Pharmaceutical composition

Abstract

This pharmaceutical composition contains a lubricant and an active ingredient having an ester bond. 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. 2023-203908, filed on December 1, 2023, 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] Patent Document 1 discloses extrusion-spheronized beads containing stavudine, a spheronizing agent, and magnesium stearate for the purpose of improving stability. In Patent Document 1, magnesium stearate is used to suppress hydrolysis of stavudine, which is sensitive to moisture, during the manufacturing process of the beads using water.

[0005] On the other hand, Patent Document 2 states that when producing stable tablets of enalapril maleate, an antihypertensive drug, if a cellulose compound or magnesium stearate is contained in the tablet composition as a formulation additive, the storage stability of enalapril deteriorates, and therefore excludes the compound from the tablet composition.

[0006] International Publication No. 2001 / 74329 Japanese Patent Application Laid-Open No. 2000-264843

[0007] The present disclosure relates to pharmaceutical compositions with improved stability of active ingredients having ester bonds.

[0008] The use of a lubricant can improve the stability of an active ingredient having an ester bond.

[0009] The present disclosure includes the following embodiments: [1] A pharmaceutical composition comprising: an active ingredient having an ester bond; and a lubricant, wherein the active ingredient is a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof: [In the formula, R １ , R２ , 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 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], wherein the lubricant comprises magnesium stearate and / or calcium stearate. [5] The pharmaceutical composition according to any one of [1] to [4], further comprising an acidic substance.

[0010] The stability of active ingredients having an ester bond can be improved.

[0011]

[0033] Figure 1 shows the results of a stability test conducted under airtight conditions at 40°C for the pharmaceutical compositions of Example 1 (with magnesium stearate) and Comparative Example 1 (without magnesium stearate). Figure 2 shows the results of a stability test conducted under airtight conditions at 60°C for the pharmaceutical compositions of Example 2 (with magnesium stearate) and Comparative Example 2 (without magnesium stearate). Figure 3 shows the results of a stability test conducted under airtight conditions at 40°C for the pharmaceutical compositions of Example 3 (with magnesium stearate; Production Method A), Example 4 (with magnesium stearate; Production Method C), Comparative Example 3 (without magnesium stearate; Production Method A), and Comparative Example 4 (without magnesium stearate; Production Method C). Figure 4 shows the results of a stability test conducted under airtight conditions at 60°C for the pharmaceutical compositions of Example 3 (with magnesium stearate; Production Method A), Example 4 (with magnesium stearate; Production Method C), Comparative Example 3 (without magnesium stearate; Production Method A), and Comparative Example 4 (without magnesium stearate; Production Method C).

[0012] 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.

[0013] <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.

[0014] 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.

[0015] 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.

[0016] In the present specification, the term "lower alkenylene group" refers to a straight or branched alkenylene group having 2 to 6 carbon atoms.

[0017] 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.

[0018] As used herein, the term "lower alkoxyl group" refers to an alkoxyl group having a lower alkyl group.

[0019] As used herein, the term "lower alkylthio group" refers to an alkylthio group having a lower alkyl group.

[0020] As used herein, the term "lower alkoxycarbonyl group" refers to a carbonyl group having a lower alkoxy group.

[0021] <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 a lubricant.

[0022] In the pharmaceutical composition according to this embodiment, the lubricant can suppress the decomposition of the active ingredient caused by the cleavage of the ester bond.

[0023] [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:

[0024] (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.

[0025] R in formula (1) １ and R ２ is preferably a hydrogen atom or a halogeno group, more preferably a hydrogen atom or fluorine.

[0026] (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.

[0027] R in formula (1) ３ and R ４ is preferably a hydrogen atom or a halogeno group, more preferably a hydrogen atom.

[0028] (R ｘ ) R in formula (1) ｘ is an amidino group or a guanidino group, preferably an amidino group.

[0029] (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).

[0030] (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.

[0031] The number of heteroatoms contained in the hetero ring is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0032] 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.

[0033] Substituents for B include, for example, a halogeno group and a lower alkyl group.

[0034] (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.

[0035] 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).

[0036] Substituents for X include, for example, a halogeno group and a lower alkyl group.

[0037] (Y) In formula (1), Y is a carbonyl group.

[0038] (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).

[0039] 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.

[0040] R ６ and R ７Examples 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.

[0041] 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.

[0042] The active ingredient in this embodiment is preferably a compound represented by the following formula (2) or (3) or a pharmaceutically acceptable salt thereof.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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).

[0047] 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.

[0048] 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.

[0049] [Lubricant] The pharmaceutical composition according to this embodiment contains 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 when used together with an active ingredient, it improves the stability of the active ingredient.

[0050] Lubricants include, for example, magnesium stearate and calcium stearate.

[0051] 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.

[0052] [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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] [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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] [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.

[0063] [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, and more preferred are tablets, pills, granules, powders, or capsules.

[0064] [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.

[0065] 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.

[0066] <Method for producing pharmaceutical composition> The method for producing the above-mentioned pharmaceutical composition is not particularly limited, and examples thereof include the following methods A to D. [Method A] A method for producing a pharmaceutical composition, comprising: a mixing step: mixing the components of the pharmaceutical composition.

[0067] [Production Method B] A method for producing a pharmaceutical composition, comprising: a grinding step: grinding additives and excipients together (preferably by jet mill grinding); and a mixing step: mixing (preferably by physical mixing) the ground additives and excipients with the remaining components of the pharmaceutical composition (active ingredients, lubricants, etc.).

[0068] [Production Method C] A method for producing a pharmaceutical composition, comprising: a coating step: spraying an additive onto an excipient to obtain an excipient coated with the additive; and a mixing step: mixing (preferably physical mixing) the excipient coated with the additive with the remaining components of the pharmaceutical composition (active ingredient, lubricant, etc.).

[0069] [Production Method D] A method for producing a pharmaceutical composition, comprising: a coating step: spraying an additive onto an active ingredient and an excipient to obtain the active ingredient and excipient coated with the additive; and a mixing step: mixing (preferably physical mixing) the active ingredient and excipient coated with the additive with the remaining components of the pharmaceutical composition (lubricant, etc.).

[0070] In Production Method C or Production Method D, the additives used in the coating step are not particularly limited as long as they are other than the above-mentioned active ingredients or excipients, and for example, lubricants, acidic substances, and other ingredients can be used. When spraying an additive, the additive can be dissolved in a suitable medium and then sprayed. The suitable medium is not particularly limited as long as it can dissolve the additive.

[0071] One embodiment of the present disclosure relates to a pharmaceutical product comprising the above-described pharmaceutical composition in an amount effective for treating fatty liver disease, stored in an appropriate container. By storing the pharmaceutical product in an appropriate container, it is possible to reduce the influence of the environment outside the container and further suppress the decomposition of the active ingredient.

[0072] The suitable container is not particularly limited as long as it can be used to store pharmaceuticals, but is preferably a container that can store pharmaceuticals under suitable airtight conditions. Examples of such containers include glass or plastic vials, ampoules or bottles, PTP sheets, aluminum packaging, etc. Furthermore, the inside of the container may be purged with an inert gas or the like as needed.

[0073] Hereinafter, the present disclosure will be described in more detail using examples and comparative examples, but the technical scope of the present disclosure is not limited thereto.

[0074] <Preparation of Pharmaceutical Compositions> Pharmaceutical compositions were prepared according to the following manufacturing method A or C and the formulations in the table below.

[0075] [Preparation Method A] The components of the pharmaceutical composition were physically mixed.

[0076] [Preparation Method C] The additives were sprayed onto the excipients and fluidized-bed granulated, and then the resulting mixture was physically mixed with the remaining components of the pharmaceutical composition.

[0077] <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.

[0078] 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.

[0079] [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

[0080] [Example 1 and Comparative Example 1] Pharmaceutical compositions were prepared according to the formulation and manufacturing method A in Table 1, and a stability test was carried out under airtight conditions (containing a desiccant) at 40° C. The results are shown in FIG.

[0081] [Example 2 and Comparative Example 2] Pharmaceutical compositions were prepared according to the formulation and manufacturing method A in Table 1, and a stability test was carried out under airtight conditions (containing a desiccant) at 60° C. The results are shown in Figure 1-2.

[0082] [Examples 3 and 4 and Comparative Examples 3 and 4] Pharmaceutical compositions were prepared according to Tables 2-1 and 2-2, and stability tests were carried out under airtight conditions at 40°C or 60°C. The results at 40°C are shown in Figure 2-1, and the results at 60°C are shown in Figure 2-2. The use of magnesium stearate improved the stability of compound (2).

[0083]

[0084]

Claims

1. A pharmaceutical composition comprising: an active ingredient having an ester bond; and a lubricant, wherein the active ingredient is a compound represented by the following formula (1) or a pharma- ceutically 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 a heterocycle which may have a substituent, 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, 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 the following formula (3) or a pharma- ceutically acceptable salt thereof:

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

4. The pharmaceutical composition according to claim 1 or 2, wherein the lubricant comprises magnesium stearate and / or calcium stearate.

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

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