[0201] Surprisingly, release kinetics are also correlated with the viscosity and sphere size distribution of the compositions. A comparison of Compositions #32 and #33 revealed that an increase in the relative concentration of the surfactant reduces the sphere size distribution and increases viscosity. This results in slower kinetics when using the more viscous Polyafron #32, which has a smaller particle size, compared to the less viscous Polyafron #33, which has a larger particle size.

[0202] Therefore, the release kinetics from polyapron can be controlled by changing the quantitative and / or qualitative formulation of the polyapron, that is, by affecting the properties and / or concentration of the surfactant.

[0203] Example 8: In vitro evaluation of the permeability of water-in-oil polyapron containing olopatadine HCl

[0204] The transdermal permeability of olopatadine HCl was evaluated using a Franz-Cell instrument equipped with a Strat-M membrane purchased from Millipore. The Strat-M membrane is a synthetic membrane used in in vitro tests to stimulate skin permeability.

[0205] The diffusion of olopatadine HCl from polyaprons having different compositions shown in Table 4 of Example 4 (compositions #21-23) was compared. The concentration of olopatadine HCl in the aqueous compartment was measured by high-performance liquid chromatography (UPLC) for 48 hours.

[0206] As shown in Fig. 3, sustained and controlled release is also possible when olopatadine HCl is diffused through polyapron.

[0207] Surprisingly, the addition of a hydrophilic co-solvent (e.g., glycerol, PEF 400) acts as a permeation enhancer and increases permeability through the Strat-M membrane in vitro.

[0208] Example 9: Method for manufacturing polyapron #34 to 38

[0209] Polyaprons #34 to #38 containing clarithromycin were used for in vivo evaluation (Examples 10-13 below).

[0210] Polyapron #34 of Table 10 below was prepared according to the following procedure: an aqueous phase (8.995 g) containing polysorbate 80SR (1 g) stirred at 200 rpm was added dropwise to an oil phase MCT (39 g) containing CKC (0.005 g), propylene glycol monocaprylate (50 g), and clarithromycin (1 g). At the start of the procedure, the rate of addition of the oil phase was slow (about 1 drop every 7 seconds), but when 20% of the oil phase was added, the rate was increased, and the total time to prepare the polyapron was about 20 minutes.

[0211] Polyaprons #35 to #38 of Table 10 below were manufactured according to the same manufacturing procedure.

[0212] 34 35 36 37 38 Clarithromycin 1 0.3 0.25 0.5 - MCT 39 39 47.88 47.75 39 Propylene glycol monocaprylate 50 50 41.89 41.78 50 Polysorbate 80 SR 1 1 0.2 0.2 1 water qs 100 qs 100 qs 100 qs 100 qs 100

[0213] Composition of polyapron #34 to #38 (amounts are expressed in % w / w).

[0214] Emulsions and ointments containing clarithromycin #39 to #42 of Table 11 below were prepared for comparison.

[0215] solution 39 40 ointments Emulsion 41 Emulsion 42 Clarithromycin 1 3 1 0.5 MCT 39 - Propylene glycol monocaprylate 50 - 25 25 White Vaseline - 77.5 - - mineral oil - 12.1 - - Polysorbate 80 SR - 2.5 2.5 PEG-40 Stearate 0.1 - - - Sorbitan monooleate - - 2.5 2.5 Sodium hydrogen phosphate 0.1 Glycerol 2 - 1.2 1.2 water qs 100 - qs 100 qs 100

[0216] Compositions of Formulations No. 39 to 42 (amounts are expressed in % w / w).

[0217] Example 10: In vivo experiment - Comparison of eyelid application of Polyapron #34 and corneal application of Solution #34

[0218] Meibomian gland occlusion is a meibomian gland dysfunction (MGD) that often causes dry eyes and can lead to blepharitis.

[0219] Polyapron #34 (1% clarithromycin w / w) was applied topically once daily for 4 weeks to the eyelids of subjects with occluded meibomian glands. For comparison, solution #39 (1% clarithromycin w / w) was applied three times daily for 4 weeks to the corneas of subjects. Each formulation was evaluated in 6 eyes (n=6). The results are shown in Figure 4.

[0220] Polyapron #34 (1% clarithromycin w / w) reduced the number of occluded glands at the same rate as solution #39 (1% clarithromycin w / w) dispersed on the cornea after 4 weeks of treatment.

[0221] Furthermore, it was clinically observed that the toxicity of Polyapron #34 applied topically on the eyelids was lower than that of Solution #39 dispersed on the cornea. While the solution injected into the cornea caused irritation and necrosis of the corneal epithelium, it was reported that there were no signs of corneal toxicity when Polyapron #34 was applied to the eyelids.

[0222] Example 11: In vivo experiment - Comparison of eyelid application of Polyapron #34 and eyelid application of Ointment #40

[0223] Polyaphron #34 (1% clarithromycin w / w) was applied topically once daily for 4 weeks to the eyelids of subjects with occluded meibomian glands. For comparison, ointment #40 (3% clarithromycin w / w) was applied topically once daily for 4 weeks to the eyelids of subjects. Each formulation was evaluated on 6 eyes (n=6). The results are shown in Figure 5.

[0224] Polyaphron #34 reduced the number of occluded glands at the same rate as ointment #40 after 4 weeks of treatment. However, the reduction in the number of occluded cells should be evaluated based on the fact that ointment #40 is three times more concentrated than polyaphron #34. Consequently, when using polyaphron #34, a reduced amount of clarithromycin is required to induce the same efficacy as ointment #40.

[0225] Although ointment #40 is three times more concentrated in clarithromycin than polyaphron #34, the toxicity profile of the polyaphron is similar to that of ointment #40. When polyaphron #34 was used, no corneal toxicity was observed.

[0226] Therefore, the ocular application of Polyaphron #34 allows for the use of reduced amounts of clarithromycin and provides a better safety profile.

[0227] Example 12: In vivo experiment - Comparison of eyelid application of Polyapron #34 and corneal application of Emulsion #41

[0228] Polyaphron #34 (1% clarithromycin w / w) was applied topically once daily for 4 weeks to the eyelids of subjects with occluded meibomian glands. For comparison, Emulsion #41 (1% clarithromycin w / w) was applied topically three times daily for 4 weeks to the eyelids of subjects. Each formulation was evaluated on 6 eyes (n=6). The results are shown in Figure 6.

[0229] Polyaphron #34 reduced the number of blocked glands much more significantly than Emulsion #41 after one week of treatment.

[0230] In addition, Polyafron #34 exhibits an improved safety profile compared to Emulsion #41 injected onto the cornea. In fact, no signs of corneal toxicity were reported after the application of Polyafron #34 onto the eyelids, whereas severe toxicity (i.e., corneal epithelial necrosis) was reported after the injection of Emulsion #41.

[0231] Example 13: Measurement of stability by quantitative analysis of clarithromycin in polyaphron #37 and oil-in-water emulsion #42

[0232] Polyafrone #37 (0.5% clarithromycin w / w) and oil-in-water emulsion #42 (0.5% clarithromycin w / w) 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 with the initial amount. The results are expressed as a percentage of the initial amount of clarithromycin and are shown in Table 12.

[0233] Temperature (°C) Clarithromycin Dose (% vs T0) Polyaphron # 37 (0,5% clarithromycin w / w) 40 98.8 60 96.0 Oil-in-water emulsion # 42 (0,5% clarithromycin w / w) 40 90.2 60 71.7

[0234] Stability of Polyafron #37 and Emulsion #42 after 1 week of experiment At 40°C, 99% of the active ingredient in polyafron #37 is recovered after one week of the experiment, whereas 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, whereas polyafron #37 still contains 96% of the active ingredient.

[0235] Therefore, polyaphron #37 enhances the stability of clarithromycin compared to oil-in-water emulsion #42.

Claims

Claim 1 A composition for use in treating an eye disease or eye condition of a subject by administering the composition onto the upper and / or lower eyelids of the subject, wherein the composition comprises a water-in-oil polyapron, said polyapron comprising: at least one hydrophilic phase selected from an aqueous composition and water; at least one hydrophobic phase selected from mineral oil; and at least one non-ionic surfactant selected from sorbitan fatty acid esters, polysorbates, sucrose alkyl esters, long-chain saturated fatty acid mono- and diesters of glycerol, and long-chain unsaturated fatty acid mono- and diesters of glycerol. A composition comprising at least one anti-allergy agent as an active ingredient, wherein the amount of non-ionic surfactant in the polyapron is in the range of 0.05 to 5% w / w based on the total weight of the polyapron, and the amount of the hydrophobic phase is 2% w / w or more and the amount of the hydrophilic phase is 50% w / w or more based on the total weight of the polyapron. Claim 2 A composition according to claim 1, wherein the polyapron further comprises glycerol. Claim 3 A composition according to claim 1, wherein the polyapron is in the form of a gel or cream. Claim 4 A composition according to claim 1, wherein the active ingredient is released in a controlled and / or sustained manner for a period of 6 hours to 1 week. Claim 5 A composition according to claim 1, wherein at least one hydrophobic phase is light mineral oil and at least one non-ionic surfactant is isopropyl myristate. Claim 6 A composition according to claim 1, wherein at least one non-ionic surfactant is selected from sorbitan oleate, sucrose stearate, and sucrose tristearate. Claim 7 A composition according to claim 1, wherein at least one anti-allergic agent is sodium cromoglycate, antazoline, chlorpheniramine, cetirizine, olopatadine, ketotifen, azelastine, emedastine, levocabastine, terfenadine, or loratadine.

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