Rebamipide crystal polymorphism

Abstract

To provide a novel crystalline polymorph form of rebamipide as a pharmaceutical compound.SOLUTION: The present invention provides a crystalline polymorph form of rebamipide as a pharmaceutical compound. In powder X-ray diffraction measurements using CuKα rays, the crystalline polymorph form shows peaks at least at 5.6±0.3°, 9.8±0.3°, 16.9±0.3°, 19.0±0.3°, 22.6±0.3°, 26.3±0.3°, and 27.0±0.3° in the range of diffraction angle (2θ)=5-35°.SELECTED DRAWING: Figure 1

Description

【Technical Field】 【0001】 The present invention relates to a new crystal polymorph of levamiside, which is a medicinal ingredient of a pharmaceutical composition. 【Background Art】 【0002】 Patent Document 1 discloses wet milling of particles of an organic compound. Here, the organic compound is poorly water-soluble and is used in medicine. Wet milling is performed by kneading a paste of the organic compound immersed in a polyol together with salt particles. The crystal polymorph of the organic compound is maintained before and after wet milling. 【0003】 Patent Document 2 discloses obtaining an amorphous solid solution of an active pharmaceutical ingredient (API) belonging to Biopharmaceutics Classification System (BCS) Class II. Among them, the API is kneaded with a water-soluble polymer (paragraph 【0023】). The API belonging to BCS Class II is, for example, levamiside (paragraph 0057). Examples of the polymer are poly(vinylpyrrolidone) and hydroxypropyl cellulose (paragraph 【0059】). 【Prior Art Documents】 【Patent Documents】 【0004】 【Patent Document 1】 Japanese Patent No. 5317960 【Patent Document 2】 Japanese Patent Application Laid-Open No. 2018-507180 【Summary of the Invention】 【Problems to be Solved by the Invention】 【0005】 The present invention provides a new crystal polymorph of levamiside, which is a pharmaceutical compound. 【Means for Solving the Problems】 【0006】 [1] A crystalline polymorph of the pharmaceutical compound rebamipide, which exhibits peaks at at least 5.6±0.3°, 9.8±0.3°, 16.9±0.3°, 19.0±0.3°, 22.6±0.3°, 26.3±0.3°, and 27.0±0.3° within the diffraction angle (2θ) = 5 to 35° in powder X-ray diffraction measurements using CuKα rays. [2] The above crystal polymorph, wherein the intensity of each peak is 50% or more of the intensity of the peak at the diffraction angle (2θ) = 22.6°. [3] The peak with diffraction angle (2θ) = 22.6° is the peak with the highest intensity within the range of diffraction angle (2θ), as described above. [4] Rebamipide nanoparticles comprising the above-mentioned crystalline polymorph of rebamipide. [5] The above-mentioned rebamipide microparticles to which one of trehalose, polyvinylpyrrolidone, polysorbate 80, deoxycholic acid, and hydroxypropylcellulose is added. [6] A pharmaceutical composition comprising the above-mentioned rebamipide microparticles. [7] A suspension in which the above-mentioned rebamipide microparticles are dispersed in water. [8] A method for producing the above-mentioned rebamipide nanoparticles, comprising: (a) kneading a slurry in which the raw material of rebamipide and particles of an inorganic salt are dispersed in an organic liquid to newly generate rebamipide nanoparticles from the raw material of rebamipide, wherein the inorganic salt and organic liquid are more water-soluble than rebamipide; and (b) purifying the rebamipide nanoparticles from the slurry by washing with water. [9] The method wherein the organic liquid (i) consists of an organic compound having a molecular weight of 100 to 350, (ii) has a total of two or more functional groups consisting of a hydroxyl group and / or an ester bond, and (iii) has a viscosity of 2 to 150 mPa·s at 60°C.

[10] (a) Rebamipide nanoparticles are newly generated from the rebamipide raw material by kneading a slurry in which the rebamipide raw material and inorganic salt particles are dispersed in an organic liquid, wherein the inorganic salt and organic liquid are more water-soluble than rebamipide, and (b) the rebamipide nanoparticles are purified from the slurry by washing with water. [Effects of the Invention] 【0007】 This invention provides a new crystalline polymorph of the pharmaceutical compound rebamipide. [Brief explanation of the drawing] 【0008】 [Figure 1] Powder X-ray diffraction measurement. [Figure 2] Manufacturing process for rebamipide microparticles. [Modes for carrying out the invention] 【0009】 <Rebamipide molecule> 【0010】 The rebamipide according to this embodiment has a structure represented by the following formula. In the formula, * indicates a chiral center. 【0011】 [ka] 【0012】 The optical isomer of rebamipide according to this embodiment may be the (R)-(+) isomer, the (S)-(-) isomer, a mixture thereof, or a racemic mixture. 【0013】 <Crystal polymorphism> 【0014】 Figure 1 is an example graph showing the results of powder X-ray diffraction measurements of rebamipide according to this embodiment. CuKα rays were used as the X-rays in the measurement. As shown by the solid line, the crystalline polymorphism, or so-called crystalline form, of rebamipide according to this embodiment is in the range of 5 to 35°, and peaks are shown at least around 5.6° for (1), around 9.8° for (3), around 16.9° for (7), around 19.0° for (9), around 22.6° for (10), around 26.3° for (11), and around 27.0° for (12). 【0015】 In FIG. 1, when considering the variation in the measured values, the peaks are expected to be found at 5.6 ± 0.3°, 9.8 ± 0.3°, 16.9 ± 0.3°, 19.0 ± 0.3°, 22.6 ± 0.3°, 26.3 ± 0.3°, and 27.0 ± 0.3°. 【0016】 As shown by the solid line in the graph of FIG. 1, the intensity of each peak is 50% or more of the intensity of the peak at the diffraction angle (2θ) = 22.6° of the (10)th. At this time, the intensity of each peak may also be greater than the intensity of the peak at the diffraction angle (2θ) = 22.6°. In one aspect, the peak at the diffraction angle (2θ) = 22.6° is the peak with the highest intensity within the above range of the diffraction angle (2θ). 【0017】 As shown by the dashed line in the graph of FIG. 1, the original form of levamisole shows peaks in the range of the diffraction angle (2θ) = 5 to 35°, near 8.2° of the (2)nd, between 9.8° of the (3)rd and 12.4 of the (4)th, near 12.4° of the (4)th, near 14.9° of the (6)th, between 17.6° of the (8)th and 19.0° of the (9)th, near 19.0° of the (9)th. Also, peaks are seen between 19.0° of the (9)th and 22.6° of the (11)th, between 22.6° of the (10)th and 26.3° of the (11)th, and between 27° of the (12)th and 30.5° of the (13)th. 【0018】 <Levamisole microparticles> 【0019】 One aspect of this embodiment is particles of levamisole having the above crystal polymorph. Hereinafter, these particles may be referred to as levamisole microparticles. In one aspect, in addition to levamisole, any one of trehalose, polyvinylpyrrolidone, polysorbate 80, deoxycholic acid, and hydroxypropylcellulose is added to the particles. In other aspects, at least one of a resin, a surfactant, and other organic compounds is added in place of or in addition to the above additives. In one aspect, the particles consist only of levamisole. 【0020】 Figure 2 shows the process for producing rebamipide fine particles 16 from the raw material 11 of rebamipide. In one embodiment of this product, the rebamipide fine particles 16 are produced by wet milling including steps (a) and (b), specifically by salt milling. 【0021】 A slurry 15 is prepared as shown in the upper part of Figure 2. In the slurry 15, particulate raw materials 11, particulate inorganic salts 12, and additives 14 are dispersed in the organic liquid 13. The use of additives 14 is optional and is not included in the slurry 15 in other embodiments. From the viewpoint of obtaining the above crystalline polymorphism, the organic liquid 13 is preferably one that has the following characteristics. 【0022】 (i) It consists of an organic compound having a molecular weight of 90 to 350, preferably 100 to 320. (ii) The organic compound has a total of two or more functional groups consisting of a hydroxyl group and / or an ester bond, preferably two to four. Unless otherwise specified, the ester bond represents the characteristic group of a carboxylic acid ester. (iii) The viscosity at 60°C is 2 to 150 mPa·s. 【0023】 Examples of organic compounds that make up organic liquid 13 shown in Figure 2 include 2-ethyl-1,3-hexanediol (16.6 mPa·s), 2,4-diethyl-1,5-pentanediol (67.2 mPa·s), monoacetin (13.7 mPa·s), diacetin (8.2 mPa·s), triacetin (4.1 mPa·s), trippropionine (2.7 mPa·s), triptyline (3.3 mPa·s), and 2-methylpentane. These are -2,4-diol (5.8 mPa·s), 2-butyl-2-ethyl-1,3-propanediol (43.7 mPa·s), 1,5-pentanediol (20.9 mPa·s), 1,6-hexanediol (25.2 mPa·s), 1,2,6-hexanetriol (137.6 mPa·s), triethyl citrate (35.2 mPa·s), and acetyltriethyl citrate (53.7 mPa·s). These organic compounds effectively break down the active ingredient 11. Other organic compounds may be used further as organic liquids. 【0024】 In Figure 2, the viscosity of the organic liquid 13 is 150 mPa·s or less, which suppresses the increase in viscosity of the slurry 15 of rebamipide and inorganic salt 12. This promotes the movement of the inorganic salt 12, causing the raw material 11 to become finely atomized. The grinding of the raw material 11 by the inorganic salt 12 will be described later. The viscosity of the organic liquid 13 can be measured using a conical plate rotational viscometer in accordance with the provisions of JIS Z 8803. An example of a viscometer is the TVE-20L manufactured by Toki Sangyo Co., Ltd. 【0025】 In Figure 2, 5 to 1000 parts by mass, more preferably 5 to 500 parts by mass, and even more preferably 40 to 160 parts by mass of organic liquid 13 are used per 100 parts by mass of raw material 11. The amount of organic liquid 13 may be any of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, and 150 parts by mass. Two or more organic compounds may be used simultaneously. A portion of the raw material 11 may be replaced with an additive. 【0026】 Examples of particulate inorganic salts 12 shown in Figure 2 include sodium chloride, potassium chloride, ammonium chloride, sodium sulfate, magnesium sulfate, potassium sulfate, calcium sulfate, sodium malate, sodium citrate, disodium citrate, sodium dihydrogen citrate, potassium dihydrogen citrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate. Sodium chloride is preferred. Other inorganic salts may also be used. 【0027】 In Figure 2, particulate inorganic salt 12 is preferably used in an amount of 50 to 2000 parts by mass, more preferably 300 to 1500 parts by mass, per 100 parts by mass of the raw material 11. The amount of inorganic salt 12 may also be 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, and 1400 parts by mass. Two or more types of inorganic salts may be used simultaneously. A portion of the mass of the raw material 11 may be replaced with an additive. 【0028】 In one embodiment shown in Figure 2, the additive 14 is a resin, surfactant, and other organic compound. Examples of the additive's action include promoting the micronization of the active ingredient 11 during kneading and suppressing the drying and aggregation of the resulting rebamipide fine particles 16. Examples of organic compounds that can also be used as additive 14 are those listed in the Pharmaceutical Additives Dictionary 2016 (Yakuji Nippo Co., Ltd.), the Pharmaceutical Additives Standards 2018 (Yakuji Nippo Co., Ltd.), and the Food Additives Dictionary Revised Second Edition (Shokuhin Kagaku Shinbunsha). Two or more additives may be used simultaneously. 【0029】 Examples of resins and other organic compounds include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyacrylic acid, carboxovinyl polymer, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, gum arabic, starch, trehalose, monoglyceride stearate, triglyceride stearate, sucrose stearate, paraffin (e.g., liquid paraffin), carnauba wax, hydrogenated oil (e.g., hydrogenated castor oil, unhydrogenated castor oil), stearic acid, stearyl alcohol, and polyethylene glycol. 【0030】 Examples of surfactants and other organic compounds include phospholipids, glycerin fatty acid esters, polyethylene glycol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan monolaurate, polysorbate, sorbitan monooleate, glyceride monostearate, monooxyethylene sorbitan monopalmitate, monooxyethylene sorbitan monostearate, and poly monooleate. These are oxyethylene sorbitan, sorbitan monopalmitate, sodium lauryl sulfate, rhamnolipid, sophorolipid, trehalose lipid, phytoglycolic acid, lipotaicoic acid, corynomicolic acid, ooeru-ringic acid, agaritic acid, sebacic acid, emulsan, kelsan, pullulan, curdlan, dextran, cyclodextrin, acacia gum, tragacanth gum, chitosan, ornithine lipid, cerilipin, surfactin, gramicidin S, lecithin, deoxycholic acid, cholic acid, lithocholic acid, chenodeoxycholic acid, ursodeoxycholic acid, glycyrrhizin, eszin, and quillaja saponin. 【0031】 The slurry 15 is kneaded in step (a) shown in Figure 2. Kneading is performed, for example, by machine. Kneading pulverizes the rebamipide raw material 11 as shown in the middle section. New rebamipide fine particles 16 are generated from the pulverized raw material 11. Examples of machines include kneaders, two-roll mills, three-roll mills, ball mills, attritors, horizontal sand mills, vertical sand mills, fret mills, Huber maulers, and disc blade kneading dispersers. The desired particle size distribution of rebamipide fine particles 16 can be obtained by changing the kneading conditions. The kneading conditions include the temperature of the slurry 15 and the rotation speed of the machine. 【0032】 The average primary particle diameter of the rebamipide fine particles 16 shown in Figure 2 is smaller than the average primary particle diameter of the active ingredient 11. In other words, the particulate active ingredient 11 of rebamipide is milled by collisions with the particulate inorganic salt 12. Milling may also occur due to collisions between the particulate active ingredients 11 of rebamipide. Milling may also cause the corners of the particulate active ingredients 11 to be worn away. 【0033】 The average primary particle diameter of the rebamipide nanoparticles 16 shown in Figure 2 is 1 to 1000 nm, preferably 5 to 300 nm, and more preferably 150 to 300 nm. The average primary particle diameter may also be any of 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, and 290 nm. Rebamipide nanoparticles 16 having an average primary particle diameter of 300 nm or less have high solubility in water. 【0034】 In this specification, the average primary particle diameter is the average particle diameter of primary particles. The average particle diameter is the average of equivalent diameters determined by Stokes diameter, light scattering equivalent diameter, diffusion equivalent diameter, volume sphere equivalent diameter, surface area sphere equivalent diameter, area circle equivalent diameter, perimeter circle equivalent diameter, and other measurement methods. The average particle diameter is preferably the surface area sphere equivalent diameter or the light scattering equivalent diameter, and more preferably the surface area sphere equivalent diameter. The surface area sphere equivalent diameter is measured by the BET method, observation of particle shape by electron microscopy, and other methods. The light scattering equivalent diameter is measured by laser diffraction scattering or dynamic light scattering. 【0035】 In step (a) of the mixing process shown in Figure 2, a transformation of the crystal polymorphism of rebamipide occurs. One possible cause is the regrowth of crystals during mixing. When rebamipide molecules dissolved from the raw material 11 into the organic liquid 13 recrystallize, the crystal polymorphism according to this embodiment may occur. The scientific principle of the transformation of crystal polymorphism is not fully understood. The description herein does not limit the present invention based on the scientific principle of the transformation of crystal polymorphism. 【0036】 The raw material 11 shown in Figure 2 may or may not have some of the novel crystal polymorphs of rebamipide according to this embodiment. Furthermore, the crystal polymorphs that the raw material itself originally possessed may remain in the generated rebamipide nanoparticles 16. The rebamipide nanoparticles 16 having the novel crystal polymorphs according to one aspect of this embodiment can be stored in a more chemically stable state than rebamipide having other crystal polymorphs. 【0037】 In step (b) shown in Figure 2, the rebamipide microparticles 16 are purified from the slurry 15 by washing with water. When preparing the slurry 15 prior to step (a), the inorganic salt 12 and organic liquid 13 are selected to have higher water solubility than rebamipide. This allows for efficient separation of the rebamipide microparticles 16 from the inorganic salt 12 and organic liquid 13 by washing with water in step (b). The additive 14 may be washed away during washing, or it may remain on the surface of the rebamipide microparticles 16. 【0038】 In step (b) shown in Figure 2, the slurry 15 is uniformly mixed with water using a stirring blade, dissolver, homogenizer, and other machinery. The mixture is filtered to separate the water containing the dissolved inorganic salt 12 and organic liquid 13 from the residue containing the rebamipide particles 16. Examples of filtration methods include vacuum filtration, pressure filtration, and ultrafiltration membrane filtration. The residue is washed with water to further wash away the inorganic salt 12 and organic liquid 13 from the rebamipide particles 16. Acetic acid, methanol, or ethanol may be added to the water used for washing. The water used for washing may also be a buffer solution with a predetermined buffer range. 【0039】 After washing in step (b) shown in Figure 2, the rebamipide particles 16 are dried to remove water. Examples of drying methods include vacuum drying, freeze-drying, spray drying, and freeze-spray drying. Freeze-drying, spray drying, and freeze-spray drying are preferred. Drying is carried out at a standard temperature of less than 20°C according to the Japanese Pharmacopoeia, preferably at a cool place of 1 to 15°C according to the Japanese Pharmacopoeia. Using an appropriate drying method keeps the rebamipide chemically stable and prevents secondary aggregation of particles. Alternatively, the aqueous dispersion described later may be prepared from the rebamipide particles 16 in a hydrated state without drying the rebamipide particles 16. 【0040】 In Figure 2, the upper limit of the residual amount of organic liquid 13 in the rebamipide fine particles 16 after washing is preferably 0.3 parts by mass, more preferably 0.25 parts by mass, per 100 parts by mass of the raw material 11. It is also not necessary to remove all of the organic liquid 13. The residual amount of organic liquid 13 suppresses aggregation of the rebamipide fine particles 16. The lower limit of the residual amount is preferably 0.003 parts by mass, more preferably 0.03 parts by mass, per 100 parts by mass of the raw material 11. A portion of the mass of the raw material 11 may be replaced with an additive. 【0041】 The organic compounds constituting the organic liquid 13 shown in Figure 2 preferably do not have hydroxyl groups and have two or more ester bonds. The hydroxyl groups of the organic liquid 13 form hydrogen bonds with the rebamipide microparticles 16. These hydrogen bonds may be involved in the bonding of rebamipide microparticles 16 with other rebamipide microparticles 16. Therefore, the hydroxyl groups of the organic liquid 13 tend to promote aggregation. Among the organic compounds constituting the organic liquid 13 described above, diacetin, triacetin, trippropionine, triptyline, triethyl citrate, and acetyltriethyl citrate are particularly preferred. 【0042】 <Other forms of rebamipide microparticles> 【0043】 Another aspect of this embodiment is rebamipide nanoparticles manufactured according to the above manufacturing process. Preferably, such rebamipide nanoparticles have the novel crystalline polymorph described above. 【0044】 <Pharmaceutical composition> 【0045】 One aspect of this embodiment is a pharmaceutical composition comprising the above levamisole microparticles. One aspect of the pharmaceutical composition is for gastric mucosal protection. In one aspect thereof, the gastric mucosal protection is carried out as part of the prevention or treatment of gastric ulcer. Another aspect of the pharmaceutical composition is an eye drop for the prevention or treatment of dry eye. Another aspect of the pharmaceutical composition is for the prevention or treatment of oral mucosal inflammation. 【0046】 <Aqueous dispersion> 【0047】 One aspect of this embodiment is a dispersion system in which the above levamisole microparticles are dispersed in water, a so-called aqueous dispersion. Examples of pharmaceutical compositions comprising an aqueous dispersion are oral administration solutions, injections, eye drops, ointments, and transdermal absorbents. One aspect of the aqueous dispersion is a water suspension of levamisole microparticles. An example of a pharmaceutical composition comprising a water suspension is an eye drop. In one aspect of this embodiment, the sedimentation in the water suspension is slower than that of particles of levamisole having other crystal polymorphs. 【0048】 The water suspension is preferably prepared by mixing 10 to 1000 parts by mass of water with 1 part by mass of levamisole microparticles. The water may be any of 50, 90, 95, 97, 97.5, 98, 98.5, 99, 99.5, 100, 105, 100 and 200 parts by mass. The mixing is carried out, for example, with a homogenizer, a homomixer, an ultrasonic disperser and a bead mill disperser. The methods of the homogenizer are, for example, ultrasonic type, stirring type and high pressure type. An ultrasonic cleaner may be substituted as the ultrasonic disperser. 【0049】 【0050】 ​As described above, immediately after washing, the rebamipide microparticles contain the washing water. An aqueous dispersion may be prepared by mixing these water-containing rebamipide microparticles with water as a dispersion medium. This method is effective in preventing the particles from aggregating when drying the rebamipide microparticles to remove the washing water. 【0051】 In one embodiment, the aqueous dispersion is further powdered by spray drying, freeze-drying, or freeze-spray drying. Since the powder has excellent redispersibility in water, it is suitably used as an injectable, eye drop, or oral preparation that is prepared immediately before use. 【0052】 The median diameter D50 of secondary particles of rebamipide microparticles in an aqueous dispersion is 400-1000 nm, preferably 430-920 nm, at the start of preparation. It is also 400-1000 nm, preferably 450-920 nm, after incubation at 25°C for 7 days from preparation. The median diameter D50 of secondary particles may be measured by dynamic light scattering (FFT power spectroscopy). 【0053】 The dispersion medium in the aqueous dispersion is a saturated aqueous solution of rebamipide containing rebamipide molecules dissolved from the rebamipide fine particles, which are the dispersed phase. The solubility of rebamipide as a solute in water varies depending on the proportion of novel crystalline polymorphs contained in the rebamipide fine particles. The solubility in water is 50 μg / mL or higher, preferably 200 μg / mL or higher. 【0054】 The solubility of rebamipide microparticles in water may be expressed, for example, as the amount of water required to dissolve rebamipide microparticles equivalent to 1 g of rebamipide (18th edition of the Japanese Pharmacopoeia, General Rule 30). The solubility of rebamipide is less than 1 mL (very soluble), 1 mL or more but less than 10 mL (easily soluble), 10 mL or more but less than 30 mL (somewhat soluble), 30 mL or more but less than 100 mL (somewhat poorly soluble), 100 mL or more but less than 1,000 mL (poorly soluble), or 100 mL or more but less than 10,000 mL (very poorly soluble), or 10,000 mL or more (almost insoluble). Solubility refers to the degree to which rebamipide microparticles dissolve within 30 minutes when placed in water and shaken vigorously for 30 seconds every 5 minutes at 20±5°C (18th edition of the Japanese Pharmacopoeia, General Rule 30). 【0055】 <Other dosage forms> 【0056】 One aspect of this embodiment is a dispersion system in which the above-mentioned rebamipide fine particles are dispersed in an oily dispersion medium. Examples of pharmaceutical compositions comprising this dispersion system are ointments, capsules, and transdermal absorbents. Examples of dispersion media include liquid paraffin, petrolatum, propylene glycol, glycerin, polyethylene glycol, and vegetable oil. Other oils may be used as dispersion media. A dispersion medium consisting of two or more types of oils may also be used. Examples of machines used for dispersion include homogenizers, homomixers, ultrasonic dispersers, two-roll mills, three-roll mills, and disc blade kneading dispersers. [Examples] 【0057】 (Summary) In Examples No. 101-122 and 201, compositions consisting of rebamipide microparticles were prepared by salt milling the raw rebamipide. In Examples No. 123-128 and 202-203, aqueous dispersions were prepared by suspending the compositions in water. The conditions for preparing the compositions and aqueous dispersions will be described later. The method for measuring the physical properties of the rebamipide microparticles is shown below. 【0058】 (Measurement of average primary particle diameter) The average primary particle diameter of levamisole microparticles was measured using a transmission electron microscope (JEM-1200EX manufactured by JEOL Ltd.). The primary particle diameters of all levamisole microparticles in the observation sample at a magnification of 100,000 were measured, and the average value was used. When the particle shape was not spherical, the long diameter and the short diameter were measured, and the value obtained by (long diameter + short diameter) / 2 was taken as the particle diameter. 【0059】 (Measurement of residual water-soluble organic liquid) The organic liquid remaining in the obtained composition was quantified by gas chromatography. The residual amount of the water-soluble organic liquid per 100 parts by mass of levamisole microparticles in the composition was calculated. 【0060】 The conditions of gas chromatography are shown below. · Separation instrument: GC2010 manufactured by Shimadzu Corporation · Column: DM-5MS (30m x 0.25mm x 0.25μm Film, Agilent Technologies) · Carrier gas: He · Pressure: 120.0 kPa · Total flow rate: 50.0 ml / min · Column flow rate: 1.77 ml / min · Linear velocity: 49.0 cm / sec · Purge flow rate: 3.0 ml / min · Column temperature: Held at 80°C for 4 minutes, then heated up in 16 minutes and held at 320°C for 5 minutes Injection mode: Split-less Mode Injection volume: 1 μL 【0061】 The conditions of the mass spectrometer are shown below. · Measuring instrument: GC2010 manufactured by Shimadzu Corporation · Interface temperature: 250°C · Ion source temperature: 200°C · Measurement mode: Scan Mode · Measurement range: m / z = 30 - 500 · Measurement time: 5 - 20 min · Event time: 0.5 sec 【0062】 (Secondary particle size of rebamipide microparticles in aqueous dispersion) The median diameter D50 of secondary particles of rebamipide microparticles in an aqueous dispersion was measured. Measurements were taken at the beginning of preparation and for 7 days after preparation, after incubation at 60% RH relative humidity and 25°C. A particle size distribution analyzer MicrotracUPA manufactured by Nikkiso was used. 【0063】 (Solubility of the composition) To measure the solubility of the composition, the aqueous dispersion was centrifuged at 86,000 rpm using a HITACHI CS150FNX centrifuge. The supernatant was filtered through a PTFE (polytetrafluoroethylene) membrane TITAN3™ with a diameter of 17 mm and a pore size of 0.2 μm. The filtrate was analyzed by HPLC. A Waters ACQUITY UPLC H-Class™ HPLC system was used. 【0064】 (Settling properties of the composition) The settling properties of the composition in an aqueous dispersion were evaluated using the Turviscan® liquid dispersion stability evaluation device. Table 3 shows the results, with 3 indicating almost no precipitation, 2 indicating some precipitation, and 1 indicating a large amount of precipitation. 【0065】 (Powder X-ray diffraction measurement using CuKα rays) 【0066】 Powder X-ray diffraction measurements were performed in accordance with the Japanese Industrial Standard JIS K0131 (General Rules for X-ray Diffraction Analysis), with diffraction angles (2θ) ranging from 3° to 35°. Figure 1 shows an example of the X-ray diffraction diagram (X-ray diffraction pattern). 【0067】 The measurement conditions were as follows: • X-ray diffractometer: RIGAK RINT2100 • Sampling width: 0.02° • Scan speed: 2.0 • Divergence slit: 1° • Divergence vertical limiting slit: 10mm • Scattering slit: 2° • Light-receiving slit: 0.3mm ·Tube: Cu • Tube voltage: 30kV ·Tube current: 30mA 【0068】 Salt milling was performed on the raw material of rebamipide in each of the following examples. 【0069】 {Example No. 101} 100 parts by mass of rebamipide raw material, 1500 parts by mass of sodium chloride, and 160 parts by mass of 2-ethyl-1,3-hexanediol were kneaded in a stainless steel 1-gallon kneader (manufactured by Inoue Seisakusho Co., Ltd.) at 60°C for 15 hours. Next, this mixture was added to 10 liters of water and stirred for 1 hour to form a slurry. The slurry mixture was repeatedly filtered and washed with water to separate the rebamipide fine particles from the sodium chloride and 2-ethyl-1,3-hexanediol. Subsequently, the rebamipide fine particles were freeze-dried to obtain 98 parts by mass of composition M-1. The average primary particle size of the obtained rebamipide fine particles was 240 nm. The amount of residual solvent was 0.050 parts by mass per 100 parts by mass of rebamipide fine particles. 【0070】 {Examples No. 102-122, 201} The mixing conditions, consisting of the amount of rebamipide, the type and amount of organic liquid, the amount of sodium chloride, the type and amount of additives, and the temperature and time, were as shown in Table 1. Compositions M-2 to M-23 were obtained under the same conditions as in Example No. 101. 【0071】 [Table 1] 【0072】 The symbols M-1 to M-23 in the "Composition" column identify the generated rebamipide microparticles. In the "Additives" column, Tre represents trehalose, PVP represents polyvinylpyrrolidone, PS80 represents polysorbate 80 (Tween 80, trademark), DCA represents deoxycholic acid, and HPC represents hydroxypropyl cellulose. The "Residual Liquid" column shows the organic liquid remaining in the obtained composition. Example No. 201 is a comparative example. 【0073】 From examples No. 101 to 201, examples No. 105, 118, and 201 were selected, and powder X-ray diffraction measurements using CuKα radiation were performed on these three compositions. The results are shown in Table 2. 【0074】 [Table 2] 【0075】 For each example, the intensity at diffraction angle (2θ) = 22.6° for (10) was set as 100%, and each value was converted accordingly. The results of the powder X-ray diffraction measurement of the raw material are shown by the dashed line in Figure 1. The results of the powder X-ray diffraction measurement for Example No. 105 are shown by the solid line in Figure 1. In each example, peaks were observed around 5.6°, 9.8°, 16.9°, 19.0°, 22.6°, 26.3°, and 27.0°. 【0076】 <Preparation and Evaluation of Aqueous Dispersions> Next, an aqueous dispersion was prepared using the generated composition. The particle size (D50: 50% median diameter) of the dispersed phase in the obtained aqueous dispersion was measured using a particle size distribution analyzer (MicrotracUPA, manufactured by Nikkiso Co., Ltd.) that uses dynamic light scattering (FFT (Fast Fourier Transform) power spectrum method) as its measurement principle. 【0077】 <Evaluation item: Stability of aqueous dispersion> The prepared aqueous dispersion was stored for 7 days in an environment with a temperature of 25°C and a relative humidity of 60%RH. The stability of the aqueous dispersion was evaluated by measuring the particle size (D50: 50% median diameter) before and after the storage period. 【0078】 <Evaluation item: Solubility of aqueous dispersion> Each component of the prepared aqueous dispersion was centrifuged at 86,000 rpm using a centrifuge (CS150FNX, HIMAC). The centrifugal acceleration was 396,000 G. The supernatant was further filtered through a PTFE filter with a pore size of 0.2 μm to recover the solid content. In parallel, the recovered aqueous dispersion filtrate was analyzed using ultra-high-performance liquid chromatography (UPLC, Waters). In Table 3, a solubility of rebamipide less than 50 μg / mL was marked "1". A solubility of rebamipide between 50 μg / mL and 200 μg / mL was marked "2". A solubility of rebamipide greater than or equal to 200 μg / mL was marked "3". 【0079】 <Evaluation item: Sedimentation evaluation of aqueous dispersion> The prepared aqueous dispersion was placed in a sample bottle and stored for 7 days at a temperature of 25°C and a relative humidity of 60% RH. The precipitate that accumulated at the bottom of the sample bottle was then visually observed. A significant precipitate was rated "1", a slight precipitate was rated "2", and no precipitate was visually observed was rated "3". 【0080】 {Example No. 123} One part by mass of composition M-5, 0.5 parts by mass of hydroxypropyl cellulose, and 98.5 parts by mass of purified water were weighed out and mixed. The mixture was subjected to ultrasonic irradiation for 2 hours using a Sharp Manufacturing Systems UT-105 ultrasonic device. Aqueous dispersion S-1 was obtained as a result. 【0081】 {Example No. 124} One part by mass of composition M-5, 0.5 parts by mass of hydroxypropyl cellulose, and 98.5 parts by mass of purified water were weighed out and mixed. The mixture was homogenized for 2 hours using a stirring homogenizer "Cleamix CLM-0.8S" manufactured by M-Technique. Aqueous dispersion S-2 was obtained as a result. 【0082】 {Example No. 125} One part by mass of composition M-5, 0.5 parts by mass of hydroxypropyl cellulose, and 98.5 parts by mass of purified water were weighed out and mixed. The mixture was subjected to a homogenization treatment at a pressure of 100 MPa 10 times using a high-pressure homogenizer (Starburst Mini) manufactured by Sugino Machine Co., Ltd. Aqueous dispersion S-3 was obtained as a result. 【0083】 {Example No. 126} One part by mass of composition M-5, 0.5 parts by mass of hydroxypropyl cellulose, and 98.5 parts by mass of purified water were weighed and mixed. The mixture was homogenized for 3 hours using zirconia beads with a diameter of 0.5 mm in an Eiger Mill Mini Model M-250 MKII pulverizer manufactured by Eiger Japan Co., Ltd. This yielded aqueous dispersion S-4. The aqueous dispersion S-4 was separated from the zirconia beads by filtering the mixture through a filter with a pore size of 5.0 μm. 【0084】 {Example No. 127} One part by mass of composition M-6, 0.5 parts by mass of hydroxypropyl cellulose, and 98.5 parts by mass of purified water were weighed and mixed. The mixture was homogenized for 3 hours using zirconia beads with a diameter of 0.5 mm in an Eiger Japan pulverizer ("Eiger Mill Mini Model M-250 MKII"). This yielded aqueous dispersion S-5. Subsequently, the aqueous dispersion S-5 was separated from the zirconia beads by filtering the mixture through a filter with a pore size of 5.0 μm. 【0085】 {Example No. 128} One part by mass of composition M-18, 0.5 parts by mass of hydroxypropyl cellulose, and 98.5 parts by mass of purified water were weighed and mixed. The mixture was homogenized for 3 hours using zirconia beads with a diameter of 0.5 mm in an Eiger Mill Mini Model M-250 MKII (manufactured by Eiger Japan Co., Ltd.). This yielded aqueous dispersion S-6. Subsequently, aqueous dispersion S-6 was separated from the zirconia beads by filtration through a filter with a pore size of 5.0 μm. 【0086】 {Example No. 202} One part by mass of composition M-23, 0.5 parts by mass of hydroxypropyl cellulose, and 98.5 parts by mass of purified water were weighed and mixed. The mixture was homogenized for 3 hours using zirconia beads with a diameter of 0.5 mm in an Eiger Japan pulverizer ("Eiger Mill Mini Model M-250 MKII"). This yielded aqueous dispersion S-7. Subsequently, aqueous dispersion S-7 was separated from the zirconia beads by filtration through a filter with a pore size of 5.0 μm. 【0087】 {Example No. 203} One part by weight of composition M-23, 0.5 parts by weight of hydroxypropyl cellulose, and 98.5 parts by weight of purified water were weighed out and mixed. The mixture was subjected to ultrasonic irradiation for 2 hours using a Sharp Manufacturing Systems UT-105 ultrasonic device. This yielded aqueous dispersion S-8. 【0088】 [Table 3] [Explanation of symbols] 【0089】 11. Active ingredient, 12. Inorganic salt, 13. Organic liquid, 14. Additive, 15. Slurry, 16. Rebamipide microparticles

Claims

[Claim 1] A crystalline polymorph of the pharmaceutical compound rebamipide, In powder X-ray diffraction measurements using CuKα rays, peaks were observed at at least 5.6±0.3°, 9.8±0.3°, 16.9±0.3°, 19.0±0.3°, 22.6±0.3°, 26.3±0.3°, and 27.0±0.3° within the diffraction angle (2θ) range of 5 to 35°. Crystal polymorphism. [Claim 2] The intensity of each peak is 50% or more of the intensity of the peak at the diffraction angle (2θ) = 22.6°. The crystalline polymorph described in claim 1. [Claim 3] The peak with a diffraction angle (2θ) = 22.6° is the peak with the highest intensity within the aforementioned range of diffraction angles (2θ). The crystalline polymorph described in claim 2. [Claim 4] A rebamipide having the crystalline polymorph described in claim 1, Rebamipide microparticles. [Claim 5] It contains one of the following additives: trehalose, polyvinylpyrrolidone, polysorbate 80, deoxycholic acid, or hydroxypropyl cellulose. Rebamipide microparticles according to claim 4. [Claim 6] The rebamipide microparticles consist of the rebamipide microparticles described in claim 4 or 5. Pharmaceutical composition. [Claim 7] The rebamipide fine particles according to claim 4 or 5 are dispersed in water. Suspension. [Claim 8] A method for producing rebamipide microparticles according to claim 4 or 5, (a) Rebamipide fine particles are newly generated from the rebamipide raw material by kneading a slurry in which the rebamipide raw material and inorganic salt particles are dispersed in an organic liquid, wherein the inorganic salt and organic liquid have higher water solubility than rebamipide, and the organic liquid is triacetin or glycerin. (b) Purify the rebamipide particles from the slurry by washing with water. method.

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