Pharmaceutical composition

Abstract

Provided is a pharmaceutical composition in which active ingredient dissolvability is maintained even after storage for a certain period of time. This pharmaceutical composition contains: an active ingredient containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof; and at least one disintegrant other than carmellose.　

Description

Pharmaceutical composition

[0001] This disclosure relates to pharmaceutical compositions.

[0002] When a drug is administered, the active ingredient is released from the drug, transforming it into a state where it can be absorbed and / or distributed. A certain concentration of the active ingredient is then delivered to the desired site of action, thereby exerting its efficacy. Designing a formulation that allows the active ingredient to reach the desired concentration quickly after administration ensures that the drug effectively exerts its efficacy.

[0003] Furthermore, when pharmaceuticals are stored for extended periods, the dissolution behavior of the active ingredient may change. Changes in dissolution behavior, particularly a decrease in the dissolution rate of the active ingredient after administration, can lead to problems such as a longer delay before the drug's efficacy is realized. Additionally, a decrease in the dissolution rate of the active ingredient can result in insufficient dissolution of the active ingredient necessary to fully exert the drug's efficacy, potentially leading to a decrease in the drug's effectiveness.

[0004] Patent Document 1 discloses a sustained-release tablet that continuously releases the active ingredient (ambroxol hydrochloride) over a long period of time with a single dose, with the aim of reducing the number of doses per day.

[0005] Patent Document 2 discloses a tablet containing tosufloxacin tosylate, a specific disintegrant, and an acidic amino acid, with the aim of providing a tablet that exhibits rapid dissolution and stable dissolution even after storage.

[0006] Patent No. 5919173 Patent No. 6600084

[0007] This disclosure relates to a pharmaceutical composition that exhibits good dissolution properties for an active ingredient (hereinafter also simply referred to as "active ingredient") containing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, and that can stably maintain good dissolution properties even after storage for a certain period of time. Patent documents 1 and 2 mentioned above do not examine the dissolution properties of an active ingredient containing a compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0008] In order to solve the above problems, the inventors of the present invention have made intensive efforts and found that by using at least one disintegrant other than carmellose, the active ingredient shows good dissolution behavior even after the pharmaceutical composition has been stored for a certain period, and good dissolution properties after administration can be maintained.

[0009] The present disclosure includes the following embodiments. [1] A pharmaceutical composition comprising an active ingredient and at least one disintegrant other than carmellose, 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 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 may together with the nitrogen atom to which they are attached form 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 disintegrant comprises at least one selected from the group consisting of carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate. [4] The pharmaceutical composition according to any one of [1] to [3], wherein the disintegrant comprises at least one selected from the group consisting of carmellose calcium and low-substituted hydroxypropyl cellulose. [5] The pharmaceutical composition according to any one of [1] to [4], wherein, after storing the pharmaceutical composition at 40°C and 75% RH for two months after manufacture, the dissolution rate of the active ingredient 20 minutes after the start of the test is 60% or more when measured using the dissolution test method described in the Japanese Pharmacopoeia (paddle method: 50 rpm, dissolution test solution: Japanese Pharmacopoeia Dissolution Test Solution No. 1 (JP1 Solution)). [6] A pharmaceutical composition according to any one of [1] to [5], wherein, after storing the pharmaceutical composition at 40°C and 75% RH for two months after manufacture, the dissolution rate of the active ingredient 20 minutes after the start of the test is 70% or more when measured using the dissolution test method described in the Japanese Pharmacopoeia (paddle method: 50 rpm, dissolution test solution: Japanese Pharmacopoeia Dissolution Test Solution No. 1 (JP1 Solution)). [7] A pharmaceutical composition according to any one of [1] to [6], further comprising a binder. [8] A pharmaceutical composition according to any one of [1] to [7], further comprising an acidic substance. [9] A pharmaceutical composition according to any one of [1] to [8], further comprising a lubricant.

[10] A pharmaceutical composition according to any one of [1] to [9], wherein the pharmaceutical composition is a tablet.

[11] A pharmaceutical composition according to any one of [1] to

[10] , wherein the pharmaceutically acceptable salt is a hydrochloride salt.

[0010] In pharmaceutical compositions, the elution properties of the active ingredient can be stably maintained even after storage for a certain period of time.

[0011] The results of dissolution tests conducted in reference experiments for the pharmaceutical compositions of formulations T1 to T11 in the initial period after manufacturing are shown. The results of dissolution tests conducted in experimental examples for the pharmaceutical composition of formulation T6 after storage for (1) 2 months at 40°C under airtight conditions (with desiccant) (40°C dry 2M), (2) 2 months at 40°C, 75% RH (40°C open 2M), or (3) 1 month at 60°C under airtight conditions (with desiccant) (60°C dry 1M) are shown together with the results of the dissolution tests conducted in reference experiments for the pharmaceutical composition of formulation T6 in the initial period after manufacturing (T6 initial). The results of dissolution tests conducted on pharmaceutical compositions of formulation T7 after storage in the following conditions: (1) 2 months at 40°C in an airtight container (with desiccant) (40°C dry 2M), (2) 2 months at 40°C and 75% RH (40°C open 2M), or (3) 1 month at 60°C in an airtight container (with desiccant) (60°C dry 1M), are shown together with the results of dissolution tests conducted on pharmaceutical compositions of formulation T7 in the initial stages after manufacturing (T7 initial). The results of dissolution tests conducted on the pharmaceutical composition of formulation T8 after storage in the following conditions: (1) 2 months at 40°C in an airtight container (with desiccant) (40°C dry 2M), (2) 2 months at 40°C and 75% RH (40°C open 2M), or (3) 1 month at 60°C in an airtight container (with desiccant) (60°C dry 1M), are shown together with the results of dissolution tests conducted on the pharmaceutical composition of formulation T8 in the initial period after manufacturing (T8 initial). The results of dissolution tests conducted on the pharmaceutical composition of formulation T9 after storage for (1) 2 months at 40°C in an airtight container (with desiccant) (40°C dry 2M), (2) 2 months at 40°C and 75% RH (40°C open 2M), or (3) 1 month at 60°C in an airtight container (with desiccant) (60°C dry 1M) are shown together with the results of dissolution tests conducted on the pharmaceutical composition of formulation T9 in a reference experiment (T9 initial) after initial storage. The results of dissolution tests conducted on the pharmaceutical composition of formulation T10 after storage for (1) 2 months at 40°C in an airtight container (with desiccant) (40°C dry 2M), (2) 2 months at 40°C and 75% RH (40°C open 2M), or (3) 1 month at 60°C in an airtight container (with desiccant) (60°C dry 1M) are shown together with the results of dissolution tests conducted on the pharmaceutical composition of formulation T10 in a reference experiment (T10 initial) performed early after manufacturing.The results of dissolution tests conducted on the pharmaceutical composition of formulation T11 after storage in the following conditions: (1) 2 months at 40°C in an airtight container (with desiccant) (40°C dry 2M), (2) 2 months at 40°C and 75% RH (40°C open 2M), or (3) 1 month at 60°C in an airtight container (with desiccant) (60°C dry 1M), are shown together with the results of dissolution tests conducted on the pharmaceutical composition of formulation T11 in the initial period after manufacturing (T11 initial). The results of dissolution tests conducted on the pharmaceutical composition of Formulation A2 after storage for (1) 2 months at 40°C in an airtight container (with desiccant) (40°C dry 2M), (2) 2 months at 40°C and 75% RH (40°C open 2M), or (3) 1 month at 60°C in an airtight container (with desiccant) (60°C dry 1M) are shown together with the results of the dissolution test conducted on the pharmaceutical composition of Formulation A2 initially after manufacturing (A2 initial). The results of dissolution tests conducted on pharmaceutical compositions of Formulation A5 after storage in the following conditions: (1) 2 months at 40°C in an airtight container (with desiccant) (40°C dry 2M), (2) 2 months at 40°C and 75% RH (40°C open 2M), or (3) 1 month at 60°C in an airtight container (with desiccant) (60°C dry 1M), are shown together with the results of the dissolution test conducted on the pharmaceutical compositions of Formulation A5 initially after manufacturing (A5 initial). The results of dissolution tests conducted on the pharmaceutical composition of formulation A6 after storage for two months (40°C dry 2M) at (1) 40°C in an airtight container with desiccant, (2) 40°C at 75% RH for two months (40°C open 2M), or (3) 60°C in an airtight container with desiccant for one month (60°C dry 1M) are shown together with the results of the dissolution test conducted on the pharmaceutical composition of formulation A6 initially after manufacturing (A6 initial). The results of dissolution tests conducted on the pharmaceutical composition of formulation A9 after storage for (1) 2 months at 40°C in an airtight container (with desiccant) (40°C dry 2M), (2) 2 months at 40°C and 75% RH (40°C open 2M), or (3) 1 month at 60°C in an airtight container (with desiccant) (60°C dry 1M) are shown together with the results of the dissolution test conducted on the pharmaceutical composition of formulation A9 initially after manufacturing (A9 initial).The dissolution test results of the pharmaceutical composition of Formulation A11 after storage for 2 months under airtight conditions (with desiccant) at 40°C (40°C dry 2M), (2) for 2 months at 40°C and 75% RH (40°C open 2M), or (3) for 1 month under airtight conditions (with desiccant) at 60°C (60°C dry 1M) after production are shown together with the dissolution test results (A11 initial) conducted at the initial stage after production for the pharmaceutical composition of Formulation A11.

[0012] Hereinafter, the embodiments of the present disclosure will be specifically described, but the present disclosure is not limited thereto, and various modifications are possible without departing from the gist thereof.

[0013] <Definition> In this specification, "comprising" means that in addition to the elements explicitly stated to be included, other elements may also be included.

[0014] In this specification, the "lower alkyl group" means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms.

[0015] In this specification, the "lower alkylene group" means a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms.

[0016] In this specification, the "lower alkenylene group" means a linear or branched alkenylene group having 2 to 6 carbon atoms.

[0017] In this specification, the "lower alkynylene group" means a linear or branched alkynylene group having 2 to 6 carbon atoms.

[0018] In this specification, the "lower alkoxyl group" means an alkoxyl group having a lower alkyl group.

[0019] In this specification, the "lower alkylthio group" means an alkylthio group having a lower alkyl group.

[0020] In this specification, the "lower alkoxylcarbonyl group" means a carbonyl group having a lower alkoxyl group.

[0021] <Pharmaceutical Composition> One embodiment of the present disclosure relates to a pharmaceutical composition containing an active ingredient and at least one disintegrant.

[0022] In the pharmaceutical composition according to this embodiment, by using at least one disintegrant, the elution property of the active ingredient from the pharmaceutical composition can be kept good. Also, even when the pharmaceutical composition is administered after being stored for a certain period, good elution property of the active ingredient after administration can be maintained.

[0023] [Active Ingredient] The active ingredient contained in the pharmaceutical composition according to this embodiment includes a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[0024] (R １ and R ２ ) In formula (1), R 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] 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.

[0026] (R ３ and R ４ ) In formula (1), 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.

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

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

[0029] (Z) In formula (1), Z 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 -(C=O)O-, the oxygen atom "O-" is bonded to B in formula (1).

[0030] (B) In formula (1), B is an optionally substituted heterocycle, preferably an optionally substituted 5- to 10-membered monocyclic or bicyclic heterocycle, more preferably an optionally substituted 5- to 10-membered monocyclic or bicyclic aromatic heterocycle, even more preferably an optionally substituted 5- or 6-membered monocyclic aromatic heterocycle, and particularly preferably a thiophene ring. A bicyclic heterocycle, such as a dihydrobenzofuran ring, is also particularly preferred.

[0031] The number of heteroatoms in the heteroring 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 oxygen atoms, sulfur atoms, and nitrogen atoms, more preferably oxygen atoms and / or sulfur atoms, and even more preferably sulfur atoms.

[0033] Examples of substituents on B include halogen groups and lower alkyl groups.

[0034] (X) In formula (1), X is an optionally substituted lower alkylene group, an optionally substituted lower alkenylene group, or an optionally substituted lower alkylylene group.

[0035] In formula (1), X is preferably a lower alkylene group which may have substituents, more preferably an alkylene group having 1 to 4 carbon atoms which may have substituents, even more preferably a branched alkylene group having 4 carbon atoms which may have substituents, and particularly preferably -CH ２ -C(CH ３ ) ２ -. Note that -CH ２ -C(CH ３ ) ２In this case, it is preferable that the carbon atom substituted with two methyl groups is bonded to Y in formula (1).

[0036] Examples of substituents on X include halogen groups and lower alkyl groups.

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

[0038] (A) A in equation (1) is selected from the following bases: -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 Each is independently a hydrogen atom, or a lower alkyl group which may have substituents, or R ６ and R ７ (These may form a cyclic amino group, which may have substituents, together with the nitrogen atom to which they are bonded.)

[0039] In formula (1), A is preferably -OH, or the above group (1A-1) (wherein R ６ is a hydrogen atom, R ７ is a lower alkyl group which may have substituents, preferably an alkyl group having 1 to 3 carbon atoms which may have substituents, more preferably an alkyl group having 1 to 3 carbon atoms which is substituted with a carboxyl group, even more preferably an ethyl group which is substituted with a carboxyl group, and particularly preferably -CH(COOH)-CH ２ It is (COOH), and more preferably -OH.

[0040] R ６ and R ７ Examples of substituents include hydroxyl groups, thiol groups, amino groups, guanidino groups, carboxyl groups, lower alkylthio groups, lower alkoxylcarbonyl groups, carbamoyl groups, optionally substituted aryl groups, and optionally substituted heterocyclic groups.

[0041] R ６ and R ７Examples of substituents on the cyclic amino group formed by the bonding of these groups include hydroxyl groups and carboxyl groups.

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

[0043] The pharmaceutically acceptable salts of the active ingredient in this embodiment are not particularly limited as long as they are usable as pharmaceuticals, but examples include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, and phosphate, and organic salts such as fumarate, maleate, malate, tartrate, citrate, succinate, methanesulfonate, p-toluenesulfonate, lactate, acetate, and palmitate. The pharmaceutically acceptable salt is preferably a hydrochloride salt.

[0044] The active ingredient in this embodiment may form a solvate, such as a hydrate. In this specification, a solvate is defined as a compound represented by the above formula or a pharmaceutically acceptable salt thereof.

[0045] If stereoisomers (e.g., enantiomers, diastereomers) exist for the active ingredient in this embodiment, the individual stereoisomers and mixtures thereof (e.g., racemates) shall be included in the compound represented by the above formula or a pharmaceutically acceptable salt thereof.

[0046] The active ingredients in this embodiment can be synthesized by referring to known methods (for example, the methods described in International Publication No. 2011 / 071048, International Publication No. 2015 / 137407, or International Publication No. 2015 / 137408).

[0047] The active ingredient may be coated with an acidic substance as described below. In this specification, "coating" includes covering the surface of an object and adhering to the surface of an object. Part of the surface of the active ingredient may be coated with an acidic substance, or the entire surface of the active ingredient may be coated with an acidic substance. By coating the active ingredient with an acidic substance, the decomposition of the active ingredient can be suppressed.

[0048] The amount of active ingredient should be a therapeutically effective amount. This therapeutically effective amount can be determined appropriately based on factors such as the type and stage of the disease, the patient's weight and condition, etc.

[0049] The pharmaceutical composition according to this embodiment may further contain additional active ingredients other than the compound represented by formula (1) or its pharmaceutically acceptable salts, to the extent that it does not impair the technical effects of this disclosure. The type and number of additional active ingredients are not limited, and additional active ingredients are selected according to the efficacy and effects of the target pharmaceutical composition.

[0050] [Disintegrant] The pharmaceutical composition according to this embodiment includes at least one disintegrant. The disintegrant has the effect of disintegrating the pharmaceutical composition and / or suppressing the decrease in the dissolution of the active ingredient, thereby stabilizing the dissolution of the active ingredient.

[0051] The type of disintegrant included in the pharmaceutical composition according to this embodiment is not particularly limited and any pharmaceutically acceptable disintegrant is acceptable, but it includes at least one disintegrant other than carmellose (carboxymethylcellulose). Preferably, the disintegrant other than carmellose includes at least one selected from the group consisting of hydroxypropylcellulose, carmellose calcium, sodium starch glycolate, partially pregelatinized starch, and croscarmellose sodium, and more preferably, at least one selected from the group consisting of hydroxypropylcellulose and carmellose calcium. The hydroxypropylcellulose used as a disintegrant is preferably low-substituted hydroxypropylcellulose, which contains, for example, 5.0 to 16% of hydroxypropoxy groups by dry weight.

[0052] The pharmaceutical composition according to this embodiment does not need to contain carmellose as a disintegrant. That is, the pharmaceutical composition according to this embodiment may contain carmellose as an additive other than a disintegrant, but in that case, the disintegrant may be at least one other disintegrant other than carmellose. Preferably, the pharmaceutical composition according to this embodiment does not contain carmellose, sodium starch glycolate, or croscarmellose sodium as a disintegrant.

[0053] The disintegrant may or may not be coated with the acidic substance described below.

[0054] The amount of disintegrant may be 1.0 to 30% by mass based on the total mass of the pharmaceutical composition. The amount may be increased or decreased as appropriate depending on the type of disintegrant described above. For example, amounts such as 2.0 to 30% by mass, 5.0 to 30% by mass, 10 to 30% by mass, 20 to 30% by mass, 1.0 to 20% by mass, 1.0 to 10% by mass, 1.0 to 5.0% by mass, 1.5 to 20% by mass, 1.5 to 5.0% by mass, 2.0 to 5.0% by mass, 3.0 to 5.0% by mass, and 2.0 to 3.0% by mass can be included. Preferably, it is 1.0 to 20% by mass, more preferably 1.5 to 10% by mass, and particularly preferably 2.0 to 5.0% by mass. [Binding agent] The pharmaceutical composition according to this embodiment may further contain a binding agent. The binding agent can suppress the decomposition of the active ingredient and improve the strength of the pharmaceutical composition. Therefore, even when a disintegrant is included, good dissolution properties after administration can be maintained.

[0055] The type of binder is not particularly limited and any pharmaceutically acceptable binder is acceptable. Examples of binders include polyvinyl alcohol, hydroxypropyl cellulose, and microcrystalline cellulose. The binder preferably contains microcrystalline cellulose. When hydroxypropyl cellulose is used as a binder, non-low-substituted hydroxypropyl cellulose is preferred. If the disintegrant contains non-low-substituted hydroxypropyl cellulose, the binder may or may not contain non-low-substituted hydroxypropyl cellulose.

[0056] The amount of binder can be adjusted to suit the manufacturing method of the pharmaceutical composition. While not particularly limited, for example, when manufacturing the pharmaceutical composition using method A described later, 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 manufacturing the pharmaceutical composition using methods B to D described later, 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.

[0057] [Acidic Substances] The pharmaceutical composition according to this embodiment may further contain acidic substances. Acidic substances can suppress the decomposition of the active ingredient.

[0058] 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. If the acidic substance has multiple pKas, the first-stage acid dissociation constant (pKa) is used. １ ) is used as the standard.

[0059] In this specification, the acid dissociation constant (pKa) of an acidic substance may be an experimentally measured acid dissociation constant, 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 Chemical Book, a known database, is given as an example of the acid dissociation constant of an acidic substance. However, those skilled in the art can refer to the said database or use a database or program with equivalent functionality to recognize values ​​recorded as the acid dissociation constant of any acidic substance within the scope of this disclosure. When measuring experimentally, it is preferable to measure according to the measurement conditions described in the above database, including temperature. If the pKa obtained from the database, program, and experiment do not match, the pKa recorded in Chemical Book shall take precedence.

[0060] The acidic substance is preferably fumaric acid (pKa １ : 3.02, pKa ２ It includes at least one selected from the group consisting of (pKa: 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.

[0061] The acidic substance more preferably comprises at least one selected from the group consisting of fumaric acid, succinic acid, adipic acid, aspartic acid, glycine, and benzoic acid, even more preferably comprising fumaric acid and / or succinic acid, and particularly preferably comprising fumaric acid and succinic acid.

[0062] 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 4.0% by mass, based on the total mass of the pharmaceutical composition.

[0063] [Excipients] The pharmaceutical composition according to this embodiment may further contain excipients. Using excipients together with acidic substances facilitates handling during the manufacturing process and efficiently suppresses the decomposition of the active ingredient.

[0064] The type of excipient is not particularly limited and any pharmaceutically acceptable excipient is acceptable. Examples of excipients include lactose monohydrate, anhydrous lactose, croscarmellose sodium, carmellose, magnesium carbonate, mannitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, methacrylic copolymer, calcium carbonate, magnesium oxide, and sodium chloride.

[0065] If the excipient contains croscarmellose sodium, the disintegrant may or may not contain croscarmellose sodium. The excipient may contain carmellose, but in that case, carmellose is not used as a disintegrant, and the disintegrant contains at least one of the above-mentioned disintegrants other than carmellose.

[0066] The excipient may be coated with an acidic substance. In the pharmaceutical composition of this embodiment, at least a portion of the surface of the excipient may be uniformly or unevenly coated with an acidic substance, or the entire surface of the excipient may be uniformly or unevenly 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, thereby suppressing the decomposition of the active ingredient.

[0067] 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.

[0068] In this case, if the disintegrant and excipient include croscarmellose sodium, the pharmaceutical composition according to this embodiment may contain an amount of croscarmellose sodium that does not exceed the upper limit of the total amount of disintegrant and excipient set based on the total mass of the pharmaceutical composition. In that case, it is preferable for a person skilled in the art to adjust the amount of croscarmellose sodium as appropriate within the above-mentioned range for each individual use, set based on the total mass of the pharmaceutical composition.

[0069] [Lubricant] The pharmaceutical composition according to this embodiment may further contain a lubricant. The lubricant can suppress the decomposition of the active ingredient. Since lubricants are usually used to improve the fluidity of pharmaceutical compositions, it is surprising that they can improve the stability of the active ingredient when used together with it.

[0070] Examples of lubricants include magnesium stearate and calcium stearate.

[0071] The amount of 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.

[0072] [Other Components] The pharmaceutical composition according to this embodiment may further contain other components, to the extent that they do not impair the technical effects of the disclosure. Examples of other components vary depending on the dosage form, etc., but include fluidizers (e.g., silicon dioxide), surfactants, suspending agents, emulsifiers, preservatives, colorants, fragrances, sweeteners, flavoring agents, and viscosity modifiers. One or more known components can be used as the above-mentioned other components.

[0073] [Dosage Form] The pharmaceutical composition according to this embodiment can be administered orally or parenterally. Examples of available dosage forms are given below, but the available dosage forms in this disclosure are not limited to these.

[0074] Oral dosage forms include, for example, tablets, pills, granules, powders, capsules, syrups, emulsions, lozenges, oral solutions, and suspensions. Parenteral dosage forms include, for example, injections, infusions, drips, eye drops, enemas, nasal drops, ear drops, ointments, gels, lotions, patches (including tapes or poultices), topical solutions, and suppositories. Oral administration is preferred, preferably in the form of tablets, pills, granules, powders, or capsules, and more preferably tablets.

[0075] [Uses] The pharmaceutical composition according to this embodiment can be used to treat diseases or alleviate symptoms depending on the type of active ingredient. For example, the pharmaceutical composition according to this embodiment can be used to treat fatty liver disease. Here, "treatment" of fatty liver disease includes preventing the onset of fatty liver disease, suppressing the progression of fatty liver disease, alleviating the symptoms of fatty liver disease, and curing fatty liver disease.

[0076] Specific examples of fatty liver disease include non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), metabolic dysfunction-related fatty liver disease (MAFLD or MASLD), metabolic dysfunction-related steatohepatitis (MASH), and fatty liver.

[0077] Furthermore, the pharmaceutical composition according to this embodiment can be used to treat obesity. Here, "treatment" of obesity includes suppressing weight gain, reducing weight, and so on.

[0078] [Dissolution of Active Ingredient] The pharmaceutical composition according to this embodiment exhibits stable dissolution of the active ingredient, and maintains good dissolution even after being stored for a certain period under arbitrary storage conditions after manufacturing. Therefore, even when a pharmaceutical composition that has been stored for a certain period under arbitrary storage conditions after manufacturing is administered, the active ingredient dissolves quickly after administration.

[0079] As for optional storage conditions, temperature and humidity can be adjusted in various ways. For example, when adjusting the temperature, there are no particular restrictions as long as the temperature does not cause the active ingredients to decompose. Examples include the standard temperature (20°C) specified in the Japanese Pharmacopoeia, a cool place (1-15°C), room temperature (1-30°C), ambient temperature (15-25°C), or low temperature (30-40°C). When adjusting the humidity, the relative humidity (RH) can be adjusted to any value from 0% to 100%, such as 40% RH, 50% RH, 60% RH, 70% RH, or 75% RH.

[0080] There are no particular limitations on the storage period as long as the effects of the present invention are achieved, but examples include 1 hour, 6 hours, 24 hours, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, or 1 year from the start of storage.

[0081] For example, when the pharmaceutical composition according to this embodiment is stored at 40°C and 75% RH for two months after manufacture, and then subjected to a dissolution test according to the dissolution test method No. 2 (paddle method) described in the Japanese Pharmacopoeia under the following conditions, the dissolution rate of the active ingredient 20 minutes after the start of the test is 60% or more, preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more. Conditions: Rotation speed: 50 rpm Dissolution test solution: Japanese Pharmacopoeia Dissolution Test Solution No. 1 (JP1 solution, pH 1.2)

[0082] Furthermore, when a similar dissolution test is performed, the dissolution rate of the active ingredient 10 minutes after the start of the test is 30% or more, preferably 40% or more, more preferably 50% or more, even more preferably 60% or more, and even more preferably 70% or more.

[0083] Furthermore, when a similar dissolution test is performed, the dissolution rate of the active ingredient 30 minutes after the start of the test is 80% or more, preferably 90% or more.

[0084] <Method for Manufacturing the Pharmaceutical Composition> The method for manufacturing the above-mentioned pharmaceutical composition is not particularly limited, but examples include the following methods A to D. Method C or method D is preferred in order to suppress the decomposition of the active ingredient. According to method C, the decomposition of the active ingredient can be further suppressed by coating the excipient with an acidic substance. According to method D, the decomposition of the active ingredient can be further suppressed by coating the active ingredient and excipient with an acidic substance. If the active ingredient decomposes, it will not be able to exhibit the desired efficacy and effects even if the dissolution rate is good, so it is preferable to select a manufacturing method that does not decompose the active ingredient in order to maintain the effectiveness of the drug.

[0085] [Manufacturing Method A] A method for producing a pharmaceutical composition, comprising: a mixing step: mixing (preferably by physical mixing) the constituent components of the pharmaceutical composition.

[0086] [Manufacturing Method B] A method for producing a pharmaceutical composition, comprising: a grinding step: grinding together an acidic substance and an excipient (preferably by jet mill grinding); and a mixing step: mixing the ground acidic substance and excipient with the remaining components of the pharmaceutical composition (preferably by physical mixing).

[0087] [Manufacturing Method C] A method for producing a pharmaceutical composition, comprising: a coating step: spraying an acidic substance onto an excipient to obtain an excipient coated with an acidic substance; and a mixing step: mixing (preferably by physical mixing) the excipient coated with an acidic substance with the remaining components of the pharmaceutical composition.

[0088] [Manufacturing Method D] A method for producing a pharmaceutical composition, comprising: a coating step: spraying an acidic substance onto the active ingredient and excipient to obtain the active ingredient and excipient coated with the acidic substance; and a mixing step: mixing (preferably by physical mixing) the active ingredient and excipient coated with the acidic substance with the remaining components of the pharmaceutical composition.

[0089] In manufacturing method C, it is preferable to granulate the acidic substance and excipient (preferably by fluidized bed granulation) simultaneously with the coating step. In manufacturing method D, it is preferable to granulate the acidic substance, active ingredient and excipient (preferably by fluidized bed granulation) simultaneously with the coating step.

[0090] In manufacturing method C or manufacturing method D, when spraying an acidic substance in the coating step, the acidic substance can be dissolved in a suitable medium before spraying. The suitable medium is not particularly limited as long as it can dissolve the acidic substance, but is preferably a solution containing a lower alcohol such as water or ethanol.

[0091] <Pharmaceuticals> One embodiment of the present disclosure relates to a pharmaceutical product in which an amount of the above-mentioned pharmaceutical composition effective for treating a disease or alleviating symptoms according to the type of active ingredient is stored in a suitable container. For example, the pharmaceutical product according to this embodiment is one in which an amount of the above-mentioned pharmaceutical composition effective for treating fatty liver disease or obesity is stored in a suitable container. By storing it in a suitable container, it is possible to reduce the influence of the external environment and suppress the decomposition of the active ingredient.

[0092] The appropriate container is not particularly limited and can be any container that can be used to store pharmaceuticals, but preferably one that can maintain an appropriate airtight seal inside. Examples of such containers include glass or plastic vials, ampoules or bottles, PTP sheets, aluminum packaging, etc. The inside of the container may also be replaced with an inert gas or the like as needed.

[0093] The present disclosure will be described in more detail below using examples and comparative examples, but the technical scope of the present disclosure is not limited thereto.

[0094] <Preparation of Pharmaceutical Compositions> Pharmaceutical compositions were prepared according to the following manufacturing methods a or c, and the formulations T1 to T11, A2, A5, A6, A9, and A11 in Tables 1-1 and 1-2 below. Manufacturing method a corresponds to manufacturing method A described above, and manufacturing method c corresponds to manufacturing method C described above.

[0095] [Manufacturing method a] The components of the pharmaceutical composition were physically mixed, and the mixture was compressed using a rotary tablet press to obtain tablets.

[0096] [Manufacturing method c] The excipient was placed in a fluid bed granulator. Granulation was carried out while spraying a binding solution in which an acidic substance was dissolved in an ethanol aqueous solution, and the mixture was dried in a fluid bed, then sieved to obtain granules. The active ingredient, the granules, and the remaining components of the pharmaceutical composition were mixed, and the mixture was compressed into tablets using a rotary tablet press or a single-shot tablet press to obtain tablets.

[0097] Formulations T1 and T3 were prepared according to method a, and T2, T4-T11, A2, A5, A6, A9, and A11 were prepared according to method c.

[0098] The active ingredient used in prescriptions T1 to T11 is the hydrochloride salt of the compound represented by formula (2) (hereinafter referred to as "compound (2) HCl").

[0099] The active ingredient used in prescriptions A2, A5, A6, A9, and A11 is acetaminophen.

[0100] The acidic substance granules used in formulations T2, T5-T11, A2, A5, A6, A9, and A11 were granules of lactose (78 mg), fumaric acid (4 mg), and succinic acid (4 mg), while the acidic substance granules used in formulation T4 were granules of mannitol (78 mg), fumaric acid (4 mg), and succinic acid (4 mg).

[0101] The disintegrants used in formulations T6-T11, A6, A9, and A11 are as follows: T6, A6: Carmellose; T7, T10: Low-substituted hydroxypropylcellulose (L-HPC); T8: Carmellose calcium; T9, A9: Sodium starch glycolate; T11, A11: Croscarmellose sodium

[0102] The binder used in formulations T5, A5, and T10 is microcrystalline cellulose.

[0103]

[0104] Of the prepared pharmaceutical compositions, formulations T7 to T11 are examples included in the embodiments of this disclosure, while formulations T1 to T6, A2, A5, A6, A9, and A11 are comparative examples.

[0105] <Dissolution Test> Dissolution tests were conducted on the pharmaceutical composition under the following conditions, in accordance with Dissolution Test Method No. 2 (Paddle Method) described in the Japanese Pharmacopoeia. Conditions: Rotation speed: 50 rpm Dissolution test solution: Japanese Pharmacopoeia Dissolution Test Solution No. 1 (JP1 solution, pH 1.2)

[0106] <Example of experimental study: Examination of dissolution properties in the initial period after manufacturing> Dissolution tests were performed on the pharmaceutical compositions of formulations T1 to T11 in the initial period after manufacturing. Here, "initial period after manufacturing" or "initial" refers to samples that were stored and analyzed immediately after manufacturing under conditions of 4°C. The results are shown in Figure 1.

[0107] As shown in Figure 1, the pharmaceutical compositions of formulations T6 to T11, which contain disintegrants, showed better dissolution of the active ingredient in the initial period after manufacturing compared to the pharmaceutical compositions of formulations T1 to T5, which do not contain disintegrants. The pharmaceutical composition of formulation T5, which contains a binder, showed better dissolution than the pharmaceutical compositions of formulations T1 to T4, but its dissolution was lower than that of the pharmaceutical compositions of formulations T6 to T11. The pharmaceutical compositions of formulations T1, T2, and T4 showed almost equivalent dissolution, and the pharmaceutical composition of formulation T3 showed slightly better dissolution than the pharmaceutical compositions of formulations T1, T2, and T4. The pharmaceutical compositions of formulations T7, T8, T10, and T11, which contain low-substituted hydroxypropyl cellulose, carmellose calcium, or croscarmellose sodium as disintegrants, showed particularly good dissolution, showing dissolution of over 80% at 20 minutes from the start of the test. As can be seen from the comparison of the results of the pharmaceutical compositions of formulation T7 and T10, even when a binder (microcrystalline cellulose) was added to the pharmaceutical composition of formulation T7, which had good dissolution, it maintained equivalent or better dissolution.

[0108] <Experimental Example 1: Examination of Dissolution after Storage for a Certain Period> Pharmaceutical compositions were prepared according to formulations T6 to T11 and manufacturing method c in Table 1-2, and dissolution tests were performed after storage for (1) 2 months at 40°C in an airtight container (with desiccant) (40°C dry 2M), (2) 2 months at 40°C and 75% RH (40°C open 2M), or (3) 1 month at 60°C in an airtight container (with desiccant) (60°C dry 1M). The results are shown in Figures 2-1 to 2-6. The initial values ​​in Figures 2-1 to 2-6 represent the dissolution test results for formulations T6 to T11 in the initial post-manufacturing period (before storage) obtained in the reference experimental example.

[0109] As shown in Figure 2-1, the pharmaceutical composition of formulation T6, which contains carmellose as a disintegrant, showed a decrease in the dissolution of the active ingredient after a certain period of storage under any of the above conditions (1) to (3), compared to the initial state after manufacturing. In particular, the dissolution decreased significantly after storage at 40°C and 75% RH for two months (40°C open 2M). Furthermore, as shown in Figures 2-4 and 2-6, the pharmaceutical compositions of formulations T9 and T11, which contain sodium starch glycolate or croscarmellose sodium as a disintegrant, showed dissolution close to the initial state after storage at 40°C in an airtight condition (with desiccant) for two months (40°C dry 2M) or at 60°C in an airtight condition (with desiccant) for one month (60°C dry 1M), but the dissolution decreased significantly after storage at 40°C and 75% RH for two months (40°C open 2M). On the other hand, as shown in Figure 2-3, the pharmaceutical composition of formulation T8, which contains carmellose calcium as a disintegrant, showed only a slight decrease in dissolution after 20 minutes from the start of the test after storage at 40°C and 75% RH for 2 months (40°C open 2M), and under other storage conditions, the dissolution did not decrease at all after storage. Furthermore, as shown in Figures 2-2 and 2-5, the pharmaceutical compositions of formulations T7 and T10, which contain low-substituted hydroxypropyl cellulose as a disintegrant, showed almost no decrease in dissolution after storage for a certain period under any of the above conditions (1) to (3).

[0110] As can be seen from the comparison of the results for the pharmaceutical compositions of formulation T7 and formulation T10 shown in Figures 1, 2-2, and 2-5, the pharmaceutical composition of formulation T7, which had good dissolution properties in the initial period after manufacturing (before storage), surprisingly did not experience a decrease in dissolution properties even after storage for a certain period. Furthermore, even when a binder (microcrystalline cellulose) was added to the pharmaceutical composition of formulation T7, the dissolution properties did not decrease even after storage for a certain period.

[0111] <Experimental Example 2: Examination of Differences in Dissolution Properties Depending on the Active Ingredient> Pharmaceutical compositions were prepared according to formulations A2, A5, A6, A9, A11 and manufacturing method c in Tables 1-1 and 1-2, and dissolution tests were performed on each in the initial post-manufacturing period. Here, the initial post-manufacturing dissolution tests were performed using samples stored at 4°C immediately after manufacturing, as in the reference experimental example above. Dissolution tests were also performed after (1) storage for 2 months under airtight conditions (with desiccant) at 40°C (40°C dry 2M), (2) storage for 2 months at 40°C and 75% RH (40°C open 2M), or (3) storage for 1 month under airtight conditions (with desiccant) at 60°C (60°C dry 1M). The results are shown in Figures 3-1 to 3-5.

[0112] As shown in Figures 3-1 and 3-2, the pharmaceutical compositions A2 and A5, which contain acetaminophen as the active ingredient and do not contain a disintegrant, showed a decrease in the dissolution rate of the active ingredient after a certain period of storage compared to the initial state after manufacturing. The decrease in dissolution rate was particularly significant after storage at 40°C, 75% RH for two months (40°C open 2M) or at 60°C under airtight conditions (with desiccant) for one month (60°C dry 1M).

[0113] As shown in Figures 3-3 to 3-5, the pharmaceutical compositions of formulations A6, A9, and A11, which contain acetaminophen as the active ingredient and carmellose, sodium starch glycolate, or croscarmellose sodium as disintegrants, showed no change in the dissolution of the active ingredient after a certain period of storage, regardless of storage conditions, compared to the dissolution at the initial stage (before storage). More specifically, as shown in Figure 3-3, the pharmaceutical composition of formulation A6 showed low dissolution of the active ingredient for the first 5 to 15 minutes after the start of the test after being stored at 40°C and 75% RH for two months (40°C open 2M), but after 20 minutes from the start of the test, it was the same as the dissolution at the initial stage. Even when the pharmaceutical composition of formulation A6 was stored for a certain period under other conditions, no decrease in the dissolution of the active ingredient compared to the initial stage was observed after 20 minutes from the start of the test. As shown in Figure 3-4, the pharmaceutical composition of formulation A9 showed almost the same active ingredient dissolution behavior as immediately after manufacturing, even after being stored for a certain period, except that the dissolution was slightly lower for the first 5 minutes after the start of the test, except that the dissolution was slightly lower for the first 5 minutes after the start of the test. As shown in Figure 3-5, the pharmaceutical composition of formulation A11 did not show any decrease in the dissolution of the active ingredient compared to immediately after manufacturing after being stored for a certain period, under any of the above conditions (1) to (3). Thus, the dissolution behavior of the active ingredient (acetaminophen) shown in Figures 3-3 to 3-5 differed from the dissolution behavior of the active ingredient (compound (2) HCl) of the pharmaceutical compositions shown in Figures 2-1 to 2-6, which showed a decrease in dissolution after being stored for a certain period. From these results, it was found that the phenomenon of decreased dissolution of the active ingredient after being stored for a certain period is a phenomenon specific to the active ingredient.

[0114] Furthermore, comparisons of the results for the pharmaceutical compositions of formulations T9 and A9 shown in Figures 2-4 and 3-4, and comparisons of the results for the pharmaceutical compositions of formulations T11 and A11 shown in Figures 2-6 and 3-5, confirmed that the decrease in dissolution after storage for a certain period under specific conditions was not observed when the active ingredient was acetaminophen, but was observed when the active ingredient was a compound represented by formula (1), which is an example of compound (2)HCl, or a salt thereof, and that this is a phenomenon specific to the active ingredient.

[0115] Furthermore, when comparing the results of the pharmaceutical compositions T6 and A6 shown in Figures 2-1 and 3-3, it was confirmed that the phenomenon of decreased elution of the active ingredient in pharmaceutical compositions containing carmellose as a disintegrant after a certain period of storage was not observed when the active ingredient was acetaminophen, but was observed when the active ingredient was a compound represented by formula (1), which is an example of compound (2) HCl, or a salt thereof, and that this is a phenomenon specific to the active ingredient.

Claims

1. A pharmaceutical composition comprising an active ingredient and at least one disintegrant other than carmellose, wherein the active ingredient is a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof. [In the formula, １ R ２ R ３ R ４ and R ｘ 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, ｘ R ５ is an amidino group or a guanidino group, ５ Z is -O(C=O)- or -(C=O)O-, Z is -O(C=O)- or -(C=O)O-, B is a heterocycle which may have a substituent, 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, 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, Y is a carbonyl group, A is selected from the following groups: A is selected from the following groups: ６ R ７ ・ -OR ６ R ７ (R ５ is a hydrogen atom or a lower alkyl group); or is a hydrogen atom or a lower alkyl group); or ・ the following group (1A-1): ・ the following group (1A-1): (In the formula, ６ R ７ and R ７ are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or ６ R ７ and R ７ may together with the nitrogen atom to which they are attached form 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 pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein the disintegrant comprises at least one selected from the group consisting of carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate.

4. The pharmaceutical composition according to claim 1 or 2, wherein the disintegrant comprises at least one selected from the group consisting of carmellose calcium and low-substituted hydroxypropyl cellulose.

5. The pharmaceutical composition according to claim 1 or 2, wherein, after storing the pharmaceutical composition at 40°C and 75% RH for two months after manufacture, the dissolution rate of the active ingredient 20 minutes after the start of the test is 60% or more when measured using the dissolution test method described in the Japanese Pharmacopoeia (paddle method: 50 rpm, dissolution test solution: Japanese Pharmacopoeia Dissolution Test Solution No. 1 (JP1 Solution)).

6. The pharmaceutical composition according to claim 1 or 2, wherein, after storing the pharmaceutical composition at 40°C and 75% RH for two months after manufacture, the dissolution rate of the active ingredient at 20 minutes after the start of the test is 70% or more when measured using the dissolution test method described in the Japanese Pharmacopoeia (paddle method: 50 rpm, dissolution test solution: Japanese Pharmacopoeia Dissolution Test Solution No. 1 (JP1 Solution)).

7. The pharmaceutical composition according to claim 1 or 2, further comprising a binder.

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

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

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

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

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