Aqueous suspension composition containing sirolimus or salt thereof

Abstract

To provide an aqueous suspension composition comprising poorly water-soluble sirolimus for ophthalmology, in particular, used for topical administration, such as a less invasive eye drop.SOLUTION: The present invention is an ophthalmic aqueous suspension composition comprising sirolimus or a salt thereof and a surfactant, wherein the aqueous suspension composition has a pH of 4 to 6.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an aqueous suspension composition containing sirolimus or a salt thereof (hereinafter, these are collectively referred to simply as "sirolimus"). The present invention also relates to a method for suppressing the decomposition and / or aggregation of sirolimus in an aqueous suspension composition containing sirolimus or a salt thereof.

Background Art

[0002] Sirolimus (also called rapamycin) is a macrolide compound found from the metabolites of actinomycetes and has an immunosuppressive effect. Therefore, oral preparations for preventing rejection during organ transplantation or treating lymphangioleiomyomatosis have been approved as pharmaceuticals. Sirolimus is also known to be useful for the treatment of autoimmune diseases, inflammatory diseases, fungal infections, leukemia / lymphoma, proliferative vascular diseases, and the like.

[0003] In the field of ophthalmology, for example, Patent Document 1 describes a method for treating eye inflammation in mammals that requires a treatment including administering an anti-inflammatory effective amount of rapamycin to the mammals. Patent Document 2 describes an ophthalmic composition containing an mTOR inhibitor such as sirolimus, everolimus, temsirolimus, a first surfactant having an HLB index of more than about 10, and a second surfactant having an HLB index of more than about 13. Patent Document 3 describes a prophylactic and / or therapeutic agent for meibomian gland dysfunction containing a compound such as sirolimus, deforolimus, or a pharmaceutically acceptable salt thereof as an active ingredient. On the other hand, since the chemical structure of sirolimus does not contain a functional group that ionizes in any pH range of weakly acidic, neutral, or weakly basic, it is hardly soluble in water.

[0004] In addition, the General Rules of Preparations in the Seventeenth Revised Japanese Pharmacopoeia describe that the particles in a suspending eye drop usually have a maximum particle diameter of 75 μm or less.

Prior Art Documents

Patent Documents

[0005] Patent Document 1 Japanese Unexamined Patent Application Publication No. 5-194212 Patent Document 2 Japanese Translation of PCT International Publication No. 2010-540682 Patent Document 3 International Publication WO2014 / 142146 Summary of the Invention Problems to be Solved by the Invention

[0006] It is an interesting problem to provide an aqueous suspension composition containing sirolimus, which is poorly water-soluble, for topical administration such as ophthalmic preparations, particularly eye drops with low invasiveness. Means for Solving the Problems

[0007] Although the present inventors can prepare a solubilized aqueous composition by adding a solubilizer to poorly water-soluble sirolimus, sirolimus in the composition is liable to decompose. On the other hand, it has been clarified that in an aqueous composition in which sirolimus is simply suspended in water, the suspension is liable to aggregate. The present inventors conducted further intensive studies on an aqueous composition for ophthalmic use containing sirolimus, and found that the pH of the aqueous composition containing sirolimus, the average particle diameter of sirolimus, the content of additives, etc. affect the decomposition and aggregation of sirolimus. Furthermore, they found that an aqueous suspension composition containing sirolimus, which will be described in detail below, can minimize the decomposition and aggregation of sirolimus, leading to the present invention.

[0008] Specifically, the present invention provides the following. (1) An aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, wherein the pH of the aqueous suspension composition is 4 to 6, an aqueous suspension composition for ophthalmic use. (2) The content ratio of the surfactant to sirolimus or a salt thereof is more than 0.01 part by weight with respect to 1 part by weight of the content of sirolimus or a salt thereof, The aqueous suspension composition according to (1), wherein the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition is 45 μm or less. (3) The content ratio of the surfactant with respect to sirolimus or a salt thereof is more than 0.01 part by weight based on 1 part by weight of the content of sirolimus or a salt thereof. The aqueous suspension composition according to (1), wherein the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition is 15 μm or less. (4) The content ratio of the surfactant with respect to sirolimus or a salt thereof is more than 0.01 part by weight based on 1 part by weight of the content of sirolimus or a salt thereof. The aqueous suspension composition according to (1), wherein the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition is 10 μm or less. (5) The aqueous suspension composition according to any one of (1) to (4), wherein the pH of the aqueous suspension composition is 5. (6) The aqueous suspension composition according to any one of (1) to (5), wherein the content of sirolimus or a salt thereof is 0.01 to 1% (w / v). (7) The aqueous suspension composition according to any one of (1) to (6), wherein the average particle diameter of sirolimus or a salt thereof is 2.5 μm or less. (8) The aqueous suspension composition according to any one of (1) to (7), wherein the surfactant is one or more selected from the group consisting of polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyl castor oil, and polyoxyethylene alkyl ether phosphates. (9) The aqueous suspension composition according to any one of (1) to (7), wherein the surfactant is one or more selected from the group consisting of polyoxyl 40 stearate, polysorbate 80, polyoxyl 35 castor oil, and sodium polyoxyethylene cetyl ether phosphate. (10) The aqueous suspension composition according to any one of (1) to (7), wherein the surfactant is polysorbate 80. (11) The aqueous suspension composition according to any one of (1) to (10), which contains a dispersant. (12) The aqueous suspension composition according to (11), wherein the dispersant is at least one selected from the group consisting of cellulose polymers, polyhydric alcohols, polyvinylpyrrolidone, and mucopolysaccharides. (13) The aqueous suspension composition according to any one of (1) to (12), further containing at least one selected from the group consisting of a buffering agent, an isotonic agent, a stabilizer, an antioxidant, a preservative, and a pH adjuster. (14) The aqueous suspension composition according to (13), wherein the preservative is at least one selected from the group consisting of reversed soaps, parabens, sorbic acid or its salts, chlorobutanol, and silver nitrate. (15) The aqueous suspension composition according to any one of (1) to (14), which is an eye drop. (16) An aqueous suspension composition containing sirolimus or its salt and polysorbate 80, wherein the content of sirolimus or its salt is 0.01 to 1% (w / v), the content ratio of polysorbate 80 to sirolimus or its salt is 0.1 to 10 parts by weight with respect to 1 part by weight of the content of sirolimus or its salt, the average particle diameter of sirolimus or its salt in the aqueous suspension composition is 2.5 μm or less, the pH of the aqueous suspension composition is 4 to 6, An aqueous suspension composition for ophthalmic use. (17) A method for suppressing aggregation of sirolimus or its salt in an aqueous suspension composition containing sirolimus or its salt and a surfactant, comprising adjusting the pH of the aqueous suspension composition to 4 to 6 and making the average particle diameter of sirolimus or its salt in the aqueous suspension composition 45 μm or less. (18) A method for suppressing aggregation of sirolimus or its salt in an aqueous suspension composition containing sirolimus or its salt and a surfactant, comprising adjusting the pH of the aqueous suspension composition to 4 to 6 and making the average particle diameter of sirolimus or its salt in the aqueous suspension composition 15 μm or less. A method for suppressing aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, characterized by adjusting the pH of the aqueous suspension composition to 4 to 6 and making the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition 10 μm or less. A method for suppressing decomposition of sirolimus in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, characterized by adjusting the pH of the aqueous suspension composition to 4 to 6. A method for suppressing aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, characterized by adjusting the pH of the aqueous suspension composition to 4 to 6. A method for suppressing aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, characterized by making the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition 45 μm or less. A method for suppressing aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, characterized by making the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition 15 μm or less. A method for suppressing aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, characterized by making the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition 10 μm or less.

[0009] Furthermore, the present invention also provides the following. A method for treating an eye disease, characterized by administering to a patient in need of treatment an aqueous suspension composition according to any one of (1) to (16) in a therapeutically effective amount. The treatment method according to (25), wherein the eye disease is an anterior eye disease. Use of an aqueous suspension composition according to any one of (1) to (16) for manufacturing a medicament for treating and / or preventing an eye disease. (28) Use according to (27), wherein the eye disease is an anterior eye disease. (29) An aqueous suspension composition according to any one of (1) to (16) for use in the treatment and / or prevention of an eye disease. (30) An aqueous suspension composition according to (29), wherein the eye disease is an anterior eye disease.

[0010] In addition, any two or more of the above-mentioned components (1) to (30) can be arbitrarily selected and combined. [Effects of the Invention]

[0011] The present invention can provide an aqueous suspension composition containing sirolimus or a salt thereof, which is poorly water-soluble and is used for topical administration such as ophthalmic eye drops with low invasiveness. [Embodiments for Carrying Out the Invention]

[0012] The present invention will be described in detail below.

[0013] In the aqueous suspension composition of the present invention, "sirolimus" is also called "rapamycin" and has the following formula: [Chemical Formula] It is a compound represented by.

[0014] In the aqueous suspension composition of the present invention, the sirolimus contained may be a racemate or an optical isomer.

[0015] In the aqueous suspension composition of the present invention, the sirolimus contained may be a salt, and there is no particular limitation as long as it is a pharmaceutically acceptable salt. Sirolimus or a salt thereof can be produced according to a conventional method in the field of organic synthetic chemistry, or a commercially available product can also be used.

[0016] In the aqueous suspension composition of the present invention, examples of pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; salts with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid; quaternary ammonium salts with methyl bromide, methyl iodide, etc.; salts with halogen ions such as bromide ions, chloride ions, and iodide ions; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as magnesium and calcium, and the like. The sirolimus contained in this aqueous suspension composition is preferably free sirolimus (free form).

[0017] In the aqueous suspension composition of the present invention, sirolimus or its salt may be in the form of a hydrate or a solvate.

[0018] In the aqueous suspension composition of the present invention, when geometric isomers or optical isomers are present in sirolimus or its salt, such isomers or their salts are also included in the scope of the present invention. Also, when proton tautomerism is present in sirolimus or its salt, such tautomers or their salts are also included in the scope of the present invention.

[0019] In the aqueous suspension composition of the present invention, when crystal polymorphs and crystal polymorph groups (crystal polymorph systems) are present in sirolimus or its salt (including hydrates or solvates), those crystal polymorphs and crystal polymorph groups (crystal polymorph systems) are also included in the scope of the present invention. Here, the crystal polymorph group (crystal polymorph system) means each individual crystal form and the entire process at each stage when the crystal form changes depending on conditions and states such as the production, crystallization, and storage of those crystals (this state also includes the formulated state).

[0020] In the aqueous suspension composition of the present invention, the upper limit of the content of sirolimus or its salt (hereinafter, the "content" is also referred to as "concentration") is 5% (w / v), and preferably 2% (w / v) or less. The lower limit of the content of sirolimus or its salt may be an amount that does not completely dissolve, and is preferably 0.001% (w / v) or more. For example, the content of sirolimus or its salt is preferably 0.001% to 5% (w / v), more preferably 0.001% to 2% (w / v), still more preferably 0.01% to 2% (w / v), even more preferably 0.01% to 1% (w / v), and particularly preferably 0.01% to 0.1% (w / v). Specifically, the content of sirolimus or its salt can be 0.01% (w / v), 0.02% (w / v), 0.025% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.075% (w / v), 0.08% (w / v), 0.09% (w / v), or 0.1% (w / v).

[0021] In the present invention, "%(w / v)" means the mass (g) of the target component contained in 100 mL of the aqueous suspension composition of the present invention. In the present invention, when a salt of sirolimus is contained, the value is the content of the salt of sirolimus. In the present invention, when sirolimus or its salt is formulated in the form of a hydrate or a solvate, the value is the content of sirolimus or its salt in the hydrate or solvate. Hereinafter, the same shall apply unless otherwise specified.

[0022] In the aqueous suspension composition of the present invention, when the average particle size of sirolimus or its salt is large, aggregation is likely to occur in the aqueous suspension composition. Therefore, the average particle size of sirolimus or its salt contained in the aqueous suspension composition is preferably small, preferably 45 μm or less, more preferably 15 μm or less, and even more preferably 10 μm or less. The average particle size of sirolimus or its salt may be 9 μm, 8 μm, 7 μm, 6.4 μm, 6 μm, 5 μm, 4 μm, or 3 μm or less, more preferably 2.5 μm or less or less than 2.5 μm, even more preferably 2 μm, 1.5 μm, or 1 μm or less, even more preferably 0.5 μm or less, and particularly preferably 0.3 μm or less. The lower limit of the average particle size is not particularly limited as long as it is a manufacturable average particle size, for example, more than 0 μm or 0.001 μm or more. Also, the average particle size of sirolimus or its salt is preferably 0.001 to 45 μm, preferably 0.001 to 15 μm or 0.001 to 10 μm, more preferably 0.001 to 8 μm, even more preferably 0.001 to 5 μm, even more preferably 0.001 to 2.5 μm, even more preferably 0.001 to 1 μm, even more preferably 0.01 to 0.5 μm or 0.1 to 1 μm, and particularly preferably 0.01 to 0.3 μm.

[0023] In the present invention, the average particle size can be determined from the particle size distribution measured by a static light scattering technique such as the laser diffraction method. The particle size distribution is a distribution weighted by the volume of each powder by the laser diffraction method or the like. In the present invention, the "average particle size" means D50 (when the powder is divided into two by particle size, the diameter at which the large particle size and the small particle size are each 50%. Also referred to as the median diameter.) unless otherwise specified.

[0024] In the aqueous suspension composition of the present invention, sirolimus or a salt thereof having a small average particle diameter may be purchased as a commercially available product, but can also be produced by various methods. For example, sirolimus or a salt thereof having a desired average particle diameter can be obtained by pulverization using a commonly used pulverizer. Pulverization methods include, for example, dry pulverization and wet pulverization roughly classified, and sirolimus or a salt thereof having a desired average particle diameter can be obtained by appropriately using pulverizers such as ball mills, bead mills, pin mills, jet mills, and hammer mills. The pulverization method of sirolimus or a salt thereof contained in the aqueous suspension composition of the present invention is not particularly limited, but pulverization by a bead mill is preferred, and wet pulverization is preferred. For example, at the time of preparation, after partially dissolving or suspending sirolimus or a salt thereof and each component added as necessary in purified water, appropriate wet pulverization treatment can be performed to obtain an aqueous suspension composition containing sirolimus or a salt thereof having a desired average particle diameter.

[0025] In the aqueous suspension composition of the present invention, for example, in order to maintain dispersibility and redispersibility and suppress aggregation, a surfactant can be blended. When a surfactant is blended in the aqueous suspension composition of the present invention, surfactants that can be used as additives for pharmaceuticals can be appropriately blended. For example, cationic surfactants, anionic surfactants, amphoteric surfactants, nonionic surfactants, etc. can be mentioned, and these may be hydrates or solvates thereof.

[0026] Examples of cationic surfactants include amine salts such as alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoesters salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxyethyl-2-alkylimidazolines; ammonium salts such as benzalkonium chloride, benzethonium chloride, and chlorhexidine gluconate.

[0027] Examples of the anionic surfactant include sulfonic acids or their salts such as alkylbenzene sulfonates, α-olefin sulfonates, and α-sulfo fatty acid ester salts; sulfuric acid esters or their salts such as alkyl sulfate esters and polyoxyethylene alkyl sulfate esters; and phosphoric acids or their salts such as polyoxyethylene alkyl ether phosphates. Specific examples of the polyoxyethylene alkyl ether phosphoric acid or its salt include polyoxyethylene alkyl (12-15) ether phosphoric acid, sodium polyoxyethylene cetyl ether phosphate, polyoxyethylene lauryl ether phosphoric acid, sodium polyoxyethylene lauryl ether phosphate, polyoxyethylene oleyl ether phosphoric acid, and sodium polyoxyethylene oleyl ether phosphate.

[0028] Examples of nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyl 45 stearate, and polyoxyl 55 stearate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65; polyoxyethylene hydrogenated castor oil such as polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, and polyoxyethylene (60) hydrogenated castor oil; polyoxyl castor oil such as polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil (also referred to as "CO-35"), and polyoxyl 40 castor oil; polyoxyethylene polyoxypropylene glycols such as polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid esters such as sucrose stearate; and tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS).

[0029] As the surfactant in the present invention, a nonionic surfactant is preferred, and polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyoxyl castor oil are more preferred. Polyoxyl 40 stearate, polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil are even more preferred. Polyoxyl 40 stearate, polysorbate 80, and polyoxyl 35 castor oil are particularly preferred. An anionic surfactant is also preferred, and polyoxyethylene alkyl ether phosphate is more preferred. Sodium polyoxyethylene cetyl ether phosphate, sodium polyoxyethylene lauryl ether phosphate, and sodium polyoxyethylene oleyl ether phosphate are even more preferred. Sodium polyoxyethylene cetyl ether phosphate is particularly preferred.

[0030] When a surfactant is blended in the aqueous suspension composition of the present invention, two or more surfactants may be used together.

[0031] When a surfactant is incorporated into the aqueous suspension composition of the present invention, the content of the surfactant can be appropriately adjusted depending on the content of sirolimus or its salt, the type of surfactant, etc. For example, from the viewpoint of maintaining the dispersibility and redispersibility in the aqueous suspension composition and suppressing the aggregation of the suspension, the lower limit is preferably 0.0001% (w / v) or more than 0.0001% (w / v), and preferably 0.001% (w / v) or more than 0.001% (w / v). 0.0001 to 5% (w / v) is preferable, 0.001 to 2% (w / v), 0.001 to 1% (w / v) or 0.002 to 1% (w / v) is more preferable, 0.005 to 1% (w / v) or 0.005 to 0.5% (w / v) is further preferable, 0.01 to 1% (w / v) or 0.01 to 0.5% (w / v) is even more preferable, and 0.01 to 0.1% (w / v) is particularly preferable.

[0032] In the aqueous suspension composition of the present invention, the content ratio of the surfactant to sirolimus or its salt can be appropriately adjusted depending on the type of surfactant, etc. For example, in order to maintain the dispersibility and redispersibility in the aqueous suspension composition and suppress aggregation, with respect to 1 part by weight of the content of sirolimus or its salt, as the content of the surfactant, the lower limit is preferably more than 0.01 part by weight, and the upper limit is 100 parts by weight. Also, it is preferably more than 0.01 to 100 parts by weight or 0.02 to 100 parts by weight, more preferably 0.05 to 50 parts by weight, further preferably 0.1 to 10 parts by weight, and particularly preferably 0.5 to 2 parts by weight. Also, 0.1 to 0.5 parts by weight, 0.1 to 1 part by weight, 0.5 to 1 part by weight, 1 to 5 parts by weight, 1 to 10 parts by weight or 5 to 10 parts by weight are also preferable.

[0033] In the aqueous suspension composition of the present invention, pharmaceutical additives can be further used as needed. Specifically, a dispersant, a buffer, an isotonic agent, a stabilizer, an antioxidant, a preservative, a pH adjuster, etc. can be added. These can be used alone respectively, or two or more of them can be used in an appropriate combination, and an appropriate amount can be incorporated.

[0034] When a dispersant is blended in the aqueous suspension composition of the present invention, a dispersant that can be used as an additive for pharmaceuticals can be appropriately blended. As the dispersant, for example, cellulose polymers such as methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose (also referred to as "HEC"), hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose (also referred to as "HPMC" or "hypromellose"), carboxymethyl cellulose (also referred to as "CMC"), sodium carboxymethyl cellulose (also referred to as "CMC sodium"), hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; polyvinyl pyrrolidone (also referred to as "PVP"); polyhydric alcohols such as polyvinyl alcohol (also referred to as "PVA") and polyethylene glycol; carboxyvinyl polymer; mucopolysaccharides such as sodium hyaluronate (also referred to as "HA") and chondroitin sulfate, and these may be hydrates or solvates.

[0035] As the dispersant of the present invention, cellulose polymers, polyvinyl pyrrolidone, polyhydric alcohols, and mucopolysaccharides are preferred, cellulose polymers are more preferred, and methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose are even more preferred, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose are even more preferred, and hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose are particularly preferred.

[0036] When a dispersant is blended in the aqueous suspension composition of the present invention, two or more dispersants may be used together.

[0037] When a dispersant is incorporated into the aqueous suspension composition of the present invention, the content of the dispersant can be appropriately adjusted depending on the type of the dispersant and the like, but is preferably 0.0001 to 0.1% (w / v), more preferably 0.0001% to 0.01% (w / v). Further, 0.0001 to 0.001% (w / v), 0.0003 to 0.001% (w / v) or 0.001 to 0.01% (w / v) is also more preferable.

[0038] When a buffering agent is incorporated into the aqueous suspension composition of the present invention, a buffering agent that can be used as an additive for pharmaceuticals can be appropriately incorporated. Examples of the buffering agent include tromethamine, phosphoric acid or its salts, boric acid or its salts, carbonic acid or its salts, or organic acids or their salts, etc., and these may be hydrates or solvates.

[0039] Examples of phosphoric acid or its salts include phosphoric acid, trisodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc.

[0040] Examples of boric acid or its salts include boric acid, sodium borate, potassium borate, etc.

[0041] Examples of carbonic acid or its salts include sodium carbonate, sodium hydrogen carbonate, etc.

[0042] Examples of organic acids or their salts include citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, amino acids or their sodium salts, potassium salts, etc.

[0043] When a buffering agent is incorporated into the aqueous suspension composition of the present invention, two or more buffering agents may be used together.

[0044] When a buffering agent is incorporated into the aqueous suspension composition of the present invention, the content of the buffering agent can be appropriately adjusted depending on the type of the buffering agent and the like, but is preferably 0.001 to 5% (w / v), more preferably 0.01 to 2% (w / v), still more preferably 0.05 to 1% (w / v), and particularly preferably 0.05 to 0.5% (w / v). Further, 0.05 to 0.1% (w / v), 0.05 to 0.2% (w / v), 0.1 to 0.5% (w / v) or 0.1 to 0.3% (w / v) is also more preferable.

[0045] When an isotonic agent is incorporated into the aqueous suspension composition of the present invention, an isotonic agent that can be used as an additive for pharmaceuticals can be appropriately incorporated. Examples of the isotonic agent include ionic isotonic agents and non-ionic isotonic agents, and hydrates or solvates thereof may also be used.

[0046] Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.

[0047] Examples of the non-ionic isotonic agent include glycerin, concentrated glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol and the like.

[0048] When an isotonic agent is incorporated into the aqueous suspension composition of the present invention, two or more kinds of isotonic agents may be used together.

[0049] When an isotonic agent is incorporated into the aqueous suspension composition of the present invention, the content of the isotonic agent can be appropriately adjusted depending on the type of the isotonic agent and the like, but is preferably 0.001 to 10% (w / v), more preferably 0.01% to 5% (w / v), still more preferably 0.1 to 3% (w / v), and particularly preferably 0.5 to 3% (w / v).

[0050] When a stabilizer is blended in the aqueous suspension composition of the present invention, a stabilizer that can be used as an additive for pharmaceuticals can be appropriately blended. Examples of the stabilizer include edetic acid or its salts, and these may be hydrates or solvates thereof.

[0051] Examples of edetic acid or its salts include edetic acid, sodium edetate, etc.

[0052] When a stabilizer is blended in the aqueous suspension composition of the present invention, two or more stabilizers may be used together.

[0053] When a stabilizer is blended in the aqueous suspension composition of the present invention, the content of the stabilizer can be appropriately adjusted depending on the type of the stabilizer, etc., but 0.001 to 1% (w / v) is preferable, 0.005% to 0.1% (w / v) is more preferable, and 0.01 to 0.05% (w / v) is even more preferable.

[0054] When an antioxidant is blended in the aqueous suspension composition of the present invention, an antioxidant that can be used as an additive for pharmaceuticals can be appropriately blended. Examples of the antioxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, etc., and these may be hydrates or solvates thereof.

[0055] When an antioxidant is blended in the aqueous suspension composition of the present invention, two or more antioxidants may be used together.

[0056] When an antioxidant is blended in the aqueous suspension composition of the present invention, the content of the antioxidant can be appropriately adjusted depending on the type of the antioxidant, etc., but 0.001 to 5% (w / v) is preferable, 0.01% to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is even more preferable.

[0057] When a preservative is incorporated into the aqueous suspension composition of the present invention, a preservative that can be used as an additive for pharmaceuticals can be appropriately incorporated. Examples of the preservative include reversed soaps, parabens, organic acids or their salts, chlorobutanol, and silver nitrate, and these may be hydrates or solvates thereof.

[0058] Examples of the reversed soaps include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzethonium bromide, chlorhexidine gluconate, and chlorhexidine hydrochloride.

[0059] Examples of the parabens include methyl paraben, ethyl paraben, propyl paraben, and butyl paraben.

[0060] Examples of the organic acids or their salts include sorbic acid or its salts, and sodium dehydroacetate. Among them, examples of sorbic acid or its salts include sodium sorbate and potassium sorbate.

[0061] When a preservative is incorporated into the aqueous suspension composition of the present invention, two or more preservatives may be used together.

[0062] When a preservative is incorporated into the aqueous suspension composition of the present invention, the content of the preservative can be appropriately adjusted depending on the type of the preservative and the like. The content of the preservative only needs to be an amount that does not adversely affect safety, and the upper limit is, for example, 1% (w / v), preferably 1% (w / v) or less, more preferably 0.5% (w / v) or less, even more preferably 0.1% (w / v) or less, and still more preferably 0.01% (w / v) or less. Also, only an amount that can exhibit the preservative effect is required, and the lower limit is, for example, 0.0001% (w / v), preferably 0.0001% (w / v) or more, more preferably 0.001% (w / v) or more. The content of the preservative is preferably 0.0001 to 1% (w / v), more preferably 0.001 to 0.5% (w / v), and even more preferably 0.001 to 0.1% (w / v).

[0063] When a pH adjuster is added to the aqueous suspension composition of the present invention, the pH adjuster can be appropriately selected from those that can be used as pharmaceutical additives. For example, it can be an acid or a base. Examples of acids include hydrochloric acid, phosphoric acid, citric acid, acetic acid, etc., and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, etc. These may be hydrates or solvates thereof.

[0064] When a pH adjuster is added to the aqueous suspension composition of the present invention, two or more pH adjusters may be used together.

[0065] The pH of the aqueous suspension composition of the present invention may be within the range acceptable for pharmaceuticals. From the viewpoint of the stability of the aqueous suspension composition, a pH around 5 is preferred. More preferably, it is 4 - 6, even more preferably 4.0 - 6.0, still more preferably 4.1 - 5.9, yet still more preferably 4.5 - 5.5, and particularly preferably 4.7 - 5.3, and most preferably 5.0. More specifically, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0 are exemplified.

[0066] The osmotic pressure ratio of the aqueous suspension composition of the present invention may be within the range acceptable for pharmaceuticals, for example, 0.5 - 2.0, preferably 0.7 - 1.6, more preferably 0.8 - 1.4, and even more preferably 0.9 - 1.2.

[0067] In the present invention, the aqueous suspension composition is a suspension composition containing water as a solvent, and the aqueous suspension composition preferably contains 80% by mass or more of water, more preferably 90% by mass or more, and even more preferably 95% by mass or more.

[0068] In the present invention, an aqueous suspension composition is a dispersion system in which solid particles are dispersed in a liquid. The components of the aqueous suspension composition may not be completely dissolved, or may be partially dissolved. When the aqueous suspension composition is allowed to stand, the solid particles may be in a precipitated state, and even in such a state, the composition can be returned to a dispersion system (also referred to as redispersion) by shaking the composition. The aqueous suspension composition of the present invention does not include a liquid state in which all components are dissolved.

[0069] Unless otherwise specified, the aqueous suspension composition of the present invention may contain an active ingredient used in ophthalmic preparations other than sirolimus or a salt thereof, or sirolimus or a salt thereof may be included as the sole active ingredient.

[0070] The aqueous suspension composition of the present invention can be administered orally or parenterally to a patient, and parenteral administration is preferred. Since the aqueous suspension composition of the present invention is used ophthalmically, parenteral administration is preferably ophthalmic topical administration, more preferably eye drop administration, subconjunctival administration, intracorneal pocket administration, sub-Tenon's capsule administration, or dermal administration, and eye drop administration is even more preferred from the viewpoint of low invasiveness. Dermal administration is preferably eyelid dermal administration.

[0071] The aqueous suspension composition of the present invention is used in ophthalmology. Therefore, the aqueous suspension composition of the present invention can be used as an ophthalmic preparation, and its dosage form is not particularly limited as long as it can be used as a pharmaceutical. Examples of dosage forms include eye drops, ointments, creams, gels, transdermal absorption type preparations, patches, injections, and the like. Eye drops are particularly preferred.

[0072] The aqueous suspension composition of the present invention is preferably administered in an appropriate amount once a day or divided into 2 to 6 times a day. In particular, when the aqueous suspension composition is an eye drop, it is preferable to instill 1 or 2 drops per eye once and divide it into 1 to 4 times a day, more preferably instill 1 drop per eye once and divide it into 1 to 4 times a day, still more preferably instill 1 drop per eye once and divide it into 1 or 2 times a day, and particularly preferably instill 1 drop per eye once a day. When the aqueous suspension composition of the present invention is instilled 2 to 4 times a day, the instillation interval is preferably at least 1 hour or more, more preferably 2 hours or more, and still more preferably 3 hours or more. One drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, more preferably about 0.02 to about 0.05 mL, and particularly preferably about 0.03 mL.

[0073] The container for accommodating the aqueous suspension composition of the present invention is not particularly limited as long as it is a container generally used as a container for accommodating pharmaceuticals. In particular, when the aqueous suspension composition is an eye drop, it may be any of a multi-dose type container, a single-use unit dose type container, or a PFMD (Preservative Free Multi Dose) container. There is no particular limitation on the material of the container, and any generally used eye drop container may be used, but a resin container is preferably used. For example, containers made of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer, etc. can be used. Also, if the material of the resin container is, for example, polyethylene, polyethylene is classified by its density, and containers made of low-density polyethylene (LDPE), medium-density polyethylene (MDPE), high-density polyethylene (HDPE), etc. can be used.

[0074] The aqueous suspension composition of the present invention can be prepared by a commonly used method. For example, sirolimus or its salt and each component added as necessary are partially dissolved or suspended in purified water, wet grinding treatment is performed as necessary, and the osmotic pressure, pH, etc. are adjusted to a predetermined range for preparation.

[0075] As described above, the aqueous suspension composition of the present invention is used in ophthalmology. For example, since it is useful for the treatment and / or prevention of eye diseases, it is, for example, an aqueous suspension composition for use in the treatment and / or prevention of eye diseases. When the aqueous suspension composition of the present invention is used for the treatment and / or prevention of eye diseases, the subject is not particularly limited whether it is an anterior eye disease or a posterior eye disease. However, since it can also be locally administered as a low-invasive eye drop, it is particularly preferably used for the treatment and / or prevention of anterior eye diseases. Specific diseases include, for example, keratitis, corneal endothelial disorders (keratendotheliitis, macular corneal dystrophy, Fuchs corneal endothelial dystrophy, bullous keratopathy), keratoconjunctivitis, conjunctivitis, blepharitis, meibomian gland dysfunction (also referred to as "MGD"), dry eye syndrome (also referred to as "dry eye"), Sjogren's syndrome, allergic conjunctivitis, uveitis, endophthalmitis, graft-versus-host disease (also referred to as "GVHD"), postoperative inflammation of the anterior eye, inflammation due to ocular tissue transplant rejection, corneal infections (bacterial, fungal, amebic), etc. When the aqueous suspension composition of the present invention is used for the treatment of eye diseases, typically, a therapeutically effective amount of the aqueous suspension composition of the present invention is administered to a patient for use.

[0076] In the present invention, the term "patient" means not only humans but also other animals such as dogs, cats, horses, etc. In the present invention, the patient is preferably a mammal, more preferably a human. In the present invention, the term "therapeutically effective amount" refers to an amount that brings about a therapeutic effect on a disease and its symptoms, or an amount that delays the progression of a disease and its symptoms, as compared with an untreated subject.

[0077] One aspect of the present invention is a method for suppressing aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, which comprises adjusting the pH of the aqueous suspension composition to 4 to 6 and / or making the average particle size of sirolimus or a salt thereof in the aqueous suspension composition 45 μm or less. The method of the present invention is characterized in that, as described above, in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, the pH is adjusted to 4 to 6 and / or the average particle size of sirolimus or a salt thereof is made 45 μm or less. In addition, the detailed description of the aqueous suspension composition of the present invention above also applies to the method for suppressing aggregation of sirolimus or a salt thereof of the present invention.

[0078] One aspect of the present invention is a method for suppressing decomposition of sirolimus in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, which comprises adjusting the pH of the aqueous suspension composition to 4 to 6. The method of the present invention is characterized in that, as described above, in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, the pH is adjusted to 4 to 6. In addition, the detailed description of the aqueous suspension composition of the present invention above also applies to the method for suppressing decomposition of sirolimus of the present invention.

[0079] One aspect of the present invention is a method for treating an eye disease, which comprises administering a therapeutically effective amount of the aqueous suspension composition of the present invention to a patient in need of treatment. The method for treating an eye disease of the present invention is characterized in that, as described above, a therapeutically effective amount of the aqueous suspension composition of the present invention is administered to a patient in need of treatment for an eye disease. In the method for treating an eye disease of the present invention, the eye disease is preferably an anterior eye disease. In addition, the detailed description of the aqueous suspension composition of the present invention above also applies to the method for treating an eye disease of the present invention.

[0080] One aspect of the present invention is the use of the aqueous suspension composition of the present invention for manufacturing a medicament for treating and / or preventing eye diseases. The use of the present invention is characterized by using the aqueous suspension composition of the present invention for manufacturing a medicament for treating and / or preventing eye diseases, as described above. In the use of the present invention, the eye disease is preferably an anterior eye disease. Note that the detailed description of the aqueous suspension composition of the present invention also applies to the use of the present invention.

Examples

[0081] Formulation examples and test examples are shown below. These are for better understanding of the present invention and do not limit the scope of the present invention.

[0082] Formulation Examples Typical formulation examples of the present invention are shown below. Note that the blending amounts of each component in the following formulation examples are the contents in 100 mL of the formulation.

[0083] Formulation Example 1 Sirolimus 0.01 g Polysorbate 80 0.01 g Hypromellose 0.0001 g Sodium citrate hydrate 0.1 g Sodium edetate hydrate 0.01 g Concentrated glycerin 2.0 g Benzalkonium chloride 0.001 g Sodium hydroxide / dilute hydrochloric acid appropriate amount Purified water appropriate amount pH 5.0

[0084] Formulation Example 2 Sirolimus 0.1 g Polysorbate 80 0.01 g CMC sodium 0.01 g Sodium citrate hydrate 0.1 g Sodium edetate hydrate 0.01 g Concentrated glycerin 1.5 g Benzalkonium chloride 0.001g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0085] Formulation Example 3 Sirolimus 0.05g Polyoxyl 40 stearate 0.1g CMC sodium 0.001g Sodium hydrogen phosphate hydrate 0.05g Disodium edetate hydrate 0.02g Sodium chloride 0.8g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0086] Formulation Example 4 Sirolimus 0.2g Polyoxyl 40 stearate 0.2g Hypromellose 0.0005g Sodium hydrogen phosphate hydrate 0.05g Disodium edetate hydrate 0.075g Sodium chloride 1.2g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0087] Formulation Example 5 Sirolimus 0.1g Polysorbate 80 0.005g CMC sodium 0.01g Sodium citrate hydrate 0.05g Disodium edetate hydrate 0.02g Sodium chloride 0.9g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0088] Formulation Example 6 Sirolimus 0.1 g Polysorbate 80 0.05 g CMC Sodium 0.01 g Sodium Citrate Hydrate 0.1 g Sodium Edetate Hydrate 0.01 g Concentrated Glycerin 1.8 g Sodium Hydroxide / Dilute Hydrochloric Acid Q.S. Purified Water Q.S. pH 5.0

[0089] Formulation Example 7 Sirolimus 0.03 g Polysorbate 80 0.01 g CMC Sodium 0.005 g Disodium Hydrogen Phosphate Hydrate 0.1 g Sodium Edetate Hydrate 0.01 g Sodium Chloride 0.75 g Benzalkonium Chloride 0.001 g Sodium Hydroxide / Dilute Hydrochloric Acid Q.S. Purified Water Q.S. pH 5.0

[0090] Formulation Example 8 Sirolimus 0.03 g Polysorbate 80 0.05 g Hydroxyethyl Cellulose 0.01 g Disodium Hydrogen Phosphate Hydrate 0.1 g Sodium Edetate Hydrate 0.01 g Concentrated Glycerin 2.0 g Sodium Hydroxide / Dilute Hydrochloric Acid Q.S. Purified Water Q.S. pH 5.0

[0091] Formulation Example 9 Sirolimus 0.03 g Polysorbate 80 0.1 g Hypromellose 0.001 g Sodium Citrate Hydrate 0.05 g 1.8 g of thick glycerin 0.001 g of benzalkonium chloride Appropriate amount of sodium hydroxide / dilute hydrochloric acid Appropriate amount of purified water pH 5.0

[0092] Formulation Example 10 0.03 g of sirolimus 0.03 g of polysorbate 80 0.0003 g of hypromellose 0.1 g of sodium citrate hydrate 0.01 g of sodium edetate hydrate 0.85 g of sodium chloride Appropriate amount of sodium hydroxide / dilute hydrochloric acid Appropriate amount of purified water pH 5.0

[0093] Formulation Example 11 0.1 g of sirolimus 0.05 g of polyoxyl 35 castor oil 0.001 g of hydroxyethyl cellulose 0.1 g of sodium citrate hydrate 0.01 g of sodium edetate hydrate 0.7 g of sodium chloride 0.001 g of benzalkonium chloride Appropriate amount of sodium hydroxide / dilute hydrochloric acid Appropriate amount of purified water pH 5.0

[0094] Formulation Example 12 0.1 g of sirolimus 0.05 g of polyoxyl 35 castor oil 0.01 g of polyvinylpyrrolidone 0.05 g of sodium hydrogen phosphate hydrate 0.02 g of sodium edetate hydrate 1.4 g of thick glycerin 0.002 g of benzalkonium chloride Sodium hydroxide / Dilute hydrochloric acid appropriate amount Purified water appropriate amount pH 5.0

[0095] Formulation Example 13 Sirolimus 0.1 g Poloxyl 35 castor oil 0.1 g Hypromellose 0.005 g Sodium hydrogen phosphate hydrate 0.1 g Sodium edetate hydrate 0.05 g Concentrated glycerin 1.2 g Sodium hydroxide / Dilute hydrochloric acid appropriate amount Purified water appropriate amount pH 5.0

[0096] Formulation Example 14 Sirolimus 0.1 g Polysorbate 80 0.05 g Polyvinyl alcohol 0.01 g Sodium hydrogen phosphate hydrate 0.05 g Sodium edetate hydrate 0.03 g Concentrated glycerin 1.5 g Sodium hydroxide / Dilute hydrochloric acid appropriate amount Purified water appropriate amount pH 5.0

[0097] Formulation Example 15 Sirolimus 0.1 g Polysorbate 80 0.1 g Hypromellose 0.0003 g Sodium citrate hydrate 0.1 g ... Sodium edetate hydrate 0.01 g Sodium chloride 0.85 g Sodium hydroxide / Dilute hydrochloric acid appropriate amount Purified water appropriate amount pH 5.0

[0098] Formulation Example 16 Sirolimus 0.1 g 0.1 g of polysorbate 80 0.01 g of hypromellose 0.05 g of sodium citrate hydrate 0.03 g of sodium edetate hydrate 0.7 g of sodium chloride 0.005 g of silver nitrate An appropriate amount of sodium hydroxide / dilute hydrochloric acid An appropriate amount of purified water pH 5.0

[0099] Formulation Example 17 0.1 g of sirolimus 0.05 g of polyoxyl 35 castor oil 0.001 g of hypromellose 0.1 g of sodium citrate hydrate 0.03 g of sodium edetate hydrate 1.5 g of concentrated glycerin 0.01 g of chlorobutanol An appropriate amount of sodium hydroxide / dilute hydrochloric acid An appropriate amount of purified water pH 5.0

[0100] Formulation Example 18 0.1 g of sirolimus 0.05 g of polysorbate 80 0.01 g of sodium CMC 0.1 g of sodium hydrogen phosphate hydrate 0.01 g of sodium edetate hydrate 0.9 g of sodium chloride 0.01 g of chlorobutanol An appropriate amount of sodium hydroxide / dilute hydrochloric acid An appropriate amount of purified water pH 5.0

[0101] Formulation Example 19 0.3 g of sirolimus 0.5 g of polysorbate 80 0.01 g of hydroxyethyl cellulose 0.085 g of sodium hydrogen phosphate hydrate 0.01 g of sodium edetate hydrate 2.0 g of concentrated glycerin An appropriate amount of sodium hydroxide / dilute hydrochloric acid An appropriate amount of purified water pH 5.0

[0102] Formulation Example 20 0.5 g of sirolimus 0.5 g of polysorbate 80 0.01 g of sodium CMC 0.085 g of sodium hydrogen phosphate hydrate 0.01 g of sodium edetate hydrate 1.8 g of concentrated glycerin An appropriate amount of sodium hydroxide / dilute hydrochloric acid An appropriate amount of purified water pH 5.0

[0103] Test Examples 1. Stability test (1) Preparation of test formulations Ground sirolimus (average particle size: 15 μm), polysorbate 80, hypromellose TC5 (registered trademark), concentrated glycerin, sodium dihydrogen phosphate hydrate, sodium edetate hydrate and purified water were mixed so that the concentration of each component contained became the set value, and a pH regulator (hydrochloric acid and / or sodium hydroxide) and purified water were added to make the total volume 100 mL, and a test formulation of Composition 1 (pH 3.0; suspension) was prepared. Also, Compositions 2 to 4 (pH 5.0 to pH 9.0; all suspensions) were prepared in the same manner as the test formulation of Composition 1 except for pH adjustment. The concentration of each component contained in each test formulation is as shown in Table 1.

[0104]

Table 1

[0105] (2) Test method The test preparations of Compositions 1 to 4 were each filled with 5 mL into sterilized containers, sealed, and stored in an incubator at 60°C (humidity as it comes) or an incubator at 40°C and 20% humidity for 4 weeks respectively. Immediately after filling and after 4 weeks of storage, after sufficiently dispersing the solid particles in the composition, a small amount was taken as a sample, and the remaining amount of sirolimus contained in the composition was measured by a general method using ultra-high performance liquid chromatography (UPLC), and further the remaining rate of sirolimus was calculated. The remaining rate of sirolimus was calculated by the following formula. Remaining rate (%) = 100 × [(remaining amount of sirolimus after storage) / (remaining amount of sirolimus immediately after filling)] In addition, the more detailed measurement conditions of UPLC are as follows. [Column] ACQUITY UPLC BEH C18 (1.7 μm, 2.1 mm × 50 mm) [Guard column] ACQUITY UPLC BEH C18 VangurardPre-column (1.7 μm, 2.1 mm × 5 mm) [Column temperature] 45°C [Mobile phase] Gradient with Solution A (20 mM ammonium acetate buffer solution) and Solution B (mixed solution of methanol - acetonitrile (1:1))

[0106] (3) Test results and discussion The test results are shown in Table 2.

[0107]

Table 2

[0108] As shown in Table 2, it was revealed that the stability of the composition containing sirolimus depends on pH, and it was shown that it is particularly stable around pH 5.

[0109] 2. Aggregation evaluation and stability test (1) Preparation of test preparations After mixing uncrushed sirolimus, polysorbate 80, and purified water, wet grinding was performed with a bead mill until the average particle size reached 0.50 μm or less. Thereafter, hypromellose TC5 (registered trademark), sodium citrate hydrate, sodium edetate hydrate, and sodium chloride were mixed, and a pH adjuster (hydrochloric acid and / or sodium hydroxide) and purified water were added to make the total volume 100 mL, and a test preparation of Composition 5 (pH 3.0; suspension) was prepared. Also, Compositions 6 to 10 (pH 4.0 to pH 6.0; all suspensions) were prepared in the same manner as the test preparation of Composition 5 except for pH adjustment. For the test preparation of Composition 11, it was prepared in the same manner as the test preparation of Composition 8 except that wet grinding was performed with a bead mill until the average particle size reached 0.30 μm or less. Also, for the test preparation of Composition 12, ground sirolimus (average particle size: 2.5 μm) was used, and it was prepared in the same manner as the test preparation of Composition 8 except that wet grinding was not performed. The concentration of each component contained in each test preparation is as shown in Table 3.

[0110]

Table 3

[0111] (2) Test method The test preparations of Compositions 5 to 12 were each filled with 5 mL into a sterilized container and sealed. They were stored in an incubator at 60°C (humidity was as it came) for 4 weeks or in an incubator at 40°C and 20% humidity for 2 weeks. At the time immediately after filling and after 4 weeks or 2 weeks of storage, the average particle size of each test preparation was measured using a zeta potential and particle size measurement system (manufactured by Otsuka Electronics Co., Ltd., ELSZ-1000ZS), and the particle size increase ratio was calculated. The particle size increase ratio was calculated by the following formula. Particle size increase ratio = (Average particle size after storage) / (Average particle size immediately after filling) The more detailed measurement conditions for the average particle size are as follows. [Measurement conditions] Temperature: 25°C, refractive index of solvent: 1.3328, viscosity of solvent: 0.89, scattering intensity: Auto, incident light filter: Auto [Cell Conditions] Number of integration cycles: 70 times, Dust cut: 10 times [Analysis Conditions] Average particle size analysis: Cumulant method, Particle size distribution analysis: Marquardt method

[0112] Also, for those stored at a temperature of 60 °C (humidity is as it happens), the residual rate of sirolimus was calculated for each test preparation in the same manner as in the above-mentioned "1. Stability Test".

[0113] (3) Test Results and Discussion The test results are shown in Table 4. Note that "-" in the table indicates not implemented.

[0114]

Table 4

[0115] As shown in Table 4, it was revealed that the particle size increase ratio depends on pH, and in particular, it was shown that the particle size increase ratio is minimized near pH 5 and increases as the pH deviates from 5. The particle size increase ratio can also be regarded as an index indicating the degree of particle aggregation, that is, it was suggested that aggregation is less likely to occur near pH 5, and aggregation becomes easier during storage as the pH deviates from 5. Also, when the particle size of sirolimus used in the test preparation is large (Composition 12), it was suggested that aggregation is likely to occur at the time of preparing the test preparation, while it was shown that even if the particle size is large at the time of preparation, aggregation is less likely to occur during storage near pH 5.

[0116] Also, from the results of Table 4 and Table 2 of the above-mentioned "1. Stability Test", it was shown that the aqueous suspension composition containing sirolimus is stable and less likely to aggregate near pH 5.

[0117] 3. Aggregation Test (1) Preparation of Test Preparations After mixing uncrushed Shiromimus, various surfactants, and purified water, wet grinding was performed using a bead mill until the average particle size reached 0.50 μm or less. Subsequently, the other components were mixed, and a pH regulator (hydrochloric acid and / or sodium hydroxide) and purified water were added to make the total volume 100 mL, and Compositions 13 to 24 (all suspensions) were prepared. The concentrations of the components contained in each test preparation are as shown in Tables 5 and 6. In Table 5, "MYS40" means polyoxyl 40 stearate, and "TCP5" means sodium polyoxyethylene cetyl ether phosphate.

[0118]

Table 5

[0119]

Table 6

[0120] (2) Test method The test preparations of Compositions 13 to 24 were each filled with 5 mL into sterilized containers and sealed. They were stored at a temperature of 40°C and a humidity of 20% for 4 weeks. At the time immediately after filling and after 4 weeks of storage, the average particle size was measured and the particle size increase ratio was calculated by the same method as in the above "2. Aggregation evaluation and stability test".

[0121] (3) Test results and discussion The test results are shown in Tables 7 and 8. In the tables, "unsuitable" indicates that no storage was performed because a large amount of aggregation was visually confirmed at the time of preparing the test preparation.

[0122]

Table 7

[0123]

Table 8

[0124] As shown in Tables 7 and 8, when the amount of surfactant is sufficiently small relative to the amount of sirolimus and the composition contains 0.01 parts by weight of surfactant per 1 part by weight of sirolimus (Composition 13, Composition 19, Composition 23), it was shown that aggregation increased in all cases. Also, it was shown that the type of surfactant and the type of dispersant do not have a significant effect on particle aggregation.

[0125] 4. Aggregation Test (1) Preparation of Test Formulations Uncrushed sirolimus, polysorbate 80, hypromellose TC5 (registered trademark), sodium chloride, sodium citrate hydrate, sodium edetate hydrate, and purified water were mixed, and a pH adjuster (hydrochloric acid and / or sodium hydroxide) and purified water were added to make the total volume 100 mL, thereby preparing a test formulation (suspension) of Composition 25. Also, Composition 26 (suspension) was prepared in the same manner as the test formulation of Composition 25 except that polysorbate 80 was excluded. Further, after mixing uncrushed sirolimus, polysorbate 80, and purified water, wet grinding was performed using a bead mill for about 1 minute, and then hypromellose TC5 (registered trademark), sodium citrate hydrate, sodium edetate hydrate, and sodium chloride were mixed, and a pH adjuster (hydrochloric acid and / or sodium hydroxide) and purified water were added to make the total volume 100 mL, thereby preparing a test formulation (suspension) of Composition 27. The concentrations of each component contained in each test formulation are as shown in Table 9.

[0126]

Table 9

[0127] (2) Test Method Each of the test formulations of Compositions 25 to 27 was filled into a sterilized container in an amount of 5 mL each and sealed. They were stored at a temperature of 40 °C and a humidity of 20% for 2 weeks, and at the time immediately after filling and after 2 weeks of storage, the average particle diameter was measured and the particle diameter increase ratio was calculated by the same method as in the above "2. Aggregation Evaluation and Stability Test".

[0128] (3) Test Results and Discussion The test results are shown in Table 10.

[0129]

Table 10

[0130] As shown in Table 10, it was shown that in the test preparations containing unground sirolimus or the test preparations subjected to short-time grinding treatment, the average particle size was large immediately after filling, and aggregation was likely to occur even during storage. Therefore, it was shown that the larger the average particle size of sirolimus, the more likely aggregation was to occur.

[0131] 5. Aggregation Test (1) Preparation of Test Preparations Test preparations of Compositions 28 and 29 (both suspensions) were prepared in the same manner as the test preparations of Composition 5 in the above-mentioned "2. Aggregation Evaluation and Stability Test". The concentrations of each component contained in each test preparation are as shown in Table 11.

[0132]

Table 11

[0133] (2) Test Method The test preparations of Compositions 28 and 29 were each filled with 5 mL into a sterilized container and sealed. They were stored at a temperature of 40 °C and a humidity of 20% for 2 weeks. At the time immediately after filling and after 2 weeks of storage, the average particle size was measured and the particle size increase ratio was calculated by the same method as in the above-mentioned "2. Aggregation Evaluation and Stability Test".

[0134] (3) Test Results and Discussion The test results are shown in Table 12.

[0135]

Table 12

[0136] As shown in Table 12, when the composition contains 1 part by weight of surfactant with respect to 1 part by weight of sirolimus (Composition 28), and when it contains 0.1 part by weight of surfactant with respect to 1 part by weight of sirolimus (Composition 29), it was shown that aggregation is less likely to occur even when the concentration of the surfactant in the test preparation is low.

[0137] 6. Aggregation Test (1) Preparation of Test Preparations Test preparations (all suspensions) of Compositions 30 to 35 containing the components shown in Table 13 were prepared in the same manner as the test preparation of Composition 5 in the above-mentioned "2. Aggregation Evaluation and Stability Test". The concentration of each component contained in each test preparation is as shown in Table 13.

[0138]

Table 13

[0139] (2) Test Method 5 mL each of the test preparations of Compositions 30 to 35 were filled into sterilized containers and sealed. Compositions 30 and 31 were stored at room temperature for 19 months, and Compositions 32 to 35 were stored at room temperature for 28 months. At the time immediately after filling and after storage, the average particle diameter was measured and the particle diameter increase ratio was calculated by the same method as in the above-mentioned "2. Aggregation Evaluation and Stability Test".

[0140] (3) Test Results and Discussion The test results are shown in Table 14.

[0141]

Table 14

[0142] As shown in Table 14, it was shown that the type of surfactant and the type of dispersant do not have a significant effect on the aggregation of particles.

Industrial Applicability

[0143] The present invention provides an aqueous suspension composition containing sirolimus, which is poorly water-soluble, for use in topical administration such as ophthalmic eye drops with particularly low invasiveness.

Claims

1. A method for suppressing aggregation and decomposition of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, comprising: adjusting the pH of the aqueous suspension composition to 4 to 6; making the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition 45 μm or less; and characterized in that the content ratio of the surfactant to sirolimus or a salt thereof in the aqueous suspension composition exceeds 0.01 part by weight with respect to 1 part by weight of the content of sirolimus or a salt thereof.

2. The method according to claim 1, characterized in that the pH of the aqueous suspension composition is adjusted to 4 to 5.

5.

3. The method according to claim 1, characterized in that the pH of the aqueous suspension composition is adjusted to 4.5 to 5.

5.

4. The method according to claim 1, characterized in that the pH of the aqueous suspension composition is adjusted to 4.7 to 5.

3.

5. The method according to claim 1, characterized in that the pH of the aqueous suspension composition is adjusted to 5.

6. The method according to claim 1, characterized in that the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition is 15 μm or less.

7. The method according to claim 1, characterized in that the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition is 10 μm or less.

8. The method according to claim 1, characterized in that the average particle diameter of sirolimus or a salt thereof in the aqueous suspension composition is 2.5 μm or less.

9. The method according to claim 1, characterized in that the content ratio of the surfactant to sirolimus or a salt thereof in the aqueous suspension composition is 0.1 to 10 parts by weight with respect to 1 part by weight of the content of sirolimus or a salt thereof.

10. The method according to claim 1, characterized in that the content ratio of the surfactant to sirolimus or a salt thereof in the aqueous suspension composition is 0.5 to 2 parts by weight with respect to 1 part by weight of the content of sirolimus or a salt thereof.

11. The method according to claim 1, wherein the surfactant is one or more selected from the group consisting of polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyl castor oil, and polyoxyethylene alkyl ether phosphates.

12. The method according to claim 1, wherein the surfactant is one or more selected from the group consisting of polyoxyl 40 stearate, polysorbate 80, polyoxyl 35 castor oil, and sodium polyoxethylene cetyl ether phosphate.

13. The method according to claim 1, wherein the surfactant is polysorbate 80.

14. The method according to any one of claims 1 to 13, wherein the content of sirolimus or a salt thereof in the aqueous suspension composition is 0.01 to 0.1% (w / v).

15. The method according to any one of claims 1 to 13, wherein the aqueous suspension composition contains a dispersant.

16. The method according to claim 15, wherein the dispersant is one or more selected from the group consisting of cellulose-based polymers, polyhydric alcohols, polyvinylpyrrolidone, and mucopolysaccharides.

17. The method according to claim 15, wherein the aqueous suspension composition further contains one or more selected from the group consisting of a buffer, an isotonic agent, a stabilizer, an antioxidant, a preservative, and a pH adjuster.

18. The method according to claim 17, wherein the preservative is one or more selected from the group consisting of reverse soaps, parabens, sorbic acid or a salt thereof, chlorobutanol, and silver nitrate.

19. The method according to any one of claims 1 to 13, wherein the aqueous suspension composition is an eye drop.

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