Aqueous suspension composition containing sirolimus or a salt thereof

Abstract

The purpose of the present invention is to provide an aqueous suspension composition that contains poorly soluble sirolimus and that is for use in ophthalmology, especially in topical administration of less-invasive eye drops or the like.　This aqueous suspension composition is for use in ophthalmology, contains a surfactant and sirolimus or a salt thereof, and has a pH of 4-6.

Description

[Technical field]

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

[0002] Sirolimus (also called rapamycin) is a macrolide compound found in the metabolic products of actinomycetes, and has been approved as an oral drug for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis due to its immunosuppressive effect. Sirolimus is also known to be useful in the treatment of autoimmune diseases, inflammatory diseases, fungal infections, leukemia / lymphoma, hyperproliferative vascular diseases, etc.

[0003] In the field of ophthalmology, for example, Patent Document 1 describes a method for treating ocular inflammation in a mammal that requires treatment including administering an anti-inflammatory effective amount of rapamycin to the mammal. Patent Document 2 describes an ophthalmic composition containing an mTOR inhibitor such as sirolimus, everolimus, or 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 preventive and / or therapeutic agent for meibomian dysfunction that contains a compound such as sirolimus or deforolimus or a pharma- ceutical acceptable salt thereof as an active ingredient. On the other hand, the chemical structure of sirolimus does not contain a functional group that ionizes in any pH range of weak acid, neutral, or weak base, and therefore is almost insoluble in water.

[0004] In addition, the General Provisions for Preparations in the 17th Edition of the Japanese Pharmacopoeia states that the maximum particle size of particles in eye drop suspensions is usually 75 μm or less. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 5-194212 [Patent Document 2] Special Publication No. 2010-540682 [Patent Document 3] International Publication No. WO2014 / 142146 Summary of the Invention [Problem to be solved by the invention]

[0006] It is an interesting task to provide an aqueous suspension composition for ophthalmic use, particularly for topical administration such as minimally invasive eye drops, which contains sirolimus, which is poorly water-soluble. [Means for solving the problem]

[0007] The present inventors have clarified that although a dissolving type aqueous composition can be prepared by adding a solubilizer to poorly water-soluble sirolimus, the sirolimus in the composition is prone to decomposition, while an aqueous composition in which sirolimus is simply suspended in water is prone to aggregation. The present inventors have further intensively studied aqueous ophthalmic compositions containing sirolimus, and have found that the pH of an aqueous composition containing sirolimus, the average particle size of sirolimus, the content of additives, etc., affect the decomposition and aggregation of sirolimus, and further that an aqueous suspension composition containing sirolimus, which will be described in detail below, can minimize the decomposition and aggregation of sirolimus, thereby arriving at the present invention.

[0008] Specifically, the present invention provides the following: (1) An aqueous suspension composition comprising sirolimus or a salt thereof and a surfactant, The aqueous suspension composition has a pH of 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 per 1 part by weight of the content of sirolimus or a salt thereof; 2. The aqueous suspension composition according to claim 1, wherein the average particle size of sirolimus or a salt thereof in the aqueous suspension composition is 45 μm or less. (3) The content ratio of the surfactant to sirolimus or a salt thereof is more than 0.01 part by weight per 1 part by weight of the content of sirolimus or a salt thereof; 2. The aqueous suspension composition according to claim 1, wherein the average particle size of sirolimus or a salt thereof in the aqueous suspension composition is 15 μm or less. (4) The content ratio of the surfactant to sirolimus or a salt thereof is more than 0.01 part by weight per 1 part by weight of the content of sirolimus or a salt thereof; 2. The aqueous suspension composition according to claim 1, wherein the average particle size 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 aqueous suspension composition has a pH of 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 size 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 one or more selected from the group consisting of cellulose-based polymers, polyhydric alcohols, polyvinylpyrrolidone, and mucopolysaccharides. (13) The aqueous suspension composition according to any one of (1) to (12), further comprising one or more selected from the group consisting of a buffering agent, an isotonicity agent, a stabilizer, an antioxidant, a preservative, and a pH adjusting agent. (14) The aqueous suspension composition according to (13), wherein the preservative is one or more selected from the group consisting of cationic soaps, parabens, sorbic acid or a salt thereof, 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 a salt thereof and polysorbate 80, The content of sirolimus or a salt thereof is 0.01 to 1% (w / v); the content ratio of polysorbate 80 to sirolimus or a salt thereof is 0.1 to 10 parts by weight per 1 part by weight of the content of sirolimus or a salt thereof; the average particle size of sirolimus or a salt thereof in the aqueous suspension composition is 2.5 μm or less; The aqueous suspension composition has a pH of 4 to 6. An aqueous suspension composition for ophthalmic use. (17) 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, the method comprising adjusting the pH of the aqueous suspension composition to 4 to 6 and adjusting the average particle size of sirolimus or a salt thereof in the aqueous suspension composition to 45 μm or less. (18) 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, the method comprising adjusting the pH of the aqueous suspension composition to 4 to 6 and adjusting the average particle size of sirolimus or a salt thereof in the aqueous suspension composition to 15 μm or less. (19) 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, the method comprising adjusting the pH of the aqueous suspension composition to 4 to 6 and adjusting the average particle size of sirolimus or a salt thereof in the aqueous suspension composition to 10 μm or less. (20) A method for suppressing decomposition of sirolimus 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. (21) A method for inhibiting aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, the method comprising adjusting the pH of the aqueous suspension composition to 4 to 6. (22) A method for inhibiting aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, the method comprising controlling the average particle size of sirolimus or a salt thereof in the aqueous suspension composition to 45 μm or less. (23) A method for inhibiting aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, the method comprising controlling the average particle size of sirolimus or a salt thereof in the aqueous suspension composition to 15 μm or less. (24) A method for inhibiting aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, characterized in that the average particle size of sirolimus or a salt thereof in the aqueous suspension composition is 10 μm or less.

[0009] In addition, the present invention also provides the following: (25) A method for treating an eye disease, comprising administering to a patient in need of treatment a therapeutically effective amount of the aqueous suspension composition according to any one of (1) to (16). (26) The method for treatment according to (25), wherein the eye disease is an anterior eye disease. (27) Use of the aqueous suspension composition according to any one of (1) to (16) for producing a medicament for treating and / or preventing an eye disease. (28) The use according to (27), wherein the eye disease is an anterior eye disease. (29) The aqueous suspension composition according to any one of (1) to (16) for use in the treatment and / or prevention of an eye disease. (30) The aqueous suspension composition according to (29), wherein the eye disease is an anterior eye disease.

[0010] In addition, any two or more of the configurations (1) to (30) above can be selected and combined. Effect of the Invention

[0011] INDUSTRIAL APPLICABILITY The present invention provides an aqueous suspension composition containing poorly water-soluble sirolimus or a salt thereof, which is used for local administration in ophthalmic applications, particularly for minimally invasive eye drops and the like. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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: [ka] It is a compound represented by the formula:

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

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

[0016] In the aqueous suspension composition of the present invention, examples of medicamentously acceptable salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; salts with acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic 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, Examples of the salt include salts with organic acids such as tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid; quaternary ammonium salts with methyl bromide and methyl iodide; salts with halogen ions such as bromide ion, chloride ion, and iodide ion; salts with alkali metals such as sodium and potassium; and salts with alkaline earth metals such as magnesium and calcium. The sirolimus contained in the present aqueous suspension composition is preferably in a free form.

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

[0018] In the aqueous suspension composition of the present invention, when sirolimus or a salt thereof has a geometric isomer or an optical isomer, the isomer or a salt thereof is also included in the scope of the present invention. In addition, when sirolimus or a salt thereof has a proton tautomerism, the tautomer or a salt thereof is also included in the scope of the present invention.

[0019] In the aqueous suspension composition of the present invention, when sirolimus or its salt (including hydrate or solvate) has a crystal polymorph and a crystal polymorph group (crystal polymorph system), the crystal polymorph and the crystal polymorph group (crystal polymorph system) are also included in the scope of the present invention. Here, the crystal polymorph group (crystal polymorph system) means the individual crystal forms at each stage and the whole process when the crystal form changes depending on the conditions and states (including the state of formulation) of the production, crystallization, storage, etc. of the crystals.

[0020] In the aqueous suspension composition of the present invention, the upper limit of the content of sirolimus or a salt thereof (hereinafter, "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 a salt thereof may be any amount that does not completely dissolve, and is preferably 0.001% (w / v) or more. For example, the content of sirolimus or a salt thereof is preferably 0.001% to 5% (w / v), more preferably 0.001% to 2% (w / v), even 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). Specific examples of the content of sirolimus or a salt thereof include 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 a salt thereof is formulated in the form of a hydrate or solvate, the value is the content of the hydrate or solvate of sirolimus or a salt thereof. The same applies hereinafter unless otherwise specified.

[0022] In the aqueous suspension composition of the present invention, if the average particle size of sirolimus or its salt is large, aggregation is likely to occur in the aqueous suspension composition, so 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, 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. There is no particular limit to the lower limit of the average particle size as long as it is a manufacturable average particle size, and it is, for example, more than 0 μm or 0.001 μm or more. The average particle size of sirolimus or a salt thereof 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, particularly preferably 0.001 to 1 μm, more particularly 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 laser diffraction. The particle size distribution is a distribution weighted by the volume of each powder by laser diffraction, and the "average particle size" in the present invention is D50 (the diameter at which the larger particle size and the smaller particle size are 50% each when the powder is divided into two based on the particle size. It is also called the median diameter) unless otherwise specified.

[0024] In the aqueous suspension composition of the present invention, the sirolimus or its salt having a small average particle size may be purchased from a commercial source, but may also be produced by various methods. For example, sirolimus or its salt having a desired average particle size can be obtained by grinding using a general-purpose grinder. Grinding methods are broadly divided into dry grinding and wet grinding, and sirolimus or its salt having a desired average particle size can be obtained by appropriately using grinders such as ball mills, bead mills, pin mills, jet mills, and hammer mills. The grinding method of sirolimus or its salt contained in the aqueous suspension composition of the present invention is not particularly limited, but grinding using a bead mill is preferred, and wet grinding is preferred. For example, during preparation, sirolimus or its salt and each component added as necessary are partially dissolved or suspended in purified water, and then appropriately wet-grinded to obtain an aqueous suspension composition containing sirolimus or its salt having a desired average particle size.

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

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

[0027] Examples of the anionic surfactant include sulfonic acids or salts thereof, such as alkylbenzenesulfonates, α-olefinsulfonates, and α-sulfofatty acid ester salts; sulfates or salts thereof, such as alkyl sulfates and polyoxyethylene alkyl sulfates; and phosphoric acids or salts thereof, such as polyoxyethylene alkyl ether phosphates. Specific examples of polyoxyethylene alkyl ether phosphoric acids or salts thereof 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 oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil, polyoxyl 9 castor oil, and polyoxyl 15 castor oil. polyoxyl castor oils such as castor oil, polyoxyl 35 castor oil (also known 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, with polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyoxyl castor oil being more preferred, with 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 being even more preferred, with polyoxyl 40 stearate, polysorbate 80, and polyoxyl 35 castor oil being particularly preferred. Anionic surfactants are also preferred, with polyoxyethylene alkyl ether phosphates being more preferred, with polyoxyethylene cetyl ether sodium phosphate, polyoxyethylene lauryl ether sodium phosphate and polyoxyethylene oleyl ether sodium phosphate being even more preferred, and polyoxyethylene cetyl ether sodium phosphate being particularly preferred.

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

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

[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 dispersibility and redispersibility in the aqueous suspension composition and suppress aggregation, the content of the surfactant is preferably more than 0.01 parts by weight and the upper limit is 100 parts by weight per part by weight of sirolimus or its salt. In addition, 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, even more preferably 0.1 to 10 parts by weight, and particularly preferably 0.5 to 2 parts by weight. In addition, it is also preferably 0.1 to 0.5 parts by weight, 0.1 to 1 parts by weight, 0.5 to 1 parts by weight, 1 to 5 parts by weight, 1 to 10 parts by weight, or 5 to 10 parts by weight.

[0033] The aqueous suspension composition of the present invention may further contain pharmaceutical additives as necessary. Specifically, dispersants, buffers, isotonicity agents, stabilizers, antioxidants, preservatives, pH regulators, etc. may be added. These may be used alone or in appropriate combinations of two or more, and may be blended in appropriate amounts.

[0034] When dispersing agent is added to the aqueous suspension composition of the present invention, dispersing agent that can be used as an additive for pharmaceuticals can be appropriately added.As dispersing agent, for example, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose (also called "HEC"), hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose (also called "HPMC" or "hypromellose"), carboxymethyl cellulose (also called "CMC"), carboxymethyl cellulose sodium (also called "CMC sodium"), hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate and other cellulose polymers; polyvinylpyrrolidone (also called "PVP"); polyvinyl alcohol (also called "PVA"), polyethylene glycol and other polyhydric alcohols; carboxyvinyl polymers; sodium hyaluronate (also called "HA"), mucopolysaccharides such as chondroitin sulfate and the like can be hydrates or solvates thereof.

[0035] As the dispersant of the present invention, a cellulose-based polymer, polyvinylpyrrolidone, a polyhydric alcohol, or a mucopolysaccharide is preferred, a cellulose-based polymer is more preferred, 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, or carboxymethyl ethyl cellulose is even more preferred, and hydroxyethyl cellulose, hydroxypropyl methyl cellulose, or sodium carboxymethyl cellulose is particularly preferred.

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

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

[0038] When a buffer is added to the aqueous suspension 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 trometamol, phosphoric acid or a salt thereof, boric acid or a salt thereof, carbonic acid or a salt thereof, organic acid or a salt thereof, and the like, and may be a hydrate or solvate thereof.

[0039] Examples of phosphoric acid or salts thereof include phosphoric acid, trisodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate (disodium hydrogen phosphate), tripotassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.

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

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

[0042] Examples of the organic acid or its salt 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 their sodium salts and potassium salts.

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

[0044] When a buffer is added to the aqueous suspension composition of the present invention, the content of the buffer can be appropriately adjusted depending on the type of the buffer, and is preferably 0.001 to 5% (w / v), more preferably 0.01 to 2% (w / v), even more preferably 0.05 to 1% (w / v), particularly preferably 0.05 to 0.5% (w / v), and more preferably 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).

[0045] When an isotonicity agent is added to the aqueous suspension composition of the present invention, an isotonicity agent that can be used as an additive for pharmaceuticals can be appropriately added. Examples of the isotonicity agent include ionic isotonicity agents and nonionic isotonicity agents, and may be hydrates or solvates thereof.

[0046] Ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like.

[0047] Examples of non-ionic tonicity agents include glycerin, concentrated glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, and xylitol.

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

[0049] When an isotonicity agent is blended into the aqueous suspension composition of the present invention, the content of the isotonicity agent can be adjusted as appropriate depending on the type of isotonicity agent, etc., and is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.1 to 3% (w / v), and particularly preferably 0.5 to 3% (w / v).

[0050] When a stabilizer is added to the aqueous suspension 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 a salt thereof, and may be a hydrate or solvate thereof.

[0051] Examples of edetic acid or a salt thereof include edetic acid, sodium edetate, and the like.

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

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

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

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

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

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

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

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

[0060] Examples of the organic acid or its salt include sorbic acid or its salt, and sodium dehydroacetate. Among these, examples of the sorbic acid or its salt include sodium sorbate and potassium sorbate.

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

[0062] When a preservative is blended in the aqueous suspension composition of the present invention, the content of the preservative can be appropriately adjusted depending on the type of the preservative. The content of the preservative may 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 even more preferably 0.01% (w / v) or less. Also, the amount may be an amount that can exert a preservative effect, and the lower limit is, for example, 0.0001% (w / v), preferably 0.0001% (w / v) or more, and 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 incorporated into the aqueous suspension composition of the present invention, the pH adjuster can be any pH adjuster that can be used as an additive for pharmaceuticals, and is, for example, 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 bicarbonate, etc., and may be hydrates or solvates of these.

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

[0065] The pH of the aqueous suspension composition of the present invention may be within a range acceptable for pharmaceutical use, but from the viewpoint of the stability of the aqueous suspension composition, it is preferably around 5. It is more preferably 4 to 6, even more preferably 4.0 to 6.0, even more preferably 4.1 to 5.9, especially preferably 4.5 to 5.5, even more preferably 4.7 to 5.3, and particularly preferably 5.0. More specifically, it may be 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, or 6.0.

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

[0067] In the present invention, an 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, the aqueous suspension composition is a dispersion system in which solid particles are dispersed in a liquid, and the components of the aqueous suspension composition may not be dissolved at all or may be partially dissolved.In addition, when the aqueous suspension composition is left standing, the solid particles may be in a precipitated state, and even if the solid particles are in a precipitated state, they can be returned to a dispersion system by shaking the composition (also called redispersion).The aqueous suspension composition of the present invention does not include a liquid state in which all the components are dissolved.

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

[0070] The aqueous suspension composition of the present invention can be administered orally or parenterally to a patient, but is preferably administered parenterally.Since the aqueous suspension composition of the present invention is used for ophthalmic purposes, the parenteral administration is preferably administered locally to the eye, more preferably by eye drops, subconjunctival administration, intraconjunctival sac administration, sub-Tenon's administration, or skin administration, and eye drops are even more preferred from the viewpoint of low invasiveness.In addition, the skin administration is preferably administered to the eyelid skin.

[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 the dosage form include eye drops, ointments, creams, gels, transdermal preparations, patches, injections, etc. Particularly preferred is eye drops.

[0072] The aqueous suspension composition of the present invention is preferably administered in an appropriate amount once or twice to six 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 or twice to four times a day, more preferably 1 drop per eye once or twice to four times a day, more preferably 1 drop per eye once or twice a day, and particularly preferably 1 drop per eye once a day. When the aqueous suspension composition of the present invention is instilled twice to four times a day, the interval between instillations is preferably at least 1 hour, more preferably 2 hours or more, and 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 containing the aqueous suspension composition of the present invention is not particularly limited as long as it is a container generally used for containing medicines, but 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. The material of the container is not particularly limited, and it may be any generally used eye drop container, but it is preferably a resin container, for example, a container 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. In addition, if the material of the resin container is, for example, polyethylene, polyethylene is classified according to its density, and a container 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, by partially dissolving or suspending sirolimus or a salt thereof and each component to be added as necessary in purified water, subjecting the mixture to wet grinding treatment as necessary, and adjusting the osmotic pressure, pH, etc. to a predetermined range.

[0075] As described above, the aqueous suspension composition of the present invention is used in ophthalmology, and since it is useful, for example, 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 ocular diseases, there is no particular limitation as to whether the target is a disease of the anterior segment or a disease of the posterior segment. However, since the composition can be locally administered as a less invasive eye drop, it is particularly preferable to use the composition for the treatment and / or prevention of diseases of the anterior segment. Specific diseases include, for example, keratitis, corneal endothelial disorders (endothelialitis, patchy corneal dystrophy, Fuchs' endothelial corneal dystrophy, bullous keratopathy), keratoconjunctivitis, conjunctivitis, blepharitis, meibomian gland dysfunction (also referred to as "MGD"), xerophthalmia (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 segment, inflammation due to ocular tissue transplant rejection, corneal infections (bacterial, fungal, amoebic), and the like. When the aqueous suspension composition of the present invention is used to treat an eye disease, it is typically used by administering a therapeutically effective amount of the aqueous suspension composition of the present invention to a patient.

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

[0077] One aspect of the present invention is a method for inhibiting aggregation of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, the method being characterized by 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. As described above, the method of the present invention is characterized by adjusting the pH of an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant to 4 to 6 and / or making the average particle size of sirolimus or a salt thereof 45 μm or less. The above detailed description of the aqueous suspension composition of the present invention also applies to the method for inhibiting 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 is characterized by adjusting the pH of the aqueous suspension composition to 4 to 6. As described above, the method of the present invention is characterized by adjusting the pH of an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant to 4 to 6. The above detailed description of the aqueous suspension composition of the present invention also applies to the method of suppressing decomposition of sirolimus of the present invention.

[0079] One aspect of the present invention is a method for treating an eye disease, which is characterized by administering a therapeutically effective amount of the aqueous suspension composition of the present invention to a patient in need of treatment. As described above, the method for treating an eye disease of the present invention is characterized by administering a therapeutically effective amount of the aqueous suspension composition of the present invention 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. 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 producing a medicament for treating and / or preventing an eye disease. As described above, the use of the present invention is characterized by using the aqueous suspension composition of the present invention for producing a medicament for treating and / or preventing an eye disease. In the use of the present invention, the eye disease is preferably an anterior eye disease. The detailed description of the aqueous suspension composition of the present invention above also applies to the use of the present invention. EXAMPLES

[0081] The following formulation examples and test examples are provided to aid in better understanding of the present invention and are not intended to limit the scope of the present invention.

[0082] Formulation examples Representative formulation examples of the present invention are shown below. Note that the amount of each ingredient in the following formulation examples is the content in 100 mL of the formulation.

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

[0084] Formulation Example 2 Sirolimus 0.1g Polysorbate 80 0.01g CMC sodium 0.01g Sodium citrate hydrate 0.1g Sodium edetate hydrate 0.01g Concentrated glycerin 1.5g 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 Sodium 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 Sodium 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 Sodium 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 0.1g Polysorbate 80 0.05g CMC sodium 0.01g Sodium citrate hydrate 0.1g Sodium edetate hydrate 0.01g Concentrated glycerin 1.8g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0089] Formulation Example 7 Sirolimus 0.03g Polysorbate 80 0.01g CMC sodium 0.005g Sodium hydrogen phosphate hydrate 0.1g Sodium edetate hydrate 0.01g Sodium chloride 0.75g Benzalkonium chloride 0.001g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0090] Formulation Example 8 Sirolimus 0.03g Polysorbate 80 0.05g Hydroxyethyl cellulose 0.01g Sodium hydrogen phosphate hydrate 0.1g Sodium edetate hydrate 0.01g Concentrated glycerin 2.0g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0091] Formulation Example 9 Sirolimus 0.03g Polysorbate 80 0.1g Hypromellose 0.001g Sodium citrate hydrate 0.05g Concentrated glycerin 1.8g Benzalkonium chloride 0.001g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0092] Formulation Example 10 Sirolimus 0.03g Polysorbate 80 0.03g Hypromellose 0.0003g Sodium citrate hydrate 0.1g Sodium edetate hydrate 0.01g Sodium chloride 0.85g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0093] Formulation Example 11 Sirolimus 0.1g Polyoxyl 35 Castor Oil 0.05g Hydroxyethyl cellulose 0.001g Sodium citrate hydrate 0.1g Sodium edetate hydrate 0.01g Sodium chloride 0.7g Benzalkonium chloride 0.001g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0094] Formulation Example 12 Sirolimus 0.1g Polyoxyl 35 Castor Oil 0.05g Polyvinylpyrrolidone 0.01g Sodium hydrogen phosphate hydrate 0.05g Sodium edetate hydrate 0.02g Concentrated glycerin 1.4g Benzalkonium chloride 0.002g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0095] Formulation Example 13 Sirolimus 0.1g Polyoxyl 35 Castor Oil 0.1g Hypromellose 0.005g Sodium hydrogen phosphate hydrate 0.1g Sodium edetate hydrate 0.05g Concentrated glycerin 1.2g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

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

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

[0098] Formulation Example 16 Sirolimus 0.1g Polysorbate 80 0.1g Hypromellose 0.01g Sodium citrate hydrate 0.05g Sodium edetate hydrate 0.03g Sodium chloride 0.7g Silver nitrate 0.005g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0099] Formulation Example 17 Sirolimus 0.1g Polyoxyl 35 Castor Oil 0.05g Hypromellose 0.001g Sodium citrate hydrate 0.1g Sodium edetate hydrate 0.03g Concentrated glycerin 1.5g Chlorobutanol 0.01g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0100] Formulation Example 18 Sirolimus 0.1g Polysorbate 80 0.05g CMC sodium 0.01g Sodium hydrogen phosphate hydrate 0.1g Sodium edetate hydrate 0.01g Sodium chloride 0.9g Chlorobutanol 0.01g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0101] Formulation Example 19 Sirolimus 0.3g Polysorbate 80 0.5g Hydroxyethyl cellulose 0.01g Sodium hydrogen phosphate hydrate 0.085g Sodium edetate hydrate 0.01g Concentrated glycerin 2.0g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0102] Formulation Example 20 Sirolimus 0.5g Polysorbate 80 0.5g CMC sodium 0.01g Sodium hydrogen phosphate hydrate 0.085g Sodium edetate hydrate 0.01g Concentrated glycerin 1.8g Sodium hydroxide / dilute hydrochloric acid (appropriate amount) Purified water (appropriate amount) pH 5.0

[0103] Test Example 1. Stability testing (1) Preparation of test formulations Pulverized 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 was set to a set value, and a pH adjuster (hydrochloric acid and / or sodium hydroxide) and purified water were added to make the total volume 100 mL to prepare a test formulation of composition 1 (pH 3.0; suspension). In addition, 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 the adjustment of pH. The concentrations of each component contained in each test formulation are as shown in Table 1.

[0104] [Table 1]

[0105] (2) Test method The test formulations of compositions 1 to 4 were filled in 5 mL portions into sterilized containers, sealed, and stored for 4 weeks in an insulated cabinet at 60°C (humidity at random) or in an insulated cabinet at 40°C and 20% humidity. Immediately after filling and after 4 weeks of storage, the solid particles in the composition were thoroughly dispersed, and a small amount of the sample was taken and the remaining amount of sirolimus contained in the composition was measured by a general method using ultra-performance liquid chromatography (UPLC), and the remaining percentage of sirolimus was calculated. The remaining percentage of sirolimus was calculated using the following formula. Residual rate (%) = 100 × [(remaining amount of sirolimus after storage) / (remaining amount of sirolimus immediately after filling)] More detailed measurement conditions for UPLC are as follows: [Column] ACQUITY UPLC BEH C18 (1.7 μm, 2.1 mm x 50 mm) [Guard column] ACQUITY UPLC BEH C18 Vangurard Pre-column (1.7 μm, 2.1 mm x 5 mm) [Column temperature] 45℃ [Mobile phase] Gradient with solution A (20 mM ammonium acetate buffer) and solution B (methanol-acetonitrile mixture (1:1))

[0106] (3) Test results and considerations 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 to be particularly stable around pH 5.

[0109] 2. Aggregation evaluation and stability testing (1) Preparation of test formulations Unground sirolimus, polysorbate 80 and purified water were mixed, and then wet-milled in a bead mill until the average particle size was 0.50 μm or less. 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 to prepare a test formulation of composition 5 (pH 3.0; suspension). Compositions 6 to 10 (pH 4.0 to pH 6.0; all suspensions) were prepared in the same manner as the test formulation of composition 5, except for the pH adjustment. The test formulation of composition 11 was prepared in the same manner as the test formulation of composition 8, except for the wet-milling in a bead mill until the average particle size was 0.30 μm or less. The test formulation of Composition 12 was prepared in the same manner as the test formulation of Composition 8, except that pulverized sirolimus (average particle size: 2.5 μm) was used but wet pulverization was not performed. The concentrations of each component contained in each test formulation are shown in Table 3.

[0110] [Table 3]

[0111] (2) Test method The test formulations of compositions 5 to 12 were filled in 5 mL portions into sterilized containers and sealed. They were stored in an insulated cabinet at 60°C (humidity at random) for 4 weeks or in an insulated cabinet at 40°C and 20% humidity for 2 weeks. Immediately after filling and after 4 or 2 weeks of storage, the average particle size of each test formulation was measured using a zeta potential / particle size measurement system (ELSZ-1000ZS, manufactured by Otsuka Electronics Co., Ltd.) and the particle size increase ratio was calculated. The particle size increase ratio was calculated using the following formula. Particle size increase ratio = (average particle size after storage) / (average particle size immediately after filling) 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 times of accumulation: 70 times, dust cut: 10 times [Analysis conditions] Average particle size analysis: Cumulant method, particle size distribution analysis: Marquardt method

[0112] For those stored at a temperature of 60°C (with humidity at normal levels), the remaining percentage of sirolimus was calculated for each test preparation in the same manner as in "1. Stability test" above.

[0113] (3) Test results and considerations The test results are shown in Table 4. In the table, "-" indicates that the test was not carried out.

[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 minimum around pH 5 and increases as the pH moves away from 5. The particle size increase ratio can also be regarded as an index showing the degree of particle aggregation, that is, it was suggested that aggregation is difficult at around pH 5, and aggregation becomes more likely during storage as the pH moves away from 5. In addition, it was suggested that when the particle size of sirolimus used in the test formulation is large (composition 12), aggregation becomes more likely at the time of preparation of the test formulation, while it was shown that aggregation is difficult during storage at around pH 5 even if the particle size is large at the time of preparation.

[0116] Furthermore, the results of Table 4 and Table 2 in "1. Stability test" above demonstrate that the aqueous suspension composition containing sirolimus is stable and does not easily aggregate at a pH of around 5.

[0117] 3. Agglutination test (1) Preparation of test formulations Unground sirolimus, various surfactants and purified water were mixed, and then wet-ground in a bead mill until the average particle size was 0.50 μm or less. The other components were then mixed, and a pH adjuster (hydrochloric acid and / or sodium hydroxide) and purified water were added to make the total volume 100 mL to prepare compositions 13 to 24 (all suspensions). The concentrations of each component contained in each test formulation 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 formulations of Compositions 13 to 24 were filled in 5 mL portions into sterilized containers and sealed. They were stored for 4 weeks at a temperature of 40°C and humidity of 20%, and the average particle size was measured and the particle size increase ratio was calculated immediately after filling and after 4 weeks of storage using the same method as in "2. Aggregation evaluation and stability test" above.

[0121] (3) Test results and considerations The test results are shown in Tables 7 and 8. In the tables, "Not suitable" indicates that storage was not performed because a large amount of aggregation was visually confirmed at the time of preparation of the test preparation.

[0122] [Table 7]

[0123] [Table 8]

[0124] As shown in Tables 7 and 8, when the amount of surfactant relative to the amount of sirolimus was sufficiently small, i.e., when 0.01 part by weight of surfactant was contained per 1 part by weight of sirolimus (compositions 13, 19, and 23), aggregation was observed to be high in all cases. It was also shown that the type of surfactant or the type of dispersant did not have a significant effect on particle aggregation.

[0125] 4. Agglutination test (1) Preparation of test formulations Unground 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, to prepare a test formulation (suspension) of composition 25. In addition, composition 26 (suspension) was prepared in the same manner as the test formulation of composition 25, except that polysorbate 80 was excluded. In addition, after unground sirolimus, polysorbate 80, and purified water were mixed, the mixture was wet-milled in 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, to prepare 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 The test formulations of Compositions 25 to 27 were filled in 5 mL portions into sterilized containers and sealed. They were stored for 2 weeks at a temperature of 40°C and humidity of 20%, and the average particle size was measured and the particle size increase ratio was calculated immediately after filling and after 2 weeks of storage using the same method as in "2. Aggregation evaluation and stability test" above.

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

[0129] [Table 10]

[0130] As shown in Table 10, the test formulations containing unmilled sirolimus or those milled for a short time had a large mean particle size immediately after filling and were prone to aggregation during storage. This indicates that the larger the mean particle size of sirolimus, the more likely it is that aggregation will occur.

[0131] 5. Agglutination Test (1) Preparation of test formulations Test formulations of compositions 28 and 29 (both suspensions) were prepared in the same manner as the test formulation of composition 5 in "2. Aggregation evaluation and stability test" above. The concentrations of each component contained in each test formulation are as shown in Table 11.

[0132] [Table 11]

[0133] (2) Test method The test formulations of Compositions 28 and 29 were filled in 5 mL portions into sterilized containers and sealed. They were stored for 2 weeks at a temperature of 40°C and humidity of 20%, and the average particle size was measured and the particle size increase ratio was calculated immediately after filling and after 2 weeks of storage using the same method as in "2. Aggregation evaluation and stability test" above.

[0134] (3) Test results and considerations 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 per 1 part by weight of sirolimus (composition 28) and when the composition contains 0.1 part by weight of surfactant per 1 part by weight of sirolimus (composition 29), aggregation is less likely to occur even when the concentration of surfactant in the test formulation is low.

[0137] 6. Agglutination Test (1) Preparation of test formulations Test formulations of compositions 30 to 35 (all suspensions) containing the components shown in Table 13 were prepared in the same manner as the test formulation of composition 5 in "2. Aggregation evaluation and stability test" above. The concentrations of each component contained in each test formulation are as shown in Table 13.

[0138] [Table 13]

[0139] (2) Test method 5 mL of each of the test formulations of compositions 30 to 35 was filled into a sterilized container 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. Immediately after filling and after storage, the average particle size was measured and the particle size increase ratio was calculated using the same method as in "2. Aggregation evaluation and stability test" above.

[0140] (3) Test results and considerations 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 did not have a significant effect on particle aggregation. [Industrial Applicability]

[0143] The present invention provides an aqueous suspension composition containing poorly water-soluble sirolimus for use in ophthalmic applications, particularly for topical administration such as minimally invasive eye drops.

Claims

1. An aqueous suspension composition comprising sirolimus or a salt thereof and a surfactant, The aqueous suspension composition has a pH of 4 to 6; the content ratio of the surfactant to the sirolimus or a salt thereof is more than 0.01 part by weight per 1 part by weight of the content of the sirolimus or a salt thereof; The surfactant is at least one 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; An aqueous suspension composition for ophthalmic use.

2. 2. The aqueous suspension composition according to claim 1, wherein the aqueous suspension composition has a pH of 4 to 5.

5.

3. 2. The aqueous suspension composition according to claim 1, wherein the pH of the aqueous suspension composition is 4.5 to 5.

5.

4. 2. The aqueous suspension composition according to claim 1, wherein the pH of the aqueous suspension composition is from 4.7 to 5.

3.

5. 2. The aqueous suspension composition of claim 1, wherein the aqueous suspension composition has a pH of 5.

6. 2. The aqueous suspension composition according to claim 1, wherein the content ratio of the surfactant to the sirolimus or a salt thereof is 0.1 to 10 parts by weight per 1 part by weight of the content of sirolimus or a salt thereof.

7. 3. The aqueous suspension composition according to claim 2, wherein the content ratio of the surfactant to the sirolimus or a salt thereof is 0.1 to 10 parts by weight per 1 part by weight of the content of sirolimus or a salt thereof.

8. 2. The aqueous suspension composition according to claim 1, wherein the content ratio of the surfactant to the sirolimus or a salt thereof is 0.5 to 2 parts by weight per 1 part by weight of the content of sirolimus or a salt thereof.

9. The aqueous suspension composition according to claim 2, wherein the content ratio of the surfactant to sirolimus or a salt thereof is 0.5 to 2 parts by weight per 1 part by weight of the content of sirolimus or a salt thereof.

10. 2. The aqueous suspension composition according to claim 1, wherein the average particle size of sirolimus or a salt thereof in the aqueous suspension composition is 45 μm or less.

11. 2. The aqueous suspension composition according to claim 1, wherein the average particle size of sirolimus or a salt thereof in the aqueous suspension composition is 15 μm or less.

12. 2. The aqueous suspension composition according to claim 1, wherein the average particle size of sirolimus or a salt thereof in the aqueous suspension composition is 10 μm or less.

13. 2. The aqueous suspension composition according to claim 1, wherein the average particle size of sirolimus or a salt thereof in the aqueous suspension composition is 2.5 μm or less.

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

15. The aqueous suspension composition according to any one of claims 1 to 13, 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.

16. 14. The aqueous suspension composition according to any one of claims 1 to 13, wherein the surfactant is polysorbate 80.

17. The aqueous suspension composition according to any one of claims 1 to 13, which contains a dispersant.

18. 18. The aqueous suspension composition according to claim 17, wherein the dispersant is one or more selected from the group consisting of cellulose-based polymers, polyhydric alcohols, polyvinylpyrrolidone, and mucopolysaccharides.

19. The aqueous suspension composition according to claim 17, further comprising one or more selected from the group consisting of a buffering agent, an isotonicity agent, a stabilizer, an antioxidant, a preservative, and a pH adjusting agent.

20. 20. The aqueous suspension composition according to claim 19, wherein the preservative is one or more selected from the group consisting of cationic soaps, parabens, sorbic acid or a salt thereof, chlorobutanol, and silver nitrate.

21. The aqueous suspension composition according to any one of claims 1 to 13, which is an eye drop.

22. An aqueous suspension composition comprising sirolimus or a salt thereof and polysorbate 80, The content of sirolimus or a salt thereof is 0.01 to 1% (w / v); the content ratio of polysorbate 80 to sirolimus or a salt thereof is 0.1 to 10 parts by weight per 1 part by weight of the content of sirolimus or a salt thereof; the average particle size of sirolimus or a salt thereof in the aqueous suspension composition is 2.5 μm or less; The aqueous suspension composition has a pH of 4 to 6. An aqueous suspension composition for ophthalmic use.

23. 23. The aqueous suspension composition according to claim 22, wherein the pH of the aqueous suspension composition is from 4 to 5.

5.

24. 24. The aqueous suspension composition according to claim 23, wherein the pH of the aqueous suspension composition is from 4.5 to 5.

5.

25. 25. The aqueous suspension composition according to claim 24, wherein the pH of the aqueous suspension composition is from 4.7 to 5.

3.

26. 25. The aqueous suspension composition of claim 24, wherein the pH of the aqueous suspension composition is 5.

27. The aqueous suspension composition according to claim 22, wherein the content ratio of polysorbate 80 to sirolimus or a salt thereof is 0.5 to 2 parts by weight per 1 part by weight of the content of sirolimus or a salt thereof.

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