Pharmaceutical composition comprising chlorpheniramine maleate

Abstract

To provide an ophthalmic pharmaceutical composition comprising chlorpheniramine maleate as an active ingredient, the pharmaceutical composition being capable of sustaining therapeutic efficacy with reduced dosing frequency compared to eye drops.SOLUTION: The present invention provides a pharmaceutical composition comprising chlorpheniramine maleate as an active ingredient, the pharmaceutical composition being for use in administration to eyelid skin.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic pharmaceutical composition containing chlorpheniramine maleate as an active ingredient. [Background technology]

[0002] Eye drops are the most common ophthalmic pharmaceutical compositions that are applied locally to the eye. However, eye drops have low bioavailability of the active ingredient drug in the local area of ​​the eye due to the turnover of tears on the ocular surface, and frequent administration may be required to maintain the efficacy of the drug for a long period of time.

[0003] For ophthalmic pharmaceutical compositions, the selection of administration methods other than eye drops is being considered. For example, Patent Document 1 describes the administration of an ophthalmic transdermal preparation comprising an ophthalmic drug and a vasoconstrictor to the eyelid skin surface. Patent Document 2 describes the administration of a pharmaceutical composition for topical administration containing epinastine or a salt thereof at a concentration of 0.05 to 1% (w / w) as an active ingredient to the eyelid skin. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2010-502564 [Patent Document 2] Patent No. 7124248 Summary of the Invention [Problem to be solved by the invention]

[0005] Chlorpheniramine maleate is known as an ingredient that blocks the action of histamine and improves inflammatory symptoms caused by allergic reactions, such as redness, edema, and itching. Therefore, it is sometimes mixed into eye drops, expecting its effect on allergic symptoms such as conjunctival congestion, eye itching, and blepharitis. However, the details of the percutaneous absorption of chlorpheniramine maleate are unknown, and it is unclear whether it can exert its medicinal effect on allergic symptoms in the eyeball, conjunctiva, and eyelid skin, especially when administered to the eyelid skin. The present invention aims to provide an ophthalmic pharmaceutical composition containing chlorpheniramine maleate as an active ingredient, which can maintain its medicinal effect even when administered less frequently than eye drops. [Means for solving the problem]

[0006] As a result of intensive research conducted by the present inventors to solve the above problems, it was discovered that when a pharmaceutical composition containing chlorpheniramine maleate is administered to the eyelid skin, it is easy to spread, the preparation is less likely to drip into the eye, it is highly safe, and furthermore, the desired medicinal effect can be sustained for a long period of time, which led to the completion of the present invention.

[0007] That is, according to the present invention, the following inventions are provided. <1> A pharmaceutical composition for use in administration to the eyelid skin, comprising chlorpheniramine maleate as an active ingredient. <2> Contains chlorpheniramine maleate at a concentration of 0.005 to 1% by mass. <1> The pharmaceutical composition described in <3> It is administered to patients one to three times a day. <1> or <2> The pharmaceutical composition described in <4> Viscosity of 100 Pa·s or less at 20°C. <1> ~ <3> 13. The pharmaceutical composition according to any one of the preceding claims. <5> It is an ointment, cream or gel. <1> ~ <4> 13. The pharmaceutical composition according to any one of the preceding claims. <6> It is an oil-in-water (O / W) emulsion. <1> ~ <5> 13. The pharmaceutical composition according to any one of the preceding claims. <7> The pH is 4.0 to 8.0. <6> The pharmaceutical composition described in <8> It is a water-in-oil (W / O) emulsion. <1> ~ <5> 13. The pharmaceutical composition according to any one of the preceding claims. <9> Contains one or more oil components selected from the group consisting of hydrocarbons, waxes, oils and fats, aliphatic carboxylic acids or salts thereof, fatty acid esters, and higher alcohols; <1> ~ <8> 13. The pharmaceutical composition according to any one of the preceding claims. <10> Contains a surfactant, <9> The pharmaceutical composition described in <11> Contains a solvent, <9> or <10> The pharmaceutical composition described in <12> A pharmaceutical composition for treating allergic conjunctivitis and / or blepharitis, <1> ~ <11> 13. The pharmaceutical composition according to any one of the preceding claims. <13> Further containing cromoglycate, <1> ~ <12> 13. The pharmaceutical composition according to any one of the preceding claims.

[0008] (A) A method for transferring chlorpheniramine maleate to ocular tissue, comprising administering to the eyelid skin a pharmaceutical composition containing chlorpheniramine maleate as an active ingredient. (B) A method for sustained release of chlorpheniramine maleate from the eyelid skin to ocular tissue, comprising administering to the eyelid skin a pharmaceutical composition containing chlorpheniramine maleate as an active ingredient. (C) administering to a patient in need of treatment a therapeutically effective amount of <1> ~ <12> A method for treating allergic conjunctivitis and / or blepharitis, comprising administering the pharmaceutical composition according to any one of the above items. (D) for the manufacture of a medicament for treating allergic conjunctivitis and / or blepharitis, <1> ~ <12> 2. Use of the pharmaceutical composition according to any one of claims 1 to 11. Effect of the Invention

[0009] According to the pharmaceutical composition of the present invention, the medicinal effect of chlorpheniramine maleate can be maintained for a long time locally in the eye, which is expected to improve inflammatory symptoms in eye tissues such as the eyeball, conjunctiva, and eyelid. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the cumulative permeation amount (Q) of chlorpheniramine. [Diagram 2] FIG. 2 shows the cumulative permeation amount of chlorpheniramine in the preparation of Example 1. [Diagram 3] FIG. 3 shows the evaluation of the change in pigment concentration for the preparation of Example 2 using a histamine-induced conjunctivitis model in guinea pigs. [Figure 4] FIG. 4 shows the evaluation of the change in pigment concentration for the preparations of Example 2 and Comparative Example 1 using a histamine-induced conjunctivitis model in guinea pigs. [Diagram 5] FIG. 5 shows the cumulative permeation amount (Q) of chlorpheniramine. [Figure 6] FIG. 6 shows the cumulative permeation amount (Q) of chlorpheniramine. [Figure 7] FIG. 7 shows the cumulative permeation amount (Q) of cromoglycate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The topical skin preparation of the present invention is a pharmaceutical composition which contains chlorpheniramine maleate as an active ingredient and is intended for administration to the eyelid skin.

[0012] Chlorpheniramine maleate may be either d-chlorpheniramine maleate or dl-chlorpheniramine maleate, with dl-chlorpheniramine maleate being preferred.

[0013] Chlorpheniramine maleate may be in the form of a hydrate or solvate.

[0014] The concentration of chlorpheniramine maleate in the pharmaceutical composition of the present invention is not particularly limited, but the pharmaceutical composition of the present invention preferably contains chlorpheniramine maleate at a concentration of 0.005 to 1% by mass, more preferably 0.006 to 1% by mass, and even more preferably 0.006 to 0.03%. The concentration of chlorpheniramine maleate is 0.005% by mass or more, so that the desired therapeutic effect can be fully exerted. The concentration of chlorpheniramine maleate is 1% by mass or less, so that the risk of unexpected side effects occurring due to a large amount of chlorpheniramine maleate remaining at the administration site can be reduced.

[0015] The pharmaceutical composition of the present invention can be prepared for use in administration to the eyelid skin, can be prepared as an external preparation for ophthalmic use, or can be prepared as an external preparation for transdermal administration.

[0016] The eyelid skin includes the eyelids such as the upper eyelid and the lower eyelid and the vicinity thereof, or the skin around the orbit. Administration to the eyelid skin includes, for example, administration to the eyelid skin and the vicinity of the upper eyelid, the lower eyelid, or both, or administration to the skin around the orbit. The eyelid margin may be included in the eyelid skin, but it is more preferable not to administer to the eyelid margin, and even more preferable not to administer to the eyelid, since a part of the pharmaceutical composition administered to the eyelid margin may come into contact with the sensitive ocular surface due to blinking, which may easily cause eye irritation.

[0017] In the present invention, allergic conjunctivitis may be any of seasonal, perennial, or both seasonal and perennial disease types. Allergens include pollen, but are not limited to pollen, and also include other allergens such as house dust and mites.

[0018] When the present invention is administered to the eyelid skin, it can be administered to eyes wearing or not wearing contact lenses. The contact lenses used in the present invention may be soft contact lenses or hard contact lenses, and the type is not limited.

[0019] The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical, and examples thereof include ointments, creams, gels, external liquids (lotions, liniments), external solids (external powders), etc. The pharmaceutical composition of the present invention is preferably an ointment, cream, gel, or external liquid, more preferably an ointment, cream, or gel, and particularly preferably a cream. These can be manufactured according to conventional methods in the art.

[0020] When administering the pharmaceutical composition of the present invention, it is preferable that the pharmaceutical composition be applied easily and uniformly on the eyelid skin by smoothly spreading, rather than by applying it by spreading it on the eyelid skin while pressing strongly.In addition, when the pharmaceutical solution is a liquid such as water, it can be easily applied to the eyelid skin without pressing, but there is a concern that the pharmaceutical solution may drip and get into the eyes or mouth, causing irritation or discomfort.Therefore, it is preferable that the pharmaceutical composition of the present invention has a viscosity that does not drip when administered to the eyelid skin.

[0021] The viscosity of the pharmaceutical composition of the present invention at 20°C is, for example, 100 Pa·s (pascal·seconds) or less, preferably 80 Pa·s or less, more preferably 50 Pa·s or less, even more preferably 20 Pa·s or less, and particularly preferably 10 Pa·s or less. Also, the viscosity is, for example, 0.001 Pa·s or more, preferably 0.01 Pa·s or more, more preferably 0.1 Pa·s or more, and even more preferably 1 Pa·s or more.

[0022] The viscosity of the pharmaceutical composition of the present invention can be measured using a measuring device: AntonPaar MCR302, at a measurement temperature of 20° C., a tool: cone plate Φ50, and a shear rate of 100 (1 / S).

[0023] Pharmaceutical additives may be used in the pharmaceutical composition of the present invention as necessary, for example, pH regulators, buffers, isotonicity agents, thickening agents, stabilizers, antioxidants, preservatives, surfactants, cooling agents, oil components, humectants, moisturizers, softeners, transdermal absorption enhancers, solubilizers, etc. These may be used alone or in appropriate combinations of two or more, and may be blended in appropriate amounts.

[0024] When a pH regulator is added to the pharmaceutical composition of the present invention, a pH regulator that can be used as an additive for pharmaceuticals can be appropriately added. Examples of pH regulators include acids and bases. Examples of acids include hydrochloric acid, phosphoric acid, acetic acid, citric acid, and salts thereof, and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and triethanolamine. These may also be hydrates or solvates.

[0025] The pH of the pharmaceutical composition of the present invention may be within a medicament acceptable range, for example, within the range of 4.0 to 8.0, preferably 4.0 to 7.0, more preferably 4.0 to 6.5, and particularly preferably 4.5 to 5.5. For example, the pH may be 4.7 to 5.3, or 5.0 to 5.1.

[0026] When a buffer is added to the pharmaceutical composition of the present invention, a buffer that can be used as an additive for pharmaceuticals can be appropriately added. Examples of the buffer include phosphoric acid or a salt thereof, boric acid, borax, trometamol, an organic acid or a salt thereof, and the like, and may be a hydrate or solvate thereof.

[0027] Examples of phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.

[0028] Examples of organic acids include citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, amino acids, and the like, and examples of their salts include sodium salts and potassium salts.

[0029] When a buffering agent is added to the pharmaceutical composition of the present invention, the content of the buffering agent can be appropriately adjusted depending on the type of the buffering agent, and is, for example, 0.01 to 5% (w / w), preferably 0.05 to 3% (w / w), more preferably 0.1 to 2% (w / w), and even more preferably 0.1 to 1% (w / w), but is not limited to this when the buffering agent has an effect other than that of a buffering agent. Furthermore, when a buffering agent is added to the pharmaceutical composition of the present invention, one type of buffering agent or two or more types of buffering agents may be used together.

[0030] The phosphoric acid or a salt thereof and the organic acid or a salt thereof incorporated in the pharmaceutical composition of the present invention may act as a pH adjuster and a buffering agent.

[0031] When an isotonicity agent is added to the pharmaceutical composition of the present invention, the isotonicity agent can be appropriately added as an additive for pharmaceuticals. Examples of the isotonicity agent include ionic isotonicity agents and nonionic isotonicity agents. Ionic isotonicity agents are preferred.

[0032] Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like, and may be hydrates or solvates thereof.

[0033] Examples of non-ionic tonicity agents include glycerin (concentrated glycerin), propylene glycol, 1,3-butylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol, and the like, and these may be hydrates or solvates.

[0034] When an isotonicity agent is added to the pharmaceutical composition of the present invention, the content of the isotonicity agent can be appropriately adjusted depending on the type of the isotonicity agent, and is, for example, 0.01 to 5% (w / w), preferably 0.05 to 3% (w / w), more preferably 0.1 to 2% (w / w), and even more preferably 0.1 to 1% (w / w), but is not limited to this when the isotonicity agent has an action other than that of an isotonicity agent. Furthermore, when an isotonicity agent is added to the pharmaceutical composition of the present invention, one or more types of isotonicity agents may be used together.

[0035] When a thickening agent is added to the pharmaceutical composition of the present invention, the thickening agent can be appropriately added as a thickening agent that can be used as an additive for pharmaceuticals. Examples of thickening agents include cellulose-based polymers (e.g., hydroxypropylmethylcellulose, also known as hypromellose), polyvinylpyrrolidone, carboxyvinyl polymers, mucopolysaccharides, or polyhydric alcohols, and may further include salts, hydrates, or solvates thereof. Examples of cellulose-based polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, and cellulose acetate phthalate. Examples of carboxyvinyl polymers include carbopol. Examples of polyhydric alcohols include polyvinyl alcohol and polyethylene glycol. Examples of mucopolysaccharides include hyaluronic acid, sodium hyaluronate, and chondroitin sulfate. A cellulosic polymer is preferred.

[0036] The content of the thickener when blending the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of thickener, for example, 0.01-20% (w / w), preferably 0.1-10% (w / w), more preferably 1-10% (w / w), but not limited to this when it has an action other than that of a thickener. In addition, if the pharmaceutical composition of the present invention is in the form of a gel, it may contain, for example, 20% (w / w) or more. In addition, when blending the pharmaceutical composition of the present invention with a thickener, one or more types of thickeners may be used together.

[0037] When a stabilizer is added to the pharmaceutical composition of the present invention, a stabilizer that can be used as an additive for pharmaceuticals can be appropriately added. Examples of the stabilizer include edetic acid or its salt, cyclodextrin, dimethylpolysiloxane, etc., and may further be hydrates or solvates thereof. Preferred is edetic acid or its salt.

[0038] Examples of edetic acid or a salt thereof include edetic acid, disodium edetate (sodium edetate), tetrasodium edetate, and the like.

[0039] When a stabilizer is added to the aqueous pharmaceutical composition of the present invention, the content of the stabilizer can be appropriately adjusted depending on the type of stabilizer, and is, for example, 0.01 to 5% (w / w), preferably 0.01 to 3% (w / w), and more preferably 0.01 to 1% (w / w), but is not limited to this when the stabilizer has an action other than as a stabilizer. When a stabilizer is added to the pharmaceutical composition of the present invention, one type of stabilizer or two or more types of stabilizers may be used together.

[0040] When an antioxidant is added to the pharmaceutical composition of the present invention, an antioxidant that can be used as an additive for pharmaceuticals can be appropriately added. Examples of antioxidants include ascorbic acid, sodium ascorbate, tocopherol, tocopherol acetate, citric acid, sodium citrate, potassium citrate, dibutylhydroxytoluene, propyl gallate, cysteine, N-acetylcysteine, methionine, sodium hydrogen sulfite, sodium sulfite, sodium thiosulfate, benzotriazole, and 2-mercaptobenzimidazole, and may also be hydrates or solvates thereof. In addition, when the antioxidant contained has a chiral center, it may be a racemate or an optical isomer. Dibutylhydroxytoluene and 2-mercaptobenzimidazole are preferable.

[0041] When an antioxidant is added to the aqueous pharmaceutical composition of the present invention, the content of the antioxidant can be appropriately adjusted depending on the type of antioxidant, and is, for example, 0.01 to 2% (w / w), preferably 0.01 to 1% (w / w), and more preferably 0.01 to 0.5% (w / w), but is not limited to this when the antioxidant has an effect other than as an antioxidant. Furthermore, when an antioxidant is added to the pharmaceutical composition of the present invention, one type of antioxidant may be used, or two or more types of antioxidants may be used together.

[0042] When a preservative is incorporated into the pharmaceutical composition of the present invention, the preservative can be appropriately selected from preservatives that can be used as an additive in pharmaceuticals, and examples of the preservative include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, chlorhexidine hydrochloride, paraben, sodium chlorite, phenoxyethanol, thymol, sorbic acid or chlorobutanol, aminoethylsulfonic acid, etc. Examples of parabens include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, and propyl parahydroxybenzoate.

[0043] When a preservative is added to the pharmaceutical composition of the present invention, the content of the preservative can be appropriately adjusted depending on the type of preservative, and is, for example, 0.001 to 1% (w / w), but is not limited to this when the preservative has an action other than as a preservative. When a preservative is added to the pharmaceutical composition of the present invention, one type of preservative or two or more types of preservatives may be used together.

[0044] When a surfactant is added to the pharmaceutical composition of the present invention, a surfactant that can be used as an additive for pharmaceuticals can be appropriately added. Examples of the surfactant include cationic surfactants, anionic surfactants, and nonionic surfactants.

[0045] Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxyethyl-2-alkylimidazolines.

[0046] Examples of the anionic surfactant include sodium alkylbenzenesulfonate, sodium dodecyl sulfate, and phospholipids such as lecithin.

[0047] Examples of nonionic surfactants include polyoxyethylene fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyl castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene alkyl ethers, glycerin fatty acid esters, (poly)glycerin fatty acid esters, and sucrose fatty acid esters.

[0048] Examples of polyoxyethylene fatty acid esters include polyoxyl 40 stearate, polyoxyl 45 stearate, polyoxyl 55 stearate, polyethylene glycol myristate, polyethylene glycol monooleate, polyethylene glycol monostearate, polyethylene glycol monoisostearate, and polyethylene glycol monolaurate.

[0049] Examples of sorbitan fatty acid esters include sorbitan caprylate, sorbitan laurate, sorbitan stearate, sorbitan isostearate, sorbitan tristearate, sorbitan behenate, sorbitan tribehenate, sorbitan oleate, and sorbitan trioleate.

[0050] Examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65, and the like.

[0051] Examples of polyoxyethylene hydrogenated castor oils include polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene hydrogenated castor oil 100.

[0052] Examples of polyoxyl castor oils include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, and the like.

[0053] Examples of polyoxyethylene polyoxypropylene glycols include polyoxyethylene (3) polyoxypropylene (17) glycol, polyoxyethylene (20) polyoxypropylene (20), polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, and polyoxyethylene (196) polyoxypropylene (67) glycol.

[0054] Examples of polyoxyethylene polyoxypropylene cetyl ether include polyoxyethylene (20) polyoxypropylene (4) cetyl ether and polyoxyethylene (20) polyoxypropylene (8) cetyl ether. Examples of polyoxyethylene alkyl ethers include polyoxyethylene cetyl ether, polyoxyethylene lauryl ether, polyoxyethylene behenyl ether, and polyoxyethylene arachyl ether. Examples of glycerin fatty acid esters include glyceryl monocaprylate, glyceryl dicaprylate, glyceryl tricaprylate, polyglyceryl monocaprylate, polyglyceryl dicaprylate, polyglyceryl tricaprylate, glyceryl monocaprate, glyceryl dicaprate, glyceryl tricaprate, polyglyceryl monocaprate, polyglyceryl dicaprate, polyglyceryl tricaprate, glyceryl monolaurate, glyceryl dilaurate, glyceryl trilaurate, polyglyceryl monolaurate, polyglyceryl dilaurate, Ceryl, Polyglyceryl Trilaurate, Glyceryl Monomyristate, Glyceryl Dimyristate, Glyceryl Trimyristate, Polyglyceryl Monomyristate, Polyglyceryl Dimyristate, Polyglyceryl Trimyristate, Glyceryl Monopalmitate, Glyceryl Dipalmitate, Glyceryl Tripalmitate, Polyglyceryl Monopalmitate, Polyglyceryl Dipalmitate, Polyglyceryl Tripalmitate, Glyceryl Monostearate, Glyceryl Distearate, Glyceryl Tristearate, Polyglyceryl Monostearate glyceryl, polyglyceryl distearate, polyglyceryl tristearate, glyceryl monoisostearate, glyceryl diisostearate, glyceryl triisostearate, polyglyceryl monoisostearate, polyglyceryl diisostearate, polyglyceryl triisostearate, glyceryl monobehenate, glyceryl dibehenate, glyceryl tribehenate, polyglyceryl monobehenate, polyglyceryl dibehenate, polyglyceryl tribehenate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, Polyglyceryl monooleate, polyglyceryl dioleate, polyglyceryl trioleate, glyceryl monolinoleate, glyceryl dilinoleate, glyceryl trilinoleate, polyglyceryl monolinoleate, polyglyceryl dilinoleate, polyglyceryl trilinoleate, glyceryl monolinolenate, glyceryl dilinolenate, glyceryl trilinolenate, polyglyceryl monolinolenate, polyglyceryl dilinolenate, polyglyceryl trilinolenate, glyceryl monoricinoleate, glyceryl diricinoleate, glyceryl triricinoleate,Examples of such polyglyceryl monoricinoleate include polyglyceryl diricinoleate, polyglyceryl triricinoleate, polyglyceryl condensed ricinoleate (also called polyglyceryl polyricinoleate, polyglyceryl condensed ricinoleate, or polyglyceryl polyricinoleate), glyceryl monoarachidonate, glyceryl diarachidonate, glyceryl triarachidonate, polyglyceryl monoarachidonate, polyglyceryl diarachidonate, and polyglyceryl triarachidonate. Examples of sucrose fatty acid esters include sucrose stearate, sucrose palmitate, and sucrose oleate. More preferably, it is a nonionic surfactant, and even more preferably, it is a glycerin fatty acid ester, for example, polyglyceryl condensed ricinoleate.

[0055] When a surfactant is added to the pharmaceutical composition of the present invention, the content of the surfactant can be appropriately adjusted depending on the type of surfactant, and is, for example, 0.1 to 20% (w / w), preferably 0.5 to 10% (w / w), and more preferably 1 to 5% (w / w), but is not limited to this when the surfactant has an action other than that of a surfactant. When a surfactant is added to the pharmaceutical composition of the present invention, one or more surfactants may be used together, or a mixture of two or more surfactants may be used. Surfactants are characterized by the balance between the hydrophilic and lipophilic parts of their molecule and have a hydrophilic-lipophilic balance (HLB) number. HLB increases with increasing hydrophilicity, and different manufacturers may have different HLB numbers for the same ingredient name.

[0056] When a surfactant is blended in the pharmaceutical composition of the present invention, the HLB of the surfactant is not particularly limited as long as it can be prepared as a preparation for topical administration, but in the case of an oil-in-water (O / W) emulsion, the HLB is, for example, 1 to 20, preferably 5 to 20, more preferably 10 to 20, and even more preferably 13 to 18, and in the case of a water-in-oil (W / O) emulsion, the HLB is, for example, 1 to 20, preferably 1 to 15, more preferably 1 to 10, and even more preferably 1 to 7. In addition, in W / O preparations, lipophilic surfactants having bulky alkyl chains are generally preferred, and glycerin fatty acid esters or sorbitan fatty acid esters are more preferred.

[0057] When a cooling agent is added to the pharmaceutical composition of the present invention, the cooling agent may be any cooling agent that can be used as an additive for pharmaceuticals. Examples of cooling agents include terpenoids and essential oils containing terpenoids.

[0058] Examples of terpenoids include menthol, camphor, borneol, geraniol, nerol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, and the like, and they may be in any of the d-, l-, and dl-forms.

[0059] Examples of essential oils containing terpenoids include eucalyptus oil, bergamot oil, peppermint oil, fennel oil, rose oil, cinnamon oil, spearmint oil, camphor oil, cool mint, and peppermint oil.

[0060] When a cooling agent is added to the pharmaceutical composition of the present invention, the content of the cooling agent can be appropriately adjusted depending on the type of cooling agent, and is, for example, 0.001 to 1% (w / w). When a cooling agent is added to the pharmaceutical composition of the present invention, one type of cooling agent or two or more types of cooling agents may be used together.

[0061] When an oil component is blended in the pharmaceutical composition of the present invention, the content of the oil component can be an oil component that can be used as an additive for pharmaceuticals, such as hydrocarbons, waxes, oils and fats, aliphatic carboxylic acids or salts thereof, fatty acid esters, and higher alcohols.

[0062] Examples of hydrocarbons include petrolatum, white petrolatum, liquid paraffin (light liquid paraffin, heavy liquid paraffin), solid paraffin (paraffin), squalene, squalane, ceresin, microcrystalline wax, etc., and mixtures of these may also be used, such as a mixture of paraffin and microcrystalline wax.

[0063] Examples of waxes include beeswax, white beeswax, lanolin, and the like.

[0064] Examples of fats and oils include olive oil, castor oil, sesame oil, and soybean oil.

[0065] Examples of the aliphatic carboxylic acid include short-chain fatty acids such as butyric acid, valeric acid, caproic acid, etc., medium-chain fatty acids such as caprylic acid, capric acid, etc., long-chain fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, ricinoleic acid (ricinoleic acid), arachidonic acid, etc., and aliphatic dicarboxylic acids such as succinic acid, glutaric acid, adipic acid, sebacic acid, etc., including branched aliphatic carboxylic acids. Examples of the salts of the aliphatic carboxylic acids include the sodium salts of these.

[0066] In the present invention, fatty acid ester refers to a compound in which the carboxyl group of an aliphatic carboxylic acid and an alcohol are ester-bonded. Examples of the alcohol that may be ester-bonded to the carboxyl group of an aliphatic carboxylic acid include monohydric alcohols such as methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol, isopropanol, isobutanol, sec-butanol, and isopentanol, polyhydric alcohols such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, and glycerin, and polyhydric alcohol polymers such as dipolyethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, diglycerin, triglycerin, and polyglycerin. Examples include polyethylene glycol laurate, isopropyl myristate, octyl myristate, glycol palmitate, polyethylene glycol stearate, isopropyl oleate, propylene glycol linoleate, ethyl linolenate, ethylene glycol ricinoleate (ricinoleic acid), diisopropyl adipate, sorbitan sesquioleate, etc. When the aliphatic ester has two or more ester bonds, the alcohols constituting the ester bonds may be the same or different.

[0067] Examples of higher alcohols include lauryl alcohol, myristyl alcohol, palmityl alcohol (also called cetyl alcohol or cetanol), stearyl alcohol, behenyl alcohol, oleyl alcohol, linolyl alcohol, linolenyl alcohol, and octyldodecanol.

[0068] When the oil component incorporated in the pharmaceutical composition of the present invention acts as a surfactant, the oil component may be read as a surfactant.

[0069] When the oil component incorporated in the pharmaceutical composition of the present invention acts as a solubilizer (solubilizer), the oil component may be interpreted as a solubilizer.

[0070] When an oil component is blended in the pharmaceutical composition of the present invention, the content of the oil component can be appropriately adjusted depending on the type of oil component, and is, for example, 1 to 50% (w / w), preferably 1 to 45% (w / w), and more preferably 10 to 45% (w / w), but if the pharmaceutical composition of the present invention is in the form of an ointment, it may contain, for example, 50% (w / w) or more. Furthermore, when an oil component is blended in the pharmaceutical composition of the present invention, one type or two or more types of oil components may be used together.

[0071] As the wetting agent, for example, hyaluronic acid, sodium dl-pyrrolidone carboxylate or a salt thereof (eg, sodium dl-pyrrolidone carboxylate), etc. can be used. As the moisturizing agent, for example, polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol can be used.

[0072] Examples of softeners that can be used include petroleum-based oils such as paraffinic process oil, naphthenic process oil, and aromatic process oil; squalane; squalene; vegetable oils such as cottonseed oil, palm oil, coconut oil, almond oil, rapeseed oil, olive oil, camellia oil, castor oil, tall oil, and peanut oil; silicone oil; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate, and diisopropyl sebacate; diethylene glycol; polyethylene glycol; glycol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; crotamiton; glycerin, and the like.

[0073] Examples of the percutaneous absorption enhancer that can be used include alcohols, fatty acids, fatty acid esters such as diisopropyl adipate, fatty acid ethers, lactate esters, acetate esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, propylene carbonate, azone or derivatives thereof, and the like.

[0074] Examples of solubilizing agents that can be used include benzyl alcohol; pyrrothiodecane; isopropyl myristate; crotamiton; pyrrolidones such as N-methyl-2-pyrrolidone; higher alcohols; polybasic acids such as diethyl adipate, isopropyl adipate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, di(2-heptylundecyl) adipate, diisopropyl sebacate, and diethyl sebacate; polyalkylene glycols such as polyethylene glycol (PEG) and polybutylene glycol; and oxyalkylene fatty acid esters such as polyethylene glycol monostearate.

[0075] The pharmaceutical composition of the present invention may further contain a solvent and / or a dispersion medium. The pharmaceutical composition of the present invention containing a solvent and / or a dispersion medium may have all of its components dissolved or partially suspended, or may be in the form of an emulsion or semi-solid. Examples of the solvent and / or dispersion medium include, but are not limited to, water (purified water), ethanol, polyol (e.g., glycerin (glycerol), propylene glycol, 1,3-butylene glycol, liquid polyethylene glycol, macrogol, etc.), etc.

[0076] The content of the solvent and / or dispersion medium when blending the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the solvent and / or dispersion medium, and is preferably 10% (w / w) or more, more preferably 30% (w / w) or more, based on the total weight of the pharmaceutical composition. When blending the solvent and / or dispersion medium in the pharmaceutical composition of the present invention, one type or two or more types of the solvent and / or dispersion medium may be used together.

[0077] When the pharmaceutical composition of the present invention is used as an emulsion, the pharmaceutical composition of the present invention may be an oil-in-water (O / W) emulsion (an emulsion in which the aqueous phase is the continuous phase and oily droplets are dispersed in the aqueous phase) or a water-in-oil (W / O) emulsion (an emulsion in which the oil phase is the continuous phase and aqueous droplets are dispersed in the oil). The pharmaceutical composition of the present invention is preferably an oil-in-water (O / W) emulsion.

[0078] The pharmaceutical composition of the present invention can be manufactured according to a conventional method commonly used in the art. For example, it can be manufactured by mixing, in addition to the active ingredient, additives such as stabilizers, antioxidants, preservatives, surfactants, oil components, and solvents and / or dispersion media such as water. If necessary, it can be manufactured as a sterile preparation according to a conventional sterilization method commonly used in the art. There is no particular limitation on the sterilization method as long as it is a method that can be used during the manufacturing process, and examples of the sterilization method include high-pressure steam sterilization, filtration sterilization, dry heat sterilization, electron beam (EB) sterilization, gamma ray sterilization, ethylene oxide gas (EOG) sterilization, and hydrogen peroxide gas sterilization.

[0079] The pharmaceutical composition of the present invention may contain a medicament active ingredient other than chlorpheniramine maleate, unless otherwise specified. Examples of the other medicament active ingredients include anti-inflammatory agents, steroids, antihistamines, bactericides, congestion removers, eye muscle regulators, corneal protectors, antibacterial agents, antiviral agents, vitamins, vasoconstrictors, mydriatics, miotics, intraocular pressure lowering agents, dry eye treatment agents, local anesthetics, etc. The pharmaceutical composition of the present invention may also contain chlorpheniramine maleate as the only active ingredient.

[0080] Anti-inflammatory agents include, for example, epsilon-aminocaproic acid, allantoin, berberine, sodium azulene sulfonate, dipotassium glycyrrhizinate, glycyrrhizic acid, glycyrrhetinic acid, zinc sulfate, zinc lactate, lysozyme chloride, and the like.

[0081] Examples of steroids include cortisone acetate, dexamethasone acetate, dexamethasone, hydrocortisone acetate, hydrocortisone, prednisolone acetate, prednisolone, hydrocortisone butyrate, prednisolone valerate acetate, betamethasone, betamethasone valerate, and fluocinolone acetonide.

[0082] Examples of antihistamines or antiallergic agents include ketotifen fumarate, iproheptin, diphenhydramine hydrochloride, pemirolast potassium, chlorpheniramine maleate, cromoglycate (eg, sodium cromoglycate), and the like.

[0083] Examples of vasoconstrictors include tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, phenylephrine hydrochloride, and the like.

[0084] Examples of the disinfectant include acrinol, cetylpyridinium chloride hydrate, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biguanide hydrochloride, isopropylmethylphenol, benzalkonium chloride, and benzethonium chloride.

[0085] Examples of decongestants include tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, phenylephrine hydrochloride, and the like.

[0086] Examples of mydriatics include tropicamide, cyclopentolate hydrochloride, atropine, atropine sulfate, phenylephrine hydrochloride, dipivefrin hydrochloride, and the like.

[0087] Miotics include, for example, pilocarpine hydrochloride, distigmine bromide, and the like.

[0088] Examples of therapeutic agents for dry eye include rebamipide, chondroitin sulfate, aminoethylsulfonic acid, potassium aspartate, magnesium aspartate, taurine, and the like.

[0089] Examples of local anesthetics include oxybuprocaine hydrochloride, ethyl aminobenzoate, dibucaine, dibucaine hydrochloride, lidocaine, lidocaine hydrochloride, and the like.

[0090] Examples of vitamin preparations include flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, retinol acetate, retinol palmitate, tocopherol acetate, vitamin A oil, and retinol palmitate.

[0091] Examples of eye muscle regulating components include neostigmine methylsulfate.

[0092] Examples of corneal protective ingredients include chondroitin sulfate, aminoethylsulfonic acid, potassium aspartate, magnesium aspartate, and taurine.

[0093] The pharmaceutical composition of the present invention is particularly useful as a pharmaceutical composition for treating allergic conjunctivitis and / or blepharitis. In the present invention, "treating allergic conjunctivitis and / or blepharitis" includes any treatment (e.g., improvement, alleviation, inhibition of progression, etc.) and prevention of allergic conjunctivitis and / or blepharitis and their symptoms.

[0094] Ocular tissues include the conjunctiva, cornea, tears, aqueous humor, anterior chamber, etc. For the treatment of allergic conjunctivitis, it is preferred that chlorpheniramine maleate penetrates into the conjunctiva.

[0095] In the present invention, a patient refers not only to humans but also to other animals, such as dogs, cats, horses, etc. The patient is preferably a mammal, more preferably a human.

[0096] The pharmaceutical composition of the present invention is preferably administered to a patient 1 to 3 times a day (particularly preferably once a day), but the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect.

[0097] When the pharmaceutical composition of the present invention is used as an ointment, cream or gel, the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, and also varies depending on the content of the active ingredient contained and the patient. For example, in the case of a cream, for example, in the case of an adult, an appropriate amount per application, specifically about 1 mg to about 5 g, preferably about 5 mg to about 1 g, more preferably about 10 mg to about 500 mg, particularly preferably about 20 mg to about 100 mg, can be applied to the skin. For example, the dosage is 30 mg. As an example of administration, the patient himself takes an appropriate amount of the pharmaceutical composition, for example about 20 to about 40 mg, on his finger, distributes it so that it is about half each on the upper eyelid skin and the lower eyelid skin of one eye, and applies it to each eye in the same manner. In actual use, the patient himself may take out the pharmaceutical composition by eyeballing it, without weighing it, using the above-mentioned dosage per eye as a guide.

[0098] When applied to the skin, the application time is preferably 2 to 24 hours, more preferably 4 to 24 hours, and still more preferably 8 to 24 hours. After the application time has elapsed, even if the pharmaceutical composition on the skin is removed, a sufficient amount of the active ingredient remains in the skin tissue, and the sustained release of the active ingredient is expected to result in sustained efficacy.

[0099] The pharmaceutical composition of the present invention can be housed and sealed in, for example, a glass container or package, or a container or package made of a metal such as aluminum, or a container or package made of an olefin resin such as polyethylene or polypropylene, and can further be housed in a moisture-proof bag containing a metal such as aluminum. In addition, the container or package may be a container or package containing environmentally friendly raw materials such as recycled plastics or biomass raw materials, and if necessary, any material that prevents deterioration of the pharmaceutical composition due to factors, elements, or environmental changes from outside the pharmaceutical container or package, such as heat or light in a high-temperature environment, and appropriately maintains the quality of the pharmaceutical composition, may be used. In one embodiment of the present invention, the pharmaceutical composition may be housed in a suitable container or package.

[0100] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples in any way. EXAMPLES

[0101] (List of raw materials and manufacturers) White petrolatum: Ogi Pharmaceutical Co., Ltd. Stearyl alcohol: Kao Corporation Japanese Pharmacopoeia Cetanol: Kao Corporation Dimethylpolysiloxane: Shin-Etsu Chemical Co., Ltd. Liquid Paraffin: MORESCO Corporation Isopropyl myristate: Japan Surfactant Co., Ltd. Polyoxyl 40 stearate: Nippon Surfactant Co., Ltd. Polyoxyethylene polyoxypropylene cetyl ether: Japan Surfactant Co., Ltd. Glycerol fatty acid ester: Japan Surfactant Co., Ltd. (Poly)glycerin fatty acid ester: Japan Surfactant Co., Ltd. Polyoxyethylene cetyl ether: Japan Surfactant Co., Ltd. Polyoxyethylene behenyl ether: Japan Surfactant Co., Ltd. dl-Chlorpheniramine maleate: Kongo Chemical Co., Ltd. Concentrated glycerin: Kosaka Pharmaceutical Co., Ltd. Citric acid: Fujifilm WAKO Pure Chemical Co., Ltd. Sodium citrate: Nikko Pharmaceutical Co., Ltd.

[0102] (Test Example 1) Skin permeability test 1 using 3D cultured skin The permeability of a composition containing chlorpheniramine maleate through three-dimensional cultured skin was investigated. <Preparation of test substance> (1) Liquid The active ingredient, chlorpheniramine maleate, was dissolved in purified water.

[0103] [Table 1]

[0104] (2) Creams The cream was prepared using standard methods. White petrolatum, stearyl alcohol, dimethylpolysiloxane, liquid paraffin, and polyoxyl stearate were placed in beaker A and dissolved at 80° C. In another beaker B, the active ingredients chlorpheniramine maleate, concentrated glycerin, citric acid, sodium citrate, and water were placed and dissolved at 80° C. Beaker A and beaker B were mixed together using a homomixer (Primix Corporation, Lab-lution) to prepare the cream of Example 1.

[0105] [Table 2]

[0106] The viscosity of the cream of Example 1 was 2090 mPa·s at a shear rate of 100 (1 / S) (average of measurements n=3). Measuring equipment: AntonPaar MCR302 Measurement temperature: 20℃ Jig: Corn plate Φ50

[0107] The pH of the cream of Example 1 was 5.0 to 5.1.

[0108] <In vitro skin permeability test> After applying the test substance cream containing chlorpheniramine maleate described above to 3D cultured skin (LSE-high), each permeation parameter was calculated from the permeation profile of the measurement target substance obtained, and the in vitro skin permeability of the measurement target substance in the preparation was evaluated.

[0109] <Test method> LSE-high was placed on the receiver cell of a vertical diffusion cell sandwiched with a silicone ring so that the epidermal side of LSE-high faced upward, and a donor cell was placed thereon. A specified amount of PBS was added to the receiver cell. Using a micropipette, 500 μL of the test substance was applied to each of the donor cells (LSE-high stratum corneum), and the vertical diffusion cell was placed on a multi-stirrer installed in a thermostat (set at 32°C). At 2, 4, 6, 8, and 10 hours after the application of the preparation, 500 μL of the receiver solution was collected. After collection, the same amount of the receiver solution was replenished. After adding 100 μL of acetonitrile to 100 μL of the collected receiver solution, centrifugation (15,000 rpm, 5 min, 4°C) was performed, and the obtained supernatant was measured by LC / MS / MS.

[0110] <Test results and discussion> (1) When calculating the lag time, cumulative permeation amount (Q), and permeation rate of chlorpheniramine in the test substance of the liquid preparation from three points at 6 - 10 hours after the preparation application, they were 1.20 ± 0.20 (h), 60.0 ± 20.6 (μg / cm2), and 6.83 ± 2.42 (μg / cm2 / h), respectively. (n = 3 average). Figure 1 shows the cumulative permeation amount (Q) of chlorpheniramine.

[0111]

Table 3

[0112] (2) The lag time, cumulative permeation amount, and permeation rate of chlorpheniramine in the test substance of the cream were 0.884±0.582(h), 80.1±4.8(μg / cm2), and 8.78±0.29(μg / cm2 / h) (n=3 average). Figure 2 shows the cumulative permeation amount of chlorpheniramine in the preparation of Example 1.

[0113] [Table 4]

[0114] These results confirmed that chlorpheniramine maleate in both the liquid and cream formulations penetrates the skin. The cream formulation had a higher cumulative permeation amount, which demonstrated that chlorpheniramine maleate in the cream penetrates the 3D cultured skin better than the liquid formulation. This suggests that the cream formulation can reach the site of action more efficiently than the liquid formulation.

[0115] (Test Example 2) Pharmacological efficacy test using an allergic conjunctivitis model In order to evaluate the anti-inflammatory effect on allergic conjunctivitis, an allergic conjunctivitis model was created using guinea pigs, and pharmacological tests were carried out.

[0116] (1) Preparation of test substances The cream was prepared using standard methods. White petrolatum, stearyl alcohol, dimethylpolysiloxane, liquid paraffin, and polyoxyl stearate were placed in beaker A and dissolved at 80° C. In another beaker B, the active ingredients chlorpheniramine maleate, concentrated glycerin, citric acid, sodium citrate, and water were placed and dissolved at 80° C. Beaker A and beaker B were mixed together using a homomixer (Primix Corporation, Lab-lution) to prepare the cream of Example 2. In Comparative Example 1, a cream was prepared in the same manner, but without adding chlorpheniramine maleate.

[0117] [Table 5]

[0118] The viscosity of the creams of Example 2 and Comparative Example 1 was measured under the following conditions. Measuring equipment: AntonPaar MCR302 Measurement temperature: 20℃ Jig: Corn plate Φ50 Shear rate: 100 (1 / S)

[0119] The viscosity of the cream of Example 2 was 1.8267 Pa·s. The viscosity of the cream of Comparative Example 1 was 1.7777 Pa·s, which was equivalent to that of Example 2.

[0120] The creams of Example 2 and Comparative Example 1 had a pH of 5.4 to 5.6.

[0121] (2) Drug efficacy evaluation test 1 using allergic conjunctivitis model Six-week-old guinea pigs (Hartley, male) that had completed the quarantine and acclimation period were divided into three groups according to the time of formulation application by a stratified sequential randomization method. To administer the test substance, the hair around the right eyelid was clipped with clippers under isoflurane anesthesia, and the test substance was applied to the entire right eyelid skin using a spatula. 2, 4, and 8 hours after administration of the test substance, 1% Evans blue saline was administered intravenously, and 30 minutes after intravenous injection of the dye, a histamine solution, an inflammation-causing substance, was administered into both conjunctival sacs. 30 minutes after administration of histamine, the animals were decapitated under isoflurane anesthesia, and the bulbar and palpebral conjunctivas were removed and cut into small pieces, then placed in an extraction solution and extracted at room temperature. The absorbance of the supernatant of the extract was measured at a measurement wavelength of 620 nm using a plate reader, and the dye concentration in the extract was calculated. As an index for evaluating the effect of the drug, the difference (change) in the dye concentration of the right eye relative to the dye concentration of the left eye was calculated for each animal. However, if the difference in dye concentration was negative, it was determined that the drug had no effect, and the amount of change was recorded as zero.

[0122] 3 shows an evaluation of the amount of change in pigment concentration in the preparation of Example 2 using a histamine-induced conjunctivitis model in guinea pigs. Each value represents the average value of six cases ± standard error.

[0123] [Table 6]

[0124] Each value represents the mean value ± standard error of six cases. * p<0.05, ** p<0.01, significant difference by t-test compared to 2-hour application. No significant difference between 4-hour application and 8-hour application.

[0125] <Results and Discussion> At 2 hours application, the change in pigment concentration in the right eye relative to the left eye was 3.921 ± 1.019 μg / mL. After 4 hours of application, the change in pigment concentration in the right eye relative to the left eye was 6.240 ± 2.396 μg / mL. In addition, a significant difference was observed in the change in pigment concentration as an evaluation of efficacy compared to A: 2 hours of application (p < 0.05, t-test). After 8 hours of application, the change in pigment concentration in the right eye relative to the left eye was 5.025 ± 1.794 μg / mL. In the change in pigment concentration as an evaluation of efficacy compared to A: 2 hours of application (p < 0.05, t-test). Under all conditions, efficacy was observed according to the application time.

[0126] (3) Drug efficacy evaluation test 2 using allergic conjunctivitis model Six-week-old guinea pigs (Hartley, male) that had completed the quarantine and acclimation period were divided into two groups, a test substance administration group and a placebo administration group, by a stratified sequential randomization method. To administer the test substance and placebo preparation, the hair around the right eyelid was clipped with clippers under isoflurane anesthesia, and the right eyelid skin was painted with a spatula. Four hours after administration of the test substance and placebo preparation, 1% Evans blue saline was administered intravenously, and 30 minutes after intravenous injection of the dye, a histamine solution, an inflammation-causing substance, was administered into both conjunctival sacs. 30 minutes after administration of histamine, the animals were decapitated under isoflurane anesthesia, and the bulbar and palpebral conjunctivas were removed and cut into pieces, then placed in an extraction solution and extracted at room temperature. The absorbance of the supernatant of the extraction solution was measured at a measurement wavelength of 620 nm using a plate reader, and the dye concentration in the extraction solution was calculated. As an index for evaluating the efficacy of the drug, the difference (change) in the pigment concentration of the right eye relative to the pigment concentration of the left eye was calculated for each animal. However, if the difference in pigment concentration was negative, it was considered that the drug had no effect and the change was set to 0.

[0127] FIG. 4 shows the evaluation of the change in pigment concentration for the preparations of Example 2 and Comparative Example 1 using a histamine-induced conjunctivitis model in guinea pigs.

[0128] [Table 7]

[0129] Each value represents the mean ± standard error of 10 cases. ** p < 0.01, significant difference compared to the control by t-test.

[0130] <Results and Discussion> In the control group, the change in pigment concentration in the right eye relative to the left eye was 1.286 ± 1.102 μg / mL. On the other hand, in the test substance group, the change in pigment concentration in the right eye relative to the left eye was 11.297 ± 2.937 μg / mL. Regarding the change in pigment concentration as a measure of drug efficacy, A: A significant difference was observed compared to the control (p < 0.01, t-test). From the above results, a statistically significant anti-allergic effect was recognized in the test substance, and it is considered that allergic conjunctivitis can be treated by simply applying a cream containing chlorpheniramine maleate around the eyelids.

[0131] (Test Example 3) Skin Permeability Test 2 Using 3D Cultured Skin The 3D cultured skin permeability of the composition containing chlorpheniramine maleate was investigated. <Preparation of Test Substance> (1) Cream Cream preparations of Examples 3 to 7 were prepared in the same manner as the preparation of the cream of Example 1.

[0132] [Table 8]

[0133] <In Vitro Skin Permeability Test> An in vitro skin permeability test was conducted and the in vitro skin permeability was evaluated in the same manner as the <In Vitro Skin Permeability Test> of Test Example 1.

[0134] <Test Results and Discussion> The lag time, cumulative permeation amount (Q), and permeation rate of chlorpheniramine in the test substances of the cream preparations of Examples 3 to 7 are shown in Table 9.

[0135] [Table 9]

[0136] Figure 5 shows the cumulative permeation amount of chlorpheniramine in the cream preparations of Examples 3 to 7.

[0137] From the above results, it was confirmed that chlorpheniramine maleate in the cream preparations of Examples 3 to 7 also permeated the skin.

[0138] (Test Example 4) Skin permeability test 3 using 3D cultured skin <Method> The cream of Example 8, the ointment of Example 9, and the gel of Example 10 were each prepared as follows. The cream was prepared using standard methods. White petrolatum, stearyl alcohol, dimethylpolysiloxane, liquid paraffin, and polyoxyl stearate were placed in beaker A and dissolved at 80° C. In another beaker B, the active ingredients chlorpheniramine maleate, sodium cromoglycate, concentrated glycerin, citric acid, sodium citrate, and water were placed and dissolved at 80° C. Beaker A and beaker B were mixed together using a homomixer (Primix Corporation, Lab-lution) to prepare the cream of Example 8. The ointment was prepared using standard methods. White petrolatum and liquid paraffin were placed in beaker A and dissolved at 75°C. The active ingredients chlorpheniramine maleate, sodium cromoglycate, and concentrated glycerin were placed in another beaker B and heated to 75°C to dissolve. Beaker A and beaker B were mixed and stirred at 3500 rpm for 1 minute using a tabletop speed mixer (Hauschild Engineering SpeedMixer DAC150.1FVZ), and then cooled to prepare the ointment of Example 9. The gel was prepared using standard methods. Water was placed in a beaker, and a small amount of carboxyvinyl polymer was added while mixing and dissolving using a Disper Mixer (Primix Corporation, Laborution) (pre-prepared solution A). Chlorpheniramine maleate, sodium cromoglycate, and water were placed in a beaker and dissolved (pre-prepared solution B). Triethanolamine and water were placed in a beaker and dissolved (pre-prepared solution C). Warm water and hypromellose were added to a beaker, and the mixture was stirred and mixed using a stirrer, and the hypromellose was completely dissolved while cooling. Pre-prepared solutions A, B, and C were added thereto, and mixed using a Three-One Motor (Shinto Scientific Co., Ltd.) to prepare the gel of Example 10.

[0139] (List of raw materials and manufacturers) White petrolatum: Ogi Pharmaceutical Co., Ltd. Stearyl alcohol: Kao Corporation Dimethylpolysiloxane: Shin-Etsu Chemical Co., Ltd. Liquid Paraffin: MORESCO Corporation Polyoxyl 40 stearate: Nippon Surfactant Co., Ltd. Sorbitan sesquioleate: Japan Surfactant Co., Ltd. Isopropyl myristate: Japan Surfactant Co., Ltd. Chlorpheniramine maleate: Kongo Chemical Co., Ltd. Sodium cromoglycate: AventisPharma Concentrated glycerin: Kosaka Pharmaceutical Co., Ltd. Citric acid: Fujifilm WAKO Pure Chemical Co., Ltd. Sodium citrate: Nikko Pharmaceutical Co., Ltd. Hypromellose: Shin-Etsu Chemical Co., Ltd. Carboxyvinyl Polymers: Lubrizol Advanced Materials Triethanolamine: Fujifilm Wako Pure Chemical Corporation

[0140] [Table 10]

[0141]

Table 11

[0142]

Table 12

[0143] For the cream of Example 8, the ointment of Example 9, and the gel of Example 10, tests were conducted in the same manner as the <in vitro skin permeability test> of Test Example 1.

[0144] <Test Results and Discussion> The lag time, cumulative permeation amount (Q), and permeation rate of chlorpheniramine in the test substances of each preparation were calculated from three points at 6, 8, and 10 hours after formulation application, and the results are shown in Table 13. Figure 5 shows the cumulative permeation amount (Q) of chlorpheniramine.

[0145]

Table 13

[0146] The lag time, cumulative permeation amount (Q), and permeation rate of cromolyn sodium in the test substances of each preparation were calculated from three points at 6, 8, and 10 hours after formulation application, and the results are shown in Table 14. Figure 6 shows the cumulative permeation amount (Q) of cromolyn sodium.

[0147]

Table 14

[0148] From the above results, it was confirmed that chlorpheniramine maleate and cromolyn sodium formulated in the cream, ointment, and gel permeated through the skin. For both chlorpheniramine maleate and cromolyn sodium, the skin permeation amounts were high in the order of cream, gel, and ointment. [Industrial Applicability]

[0149] The pharmaceutical compositions of the present invention are useful for use in administration to the eyelid skin.

Claims

1. A pharmaceutical composition for use in administration to the eyelid skin, comprising chlorpheniramine maleate as an active ingredient.

2. 2. The pharmaceutical composition according to claim 1, comprising chlorpheniramine maleate in a concentration of 0.005 to 1% by weight.

3. The pharmaceutical composition according to claim 1 or 2, which is administered to a patient 1 to 3 times daily.

4. 3. The pharmaceutical composition according to claim 1, having a viscosity of 100 Pa·s or less at 20°C.

5. 3. The pharmaceutical composition according to claim 1 or 2, which is an ointment, cream or gel.

6. 3. The pharmaceutical composition according to claim 1 or 2, which is an oil-in-water (O / W) emulsion.

7. The pharmaceutical composition according to claim 6, wherein the pH is from 4.0 to 8.

0.

8. 3. The pharmaceutical composition according to claim 1 or 2, which is a water-in-oil (W / O) emulsion.

9. 2. The pharmaceutical composition according to claim 1, comprising one or more oil components selected from the group consisting of hydrocarbons, waxes, fats and oils, aliphatic carboxylic acids or salts thereof, fatty acid esters and higher alcohols.

10. The pharmaceutical composition according to claim 9, further comprising a surfactant.

11. The pharmaceutical composition according to claim 9 or 10, which contains a solvent.

12. The pharmaceutical composition according to claim 1 or 2, which is a pharmaceutical composition for treating allergic conjunctivitis and / or blepharitis.

13. 3. The pharmaceutical composition according to claim 1 or 2, further comprising cromoglycate.

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