Stable pharmaceutical compositions

Abstract

This application relates to stable pharmaceutical compositions. The present invention provides stable pharmaceutical compositions containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or salts thereof, and stabilization methods for (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or salts thereof.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180005606.2 (PCT application number PCT / JP2021 / 037841), filed on October 13, 2021, entitled "Stable Pharmaceutical Composition". Technical Field

[0002] This invention relates to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine A stable pharmaceutical composition of 6-one (hereinafter, sometimes referred to as "AFDX0250") or a salt thereof (hereinafter, sometimes referred to as "the compound of the present invention"), and a method for stabilizing AFDX0250 or a salt thereof in the pharmaceutical composition. Background Technology

[0003] In order to develop useful compounds that are active pharmaceutical ingredients into pharmaceutical products, the efficacy and safety of the products go without saying. Various requirements must be met, including the stability of the compound within the pharmaceutical composition, the stability of the composition itself, and the guarantee of its preservative effect. Among these, ensuring the stability of the compound within the pharmaceutical composition is extremely important for ensuring the stable efficacy of the medicine.

[0004] Compounds useful as active ingredients in pharmaceuticals may exhibit the following characteristics: even if stable in the solid state, they can become unstable in pharmaceutical compositions such as aqueous solutions, leading to problems such as the formation or increase in the amount of decomposition products. For example, sometimes the compound reacts with moisture contained in pharmaceutical additives and decomposes, becoming unstable in the pharmaceutical composition. Furthermore, the stability of pharmaceutical compositions is sometimes affected by various physical factors such as pH, heat, humidity, and light. Therefore, it is important that the pharmaceutical composition remains stable relative to these factors.

[0005] On the other hand, it is not uncommon for problems with the stability of compounds to be discovered only after the actual manufacture of pharmaceutical compositions. Therefore, for the stabilization of compounds, a general method is not usually established; instead, a stabilization method suitable for the specific compound is identified.

[0006] Patent document 1 discloses 11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine -6-keto (hereinafter, sometimes also referred to as "AFDX0116") is useful for the treatment of glaucoma and / or ocular hypertension, demonstrating that intraocular pressure can be lowered by intra-anterior chamber injection. Additionally, AFDX0250, a dextrorotatory (+) enantiomer of AFDX0116, is disclosed as one of the compounds that lower intraocular pressure.

[0007] However, there are no reports to date regarding the stability of AFDX0250 or its salts in pharmaceutical compositions. Therefore, there are no reports on the instability of this compound when it is prepared into pharmaceutical compositions, or on methods for stabilizing this compound.

[0008] Existing technical documents

[0009] Patent documents

[0010] Patent Document 1: International Publication No. 93 / 18772 Summary of the Invention

[0011] The problem that the invention aims to solve

[0012] The inventors of this application discovered during the development of pharmaceutical compositions containing AFDX0250 or its salts that, when preparing aqueous compositions by dissolving the compounds of the present invention, the compounds are readily hydrolyzed, readily precipitating 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine, which is a hydrolysate of AFDX0250. -6-keto. Furthermore, it was discovered that the compounds of this invention readily decompose under light irradiation.

[0013] Therefore, the objective of this invention is to provide a pharmaceutical composition containing the compound of the present invention and capable of inhibiting the hydrolysis of the compound of the present invention thereby inhibiting the formation of hydrolysates, and to provide a pharmaceutical composition that is stable relative to light, and further to provide a method for stabilizing the compound of the present invention.

[0014] Methods for solving problems

[0015] In order to solve the above-mentioned problems, the inventors of this application conducted in-depth research and found that, in a pharmaceutical composition containing the compound of the present invention, by adjusting its pH to below 6.5, the hydrolysis of the compound of the present invention can be inhibited, and the formation of hydrolysates can be suppressed. In addition, by adding one or more buffers selected from the group consisting of citric acid, acetic acid, malic acid, amines, amino acids and their salts, the stability of the compound of the present invention relative to light is improved, thereby completing the present invention.

[0016] Specifically, the present invention provides the following solutions.

[0017] (1) A pharmaceutical composition containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine -6-one or its salt, and the pH is below 6.5.

[0018] (2) The pharmaceutical composition as described in (1) above has a pH of 4 to 6.5.

[0019] (3) A pharmaceutical composition containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine -6-one or its salt, and one or more buffers selected from the group consisting of citric acid, acetic acid, malic acid, amine, amino acids and their salts.

[0020] (4) The pharmaceutical composition as described in (1) or (2) above contains one or more buffers selected from the group consisting of citric acid, acetic acid, malic acid, amines, amino acids and their salts.

[0021] (5) The pharmaceutical composition as described in (3) or (4) above contains citric acid or a salt thereof, and, as a buffer, also contains any buffer of acetic acid or a salt thereof, malic acid or a salt thereof, amine or a salt thereof, or an amino acid or a salt thereof.

[0022] (6) The pharmaceutical composition as described in any one of (3) to (5) above, wherein the amine is tromethamine.

[0023] (7) The pharmaceutical composition as described in any one of (3) to (6) above, wherein the amino acid is ε-aminocaproic acid, glycine or L-glutamine.

[0024] (8) The pharmaceutical composition as described in any one of (3) to (5) above, wherein the buffer is citric acid or a salt thereof, and tromethamine or a salt thereof.

[0025] (9) The pharmaceutical composition as described in any one of (1) to (8) above, wherein the pharmaceutical composition contains (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of 6-one or its salt is 0.0001 to 5% (w / v).

[0026] (10) The pharmaceutical composition as described in any one of (3) to (9) above, wherein the content of the buffer in the pharmaceutical composition is 0.001 to 10% (w / v).

[0027] (11) The pharmaceutical composition as described in any one of (3) to (10) above, wherein the content of the buffer in the pharmaceutical composition is relative to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The amount of 6-one or its salt is 0.1 to 20,000 parts by mass or 0.01 to 1,000 parts by mass per part by mass.

[0028] (12) The pharmaceutical composition as described in any one of (1) to (11) above, for topical application to the eye.

[0029] (13) The pharmaceutical composition as described in (12) above, wherein the topical ocular application is an eye drop application, an intraconjunctival sac application, an intravitreal application, a subconjunctival application, or a subtenonian sac application.

[0030] (14) The pharmaceutical composition as described in any one of (1) to (13) above is an eye drop, an eye gel or an injection.

[0031] (15) The pharmaceutical composition as described in any one of (1), (2) and (4) to (14) above shall be stored at 50°C or below.

[0032] (16) The (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine in the pharmaceutical composition A method for stabilizing 6-one or its salts, characterized in that the stabilization is carried out in a solution containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine In pharmaceutical compositions of 6-one or its salts, the pH is adjusted to below 6.5.

[0033] (17) The (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine in the pharmaceutical composition A method for stabilizing 6-one or its salts, characterized in that the stabilization is carried out in a solution containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine In a pharmaceutical composition of 6-one or its salt, one or more buffers selected from the group consisting of citric acid, acetic acid, malic acid, amines, amino acids and their salts are added.

[0034] (18) Inhibition of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The method for generating 6-one is characterized by using a mixture containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine In pharmaceutical compositions of 6-one or its salts, the pH is adjusted to below 6.5.

[0035] (19) Inhibition of (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine A method for photodecomposing 6-one or its salts, characterized in that the photodecomposition is carried out in a solution containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine In a pharmaceutical composition of 6-one or its salt, one or more buffers selected from the group consisting of citric acid, acetic acid, malic acid, amines, amino acids and their salts are added.

[0036] (20) The method as described in (16) or (18) above, characterized in that the pharmaceutical composition is further stored at a temperature below 50°C.

[0037] (21) The method as described in (17) or (19) above, wherein the buffer is citric acid or a salt thereof and tromethamine or a salt thereof.

[0038] Each of the components (1) to (21) above can be selected in any way to form a combination of two or more.

[0039] Invention Effects

[0040] According to the present invention, the formation of hydrolysates of the compounds of the present invention can be suppressed in pharmaceutical compositions, and pharmaceutical compositions that can be stabilized over a long period of time can be provided. Furthermore, according to the present invention, a method for stabilizing the compounds of the present invention in a pharmaceutical composition over a long period of time can be provided.

[0041] Furthermore, the pharmaceutical composition and stabilization method of the present invention can provide a stable formulation containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine Preparations of 6-one or its salts exhibit excellent storage stability and safety, enabling long-term use and storage. Detailed Implementation

[0042] The present invention will now be described in detail.

[0043] This invention provides a product containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine Stable pharmaceutical compositions of 6-one (hereinafter, sometimes also referred to as "AFDX0250") or its salts.

[0044] In this invention, “(+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine "-6-keto" or "AFDX0250" refers to compounds represented by the following formula (CAS Registry No.: 121029-35-4).

[0045] [Chemical Formula 1]

[0046]

[0047] Furthermore, in this invention, (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine -6-keto refers to (R)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine -6-keto, also represented by the following formula.

[0048] [Chemical Formula 2]

[0049]

[0050] In this invention, (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine -6-Ketones can be in salt form, and there are no particular restrictions as long as the salt is permitted for medicinal use. Examples of its salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; those formed 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, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, hydroxyethanesulfonic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid; those formed with metals such as sodium, potassium, calcium, and magnesium; those formed with inorganic compounds such as ammonia; and those formed with organic amines such as triethylamine and guanidine.

[0051] The pharmaceutical composition of the present invention contains (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine 6-ones or their salts can be in the form of hydrates or solvates.

[0052] In this invention, (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine -6-ones or their salts can be manufactured according to methods known in the field of organic chemistry, and are also available in commercially available forms. For example, (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine -6-keto can be obtained by the process described in J. Med. Chem., 32(8), 1718-24, 1989.

[0053] In this invention, the pharmaceutical composition contains (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine There is no particular limitation on the content of 6-one or its salt. The lower limit of the content is preferably 0.0001% (w / v), more preferably 0.0003% (w / v), further preferably 0.0005% (w / v), further more preferably 0.001% (w / v), particularly preferably 0.0013% (w / v), even more preferably 0.0015% (w / v), further particularly 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), further preferably 2% (w / v), even more preferably 1% (w / v), particularly preferably 0.5% (w / v), even more particularly preferably 0.2% (w / v), and most preferably 0.1% (w / v). From preventing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine Considering the precipitation of decomposition products of 6-one or its salts, 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). (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of 6-one or its salt 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), even more preferably 0.0015 to 0.2% (w / v), even more preferably 0.0017 to 0.1% (w / v), and most preferably 0.002 to 0.1% (w / v).

[0054] It should be noted that in this invention, "% (w / v)" refers to the mass (g) of the target ingredient contained in 100 mL of the pharmaceutical composition of this invention. In this invention, it contains (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine In the case of salts of 6-ones, the value can be (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The salt content of 6-ones can also be expressed as (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of -6-one. Additionally, in this invention, (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine When 6-ones or their salts are formulated in hydrate or solvate form, their values ​​can be (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of hydrates or solvates of 6-ones or their salts may also be (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of 6-one or its salts. Unless otherwise specified, the same applies below.

[0055] In one embodiment of the pharmaceutical composition of the present invention, the pH is 6.5 or less, preferably 4 to 6.5, more preferably 5 to 6.3, further preferably 5.3 to 6.2, and most preferably 5.5 to 6. For the pharmaceutical composition of the present invention, as long as its pH is within these ranges, (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The hydrolysis of 6-ones was inhibited, thereby suppressing the hydrolysis of its hydrolysate, 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine. The formation of 6-keto.

[0056] In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition comprises a buffer. In the present invention, the buffer is one or more buffers selected from the group consisting of citric acid, acetic acid, malic acid, amines, amino acids, and their salts. By containing these buffers, the pharmaceutical composition of the present invention becomes photostable. In the present invention, further improvements are made to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine From the viewpoint of the stability of 6-ones or their salts relative to light, the buffer preferably comprises citric acid or its salt, and is further combined with any buffer from acetic acid or its salt, malic acid or its salt, amine or its salt, or amino acid or its salt.

[0057] Examples of salts of citric acid include sodium citrate, disodium citrate, and trisodium citrate.

[0058] Examples of salts of acetic acid include sodium acetate and potassium acetate.

[0059] Malic acid can be a racemic mixture or an enantiomer (L-form or D-form). Examples of salts of malic acid include sodium malate and disodium malate.

[0060] Examples of amines include tromethamine, monoethanolamine, diethanolamine, triethanolamine, and meglumine. Examples of salts of amines include their hydrochloride and acetate salts. In this invention, the amine is preferably tromethamine, and examples of its salts include tromethamine hydrochloride.

[0061] Examples of amino acids include ε-aminohexanoic acid, glycine, alanine, valine, leucine, serine, threonine, methionine, glutamine, glutamic acid, asparagine, aspartic acid, arginine, lysine, and histidine. Where optical isomers exist, these can be racemic or enantiomers (L-form, D-form). Examples of salts of amino acids include their hydrochloride and acetate salts. In this invention, the preferred amino acids are ε-aminohexanoic acid, glycine, and L-glutamine, and examples of their salts include glycine hydrochloride and L-glutamine hydrochloride.

[0062] In this invention, the buffer can be in the form of a hydrate or a solvate. Examples of such buffers include citric acid hydrate and sodium citrate hydrate.

[0063] The lower limit of the buffer content in the pharmaceutical composition of the present invention is preferably 0.001% (w / v), more preferably 0.005% (w / v), further 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 buffer content in the pharmaceutical composition of the present invention is, for example, 20% (w / v), preferably 10% (w / v), more preferably 5% (w / v), further 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 buffer in the 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), further 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 buffer in the 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).

[0064] Furthermore, in one embodiment of the pharmaceutical composition of the present invention, the lower limit of the content of the buffer in the pharmaceutical composition of the present invention is relative to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of the buffer in the pharmaceutical composition of the present invention is preferably 0.1 parts by weight, more preferably 1 part by weight, further preferably 10 parts by weight, more preferably 50 parts by weight, particularly preferably 100 parts by weight, and most preferably 500 parts by weight, with respect to 1 part by weight of 6-one or its salt. In another embodiment of the pharmaceutical composition of the present invention, the lower limit of the content of the buffer in the pharmaceutical composition of the present invention is relative to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of 1 part by weight of 6-one or its salt is preferably 0.01 parts by weight, more preferably 0.03 parts by weight, further preferably 0.05 parts by weight, even more preferably 0.1 parts by weight, particularly preferably 0.3 parts by weight, and most preferably 0.5 parts by weight. Furthermore, in one embodiment of the pharmaceutical composition of the present invention, the upper limit of the buffer content in the pharmaceutical composition of the present invention is relative to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of the buffer in the pharmaceutical composition of the present invention is preferably 20,000 parts by weight, more preferably 10,000 parts by weight, further preferably 5,000 parts by weight, further preferably 3,000 parts by weight, particularly preferably 2,000 parts by weight, and most preferably 1,000 parts by weight, with respect to 1 part by weight of 6-one or its salt. In another embodiment of the pharmaceutical composition of the present invention, the upper limit of the content of the buffer in the pharmaceutical composition of the present invention is relative to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of the buffer in the pharmaceutical composition of the present invention is preferably 1000 parts by mass, more preferably 100 parts by mass, further preferably 50 parts by mass, further preferably 10 parts by mass, particularly preferably 6 parts by mass, and most preferably 3 parts by mass, with respect to 1 part by mass of 6-one or its salt. Additionally, in one embodiment of the pharmaceutical composition of the present invention, the content of the buffer in the pharmaceutical composition of the present invention is relative to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of the buffer in the pharmaceutical composition of the present invention is preferably 0.1 to 20,000 parts by weight, more preferably 1 to 10,000 parts by weight, further preferably 10 to 5,000 parts by weight, more preferably 50 to 3,000 parts by weight, particularly preferably 100 to 2,000 parts by weight, and most preferably 500 to 1,000 parts by weight, with respect to 1 part by weight. In another embodiment of the pharmaceutical composition of the present invention, the content of the buffer in the pharmaceutical composition of the present invention is relative to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The amount of 1 part by weight of 6-one or its salt is preferably 0.01 to 1000 parts by weight, more preferably 0.03 to 100 parts by weight, even more preferably 0.05 to 50 parts by weight, even more preferably 0.1 to 10 parts by weight, particularly preferably 0.3 to 6 parts by weight, and most preferably 0.5 to 3 parts by weight.

[0065] In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition comprises citric acid or a salt thereof, and tromethamine or a salt thereof as a buffer. In this case, the lower limit of the content of citric acid or a salt thereof and tromethamine or a salt thereof in the pharmaceutical composition of the present invention is preferably 0.0005% (w / v), more preferably 0.001% (w / v), further preferably 0.005% (w / v), further more preferably 0.01% (w / v), particularly preferably 0.05% (w / v), and most preferably 0.1% (w / v). The upper limit of the content is preferably 10% (w / v), more preferably 5% (w / v), further 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 citric acid or its salt and tromethamine or its salt in the pharmaceutical composition of the present invention is preferably 0.0005 to 10% (w / v), more preferably 0.001 to 5% (w / v), further preferably 0.005 to 4% (w / v), 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). Furthermore, the lower limit of the content of citric acid or its salt and tromethamine or its salt in the pharmaceutical composition of the present invention is relative to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The content of citric acid or its salt or 1 part by weight is preferably 0.005 parts by weight, more preferably 0.01 parts by weight, further preferably 0.03 parts by weight, even more preferably 0.05 parts by weight, particularly preferably 0.1 parts by weight, and most preferably 0.3 parts by weight. Regarding the upper limit of the content of citric acid or its salt and tromethamine or its salt in the pharmaceutical composition of the present invention, each is relative to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine -6-one or its salt is preferably 100 parts by mass, more preferably 50 parts by mass, further preferably 10 parts by mass, more preferably 6 parts by mass, particularly preferably 3 parts by mass, and most preferably 2 parts by mass in 1 part by mass. The content of citric acid or its salt and tromethamine or its salt in the pharmaceutical composition of the present invention is each relative to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The amount of 1 part by weight of 6-one or its salt is preferably 0.005 to 100 parts by weight, more preferably 0.01 to 50 parts by weight, even more preferably 0.03 to 10 parts by weight, even more preferably 0.05 to 6 parts by weight, particularly preferably 0.1 to 3 parts by weight, and most preferably 0.3 to 2 parts by weight.

[0066] For the pharmaceutical composition of the present invention, it may also contain, in addition to (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine, as long as it does not impair the effect of the present invention. Other pharmaceutically permissible active ingredients, such as those showing therapeutic effects on eye diseases like myopia, besides 6-ones or their salts. Additionally, the pharmaceutical compositions of the present invention may also be free of (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepines. Other pharmaceutically permissible active ingredients besides 6-one or its salts.

[0067] In the pharmaceutical composition of the present invention, additives may be used as needed. As additives, surfactants, isotonic agents, stabilizers, preservatives, antioxidants, high molecular weight polymers, pH adjusters, base agents, etc. may be added.

[0068] In the pharmaceutical composition of the present invention, surfactants that can be used as pharmaceutical additives, such as cationic surfactants, anionic surfactants, and nonionic surfactants, may be appropriately incorporated.

[0069] Examples of anionic surfactants include phospholipids. Examples of phospholipids include lecithin.

[0070] Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkyl trimethylammonium salts, dialkyl dimethylammonium salts, alkyl dimethyl benzylammonium salts, alkylpyridinium salts, acylamino alkyl ammonium salts, acylamino alkylpyridinium salts, diacyloxyethylammonium salts, alkyl imidazolines, 1-acylaminoethyl-2-alkylimidazoline, and 1-hydroxyethyl-2-alkylimidazoline. Examples of alkyl dimethyl benzylammonium salts include benzalkonium chloride and cetalkonium chloride.

[0071] 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.

[0072] Examples of polyoxyethylene fatty acid esters include, for example, polyoxyethylene stearate 40.

[0073] Examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 80, polysorbate 65, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan trioleate.

[0074] As polyoxyethylene hydrogenated castor oil, various polyoxyethylene hydrogenated castor oils with different polymerization numbers of ethylene oxide can be used. 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, and polyoxyethylene hydrogenated castor oil 60.

[0075] As polyoxyethylene castor oil, various polyoxyethylene castor oils with different polymerization numbers of ethylene oxide can be used. 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 castor oil polyoxyethylene ester 5, castor oil polyoxyethylene ester 9, castor oil polyoxyethylene ester 15, castor oil polyoxyethylene ester 35, and castor oil polyoxyethylene ester 40.

[0076] Examples of polyoxyethylene polyoxypropylene diols include polyoxyethylene (160) polyoxypropylene (30) diol, polyoxyethylene (42) polyoxypropylene (67) diol, polyoxyethylene (54) polyoxypropylene (39) diol, polyoxyethylene (196) polyoxypropylene (67) diol, and polyoxyethylene (20) polyoxypropylene (20) diol.

[0077] Examples of sucrose fatty acid esters include sucrose stearate.

[0078] Vitamin E TPGS is also known as tocopherol polyethylene glycol 1000 succinate.

[0079] When a surfactant is incorporated into the pharmaceutical composition of the present invention, the content of the surfactant can be appropriately adjusted according to the type of surfactant, etc., but is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), further preferably 0.05 to 3% (w / v), and most preferably 0.1 to 2% (w / v).

[0080] In the pharmaceutical composition of the present invention, an isotonic agent that can be used as an additive in pharmaceutical products can be appropriately incorporated to adjust the osmotic pressure. The osmotic pressure ratio of the pharmaceutical composition of the present invention is, for example, 1, and is not particularly limited as long as it is within the range permissible for pharmaceutical products. Examples of isotonic agents include ionic isotonic agents and nonionic isotonic agents.

[0081] Examples of ionic isotonic agents include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; examples of nonionic isotonic agents include glycerol, propylene glycol, sorbitol, and mannitol.

[0082] When an isotonic agent is incorporated into the pharmaceutical composition of the present invention, the content of the isotonic agent can be appropriately adjusted according to the type of isotonic agent, etc., but is preferably 0.01 to 10% (w / v), more preferably 0.02 to 7% (w / v), further preferably 0.1 to 5% (w / v), particularly preferably 0.3 to 4% (w / v), and most preferably 0.5 to 3% (w / v).

[0083] In the pharmaceutical composition of the present invention, a stabilizer that can be used as an additive in a pharmaceutical product may be appropriately incorporated. Examples of stabilizers include ethylenediaminetetraacetic acid (EDTA) and sodium EDTA.

[0084] When a stabilizer is incorporated into the pharmaceutical composition of the present invention, the content of the stabilizer may be appropriately adjusted according to the type of stabilizer, etc., but is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), further preferably 0.05 to 3% (w / v), and most preferably 0.1 to 2% (w / v).

[0085] In the pharmaceutical composition of the present invention, a preservative that can be used as an additive in a pharmaceutical product may be appropriately incorporated. Examples of preservatives include benzalkonium chloride, benzalkonium bromide, benzyl chloride, sorbic acid, potassium sorbate, methylparaben, propylparaben, chlorobutanol, etc.

[0086] When a preservative is incorporated into the pharmaceutical composition of the present invention, the content of the preservative may be appropriately adjusted according to the type of preservative, etc., 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).

[0087] In the pharmaceutical composition of the present invention, an antioxidant that can be used as an additive in pharmaceutical products may be appropriately incorporated. Examples of antioxidants include tocophenol, butylated hydroxytoluene, butylated hydroxyanisole, sodium isoascorbate, propyl gallate, and sodium sulfite.

[0088] When an antioxidant is incorporated into the pharmaceutical composition of the present invention, the content of the antioxidant can be appropriately adjusted according to the type of antioxidant, etc., 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).

[0089] In the pharmaceutical composition of the present invention, a high molecular weight polymer that can be used as an additive in pharmaceutical products may be appropriately incorporated. Examples of high molecular weight polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (hydroxypropyl methylcellulose), carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymers, polyethylene glycol, etc. In the present invention, the high molecular weight polymer is preferably hydroxypropyl methylcellulose (hydroxypropyl methylcellulose).

[0090] In the pharmaceutical composition of the present invention, when a high molecular weight polymer is incorporated, the content of the high molecular weight polymer can be appropriately adjusted according to the type of high molecular weight polymer, etc., 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).

[0091] In the pharmaceutical composition of the present invention, as long as the pH is below 6.5, a pH adjuster that can be used as an additive in a pharmaceutical product can be appropriately added. Examples of pH adjusters include hydrochloric acid, sodium hydroxide, potassium hydroxide, etc.

[0092] When a pH adjuster is incorporated into the pharmaceutical composition of the present invention, the content of the pH adjuster may be appropriately adjusted according to the type of pH adjuster, etc., 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).

[0093] In the pharmaceutical composition of the present invention, a base agent that can be used as an additive in a pharmaceutical product may be appropriately incorporated. Examples of base agents include water, purified water, and physiological saline.

[0094] The pharmaceutical composition of the present invention is preferably an aqueous pharmaceutical composition, but it can also be a non-aqueous pharmaceutical composition.

[0095] In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition is free of surfactants. In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition is free of isotonic agents. In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition is free of stabilizers. In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition is free of preservatives. In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition is free of antioxidants. In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition is free of high molecular weight polymers. In one embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition is free of pH adjusters.

[0096] When stored at temperatures below 50°C, the pharmaceutical composition of the present invention can inhibit the formation of hydrolysates of the compound of the present invention, thus exhibiting excellent stability at temperatures below 50°C. Furthermore, the pharmaceutical composition of the present invention can be maintained more stably by storing it at even lower temperatures, preferably below 30°C, more preferably below 25°C, further preferably below 10°C, further more preferably below 5°C, especially more preferably below 0°C, particularly preferably below -10°C, and most preferably below -20°C. The minimum temperature for storing the pharmaceutical composition of the present invention is preferably -80°C, more preferably -60°C, further preferably -50°C, particularly preferably -40°C, and most preferably -30°C. The temperature for storing the pharmaceutical composition of the present invention is, for example, -80°C to 50°C, preferably -80°C to 30°C, more preferably -60°C to 25°C, further preferably -50°C to 10°C, further more preferably -40°C to 5°C, particularly more preferably -30°C to 0°C, particularly preferably -30°C to -10°C, and most preferably -30°C to -20°C.

[0097] The pharmaceutical composition of the present invention can be administered orally or non-orally. Examples of routes of administration include oral administration, intravenous administration, percutaneous administration, and topical ocular administration (e.g., ophthalmic drops, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, and subcapsular administration).

[0098] Regarding the dosage form of the pharmaceutical composition of the present invention, there are no particular limitations as long as it can be used as a pharmaceutical product; examples include eye drops, eye gels, and injections. Eye drops are particularly preferred for the pharmaceutical composition of the present invention. Furthermore, when using the pharmaceutical composition of the present invention as a non-aqueous pharmaceutical composition, it can be formulated as a non-aqueous preparation.

[0099] They can be manufactured using methods commonly found in this field.

[0100] The pharmaceutical compositions of the present invention can be stored in containers made from various raw materials.

[0101] In addition, the present invention provides a method for incorporating (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine into a pharmaceutical composition. -6-one or its salts for stabilization. The detailed description of the pharmaceutical compositions of the present invention described above also applies to the method of stabilizing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine in the pharmaceutical compositions of the present invention. Methods for stabilizing 6-one or its salts.

[0102] In this invention, the (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine in the pharmaceutical composition is used. The method of stabilizing 6-one or its salts includes the following method of stabilizing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine in the pharmaceutical composition. A method for stabilizing 6-one or its salts, characterized in that the stabilization is carried out in a solution containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine In pharmaceutical compositions of 6-one or its salts, the pH is adjusted to below 6.5. By this method, (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The hydrolysis of 6-ones was inhibited, thereby suppressing the hydrolysis of its hydrolysate, 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine. The formation of 6-keto.

[0103] In this invention, the (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine in the pharmaceutical composition is used. The method of stabilizing 6-ones or their salts further includes the following method of stabilizing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine A method for stabilizing 6-one or its salts, characterized in that the stabilization is carried out in a solution containing (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine In pharmaceutical compositions of 6-ones or their salts, one or more buffers selected from the group consisting of citric acid, acetic acid, malic acid, amines, amino acids, and their salts are added. By the method described, under light irradiation, (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepines are... The decomposition of 6-ones or their salts is inhibited, (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine -6-ones or their salts become stable relative to light.

[0104] Example

[0105] The following are examples of formulations and test results, but these are for the purpose of better understanding the invention and do not limit the scope of the invention.

[0106] Formulation example

[0107] The following are representative formulation examples using the pharmaceutical compositions of the present invention. It should be noted that the amount (% (w / v)) of each component in the following formulation examples refers to the content (g) in 100 mL of the composition.

[0108] [Table 1]

[0109]

[0110] [Table 2]

[0111]

[0112] [Table 3]

[0113]

[0114] [Table 4]

[0115]

[0116] [Table 5]

[0117]

[0118] [Formulation Example 51]

[0119] Eye drops (100mL)

[0120]

[0121] [Formulation Example 52]

[0122] Eye drops (100mL)

[0123]

[0124]

[0125] [Formulation Example 53]

[0126] Eye drops (100mL)

[0127]

[0128] It should be noted that the types and amounts of AFDX0250, buffers, and additives in the aforementioned formulation examples 1 to 53 can be appropriately adjusted to obtain the desired composition.

[0129] 1. Stability evaluation test (1)

[0130] The effect of pH on the stability of pharmaceutical compositions containing the compounds of the present invention was investigated.

[0131] 1-1. Preparation of the test formulation

[0132] 5 g of sodium citrate hydrate was dissolved in purified water to a final volume of 200 mL, thus preparing a 2.5% sodium citrate hydrate solution. (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine 0.075 g of 6-one (AFDX0250) was dissolved in purified water to make a volume of 150 mL, thereby preparing a 0.05% AFDX0250 solution.

[0133] 10 mL each of 2.5% sodium citrate hydrate solution, 10 mL each of 0.05% AFDX0250 solution, and 20 mL each of purified water were mixed separately. The pH was adjusted to 5, 5.5, 6.5, and 7 respectively using sodium hydroxide or dilute hydrochloric acid. Then, the pH was accurately adjusted to 50 mL each using purified water. This is how Examples 1, 2, 4 and Comparative Example 1 were prepared.

[0134] 20 mL of 2.5% sodium citrate hydrate solution, 20 mL of 0.05% AFDX0250 solution, and 40 mL of purified water were mixed. The pH was adjusted to 6 using sodium hydroxide or dilute hydrochloric acid, and then the volume was accurately adjusted to 100 mL using purified water. This is how Example 3 was prepared.

[0135] 1-2. Test Methods

[0136] Each test formulation prepared in 1-1 above was filled into a container with 3 mL of the solution and stored at 25°C / 40% RH for 3 months. High-performance liquid chromatography (HPLC) was used to analyze the 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepines generated by the hydrolysis of AFDX0250 in the test formulations after 3 months of storage. The content of 6-one (hereinafter referred to as "hydrolysate") was quantified, and its formation rate (%) was calculated. It should be noted that the formation rate (%) is the proportion (%) when the mass of AFDX0250 contained in the test formulation is taken as 100%.

[0137] 1-3. Experimental Results and Discussion

[0138] The experimental results are shown in Table 6.

[0139] [Table 6]

[0140]

[0141] As can be confirmed from Table 6, the hydrolysate formation rate of the formulations in Examples 1-4 was suppressed to a low level compared to the formulation of Comparative Example 1. The results confirm that AFDX0250 exhibits excellent stability in pharmaceutical compositions of the present invention at pH 6.5 or below.

[0142] 2. Stability evaluation test (2)

[0143] The stability of pharmaceutical compositions containing the compounds of the present invention relative to light irradiation was investigated.

[0144] 2-1. Preparation of the test formulation

[0145] A 2% sodium citrate hydrate solution was prepared by dissolving 4 g of sodium citrate hydrate in purified water to a final volume of 200 mL. A 0.01% AFDX0250 solution was prepared by dissolving 0.02 g of AFDX0250 in purified water to a final volume of 200 mL. A 10% tromethamine solution was prepared by dissolving 10 g of tromethamine in purified water to a final volume of 100 mL. A 5% boric acid solution was prepared by dissolving 10 g of boric acid in purified water to a final volume of 200 mL. A 5% hydroxypropyl methylcellulose solution was prepared by dissolving 5 g of hydroxypropyl methylcellulose in purified water to a final volume of 100 mL.

[0146] 10 mL of 2% sodium citrate hydrate solution, 10 mL of 0.01% AFDX0250 solution and 50 mL of purified water were mixed. The pH was adjusted to 6 using sodium hydroxide or dilute hydrochloric acid, and then the purified water was used to accurately bring the volume to 100 mL. This is how Example 5 was prepared.

[0147] In Example 5, 1g of sodium acetate hydrate, 10mL of 10% tromethamine solution, 1g of ε-aminocaproic acid, 1g of glycine, 1g of L-glutamine, 1g of DL-malic acid, and 20mL of 5% hydroxypropyl methylcellulose solution were respectively added. Examples 6, 7, 8, 9, 10, 11, and 12 were prepared using the same method as in Example 5. It should be noted that the amount of purified water added was appropriately varied depending on the amount of additives.

[0148] In Example 7, 0.75g of sodium chloride, 2g of glycerol, 4g of mannitol, 2g of propylene glycol, and 20mL of 5% hydroxypropyl methylcellulose were respectively added. Examples 13, 14, 15, 16, and 17 were prepared using the same method as in Example 7. It should be noted that the amount of purified water added was appropriately varied depending on the amount of additives.

[0149] In Example 5, 3g of sodium dihydrogen phosphate hydrate, 20mL of 5% boric acid solution, 1g of L-ascorbic acid, and 1g of ethyl pyruvate were respectively added. Comparative Examples 2, 3, 4, and 5 were prepared using the same method as in Example 5. It should be noted that the amount of purified water added was appropriately varied depending on the amount of additives.

[0150] 2-2. Test Methods

[0151] Each test formulation prepared in 2-1 above was filled into a container with 3 mL of the solution, and exposed to light at 1000 lux / hr or 1.2 million lux·hr, or shielded with aluminum foil. High-performance liquid chromatography (HPLC) was used to analyze the (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepines under exposure or shielding conditions. The content of 6-one (AFDX0250) was quantified, and its residual rate (%) was calculated. It should be noted that the residual rate (%) is the proportion (%) when the mass of AFDX0250 contained in the test formulation is taken as 100%.

[0152] 2-3. Experimental Results and Discussion

[0153] The experimental results are shown in Tables 7-10.

[0154] [Table 7]

[0155]

[0156] [Table 8]

[0157]

[0158] [Table 9]

[0159]

[0160] [Table 10]

[0161]

[0162] As confirmed by Tables 7-10, the formulations of Examples 5-17 exhibited higher residual rates of AFDX0250 even under light irradiation compared to the formulations of Comparative Examples 2-5. In particular, Examples 7, 8, 10, 11, and 13-17, which contained sodium citrate hydrate, tromethamine, ε-aminocaproic acid, L-glutamine, or DL-malic acid, showed high residual rates. On the other hand, Comparative Example 4, which contained sodium citrate hydrate and L-ascorbic acid, showed low residual rates even under light-shielding conditions. These results confirm that the pharmaceutical compositions of the present invention exhibit excellent light stability.

[0163] 3. Stability evaluation test (3)

[0164] The stability of pharmaceutical compositions containing the compounds of the present invention relative to light irradiation was investigated.

[0165] 3-1. Preparation of the test formulation

[0166] 2.5 g of sodium citrate hydrate, 0.2 g of citric acid hydrate, and 7.8 g of sodium chloride were dissolved in purified water to a final volume of 100 mL, thus preparing a 2.5% sodium citrate hydrate / 0.2% citric acid hydrate / 7.8% sodium chloride solution. 0.01 g of AFDX0250 was dissolved in purified water to a final volume of 100 mL, thus preparing a 0.01% AFDX0250 solution. 5 g of tromethamine was dissolved in purified water to a final volume of 100 mL, thus preparing a 5% tromethamine solution. This 5% tromethamine solution was then diluted to prepare 0.5% and 0.05% tromethamine solutions.

[0167] 10 mL of a 2.5% sodium citrate hydrate / 0.2% citric acid hydrate / 7.8% sodium chloride solution, 10 mL of a 0.01% AFDX0250 solution, and purified water were mixed. The pH was adjusted to 6 using sodium hydroxide or dilute hydrochloric acid, and then the volume was accurately adjusted to 100 mL using purified water. This is how Example 18 was prepared.

[0168] In the composition of Example 18, 10 mL or 20 mL of 0.05%, 0.5%, or 5% tromethamine solution was added. Otherwise, Examples 19-23 were prepared using the same method as in Example 18. It should be noted that the amount of purified water added was appropriately varied depending on the amount of additives.

[0169] 3-2. Test Methods

[0170] Each test formulation prepared in step 3-1 above was filled into a container and exposed to light at 1000 lux / hr or 1.2 million lux·hr, or shielded from light with aluminum foil. The content of AFDX0250 under exposure or shielding conditions was quantified using high-performance liquid chromatography (HPLC), and its residual rate (%) was calculated. It should be noted that the residual rate (%) is the percentage (%) when the mass of AFDX0250 contained in the test formulation is taken as 100%.

[0171] 3-3. Experimental Results and Discussion

[0172] The experimental results are shown in Table 11.

[0173] [Table 11]

[0174]

[0175] As can be confirmed from Table 11, the formulations of Examples 18-23 exhibited high residual rates of AFDX0250 even under light irradiation. The results confirm that the pharmaceutical compositions of the present invention possess excellent stability relative to light.

[0176] 4. Stability evaluation test (4)

[0177] The effect of temperature on the stability of pharmaceutical compositions containing the compounds of the present invention was investigated.

[0178] 4-1. Preparation of the test formulation

[0179] Examples 24-27 were prepared using the same method as in Example 18. It should be noted that the amounts of AFDX0250 and each additive are shown in Table 12, and the amount of purified water added was appropriately varied according to the amount of additives.

[0180] 4-2. Test Methods

[0181] Each test formulation prepared in section 4-1 above was stored at -20°C and 5°C for 3 months. The content of AFDX0250 in the test formulations after 3 months of storage at each temperature was quantified using high-performance liquid chromatography (HPLC), and the residual rate (%) was calculated. It should be noted that the residual rate (%) is the percentage (%) when the content of AFDX0250 in the test formulation before storage is taken as 100%.

[0182] 4-3. Experimental Results and Discussion

[0183] The experimental results are shown in Table 12.

[0184] [Table 12]

[0185]

[0186] As can be confirmed from Table 12, the formulations of Examples 24-27 exhibited high residual rates of AFDX0250 at low temperatures of -20°C and 5°C. The results confirm that AFDX0250 exhibits excellent stability in pharmaceutical compositions when stored at low temperatures.

[0187] 5. Stability evaluation test (5)

[0188] The effect of temperature on the stability of pharmaceutical compositions containing the compounds of the present invention was investigated.

[0189] 5-1. Preparation of the test formulation

[0190] Examples 28-31 were prepared using the same method as in Example 5. It should be noted that the amounts of AFDX0250 and each additive are shown in Table 13, and the amount of purified water added was appropriately varied according to the amounts of the additives. Furthermore, the pH was adjusted to 5, 5.5, and 6.5 in Examples 28, 29, and 31, respectively.

[0191] 5-2. Test Methods

[0192] Each test formulation prepared in step 5-1 above was stored for 6 months under conditions of 5°C and 25°C / 40% RH. The content of AFDX0250 in the test formulations after 6 months of storage was quantified using high-performance liquid chromatography (HPLC), and the residual rate (%) was calculated. It should be noted that the residual rate (%) is the percentage (%) when the content of AFDX0250 in the test formulation before storage is taken as 100%.

[0193] 5-3. Experimental Results and Discussion

[0194] The experimental results are shown in Table 13.

[0195] [Table 13]

[0196]

[0197] As can be confirmed from Table 13, for the formulations of Examples 28-31, the residual rate of AFDX0250 is high at 5°C and 25°C. The results confirm that AFDX0250 exhibits excellent stability in pharmaceutical compositions when stored at room temperature with a pH below 6.5.

[0198] 6. Stability evaluation test (6)

[0199] The stability of pharmaceutical compositions containing compounds of the present invention under high-temperature storage was investigated.

[0200] 6-1. Preparation of the test formulation

[0201] Examples 32-35 and Comparative Example 6 were prepared using the same method as in Example 5. It should be noted that the amounts of AFDX0250 and each additive are shown in Table 14, and the amount of purified water added was appropriately varied according to the amount of additives. Furthermore, the pH was adjusted to 5, 5.5, 6.5, and 7 in Examples 32, 33, 35, and Comparative Example 6, respectively.

[0202] 6-2. Test Methods

[0203] Each test formulation prepared in step 6-1 above was stored at 50°C, and samples were taken after 1, 2, and 4 weeks. The content of AFDX0250 in the test formulations at each time point was quantified using high-performance liquid chromatography (HPLC), and the residual rate (%) was calculated. It should be noted that the residual rate (%) is the percentage (%) when the content of AFDX0250 in the test formulation before storage is taken as 100%.

[0204] 6-3. Experimental Results and Discussion

[0205] The experimental results are shown in Table 14.

[0206] [Table 14]

[0207]

[0208] As can be confirmed from Table 14, the formulations of Examples 32-35 exhibited a higher residual rate of AFDX0250 at a high temperature of 50°C compared to the formulation of Comparative Example 6. The results confirm that AFDX0250 exhibits excellent stability in pharmaceutical compositions of the present invention when stored at high temperatures with a pH below 6.5.

[0209] Industrial availability

[0210] Contains (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine The pharmaceutical compositions of the present invention containing 6-one or its salts are stable and therefore can be used stably as medicine over a long period of time.

Claims

1. A pharmaceutical composition comprising (+)-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, and water, and further comprising citric acid or a salt thereof as a buffer, and further comprising any one of acetic acid or a salt thereof, malic acid or a salt thereof, tromethamine or a salt thereof, ε-aminohexanoic acid or a salt thereof, glycine or a salt thereof, or L-glutamine or a salt thereof. The content of (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or its salt in the pharmaceutical composition is 0.001~3% (w / v). The buffer content in the pharmaceutical composition is 0.1-3% (w / v). The pH of the pharmaceutical composition is 5 to 6.

5.

2. The pharmaceutical composition of claim 1, wherein the pH is 5 to 6.

3.

3. The pharmaceutical composition according to claim 1 or 2, wherein, The buffer may further include any of the following: malic acid or its salt, tromethamine or its salt, ε-aminocaproic acid or its salt, or L-glutamine or its salt.

4. The pharmaceutical composition according to claim 1 or 2, wherein, The buffer is citric acid or its salt, and tromethamine or its salt.

5. The pharmaceutical composition according to claim 1 or 2, wherein, The content of (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or its salt in the pharmaceutical composition is 0.002~2% (w / v).

6. The pharmaceutical composition according to claim 1 or 2, wherein, The buffer content in the pharmaceutical composition is 0.2-3% (w / v).

7. The pharmaceutical composition according to claim 1 or 2, wherein, The content of the buffer in the pharmaceutical composition is 0.01 to 1000 parts by weight relative to 1 part by weight of (+)-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.

8. The pharmaceutical composition of claim 4, wherein, The content of citric acid or its salt in the pharmaceutical composition is 0.05~1.5% (w / v). The content of tromethamine or its salt in the pharmaceutical composition is 0.05~1.5% (w / v).

9. The pharmaceutical composition of claim 1 or 2, for topical application to the eye.

10. The pharmaceutical composition of claim 9, wherein, Local ocular administration includes eye drops, intraconjunctival sac administration, intravitreal administration, subconjunctival administration, or subtenonic administration.

11. The pharmaceutical composition of claim 1 or 2, wherein it is an eye drop, an ophthalmic gel, or an injection.

12. The pharmaceutical composition as claimed in claim 1 or 2, wherein it is stored at a temperature below 50°C.

13. A method for stabilizing (+)-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 a pharmaceutical composition, characterized in that, In a pharmaceutical composition containing 0.001 to 3% (w / v) of (+)-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 and containing water, citric acid or a salt thereof is added in an amount of 0.1 to 3% (w / v) in the pharmaceutical composition, and any one of acetic acid or a salt thereof, malic acid or a salt thereof, tromethamine or a salt thereof, ε-aminocaproic acid or a salt thereof, glycine or a salt thereof, or L-glutamine or a salt thereof is added as a buffer to adjust the pH to 5 to 6.

5.

14. The method of claim 13, wherein, The buffer is any one of malic acid or its salt, tromethamine or its salt, ε-aminocaproic acid or its salt, or L-glutamine or its salt.

15. The method of claim 13, wherein, The buffer is tromethamine or its salt.

16. The method of claim 13, wherein, The content of (+)-11-[2-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one or its salt in the pharmaceutical composition is 0.002~2% (w / v).

17. The method of claim 15, wherein, The content of citric acid or its salt in the pharmaceutical composition is 0.05~1.5% (w / v). The content of tromethamine or its salt in the pharmaceutical composition is 0.05~1.5% (w / v).

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