Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions

Definitions

• the present invention relates to an aqueous suspension composition containing sirolimus or a salt thereof (hereinafter, these are collectively simply referred to as "sirolimus”). It 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.
• Sirolimus also called rapamycin
• rapamycin is a macrolide compound found in metabolites of actinomycetes and has an immunosuppressive effect, which prevents rejection during organ transplantation or causes lymphangioleiomyomatosis.
• Oral agents for treatment are approved as pharmaceuticals.
• Shirolimus is also known to be useful for the treatment of autoimmune diseases, inflammatory diseases, fungal infections, leukemia / lymphoma, hyperproliferative vascular disease, and the like.
• Patent Document 1 describes a method for treating ocular inflammation in mammals, which requires treatment including administration of an anti-inflammatory effective amount of rapamycin to the mammal.
• Patent Document 2 describes mTOR inhibitors such as sirolimus, everolimus, and 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.
• the ophthalmic compositions contained are described.
• Patent Document 3 describes a prophylactic and / or therapeutic agent for meibomian dysfunction, which contains a compound such as sirolimus or defololimus or a pharmaceutically acceptable salt thereof as an active ingredient.
• the chemical structure of sirolimus does not contain a functional group that ionizes in any of the weakly acidic, neutral and weakly basic pH ranges, it is almost insoluble in water.
• the 17th revised Japanese Pharmacopoeia's general formulation rules state that the particles in suspension eye drops usually have a maximum particle size of 75 ⁇ m or less.
• aqueous suspension composition containing sirolimus which is poorly water-soluble, for ophthalmology, especially for topical administration of less invasive eye drops.
• the present inventors can prepare a soluble aqueous composition by adding a solubilizer to poorly water-soluble sirolimus, the decomposition of sirolimus in the composition is likely to occur, while sirolimus is simply suspended in water. It was clarified that the suspension was easily aggregated in the aqueous composition.
• the present inventors conducted further diligent studies on an aqueous composition for ophthalmology containing sirolimus, and found that the pH of the aqueous composition containing sirolimus, the average particle size of sirolimus, the content of additives, etc. were found to be sirolimus. Further, they have found that an aqueous suspension composition containing sirolimus, which will be described in detail below, can suppress the decomposition and aggregation of sirolimus to a minimum, leading to the present invention.
• the present invention provides: (1) An aqueous suspension composition containing sirolimus or a salt thereof and a surfactant.
• the aqueous suspension composition has a pH of 4-6.
• 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 size of sirolimus or a salt thereof in the aqueous suspension composition is 45 ⁇ m or less.
• 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 size of sirolimus or a salt thereof in the aqueous suspension composition is 15 ⁇ m or less.
• 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 size of sirolimus or a salt thereof in the aqueous suspension composition is 10 ⁇ m or less.
• the surfactant is selected from the group consisting of polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl castor oil, and polyoxyethylene alkyl ether phosphate.
• 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, according to (1) to (7).
• the aqueous suspension composition according to any one. (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.
• the dispersant is one or more selected from the group consisting of a cellulosic polymer, a polyhydric alcohol, polyvinylpyrrolidone, and a mucopolysaccharide.
• 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 with respect to 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 ⁇ m or less.
• the aqueous suspension composition has a pH of 4-6.
• Aqueous suspension composition for ophthalmology. (17) A method for suppressing aggregation of silolims or a salt thereof in an aqueous suspension composition containing silolims or a salt thereof and a surfactant, and adjusting the pH of the aqueous suspension composition to 4 to 6. A method, wherein the average particle size of silolims or a salt thereof in the aqueous suspension composition is 45 ⁇ m 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, and the average of sirolimus or a salt thereof in the aqueous suspension composition A method comprising a particle size of 45 ⁇ m 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, and the average of sirolimus or a salt thereof in the aqueous suspension composition A method comprising a particle size of 10 ⁇ m or less.
• the present invention also provides: (25) A method for treating an eye disease, which comprises administering a therapeutically effective amount of the aqueous suspension composition according to any one of (1) to (16) to a patient in need of treatment. .. (26) The treatment method according to (25), wherein the eye disease is an anterior ocular 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 ocular disease. (29) The aqueous suspension composition according to any one of (1) to (16) for use in the treatment and / or prevention of eye diseases. (30) The aqueous suspension composition according to (29), wherein the eye disease is an anterior ocular disease.
• each of the configurations (1) to (30) can be arbitrarily selected and combined with two or more.
• aqueous suspension composition containing sirolimus which is poorly water-soluble, or a salt thereof, for ophthalmology, particularly for topical administration of a less invasive eye drop.
• sirolimus is also called “rapamycin” and has the following formula: It is a compound represented by.
• the contained sirolimus may be a racemate or an optical isomer.
• the contained sirolimus may be a salt, and is not particularly limited 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 synthetic organic chemistry, and commercially available ones can also be used.
• pharmaceutically acceptable salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; acetic acid, fumal.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid
• acetic acid fumal.
• Acids maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, horseuric acid, 1,2-ethanedisulfonic acid, isetionic 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, sulfosalicylic acid and other organic acids Salts; quaternary ammonium salts with methyl bromide, methyl iodide, etc .; salts with halogen ions such as bromine ions, chlorine ions,
• sirolimus or a salt thereof may be in the form of a hydrate or a solvate.
• aqueous suspension composition of the present invention when geometric isomers or optical isomers are present in silolims or salts thereof, the isomers or salts thereof are also included in the scope of the present invention.
• sirolimus or a salt thereof has proton tautomerism, the tautomer or a salt thereof is also included in the scope of the present invention.
• crystal polymorph system In the aqueous suspension composition of the present invention, if polymorphs and polymorphs (crystal polymorph system) are present in silolims or salts thereof (including hydrates or solvates), their crystals. Polymorphs and polymorphs of crystals (polymorphic systems of crystals) are also included within the scope of the present invention.
• the crystal polymorph group means that the crystal form changes depending on the conditions and conditions such as production, crystallization, and storage of those crystals (note that this state includes the formulated state). It means the individual crystal form at each stage and the whole process.
• 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 2% (w / v). v)
• the lower limit of the content of sirolimus or a salt thereof may be an amount that does not completely dissolve, and is preferably 0.001% (w / v) or more.
• the content of sirolimus or a salt thereof is preferably 0.001% to 5% (w / v), more preferably 0.001% to 2% (w / v), and 0.01% to 2% (w / v).
• w / v is even more preferable, 0.01% to 1% (w / v) is even more preferable, and 0.01% to 0.1% (w / v) is particularly preferable.
• the content of silolimus or a salt thereof is 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) can be mentioned.
• % (w / v) means the mass (g) of the target component contained in 100 mL of the aqueous suspension composition of the present invention.
• sirolimus salt when sirolimus salt is contained, the value is the content of sirolimus salt.
• silolimus or a salt thereof when silolimus or a salt thereof is blended in the form of a hydrate or a solvate, the value is the content of the hydrate or the solvate of silolimus or a salt thereof.
• the sirolimus or a salt thereof contained in the aqueous suspension composition is likely to be aggregated.
• the average particle size is preferably smaller, preferably 45 ⁇ m or less, more preferably 15 ⁇ m or less, and even more preferably 10 ⁇ m or less.
• the average particle size of sirolimus or a salt thereof may be 9 ⁇ m, 8 ⁇ m, 7 ⁇ m, 6.4 ⁇ m, 6 ⁇ m, 5 ⁇ m, 4 ⁇ m or 3 ⁇ m or less, more preferably 2.5 ⁇ m or less or less than 2.5 ⁇ m, or 2 ⁇ m, 1.5 ⁇ m or It is more preferably 1 ⁇ m or less, further preferably 0.5 ⁇ m or less, and particularly preferably 0.3 ⁇ m or less.
• the lower limit of the average particle size is not particularly limited as long as it can be produced, and is, for example, more than 0 ⁇ m or 0.001 ⁇ m or more.
• the average particle size of silolimus or a salt thereof is preferably 0.001 to 45 ⁇ m, preferably 0.001 to 15 ⁇ m or 0.001 to 10 ⁇ m, more preferably 0.001 to 8 ⁇ m, and further preferably 0.001 to 5 ⁇ m.
• 0.001 to 2.5 ⁇ m is even more preferable
• 0.001 to 1 ⁇ m is particularly preferable
• 0.01 to 0.5 ⁇ m or 0.1 to 1 ⁇ m is even more preferable
• 0.01 to 0.3 ⁇ m is particularly preferable. preferable.
• the average particle size can be obtained from the particle size distribution measured by a static light scattering technique such as a laser diffraction method.
• the particle size distribution is a distribution weighted by the volume of each powder by a laser diffraction method or the like, and the "average particle size" in the present invention is D50 (powder is reduced to two from the particle size) unless otherwise specified.
• the diameter is such that the large particle diameter and the small particle diameter are 50% each. Also referred to as median diameter).
• silolims having a small average particle size or a salt thereof may be purchased commercially, but can also be produced by various methods, for example, a general-purpose pulverization.
• sirolimus having a desired average particle size or a salt thereof can be obtained.
• the crushing method is roughly divided into dry crushing and wet crushing, and sirolimus having a desired average particle size or a salt thereof can be obtained by appropriately using a crusher such as a ball mill, a bead mill, a pin mill, a jet mill, or a hammer mill. Obtainable.
• the method for pulverizing 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 preferable, and wet pulverization is preferable.
• sirolimus or a salt thereof and a salt thereof are partially dissolved or suspended in purified water and then appropriately wet-ground and subjected to a wet pulverization treatment to obtain sirolimus or a salt thereof having a desired average particle size.
• An aqueous suspension composition containing the above can be obtained.
• a surfactant in the aqueous suspension composition of the present invention, for example, can be blended in order to maintain dispersibility and redispersibility and suppress aggregation.
• a surfactant that can be used as an additive for pharmaceuticals can be appropriately blended as the surfactant, for example, cationic surfactant.
• examples thereof include agents, anionic surfactants, amphoteric surfactants, nonionic surfactants and the like, and these hydrates or solvates may be used.
• Cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolin, 1-acylaminoethyl-2.
• -Amine salts such as alkylimidazolin and 1-hydroxylethyl-2-alkylimidazolin
• ammonium salts such as benzalkonium chloride, benzethonium chloride and chlorhexidine gluconate can be mentioned.
• anionic surfactant examples include sulfonic acids such as alkylbenzene sulfonates, ⁇ -olefin sulfonates and ⁇ -sulfo fatty acid ester salts, or salts thereof; sulfuric acids such as alkyl sulfate ester salts and polyoxyethylene alkyl sulfate ester salts. Ester or salt thereof; examples thereof include phosphoric acid such as polyoxyethylene alkyl ether phosphate or a salt thereof.
• polyoxyethylene alkyl ether phosphoric acid or a salt thereof examples include polyoxyethylene alkyl (12-15) ether phosphoric acid, polyoxyethylene cetyl ether phosphate sodium, polyoxyethylene lauryl ether phosphoric acid, and polyoxy.
• examples thereof include sodium ethylenelauryl ether phosphate, polyoxyethylene oleyl ether phosphoric acid, and sodium polyoxyethylene oleyl ether phosphate.
• nonionic surfactant examples include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyl 45 stearate, and polyoxyl 55 stearate; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, and poly.
• Polyoxyethylene sorbitan fatty acid esters such as oxyethylene sorbitan triolate and polysorbate 65; polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc.
• Polyoxyethylene hydrogenated bean oil polyoxyl 5 bean oil, polyoxyl 9 bean oil, polyoxyl 15 bean oil, polyoxyl 35 bean oil (also referred to as "CO-35"), polyoxyl 40 bean oil, etc.
• Polyoxypropylene (30) Glycol, Polyoxyethylene (42) Polyoxypropylene (67) Glycol, Polyoxyethylene (54) Polyoxypropylene (39) Glycol, Polyoxyethylene (196) Polyoxypropylene (67) ) Polyoxyethylene polyoxypropylene glycol such as glycol, polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid ester such as sucrose stearate; tocopherol polyethylene glycol 1000 succinic acid ester (vitamin E TPGS) And so on.
• a nonionic surfactant is preferable, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyoxyl castor oil are more preferable, and polyoxyl stearate is more preferable.
• Polysorbate 80 Polysorbate 60, Polysorbate 40, Polyoxyethylene sorbitan monolaurate, Polyoxyethylene sorbitan triolate, 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, polyoxyl 40 castor oil are more preferable, polyoxyl 40 stearate, polysorbate 80, polyoxyl 35 castor oil. Oil is particularly preferred.
• Anionic surfactants are also preferred, polyoxyethylene alkyl ether phosphates are more preferred, and sodium polyoxyethylene cetyl ether phosphate, sodium polyoxyethylene lauryl ether phosphate, and sodium polyoxyethylene oleyl ether phosphate are further preferred.
• polyoxyethylene cetyl ether sodium phosphate is particularly preferred.
• a surfactant When a surfactant is blended in the aqueous suspension composition of the present invention, two or more kinds of surfactants may be used together.
• the content of the surfactant when the surfactant is blended in the aqueous suspension composition of the present invention can be appropriately adjusted depending on the content of silolims or a salt thereof, the type of the surfactant, and the like.
• the lower limit thereof is 0.0001% (w / v) or 0.0001% ( More than w / v) is preferable, and more than 0.001% (w / v) or 0.001% (w / v) is preferable.
• w / v It is preferably 0.0001 to 5% (w / v), preferably 0.001 to 2% (w / v), 0.001 to 1% (w / v) or 0.002 to 1% (w / v). More preferably, 0.005 to 1% (w / v) or 0.005 to 0.5% (w / v) is even more 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.
• the content ratio of the surfactant to silolims or a salt thereof can be appropriately adjusted depending on the type of the surfactant and the like.
• the lower limit of the content of the surfactant is more than 0.01 parts by weight with respect to 1 part by weight of the content of silolimus or a salt thereof.
• the upper limit is 100 parts by weight. Further, it is preferably more than 0.01 parts by weight or 0.02 to 100 parts by weight, more preferably 0.05 to 50 parts by weight, and further preferably 0.1 to 10 parts by weight.
• the content is 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. ..
• compositions of the present invention can be further used in the aqueous suspension composition of the present invention, if necessary. Specifically, dispersants, buffers, tonicity agents, stabilizers, antioxidants, preservatives, pH regulators and the like can be added. These may be used alone or in combination of two or more as appropriate, and an appropriate amount may be blended.
• Dispersants include, for example, 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 ("" Cellulose-based polymers such as CMC), sodium carboxymethyl cellulose (also referred to as "CMC sodium”), hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; polyvinylpyrrolidone (“PVP”) ”; Polyhydric alcohol (also referred to as“ PVA ”), polyhydric alcohol (also referred to as“ PVA ”), polyhydric alcohol (also referred to as“ PVA ”), polyhydric alcohol (also referred to as“ PVA
• cellulosic polymers polyvinylpyrrolidone, polyhydric alcohols, and mucopolysaccharides are preferable, cellulosic polymers are more preferable, and methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxyethylmethylcellulose are preferable.
• a dispersant When a dispersant is blended in the aqueous suspension composition of the present invention, two or more kinds of dispersants may be used together.
• the content of the dispersant when the dispersant is blended in the aqueous suspension composition of the present invention can be appropriately adjusted depending on the type of the dispersant and the like, but is 0.0001 to 0.1% (w / v). Is preferable, and 0.0001% to 0.01% (w / v) is more preferable. Further, 0.0001 to 0.001% (w / v), 0.0003 to 0.001% (w / v) or 0.001 to 0.01% (w / v) are also more preferable.
• a buffer that can be used as an additive for pharmaceutical products can be appropriately added.
• the buffer include tromethamole, phosphoric acid or a salt thereof, boric acid or a salt thereof, carbonic acid or a salt thereof or an organic acid or a salt thereof, and may be a hydrate or a solvate thereof.
• Phosphoric acid or a salt thereof includes phosphoric acid, trisodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate (disodium hydrogen phosphate), tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate. And so on.
• boric acid or a salt thereof examples include boric acid, sodium borate, potassium borate and the like.
• Examples of carbonic acid or a salt thereof include sodium carbonate, sodium hydrogencarbonate and the like.
• organic acid or a salt thereof examples include citric acid, acetic acid, ⁇ -aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, amino acids or their sodium salts and potassium salts. Can be mentioned.
• a buffer When a buffer is added to the aqueous suspension composition of the present invention, two or more buffers may be used together.
• the content of the buffer when the buffer is added to the aqueous suspension composition of the present invention can be appropriately adjusted depending on the type of the buffer and the like, but is preferably 0.001 to 5% (w / v). , 0.01 to 2% (w / v) is more preferable, 0.05 to 1% (w / v) is further preferable, and 0.05 to 0.5% (w / v) is particularly preferable. 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.
• the isotonic agent When the isotonic agent is blended in the aqueous suspension composition of the present invention, the isotonic agent that can be used as an additive for pharmaceutical products can be appropriately blended.
• the isotonic agent include an ionic isotonic agent, a nonionic isotonic agent, and the like, and these hydrates or solvates may be used.
• ionic isotonic agent examples include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
• nonionic isotonic agent examples include glycerin, concentrated glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol and the like.
• the isotonic agent When the isotonic agent is blended in the aqueous suspension composition of the present invention, two or more isotonic agents may be used together.
• the content of the tonicity agent when the tonicity agent is blended in the aqueous suspension composition of the present invention can be appropriately adjusted depending on the type of the tonicity agent and the like, but is 0.001 to 10% ( w / v) is preferable, 0.01% to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is further preferable, and 0.5 to 3% (w / v) is preferable. Especially preferable.
• a stabilizer that can be used as an additive for pharmaceutical products can be appropriately added.
• the stabilizer include edetic acid or a salt thereof, and hydrates or solvates thereof may be used.
• edetic acid or a salt thereof examples include edetic acid and sodium edetate.
• a stabilizer When a stabilizer is blended in the aqueous suspension composition of the present invention, two or more stabilizers may be used together.
• the content of the stabilizer when the stabilizer is added to the aqueous suspension composition of the present invention can be appropriately adjusted depending on the type of the stabilizer and the like, but is 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.
• an antioxidant that can be used as an additive for pharmaceutical products can be appropriately added.
• the antioxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite and the like, and these hydrates or solvates may be used.
• antioxidants When an antioxidant is added to the aqueous suspension composition of the present invention, two or more antioxidants may be used together.
• the content of the antioxidant when the antioxidant is added to the aqueous suspension composition of the present invention can be appropriately adjusted depending on the type of the antioxidant and the like, but is 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.
• a preservative that can be used as an additive for pharmaceutical products can be appropriately blended.
• Preservatives include, for example, inverted soaps, parabens, organic acids or salts thereof, chlorobutanol and silver nitrate, and may be hydrates or solvates thereof.
• inverted soaps examples include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzethonium bromide, chlorhexidine gluconate, and chlorhexidine hydrochloride.
• parabens examples include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.
• Examples of the organic acid or a salt thereof include sorbic acid or a salt thereof and sodium dehydroacetate, and examples of the sorbic acid or a salt thereof include sodium sorbate and potassium sorbate.
• a preservative When a preservative is added to the aqueous suspension composition of the present invention, two or more preservatives may be used together.
• the content of the preservative when the preservative is added to the aqueous suspension composition of the present invention can be appropriately adjusted depending on the type of the preservative and the like.
• the content of the preservative may be an amount that does not adversely affect safety, and the upper limit thereof is, for example, 1% (w / v), preferably 1% (w / v) or less, and 0. 5% (w / v) or less is more preferable, 0.1% (w / v) or less is further preferable, and 0.01% (w / v) or less is even more preferable.
• an amount capable of exerting an antiseptic effect is sufficient, and the lower limit thereof is, for example, 0.0001% (w / v), preferably 0.0001% (w / v) or more, and 0.001% (w / v). v)
• the above is more preferable.
• the content of the preservative is preferably 0.0001 to 1% (w / v), more preferably 0.001 to 0.5% (w / v), and 0.001 to 0.1% (w / v). v) is more preferred.
• the pH adjuster that can be used as an additive for pharmaceuticals can be appropriately added, and is, for example, an acid or a base.
• the acid include hydrochloric acid, phosphoric acid, citric acid, acetic acid and the like
• the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like, and hydrates or solvents thereof. It may be Japanese.
• pH adjuster When a pH adjuster is added to the aqueous suspension composition of the present invention, two or more pH adjusters may be used together.
• the pH of the aqueous suspension composition of the present invention may be within the range acceptable for pharmaceutical products, but is preferably around 5 from the viewpoint of stability of the aqueous suspension composition.
• 4 to 6 is more preferable
• 4.0 to 6.0 is further preferable
• 4.1 to 5.9 is more preferable
• 4.5 to 5.5 is particularly preferable
• 4.7 to 5.3 is more preferable.
• 5.0 is particularly preferable. More specifically, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, Examples include 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, and 6.0.
• the osmotic pressure ratio of the aqueous suspension composition of the present invention may be within the range acceptable for pharmaceutical products, for example, 0.5 to 2.0, preferably 0.7 to 1.6, and 0.8 to 0.8. 1.4 is more preferable, and 0.9 to 1.2 is even more preferable.
• 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, and 90% by mass or more. It is more preferable, and it is further preferable that the content is 95% by mass or more.
• the aqueous suspension composition is a dispersion system in which solid particles are dispersed in a liquid, and the constituent components of the aqueous suspension composition may not be dissolved at all or may be partially dissolved. May be good.
• the aqueous suspension composition is allowed to stand, the solid particles may be in a precipitated state, and even if the solid particles are precipitated, the composition is shaken to return the composition to the dispersion system again. Can be done (also called redispersion).
• the aqueous suspension composition of the present invention does not contain a liquid in which all the constituents are dissolved.
• the aqueous suspension composition of the present invention may contain an active ingredient used in eye drops other than sirolimus or a salt thereof, but sirolimus or a salt thereof is contained as the only active ingredient. You may.
• the aqueous suspension composition of the present invention can be orally or parenterally administered to a patient, for example, but is preferably parenterally administered. Since the aqueous suspension composition of the present invention is used for ophthalmology, topical ocular administration is preferable as parenteral administration, and eye drops, subconjunctival administration, intraconjunctival administration, subconjunctival administration, and skin administration are preferable. It is more preferable, and ophthalmic administration is further preferable from the viewpoint of minimal invasiveness. In addition, as skin administration, eyelid skin administration is preferable.
• 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 product. Examples of the dosage form include eye drops, ointments, creams, gels, transdermal preparations, patches, injections and the like. Particularly preferably, it is an eye drop.
• 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.
• the aqueous suspension composition is an eye drop, it is preferable to instill one or two drops per eye once or divided into two to four times a day. It is more preferable to instill one drop per eye once or divided into two to four times a day, and one drop per eye may be instilled once or twice a day. It is more preferable, and it is particularly preferable to instill one drop per eye once a day.
• the instillation interval is preferably at least 1 hour or more, preferably 2 hours or more, and more preferably 3 hours or more. ..
• One drop is usually from about 0.01 to about 0.1 mL, preferably from about 0.015 to about 0.07 mL, more preferably from about 0.02 to about 0.05 mL, and particularly preferably from about 0.03 mL. ..
• 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, but particularly when the aqueous suspension composition is an eye drop. , Multi-dose type container, single-use unit dose type container or PFMD (Preservative Free Multi Dose) container.
• PFMD Preservative Free Multi Dose
• the material of the container is not particularly limited, and any container for eye drops that is generally used may be used, but a resin container is preferable, and for example, polyethylene (PE), polypropylene (PP), or polyethylene terephthalate ( Containers made of PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer and the like can be used. If the material of the resin container is, for example, polyethylene, polyethylene is classified according to its density, and containers made of low-density polyethylene (LDPE), medium-density polyethylene (MDPE), high-density polyethylene (HDPE), etc. are used. Can be used.
• LDPE low-density polyethylene
• MDPE medium-density polyethylene
• HDPE high-density polyethylene
• the aqueous suspension composition of the present invention can be prepared by a general-purpose method. For example, sirolimus or a salt thereof and each component to be added as necessary are partially dissolved or suspended in purified water, and wet pulverization treatment is performed as necessary to adjust the osmotic pressure, pH, etc. within a predetermined range. Can be prepared with.
• the aqueous suspension composition of the present invention is used in ophthalmology as described above, but since it is useful for, for example, the treatment and / or prevention of eye diseases, for example, the treatment and / or prevention of eye diseases. It is an aqueous suspension composition for use in.
• the subject is not particularly limited whether it is a disease of the anterior segment or a disease of the posterior eye. Since it can be locally administered as a less invasive eye drop, it is particularly preferable to be used for the treatment and / or prevention of diseases of the anterior segment of the eye, and specific diseases include, for example, meibomian gland and meibomian gland.
• Endophilic disorders corneal endothelitis, patchy corneal dystrophy, Fuchs corneal endothelial dystrophy, bullous keratopathy), keratoconjunctivitis, conjunctivitis, eyelid inflammation, meibomian gland dysfunction (also called “MGD”), dry eye syndrome (“dry eye”) , Sjogren's syndrome, allergic conjunctivitis, meibomian gland, endophthalmitis, implant-to-host disease (also called "GVHD”), postoperative inflammation of the anterior segment of the eye, inflammation due to ocular tissue transplant rejection, and corneal infection. Diseases (bacterial, fungal, meibomian) and the like can be mentioned.
• a therapeutically effective amount of the aqueous suspension composition of the present invention is typically administered to a patient for use.
• the "patient” means not only humans but also other animals such as dogs, cats and horses.
• the patient is preferably a mammal, more preferably a human.
• the "therapeutically effective amount” refers to an amount that brings about a therapeutic effect on a disease and its symptoms, or an amount that causes a delay in the progression of the disease and its symptoms, as compared with an untreated subject.
• One aspect of the present invention is a method for suppressing aggregation of silolims or a salt thereof in an aqueous suspension composition containing silolims or a salt thereof and a surfactant, and the pH of the aqueous suspension composition is set to 4.
• the method is characterized by adjusting to ⁇ 6 and / or having an average particle size of silolims or a salt thereof in the aqueous suspension composition of 45 ⁇ m or less.
• the method of the present invention adjusts the pH to 4-6 in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, as described above, and / or the average particle size of sirolimus or a salt thereof. Is 45 ⁇ m or less.
• the detailed description of the aqueous suspension composition of the present invention also applies to the method of suppressing the aggregation of sirolimus or a salt thereof of the present invention.
• One aspect of the present invention is a method for suppressing the decomposition of sirolimus in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, and the pH of the aqueous suspension composition is set to 4 to 6. It is a method characterized by adjustment. As described above, the method of the present invention is characterized in that the pH of an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant is adjusted to 4 to 6. The detailed description of the aqueous suspension composition of the present invention also applies to the method of suppressing the decomposition of sirolimus of the present invention.
• 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 a therapeutically effective amount of the aqueous suspension composition of the present invention is administered to a patient in need of treatment for the eye disease.
• the eye disease is preferably an anterior ocular disease.
• the detailed description of the aqueous suspension composition of the present invention also applies to the method for treating eye diseases of the present invention.
• 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.
• the use of the present invention is characterized by using the aqueous suspension composition of the present invention to produce a medicament for treating and / or preventing an eye disease, as described above.
• the eye disease is preferably an anterior ocular disease.
• the detailed description of the aqueous suspension composition of the present invention also applies to the use of the present invention.
• preparations Typical examples of preparations of the present invention are shown below.
• the blending amount of each component is the content in 100 mL of the formulation.
• Test example 1 Stability test (1) Preparation of test product So that the concentration of each component contained is the set value, crushed silolims (average particle size: 15 ⁇ m), polysorbate 80, hypromerose TC5®, concentrated glycerin, phosphorus Mix sodium dihydrogen acid hydrate, sodium edetate hydrate and purified water, add pH adjuster (hydrochloric acid and / or sodium hydroxide) and purified water to make the total volume 100 mL, and make the total volume 100 mL. (PH 3.0; suspension) was prepared. In addition, compositions 2 to 4 (pH 5.0 to pH 9.0; all suspended) were prepared by the same method as the test preparation of composition 1 except for the adjustment of pH. The concentration of each component contained in each test preparation is as shown in Table 1.
• test method Each of the test products of the compositions 1 to 4 is filled in 5 mL each in a sterilized container, sealed, and placed in a heat insulator at a temperature of 60 ° C (humidity is normal) or a heat insulator at a temperature of 40 ° C and a humidity of 20%. Each was stored for 4 weeks. Immediately after filling and after storage for 4 weeks, after the solid particles in the composition were sufficiently dispersed, a small amount was withdrawn as a sample and contained in the composition by a general-purpose method using ultra-high performance liquid chromatography (UPLC). The residual amount of sirolimus was measured, and the residual rate of sirolimus was calculated. The residual rate of sirolimus was calculated by the following formula.
• UPLC ultra-high performance liquid chromatography
• Residual rate (%) 100 ⁇ [(Residual amount of sirolimus after storage) / (Residual amount of sirolimus immediately after filling)]
• the more detailed measurement conditions of UPLC are as follows. [Column] ACQUITY UPLC BEH C18 (1.7 ⁇ m, 2.1 mm ⁇ 50 mm) [Guard Column] ACQUITY UPLC BEH C18 Vangurard Pre-volume (1.7 ⁇ m, 2.1 mm ⁇ 5 mm) [Column temperature] 45 ° C. [Mobile phase] Gradient with solution A (20 mM ammonium acetate buffer) and solution B (methanol-acetonitrile mixed solution (1: 1))
• the test product of the composition 11 was prepared in the same manner as the test product of the composition 8 except that it was wet-milled with a bead mill until the average particle size became 0.30 ⁇ m or less.
• crushed sirolimus crushed sirolimus (average particle size: 2.5 ⁇ m) was used, but it was prepared by the same method as the test preparation of the composition 8 except that wet pulverization was not performed.
• the concentration of each component contained in each test product is as shown in Table 3.
• test method The test products of the compositions 5 to 12 were filled in 5 mL each in a sterilized container and sealed. It was stored in a heat insulator with a temperature of 60 ° C. (humidity is a matter of course) for 4 weeks or in a heat insulator with a temperature of 40 ° C. and a humidity of 20% for 2 weeks. Immediately after filling and after storage for 4 or 2 weeks, the average particle size of each test preparation 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 measured. 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 integrations: 70 times, Dust cut: 10 [Analysis conditions] Average particle size analysis: Cumulant method, Particle size distribution analysis: Marquardt method
• Test results and discussion Table 4 shows the test results. "-" In the table indicates that it has not been implemented.
• the particle size increase ratio depends on the pH, and it was shown that the particle size increase ratio increases as the pH deviates from 5, especially in the vicinity of pH 5. It was suggested that the particle size increase ratio can be regarded as an index indicating the degree of particle agglomeration, that is, it is difficult to agglomerate at around pH 5, and it becomes easier to agglomerate during storage as the pH deviates from 5. It was also suggested that when the particle size of sirolimus used in the test product is large (composition 12), it tends to aggregate at the time of preparation of the test product, but at the time of preparation, even if the particle size is large, it is around pH 5. If there is, it is shown that it is difficult to aggregate during storage.
• Test method The test preparations of the compositions 13 to 24 were filled in 5 mL each in a sterilized container and sealed. Store at a temperature of 40 ° C. and a humidity of 20% for 4 weeks, and immediately after filling and after storage for 4 weeks, measure the average particle size and measure the particle size increase ratio by the same method as in "2. Aggregation evaluation and stability test”. Calculated.
• Test results and discussion The test results are shown in Tables 7 and 8. “Inappropriate” in the table indicates that the test product was not stored because it was visually confirmed that a large amount of agglomeration was generated at the time of preparation.
• the amount of the surfactant is sufficiently small with respect to the amount of sirolimus, and 0.01 part by weight of the surfactant is contained with respect to 1 part by weight of sirolimus (composition).
• the composition 19 it was shown that the aggregation was increased in all of them. It was also shown that the type of surfactant and the type of dispersant do not significantly affect the aggregation of particles.
• Test method The test products of the compositions 25 to 27 were filled in 5 mL each in a sterilized container and sealed. Store at a temperature of 40 ° C. and a humidity of 20% for 2 weeks, and immediately after filling and after 2 weeks of storage, measure the average particle size and measure the particle size increase ratio by the same method as in "2. Aggregation evaluation and stability test”. Calculated.
• Test method The test products of the compositions 28 and 29 were filled in 5 mL each in a sterilized container and sealed. Store at a temperature of 40 ° C. and a humidity of 20% for 2 weeks, and immediately after filling and after 2 weeks of storage, measure the average particle size and measure the particle size increase ratio by the same method as in "2. Aggregation evaluation and stability test”. Calculated.
• composition 28 when 1 part by weight of the surfactant is contained in 1 part by weight of silolims (composition 28), 0.1 parts by weight of the surfactant is contained in 1 part by weight of silolims. In the case of (Composition 29), it was shown that aggregation is unlikely to occur even if the concentration of the surfactant in the test preparation is low.
• Test preparations of the compositions 30 to 35 were filled in 5 mL each in a sterilized container and sealed.
• the compositions 30 and 31 are stored at room temperature for 19 months, and the compositions 32 to 35 are stored at room temperature for 28 months.
• the average particle size was measured and the particle size increase ratio was calculated by the method.
• the present invention provides an aqueous suspension composition containing sirolimus, which is poorly water-soluble, and is used for topical administration of ophthalmic agents, particularly less invasive eye drops.

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