Pharmaceutical composition

Abstract

A pharmaceutical composition that contains an active ingredient having an ester bond, and at least one binder selected from the group consisting of polyvinyl alcohol, hydroxypropyl cellulose, and microcrystalline cellulose, wherein the active ingredient is a compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

Description

Pharmaceutical Composition

[0001] The present disclosure relates to pharmaceutical compositions.

[0002] This application claims priority based on Japanese Patent Application No. 2024-60714, filed on April 4, 2024, the contents of which are incorporated herein by reference.

[0003] In order to provide effective and safe pharmaceuticals, it is necessary to guarantee their stability. Problems with pharmaceutical stability can lead to problems such as the active ingredient decomposing and reducing its content, resulting in a decrease in efficacy, or the decomposition products of the active ingredient adversely affecting safety.

[0004] U.S. Patent No. 5,629,999 discloses that the formation of pharmaceutical spheroids requires the inclusion of a spheronization aid to provide the formulation with the structural integrity, plasticity, and water absorption required for successful spheroid formation, and that the use of microcrystalline cellulose, a spheronization aid routinely used in the pharmaceutical industry, results in the degradation of certain drugs (e.g., hydromorphone hydrochloride) during long-term storage.

[0005] Patent Document 1 also discloses that Non-Patent Document 1 reports the instability of ranitidine in a pellet dosage form containing microcrystalline cellulose, and Non-Patent Document 2 reports the preparation of pharmaceutical spheroids containing barium sulfate or diclofenac sodium and glyceryl monostearate as a substitute for microcrystalline cellulose.

[0006] Patent Document 2 lists diluents, binders, excipients, lubricants, disintegrants, wetting agents, suspending agents, and buffers as pharmaceutically acceptable carriers in compositions containing gastrointestinal protease inhibitors.

[0007] Patent Publication No. 2009-530258 International Publication No. 2021 / 166899

[0008] Basit, A. W, Newton, J. M, Lacey, LF,1999. Pharm. Dev. Technol. 4, 499-505. Newton, JM, Boutel, S., Chatchawalsaisin, J. Podczeck, F., 2004. Pharm. Technol, Eur, October 2004, 21-27.

[0009] The present disclosure relates to a pharmaceutical composition having an improved stability of an active ingredient having an ester bond. The above-mentioned Patent Document 2 does not consider at all the influence on the stability of a gastrointestinal protease inhibitor having an ester bond by combining the inhibitor with a pharmaceutically acceptable carrier.

[0010] The present inventors have conducted extensive research based on the hypothesis that active ingredients having an ester bond (hereinafter simply referred to as "active ingredients") are decomposed due to the influence of water contained in pharmaceutical compositions. Based on this hypothesis, it was predicted that the active ingredient would be decomposed due to the influence of water retained by, for example, a binder, which is a component of a pharmaceutical composition, and that the decomposition of the active ingredient could be suppressed by using a binder with low water retention. However, the present inventors have surprisingly and unexpectedly found that the decomposition of the active ingredient can be suppressed (specifically, the degree of decomposition of the active ingredient can be reduced) when a specific type of binder is used, regardless of the binder's water retention ability.

[0011] The present disclosure includes the following embodiments: [1] A pharmaceutical composition comprising: an active ingredient having an ester bond; and at least one binder selected from the group consisting of polyvinyl alcohol, hydroxypropyl cellulose, and microcrystalline cellulose, wherein the active ingredient is a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [In the formula, R １ , R ２ , R ３ , and R ４ are each independently a hydrogen atom, a nitro group, a halogeno group, a cyano group, a hydroxyl group, a lower alkyl group, or a lower alkoxyl group; R ｘis an amidino group or a guanidino group, Z is —O(C═O)— or —(C═O)O—, B is an optionally substituted heterocycle, X is an optionally substituted lower alkylene group, an optionally substituted lower alkenylene group, or an optionally substituted lower alkynylene group, Y is a carbonyl group, and A is selected from the following groups: —OR ５ (R ５ is a hydrogen atom or a lower alkyl group); or the following group (1A-1): (In the formula, R ６ and R ７ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or R ６ and R ７ may form, together with the nitrogen atom to which they are bonded, a cyclic amino group which may have a substituent.) [2] The pharmaceutical composition according to [1], wherein the active ingredient is a compound represented by the following formula (2) or the following formula (3) or a pharmaceutically acceptable salt thereof: [3] The pharmaceutical composition according to [1] or [2], wherein the pharmaceutically acceptable salt is a hydrochloride. [4] The pharmaceutical composition according to any one of [1] to [3], further comprising an acidic substance. [5] The pharmaceutical composition according to any one of [1] to [4], further comprising a lubricant. [6] The pharmaceutical composition according to any one of [1] to [5], wherein the pharmaceutical composition is for oral administration. [7] The pharmaceutical composition according to any one of [1] to [6], wherein the pharmaceutical composition is in the form of a tablet or capsule.

[0012] The stability of active ingredients having an ester bond can be improved.

[0013] The results of stability tests conducted under airtight conditions at 60°C for the pharmaceutical compositions of Reference Examples, Examples, and Comparative Examples are shown. The results of stability tests conducted under airtight conditions at 40°C for the pharmaceutical compositions of Reference Examples, Examples, and Comparative Examples are shown. The results of stability tests conducted under airtight conditions at 40°C for the pharmaceutical compositions of Reference Examples, Examples, and Comparative Examples are shown. The results of stability tests conducted under airtight conditions at 40°C for the pharmaceutical compositions of Reference Examples and Examples are shown.

[0014] Hereinafter, embodiments of the present disclosure will be described in detail, but the present disclosure is not limited to these and various modifications are possible without departing from the spirit of the present disclosure.

[0015] <Definitions> In this specification, the word "comprise" means that in addition to the elements explicitly stated to be included, other elements may also be included.

[0016] In this specification, the term "lower alkyl group" refers to a straight-chain, branched-chain or cyclic alkyl group having 1 to 6 carbon atoms.

[0017] In this specification, the term "lower alkylene group" refers to a straight-chain, branched-chain or cyclic alkylene group having 1 to 6 carbon atoms.

[0018] In the present specification, the term "lower alkenylene group" refers to a straight or branched alkenylene group having 2 to 6 carbon atoms.

[0019] In the present specification, the term "lower alkynylene group" refers to a straight or branched chain lower alkynylene group having 2 to 6 carbon atoms.

[0020] As used herein, the term "lower alkoxyl group" refers to an alkoxyl group having a lower alkyl group.

[0021] As used herein, the term "lower alkylthio group" refers to an alkylthio group having a lower alkyl group.

[0022] As used herein, the term "lower alkoxycarbonyl group" refers to a carbonyl group having a lower alkoxy group.

[0023] <Pharmaceutical Composition> One embodiment of the present disclosure relates to a pharmaceutical composition comprising an active ingredient having an ester bond (hereinafter also simply referred to as "active ingredient") and at least one binder selected from the group consisting of polyvinyl alcohol, hydroxypropyl cellulose, and microcrystalline cellulose.

[0024] In the pharmaceutical composition according to this embodiment, the degree of decomposition of the active ingredient due to cleavage of the ester bond can be reduced by using a specific type of binder.

[0025] [Active Ingredient] The pharmaceutical composition according to this embodiment contains an active ingredient having an ester bond. The active ingredient is preferably a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[0026] (R １ and R ２ ) R in formula (1) １ and R ２ are each independently a hydrogen atom, a nitro group, a halogeno group, a cyano group, a hydroxyl group, a lower alkyl group, or a lower alkoxyl group.

[0027] R in formula (1) １ and R ２ is preferably a hydrogen atom or a halogeno group, more preferably a hydrogen atom or fluorine.

[0028] (R ３ and R ４ ) R in formula (1) ３ and R ４ are each independently a hydrogen atom, a nitro group, a halogeno group, a cyano group, a hydroxyl group, a lower alkyl group, or a lower alkoxyl group.

[0029] R in formula (1) ３ and R ４ is preferably a hydrogen atom or a halogeno group, more preferably a hydrogen atom.

[0030] (R ｘ ) R in formula (1) ｘ is an amidino group or a guanidino group, preferably an amidino group.

[0031] (Z) Z in formula (1) is -O(C=O)- or -(C=O)O-, preferably -O(C=O)-. In -O(C=O)-, the carbonyl group "(C=O)-" is bonded to B in formula (1). In addition, in -(C=O)O-, the oxygen atom "O-" is bonded to B in formula (1).

[0032] (B) In formula (1), B is a heterocycle which may have a substituent, preferably a 5- to 10-membered monocyclic or bicyclic heterocycle which may have a substituent, more preferably a 5- to 10-membered monocyclic or bicyclic aromatic heterocycle which may have a substituent, even more preferably a 5- or 6-membered monocyclic aromatic heterocycle which may have a substituent, and particularly preferably a thiophene ring. A dihydrobenzofuran ring, which is a bicyclic heterocycle, is also particularly preferred.

[0033] The number of heteroatoms contained in the hetero ring is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0034] The heteroatom is preferably at least one selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom, more preferably an oxygen atom and / or a sulfur atom, and even more preferably a sulfur atom.

[0035] Substituents for B include, for example, a halogeno group and a lower alkyl group.

[0036] (X) In formula (1), X is a lower alkylene group which may have a substituent, a lower alkenylene group which may have a substituent, or a lower alkynylene group which may have a substituent.

[0037] X in formula (1) is preferably a lower alkylene group which may have a substituent, more preferably an alkylene group having 1 to 4 carbon atoms which may have a substituent, even more preferably a branched alkylene group having 4 carbon atoms which may have a substituent, and particularly preferably -CH ２ -C(CH ３ ) ２ -. In addition, -CH ２ -C(CH ３ ) ２ In -, the carbon atom substituted with two methyl groups is preferably bonded to Y in formula (1).

[0038] Substituents for X include, for example, a halogeno group and a lower alkyl group.

[0039] (Y) In formula (1), Y is a carbonyl group.

[0040] (A) A in formula (1) is selected from the following groups: -OR ５ (R ５ is a hydrogen atom or a lower alkyl group); or the following group (1A-1): (In the formula, R ６ and R ７ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or R ６ and R ７ may form, together with the nitrogen atom to which they are attached, a cyclic amino group which may have a substituent).

[0041] A in formula (1) is preferably —OH or the above group (1A-1) (wherein R ６ is a hydrogen atom, and R ７ is a lower alkyl group which may have a substituent, preferably an alkyl group having 1 to 3 carbon atoms which may have a substituent, more preferably an alkyl group having 1 to 3 carbon atoms substituted with a carboxyl group, even more preferably an ethyl group substituted with a carboxyl group, particularly preferably —CH(COOH)—CH ２ (COOH), more preferably —OH.

[0042] R ６ and R ７ Examples of the substituent include a hydroxyl group, a thiol group, an amino group, a guanidino group, a carboxyl group, a lower alkylthio group, a lower alkoxylcarbonyl group, a carbamoyl group, an aryl group which may have a substituent, and a heterocyclic group which may have a substituent.

[0043] R ６ and R ７ Examples of the substituents of the cyclic amino group formed by bonding include a hydroxy group and a carboxyl group.

[0044] The active ingredient in this embodiment is preferably a compound represented by the following formula (2) or (3) or a pharmaceutically acceptable salt thereof.

[0045] The pharmaceutically acceptable salt of the active ingredient in this embodiment is not particularly limited as long as it is usable as a pharmaceutical, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc., and organic acid salts such as fumarate, maleate, malate, tartrate, citrate, succinate, methanesulfonate, p-toluenesulfonate, lactate, acetate, palmitate, etc. The pharmaceutically acceptable salt is preferably hydrochloride.

[0046] The active ingredient in this embodiment may form a solvate such as a hydrate. In this specification, solvates are encompassed by the compound represented by the above formula or a pharmaceutically acceptable salt thereof.

[0047] In the present embodiment, when the active ingredient has stereoisomers (e.g., enantiomers, diastereomers), the individual stereoisomers and mixtures thereof (e.g., racemates) are intended to be encompassed by the compound represented by the above formula or a pharmaceutically acceptable salt thereof.

[0048] The active ingredient in this embodiment can be synthesized with reference to known methods (for example, the methods described in WO 2011 / 071048, WO 2015 / 137407, or WO 2015 / 137408).

[0049] The active ingredient may be coated with an acidic substance as described below. A part of the surface of the active ingredient may be coated with the acidic substance, or the entire surface of the active ingredient may be coated with the acidic substance. By coating the active ingredient with an acidic substance, decomposition of the active ingredient can be further suppressed.

[0050] The amount of the active ingredient may be any amount that is therapeutically effective, and may be determined appropriately depending on, for example, the type and progression of the disease, the weight and condition of the patient, etc.

[0051] [Binder] The pharmaceutical composition according to this embodiment contains at least one binder selected from the group consisting of polyvinyl alcohol, hydroxypropyl cellulose, and microcrystalline cellulose. The use of these binders can suppress the decomposition of the active ingredient and improve the strength of the pharmaceutical composition.

[0052] As mentioned above, it was expected that the active ingredient having an ester bond would be decomposed due to the influence of water held by the binder. However, surprisingly, it was actually possible to suppress the decomposition of the active ingredient by using a specific type of binder, regardless of the water retention (hygroscopicity) of the binder.

[0053] The amount of binder can be adjusted to an appropriate amount depending on the method for producing the pharmaceutical composition. For example, when producing a pharmaceutical composition by Production Method 1 described below, the amount of binder is preferably 0.1 to 10% by mass, more preferably 0.5 to 5.0% by mass, and even more preferably 1.0 to 3.0% by mass, based on the total mass of the pharmaceutical composition. Furthermore, when producing a pharmaceutical composition by Production Methods 2 to 4 described below, the amount of binder is preferably 0.1 to 70% by mass, more preferably 5 to 50% by mass, and even more preferably 15 to 30% by mass, based on the total mass of the pharmaceutical composition.

[0054] [Acidic Substance] The pharmaceutical composition according to this embodiment may further contain an acidic substance, which can further suppress the decomposition of the active ingredient.

[0055] The acid dissociation constant (pKa) of the acidic substance is preferably 1.0 to 6.0, more preferably 1.5 to 5.5, even more preferably 2.0 to 5.0, particularly preferably 2.5 to 4.5, and most preferably 3.0 to 4.5. By using an acidic substance having such a pKa, the decomposition of the active ingredient can be further suppressed. When the acidic substance has multiple pKa values, the first acid dissociation constant (pKa １ ) is used as the standard.

[0056] In this specification, the acid dissociation constant (pKa) of an acidic substance may be an experimentally measured acid dissociation constant, or may be an acid dissociation constant recorded in a known database such as the CAS database or Chemical Book, or an acid dissociation constant estimated by a known program. In this specification, pKa values ​​recorded in the Chemical Book, a known database of acid dissociation constants of acidic substances, are exemplified. However, those skilled in the art can refer to this database or use a database or program with equivalent functionality to recognize values ​​recorded as the acid dissociation constant of any acidic substance as falling within the scope of the present disclosure. When experimentally measuring, it is preferable to measure according to the measurement conditions, including temperature, described in the database. If the pKa values ​​obtained from the database, program, and experiment do not match, the pKa value described in the Chemical Book takes precedence.

[0057] The acidic substance is preferably fumaric acid (pKa １ : 3.02, pKa ２ citric acid (pKa: 3.14), tartaric acid (pKa: 3.03), lactic acid (pKa: 3.86), maleic acid (pKa: 1.83), and malic acid (pKa: 3.4). These acidic substances also include salts, acid anhydrides, and solvates thereof.

[0058] The acidic substance more preferably includes at least one selected from the group consisting of fumaric acid, succinic acid, adipic acid, aspartic acid, glycine, and benzoic acid, even more preferably includes fumaric acid and / or succinic acid, and particularly preferably includes fumaric acid and succinic acid.

[0059] The amount of the acidic substance is preferably 0.1 to 30% by mass, more preferably 0.2 to 10.0% by mass, even more preferably 0.3 to 5.0% by mass, and particularly preferably 0.5 to 3.0% by mass, based on the total mass of the pharmaceutical composition.

[0060] [Lubricant] The pharmaceutical composition according to this embodiment may further contain a lubricant. The lubricant can suppress the decomposition of the active ingredient. Since a lubricant is usually used for the purpose of increasing the fluidity of a pharmaceutical composition, it is surprising that a lubricant can improve the stability of the active ingredient when used together with the active ingredient.

[0061] Lubricants include, for example, magnesium stearate and calcium stearate.

[0062] The amount of the lubricant is preferably 0.1 to 10% by mass, more preferably 0.5 to 5.0% by mass, and even more preferably 0.7 to 3.0% by mass, based on the total mass of the pharmaceutical composition.

[0063] [Excipient] The pharmaceutical composition according to this embodiment may further contain an excipient. Using an excipient together with an acidic substance can facilitate handling during the manufacturing process and more efficiently suppress decomposition of the active ingredient.

[0064] The type of excipient is not particularly limited as long as it is a pharmaceutically acceptable excipient, and examples of the excipient include lactic acid hydrate, anhydrous lactose, croscarmellose sodium, carmellose, magnesium carbonate, mannitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, methacrylic copolymer, calcium carbonate, magnesium oxide, and sodium chloride.

[0065] The excipient may be coated with an acidic substance. At least a portion of the surface of the excipient may be coated with the acidic substance, or the entire surface of the excipient may be coated uniformly or non-uniformly with the acidic substance. By using an excipient coated with an acidic substance, the contact area between the active ingredient and the acidic substance can be increased, further suppressing decomposition of the active ingredient.

[0066] The amount of the excipient is preferably 5 to 95% by mass, more preferably 10 to 90% by mass, and even more preferably 20 to 80% by mass, based on the total mass of the pharmaceutical composition.

[0067] [Other Components] The pharmaceutical composition according to this embodiment may further contain other components as long as the technical effects of the present disclosure are not impaired. The other components vary depending on the dosage form, etc., and include, for example, a fluidizer (e.g., silicon dioxide), a disintegrant, a surfactant, a suspending agent, an emulsifier, a preservative, a colorant, a flavoring agent, a sweetener, a flavoring agent, and a thickener. As the other components, one or a combination of two or more known components can be used as appropriate.

[0068] [Dosage Form] The pharmaceutical composition according to this embodiment can be administered orally or parenterally. Examples of dosage forms for oral administration include tablets, pills, granules, powders, capsules, syrups, emulsions, and suspensions. Examples of dosage forms for parenteral administration include injections, infusions, drip infusions, eye drops, and suppositories. Oral administration is preferred, more preferably tablets, pills, granules, powders, or capsules, and even more preferably tablets or capsules.

[0069] [Use] The pharmaceutical composition according to this embodiment can be used to treat fatty liver disease. Here, "treatment" includes preventing the onset of fatty liver disease, inhibiting the progression of fatty liver disease, alleviating the symptoms of fatty liver disease, curing fatty liver disease, etc.

[0070] Specific examples of fatty liver disease include, for example, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolically associated fatty liver disease (MAFLD or MASLD), metabolically associated steatohepatitis (MASH), and fatty liver.

[0071] <Method for Producing Pharmaceutical Composition> The method for producing the above-mentioned pharmaceutical composition is not particularly limited, but examples thereof include the following production methods.

[0072] [Production Method 1] A method for producing a pharmaceutical composition, comprising: a step of mixing an active ingredient and an excipient to obtain a mixture; and a step of granulating the mixture while spraying a binding liquid containing a binder to obtain a granulated product.

[0073] [Production Method 2] A method for producing a pharmaceutical composition, comprising: mixing an active ingredient and an excipient to obtain a mixture; granulating the mixture while spraying a binder to obtain a granulated product; and mixing the granulated product with a binder.

[0074] [Production Method 3] A method for producing a pharmaceutical composition, comprising: a step of granulating an excipient while spraying a binder liquid to obtain a granulated product; and a step of mixing the granulated product, an active ingredient, and a binder.

[0075] [Production Method 4] A method for producing a pharmaceutical composition, comprising the steps of: mixing an active ingredient, an excipient, and a binder.

[0076] Preparation method 1 is preferably used when the binder is polyvinyl alcohol or hydroxypropyl cellulose, and preparation methods 2 to 4 are preferably used when the binder is microcrystalline cellulose.

[0077] The process for obtaining the granulated product in Production Methods 1 to 3 is not particularly limited as long as it is wet granulation, and any of fluidized bed granulation, agitation granulation, and extrusion granulation can be used, but fluidized bed granulation is preferred. The medium for the binder liquid used in this process is not particularly limited, and water, lower alcohols such as ethanol, and mixtures thereof can be used as appropriate. In this process, an acidic substance may also be dissolved or dispersed in the binder liquid.

[0078] In the mixing step in Production Methods 1 to 4, an acidic substance and / or other components may be further added and mixed.

[0079] Hereinafter, the present disclosure will be described in more detail using examples, comparative examples, and reference examples, but the technical scope of the present disclosure is not limited thereto.

[0080] <Binder> The following binders were used in the examples and comparative examples: PVA: polyvinyl alcohol HPC: hydroxypropyl cellulose HPMC: hydroxypropylmethyl cellulose MC: methyl cellulose EC: ethyl cellulose MCC: microcrystalline cellulose

[0081] <Binder Moisture Absorption (Water Retention) Test> Each binder was stored under a predetermined relative humidity, and the amount of moisture absorbed (%) by each binder was measured. The results are shown in Table 1.

[0082]

[0083] When the relative humidity was 94%, the moisture absorption of each binder had the following relationship: (moisture absorption: low) EC<<MC<PVA<HPC<HPMC (moisture absorption: high)

[0084] <Preparation of Pharmaceutical Compositions> Pharmaceutical compositions were prepared according to the following manufacturing methods A to F and the formulations in Tables 2 to 4 below.

[0085] [Production Method A] The components of the pharmaceutical composition were mixed, and the mixture was filled into an HPMC capsule (No. 1).

[0086] [Process B] The active ingredient and excipients were mixed, and the mixture was placed in a fluidized bed granulator. Granulation was performed while spraying a binder solution prepared by dissolving a binder in an aqueous ethanol solution. The mixture was then fluidized bed dried and sieved to obtain a granulated product. The granulated product was mixed with a fluidizer, and the mixture was filled into HPMC capsules (size 1).

[0087] [Process C] The active ingredient and excipients were mixed, and the mixture was placed in a fluidized bed granulator. Granulation was performed while spraying a binder solution prepared by dissolving an acidic substance in an aqueous ethanol solution. The mixture was then fluidized bed dried and sieved to obtain granules. The granules were mixed with a flow agent and a lubricant, and the mixture was filled into HPMC capsules (size 1).

[0088] [Process D] The active ingredient and excipients were mixed, and the mixture was placed in a fluidized bed granulator. Granulation was carried out while spraying a binder solution prepared by dissolving a binder and an acidic substance in an aqueous ethanol solution. The mixture was then fluidized bed dried and sieved to obtain granules. The granules were mixed with a fluidizer and a lubricant, and the mixture was filled into HPMC capsules (size 1).

[0089] [Production Method E] The excipients were placed in a fluidized bed granulator. Granulation was carried out while spraying a binder solution prepared by dissolving an acidic substance in an aqueous ethanol solution, followed by fluidized bed drying and sieving to obtain granules. The active ingredient, granules, glidant, and lubricant were mixed, and the mixture was compressed into tablets using a rotary tablet press to obtain tablets.

[0090] [Production Method F] The excipients were placed in a fluidized bed granulator. Granulation was carried out while spraying a binder solution prepared by dissolving an acidic substance in an aqueous ethanol solution, followed by fluidized bed drying and sieving to obtain granules. The active ingredient, granules, flow agent, lubricant, and binder were mixed, and the mixture was compressed into tablets using a rotary tablet press to obtain tablets.

[0091] <Stability Test> When the hydrochloride salt of the compound represented by formula (2) (hereinafter referred to as "compound (2) HCl") is decomposed, the following decomposition products 1 and 2 are generated.

[0092] The stability of the pharmaceutical composition was evaluated by measuring the amount of decomposition product 1 over time by HPLC. The HPLC analysis conditions are as follows. When airtight conditions were adopted in the stability test, aluminum packaging was used.

[0093] [HPLC conditions] Detector: ultraviolet absorptiometer (measurement wavelength: 256 nm) Column: InertSustain AQ-C １８ HP 3 μm, 3.0 × 150 mm (reverse phase C １８ Column) Column temperature: constant temperature around 25°C Mobile phase A: 50 mmol / L ammonium formate buffer (pH 4) Mobile phase B: 50 mmol / L ammonium formate buffer (pH 4): acetonitrile = 1:4 Flow rate: 1.0 ml / min Gradient conditions Time: 0 → 20 Mobile phase A (%): 95 → 0 Mobile phase B (%): 5 → 100

[0094] [Reference Example 1] Pharmaceutical compositions were prepared according to Reference Formulation 1 and Manufacturing Method A in Table 2, and stability tests were carried out under airtight conditions (containing a desiccant) at 60°C and 40°C. The results are shown in Figures 1-1 and 1-2.

[0095] [Examples 1-1 and 1-2] Pharmaceutical compositions were prepared according to Formulations 1-1 and 1-2 and Manufacturing Method B in Table 2, and stability tests were carried out under airtight conditions (containing a desiccant) at 60°C and 40°C. The results are shown in Figures 1-1 and 1-2.

[0096] Comparative Examples 1-1 to 1-3 Pharmaceutical compositions were prepared according to comparative formulations 1-1 to 1-3 and manufacturing method B in Table 2, and stability tests were carried out under airtight conditions (containing a desiccant) at 60° C. and 40° C. The results are shown in Figures 1-1 and 1-2.

[0097]

[0098] [Reference Example 2] A pharmaceutical composition was prepared according to Reference Formulation 2 and Manufacturing Method C in Table 3, and a stability test was carried out under airtight conditions at 40°C. The results are shown in Figure 2.

[0099] [Examples 2-1 and 2-2] Pharmaceutical compositions were prepared according to Formulations 2-1 and 2-2 and Manufacturing Method D in Table 3, and a stability test was carried out under airtight conditions at 40° C. The results are shown in FIG.

[0100] Comparative Examples 2-1 to 2-3 Pharmaceutical compositions were prepared according to comparative formulations 2-1 to 2-3 and manufacturing method D in Table 3, and stability tests were carried out under airtight conditions at 40° C. The results are shown in FIG.

[0101]

[0102] [Reference Example 3] A pharmaceutical composition was prepared according to Reference Formulation 3 and Production Method E in Table 4, and a stability test was carried out under airtight conditions at 40°C. The results are shown in Figure 3.

[0103] [Example 3] A pharmaceutical composition was prepared according to Formulation 3 and Manufacturing Method F in Table 4, and a stability test was carried out under airtight conditions at 40°C. The results are shown in Figure 3.

[0104]

[0105] As can be seen from Figures 1-1, 1-2, and 2, when PVA or HPC was used as the binder, the decomposition of the active ingredient was suppressed compared to when HPMC, MC, or EC was used. This result was surprising because no correlation was observed between the amount of decomposition of the active ingredient and the hygroscopicity of each binder.

[0106] As can be seen from Figure 3, the decomposition of the active ingredient was suppressed even when microcrystalline cellulose was used as a binder. This result was surprising, since Patent Document 1 mentioned above reports that the use of microcrystalline cellulose makes the active ingredient unstable.

[0107] <Tablet hardness test> [Reference Example 4] Using a single punch tablet press with punches and dies coated with magnesium stearate, the contents of the capsules prepared in Reference Example 1 were compressed into tablets, and the hardness was measured. The results are shown in Table 5.

[0108] [Examples 4-1 and 4-2] Using a single punch tablet press with punches and dies coated with magnesium stearate, the contents of the capsules prepared in Examples 1-1 and 1-2 were compressed into tablets, and the hardness was measured. The results are shown in Table 5.

[0109] [Comparative Examples 4-1 to 4-3] Using a single punch tablet press with punches and dies coated with magnesium stearate, the contents of the capsules prepared in Comparative Examples 1-1 to 1-3 were compressed into tablets, and the hardness was measured. The results are shown in Table 5.

[0110]

[0111] [Reference Example 5] The hardness of the tablets prepared in Reference Example 3 was measured. The results are shown in Table 6.

[0112] [Example 5] The hardness of the tablets prepared in Example 3 was measured. The results are shown in Table 6.

[0113]

[0114] As can be seen from Tables 5 and 6, when produced at any tableting pressure, sufficient tablet hardness was not obtained in Reference Example 3, which did not use a binder, but improved hardness was observed in the tablets of Example 3, which did use a binder.

Claims

1. A pharmaceutical composition comprising: an active ingredient having an ester bond; and at least one binder selected from the group consisting of polyvinyl alcohol, hydroxypropyl cellulose, and microcrystalline cellulose, wherein the active ingredient is a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [In the formula, R １ , R ２ , R ３ , and R ４ are each independently a hydrogen atom, a nitro group, a halogeno group, a cyano group, a hydroxyl group, a lower alkyl group, or a lower alkoxyl group; R ｘ is an amidino group or a guanidino group, Z is —O(C═O)— or —(C═O)O—, B is an optionally substituted heterocycle, X is an optionally substituted lower alkylene group, an optionally substituted lower alkenylene group, or an optionally substituted lower alkynylene group, Y is a carbonyl group, and A is selected from the following groups: —OR ５ (R ５ is a hydrogen atom or a lower alkyl group); or the following group (1A-1): (In the formula, R ６ and R ７ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or R ６ and R ７ may form, together with the nitrogen atom to which they are attached, a cyclic amino group which may have a substituent.

2. The pharmaceutical composition according to claim 1, wherein the active ingredient is a compound represented by the following formula (2) or (3) or a pharmaceutically acceptable salt thereof:

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

4. The pharmaceutical composition according to claim 1 or 2, further comprising an acidic substance.

5. The pharmaceutical composition according to claim 1 or 2, further comprising a lubricant.

6. The pharmaceutical composition according to claim 1 or 2, which is a pharmaceutical composition for oral administration.

7. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is a tablet or capsule.

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