Sterilization method of pharmaceutical preparation and packaging

Abstract

The present invention provides a pharmaceutical preparation in which an aqueous pharmaceutical composition, which contains (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof, is housed in a packaging that blocks light rays of 210-380 nm in wavelength. In this pharmaceutical preparation, the stability of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in the aqueous pharmaceutical composition has been improved.

Description

Sterilization methods and packaging for pharmaceutical preparations

[0001] The present invention relates to pharmaceutical formulations.

[0002] In order to develop a compound useful as an active ingredient into a pharmaceutical product, various requirements must be met, including not only the efficacy and safety of the drug, but also the stability of the compound in a pharmaceutical composition, the stability of the pharmaceutical composition itself, and preservative effectiveness. In particular, ensuring the stability of the compound in a pharmaceutical composition is extremely important for the stable delivery of pharmaceutical effects. Even if a compound useful as an active ingredient in a drug is stable in the solid state, it may become unstable in a pharmaceutical composition such as an aqueous solution, resulting in problems such as the generation of degradation products or an increase in the amount of degradation products. For example, the compound may react with moisture contained in pharmaceutical excipients and decompose, causing the compound to become unstable in the pharmaceutical composition. Furthermore, the stability of a pharmaceutical composition can be affected by various physical factors such as pH, heat, humidity, and light. Therefore, it is important that pharmaceutical compositions are stable against these various factors. However, compound stability issues are often only discovered after the pharmaceutical composition is actually manufactured. Therefore, no general method for compound stabilization has been established, and it is common to find a stabilization method appropriate for each compound.

[0003] (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (hereinafter, sometimes referred to as "AFDX0250") is (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, has the structure shown below, and is known to be useful in the treatment of eye diseases such as glaucoma, ocular hypertension, and myopia (Patent Documents 1 and 2).

[0004] However, there have been no reports to date on the stability of AFDX0250 or a salt thereof in an aqueous pharmaceutical composition.

[0005] International Publication No. 93 / 18772 Pamphlet International Publication No. 2022 / 030489 Pamphlet

[0006] During the development of an aqueous pharmaceutical composition containing AFDX0250 or a salt thereof, the present inventors discovered that when AFDX0250 was dissolved to prepare an aqueous pharmaceutical composition, AFDX0250 was susceptible to hydrolysis, and that the hydrolyzed form of AFDX0250, 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, was prone to precipitation. Furthermore, they discovered that AFDX0250 or a salt thereof is susceptible to decomposition upon exposure to light. While conventional formulations have been able to sufficiently suppress the production of degradation products, further suppressing such degradation products would improve the quality of the formulation compared to conventional formulations, leading to further improvements in efficacy and safety, and would be extremely beneficial in the development of pharmaceutical formulations.

[0007] Therefore, an object of the present invention is to provide a pharmaceutical preparation of AFDX0250 or a salt thereof that has improved stability (for example, thermal stability and light stability) in an aqueous pharmaceutical composition.

[0008] As a result of extensive research aimed at solving the above-mentioned problems, the present inventors have found that by packaging an aqueous pharmaceutical composition containing AFDX0250 or a salt thereof in a package that blocks light with wavelengths of 210 to 380 nm (particularly 216 to 310 nm and 372 nm), it is possible to suppress the decomposition of AFDX0250 or a salt thereof due to exposure to light, thereby ensuring formulation stability. The present inventors have also found that packaging an aqueous pharmaceutical composition containing AFDX0250 or a salt thereof in a plastic container (particularly a polyethylene (PE)-based resin container, a polypropylene (PP)-based resin container, or a polyethylene terephthalate (PET)-based resin container) suppresses the formation of hydrolysates of AFDX0250. Furthermore, the present inventors have found that the formation of hydrolysates and AFDX0250-derived analogs in an aqueous pharmaceutical composition can be effectively suppressed by selecting a sterilization method (particularly filter sterilization) for the aqueous pharmaceutical composition containing AFDX0250 or a salt thereof. The present invention was completed based on these findings.

[0009] Specifically, the present invention provides the following: [Item 1] A pharmaceutical formulation comprising an aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof, housed in a package that blocks light with wavelengths of 210 to 380 nm. [Item 2] The pharmaceutical formulation according to Item 1, wherein the package has a light transmittance, or an average light transmittance, for light with wavelengths of 210 to 380 nm of 20% or less. [Item 3] The pharmaceutical formulation according to Item 1, wherein the package has a light transmittance, or an average light transmittance, for light with wavelengths of 210 to 380 nm of 10% or less. [Item 4] The pharmaceutical formulation according to any one of Items 1 to 3, wherein the package comprises a primary package and a secondary package. [Item 5] The pharmaceutical formulation according to Item 4, wherein the primary package is a plastic container. [Item 6] The pharmaceutical formulation according to Item 5, wherein the plastic container is a polyethylene resin container or a polyethylene terephthalate resin container. [Item 7] The pharmaceutical formulation according to any one of Items 1 to 6, wherein the aqueous pharmaceutical composition is an aqueous pharmaceutical composition that has been sterilized by filter filtration. [Item 8] A pharmaceutical formulation in which an aqueous pharmaceutical composition comprising (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof is housed in a plastic container. [Item 9] The pharmaceutical formulation according to Item 8, wherein the plastic container is a polyethylene resin container or a polyethylene terephthalate resin container. [Item 10] The pharmaceutical formulation according to Item 8 or 9, wherein the aqueous pharmaceutical composition is an aqueous pharmaceutical composition that has been sterilized by filter filtration. [Item 11] A pharmaceutical formulation comprising an aqueous pharmaceutical composition that has been sterilized by filtration and contains (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof. [Item 12] The pharmaceutical formulation according to any one of Items 1 to 11, which is an eye drop.[Item 13] A method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in an aqueous pharmaceutical composition, the method comprising the step of placing the aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in a package that blocks light with wavelengths of 210 to 380 nm. [Item 14] A method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in an aqueous pharmaceutical composition, the method comprising the step of placing the aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in a plastic container. [Item 15] A method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in an aqueous pharmaceutical composition, the method comprising a step of sterilizing the aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof by filter filtration. [Item 16] A method for suppressing photodecomposition of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof, comprising the step of placing an aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in a package that blocks light with wavelengths of 210 to 380 nm.[Item 17] A method for improving the thermal stability of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof, comprising the step of placing an aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in a plastic container. [Item 18] A method for inhibiting the production of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in an aqueous pharmaceutical composition, comprising the step of placing the aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in a plastic container. [Item 19] A method for suppressing the production of an analogue of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in an aqueous pharmaceutical composition, the method comprising the step of sterilizing the aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof by filter filtration.

[0010] Any two or more of the above configurations [Item 1] to [Item 19] can be selected and combined.

[0011] According to the present invention, the thermal stability, light stability, and other stability of AFDX0250 or a salt thereof in an aqueous pharmaceutical composition can be improved. Therefore, it is not necessary to convert a pharmaceutical composition containing AFDX0250 or a salt thereof into a non-aqueous formulation for stabilization. Furthermore, since the pharmaceutical formulation of the present invention has a stable content of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof, the formulation has excellent storage stability and safety, allowing for long-term use and storage.

[0012] The figure shows the absorption spectrum of AFDX0250 measured using an ultraviolet-visible spectrometer. The figure shows the content (residual rate (%)) of AFDX0250 in the test formulations (Formulations 1 and 2) at each irradiation wavelength 24 hours after irradiation. The figure shows the results of measuring the light transmittance (%) of light at each wavelength for various containers and secondary packages packaged in the containers.

[0013] The present invention will be described in detail below.

[0014] The present invention provides a pharmaceutical preparation, which comprises an aqueous pharmaceutical composition comprising (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof, contained in a package that blocks light with wavelengths of 210 to 380 nm.

[0015] In the present invention, the salt of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; salts with organic acids such as acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfuric acid, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid; salts with metals such as sodium, potassium, calcium, and magnesium; salts with inorganic compounds such as ammonia; and salts with organic amines such as triethylamine and guanidine.

[0016] In the present invention, (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof may be in the form of a hydrate or a solvate.

[0017] In the present invention, (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof may be produced according to a method known in the field of organic chemistry, or may be commercially available. For example, (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one can be obtained by the process described in J. Med. Chem., 32(8), 1718-24, 1989.

[0018] In the present invention, the content of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in the aqueous pharmaceutical composition is not particularly limited. The lower limit of the content is preferably 0.0001% (w / v), more preferably 0.0003% (w / v), even more preferably 0.0005% (w / v), even more preferably 0.001% (w / v), particularly preferably 0.0013% (w / v), particularly more preferably 0.0015% (w / v), particularly more preferably 0.0017% (w / v), and most preferably 0.002% (w / v). The upper limit of the content is preferably 5% (w / v), more preferably 3% (w / v), even more preferably 2% (w / v), even more preferably 1% (w / v), particularly preferably 0.5% (w / v), particularly more preferably 0.2% (w / v), and most preferably 0.1% (w / v). From the viewpoint of preventing precipitation of decomposition products of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof, the upper limit of the content is preferably 0.5% (w / v), more preferably 0.2% (w / v), and most preferably 0.1% (w / v). The content of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof is preferably 0.0001 to 5% (w / v), more preferably 0.0003 to 3% (w / v), even more preferably 0.0005 to 2% (w / v), even more preferably 0.001 to 1% (w / v), particularly preferably 0.0013 to 0.5% (w / v), particularly more preferably 0.0015 to 0.2% (w / v), particularly still more preferably 0.0017 to 0.1% (w / v), and most preferably 0.002 to 0.1% (w / v). In the present invention, "% (w / v)" refers to the mass (g) of the target ingredient contained in 100 mL of the aqueous pharmaceutical composition of the present invention.In the present invention, when a salt of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one is contained, the value may be the content of a salt of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, or the content of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one. Furthermore, in the present invention, when (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof is formulated in the form of a hydrate or solvate, the value may be the content of the hydrate or solvate of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof, or the content of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof. The same applies hereinafter unless otherwise specified.

[0019] In the present invention, "aqueous pharmaceutical composition" refers to a pharmaceutical composition containing water. The content of water in the aqueous pharmaceutical composition of the present invention is not particularly limited, but is preferably 50% (w / v) or more, more preferably 70% (w / v) or more, and even more preferably 80% (w / v) or more, based on the aqueous pharmaceutical composition. In particular, it is preferably 90% (w / v) or more, more preferably 95% (w / v) or more, and even more preferably 98% (w / v) or more.

[0020] In the present invention, the pH of the aqueous pharmaceutical composition is not particularly limited, but is, for example, 6.5 or less, preferably 4 to 6.5, more preferably 5 to 6.3, even more preferably 5.3 to 6.2, and most preferably 5.5 to 6.

[0021] In the present invention, the aqueous pharmaceutical composition may contain a pharmaceutically acceptable active ingredient other than (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof, for example, an active ingredient that exhibits a therapeutic effect against ocular diseases such as glaucoma, ocular hypertension, myopia, etc. Alternatively, the aqueous pharmaceutical composition may be free of a pharmaceutically acceptable active ingredient other than (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof, as long as the effects of the present invention are not impaired. That is, the composition may contain (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof as the only active ingredient.

[0022] In the present invention, additives can be used in the aqueous pharmaceutical composition as needed, and examples of additives that can be added include buffers, surfactants, isotonicity agents, stabilizers, preservatives, antioxidants, high-molecular-weight polymers, pH adjusters, and bases.

[0023] In the present invention, the aqueous pharmaceutical composition may be appropriately blended with a buffer that can be used as a pharmaceutical additive. Examples of buffers include citric acid, acetic acid, malic acid, amines, amino acids, and salts thereof. In the present invention, the buffer preferably contains citric acid or a salt thereof, and further contains any one of acetic acid or a salt thereof, malic acid or a salt thereof, amines or salts thereof, or amino acids or salts thereof.

[0024] Examples of salts of citric acid include sodium citrate, disodium citrate, and trisodium citrate.

[0025] Examples of acetic acid salts include sodium acetate and potassium acetate.

[0026] Malic acid may be in the form of a racemate or an enantiomer (L or D form). Salts of malic acid include sodium malate and disodium malate.

[0027] Examples of amines include trometamol, monoethanolamine, diethanolamine, triethanolamine, meglumine, etc. Examples of amine salts include their hydrochlorides, acetate salts, etc. In the present invention, the amine is preferably trometamol, and examples of its salts include trometamol hydrochloride, etc.

[0028] Examples of amino acids include ε-aminocaproic acid, glycine, alanine, valine, leucine, serine, threonine, methionine, glutamine, glutamic acid, asparagine, aspartic acid, arginine, lysine, and histidine. When optical isomers exist, these may be racemates or enantiomers (L-form or D-form). Examples of amino acid salts include hydrochlorides and acetate salts thereof. In the present invention, preferred amino acids are ε-aminocaproic acid, glycine, and L-glutamine, and examples of their salts include glycine hydrochloride and L-glutamine hydrochloride.

[0029] In the present invention, the buffering agent may be in the form of a hydrate or solvate, examples of which include citric acid hydrate and sodium citrate hydrate.

[0030] The lower limit of the content of the buffering agent in the aqueous pharmaceutical composition of the present invention is preferably 0.001% (w / v), more preferably 0.005% (w / v), even more preferably 0.01% (w / v), even more preferably 0.05% (w / v), particularly preferably 0.1% (w / v), and most preferably 0.2% (w / v). The upper limit of the content of the buffering agent in the aqueous pharmaceutical composition of the present invention is, for example, 20% (w / v), preferably 10% (w / v), more preferably 5% (w / v), even more preferably 4% (w / v), even more preferably 3% (w / v), particularly preferably 2% (w / v), and most preferably 1.5% (w / v). The content of the buffer in the aqueous pharmaceutical composition of the present invention is, for example, 0.001 to 20% (w / v), preferably 0.001 to 10% (w / v), more preferably 0.005 to 5% (w / v), even more preferably 0.01 to 4% (w / v), even more preferably 0.05 to 3% (w / v), particularly preferably 0.1 to 2% (w / v), and most preferably 0.2 to 1.5% (w / v). For example, the content of the buffering agent in the aqueous pharmaceutical composition of the present invention may be 0.001% (w / v), 0.002% (w / v), 0.005% (w / v), 0.01% (w / v), 0.02% (w / v), 0.05% (w / v), 0.1% (w / v), 0.2% (w / v), 1.5% (w / v), 2% (w / v), 3% (w / v), 4% (w / v), 5% (w / v), 6% (w / v), 8% (w / v), 10% (w / v), or 20% (w / v).

[0031] In one embodiment of the pharmaceutical preparation of the present invention, the aqueous pharmaceutical composition preferably contains citric acid or a salt thereof and trometamol or a salt thereof as buffers. In this case, the lower limits of the contents of citric acid or a salt thereof and trometamol or a salt thereof in the aqueous pharmaceutical composition are preferably 0.0005% (w / v), more preferably 0.001% (w / v), even more preferably 0.005% (w / v), even more preferably 0.01% (w / v), particularly preferably 0.05% (w / v), and most preferably 0.1% (w / v). The upper limits of these contents are preferably 10% (w / v), more preferably 5% (w / v), even more preferably 4% (w / v), even more preferably 3% (w / v), particularly preferably 2% (w / v), and most preferably 1.5% (w / v). In the present invention, the contents of citric acid or a salt thereof, and trometamol or a salt thereof in the aqueous pharmaceutical composition are each preferably 0.0005 to 10% (w / v), more preferably 0.001 to 5% (w / v), even more preferably 0.005 to 4% (w / v), even more preferably 0.01 to 3% (w / v), particularly preferably 0.05 to 2% (w / v), and most preferably 0.1 to 1.5% (w / v).

[0032] In the present invention, the aqueous pharmaceutical composition may contain, as appropriate, surfactants that can be used as additives for pharmaceuticals, such as cationic surfactants, anionic surfactants, and nonionic surfactants.

[0033] Examples of anionic surfactants include phospholipids, such as lecithin.

[0034] Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkyltrimethylammonium salts, dialkyldimethylammonium salts, alkyldimethylbenzylammonium salts, alkylpyridinium salts, acylaminoalkyl ammonium salts, acylaminoalkylpyridinium salts, diacyloxyethylammonium salts, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, 1-hydroxylethyl-2-alkylimidazolines, etc. Examples of alkyldimethylbenzylammonium salts include benzalkonium chloride and cetalkonium chloride.

[0035] Examples of nonionic surfactants include polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, and vitamin E TPGS.

[0036] Examples of polyoxyethylene fatty acid esters include polyoxyl 40 stearate.

[0037] Examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 80, polysorbate 65, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan trioleate.

[0038] As the polyoxyethylene hydrogenated castor oil, various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, particularly preferably 40 to 70, and most preferably 60. Specific examples of polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc.

[0039] As the polyoxyethylene castor oil, various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 5 to 100, more preferably 20 to 50, particularly preferably 30 to 40, and most preferably 35. Specific examples of polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil.

[0040] Examples of polyoxyethylene polyoxypropylene glycols include polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol.

[0041] Examples of sucrose fatty acid esters include sucrose stearate.

[0042] Vitamin E TPGS is also known as tocopherol polyethylene glycol 1000 succinate.

[0043] When a surfactant is incorporated into the aqueous pharmaceutical composition, the content of the surfactant can be adjusted as appropriate depending on the type of surfactant, etc., but is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.05 to 3% (w / v), and most preferably 0.1 to 2% (w / v).

[0044] In the present invention, the aqueous pharmaceutical composition can be appropriately blended with an isotonicity agent that can be used as an additive for pharmaceuticals to adjust the osmotic pressure. The osmotic pressure ratio of the aqueous pharmaceutical composition is, for example, 1, and is not particularly limited as long as it is within a range acceptable for pharmaceuticals. Examples of the isotonicity agent include ionic isotonicity agents and nonionic isotonicity agents.

[0045] Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride, and examples of nonionic tonicity agents include glycerin, propylene glycol, sorbitol, and mannitol.

[0046] When an isotonic agent is incorporated into the aqueous pharmaceutical composition, the content of the isotonic agent can be adjusted as appropriate depending on the type of isotonic agent, etc., but is preferably 0.01 to 10% (w / v), more preferably 0.02 to 7% (w / v), even more preferably 0.1 to 5% (w / v), particularly preferably 0.3 to 4% (w / v), and most preferably 0.5 to 3% (w / v).

[0047] In the present invention, a stabilizer that can be used as an additive for pharmaceuticals can be appropriately blended into the aqueous pharmaceutical composition. Examples of stabilizers include edetic acid and sodium edetate. When a stabilizer is blended into the aqueous pharmaceutical composition, the content of the stabilizer can be appropriately adjusted depending on the type of stabilizer, etc., but is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.05 to 3% (w / v), and most preferably 0.1 to 2% (w / v).

[0048] In the present invention, a preservative that can be used as an additive for pharmaceuticals can be appropriately blended into the aqueous pharmaceutical composition. Examples of preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and chlorobutanol. When a preservative is blended into the aqueous pharmaceutical composition, the content of the preservative can be appropriately adjusted depending on the type of preservative, but is preferably 0.0001 to 1% (w / v), more preferably 0.0005 to 0.1% (w / v), even more preferably 0.001 to 0.05% (w / v), and most preferably 0.002 to 0.01% (w / v).

[0049] In the present invention, an antioxidant that can be used as an additive for pharmaceuticals can be appropriately blended into the aqueous pharmaceutical composition. Examples of antioxidants include tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, and sodium sulfite. When an antioxidant is blended into the aqueous pharmaceutical composition, the content of the antioxidant can be adjusted appropriately depending on the type of antioxidant, but is preferably 0.0001 to 1% (w / v), more preferably 0.0005 to 0.1% (w / v), even more preferably 0.001 to 0.02% (w / v), and most preferably 0.005 to 0.010% (w / v).

[0050] In the present invention, the aqueous pharmaceutical composition can be appropriately blended with a high-molecular-weight polymer that can be used as an additive for pharmaceuticals. Examples of high-molecular-weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (hypromellose), carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, and polyethylene glycol. In the present invention, the high-molecular-weight polymer is preferably hydroxypropylmethylcellulose (hypromellose). When a high-molecular-weight polymer is blended into the aqueous pharmaceutical composition, the content of the high-molecular-weight polymer can be appropriately adjusted depending on the type of high-molecular-weight polymer, but is preferably 0.001 to 5% (w / v), more preferably 0.01 to 1% (w / v), and even more preferably 0.1 to 0.5% (w / v).

[0051] In the present invention, the aqueous pharmaceutical composition can be appropriately blended with a pH adjuster that can be used as a pharmaceutical additive, so long as the pH is 6.5 or less. Examples of pH adjusters include hydrochloric acid, sodium hydroxide, and potassium hydroxide. When a pH adjuster is blended into the aqueous pharmaceutical composition, the content of the pH adjuster can be appropriately adjusted depending on the type of pH adjuster, and is preferably 0.001 to 5% (w / v), more preferably 0.01 to 1% (w / v), and even more preferably 0.1 to 0.5% (w / v).

[0052] In the present invention, the aqueous pharmaceutical composition may contain a base that can be used as an additive for pharmaceuticals, such as water, purified water, or physiological saline.

[0053] In the present invention, the aqueous pharmaceutical composition can be administered orally or parenterally, and examples of routes of administration include oral administration, intravenous administration, transdermal administration, and topical ocular administration (e.g., eye drops, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, and sub-Tenon administration).

[0054] The pharmaceutical preparation of the present invention is not particularly limited as long as it is in a dosage form that can be accommodated in a package described below, and can be used in the dosage form of a preparation for ophthalmic diseases, such as eye drops, eye gels, injections, etc. It is particularly preferable that the pharmaceutical preparation of the present invention is used as eye drops. These dosage forms can be produced according to conventional methods in the art.

[0055] The pharmaceutical formulation of the present invention is provided by housing the aqueous pharmaceutical composition in a package that blocks light in a specific wavelength range. The package may be any package that can block light in a specific wavelength range under storage conditions typically expected for pharmaceutical formulations, and its sealability is not particularly limited. The aqueous pharmaceutical composition may be contained in the package by filling it in a conventional manner according to the shape of the package.

[0056] In the present invention, the term "packaging" refers to a package that directly or indirectly contains the aqueous pharmaceutical composition of the present invention. Among packages, those that directly contain the aqueous pharmaceutical composition of the present invention are referred to as "primary packages," and those that indirectly contain the aqueous pharmaceutical composition of the present invention are referred to as "secondary packages."

[0057] Examples of primary packaging include eye drop containers, injection containers, tube-shaped containers, bottle-shaped containers, spray containers, etc. Examples of secondary packaging include medicine bags, aluminum pillowcases, boxes, shrink wrap, paper labels, etc. Primary packaging and secondary packaging do not include aluminum packaging such as aluminum foil.

[0058] In the present invention, the wavelength range of light blocked by the package is 210 to 380 nm, preferably 215 to 340 nm and 350 to 380 nm, more preferably 216 to 310 nm and 370 to 380 nm, and most preferably 216, 247, 278, 310 or 372 nm.

[0059] In the present invention, "blocking light" in the wavelength range means that the light transmittance of light in that wavelength range is 50% or less, or that the light blocking rate is greater than 50%, or that the average light transmittance of light in that wavelength range is 50% or less, or that the average light blocking rate is greater than 50%. For example, "a package that blocks light with a wavelength of 210 to 380 nm" refers to a package in which the light transmittance of light with a wavelength of 210 to 380 nm or the average light transmittance of light with a wavelength of 210 to 380 nm is 50% or less. In the present invention, from the viewpoint of further improving stability against light, the light transmittance or its average value is preferably 30% or less, more preferably 20% or less, even more preferably 15% or less, particularly preferably 10% or less, and most preferably 5% or less. In addition, in the present invention, the light transmittance can be measured and calculated by measuring the light transmittance of light with a wavelength of 210 to 800 nm using an ultraviolet-visible spectrometer. Although it is not necessary for the entire packaging to block light within the wavelength range, it is preferable that 50% or more of the total area of ​​the inner surface of the packaging block light within the wavelength range, more preferably 60% or more, even more preferably 70% or more, even more preferably 80% or more, particularly preferably 90% or more, particularly preferably 95% or more, and most preferably 100%. A preferred embodiment in which a portion of the total area of ​​the inner surface of the packaging blocks light within the wavelength range is, for example, a primary packaging (such as an eye drop container) that does not block light within the wavelength range, with a secondary packaging (such as a shrink wrap or a paper label) that blocks light within the wavelength range wrapped around the side of the primary packaging.

[0060] When the pharmaceutical formulation of the present invention includes a secondary package, it is sufficient that either the primary package or the secondary package blocks light in the wavelength range. Furthermore, even if the primary package and the secondary package cannot block light in the wavelength range individually, the combination of the primary package and the secondary package may be able to block light in the wavelength range. In this case, multiple secondary packages may be used. From the viewpoint of suppressing decomposition of AFDX0250 or a salt thereof not only during distribution and storage but also during use, it is desirable that the primary package block light in a specific wavelength range.

[0061] In the present invention, the material of the packaging body is not particularly limited, but examples thereof include plastic, cellulose, pulp, rubber, and metal.

[0062] The primary packaging that directly contains the aqueous pharmaceutical composition is preferably a plastic container, and from the viewpoint of further stabilizing AFDX0250 or a salt thereof, polyethylene-based resin containers, polypropylene containers, and polyethylene terephthalate-based resin containers are more preferred, and from the viewpoint of stabilizing AFDX0250 or a salt thereof over a longer period of time, polyethylene-based resin containers and polyethylene terephthalate-based resin containers are most preferred. Furthermore, from the viewpoint of visibility of the interior, the primary packaging is preferably a transparent container. In the case of a transparent container, it is sufficient that the interior is transparent to the extent that it can be seen. Visibly transparent means that the transmittance or average value of visible light (wavelengths of about 400 nm to about 800 nm) is, for example, 20% or more, preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, even more preferably 60% or more, particularly preferably 70% or more, particularly more preferably 80% or more, and most preferably 90% or more. Although it is not necessary for the entire container to be transparent enough to allow the interior to be seen, it is preferable that 30% or more of the total area of ​​the outer surface of the container be transparent, more preferably 50% or more, even more preferably 70% or more, even more preferably 80% or more, particularly preferably 90% or more, and most preferably 95% or more. Furthermore, the primary packaging does not have to be a transparent container. From the viewpoint of processability and the like, the material of the secondary packaging that indirectly contains the aqueous pharmaceutical composition is preferably plastic, cellulose, pulp, paper, or the like. Furthermore, the secondary packaging does not have to be transparent, but from the viewpoint of visibility of the interior, the secondary packaging may also be transparent. When the secondary packaging body is transparent, it is sufficient that it is transparent enough to allow the interior to be seen, and being transparent enough to allow the interior to be seen means that the transmittance or its average value of visible light (wavelength of approximately 400 nm to approximately 800 nm) is, for example, 20% or more, preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, even more preferably 60% or more, particularly preferably 70% or more, especially more preferably 80% or more, and most preferably 90% or more.Although it is not necessary for the entire secondary packaging to be transparent enough to allow the interior to be seen, it is preferable that 1% or more of the total area of ​​the outer surface of the secondary packaging be transparent, preferably 5% or more, more preferably 10% or more, even more preferably 30% or more, even more preferably 50% or more, particularly preferably 90% or more, and most preferably 95% or more. The secondary packaging does not have to be a transparent container, and may have a transparent slit (viewing window) to allow the interior to be seen.

[0063] In the present invention, a "polyethylene (PE)-based resin container" (hereinafter sometimes referred to as a "PE container") refers to a container in which at least the portion of the container that comes into contact with the aqueous pharmaceutical composition is made of a polyethylene-based resin. Examples of polyethylene include low-density polyethylene (LDPE), medium-density polyethylene (MDPE), and high-density polyethylene (HDPE). Furthermore, a "polypropylene (PP)-based resin container" (hereinafter sometimes referred to as a "PP container") refers to a container in which at least the portion of the container that comes into contact with the aqueous pharmaceutical composition is made of a polypropylene-based resin. A "polyethylene terephthalate (PET)-based resin container" (hereinafter sometimes referred to as a "PET container") refers to a container in which at least the portion of the container that comes into contact with the aqueous pharmaceutical composition is made of a polyethylene terephthalate-based resin.

[0064] Furthermore, the pharmaceutical formulation of the present invention preferably contains a sterilized aqueous pharmaceutical composition. Examples of methods for sterilizing aqueous pharmaceutical compositions include electron beam (EB) sterilization, ethylene oxide gas (EOG) sterilization, hydrogen peroxide sterilization, gamma ray sterilization, filter sterilization, and autoclave (AC) sterilization. In the pharmaceutical formulation of the present invention, filter sterilization is particularly preferred as a method for sterilizing the aqueous pharmaceutical composition.

[0065] In the present invention, "electron beam sterilization" or "EB sterilization" refers to a sterilization method that can kill bacteria and the like by utilizing electron beams, and is not particularly limited as long as it is a method of sterilization using electron beams. For example, the irradiation dose can be selected appropriately from 1 to 100 kGy, and the irradiation time can be selected appropriately from several seconds to several minutes.

[0066] In the present invention, "ethylene oxide gas sterilization" or "EOG sterilization" refers to a sterilization method that can kill bacteria and the like using ethylene oxide gas, and is not particularly limited as long as it is a method of sterilization using ethylene oxide gas. For example, the sterilization temperature is 30 to 60°C, the sterilization time is 1 to 10 hours, and the gas used may be ethylene oxide gas alone or a mixed gas of ethylene oxide gas and carbon dioxide or the like, and can be selected appropriately.

[0067] In the present invention, "hydrogen peroxide sterilization" refers to a sterilization method that can kill bacteria and the like using hydrogen peroxide, and is not particularly limited as long as it is a method of sterilization using hydrogen peroxide.

[0068] In the present invention, "gamma ray sterilization" refers to a sterilization method that can kill bacteria and the like by utilizing gamma rays, and is not particularly limited as long as it is a method that uses gamma rays for sterilization treatment.

[0069] In the present invention, "filter sterilization" refers to a sterilization method in which bacteria and the like are removed by filtration using a membrane filter with a pore size of 0.22 μm. The membrane filter may be made of a material such as PVDF (polyvinylidene fluoride), PES (polyethersulfone), PTFE (polytetrafluoroethylene), or MCE (mixed cellulose esters), and may have different pore sizes, such as 0.1-0.3 μm, 0.2-0.25 μm, 0.2 μm, 0.21 μm, 0.23 μm, 0.24 μm, or 0.25 μm.

[0070] In the present invention, "high-pressure steam (AC) sterilization" refers to a sterilization method that can kill bacteria and the like using a high-pressure steam sterilizer (autoclave), and is not particularly limited as long as it is a method that performs sterilization using a high-pressure steam sterilizer (autoclave). For example, AC sterilization is preferably carried out under conditions such as 115 to 118°C for 30 minutes, 121 to 124°C for 15 to 20 minutes, or 126 to 129°C for 10 minutes, and is continued until the object reaches a sterile state.

[0071] When the pharmaceutical preparation of the present invention is used as eye drops, the eye drop container may be composed of one component or multiple components. In the present invention, the aqueous pharmaceutical composition may be contained in, for example, a one-piece eye drop container composed of one component, a two-piece eye drop container composed of two components, or a three-piece eye drop container composed of three components. For example, a three-piece eye drop container is formed from three components: a container body that contains the aqueous pharmaceutical composition, an inner stopper, and a cap. Furthermore, an integrally molded container that simultaneously undergoes blow molding and drug solution filling is also included in the above-mentioned eye drop container, depending on the number of components. When the container is formed from multiple components, the components may be formed from the same material or from different materials.

[0072] When the pharmaceutical preparation of the present invention is used as an eye drop, it may be contained in any of a multi-dose container, a single-use unit-dose container, or a PFMD (Preservative Free Multi-Dose) container.

[0073] The pharmaceutical preparation of the present invention can be used to treat eye diseases such as glaucoma, ocular hypertension, and myopia.

[0074] The present invention provides a pharmaceutical preparation in which an aqueous pharmaceutical composition comprising (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof is contained in a plastic container. The above detailed description of the present invention also applies to the pharmaceutical preparation in which an aqueous pharmaceutical composition comprising (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof is contained in a plastic resin container. In the present invention, the aqueous pharmaceutical composition is contained in a plastic container, preferably a polyethylene-based resin container, a polypropylene-based resin container, or a polyethylene terephthalate-based resin container from the viewpoint of further stabilizing AFDX0250 or a salt thereof, and most preferably a polyethylene-based resin container or a polyethylene terephthalate-based resin container from the viewpoint of stabilizing AFDX0250 or a salt thereof for a longer period of time. By containing the composition in a plastic container, (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in the aqueous pharmaceutical composition is particularly stabilized compared to other containers.

[0075] The present invention provides a pharmaceutical formulation comprising an aqueous pharmaceutical composition sterilized by filter filtration containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof. The above detailed description of the present invention also applies to pharmaceutical formulations comprising an aqueous pharmaceutical composition sterilized by filter filtration containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof. In the present invention, the aqueous pharmaceutical composition is an aqueous pharmaceutical composition sterilized by filter filtration. Filter sterilization particularly stabilizes (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in the aqueous pharmaceutical composition compared to other sterilization methods.

[0076] The present invention provides a method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in an aqueous pharmaceutical composition. The above detailed description of the present invention also applies to the method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in an aqueous pharmaceutical composition.

[0077] In the present invention, the method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in an aqueous pharmaceutical composition comprises a method characterized by containing an aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in a package that blocks light with wavelengths of 210 to 380 nm. In this method, decomposition of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof due to light irradiation is suppressed, and (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof becomes stable to light.

[0078] In the present invention, the method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in an aqueous pharmaceutical composition comprises a method characterized by containing an aqueous pharmaceutical composition comprising (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in a plastic container; from the viewpoint of further stabilizing AFDX0250 or a salt thereof, the composition is preferably contained in a polyethylene-based resin container, a polypropylene-based resin container, or a polyethylene terephthalate-based resin container; and from the viewpoint of stabilizing AFDX0250 or a salt thereof for a longer period of time, the composition is most preferably contained in a polyethylene-based resin container or a polyethylene terephthalate-based resin container. In this method, hydrolysis of (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one is suppressed, and production of its hydrolyzed product, 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, can be suppressed. In addition, in this method, (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof becomes stable to heat.

[0079] In the present invention, the method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof in an aqueous pharmaceutical composition comprises a step of sterilizing the aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one or a salt thereof by filtration. This method can effectively suppress the production of hydrolysates and analogues derived from (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in the aqueous pharmaceutical composition.

[0080] The following examples are provided to aid in a better understanding of the present invention and are not intended to limit the scope of the present invention.

[0081] Formulation Examples Representative formulation examples of the present invention are shown below. Note that the blending amount (% (w / v)) of each component in the following formulation examples is the content (g) in 100 mL of the composition.

[0082] Formulation Example 1 Eye drops (in 100 mL) AFDX0250 0.1 g Sodium citrate hydrate 0.5 g Trometamol 0.5 g Glycerin 2.0 g Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount Sterilization method: Filter sterilization Container: Polyethylene resin container (light transmittance of 10% or less for light with a wavelength of 210 to 380 nm)

[0083] Formulation Example 2 Eye drops (in 100 mL) AFDX0250 0.3 g Sodium citrate hydrate 0.25 g Citric acid hydrate 0.02 g ε-aminocaproic acid 0.5 g Sodium chloride 0.5 g Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount Sterilization method: Filter sterilization Container: Polyethylene terephthalate resin container (light transmittance of 10% or less for light with a wavelength of 210 to 380 nm)

[0084] Formulation Example 3 Eye drops (in 100 mL) AFDX0250 0.5 g Sodium citrate hydrate 0.25 g Citric acid hydrate 0.02 g L-Malic acid 0.5 g Sodium chloride 0.5 g Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount Sterilization method: Filter sterilization Container: Polyethylene resin container (light transmittance of 10% or less for light with a wavelength of 210 to 380 nm)

[0085] The types and amounts of AFDX0250, buffers, and additives in the above Preparation Examples 1 to 3 can be appropriately adjusted to obtain a desired composition.

[0086] Example 1: Thermal stability test (1) The thermal stability of AFDX0250 in a pharmaceutical formulation was evaluated by checking the amount of hydrolyzed AFDX0250 by-product produced after storage under certain conditions.

[0087] (1) Test Preparations An aqueous pharmaceutical composition (Preparation 1) having the formulation shown in Table 1 was prepared by a conventional method, and then the composition was filled into a PE container, a PP container, a PET container, and a glass container to prepare test preparations.

[0088] (2) Test Method The prepared test formulations were stored at 25°C for one month. After one month of storage, the content of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (hereinafter sometimes referred to as "hydrolyzate") produced by hydrolysis of AFDX0250 in each test formulation was quantified using high-performance liquid chromatography, and the production rate (%) was calculated. The production rate (%) is a percentage (%) when the mass of AFDX0250 contained in the test formulation is taken as 100%.

[0089] (3) Results Table 2 shows the production rate (%) of AFDX0250 hydrolysate in each test preparation.

[0090] As shown by the test results, the rate of hydrolysis of an aqueous pharmaceutical composition containing AFDX0250 or a salt thereof was reduced by storing it in a plastic container compared to a glass container. This confirmed that storing AFDX0250 in a plastic container provides excellent stability in the aqueous pharmaceutical composition.

[0091] Example 2: Thermal stability test (2) The thermal stability of AFDX0250 in a pharmaceutical formulation was evaluated by visually checking for precipitates in the test formulation after storage under certain conditions.

[0092] (1) Test Preparations Test preparations were prepared by filling Preparation 1 prepared in Example 1 into PE containers, PET containers, PP containers and glass containers.

[0093] (2) Test Method The prepared test preparations were stored for 2 weeks at 40° C. After storage, the test preparations were visually inspected for the presence or absence of precipitates.

[0094] (3) Results The test results are shown in Table 3. In the table, "-" indicates that no precipitates were formed.

[0095] As shown by the test results, when an aqueous pharmaceutical composition containing AFDX0250 or a salt thereof was stored in a glass container, the formation of precipitates was observed after two weeks, but when stored in a plastic container, no precipitates were observed. This confirms that storing AFDX0250 in a plastic container provides excellent storage stability in the aqueous pharmaceutical composition.

[0096] Example 3: Absorption wavelength measurement test The absorption wavelength of AFDX0250 was measured.

[0097] (1) Test formulation AFDX0250 (10 mg) was dissolved in acetonitrile and the resulting solution was adjusted to exactly 100 mL to prepare a 0.01% AFDX0250 solution. This solution was diluted 4 times to prepare a 0.0025% AFDX0250 solution, which was used as the test formulation.

[0098] (2) Test Method The absorption spectrum of the test preparation was measured using an ultraviolet-visible spectrometer.

[0099] (3) Results The test results are shown in Figure 1.

[0100] As shown by the test results, no absorption of AFDX0250 was observed at wavelengths longer than about 330 nm.

[0101] Example 4: Photostability test (1) The stability of an aqueous pharmaceutical composition containing AFDX0250 or a salt thereof against light irradiation was examined.

[0102] (1) Test Preparations Preparation 1 having the formulation shown in Table 1 above and preparation 2 having the formulation shown in Table 4 above were prepared by a conventional method and used as test preparations.

[0103] (2) Test method: The prepared test formulation was irradiated with specific wavelengths using a multi-wavelength irradiation spectrometer for 24 hours, and the content of AFDX0250 in the test formulation at each irradiation wavelength after irradiation was quantified using high performance liquid chromatography, and the residual rate (%) was calculated. Note that the residual rate (%) is a percentage (%) when the mass of AFDX0250 contained in the test formulation is taken as 100%.

[0104] (3) Results The test results are shown in Figure 2.

[0105] As shown by the results of this test, AFDX0250 was decomposed at wavelengths of 216-310 nm and 372 nm. In particular, decomposition of AFDX0250 was observed at 370 nm, which is not an absorption wavelength of AFDX0250. This result indicates that although AFDX is unstable to light, it is limited to these specific wavelengths, and suggests that the photostability of AFDX0250 in an aqueous pharmaceutical composition can be ensured by blocking light in wavelength ranges including these wavelengths.

[0106] Example 5: Photostability test (2) The stability of a pharmaceutical preparation containing an aqueous pharmaceutical composition containing AFDX0250 or a salt thereof in a package against light irradiation was examined.

[0107] (1) Test Formulations Test formulations were prepared by filling Formulation 2 prepared in Example 4 into a glass container, an eye drop container (A), a shrink-packaged eye drop container (A), an eye drop container packaged with a paper label (A), a box-packaged eye drop container (A), a medicine bag (A), a medicine bag (B), a medicine bag (C), an eye drop container packaged in a medicine bag (D), an aluminum pillow-packaged eye drop container (A), an eye drop container (B), an eye drop container (C), and an eye drop container (D).

[0108] (2) Test Method: The prepared test formulation was exposed to light of 1.2 million lux-hr or more, and the AFDX0250 content was quantified using high-performance liquid chromatography, and the residual rate (%) was calculated. The residual rate (%) is a percentage (%) when the mass of AFDX0250 contained in the test formulation is taken as 100%. In addition, the light transmittance at each wavelength of various containers and secondary packages packaged in the containers was measured.

[0109] (3) Results The residual rate (%) of AFDX0250 in each package is shown in Table 5. The results of measuring the light transmittance at each wavelength for various containers and secondary packages packaged in the containers are shown in Figure 3. The wavelengths at which the light transmittance of various containers and secondary packages packaged in the containers was 10% or less, 20% or less, 30% or less, and 50% or less are shown in Table 6. The light transmittance of various containers at a wavelength of 370 nm is shown in Table 7.

[0110]

[0111]

[0112] The results of this test confirmed that photodecomposition of AFDX0250 can be suppressed by containing an aqueous pharmaceutical composition containing AFDX0250 or a salt thereof in a package that reduces the light transmittance of light in the wavelength ranges of 216 to 310 nm and 372 nm to 50% or less. This result demonstrated that the photostability of AFDX0250 in an aqueous pharmaceutical composition can be ensured by using a package that reduces the light transmittance of light in wavelength ranges that include these specific wavelengths to 50% or less.

[0113] Example 6: Stability evaluation test An aqueous pharmaceutical composition containing AFDX0250 or a salt thereof was sterilized, and the stability of AFDX0250 in the formulation was examined.

[0114] (1) Test Formulations 2.5 g of sodium citrate hydrate was dissolved in purified water to make exactly 100 mL to prepare a 2.5% sodium citrate hydrate solution. 0.2 g of citric acid hydrate was dissolved in purified water to make exactly 100 mL to prepare a 0.2% citric acid hydrate solution. 5 g of sodium chloride was dissolved in purified water to make exactly 50 mL to prepare a 10% sodium chloride solution. 0.25 g of AFDX0250 was weighed out, and 10 mL each of 2.5% sodium citrate hydrate solution, 0.2% citric acid hydrate solution, and 10% sodium chloride solution was measured and added, and the test formulation was prepared by making exactly 50 mL using purified water.

[0115] (2) Test Method The prepared test formulations were subjected to gamma ray sterilization, filter sterilization, or autoclaved steam (AC) sterilization to obtain sterile formulations. The content of AFDX0250 after sterilization was quantified using high-performance liquid chromatography, and the residual rate (%) was calculated. The residual rate (%) is a percentage relative to the mass of AFDX0250 contained in the test formulation, taken as 100%. In addition, the amount of AFDX0250-derived hydrolysate (5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) was quantified using high-performance liquid chromatography, excluding test formulations subjected to gamma ray sterilization.

[0116] (3) Results Table 8 shows the residual rate (%) of AFDX0250 and the content (%) of hydrolysate in the test preparations subjected to each sterilization treatment.

[0117] The test results confirmed that the filter sterilization treatment effectively suppressed the decrease in the residual rate of AFDX0250 and the formation of hydrolysates. As a result, it was demonstrated that the pharmaceutical preparation of the present invention can maintain even higher storage stability by undergoing filter sterilization treatment.

[0118] According to the present invention, the stability, such as thermal stability and light stability, of AFDX0250 or a salt thereof in an aqueous pharmaceutical composition can be improved, and therefore a pharmaceutical preparation with excellent stability can be provided.

Claims

1. A pharmaceutical formulation comprising an aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or a salt thereof, contained in packaging that blocks light rays with wavelengths of 210 to 380 nm.

2. The pharmaceutical preparation according to claim 1, wherein the packaging has a light transmittance or average value of 20% or less for light with a wavelength of 210 to 380 nm.

3. The pharmaceutical preparation according to claim 1, wherein the packaging has a light transmittance or average value of 10% or less for light with a wavelength of 210 to 380 nm or less.

4. A pharmaceutical preparation according to any one of claims 1 to 3, wherein the packaging includes a primary packaging and a secondary packaging.

5. The pharmaceutical preparation according to claim 4, wherein the primary packaging is a plastic container.

6. The pharmaceutical preparation according to claim 5, wherein the plastic container is a polyethylene resin container, a polypropylene resin container, or a polyethylene terephthalate resin container.

7. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the aqueous pharmaceutical composition is an aqueous pharmaceutical composition that has been filtered and sterilized.

8. A pharmaceutical formulation comprising an aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or a salt thereof, contained in a plastic container.

9. The pharmaceutical preparation according to claim 8, wherein the plastic container is a polyethylene resin container, a polypropylene resin container, or a polyethylene terephthalate resin container.

10. The pharmaceutical formulation according to claim 8 or 9, wherein the aqueous pharmaceutical composition is an aqueous pharmaceutical composition that has been filtered and sterilized.

11. A pharmaceutical formulation comprising a filter-sterilized aqueous pharmaceutical composition containing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or a salt thereof.

12. A pharmaceutical preparation according to any one of claims 1 to 3 and 8 to 11, which is an eye drop.

13. A method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or a salt thereof in an aqueous pharmaceutical composition, comprising the step of housing the composition in a packaging that blocks light rays with wavelengths of 210 to 380 nm.

14. A method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or a salt thereof in an aqueous pharmaceutical composition, comprising the step of housing the aqueous pharmaceutical composition in a plastic container.

15. A method for stabilizing (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or a salt thereof in an aqueous pharmaceutical composition, comprising the step of sterilizing the aqueous pharmaceutical composition by filtration.