WO2025115989A1 - Pharmaceutical composition - Google Patents

Abstract

Provided is a pharmaceutical composition that contains an active ingredient having an ester bond, and an acidic substance.

Description

Pharmaceutical Compositions

The present disclosure relates to pharmaceutical compositions.

This application claims priority to Japanese Patent Application No. 2023-203898, filed on December 1, 2023, the contents of which are incorporated herein by reference.

In order to provide effective and safe pharmaceutical products, it is necessary to guarantee their stability. If there is a problem with the stability of a pharmaceutical product, for example, the active ingredient may decompose, reducing its content and thus its effectiveness, or the decomposition products of the active ingredient may have a negative effect on safety.

Patent Document 1 discloses a pharmaceutical composition for the purpose of improving stability, "containing the active ingredient (R)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetraone and at least one acidic substance having a stronger acidity than the compound of the active ingredient as a stabilizer." Patent Document 2 discloses the same content as Patent Document 1.

Patent Document 3 discloses a pharmaceutical composition containing an alkaloid ether oxime salt and an acidic excipient for the purpose of improving stability.

International Publication No. WO 1999/20276 International Publication No. WO 1999/20277 International Publication No. WO 1994/07493

The present disclosure relates to a pharmaceutical composition in which the stability of an active ingredient having an ester bond is improved.

The use of acidic substances can improve the stability of active ingredients that have ester bonds.

 
［式中、
　Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は、それぞれ独立して、水素原子、ニトロ基、ハロゲノ基、シアノ基、ヒドロキシル基、低級アルキル基、又は低級アルコキシル基であり、
　Ｒ^ｘは、アミジノ基又はグアニジノ基であり、
　Ｚは、－Ｏ（Ｃ＝Ｏ）－又は－（Ｃ＝Ｏ）Ｏ－であり、
　Ｂは、置換基を有してもよいヘテロ環であり、
　Ｘは、置換基を有してもよい低級アルキレン基、置換基を有してもよい低級アルケニレン基、又は置換基を有してもよい低級アルキニレン基であり、
　Ｙは、カルボニル基であり、
　Ａは、以下の基から選択される：
　　・－ＯＲ^５（Ｒ^５は、水素原子、又は低級アルキル基である）；又は
　　・下記基（１Ａ－１）：

 
（式中、
　Ｒ^６及びＲ^７は、それぞれ独立して、水素原子、又は置換基を有してもよい低級アルキル基であるか、又は
　Ｒ^６及びＲ^７は、それらが結合している窒素原子と一緒に、置換基を有してもよい環状アミノ基を形成してもよい）］
［３］
　前記有効成分が、下記式（２）又は下記式（３）で表される化合物又はその医薬上許容される塩である、［１］又は［２］に記載の医薬組成物。

 

 
［４］
　前記医薬上許容される塩が、塩酸塩である、［２］又は［３］に記載の医薬組成物。
［５］
　前記酸性物質が、１．０～６．０のｐＫａを有する、［１］～［４］のいずれかに記載の医薬組成物。
［６］
　前記酸性物質が、フマル酸、コハク酸、アジピン酸、アスパラギン酸、グリシン、安息香酸、クエン酸、酒石酸、乳酸、マレイン酸、及びリンゴ酸からなる群から選択される少なくとも１種を含む、［１］～［５］のいずれかに記載の医薬組成物。
［７］
　前記酸性物質が、フマル酸、コハク酸、アジピン酸、アスパラギン酸、グリシン、及び安息香酸からなる群から選択される少なくとも１種を含む、［１］～［６］のいずれかに記載の医薬組成物。
［８］
　前記酸性物質が、フマル酸及び／又はコハク酸を含む、［１］～［７］のいずれかに記載の医薬組成物。
［９］
　前記酸性物質が、フマル酸及びコハク酸を含む、［１］～［８］のいずれかに記載の医薬組成物。
［１０］
　賦形剤を更に含む、［１］～［９］のいずれかに記載の医薬組成物。
［１１］
　前記賦形剤が、前記酸性物質で被覆されている、［１０］に記載の医薬組成物。
［１２］
　前記賦形剤及び前記有効成分が、前記酸性物質で被覆されている、［１０］又は［１１］に記載の医薬組成物。 The present disclosure includes the following embodiments.
[1]
An active ingredient having an ester bond;
An acidic substance;
13. A pharmaceutical composition comprising:
[2]
The pharmaceutical composition according to [1], 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 each independently represent 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;
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 together with the nitrogen atom to which they are attached may form a cyclic amino group which may have a substituent.
[3]
The pharmaceutical composition according to [1] or [2], 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:

[4]
The pharmaceutical composition according to [2] or [3], wherein the pharma- ceutically acceptable salt is a hydrochloride salt.
[5]
The pharmaceutical composition according to any one of [1] to [4], wherein the acidic substance has a pKa of 1.0 to 6.0.
[6]
The pharmaceutical composition according to any one of [1] to [5], wherein the acidic substance comprises at least one selected from the group consisting of fumaric acid, succinic acid, adipic acid, aspartic acid, glycine, benzoic acid, citric acid, tartaric acid, lactic acid, maleic acid, and malic acid.
[7]
The pharmaceutical composition according to any one of [1] to [6], wherein the acidic substance comprises at least one selected from the group consisting of fumaric acid, succinic acid, adipic acid, aspartic acid, glycine, and benzoic acid.
[8]
The pharmaceutical composition according to any one of [1] to [7], wherein the acidic substance comprises fumaric acid and/or succinic acid.
[9]
The pharmaceutical composition according to any one of [1] to [8], wherein the acidic substance comprises fumaric acid and succinic acid.
[10]
The pharmaceutical composition according to any one of [1] to [9], further comprising an excipient.
[11]
The pharmaceutical composition according to [10], wherein the excipient is coated with the acidic substance.
[12]
The pharmaceutical composition according to [10] or [11], wherein the excipient and the active ingredient are coated with the acidic substance.

　It can improve the stability of active ingredients that have ester bonds.

The results of a stability test of the pharmaceutical composition of Comparative Example 1 (containing no acidic substance) under airtight conditions at 40° C. are shown. The results of a stability test performed on the pharmaceutical composition of Comparative Example 2 (containing no acidic substance) under airtight conditions at 60° C. are shown. The results of stability tests performed under airtight conditions at 40° C. for the pharmaceutical compositions of Example 1-1 (Production Method A; Formulation 1-1), Example 1-2 (Production Method B; Formulation 1-1), and Example 1-3 (Production Method C; Formulation 1-1) are shown below. The results of stability tests performed under airtight conditions at 40° C. for the pharmaceutical compositions of Example 1-4 (Production Method A; Formulation 1-2), Example 1-5 (Production Method B; Formulation 1-2), and Example 1-6 (Production Method C; Formulation 1-2) are shown below. The results of stability tests performed under airtight conditions at 40° C. for the pharmaceutical compositions of Example 2-1 (Production Method A; Formulation 2-1), Example 2-2 (Production Method C; Formulation 2-1), and Example 2-3 (Production Method D; Formulation 2-1) are shown below. The results of stability tests performed under airtight conditions at 40° C. for the pharmaceutical compositions of Example 3-1 (Production Method C; Formulation 3-1), Example 3-2 (Production Method C; Formulation 3-2), and Example 3-3 (Production Method C; Formulation 3-3) are shown below. The results of a stability test performed on the scaled-up pharmaceutical composition of Example 5 (Production Method C; Formulation 3-3) under airtight conditions at 40° C. are shown.

Below, specific embodiments of the present disclosure are described, but the present disclosure is not limited to these, and various modifications are possible without departing from the gist of the disclosure.

<Definition>
In this specification, the word "comprise" means that in addition to the elements explicitly stated to be included, other elements may be included.

In this specification, "lower alkyl group" means a straight-chain, branched-chain, or cyclic alkyl group having 1 to 6 carbon atoms.

In this specification, "lower alkylene group" means a straight-chain, branched-chain, or cyclic alkylene group having 1 to 6 carbon atoms.

In this specification, the term "lower alkenylene group" refers to a straight-chain or branched-chain alkenylene group having 2 to 6 carbon atoms.

In this specification, the term "lower alkynylene group" refers to a straight-chain or branched-chain lower alkynylene group having 2 to 6 carbon atoms.

In this specification, "lower alkoxyl group" means an alkoxyl group having a lower alkyl group.

In this specification, the term "lower alkylthio group" refers to an alkylthio group having a lower alkyl group.

In this specification, the term "lower alkoxycarbonyl group" refers to a carbonyl group having a lower alkoxy group.

Pharmaceutical Compositions
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 an acidic substance.

In the pharmaceutical composition according to this embodiment, the acidic substance can suppress the decomposition of the active ingredient caused by the cleavage of the ester bond.

  [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 pharma- ceutically acceptable salt thereof.

( ^R1 and ^R2 )
In formula (1), R ¹ and R ² each independently represent a hydrogen atom, a nitro group, a halogeno group, a cyano group, a hydroxyl group, a lower alkyl group, or a lower alkoxyl group.

In formula (1), R ¹ and R ² are preferably a hydrogen atom or a halogeno group, and more preferably a hydrogen atom or fluorine.

( ^R3 and ^R4 )
In formula (1), ^R3 and ^R4 each independently represent a hydrogen atom, a nitro group, a halogeno group, a cyano group, a hydroxyl group, a lower alkyl group, or a lower alkoxyl group.

^R3 and ^R4 in formula (1) are preferably a hydrogen atom or a halogeno group, and more preferably a hydrogen atom.

( ^Rx )
^Rx in formula (1) is an amidino group or a guanidino group, and is preferably an amidino group.

(Z)
Z in formula (1) is —O(C═O)— or —(C═O)O—, and is preferably —O(C═O)—.
In addition, 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).

(B)
B in formula (1) 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.

The number of heteroatoms contained in the heterocycle is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

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.

Examples of the substituents for B include halogeno groups and lower alkyl groups.

(X)
X in formula (1) 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.

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 -CH2 _- C( _CH3 ) _2- .
In addition, in —CH ₂ —C(CH ₃ ) ₂ —, the carbon atom substituted with two methyl groups is preferably bonded to Y in formula (1).

Examples of the substituent for X include a halogeno group and a lower alkyl group.

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

 
（式中、
　Ｒ^６及びＲ^７は、それぞれ独立して、水素原子、又は置換基を有してもよい低級アルキル基であるか、又は
　Ｒ^６及びＲ^７は、それらが結合している窒素原子と一緒に、置換基を有してもよい環状アミノ基を形成してもよい）。 (A)
In formula (1), 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,
^R6 and ^R7 are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or ^R6 and ^R7 may together with the nitrogen atom to which they are attached form a cyclic amino group which may have a substituent.

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, and particularly preferably -CH(COOH)-CH ₂ (COOH)), more preferably -OH.

Examples of the substituents of ^R6 and ^R7 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.

Substituents for the cyclic amino group formed by combining ^R6 and ^R7 include, for example, a hydroxyl group and a carboxyl group.

 

  The active ingredient in this embodiment is preferably a compound represented by the following formula (2) or (3) or a pharma- ceutically acceptable salt thereof.

The pharma- ceutically acceptable salt of the active ingredient in this embodiment is not particularly limited as long as it can be used as a medicine, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, and phosphate, and organic acid salts such as fumarate, maleate, malate, tartrate, citrate, succinate, methanesulfonate, p-toluenesulfonate, lactate, acetate, and palmitate. The pharma-ceutically acceptable salt is preferably hydrochloride.

The active ingredient in this embodiment may form a solvate such as a hydrate. In this specification, solvates are included in the compound represented by the above formula or a pharma- ceutically acceptable salt thereof.

In the present embodiment, when the active ingredient has stereoisomers (e.g., enantiomers, diastereomers), the individual stereoisomers and mixtures thereof (e.g., racemates) are included in the compound represented by the above formula or a pharma- ceutically acceptable salt thereof.

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

The active ingredient is preferably 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.

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

[Acidic substances]
The pharmaceutical composition according to this embodiment contains an acidic substance, which can suppress the decomposition of the active ingredient.

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 an acidic substance has multiple pKa values, the first stage acid dissociation constant (pKa ₁ ) is used as the reference.

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, the pKa recorded in the Chemical Book, which is a known database of acid dissociation constants of acidic substances, is exemplified, but a person skilled in the art can recognize the value recorded as the acid dissociation constant of any acidic substance as the range of this disclosure by referring to the database or using a database or program having an equivalent function. In addition, when measuring experimentally, it is preferable to measure according to the measurement conditions described in the above database, including temperature, etc. In addition, if the pKa obtained from the database, program, and experiment do not match, the pKa described in the Chemical Book takes precedence.

The acidic substance preferably includes at least one selected from the group consisting of fumaric acid (pKa ₁ : 3.02, pKa ₂ : 4.38), succinic acid (pKa: 4.16), adipic acid (pKa: 4.43), aspartic acid (pKa: 1.99), glycine (pKa: 2.35), benzoic acid (pKa: 4.19), 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 their salts, acid anhydrides, and solvates.

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

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.

[Excipients]
The pharmaceutical composition according to the present embodiment may further include an excipient. By using an excipient together with an acidic substance, handling during the manufacturing process can be facilitated and decomposition of the active ingredient can be more efficiently suppressed.

The type of excipient is not particularly limited, and any medicamentically acceptable excipient may be used. Examples of excipients 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.

The excipient is preferably coated with an acidic substance. In this specification, "coating" includes covering the surface of an object and adhering to the surface of an object. In the pharmaceutical composition of this embodiment, at least a portion of the surface of the excipient may be uniformly or non-uniformly coated with an acidic substance, or the entire surface of the excipient may be uniformly or non-uniformly coated with an 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, and decomposition of the active ingredient can be further suppressed.

The amount of 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.

[Other ingredients]
The pharmaceutical composition according to the present embodiment may further contain other ingredients within the scope of not impairing the technical effects of the present disclosure. The other ingredients vary depending on the dosage form, etc., and include, for example, a flow agent (e.g., silicon dioxide), a disintegrant, a surfactant, a suspending agent, an emulsifier, a preservative, a colorant, an aroma, a sweetener, a flavoring agent, and a thickener. As the other ingredients, one or more of known ingredients can be appropriately used in combination.

[Dosage form]
The pharmaceutical composition according to the present embodiment can be administered orally or parenterally. For example, the dosage form for oral administration includes tablets, pills, granules, powders, capsules, syrups, emulsions, and suspensions. For example, the dosage form for parenteral administration includes injections, infusions, drops, eye drops, and suppositories. Oral administration is preferred, and more preferably, tablets, pills, granules, powders, or capsules.

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

Specific examples of fatty liver disease include nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metabolically associated fatty liver disease (MAFLD or MASLD), metabolically associated steatohepatitis (MASH), and fatty liver.

<Method of producing pharmaceutical composition>
The method for producing the above-mentioned pharmaceutical composition is not particularly limited, and examples thereof include the following Production Methods A to D. In order to further suppress the decomposition of the active ingredient, Production Method C or Production Method D is preferred. According to Production Method C, the excipient is coated with an acidic substance, thereby further suppressing the decomposition of the active ingredient. According to Production Method D, the active ingredient and excipient are coated with an acidic substance, thereby further suppressing the decomposition of the active ingredient.

[Production Method A]
Mixing step: mixing (preferably physically mixing) the components of the pharmaceutical composition;
A method for producing a pharmaceutical composition comprising the steps of:

[Production method B]
A grinding step: grinding (preferably jet mill grinding) the acidic substance and the excipient together; and A mixing step: mixing (preferably physical mixing) the ground acidic substance and the excipient with the remaining components of the pharmaceutical composition.
A method for producing a pharmaceutical composition comprising:

[Production method C]
Coating step: spraying an acidic substance onto an excipient to obtain an excipient coated with the acidic substance;
Mixing step: mixing (preferably physically mixing) the excipient coated with the acidic substance with the remaining components of the pharmaceutical composition;
A method for producing a pharmaceutical composition comprising:

[Production Method D]
Coating step: spraying an acidic substance onto an active ingredient and an excipient to obtain an active ingredient and an excipient coated with the acidic substance;
Mixing step: mixing (preferably physically mixing) the active ingredient and excipients coated with an acidic substance with the remaining components of the pharmaceutical composition;
A method for producing a pharmaceutical composition comprising:

In the preparation method C, it is preferable to carry out granulation (preferably fluidized bed granulation) of the acidic substance and excipient simultaneously with the coating step.
In the process D, it is preferable to carry out granulation (preferably fluidized bed granulation) of the acidic substance, active ingredient and excipient simultaneously with the coating step.

When spraying an acidic substance in the coating step in manufacturing method C or manufacturing method D, the acidic substance can be dissolved in a suitable medium and sprayed. There are no particular limitations on the suitable medium as long as it is capable of dissolving the acidic substance, but preferred are water and solutions containing lower alcohols such as ethanol.

<Drugs>
One embodiment of the present disclosure relates to a pharmaceutical product comprising the above-mentioned pharmaceutical composition in an amount effective for treating fatty liver disease, stored in a suitable container. By storing the pharmaceutical composition in a suitable container, the pharmaceutical product is less susceptible to the influence of the environment outside the container, and decomposition of the active ingredient can be further suppressed.

There are no particular limitations on suitable containers, and any container that can be used to store pharmaceuticals may be used, but preferably the container is one 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 atmosphere inside the container may be replaced with an inert gas, etc., if necessary.

The present disclosure will be explained in more detail below using examples and comparative examples, but the technical scope of the present disclosure is not limited to these.

Preparation of Pharmaceutical Compositions
Pharmaceutical compositions were prepared according to the following methods A to D and the formulations in the table below.

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

[Production method B]
The acidic material and excipients were jet milled together and then physically mixed with the remaining components of the pharmaceutical composition.

[Production method C]
The acidic substance was sprayed onto the excipients and fluid-bed granulated, and then physically mixed with the remaining components of the pharmaceutical composition.

[Production Method D]
The acidic substance was sprayed onto the active ingredient and excipients, fluidized bed granulated, and then physically mixed with the remaining components of the pharmaceutical composition.

  <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.

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

[HPLC conditions]
Detector: UV spectrophotometer (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: 1.0ml/min
Gradient conditions Time: 0→20
Mobile phase A (%): 95→0
Mobile phase B (%): 5 → 100

[Comparative Example 1]
A pharmaceutical composition was 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.

  [Comparative Example 2]
A pharmaceutical composition was 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 FIG.

[Examples 1-1 to 1-6: Study of manufacturing method 1]
Pharmaceutical compositions were prepared according to Tables 2-1 and 2-2, and stability tests were conducted under airtight conditions (with a desiccant) at 40°C. The results of Examples 1-1 to 1-3 are shown in Figure 2-1. The results of Examples 1-4 to 1-6 are shown in Figure 2-2. Compared to Comparative Example 1, the stability of Examples 1-1 to 1-3 was improved regardless of the manufacturing method, and the stability of Examples 1-4 to 1-6 was maintained or improved.

 

 

 

 

[Examples 2-1 to 2-3: Study of manufacturing method 2]
Pharmaceutical compositions were prepared according to Tables 3-1 and 3-2, and stability tests were carried out under airtight conditions (containing a desiccant) at 40°C. The results are shown in Figure 3. The pharmaceutical compositions prepared by either manufacturing method showed the same or higher level of stability improvement effect compared to Comparative Example 1.

 

 

 

 

[Examples 3-1 to 3-3: Examination of acidic substances 1]
Pharmaceutical compositions were prepared according to Tables 4-1 and 4-2, and stability tests were carried out under airtight conditions (with a desiccant) at 40° C. The results are shown in Figure 4. Example 3-3, which used a combination of two types of acidic substances, showed improved stability compared to Examples 3-1 and 3-2, which used one type of each.

 

 

 

 

[Examples 4-1 to 4-16: Examination of acidic substances 2]
A pharmaceutical composition was prepared by mixing the formulation in Table 5-1 (type of acidic substance is shown in Table 5-2) in a mortar, and then sealed in a glass vial. A stability test was conducted for one month under three storage conditions (4°C, airtight condition; 60°C, airtight condition; and 60°C, open condition). As a reference example, a stability test was also conducted on the active ingredient alone (without acidic substance). The results are shown in Table 5-2. The stabilizing effect of compound (2) was also observed when an acidic substance other than those used in Examples 1-1 to 3-3 was used.

 

 

 

 

[Example 5: Study of manufacturing method 3]
A pharmaceutical composition was prepared according to Preparation C. 16.0 kg of a spray liquid (50% ethanol aqueous solution) containing 400 g of fumaric acid and 400 g of succinic acid as acidic substances was prepared and sprayed onto 19.18 kg of an excipient (D-mannitol) to perform fluidized bed granulation. The obtained granules and the remaining components of the pharmaceutical composition were physically mixed in the same manner as in Formulation 3-3. The results of a stability test performed under airtight conditions at 40°C (with a desiccant) are shown in Figure 5. Even when the coating step in Preparation C was scaled up, the stabilization effect of compound (2) when an acidic substance was used was at least as good as that in Example 3-3.

Claims (12)

An active ingredient having an ester bond;
An acidic substance;
13. A pharmaceutical composition comprising: The active ingredient is a compound represented by the following formula (1) or a pharma- ceutical acceptable salt thereof:
The pharmaceutical composition of claim 1.

[In the formula,
R ¹ , R ² , R ³ , and R ⁴ each independently represent 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;
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 together with the nitrogen atom to which they are attached may form a cyclic amino group which may have a substituent. The active ingredient is a compound represented by the following formula (2) or the following formula (3) or a pharma- ceutical acceptable salt thereof:
The pharmaceutical composition according to claim 1 or 2.

The pharma- ceutically acceptable salt is a hydrochloride salt.
The pharmaceutical composition according to claim 3. The acidic substance has a pKa of 1.0 to 6.0.
The pharmaceutical composition according to claim 1 or 2. The acidic substance includes at least one selected from the group consisting of fumaric acid, succinic acid, adipic acid, aspartic acid, glycine, benzoic acid, citric acid, tartaric acid, lactic acid, maleic acid, and malic acid.
The pharmaceutical composition according to claim 1 or 2. The acidic substance includes at least one selected from the group consisting of fumaric acid, succinic acid, adipic acid, aspartic acid, glycine, and benzoic acid.
The pharmaceutical composition according to claim 6. The acidic substance includes fumaric acid and/or succinic acid.
The pharmaceutical composition according to claim 7. The acidic substance includes fumaric acid and succinic acid.
The pharmaceutical composition according to claim 8. Further comprising an excipient,
The pharmaceutical composition according to claim 1 or 2. The excipient is coated with the acidic substance.
The pharmaceutical composition according to claim 10. The excipient and the active ingredient are coated with the acidic substance.
The pharmaceutical composition according to claim 10.