A pharmaceutical composition comprising a diaminopyrimidine derivative or a pharmaceutically acceptable salt thereof, and a method for preparing the same.

Abstract

The present invention provides a pharmaceutical composition comprising (S)—N-(1-(2-((4-amino-3-nitrophenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide, which has activity as a 5-HT4 receptor agonist, or a pharmaceutically acceptable salt thereof, and an acidifying agent, as well as a method for preparing the same.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing a diaminopyrimidine derivative having an activity as a 5-HT4 receptor agonist or a pharmaceutically acceptable salt thereof, and a method for preparing the same.

Background Art

[0002] The diaminopyrimidine derivative of the following formula 1 has the chemical name of (S)-N-(1-(2-((4-amino-3-nitrophenyl)amino)-6-propylpyrimidin-4-yl)pyrrolidin-3-yl)acetamide. The diaminopyrimidine derivative of formula 1 or a pharmaceutically acceptable salt thereof (for example, hydrochloride) functions as a 5-HT4 receptor agonist, and thus can be usefully applied to prevent or treat a dysfunction of gastrointestinal motility which is one of gastrointestinal diseases, for example, gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, postoperative ileus, gastric emptying delay, gastric hypoparalysis, pseudo-obstruction, drug-induced delayed transport or diabetic gastroparesis (WO2012 / 115480).

[0003]

Chemical formula

[0004] WO2019 / 221522 discloses an improved method for preparing the diaminopyrimidine derivative of formula 1 or a salt thereof, together with a novel crystal form and a method for preparing the same.

[0005] When a diaminopyrimidine derivative of Formula 1 or a pharmaceutically acceptable salt thereof is incorporated into a composition for oral administration, it may be conceivable to incorporate it into an immediate-release (IR) pharmaceutical composition having an absorption mechanism in which the active ingredient is immediately released in the stomach and then delivered to the small intestine. To incorporate it into such an immediate-release pharmaceutical composition, it is necessary to minimize the effect of altering the pH in the stomach, for example, in relation to food or co-administered drugs (e.g., antacids). The average pH in the stomach under feeding conditions is in the range of pH 3 to pH 5 (i.e., not constant), and may be higher in some individuals. Co-administration of drugs, such as antacids, also increases the pH in the stomach. When drugs affected by the pH environment in the stomach are formulated according to conventional formulation methods, variations in drug release may occur, and therefore, the absorption rate and bioavailability may change. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] WO2012 / 115480 [Patent Document 2] WO2019 / 221522 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] The inventors have found that diaminopyrimidine derivatives of Formula 1 or pharmaceutically acceptable salts thereof exhibit pH-dependent physicochemical properties (e.g., dissolution rate), and are thus significantly affected by changes in gastric pH. The inventors have also found that when the formulation method is carried out using an acidifying agent, the acidifying agent creates a low-pH microenvironment in the stomach during the release of the diaminopyrimidine derivative of Formula 1 or pharmaceutically acceptable salts thereof (e.g., its HCl salt), thereby minimizing the effect of changes in the gastric pH environment. Consequently, it is possible to incorporate these compounds into immediate-release pharmaceutical compositions that provide not only rapid drug release but also rapid and high gastrointestinal absorption rates in various gastric pH environments.

[0008] Therefore, an object of the present invention is to provide a pharmaceutical composition (e.g., an immediate-release pharmaceutical composition) comprising a diaminopyrimidine derivative of formula 1 or a pharmaceutically acceptable salt thereof and an acidifying agent.

[0009] Another object of the present invention is to provide a method for preparing the aforementioned pharmaceutical composition. [Means for solving the problem]

[0010] According to one aspect of the present invention, a pharmaceutical composition is provided comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and an acidifying agent.

[0011] [ka]

[0012] In the pharmaceutical composition of the present invention, the pharmaceutically acceptable salt of the compound of formula 1 may be an acid addition salt of the compound of formula 1, preferably an HCl salt.

[0013] The acidifying agent is selected from the group consisting of citric acid, EDTA, malic acid, and mixtures thereof, and is preferably citric acid. The acidifying agent may preferably be present in an amount ranging from 0.1 to 10 parts by weight per 1 part by weight of the compound of formula 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the acidifying agent is present in an amount of about 1 part by weight per 1 part by weight of the compound of formula 1 or a pharmaceutically acceptable salt thereof.

[0014] The pharmaceutical composition of the present invention may further contain one or more excipients selected from the group consisting of additives, disintegrants, lubricants, and binders. The pharmaceutical composition of the present invention may be an immediate-release pharmaceutical composition, or it may be in the form of an oral solid dosage form selected from the group consisting of powders, granules, pellets, tablets, and capsules.

[0015] According to another aspect of the present invention, a method is provided for preparing a pharmaceutical composition in tablet form, comprising the step of compressing a mixture of a compound of formula 1 or a pharmaceutically acceptable salt thereof, an acidifying agent, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be one or more selected from the group consisting of additives, disintegrants, binders, and lubricants.

[0016] A further aspect of the present invention provides a method for preparing a pharmaceutical composition in tablet form, comprising the steps of (a) preparing granules comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and an acidifying agent, and (b) compressing a mixture of the granules prepared in step (a) and a pharmaceutically acceptable excipient.

[0017] In a method for preparing a pharmaceutical composition of the present invention in tablet form, the granules of step (a) may further contain an additive. In one embodiment, step (a) may be carried out by granulating by spraying an aqueous solution containing the compound of formula 1 or a pharmaceutically acceptable salt thereof and an acidifying agent onto an additive that is fluidized in a fluidized bed granulator. In the above embodiment, the additive may be microcrystalline cellulose. In a method for preparing a pharmaceutical composition of the present invention in tablet form, the pharmaceutically acceptable excipient of step (b) may be one or more selected from the group consisting of additives, disintegrants, binders and lubricants. [Effects of the Invention]

[0018] According to the present invention, it has been found that the diaminopyrimidine derivative of formula 1 or a pharmaceutically acceptable salt thereof exhibits pH-dependent physicochemical properties (e.g., dissolution rate), and thus is significantly affected by changes in gastric pH. Also according to the present invention, when a method of formulating it into an immediate-release pharmaceutical composition using an acidifying agent (preferably citric acid) is implemented, it has been found that the effect of changes in the gastric pH environment on the diaminopyrimidine derivative of formula 1 or a pharmaceutically acceptable salt thereof (e.g., its HCl salt) can be minimized. That is, the immediate-release pharmaceutical composition of the present invention can bring about not only rapid drug release but also a rapid and high gastrointestinal absorption rate in various gastric pH environments.

Brief Description of the Drawings

[0019] [Figure 1] It is a graph showing the results obtained by measuring the dissolution rate at pH 1.2 of the immediate-release tablets prepared in Example 1-1 and the Comparative Example. [Figure 2] It is a graph showing the results obtained by measuring the dissolution rate at pH 4.0 of the immediate-release tablets prepared in Example 1-1 and the Comparative Example. [Figure 3] It is a graph showing the results obtained by measuring the dissolution rate at pH 6.8 of the immediate-release tablets prepared in Example 1-1 and the Comparative Example.

Modes for Carrying Out the Invention

[0020] The present invention provides a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and an acidifying agent.

[0021]

Chemical Formula

[0022] In the pharmaceutical composition of the present invention, the pharmaceutically acceptable salt of the compound of formula 1 may be in various salt forms disclosed in WO2012 / 115480, for example, an inorganic salt, an organic salt, or a metal salt. Examples of inorganic salts include hydrochloride, phosphate, sulfate, and bisulfate. Examples of organic salts include malate, maleate, citrate, fumarate, besylate, cansylate, and edicylate. Examples of metal salts include calcium salt, sodium salt, magnesium salt, strontium salt, and potassium salt. The pharmaceutically acceptable salt of the compound of formula 1 may preferably be an acid addition salt of the compound of formula 1, more preferably an HCl salt (i.e., hydrochloride). The pharmaceutical composition of the present invention may contain, for example, a therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof in the range of 0.03 to 20 mg, preferably 0.05 to 10 mg, per unit formulation (per unit pharmaceutical composition), but not limited to these ranges.

[0023] The present invention has shown that when a formulation method is carried out using an acidifying agent, it is possible to minimize the effect of changes in the gastric pH environment on diaminopyrimidine derivatives of formula 1 or pharmaceutically acceptable salts thereof (e.g., their HCl salts) that exhibit pH-dependent physicochemical properties (e.g., dissolution rate). The acidifying agent can maintain a high dissolution rate of diaminopyrimidine derivatives of formula 1 or pharmaceutically acceptable salts thereof even in high pH environments, for example, at pH 6.8, thereby ensuring not only rapid drug release but also a rapid and high absorption rate in various pH environments.

[0024] The acidifying agent is selected from the group consisting of citric acid, EDTA, malic acid, and mixtures thereof, and is preferably citric acid. The acidifying agent may be present in an amount of 10 parts by weight or less, preferably in the range of 0.1 to 10 parts by weight, and more preferably in the range of 0.5 to 2 parts by weight, per 1 part by weight of the compound of formula 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the acidifying agent is present in an amount of about 1 part by weight per 1 part by weight of the compound of formula 1 or a pharmaceutically acceptable salt thereof. If the amount of acidifying agent exceeds 10 parts by weight per 1 part by weight of the compound of formula 1 or a pharmaceutically acceptable salt thereof, the stability of the resulting pharmaceutical composition may deteriorate. Furthermore, if the amount of acidifying agent is less than 0.1 parts by weight per 1 part by weight of the compound of formula 1 or a pharmaceutically acceptable salt thereof, it may be difficult to minimize the effect of changes in the pH environment in the stomach.

[0025] The pharmaceutical composition of the present invention may further contain, in addition to the compound of Formula 1 or a pharmaceutically acceptable salt thereof and the acidifying agent, one or more excipients selected from the group consisting of additives, disintegrants, lubricants, and binders conventionally used in immediate-release formulations. Examples of additives (or diluents) include, but are not limited to, lactose, microcrystalline cellulose, mannitol, and mixtures thereof. Examples of disintegrants include, but are not limited to, corn starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and mixtures thereof. Examples of binders include, but are not limited to, povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and mixtures thereof. Examples of lubricants include, but are not limited to, silicon dioxide, talc, stearic acid, magnesium stearate, sodium stearyl fumarate, and mixtures thereof. In one embodiment, the pharmaceutical composition of the present invention may further contain microcrystalline cellulose as an additive (or diluent), crospovidone as a disintegrant, and a mixture of silicon dioxide and sodium stearyl fumarate as a lubricant. The excipient may be used in amounts conventionally used in immediate-release formulations, and the amount is not particularly limited.

[0026] The pharmaceutical composition of the present invention may, for example, be an immediate-release pharmaceutical composition. Its dosage form is not particularly limited. For example, the pharmaceutical composition of the present disclosure may be in the form of an oral solid dosage form selected from the group consisting of powders, granules, pellets, tablets and capsules, preferably in the form of tablets.

[0027] The present invention includes, within its scope, methods for preparing the above-mentioned pharmaceutical compositions. That is, the present invention includes, within its scope, methods for preparing immediate-release pharmaceutical compositions selected from the group consisting of powders, granules, pellets, tablets, and capsules. For example, the pharmaceutical compositions of the present invention in the form of powders or capsules may be prepared by mixing an active ingredient (a compound of formula 1 or a pharmaceutically acceptable salt thereof), an acidifying agent, and a pharmaceutically acceptable excipient, or by filling the resulting mixture into capsules. The pharmaceutical compositions of the present invention in the form of granules or pellets may be prepared by granulating or pelletizing the active ingredient (a compound of formula 1 or a pharmaceutically acceptable salt thereof) and an acidifying agent together or separately with a pharmaceutically acceptable excipient.

[0028] For example, the pharmaceutical composition of the present invention in tablet form may be prepared by direct compression or indirect compression. In a method for preparing the pharmaceutical composition of the present invention in tablet form, the pharmaceutically acceptable salt and acidifying agent of the compound of Formula 1 are the same as those described above with respect to the pharmaceutical composition of the present invention.

[0029] The direct compression method may include the step of compressing a mixture of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, an acidifying agent, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be one or more selected from the group consisting of additives, disintegrants, binders, and lubricants. The mixture may be obtained by mixing all the components simultaneously, or by mixing some of the components and then adding the other components. Those skilled in the art can prepare the mixture according to methods conventionally used in the pharmaceutical field based on the disclosure described herein.

[0030] The indirect compression method may include the steps of (a) preparing granules containing the compound of formula 1 or a pharmaceutically acceptable salt thereof and an acidifying agent, and (b) compressing a mixture of the granules prepared in step (a) and a pharmaceutically acceptable excipient.

[0031] In the indirect compression method, the granules of step (a) may further contain additives. The granulation of step (a) may be carried out according to a dry granulation method or a wet granulation method. For example, the wet granulation method may be carried out by preparing a binder solution in which an acidifying agent is dissolved or dispersed, and then kneading the active ingredient and a pharmaceutically acceptable excipient with the binder solution. The present invention has found that the granulation method can be carried out without using a binder (i.e., using only water) by spraying an aqueous solution containing the compound of formula 1 or a pharmaceutically acceptable salt thereof and an acidifying agent onto an additive (or diluent) that is fluidized in a fluidized bed granulator. Thus, in one embodiment, step (a) may be carried out by granulation by spraying an aqueous solution containing the compound of formula 1 or a pharmaceutically acceptable salt thereof and an acidifying agent onto an additive that is fluidized in a fluidized bed granulator. In the above embodiment, the additive (or diluent) may be microcrystalline cellulose.

[0032] In a method for preparing tablets according to an indirect compression method, the pharmaceutically acceptable excipient in step (b) may be one or more selected from the group consisting of additives, disintegrants, binders, and lubricants. If step (a) is carried out using a fluidized bed granulator, the additive (or diluent) used in step (b) may be the same as or different from the additive (or diluent) used in step (a). The weight ratio of the additive (or diluent) used in steps (a) and (b) may be 2 to 5:1, preferably 3 to 4:1, but the weight ratio may vary depending on the type of additive (or diluent) used.

[0033] The present invention is described in further detail with reference to the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0034] In the following examples and experimental cases, "Compound 1" refers to (S)-N-(1-(2-((4-amino-3-nitrophenyl)amino)-6-propylpyrimidine-4-yl)pyrrolidine-3-yl)acetamide hydrochloride. [Examples]

[0035] [Example 1] Preparation of tablets containing an acidifying agent Immediate-release tablets containing compound 1 were prepared according to the components and quantities shown in Table 1. The quantities in Table 1 represent the weight (mg) of each component per unit tablet. Specifically, to prepare the tablets of Examples 1-1 to 1-3, compound 1 and an acidifying agent were dissolved in purified water (at a ratio of approximately 150 ml per 1 mg of compound 1). To prepare the tablets of the comparative examples, compound 1 was dissolved in purified water (at a ratio of approximately 150 ml per 1 mg of compound). Each granulation was carried out by spraying the aqueous solution prepared above onto the fluidized microcrystalline cellulose in a fluidized bed granulator (Glatt, USA) (inlet: 60-70°C, product: 35-40°C, discharge: 30-40°C). The resulting granules were mixed with microcrystalline cellulose, crospovidone, and silicon dioxide, and then further mixed with sodium stearyl fumarate. The resulting mixtures were compressed using a tablet press (XP-1, Korsch) to prepare immediate-release tablets.

[0036] [Table 1]

[0037] [Example 2] Preparation of tablets containing citric acid as an acidifying agent An immediate-release tablet containing Compound 1 was prepared in the same procedure as Example 1-1 according to the components and amounts shown in Table 2. The amounts in Table 2 represent the weight (mg) of each component per unit tablet.

[0038]

Table 2

[0039] Experimental Example 1: Dissolution Test The dissolution tests of the immediate-release tablets prepared in Example 1-1 and the comparative examples were carried out at pH 1.2, pH 4.0 and pH 6.8 according to United States Pharmacopeia Apparatus 1 (basket apparatus). The dissolution media were prepared according to the buffer compositions described in the United States Pharmacopeia. Samples were taken from each dissolution medium at predetermined times, and the amount of Compound 1 in each sample was measured by ultra-high performance liquid chromatography (UPLC) under the following conditions.

[0040] <UPLC Conditions> - Detector: UV-Vis spectrophotometer - Column: ZORBAX Eclipse Plus C18 Rapid Resolution HD (2.1×50 mm, 1.8 μm) - Flow rate: 0.2 mL / min - Injection volume: 5 μL - Mobile phase: Mobile phase A: Ammonium bicarbonate buffer (pH 7.0) Mobile phase B: A mixed solution of acetonitrile and methanol (4 / 1, v / v)

[0041]

Table 3

[0042] The results obtained by conducting the dissolution test as described above are shown in FIGS. 1 to 3. As can be seen from the results of FIGS. 1 to 3, the tablets obtained according to the present invention (that is, the tablets of Example 1-1) showed a high dissolution rate from the start regardless of the pH of the dissolution medium. On the other hand, the tablets of the comparative example showed a significantly low dissolution rate (including the initial dissolution rate) under the condition of pH 6.8. Therefore, the immediate-release tablets obtained according to the present invention can ensure not only rapid drug release but also rapid and high gastrointestinal absorption rate in various gastric pH environments.

[0043] Experimental Example 2: Stability Test The stability test under stress conditions was carried out by putting the immediate-release tablets prepared in Examples 2-1 to 2-6 into HDPE containers (high-density polyethylene bottles), and then storing them for 24 months under the conditions of a temperature of 25 ± 2 °C and a relative humidity of 60 ± 5%. Each sample stored for 24 months was dissolved in a test solution (that is, a solution obtained by mixing 1000 mL of water, 1000 mL of methanol, and 2 mL of trifluoroacetic acid), and then the amount of total decomposition products was determined by ultra-high performance liquid chromatography (UPLC) under the following conditions.

[0044] <UPLC Conditions> - Detector: UV-Vis spectrophotometer - Column: ACQUITY UPLC (registered trademark) HSS T3 (2.1 × 100 mm, 1.8 μm) - Flow rate: 0.3 mL / min - Injection volume: 5 μL - Mobile phase: Mobile phase A: Ammonium bicarbonate buffer (pH 7.0) Mobile phase B: Mixed solution of acetonitrile and methanol (4 / 1, v / v)

[0045]

Table 4

[0046] The results of the stability tests described above are shown in Table 3 below.

[0047] [Table 5]

[0048] As can be seen from the results in Table 3, the amount of decomposition products tends to increase as the ratio of the acidifying agent increases. From the above results, it can be seen that the acidifying agent may be used in an amount of 10 parts by weight or less, preferably 0.1 to 10 parts by weight, more preferably 0.5 to 2 parts by weight, and particularly preferably about 1 part by weight, per 1 part by weight of the compound. The present invention encompasses the following embodiments. (Embodiment 1) A pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and an acidifying agent. [ka] (Embodiment 2) The pharmaceutical composition according to Embodiment 1, wherein the pharmaceutically acceptable salt of the compound of Formula 1 is an acid addition salt of the compound of Formula 1. (Embodiment 3) The pharmaceutical composition according to Embodiment 2, wherein the pharmaceutically acceptable salt of the compound of Formula 1 is the HCl salt of the compound of Formula 1. (Embodiment 4) The pharmaceutical composition according to Embodiment 1, wherein the acidifying agent is selected from the group consisting of citric acid, EDTA, malic acid, and mixtures thereof. (Embodiment 5) The pharmaceutical composition according to Embodiment 4, wherein the acidifying agent is citric acid. (Embodiment 6) The pharmaceutical composition according to Embodiment 1, wherein the acidifying agent is present in an amount ranging from 0.1 to 10 parts by weight relative to 1 part by weight of the compound of Formula 1 or a pharmaceutically acceptable salt thereof. (Embodiment 7) The pharmaceutical composition according to Embodiment 6, wherein the acidifying agent is present in an amount of about 1 part by weight relative to 1 part by weight of the compound of Formula 1 or a pharmaceutically acceptable salt thereof. (Embodiment 8) The pharmaceutical composition according to Embodiment 1, further comprising one or more excipients selected from the group consisting of additives, disintegrants, lubricants, and binders. (Embodiment 9) The pharmaceutical composition according to Embodiment 1, which is an immediate-release pharmaceutical composition. (Embodiment 10) A pharmaceutical composition according to any one of Embodiments 1 to 9, in the form of an oral solid dosage form selected from the group consisting of powders, granules, pellets, tablets, and capsules. (Embodiment 11) A method for preparing a pharmaceutical composition in tablet form, comprising the step of compressing a mixture of a compound of formula 1 or a pharmaceutically acceptable salt thereof, an acidifying agent, and a pharmaceutically acceptable excipient. [ka] (Embodiment 12) A method for preparing a pharmaceutical composition in tablet form, (a) A step of preparing granules containing the compound of formula 1 or a pharmaceutically acceptable salt thereof and an acidifying agent,

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Claims

1. Compounds of formula 1 or their HCl salts: 【Chemistry 1】 A tablet comprising a compound of formula 1 or its HCl salt and the acidifying agent, wherein the compound of formula 1 or its HCl salt and the acidifying agent are present only as granular components within the tablet, the acidifying agent is present in an amount ranging from 0.1 to 10 parts by weight per 1 part by weight of the compound of formula 1 or its HCl salt, the acidifying agent is citric acid, and the tablet is a fast-release tablet.

2. The tablet according to claim 1, wherein the acidifying agent is present in an amount of about 1 part by weight per 1 part by weight of the compound of formula 1 or its HCl salt.

3. The tablet according to claim 1, further comprising one or more excipients selected from the group consisting of additives, disintegrants, lubricants, and binders.

4. A method for preparing tablets, (a) Compounds of formula 1 or their HCl salts: 【Chemistry 2】 and the step of preparing granules containing an acidifying agent, (b) A step of compressing a mixture of the granules prepared in step (a) and a pharmaceutically acceptable excipient. Includes, The method wherein the acidifying agent is present in an amount ranging from 0.1 to 10 parts by weight per 1 part by weight of the compound of formula 1 or its HCl salt, the acidifying agent is citric acid, and the tablet is an immediate-release tablet.

5. The method according to claim 4, wherein the acidifying agent is used in an amount of about 1 part by weight per 1 part by weight of the compound of formula 1 or its HCl salt.

6. The method according to claim 4, wherein the granules of step (a) further comprise an additive.

7. The method according to claim 4, wherein step (a) is carried out by granulating by spraying an aqueous solution containing the compound of formula 1 or its HCl salt and an acidifying agent onto an additive to be fluidized in a fluidized bed granulator.

8. The method according to claim 6 or 7, wherein the additive is microcrystalline cellulose.

9. The method according to claim 4, wherein the pharmaceutically acceptable excipient is one or more selected from the group consisting of additives, disintegrants, binders, and lubricants.

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