RU2842860C1 - Aqueous suspension composition containing sirolimus or salt thereof - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to ophthalmology, in particular to minimally invasive eye drops. Aqueous ophthalmic suspension composition contains sirolimus and a surfactant, wherein the sirolimus content is from 0.01 wt./vol.% to 0.1 wt./vol.%, ratio of surfactant to sirolimus ranges from 0.1 to 10 wt.pts. per 1 wt.pts. of sirolimus content, sirolimus in the aqueous suspension composition has an average particle size of 45 mcm or less. Another embodiment of the aqueous sirolimus ophthalmic suspension composition is also disclosed.

EFFECT: group of inventions provides suppression of sirolimus disintegration and/or agglomeration in the aqueous suspension composition.

25 cl, 14 tbl, 6 ex

Description

AREA OF TECHNOLOGY

[0001] The present invention relates to an aqueous suspension composition comprising sirolimus or a salt thereof (hereinafter referred to in some instances and generally as simply "sirolimus"). Furthermore, the present invention also relates to a method for suppressing the disintegration and/or agglomeration of sirolimus in an aqueous suspension composition comprising sirolimus or a salt thereof.

LEVEL OF TECHNOLOGY

[0002] Sirolimus (also called rapamycin) is a macrolide compound found in actinomycetes metabolites and has immunosuppressive effects. Thus, its oral preparation for the prevention of rejection in organ transplantation or for the treatment of lymphangioleiomyomatosis is approved as a drug. In addition, sirolimus is known to be used for the treatment of autoimmune diseases, inflammatory diseases, fungal infections, leukemia/lymphoma, hyperproliferative vascular disease, etc.

[0003] For example, in the field of ophthalmology, Patent Document 1 discloses a method for treating ocular inflammation in a mammal requiring treatment, comprising administering to the mammal an effective anti-inflammatory amount of rapamycin. Patent Document 2 discloses an ophthalmological composition comprising an mTOR inhibitor such as sirolimus, everolimus or temsirolimus, a first surfactant with a hydrophilic-lipophilic balance index of greater than about 10, and a second surfactant with a hydrophilic-lipophilic balance index of greater than about 13. Patent Document 3 discloses an agent for the prevention and/or therapy of meibomian gland dysfunction, comprising a compound such as sirolimus or deforolimus or a pharmaceutically acceptable salt thereof as an active ingredient. At the same time, sirolimus is practically insoluble in water, since its chemical structure does not contain functional groups that ionize in the slightly acidic, neutral or slightly alkaline pH range.

[0004] In addition, the General Rules for Preparation of Preparations of the Japanese Pharmacopoeia, 17th Edition, states that the particles in an ophthalmic suspension should generally have a maximum particle size of 75 µm or less.

STATE OF THE ART DOCUMENTS

[0005] Patent Document 1: JP H5-194212 A

Patent document 2: JP 2010-540682 A

Patent Document 3: WO2014/142146A1

ESSENCE OF THE INVENTION

Technical task

[0006] It is of interest to obtain an aqueous suspension composition containing poorly water-soluble sirolimus for use in ophthalmology, in particular for topical use, for example in the form of less invasive eye drops.

Solving a technical problem

[0007] The present inventors found that although a solution-type aqueous composition can be prepared by adding a solubilizing agent to poorly water-soluble sirolimus, the sirolimus in the composition is likely to disintegrate; on the other hand, in an aqueous composition in which sirolimus is simply suspended in water, the suspension is likely to agglomerate. The present inventors further conducted intensive studies on aqueous ophthalmic compositions containing sirolimus. As a result, it was found that the pH of the aqueous sirolimus-containing composition, the average particle size of sirolimus, the content of additive(s), etc. have an effect on the disintegration and agglomeration of sirolimus; and in the sirolimus-containing aqueous suspension composition described in detail below, the disintegration and/or agglomeration of sirolimus can be minimized while suppressed. Thus, the present invention was accomplished.

[0008] In particular, the present invention provides the following.

(1) An ophthalmic aqueous suspension composition comprising sirolimus or a salt thereof and a surfactant, wherein

the aqueous suspension composition has a pH value of from 4 to 6.

(2) The aqueous suspension composition according to paragraph (1), in which the content ratio of the surfactant to sirolimus or a salt thereof is more than 0.01 parts by weight per 1 part by weight of the content of sirolimus or a salt thereof, and

sirolimus or its salt in an aqueous suspension composition has a mean particle size of 45 µm or less.

(3) The aqueous suspension composition according to paragraph (1), in which the content ratio of the surfactant to sirolimus or a salt thereof is more than 0.01 parts by weight per 1 part by weight of the content of sirolimus or a salt thereof, and

sirolimus or its salt in an aqueous suspension composition has a mean particle size of 15 µm or less.

(4) An aqueous suspension composition according to paragraph (1), characterized in that the content ratio of the surfactant to sirolimus or a salt thereof is more than 0.01 parts by weight per 1 part by weight of the content of sirolimus or a salt thereof, and

sirolimus or its salt in an aqueous suspension composition has a mean particle size of 10 µm or less.

(5) An aqueous suspension composition according to any one of paragraphs (1) to (4), characterized in that the aqueous suspension composition has a pH value of 5.

(6) An aqueous suspension composition according to any one of paragraphs (1) to (5), wherein the content of sirolimus or a salt thereof is from 0.01 to 1% (w/v).

(7) The aqueous suspension composition according to any one of paragraphs (1) to (6), wherein the sirolimus or salt thereof has an average particle size of 2.5 μm or less.

(8) The aqueous suspension composition according to any one of paragraphs (1) to (7), wherein the surfactant is one or more substances selected from the group consisting of polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, hydrogenated polyoxyethylene castor oils, polyoxyl castor oils, and polyoxyethylene alkyl ether phosphates.

(9) The aqueous suspension composition according to any one of paragraphs (1) to (7), wherein the surfactant is one or more surfactants selected from the group consisting of polyoxyl 40 stearate, polysorbate 80, polyoxyl 35 castor oil, and polyoxyethylene cetyl ether phosphates.

(10) An aqueous suspension composition according to any one of paragraphs (1) to (7), wherein the surfactant is polysorbate 80.

(11) An aqueous suspension composition according to any one of paragraphs (1) to (10), containing a dispersing agent.

(12) An aqueous suspension composition according to paragraph (11), wherein the dispersing agent is one or more substances selected from the group consisting of cellulosic polymers, polyalcohols, polyvinylpyrrolidone and mucopolysaccharides.

(13) An aqueous suspension composition according to any one of paragraphs (1) to (12), further comprising one or more substances selected from the group consisting of buffering agents, tonicity adjusting agents, stabilizers, antioxidants, preservatives and pH adjusters.

(14) An aqueous suspension composition according to paragraph (13), wherein the preservatives are one or more substances selected from the group consisting of invert soaps, parabens, sorbic acid or its salts, chlorobutanol and silver nitrate.

(15) An aqueous suspension composition according to any one of paragraphs (1) to (14), which is an eye drop.

(16) An aqueous ophthalmic suspension composition comprising sirolimus or a salt thereof and polysorbate 80, wherein

the content of sirolimus or its salt is from 0.01 to 1% (weight/volume),

the ratio of polysorbate 80 to sirolimus or its salt is from 0.1 to 10 parts by weight per 1 part by weight of sirolimus or its salt,

sirolimus or a salt thereof in an aqueous suspension composition has a mean particle size of 2.5 μm or less, and

the aqueous suspension composition has a pH value of from 4 to 6.

(17) A method for suppressing agglomeration of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, comprising adjusting the pH of the aqueous suspension composition to 4-6 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 agglomeration of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, comprising adjusting the pH of the aqueous suspension composition to 4-6 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 agglomeration of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, comprising adjusting the pH of the aqueous suspension composition to 4-6 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 the degradation 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 4-6.

(21) A method for suppressing the agglomeration of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, comprising adjusting the pH of the aqueous suspension composition to 4-6.

(22) A method for suppressing agglomeration of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, comprising adjusting the average particle size of the sirolimus or a salt thereof in the aqueous suspension composition to 45 μm or less.

(23) A method for suppressing agglomeration of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, comprising adjusting the average particle size of the sirolimus or a salt thereof in the aqueous suspension composition to 15 μm or less.

(24) A method for suppressing agglomeration of sirolimus or a salt thereof in an aqueous suspension composition containing sirolimus or a salt thereof and a surfactant, comprising adjusting the average particle size of the sirolimus or a salt thereof in the aqueous suspension composition to 10 μm or less.

[0009] In addition, the present invention provides the following.

(25) A method of treating an ocular disease comprising administering to a patient in need of such treatment a therapeutically effective amount of an aqueous suspension composition according to any one of paragraphs (1) to (16).

(26) The method of treatment according to paragraph (25), wherein the eye disease is a disease of the anterior chamber of the eye.

(27) Use of an aqueous suspension composition according to any of paragraphs (1) to (16) for the manufacture of a medicinal product for the treatment and/or prevention of eye diseases.

(28) The use according to paragraph (27), characterized in that the eye disease is a disease of the anterior chamber of the eye.

(29) An aqueous suspension composition according to any one of paragraphs (1) to (16) for use in the treatment and/or prevention of eye diseases.

(30) The aqueous suspension composition according to paragraph (29), wherein the eye disease is a disease of the anterior chamber of the eye.

[0010] Any two or more of the configurations (1)-(30) described above may be selected and combined.

Positive effect of the invention

[0011] The present invention can provide an aqueous suspension composition containing poorly water-soluble sirolimus or a salt thereof for use in ophthalmology, in particular for topical use, such as in the form of less invasive eye drops.

DESCRIPTION OF IMPLEMENTATION OPTIONS

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

[0013] In the aqueous suspension composition of the present invention, “sirolimus” is also referred to as “rapamycin” and is a compound represented by the following formula:

[Chemical formula 1]

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

[0015] In the aqueous suspension composition of the present invention, the sirolimus contained therein may be a salt and is not particularly limited as long as the salt is pharmaceutically acceptable. Sirolimus or a salt thereof can be produced by a conventional method used in the field of synthetic organic chemistry. In addition, commercially available substances can be used.

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

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

[0018] In the aqueous suspension composition of the present invention, geometric or optical isomers of sirolimus or a salt thereof may be present. In this case, the isomers or salts thereof are also included in the scope of the present invention. In addition, proton tautomers of sirolimus or a salt thereof may be present. In this case, their tautomers or salts are also included in the scope of the present invention.

[0019] In the aqueous suspension composition of the present invention, crystal polymorphs as well as a group of crystal polymorphs (a crystal polymorph system) of sirolimus or a salt thereof (including hydrates or solvates) may be present. In this case, the crystal polymorphs and the group of crystal polymorphs (a crystal polymorph system) are also included in the scope of the present invention. “A group of crystal polymorphs” (a crystal polymorph system) means individual forms of crystals at each stage or during the entire process, when the forms of crystals change depending on the conditions and states of obtaining, crystallizing, storing, etc. of the crystals (It should be noted that these conditions include the state of the composition).

[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 2% (w/v) or less is preferable. Further, the lower limit of the content of sirolimus or a salt thereof should be an amount that does not cause complete dissolution, 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), still more preferably 0.01% to 2% (w/v), more preferably 0.01% to 1% (w/v), and particularly preferably 0.01% to 0.1% (w/v). In particular, the content of sirolimus or its salt may be 0.01% (w/v), 0.02% (w/v), 0.025% (w/v), 0.03% (w/v), 0.04% (w/v), 0.05% (w/v), 0.06% (w/v), 0.07% (w/v), 0.075% (w/v), 0.08% (w/v), 0.09% (w/v), or 0.1% (w/v).

[0021] It should be noted that, in the present invention, “% (weight/volume)” means the weight (g) of the component of interest contained in 100 ml of the aqueous suspension composition of the present invention. In the present invention, when a sirolimus salt is included, the quantitative value corresponds to the content of the sirolimus salt. In addition, when sirolimus or a salt thereof is added in the form of a hydrate or a solvate in the present invention, the quantitative value corresponds to the content of a hydrate or a solvate of sirolimus or a salt thereof. Hereinafter, the same applies unless otherwise specified.

[0022] In the aqueous suspension composition of the present invention, if the average particle size of sirolimus or a salt thereof is large, agglomeration is likely to occur in the aqueous suspension composition. Therefore, the smaller the average particle size of sirolimus or a salt thereof in the aqueous suspension composition, the better. The average particle size is preferably 45 μm or less, more preferably 15 μm or less, and still more preferably 10 μm or less. The average particle size of sirolimus or a salt thereof may be 9 μm or less, 8 μm or less, 7 μm or less, 6.4 μm or less, 6 μm or less, 5 μm or less, 4 μm or less, or 3 μm or less, more preferably 2.5 μm or less, or less than 2.5 μm, still more preferably 2 μm or less, 1.5 μm or less, or 1 μm or less, still more preferably 0.5 μm or less, and particularly preferably 0.3 μm or less. The lower limit of the average particle size is not particularly limited as long as the particles with the average particle size can be obtained. The average particle size is, for example, more than 0 μm or 0.001 μm or more. The average particle size of sirolimus or a salt thereof may be 0.001 to 45 μm, preferably 0.001 to 15 μm or 0.001 to 10 μm, more preferably 0.001 to 8 μm, still more preferably 0.001 to 5 μm, still more preferably 0.001 to 2.5 μm, particularly preferably 0.001 to 1 μm, more preferably 0.01 to 0.5 μm or 0.1 to 1 μm, and still more 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 method such as laser diffractometry. The particle size distribution corresponds to weighing each powder by volume using laser diffractometry or the like to obtain the distribution. Unless otherwise specified, the “average particle size” in the present invention is referred to as D50 (the diameter at which the larger particle size and the smaller particle size account for 50% each when the powder is divided into two parts depending on their particle size; this is also called the median diameter).

[0024] In the aqueous suspension composition of the present invention, sirolimus or its salt having a small average particle size can be commercially purchased. However, it can also be produced by various methods. For example, sirolimus or its salt having a desired average particle size can be obtained by grinding with a commonly used grinder. There are two main types of grinding methods, such as dry grinding and wet grinding. Sirolimus or its salt having a desired average particle size can be obtained by using a suitable grinder of any of various types, such as a ball mill, a bead mill, a pin mill, a jet mill or a hammer mill. The method for grinding sirolimus or its salt contained in the aqueous suspension composition of the present invention is not particularly limited. However, bead milling and wet grinding are preferable. For example, in the preparation process, sirolimus or its salt and the corresponding components, optionally added as needed, are partially dissolved or suspended in purified water. The mixture is then subjected to wet grinding. In this way, an aqueous suspension composition containing sirolimus or its salt with a desired average particle size can be obtained.

[0025] In the aqueous suspension composition of the present invention, for example, a surfactant may be added to maintain dispersibility and redispersibility and suppress agglomeration. Any surfactant that can be used as a pharmaceutical additive can be suitably added as a surfactant in the case of adding a surfactant to the aqueous suspension composition of the present invention. Examples include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant. Hydrates or solvates thereof are also acceptable.

[0026] Examples of the cationic surfactant include: an amine salt such as an alkylamine salt, an alkylamine polyoxyethylene adduct, a triethanolamine fatty acid monoester, an acylaminoethyl diethylamine salt, a polyamine fatty acid condensate, an alkyl imidazoline, 1-acylaminoethyl-2-alkyl imidazoline, 1-hydroxyethyl-2-alkyl imidazoline; and ammonium salts such as benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate.

[0027] Examples of the anionic surfactant include: a sulfonic acid or a salt thereof such as an alkyl benzene sulfonate, an α-olefin sulfonate, an α-sulfo fatty acid ester salt; a sulfuric acid ester or a salt thereof such as a salt of an alkyl ester of sulfuric acid, a salt of a polyoxyethylene alkyl ether of sulfuric acid; and a phosphoric acid or a salt thereof such as a polyoxyethylene alkyl ether phosphate. Specific examples of the polyoxyethylene alkyl ether of phosphoric acid or a salt thereof include: a polyoxyethylene alkyl (12-15) ether of phosphoric acid, a sodium polyoxyethylene cetyl ether phosphate, a polyoxyethylene lauryl ether of phosphoric acid, a sodium polyoxyethylene lauryl ether phosphate, a polyoxyethylene oleyl ether of phosphoric acid, and a sodium polyoxyethylene oleyl ether phosphate.

[0028] Examples of the nonionic surfactant include: a polyoxyethylene fatty acid ester such as polyoxyl 40 stearate, polyoxyl 45 stearate, polyoxyl 55 stearate; a polyoxyethylene sorbitan fatty acid ester such as polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65; polyoxyethylene hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60; polyoxyl castor oil such as polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil (also called “CO-35”), polyoxyl 40 castor oil; polyoxyethylene polyoxypropylene glycol such as polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid ester such as sucrose stearate ester; and tocopherol polyethylene glycol 1000 succinic acid ester (vitamin E TPGS).

[0029] The surfactant in the present invention is preferably a nonionic surfactant, more preferably a polyoxyethylene fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil or polyoxyl castor oil, even more preferably 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 or polyoxyl 40 castor oil, and particularly preferably polyoxyl 40 stearate, polysorbate 80 or polyoxyl 35 castor oil. In addition, an anionic surfactant is preferred. More preferred is polyoxyethylene alkyl ether phosphate. Even more preferred are sodium polyoxyethylene cetyl ether phosphate, sodium polyoxyethylene lauryl ether phosphate or sodium polyoxyethylene oleyl ether phosphate. Particularly preferred is sodium polyoxyethylene cetyl ether phosphate.

[0030] In the case of adding a surfactant to the aqueous suspension composition of the present invention, two or more surfactants may be used together.

[0031] In the case where a surfactant is added to the aqueous suspension composition of the present invention, the content of the surfactant can be appropriately adjusted according to the content of sirolimus or a salt thereof and/or the type of surfactant, etc. For example, from the viewpoint of maintaining the dispersibility and re-dispersibility of the aqueous suspension composition and suppressing the agglomeration of the suspension, the lower limit is preferably 0.0001% (w/v) or more than 0.0001% (w/v), or preferably 0.001% (w/v) or more than 0.001% (w/v). The range is preferably from 0.0001 to 5% (w/v), more preferably from 0.001 to 2% (w/v), from 0.001 to 1% (w/v) or from 0.002 to 1% (w/v), even more preferably from 0.005 to 1% (w/v) or from 0.005 to 0.5% (w/v), still more preferably from 0.01 to 1% (w/v) or from 0.01 to 0.5% (w/v), and particularly preferably from 0.01 to 0.1% (w/v).

[0032] Meanwhile, the content ratio of the surfactant to sirolimus or a salt thereof in the aqueous suspension composition of the present invention can be appropriately adjusted depending on the type of the surfactant and the like. According to the present invention, for example, from the viewpoint of maintaining dispersibility and re-dispersibility in the aqueous suspension composition and suppressing agglomeration, the lower limit of the content of the surfactant, based on 1 part by weight of sirolimus or a salt thereof, is preferably more than 0.01 parts by weight, and the upper limit is 100 parts by weight. Further, the range 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, still 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 from 0.1 to 0.5 parts by mass, from 0.1 to 1 part by mass, from 0.5 to 1 part by mass, from 1 to 5 parts by mass, from 1 to 10 parts by mass, or from 5 to 10 parts by mass.

[0033] Furthermore, in the aqueous suspension composition of the present invention, a pharmaceutical additive(s) may be optionally used. Specifically, for example, a dispersing agent, a buffering agent, a tonicity adjusting agent, a stabilizer, an antioxidant, a preservative, and/or a pH adjuster may be added. Each of these substances may be used alone, or two or more kinds thereof may be appropriately used in combination and may be added in an appropriate amount.

[0034] In the case of adding a dispersing agent to the aqueous suspension composition of the present invention, any dispersing agent that can be used as a pharmaceutical additive can be suitably added as the dispersing agent. Examples of the dispersing agent include: a cellulose polymer such as methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose (also referred to as “HEC”), hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (also referred to as “HPMC” or “hypromellose”), carboxymethylcellulose (also referred to as “CMC”), sodium carboxymethylcellulose (also referred to as “sodium CMC”), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate; polyvinylpyrrolidone (also referred to as “PVP”); polyhydric alcohol such as polyvinyl alcohol (also called “PVA”), polyethylene glycol; carboxyvinyl polymer; and mucopolysaccharides such as sodium hyaluronate (also called “HA” (hyaluronic acid)), chondroitin sulfate. Its hydrate or solvate is also acceptable.

[0035] As the dispersing agent in the present invention, a cellulose polymer, polyvinylpyrrolidone, a polyhydric alcohol or mucopolysaccharides is preferable. A cellulose polymer is more preferable. Still more preferable are methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate or carboxymethylethylcellulose. More preferable are hydroxyethylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose. Particularly preferable is hydroxypropylmethylcellulose or sodium carboxymethylcellulose.

[0036] When a dispersing agent is added to the aqueous suspension composition of the present invention, two or more dispersing agents may be used together.

[0037] In the case of adding a dispersing agent to the aqueous suspension composition of the present invention, the content of the dispersing agent can be appropriately adjusted depending on the type of the dispersing agent and the like, and is preferably 0.0001 to 0.1% (w/v), and more preferably 0.0001 to 0.01% (w/v). Further, 0.0001 to 0.001% (w/v), 0.0003 to 0.001% (w/v), or 0.001 to 0.01% (w/v) is more preferably.

[0038] Any buffering agent that can be used as a pharmaceutical additive can be suitably added as a buffering agent in the case of adding a buffering agent to the aqueous suspension composition of the present invention. Examples of the buffering agent include trometamol, phosphoric acid or its salt, boric acid or its salt, carbonic acid or its salt, and organic acid or its salt. Hydrates or solvates thereof are also acceptable.

[0039] Examples of phosphoric acid or a salt 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 salt include boric acid, sodium borate, and potassium borate.

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

[0042] Examples of the organic acid or salt thereof 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 its sodium or potassium salt.

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

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

[0045] In the case of adding a tonicity adjusting agent to the aqueous suspension composition of the present invention, any tonicity adjusting agent that can be used as a pharmaceutical additive can be suitably added as the tonicity adjusting agent. Examples of the tonicity adjusting agent include an ionic tonicity adjusting agent and a nonionic tonicity adjusting agent. A hydrate or solvate thereof is also acceptable.

[0046] Examples of ionic tonicity adjusting substance include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

[0047] Examples of nonionic tonicity adjusting agent include glycerin, concentrated glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose and xylitol.

[0048] When a tonicity adjusting agent is added to the aqueous suspension composition of the present invention, two or more tonicity adjusting agents may be used together.

[0049] In the case of adding a tonicity adjusting agent to the aqueous suspension composition of the present invention, the content of the tonicity adjusting agent can be appropriately adjusted depending on the type of the tonicity adjusting agent and the like, and is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v), still more preferably 0.1 to 3% (w/v), and particularly preferably 0.5 to 3% (w/v).

[0050] In the case of adding a stabilizer to the aqueous suspension composition of the present invention, any stabilizer that can be used as a pharmaceutical additive can be suitably added as a stabilizer. Examples of the stabilizer include edetic acid or a salt thereof. A hydrate or solvate thereof is also acceptable.

[0051] Examples of edetic acid or its salt include edetic acid and sodium edetate.

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

[0053] In the case of adding a stabilizer to the aqueous suspension composition of the present invention, the content of the stabilizer can be appropriately adjusted depending on the type of the stabilizer and the like, and is preferably 0.001 to 1% (w/v), more preferably 0.005% to 0.1% (w/v), and still more preferably 0.01 to 0.05% (w/v).

[0054] In the case of adding an antioxidant to the aqueous suspension composition of the present invention, any antioxidant that can be used as a pharmaceutical additive can be suitably added as an antioxidant. Examples of the antioxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, and sodium sulfite. Hydrates or solvates thereof are also acceptable.

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

[0056] In the case of adding an antioxidant to the aqueous suspension composition of the present invention, the content of the antioxidant can be appropriately adjusted depending on the type of the antioxidant and the like, and is preferably 0.001 to 5% (w/v), more preferably 0.01% to 3% (w/v), and still more preferably 0.1 to 2% (w/v).

[0057] In the case of adding a preservative to the aqueous suspension composition of the present invention, any preservative that can be used as a pharmaceutical additive can be suitably added as a preservative. Examples of the preservative include invert soaps, parabens, an organic acid or a salt thereof, chlorobutanol, and silver nitrate. Hydrates or solvates thereof are also acceptable.

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

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

[0060] Examples of the organic acid or salt thereof include sorbic acid or salt thereof and sodium dehydroacetate. Examples of sorbic acid or salt thereof include sodium sorbate and potassium sorbate.

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

[0062] When a preservative is added to the aqueous suspension composition of the present invention, the content of the preservative can be appropriately adjusted depending on the type of the preservative and the like. The content of the preservative may be an amount that does not adversely affect safety. The upper limit is, for example, 1% (w/v), preferably 1% (w/v) or less, more preferably 0.5% (w/v) or less, still more preferably 0.1% (w/v) or less, and more preferably 0.01% (w/v) or less. Further, the amount may be allowed if the preservative effect can be determined. 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 still more preferably 0.001 to 0.1% (w/v).

[0063] In the case of adding a pH adjuster to the aqueous suspension composition of the present invention, any pH adjuster that can be used as a pharmaceutical additive can be suitably added as a pH adjuster, for example, it can be an acid or a base. Examples of the acid include hydrochloric acid, phosphoric acid, citric acid and acetic acid. Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate and sodium hydrogen carbonate. Hydrates or solvates thereof are also acceptable.

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

[0065] The pH of the aqueous suspension composition of the present invention is acceptable if it is in a range acceptable for pharmaceutical use. However, from the viewpoint of the stability of the aqueous suspension composition, the pH is preferably about 5. More preferably, the pH is 4 to 6, even more preferably 4.0 to 6.0, even more preferably 4.1 to 5.9, particularly preferably 4.5 to 5.5, even more preferably 4.7 to 5.3, and most preferably 5.0. More specific examples include 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 and 6.0.

[0066] The osmotic pressure level of the aqueous suspension composition of the present invention is acceptable if it is in a range acceptable for pharmaceutical use. For example, the range is from 0.5 to 2.0, preferably from 0.7 to 1.6, more preferably from 0.8 to 1.4, and even more preferably from 0.9 to 1.2.

[0067] In the present invention, the aqueous suspension composition is a suspension composition containing water as a solvent. The water content in the aqueous suspension composition is preferably 80% by weight or more, more preferably 90% by weight or more, and still more preferably 95% by weight or more.

[0068] In the present invention, the aqueous suspension composition is a dispersion system in which solid particles are dispersed in a liquid. The components of the aqueous suspension composition are not necessarily completely dissolved or may be partially dissolved. In addition, when the aqueous suspension composition is allowed to settle, the solid particles may be in a precipitated state. Even if the solid particles are in a precipitated state, the composition can be shaken, as a result of which the solid particles can be resuspended in the dispersion system (also called re-dispersion). The aqueous suspension composition of the present invention does not include a liquid in which the components are completely dissolved.

[0069] Unless otherwise specified, the aqueous suspension composition of the present invention may contain an active ingredient other than sirolimus or a salt thereof and be used for eye drops. However, sirolimus or a salt thereof may be included as the only active ingredient.

[0070] The aqueous suspension composition of the present invention can be administered to a patient, for example, orally or parenterally, preferably parenterally. The aqueous suspension composition of the present invention is used in ophthalmology. Thus, parenteral administration is preferably local administration to the eye. More preferable is administration by instillation into the eye, subconjunctival administration, intraconjunctival administration, sub-Tenon's space administration or cutaneous application. Even more preferable, from the viewpoint of minimally invasive characteristics, is administration by instillation into the eye. In addition, cutaneous application is preferably administration through the eyelid.

[0071] The aqueous suspension composition of the present invention is intended for use in ophthalmology. Therefore, the aqueous suspension composition of the present invention can be used as an ophthalmological preparation. The dosage form is not particularly limited as long as it can be used as a medicine. Examples of the dosage form include eye drops, ointment, cream, gel, transdermal composition, patch, and injection. Eye drops are particularly preferable.

[0072] An appropriate amount of the aqueous suspension composition of the present invention is preferably administered once a day or administered separately two to six times a day. In the case where the aqueous suspension composition is eye drops, in particular, a single dose of one or two drops per eye is applied to the eye(s) once a day or separately applied to the eye(s) two to four times a day. A single dose of one drop per eye is even more preferably applied to the eye(s) once a day or separately applied to the eye(s) two to four times a day. A single dose of one drop per eye is more preferably applied to the eye(s) once a day or separately applied to the eye(s) twice a day. A single dose of one drop per eye is particularly preferably applied to the eye(s) once a day. It should be noted that the aqueous suspension composition of the present invention can be separately applied to the eye(s) two to four times a day. In this case, the interval of administration to the eye may be at least one hour or more, preferably two hours or more, and more preferably three 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 containing the aqueous suspension composition of the present invention is not particularly limited as long as it is a container commonly and widely used as a container containing a medicine. In the case where the aqueous suspension composition is an eye drop, any one of a multi-dose type container, a single-use unit dose container or a PFMD (preservative-free multi-dose container) container is particularly suitable. It should be noted that the material for the container is not particularly limited as long as the container can be commonly and widely used for eye drops. However, the container is preferably a container made of a resin. 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 or the like can be used. In this case, if the material for the polymer container is, for example, polyethylene, a container made of low-density polyethylene (LDPE), medium-density polyethylene (MDPE), high-density polyethylene (HDPE) or the like can be used, since polyethylene is classified according to its density.

[0074] The aqueous suspension composition of the present invention can be prepared in a general manner. For example, it can be prepared as follows: sirolimus or a salt thereof and the corresponding optionally added components are partially dissolved or suspended in purified water; the mixture is optionally subjected to wet grinding; and the osmotic pressure, pH and other parameters can be adjusted within a predetermined range.

[0075] The aqueous suspension composition of the present invention is used in ophthalmology as described above. For example, the aqueous suspension composition is effective for the treatment and/or prevention of eye diseases, thus, for example, it is an aqueous suspension composition for use in the treatment and/or prevention of eye diseases. The aqueous suspension composition of the present invention can be used for the treatment and/or prevention of eye diseases. In this case, the disease of interest is not particularly limited and may be a disease of the anterior chamber of the eye or the posterior chamber of the eye. In this case, the aqueous suspension composition of the present invention can be locally administered as minimally invasive eye drops. Accordingly, in particular, it is preferable to be used for the treatment and/or prevention of a disease of the anterior chamber of the eye. Examples of specific disease include keratitis, corneal endothelial disorder (corneal endotheliitis, macular corneal dystrophy, Fuchs endothelial dystrophy, bullous keratopathy), keratoconjunctivitis, conjunctivitis, blepharitis, meibomian gland dysfunction (also called “MGD”), dry eye syndrome (also called “keratitis sicca”), Sjogren's syndrome, allergic conjunctivitis, uveitis, endophthalmitis, graft-versus-host disease (also called “GVHD”), postoperative anterior segment inflammation, ocular graft rejection inflammation, and corneal infection (bacterial, fungal, amebic). In the case of using the aqueous suspension composition of the present invention for treating an ocular disease, a therapeutically effective amount of the aqueous suspension composition of the present invention is usually administered to a patient and used for treating him/her.

[0076] In the present invention, the term "patient" is not limited to only a human, and means, for example, a dog, a cat, or a horse. The patient of the present invention is preferably a mammal, and more preferably a human. In the present invention, the term "therapeutically effective amount" refers to an amount in which a therapeutic effect on a disease or a symptom thereof can be demonstrated, or the progression of a disease or a symptom thereof can be slowed down to a greater extent than in untreated subjects.

[0077] One aspect of the present invention is a method for suppressing the agglomeration of sirolimus or a salt thereof in an aqueous suspension composition comprising sirolimus or a salt thereof and a surfactant, comprising adjusting the pH of the aqueous suspension composition to 4-6 and/or adjusting the average particle size of sirolimus or a salt thereof in the aqueous suspension composition to 45 μm or less. The method of the present invention as described above is characterized in that in the aqueous suspension composition comprising sirolimus or a salt thereof and a surfactant, the pH is adjusted to 4-6 and/or the average particle size of sirolimus or a salt thereof is adjusted to 45 μm or less. It should be noted that the detailed description of the aqueous suspension composition of the present invention above is applicable to the method for suppressing the agglomeration of sirolimus or a salt thereof according to the present invention.

[0078] One aspect of the present invention is a method for dissolving sirolimus in an aqueous suspension composition, in the presence of sirolimus or a salt thereof and a surfactant, comprising adjusting the pH of the aqueous suspension composition to 4-6. The method of the present invention as described above is characterized in that the pH of the aqueous suspension composition containing sirolimus or a salt thereof and a surfactant is adjusted to 4-6. It should be noted that the detailed description of the aqueous suspension composition of the present invention given above is applicable to the method for suppressing the disintegration of sirolimus of the present invention.

[0079] One aspect of the present invention is a method for treating an ocular disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of the aqueous suspension composition of the present invention. The method for treating an ocular disease of the present invention, as described above, 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 of an ocular disease. In the method for treating an ocular disease of the present invention, the ocular disease is preferably a disease of the anterior chamber of the eye. It should be noted that the detailed description of the aqueous suspension composition of the present invention given above is applicable to the method for treating ocular diseases of the present invention.

[0080] One aspect of the present invention is the use of the aqueous suspension composition of the present invention for the preparation of a medicament for the treatment and/or prevention of ocular diseases. The use of the present invention as described above is characterized in that the aqueous suspension composition of the present invention is used to prepare a medicament for the treatment and/or prevention of ocular diseases. When using the present invention, the ocular disease is preferably a disease of the anterior chamber of the eye. It should be noted that the detailed description of the aqueous suspension composition of the present invention given above is applicable to the use of the present invention.

EXAMPLES

[0081] The following are examples of production and examples of testing. They are used for a better understanding of the present invention. Accordingly, the scope of the present invention should not be limited by these examples.

[0082] Examples of obtaining

Illustrative production examples of the present invention will be shown below. It should be noted that the added amount of each component in the production examples described below corresponds to the content in 100 ml of each preparation.

[0083] Receiving example 1

Sirolimus 0.01 g Polysorbate 80 0.01 g Hypromellose 0.0001 g Sodium citrate hydrate 0.1 g Sodium edetate hydrate 0.01 g Glycerin concentrated 2.0 g Benzalkonium chloride 0.001 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0084] Receiving example 2

Sirolimus 0.1 g Polysorbate 80 0.01 g Sodium carboxymethylcellulose 0.01 g Sodium citrate hydrate 0.1 g Sodium edetate hydrate 0.01 g Glycerin concentrated 1.5 g Benzalkonium chloride 0.001 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0085] Example of obtaining 3

Sirolimus 0.05 g Polyoxyl 40 stearate 0.1 g Sodium carboxymethylcellulose 0.001 g Sodium hydrogen phosphate hydrate 0.05 g Sodium edetate hydrate 0.02 g Sodium chloride 0.8 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0086] Example of obtaining 4

Sirolimus 0.2 g Polyoxyl 40 stearate 0.2 g Hypromellose 0.0005 g Sodium hydrogen phosphate hydrate 0.05 g Sodium edetate hydrate 0.075 g Sodium chloride 1.2 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0087] Example of obtaining 5

Sirolimus 0.1 g Polysorbate 80 0.005 g Sodium carboxymethylcellulose 0.01 g Sodium citrate hydrate 0.05 g Sodium edetate hydrate 0.02 g Sodium chloride 0.9 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0088] Example of obtaining 6

Sirolimus 0.1 g Polysorbate 80 0.05 g Sodium carboxymethylcellulose 0.01 g Sodium citrate hydrate 0.1 g Sodium edetate hydrate 0.01 g Glycerin concentrated 1.8 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0089] Example of obtaining 7

Sirolimus 0.03 g Polysorbate 80 0.01 g Sodium carboxymethylcellulose 0.005 g Sodium hydrogen phosphate hydrate 0.1 g Sodium edetate hydrate 0.01 g Sodium chloride 0.75 g Benzalkonium chloride 0.001 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0090] Example of obtaining 8

Sirolimus 0.03 g Polysorbate 80 0.05 g Hydroxyethylcellulose 0.01 g Sodium hydrogen phosphate hydrate 0.1 g Sodium edetate hydrate 0.01 g Glycerin concentrated 2.0 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0091] Example of obtaining 9

Sirolimus 0.03 g Polysorbate 80 0.1 g Hypromellose 0.001 g Sodium citrate hydrate 0.05 g Glycerin concentrated 1.8 g Benzalkonium chloride 0.001 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0092] Example of obtaining 10

Sirolimus 0.03 g Polysorbate 80 0.03 g Hypromellose 0.0003 g Sodium citrate hydrate 0.1 g Sodium edetate hydrate 0.01 g Sodium chloride 0.85 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0093] Example of obtaining 11

Sirolimus 0.1 g Polyoxyl 35 castor oil 0.05 g Hydroxyethylcellulose 0.001 g Sodium citrate hydrate 0.1 g Sodium edetate hydrate 0.01 g Sodium chloride 0.7 g Benzalkonium chloride 0.001 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0094] Example of obtaining 12

Sirolimus 0.1 g Polyoxyl 35 castor oil 0.05 g Polyvinylpyrrolidone 0.01 g Sodium hydrogen phosphate hydrate 0.05 g Sodium edetate hydrate 0.02 g Glycerin concentrated 1.4 g Benzalkonium chloride 0.002 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0095] Example of obtaining 13

Sirolimus 0.1 g Polyoxyl 35 castor oil 0.1 g Hypromellose 0.005 g Sodium hydrogen phosphate hydrate 0.1 g Sodium edetate hydrate 0.05 g Glycerin concentrated 1.2 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0096] Example of obtaining 14

Sirolimus 0.1 g Polysorbate 80 0.05 g Polyvinyl alcohol 0.01 g Sodium hydrogen phosphate hydrate 0.05 g Sodium edetate hydrate 0.03 g Glycerin concentrated 1.5 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0097] Example of obtaining 15

Sirolimus 0.1 g Polysorbate 80 0.1 g Hypromellose 0.0003 g Sodium citrate hydrate 0.1 g Sodium edetate hydrate 0.01 g Sodium chloride 0.85 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0098] Example of obtaining 16

Sirolimus 0.1 g Polysorbate 80 0.1 g Hypromellose 0.01 g Sodium citrate hydrate 0.05 g Sodium edetate hydrate 0.03 g Sodium chloride 0.7 g Silver nitrate 0.005 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0099] Example of obtaining 17

Sirolimus 0.1 g Polyoxyl 35 castor oil 0.05 g Hypromellose 0.001 g Sodium citrate hydrate 0.1 g Sodium edetate hydrate 0.03 g Glycerin concentrated 1.5 g Chlorobutanol 0.01 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0100] Example of getting 18

Sirolimus 0.1 g Polysorbate 80 0.05 g Sodium carboxymethylcellulose 0.01 g Sodium hydrogen phosphate hydrate 0.1 g Sodium edetate hydrate 0.01 g Sodium chloride 0.9 g Chlorobutanol 0.01 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0101] Example of obtaining 19

Sirolimus 0.3 g Polysorbate 80 0.5 g Hydroxyethylcellulose 0.01 g Sodium hydrogen phosphate hydrate 0.085 g Sodium edetate hydrate 0.01 g Glycerin concentrated 2.0 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0102] Example of obtaining 20

Sirolimus 0.5 g Polysorbate 80 0.5 g Sodium carboxymethylcellulose 0.01 g Sodium hydrogen phosphate hydrate 0.085 g Sodium edetate hydrate 0.01 g Glycerin concentrated 1.8 g Sodium hydroxide/dilute hydrochloric acid in sufficient quantity Purified water in sufficient quantity pH 5.0

[0103] Research Examples

1. Stability study

(1) Receipt of the investigational drug

To obtain a given concentration of each component contained, powdered sirolimus (average particle size: 15 μm), polysorbate 80, hypromellose TC5 (registered trade name), concentrated glycerol, sodium dihydrogen phosphate, sodium edetate hydrate and purified water hydrate were mixed. Then, a pH adjuster (hydrochloric acid and/or sodium hydroxide) and purified water were added to make the total volume 100 ml. Thus, the test product of composition 1 (pH 3.0; suspension) was prepared. In addition, to obtain compositions 2 to 4 (pH 5.0 to pH 9.0; any of them was a suspension). The concentration of each component contained in each test product was as shown in Table 1.

[0104] [Table 1]

Test drug [% (w/v)] Composition 1 Composition 2 Composition 3 Composition 4 Sirolimus 0.01 0.01 0.01 0.01 Polysorbate 80 0,1 0,1 0,1 0,1 Hypromellose 0.01 0.01 0.01 0.01 Sodium edetate hydrate 0.01 0.01 0.01 0.01 Glycerin concentrated in sufficient quantity Sodium dihydrogen phosphate hydrate in sufficient quantity pH regulator in sufficient quantity Purified water in sufficient quantity pH 3.0 5.0 7.0 9.0

[0105] (2) Research method

In this method, 5 ml of each of the test products of compositions 1-4 were placed in a sterile container and sealed. Each container was stored for 4 weeks in an incubator at 60°C (at ambient humidity) or at 40°C and 20% humidity. Immediately after filling and after 4 weeks of storage, a small amount of sample was taken from the composition to disperse the solid particles well in each composition. Then, a conventional procedure using ultra-high performance liquid chromatography (UHPLC) was used to measure the residual amount of sirolimus contained in the composition. Then, the residual content of sirolimus was determined. The residual content of sirolimus was determined using the following equation.

Residual content (%) = 100 × [(Residual amount of sirolimus after storage)/(Residual amount of sirolimus immediately after filling)].

It should be noted that the more detailed conditions of the UHPLC measurement were as follows.

[Column] ACQUITY UPLC BEH C18 (1.7 µm; 2.1 mm × 50 mm)

[Precolumn] Precolumn ACQUITY UPLC BEH C18 Vangurard (1.7 µm; 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 mixture (1:1))

[0106] (3) Research results and their consideration

Table 2 presents the results of the studies.

[0107] [Table 2]

Research results Storage conditions (temperature, humidity) Composition 1 Composition 2 Composition 3 Composition 4 Residual content (%) 60°C, ambient 56.7 97.7 59.1 65.0 40°C, 20% 89.6 107.9 82.7 72.7

[0108] It is evident from Table 2 that the stability of the sirolimus-containing composition is dependent on the pH value. In particular, it was found that the stability at a pH value of 5 or close to this value is robust.

[0109] 2. Agglomeration assessment and stability study

(1) Receipt of the investigational drug

First, unmilled sirolimus, polysorbate 80 and purified water were mixed. Then, the mixture was wet-milled using a bead mill to an average particle size of 0.50 μm or less. Then, hypromellose TC5 (registered trade name), sodium citrate hydrate, sodium edetate hydrate and sodium chloride were mixed. Then, a pH adjuster (hydrochloric acid and/or sodium hydroxide) and purified water were added to a total volume of 100 ml. Thus, the test product of composition 5 (pH 3.0; suspension) was obtained. In addition, a method similar to the method for preparing the test product of composition 8, except for adjusting the pH, was used to prepare compositions 6-10 (pH 4.0 to 6.0; any of them was a suspension). To obtain the test preparation of composition 11, a method similar to that of the test preparation of composition 8 was used, except that wet grinding using a bead mill was performed until the average particle size reached 0.30 μm or less. In addition, to obtain the test preparation of composition 12, a method similar to that of the test preparation of composition 8 was used, except that wet grinding was not performed, but milled sirolimus (with an average particle size: 2.5 μm) was used. The concentration of each component contained in each test preparation was as shown in Table 3.

[0110] [Table 3]

Investigational drug
[%(weight/volume)] Composition 5 Composition 6 Composition 7 Composition 8 Composition 9 Composition 10 Composition 11 Composition 12 Sirolimus 0,1 0,1 0,1 0,1 0,1 0,1 0,1 0,1 Polysorbate 80 0,1 0,1 0,1 0,1 0,1 0,1 0,1 0,1 Hypromellose 0,0003 0,0003 0,0003 0,0003 0,0003 0,0003 0,0003 0,0003 Sodium edetate hydrate 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 Sodium citrate hydrate in sufficient quantity Sodium chloride in sufficient quantity pH regulator in sufficient quantity Purified water in sufficient quantity pH 3.0 4.0 4.5 5.0 5.5 6.0 5.0 5.0 Estimation of mean particle size of used sirolimus 0.50 µm or less 0.30 µm or less 2.5 microns

[0111] (2) Research method

In the present study, 5 mL of each of the drugs of Formulations 5 to 12 were placed in a sterile container and sealed. Each container was stored for 4 weeks in an incubator at 60°C (under ambient humidity) or stored for 2 weeks at 40°C and 20% humidity. Immediately after placing in the container and after 4 or 2 weeks of storage, a zeta potential and particle size measurement system (ELSZ-1000ZS, manufactured by Otsuka Electronics Co., Ltd.) was used to determine the average particle size of each test drug. The particle size increase ratio was also determined. The particle size increase ratio was calculated using the following equation.

Particle size increase rate = (Average particle size after storage) / (Average particle size immediately after placing in container).

It should be noted that the conditions for measuring the average particle size are given in more detail below.

[Measuring conditions] Temperature: 25°C, Solvent refractive index: 1.3328, Solvent viscosity: 0.89, Scattering intensity: Auto, Incident filter: Auto

[Cuvette parameters] Number of integrations: 70 times, dust removal: 10 times

[Analysis conditions] Average particle size analysis: cumulant method, particle size distribution analysis: Marquardt method

[0112] For products stored at 60°C (ambient humidity), the residual sirolimus content of each study product was determined in a manner substantially similar to that described in Section “1. Stability studies” above.

[0113] (3) Research results and their analysis

Table 4 presents the results of the study. It should be noted that “-” in the table means “Not determined”.

[0114] [Table 4]

Research results Storage conditions (temperature, humidity) Composition 5 Composition 6 Composition 7 Composition 8 Composition 9 Composition 10 Composition 11 Composition 12 Average particle size (µm) Immediately after placing in the container 0.32 0.39 - 0.48 - 0.38 0.17 6.40 60°C, ambient 1.05 0.70 - 0.58 - 0.73 - - 40°C, 20% - - - 0.47 - - 0.17 6.40 Degree of increase in particle size 60°C, ambient 3.28 1.79 - 1.21 - 1.92 - - 40°C, 20% - - - 0.98 - - 1 1 Residual content (%) 60°C, ambient 79.9 97.9 100.2 100.3 99.5 95.9 - -

[0115] It is evident from Table 4 that the degree of increase in particle size depends on the pH value. In particular, it was minimal at a pH value of 5 or about 5. It was found that the degree of increase in particle size increases as the pH value deviates from 5. The degree of increase in particle size can be regarded as an indicator indicating the degree of particle aggregation. In particular, it was hypothesized that agglomeration is unlikely at a pH value of 5 or about 5, and as the pH deviates from 5, the likelihood of agglomeration during storage increases. It was also hypothesized that in the case of sirolimus, which is used for the study drug with a large particle size (formulation 12), agglomeration is likely to occur during the preparation of the study drug. On the other hand, if the pH value is 5 or close to 5, even if the particles are large at the time of preparation, agglomeration is unlikely to occur during storage.

[0116] Furthermore, the results presented in Table 4 and Table 2 in Section “1. Stability Study” demonstrated that the aqueous suspension compositions containing sirolimus are stable at pH 5 or about 5 and are unlikely to agglomerate.

[0117] 3. Study of agglomeration

(1) Receipt of the investigational drug

First, unmilled sirolimus, each surfactant, and purified water were mixed. The mixture was then wet-milled using a bead mill until the average particle size was 0.50 μm or less. The remaining components were then mixed. Then, the pH adjuster (hydrochloric acid and/or sodium hydroxide) and purified water were added to make a total volume of 100 ml. Formulations 13-24 (each of which was a suspension) were prepared. The concentration of each component contained in each test product was as shown in Table 5 or 6. Note that in Table 5, “MYS40” refers to polyoxyl 40 stearate and “TCP5” refers to sodium polyoxyethylene cetyl ether phosphate.

[0118] [Table 5]

Investigational drug
[% (w/v)] Composition 13 Composition 14 Composition 15 Composition 16 Composition 17 Composition 18 Sirolimus 0,1 0,1 0,1 0,1 0,1 0,1 Polysorbate 80 0,001 0.01 0,1 1 - - MYS40 - - - - 0,1 - TCP5 - - - - - 0,1 Sodium carboxymethylcellulose 0.01 0.01 0.01 0.01 0.01 - Sodium edetate hydrate 0.01 0.01 0.01 0.01 0.01 0.01 Glycerin concentrated in sufficient quantity Sodium citrate hydrate in sufficient quantity pH regulator in sufficient quantity Purified water in sufficient quantity pH 5.0

[0119] [Table 6]

Investigational drug
[% (w/v)] Composition 19 Composition 20 Composition 21 Composition 22 Composition 23 Composition 24 Sirolimus 1 1 0,1 0,1 0,1 0,1 Polysorbate 80 0.01 0,1 0,1 0,1 0,001 0.01 Hypromellose 0,001 0,001 - 0,0001 0,001 0,001 Sodium edetate hydrate 0.01 0.01 0.01 0.01 0.01 0.01 Glycerin concentrated in sufficient quantity Sodium citrate hydrate in sufficient quantity pH regulator in sufficient quantity Purified water in sufficient quantity pH 5.0

[0120] (2) Research method

In this method, 5 ml of each of the test preparations of compositions 13-24 were placed in a sterile container and sealed. Each container was stored for 4 weeks at 40°C and 20% humidity. Immediately after placing in the container and after 4 weeks of storage, a method similar to that described in Section “2. Agglomeration Evaluation and Stability Study” was used to determine the average particle size and calculate the particle size increase.

[0121] (3) Research results and their analysis

Tables 7 and 8 show the results of the study. It should be noted that in the tables, “unacceptable” means that the study drug was not stored because it was visually confirmed that a large number of aggregates were formed during the preparation of the study drug.

[0122] [Table 7]

Research results Storage conditions (temperature, humidity) Composition 13 Composition 14 Composition 15 Composition 16 Composition 17 Composition 18 Average particle size (µm) Immediately after placing in the container Unacceptable 0.45 0.38 1.41 0.36 0.38 40°C, 20% - 0.91 0.39 1.04 0.42 0.42 Degree of increase in particle size 40°C, 20% - 2.02 1.03 0.74 1.17 1.10

[0123] [Table 8]

Research results Storage conditions (temperature, humidity) Composition 19 Composition 20 Composition 21 Composition 22 Composition 23 Composition 24 Average particle size (µm) Immediately after placing in the container Unacceptable 0.40 0.33 0.34 Unacceptable 0.98 40°C, 20% - 0.40 0.33 0.37 - 1.19 Degree of increase in particle size 40°C, 20% - 1 1 1.09 - 1.21

[0124] As shown in Tables 7 and 8, it was found that in any of the cases where the amount of surfactant was sufficiently low relative to the amount of sirolimus, and the content of surfactant per 1 part by weight of sirolimus was 0.01 parts by weight (in the cases of compositions 13, 19 and 23), a large number of aggregates were formed. The type of surfactant or the type of dispersant did not significantly affect the aggregation of particles.

[0125] 4. Study of agglomeration

(1) Receipt of the investigational drug

First, unmilled sirolimus, polysorbate 80, hypromellose TC5 (registered trade name), sodium chloride, sodium citrate hydrate, sodium edetate hydrate and purified water were mixed. Then, a pH adjuster (hydrochloric acid and/or sodium hydroxide) and purified water were added to a total volume of 100 ml. Thus, the test product of composition 25 (suspension) was obtained. To prepare composition 26 (suspension), a method similar to the method for preparing the test product of composition 25 was used, except that polysorbate 80 was excluded. In addition, unmilled sirolimus, polysorbate 80 and purified water were mixed. Then, wet grinding was carried out using a bead mill for about 1 minute. Then, hypromellose TC5 (registered trade name), sodium citrate hydrate, sodium edetate hydrate and sodium chloride were mixed. Next, a pH regulator (hydrochloric acid and/or sodium hydroxide) and purified water were added to obtain a total volume of 100 ml. In this way, the test preparation of composition 27 (suspension) was obtained. The concentration of each component contained in each test preparation was as shown in Table 9.

[0126] [Table 9]

Investigational drug
[% (w/v)] Composition 25 Composition 26 Composition 27 Sirolimus 0,1 0,1 0,1 Polysorbate 80 0,1 - 0,1 Hypromellose 0,001 0,001 0,001 Sodium edetate hydrate 0.01 0.01 0.01 Sodium citrate hydrate in sufficient quantity Sodium chloride in sufficient quantity pH regulator in sufficient quantity Purified water in sufficient quantity pH 7.0 7.0 5.0

[0127] (2) Research method

In this study, 5 ml of each of the test preparations of compositions 25-27 were placed in a sterile container and sealed. Each container was stored for 2 weeks at 40°C and 20% humidity. Immediately after placing in the container and after 2 weeks of storage, a method similar to that described in Section “2. Agglomeration Evaluation and Stability Study” was used to measure the average particle size and calculate the particle size increase.

[0128] (3) Research results and their analysis

Table 10 shows the results of the study.

[0129] [Table 10]

Research results Storage conditions (temperature, humidity) Composition 25 Composition 26 Composition 27 Average particle size (µm) Immediately after placing in the container 63.2 82.2 45.2 40°C, 20% 183 279 101 Degree of increase in particle size 40°C, 20% 2.90 3.39 2.23

[0130] Table 10 shows that in study products containing unmilled sirolimus, or in study product obtained by milling for a short period of time, the average particle size is large immediately after placement in the container or later during storage, and further agglomeration is likely to occur. Thus, it is shown that the larger the average particle size of sirolimus, the greater the likelihood of agglomeration.

[0131] 5. Study of agglomeration

(1) Receipt of the investigational drug

To prepare each test product (each was a suspension) of composition 28 or 29, a method similar to the test product preparation method described in Section “2. Agglomeration Evaluation and Stability Study” was used. The concentration of each component contained in each test product was as shown in Table 11.

[0132] [Table 11]

Investigational drug
[% (w/v)] Composition 28 Composition 29 Sirolimus 0.01 0.01 Polysorbate 80 0.01 0,001 Hypromellose 0,001 0,001 Sodium edetate hydrate 0.01 0.01 Sodium citrate hydrate in sufficient quantity Sodium chloride in sufficient quantity pH regulator in sufficient quantity Purified water in sufficient quantity pH 5.0

[0133] (2) Research method

In this study, 5 ml of each of the test preparations of compositions 28-29 were placed in a sterile container and sealed. Each container was stored for 2 weeks at 40°C and 20% humidity. Immediately after placing in the container and after 2 weeks of storage, a method similar to that described in Section “2. Agglomeration Evaluation and Stability Study” was used to measure the average particle size and calculate the particle size increase.

[0134] (3) Research results and their analysis

Table 12 shows the results of the study.

[0135] [Table 12]

Research results Storage conditions (temperature, humidity) Composition 28 Composition 29 Average particle size (µm) Immediately after placing in the container 0.47 0.31 40°C, 20% 0.61 0.46 Degree of increase in particle size 40°C, 20% 1.30 1.48

[0136] As shown in Table 12, in the case where the content of surfactant per 1 part by weight of sirolimus was 1 part by weight (in the case of composition 28), or in the case where the content of surfactant per 1 part by weight of sirolimus was 0.1 parts by weight (in the case of composition 29), it was found that agglomeration was unlikely even when the concentration of surfactant in the test preparation was low.

[0137] 6. Study of agglomeration

(1) Receipt of the investigational drug

For the preparation of each test product (any of which was a suspension) of compositions 30-35 containing the respective components listed in Table 13, a method similar to the method for preparing the test product of composition 5 described in Section “2. Agglomeration Evaluation and Stability Study” was used. The concentration of each component contained in each active product was as shown in Table 13.

[0138] [Table 13]

Test drug [% (w/v)] Composition 30 Composition 31 Composition 32 Composition 33 Composition 34 Composition 35 Sirolimus 0,1 0,1 0,1 0,1 0,1 0,1 Polysorbate 80 0,1 - 0,1 0,1 0,1 0,1 CO-35 - 0,1 - - - - Hypromellose 0.01 0.01 - - - - Sodium carboxymethylcellulose - - 0.01 - - - HA - - - 0.01 - - PVA - - - - 0.01 - PVP - - - - - 0.01 Sodium edetate hydrate 0.01 0.01 0.01 0.01 0.01 0.01 Glycerin concentrated in sufficient quantity Sodium dihydrogen phosphate hydrate in sufficient quantity pH regulator in sufficient quantity Purified water in sufficient quantity pH 5.0

[0139] (2) Research method

In this study, 5 ml of each of the drug products of compositions 30-35 were placed in a sterile container and sealed. Compositions 30 and 31 were stored for 19 months at room temperature, and compositions 32-35 were stored for 28 months at room temperature. Immediately after placing in the container and after storage, a method similar to that described in Section “2. Agglomeration Evaluation and Stability Study” was used to measure the average particle size and calculate the particle size increase rate.

[0140] (3) Research results and their analysis

Table 14 shows the results of the study.

[0141] [Table 14]

Research results Storage conditions Composition 30 Composition 31 Composition 32 Composition 33 Composition 34 Composition 35 Average particle size (µm) Immediately after placing in the container 0.62 0.73 0.55 0.63 0.53 0.53 Store at room temperature 0.82 0.79 0.61 0.69 0.61 0.56 Degree of increase in particle size Store at room temperature 1.32 1.08 1.11 1.10 1.15 1.06

[0142] Table 14 shows that the type of surfactant or the type of dispersant does not have a significant effect on particle aggregation.

INDUSTRIAL APPLICABILITY

[0143] The present invention relates to an aqueous suspension composition containing poorly water-soluble sirolimus for use in ophthalmology, in particular for topical use, such as in the form of minimally invasive eye drops.

Claims (31)

1. An aqueous ophthalmic suspension composition comprising sirolimus and a surfactant, wherein the content of sirolimus is from 0.01 to 0.1% (w/v), the ratio of surfactant to sirolimus content is from 0.1 to 10 parts by weight per 1 part by weight of sirolimus content, and Sirolimus in an aqueous suspension composition has a mean particle size of 45 µm or less. 2. An aqueous suspension composition according to claim 1, wherein the aqueous suspension composition has a pH of from 4 to 6.0. 3. An aqueous suspension composition according to claim 1, wherein the aqueous suspension composition has a pH of 4 to 5.5. 4. An aqueous suspension composition according to claim 1, wherein the aqueous suspension composition has a pH of 4.5 to 5.5. 5. An aqueous suspension composition according to claim 1, wherein the aqueous suspension composition has a pH of from 4.7 to 5.3. 6. An aqueous suspension composition according to claim 1, wherein the aqueous suspension composition has a pH value of 5. 7. An aqueous suspension composition according to claim 1, wherein the ratio of the surfactant content to sirolimus is from 0.5 to 2 parts by weight per 1 part by weight of the sirolimus content. 8. An aqueous suspension composition according to claim 1, wherein the sirolimus has an average particle size of 15 μm or less. 9. An aqueous suspension composition according to claim 1, wherein the sirolimus has an average particle size of 10 μm or less. 10. An aqueous suspension composition according to claim 1, wherein the sirolimus has an average particle size of 2.5 μm or less. 11. An aqueous suspension composition according to any one of claims 1 to 10, wherein the surfactant is one or more substances selected from the group consisting of polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, hydrogenated polyoxyethylene castor oils, polyoxyl castor oils and polyoxyethylene alkyl ether phosphates. 12. An aqueous suspension composition according to any one of claims 1 to 10, wherein the surfactant is one or more surfactants selected from the group consisting of polyoxyl 40 stearate, hydrogenated polyoxyethylene castor oil 40, hydrogenated polyoxyethylene castor oil 60, polysorbate 80, polysorbate 60, polyoxyl 35 castor oil and sodium polyoxyethylene cetyl ether phosphate. 13. An aqueous suspension composition according to any one of claims 1 to 10, wherein the surfactant is polysorbate 80. 14. An aqueous suspension composition according to any one of claims 1 to 10, containing a dispersing agent. 15. An aqueous suspension composition according to claim 14, wherein the dispersing agent is one or more substances selected from the group consisting of cellulosic polymers, polyalcohols, polyvinylpyrrolidone and mucopolysaccharides. 16. An aqueous suspension composition according to claim 14, further comprising one or more substances selected from the group consisting of buffering agents, tonicity adjusting agents, stabilizers, antioxidants, preservatives and pH adjusters. 17. An aqueous suspension composition according to claim 16, wherein the preservatives are one or more substances selected from the group consisting of invert soaps, parabens, sorbic acid or its salts, chlorobutanol and silver nitrate. 18. An aqueous suspension composition according to any one of claims 1 to 10, which is an eye drop. 19. An aqueous ophthalmic suspension composition comprising sirolimus and polysorbate 80, wherein the content of sirolimus ranges from 0.01 to 1% (w/v), the ratio of polysorbate 80 to sirolimus is from 0.1 to 10 parts by weight per 1 part by weight of sirolimus content, Sirolimus in an aqueous suspension composition has a mean particle size of 2.5 µm or less. 20. An aqueous suspension composition according to claim 19, wherein the aqueous suspension composition has a pH of 4 to 6. 21. An aqueous suspension composition according to claim 20, wherein the aqueous suspension composition has a pH of from 4 to 5.5. 22. An aqueous suspension composition according to claim 21, wherein the aqueous suspension composition has a pH of 4.5 to 5.5. 23. An aqueous suspension composition according to claim 22, wherein the aqueous suspension composition has a pH of from 4.7 to 5.3. 24. An aqueous suspension composition according to claim 23, wherein the aqueous suspension composition has a pH value of 5. 25. An aqueous ophthalmic suspension composition according to claim 19, wherein the ratio of polysorbate 80 to sirolimus is from 0.5 to 2 parts by weight per 1 part by weight of sirolimus content.