Granular composition, method for producing granular composition, and method for improving dissolution property of granular composition

Abstract

To provide a production method for a granular composition in which the dissolution property of 2-{4-[N-(5,6-diphenylpyradin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide is improved.SOLUTION: A production method for a granular composition includes a step of compression-molding a mixture obtained by mixing 2-{4-[N-(5,6-diphenylpyradin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and at least one or more excipients selected from the group consisting of a sugar alcohol, a starch, and a saccharide, thereby obtaining a compression molded material.SELECTED DRAWING: Figure 4

Description

[Technical field]

[0001] The present invention relates to a granular composition containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as "compound (I)"). The present invention also relates to a method for producing a granular composition containing compound (I). The present invention also relates to a method for improving dissolution property of compound (I) in a granular composition containing compound (I). [Background technology]

[0002] The following structural formula: [ka] Compound (I) represented by the formula (I) has an excellent prostaglandin I2 (also called PGI2) receptor agonist effect, and is known to exhibit various medicinal effects such as platelet aggregation inhibitory effect, vasodilatory effect, bronchial muscle dilating effect, lipid deposition inhibitory effect, and leukocyte activation inhibitory effect (e.g., Patent Document 1). Compound (I) is also prescribed as a tablet. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2002 / 088084 [Non-patent literature]

[0004] [Non-Patent Document 1] Hepatology,2007,Vol.45,No.1,p159-169. [Non-Patent Document 2] Folia Pharmacologica Japonica, Vol.117, No.2, p.123-130, 2001, Abstract. [Non-Patent Document 3] International Angiology, 29, Suppl.1 to No.2, p.49 - 54, 2010.

Non - Patent Document 4

Non - Patent Document 5

Non - Patent Document 6

Non - Patent Document 7

Non - Patent Document 8

Non - Patent Document 9

Non - Patent Document 10

Non - Patent Document 11

Non - Patent Document 12

Non - Patent Document 13

Non - Patent Document 14

Summary of the Invention

Problems to be Solved by the Invention

[0005] In general, it is difficult for children and elderly people with poor swallowing ability to take tablets. Although OD tablets and chewable tablets have been developed to be easy to swallow, they are not necessarily easy to take for elderly people who do not secrete much saliva.

[0006] In contrast, granular preparations (granular compositions) such as powders, fine granules, granules, granular tablets and dry syrups are very useful because they are easy for elderly people to take, improve medication compliance, and increase the freedom to change the dosage.

[0007] In addition, when manufacturing a preparation, a formulation technique that enhances the dissolution of the active ingredient is usually used. In general, the dissolution of the active ingredient from a tablet depends on the time it takes for the tablet to disintegrate into granules or powder. For this reason, the active ingredient cannot be expected to dissolve more quickly in the case of a tablet than in the case of granules or powder.

[0008] From the above, the formulation of a granular composition containing compound (I) is desired. Granular compositions such as granules are usually granulated products, and are generally prepared by a fluidized bed granulation method or the like. However, in the process of examining the formulation of granules containing compound (I), it was revealed that the dissolution of compound (I) is low in granules obtained by a fluidized bed granulation method. That is, it was revealed that in a granular composition containing compound (I), the dissolution of compound (I) becomes slow and the dissolution is low when an excipient or the like is merely attached to compound (I).

[0009] The present invention aims to provide a method for producing a granular composition capable of improving the dissolution property of compound (I). Another object of the present invention is to provide a method for improving dissolution property capable of improving the dissolution property of compound (I) in a granular composition. Another object of the present invention is to provide a granular composition capable of improving the dissolution property of compound (I). [Means for solving the problem]

[0010] As a result of intensive research to solve the above problems, the inventors discovered that the dissolution property of compound (I) can be improved by mixing compound (I) with at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars during the production of a granular composition and compressing the mixture, thereby completing the present invention.

[0011] The present invention relates to a method for producing a granular composition containing compound (I), which comprises a compression molding step of compressing a mixture of compound (I) and at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars to obtain a compression molded product.

[0012] In addition, in the method for producing a granular composition of the present invention having the above-mentioned configuration, it is preferable that the elution property of compound (I) in the granular composition is higher than the elution property of compound (I) in the mixture before the compression molding step.

[0013] In the present invention, in the method for producing a granular composition having the above-mentioned configuration, the porosity of the granular composition is preferably 45% or less.

[0014] In the present invention, in the method for producing a granular composition having the above-mentioned configuration, the granular composition preferably has a particle size of less than 5 mm.

[0015] In the present invention, in the method for producing a granular composition having the above-mentioned configuration, the compression molding step is preferably carried out by any one of a roller compression method, a tablet compression method, a briquette method, a slug method, and an extrusion granulation method.

[0016] Furthermore, in the present invention, in the method for producing a granular composition having the above-mentioned configuration, it is preferable that in the compression molding step, the extrusion granulation method is carried out using an extruder that extrudes the mixture through holes, and the diameter of the holes is 0.2 mm to 0.5 mm.

[0017] In addition, in the method for producing a granular composition according to the present invention having the above-mentioned configuration, it is preferable that the method further comprises a crushing step of crushing the compression-molded product.

[0018] In the present invention, in the method for producing a granular composition having the above-mentioned configuration, the granular composition is preferably in the form of granules, powders, capsule fillings, granular tablets, dry syrup or fine granules.

[0019] The present invention relates to a method for improving the dissolution property of compound (I) in a granular composition containing compound (I), and includes a compression molding step of compressing a mixture of compound (I) and at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars to obtain a compression molded product.

[0020] In the present invention, in the method for improving dissolution property having the above-mentioned configuration, it is preferable that the dissolution property of compound (I) in the granular composition is higher than the dissolution property of compound (I) in the mixture before the compression molding step.

[0021] In the present invention, in the method for improving dissolution property having the above-mentioned configuration, the porosity of the granular composition is preferably 45% or less.

[0022] In the present invention, in the method for improving dissolution property having the above-mentioned configuration, the particle size of the granular composition is preferably smaller than 5 mm.

[0023] In the present invention, in the method for improving dissolution property having the above-mentioned configuration, the compression molding step is preferably carried out by any one of a roller compaction method, a tablet compression method, a briquette method, a slug method, and an extrusion granulation method.

[0024] Furthermore, in the present invention, in the dissolution improving method having the above-mentioned configuration, it is preferable that in the compression molding step, the extrusion granulation method is performed using an extruder that extrudes the mixture through holes, and the diameter of the holes is 0.2 mm to 0.5 mm.

[0025] In the present invention, in the method for improving dissolution property having the above-mentioned configuration, it is preferable that the method further comprises a crushing step of crushing the compression-molded product.

[0026] In the present invention, in the method for improving dissolution property having the above-mentioned configuration, the granular composition is preferably in the form of granules, powders, capsule fillings, granular tablets, dry syrup or fine granules.

[0027] The granular composition of the present invention is a mixture of compound (I) and at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars, and has a porosity of 45% or less.

[0028] In the present invention, in the granular composition having the above-mentioned structure, the particle size is preferably smaller than 5 mm. Effect of the Invention

[0029] According to the method for producing a granular composition of the present invention, a granular composition having improved dissolution property of compound (I) can be obtained. In addition, according to the method for improving dissolution property of the present invention, the dissolution property of compound (I) in the granular composition can be improved. In addition, according to the granular composition of the present invention, the dissolution property of compound (I) can be improved. [Brief description of the drawings]

[0030] [Figure 1] 1 is a powder X-ray diffraction spectrum chart of the I-type crystal of compound (I) contained in a granular composition according to one embodiment of the present invention, in which the vertical axis indicates peak intensity (unit: cps) and the horizontal axis indicates diffraction angle 2θ (unit: °). [Diagram 2] 1 is a powder X-ray diffraction spectrum chart of the II-type crystal of compound (I) contained in a granular composition according to one embodiment of the present invention, in which the vertical axis indicates peak intensity (unit: cps) and the horizontal axis indicates diffraction angle 2θ (unit: °). [Diagram 3] 1 is a powder X-ray diffraction spectrum chart of the III-type crystal of compound (I) contained in a granular composition according to one embodiment of the present invention, in which the vertical axis indicates peak intensity (unit: cps) and the horizontal axis indicates diffraction angle 2θ (unit: °). [Figure 4] FIG. 2 is a process diagram showing the manufacturing process of a granular composition according to one embodiment of the present invention. [Diagram 5]1 is a graph showing the time course of the dissolution rate of Compound (I) in Example 1 and Comparative Example 1. The vertical axis indicates the dissolution rate (unit: %), and the horizontal axis indicates the time (unit: minutes). [Figure 6] 1 is a graph showing the time course of the dissolution rate of Compound (I) in Example 2 and Comparative Example 2. The vertical axis indicates the dissolution rate (unit: %), and the horizontal axis indicates the time (unit: minutes). [Figure 7] 1 is a graph showing the time course of the dissolution rate of Compound (I) in Example 3 and Comparative Example 3. The vertical axis indicates the dissolution rate (unit: %), and the horizontal axis indicates the time (unit: minutes). [Figure 8] 1 is a graph showing the time course of the dissolution rate of Compound (I) in Example 4 and Comparative Example 4. The vertical axis indicates the dissolution rate (unit: %), and the horizontal axis indicates the time (unit: minutes). [Figure 9] 1 is a graph showing the time course of the dissolution rate of Compound (I) in Example 5 and Comparative Example 5. The vertical axis indicates the dissolution rate (unit: %), and the horizontal axis indicates the time (unit: minutes). [Figure 10] 1 is a graph showing the time course of the dissolution rate of Compound (I) in Examples 6 to 8 and Comparative Example 6. The vertical axis indicates the dissolution rate (unit: %), and the horizontal axis indicates the time (unit: minutes). [Figure 11] 1 is a graph showing the time course of the dissolution rate of Compound (I) in Comparative Examples 7 and 8. The vertical axis indicates the dissolution rate (unit: %), and the horizontal axis indicates the time (unit: minutes). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Hereinafter, a granular composition according to one embodiment of the present invention will be described. In this specification, the term "granular composition" refers to a powdered raw material that has been processed into larger particles than the powdered raw material through a mixing step and a compression molding step described below.

[0032] <1. Constitution of granular composition> The granular composition of the present embodiment includes, for example, granules, powders, fine granules, granular tablets, dry syrups, etc. The granular composition can also be used as, for example, a solid preparation for direct oral administration. The granular composition can also be used as a suspension dispersed in, for example, water or syrup. The granular composition can also be used by filling it into a capsule. That is, the granular composition can be used as a capsule filler.

[0033] The granular composition contains compound (I) and an excipient. For example, compound (I) can be easily produced according to the method described in Patent Document 1. Compound (I) also exists in the following three crystal forms (type I crystal, type II crystal, and type III crystal).

[0034] 1 to 3 are powder X-ray diffraction spectrum charts (powder X-ray diffraction diagrams) of the I-type crystal, II-type crystal, and III-type crystal, respectively. In each figure, the vertical axis indicates peak intensity (unit: cps), and the horizontal axis indicates diffraction angle 2θ (unit: °). Powder X-ray diffraction spectra were measured using an X-ray diffractometer (RINT-UltimaIII, manufactured by Rigaku Corporation). At this time, the target was Cu, the voltage was 40 kV, the current was 40 mA, and the scan speed was 4° / min.

[0035] (1) Form I crystals have an X-ray powder diffraction pattern obtained using Cu Kα radiation (λ=1.54 Å) and show diffraction peaks at the following diffraction angles 2θ: 9.4°, 9.8°, 17.2° and 19.4° in the X-ray powder diffraction spectrum of Compound (I). (2) The Form II crystals have an X-ray powder diffraction pattern obtained using Cu Kα radiation (λ=1.54 Å) and show diffraction peaks at the following diffraction angles 2θ: 9.0°, 12.9°, 20.7° and 22.6° in the X-ray powder diffraction spectrum of Compound (I). (3) The type III crystal has an X-ray powder diffraction pattern obtained using Cu Kα radiation (λ=1.54 Å) and exhibits diffraction peaks at the following diffraction angles 2θ: 9.3°, 9.7°, 16.8°, 20.6° and 23.5° in the X-ray powder diffraction spectrum of compound (I).

[0036] The compound (I) contained in the granular composition may be any of the above-mentioned I-type, II-type, or III-type crystals, or may be a mixture of these crystals, or may be amorphous. The crystal of compound (I) is preferably the I-type crystal.

[0037] The excipient contained in the granular composition may be at least one selected from the group consisting of sugar alcohols, starches, and saccharides. The sugar alcohols, starches, and saccharides are preferably present in an amount of 1 to 30,000 by weight, more preferably 100 to 6,000 by weight, and even more preferably 300 to 4,000 by weight, per 1 weight of compound (I).

[0038] Examples of sugar alcohols include D-mannitol, erythritol, xylitol, D-sorbitol, isomalt, maltitol, lactitol, etc. D-mannitol, erythritol, xylitol, D-sorbitol, and isomalt are preferred, and D-mannitol, erythritol, and isomalt are more preferred.

[0039] Examples of starches include corn starch, potato starch, rice starch, wheat starch, etc. Corn starch and potato starch are preferred, and corn starch is more preferred.

[0040] Examples of sugars include maltose, trehalose, lactose, glucose, fructose, sucrose, etc. Maltose, trehalose, glucose, and lactose are preferred, and glucose and lactose are more preferred.

[0041] As will be described in detail later, the granular composition is a state in which a mixture of compound (I) and an excipient is compressed and molded. This can improve the dissolution of compound (I) in the granular composition. In addition, if the porosity of the granular composition is 45% or less, it is preferable because the dissolution of compound (I) can be further improved. The details of the porosity will be described later.

[0042] In addition, if the particle size of the granular composition is smaller than 5 mm, it is easier for the recipient to take the composition and the degree of freedom in changing the dosage is increased, which is preferable. If the particle size of the granular composition is 3 mm or less, it is easier for the recipient to take the composition and the degree of freedom in changing the dosage is increased, which is more preferable. Here, "particle size" means "average particle size" and is measured by microscopy (visual method) or image analysis.

[0043] The granular composition may contain various pharmaceutical additives in addition to the excipient. The pharmaceutical additives are not particularly limited as long as they are pharmacy- and pharmacologically acceptable, and examples thereof include binders, disintegrants, lubricants, flow agents, colorants, coating agents, flavoring agents, foaming agents, sweeteners, flavorings, antioxidants, surfactants, plasticizers, sugar-coating agents, etc. These pharmaceutical additives may be used alone or in combination of two or more.

[0044] Coating the granular composition with a coating agent or sugar-coating agent by a known method is preferable because it can improve the aesthetics of the granular composition and ensure its distinctiveness. In addition, adding a colorant to the granular composition is preferable because it can improve the photostability of the granular composition and ensure its distinctiveness. In addition, adding a flavoring agent or a fragrance to the granular composition is preferable because it can easily improve the flavor of the granular composition.

[0045] Examples of binders include gelatin, pullulan, hydroxypropyl cellulose, methyl cellulose, hypromellose, polyvinylpyrrolidone, macrogol, gum arabic, dextran, polyvinyl alcohol, and pregelatinized starch.

[0046] Examples of disintegrants include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, crystalline cellulose, and corn starch.

[0047] Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, and light anhydrous silicic acid.

[0048] Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, synthetic aluminum silicate, magnesium aluminometasilicate, and calcium silicate.

[0049] Examples of coloring agents include titanium oxide, talc, ferric oxide, yellow ferric oxide, food yellow No. 4, and food yellow No. 4 aluminum lake.

[0050] Examples of coating agents include hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer, methacrylic acid copolymer LD, and hypromellose acetate succinate.

[0051] Examples of flavoring agents include fructose, xylitol, glucose, DL-malic acid, and the like.

[0052] Examples of the foaming agent include sodium bicarbonate, dry sodium carbonate, and calcium carbonate.

[0053] Examples of sweeteners include aspartame, acesulfame potassium, sucralose, thaumatin, fructose, glucose, licorice, and xylitol.

[0054] Examples of the flavoring include l-menthol and peppermint.

[0055] Antioxidants include, for example, sodium nitrite, ascorbic acid, natural vitamin E, tocopherol, and the like.

[0056] Examples of the surfactant include sodium lauryl sulfate, sorbitan monooleate, and squalane.

[0057] Examples of the plasticizer include triethyl citrate, propylene glycol, and macrogol.

[0058] Examples of sugar-coating agents include refined white sugar, precipitated calcium carbonate, gum arabic, polyvinyl alcohol, kaolin, titanium oxide, macrogol, stearic acid, and ethyl cellulose.

[0059] Compound (I) has an excellent PGI2 receptor agonist effect, and is effective in treating diseases in which PGI2 is involved, such as transient ischemic attack (TIA), diabetic neuropathy (see, for example, Non-Patent Document 1), diabetic gangrene (see, for example, Non-Patent Document 1), peripheral circulatory disorders (such as chronic arteriosclerosis and chronic arterial occlusion (see, for example, Non-Patent Document 2)), intermittent claudication (see, for example, Non-Patent Document 3), peripheral arterial embolism (see, for example, Non-Patent Document 5), Raynaud's disease (see, for example, Non-Patent Document 4), and collagen diseases (such as systemic lupus erythematosus and scleroderma) (see, for example, Non-Patent Document 6). (see, for example, Non-Patent Document 11), mixed connective tissue disease, vasculitis syndrome, reocclusion / restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute cerebral thrombosis, pulmonary embolism) (see, for example, Non-Patent Document 5, Non-Patent Document 7), hypertension, pulmonary hypertension such as pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (see, for example, Non-Patent Document 8, Non-Patent Document 9), ischemic disease (e.g., cerebral infarction, myocardial infarction (see, for example, Non-Patent Document 10)), angina pectoris (e.g., stable angina pectoris, unstable angina pectoris) (see, for example, Non-Patent Document 11), glomerulonephritis (see, for example, Non-Patent Document 12), diabetes mellitus In addition, the following diseases may be caused by the following: chronic nephropathy (see, for example, Non-Patent Document 1), chronic renal failure, allergies, bronchial asthma (see, for example, Non-Patent Document 13), ulcers, bedsores, restenosis after coronary interventions such as atherectomy and stent placement, thrombocytopenia due to dialysis, diseases involving fibrosis of organs or tissues [for example, kidney diseases (e.g., tubulointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease (see, for example, Non-Patent Document 14), etc.), digestive diseases (e.g., liver cirrhosis, viral hepatitis, chronic pancreatitis, scirrhous gastric cancer), cardiovascular diseases (e.g., myocardial infarction, fibrosis), bone and joint diseases (e.g., myelofibrosis, rheumatoid arthritis), skin diseases (e.g., postoperative scars, burn scars, keloids, hypertrophic scars), obstetric diseases (e.g., uterine fibroids), urological diseases (e.g., prostatic hyperplasia), other diseases (e.g., Alzheimer's disease, sclerotic peritonitis, type I diabetes, postoperative organ adhesions)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychopathic erectile dysfunction, erectile dysfunction due to chronic renal failure, erectile dysfunction after pelvic surgery for prostate removal, vascular erectile dysfunction due to aging or arteriosclerosis), inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease,intestinal tuberculosis, ischemic colitis, intestinal ulcers associated with Behcet's disease), gastritis, gastric ulcers, ischemic eye disease (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) The composition is useful as a preventive or therapeutic agent for intestinal injury (for example, mucosal injury such as erosion or ulcer occurring in the duodenum, small intestine, or large intestine, which is not particularly limited as long as the injury occurs in the duodenum, small intestine, or large intestine, for example, the injury occurs in the duodenum, small intestine, or large intestine) and symptoms (for example, paralysis, hypoesthesia, pain, numbness, decreased walking ability) associated with spinal canal stenosis (for example, cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffuse spinal canal stenosis, sacral stenosis). The granular composition of the present invention is also useful as a promoter of angiogenesis therapy such as gene therapy or autologous bone marrow cell transplantation, and as an angiogenesis promoter in peripheral vascular reconstruction or angiogenesis therapy.

[0060] <2. Method for producing granular composition of the present embodiment and method for improving dissolution property of compound (I)> Next, the method for producing the granular composition will be described. Figure 4 is a process diagram showing the manufacturing process of the granular composition. The manufacturing process includes a mixing process, a compression molding process, a crushing process, a classification process, and an addition process. The dissolution improvement method for improving the dissolution of compound (I) in the granular composition is also carried out in the same manner as the manufacturing method.

[0061] <2-1. Mixing process> In the mixing step, the powdered compound (I) is uniformly mixed with at least one powdered excipient selected from the group consisting of sugar alcohols, starches, and sugars to obtain a mixture. Note that "mixing" also includes the case where the compound (I) and the excipient are uniformly mixed, and a plurality of small particles are caused to adhere to each other and aggregate to grow into larger particles, which is called "granulation."

[0062] The mixing step is carried out using a mixer. There is no particular limitation on the mixer, and for example, a container rotary mixer, a mechanical stirring mixer, an airflow mixer, or a kneading mixer can be used. The mixing step may also be carried out using a granulator as the mixer. There is no particular limitation on the granulator, and for example, a fluidized bed granulator, an agitation granulator, a rotary granulator, or the like can be used.

[0063] <2-2. Compression molding process> In the compression molding process after the mixing process, the mixture prepared in the mixing process is compression molded to obtain a compression molded product. At this time, the porosity of the compression molded product is preferably 45% or less. The compression molding process is carried out using a compression molding machine. There is no particular limitation on the compression molding method, and for example, a roller compression method, a tablet compression method, a briquette method, a slug method, or an extrusion granulation method is preferable.

[0064] In the roller compaction method, a roller compactor is used as a compression molding machine. The roller compactor has two rolls with horizontally arranged rotation axes. The two rolls are arranged facing each other in a direction perpendicular to the rotation axis. A certain gap is provided between the two rolls, and the two rolls rotate in opposite directions.

[0065] The mixture obtained in the mixing step is fed into the gap between two rotating rolls, and the mixture is compressed and molded by the two rolls. This allows the compression molding step to be performed by roller compression, and a sheet-like (thin plate-like) or flake-like compression molded product is formed. The surface of the roll may be smooth or may have a plurality of minute irregularities. Providing a plurality of minute irregularities on the surface of the roll is preferable because it makes it easier for the mixture to be held on the roll, improving the compression efficiency.

[0066] At this time, the magnitude of the pressure applied to the mixture is not particularly limited as long as it is a magnitude that can improve the dissolution of compound (I), and is preferably 0.5 N / mm 2 It is preferable that the resistance is 0.5 to 25 N / mm 2 More preferably, the resistance is 0.5 to 10 N / mm 2 It is even more preferable that:

[0067] In the tablet compression method (tabletting method), a tablet press is used as a compression molding machine. For example, a single shot tablet press or a rotary tablet press can be used as the tablet press. The tablet press has a cylindrical mortar and a pair of upper and lower metal rods (upper and lower punches). In the compression molding process, the upper and lower punches sandwich the mixture filled in the mortar from above and below to compress and mold it. This causes the compression molding process to be performed in the tablet compression method, and a disk-shaped compression molded product is formed.

[0068] At this time, the magnitude of the pressure applied to the mixture is not particularly limited as long as it is a magnitude that can improve the dissolution of compound (I), and is preferably 10 N / mm 2 The pressure applied to the mixture is preferably 10 to 1500 N / mm 2 More preferably, it is 10 to 700 N / mm 2 It is even more preferable that:

[0069] In the briquette method, a briquette machine is used as the compression molding machine. The briquette machine has two rolls with horizontally arranged rotation axes. The two rolls are arranged facing each other in a direction perpendicular to the rotation axis. A certain gap is provided between the two rolls, and the two rolls rotate in opposite directions. A number of pockets are recessed into the surface of the rolls, aligned in the direction of rotation of the rolls. The pockets are the matrix for the briquettes, and the volume of the pockets is approximately 0.3 cm. 3 ~about 200cm 3 It is preferable that:

[0070] In the compression molding process, the mixture prepared in the mixing process is fed into the gap between two rotating rolls, and the mixture is compressed and molded by the two rolls. This completes the compression molding process using the briquetting method, forming a briquette (compressed product).

[0071] At this time, the magnitude of the pressure applied to the mixture is not particularly limited as long as it is a magnitude that can improve the dissolution of compound (I), and is preferably 10 N / mm 2The pressure applied to the mixture is preferably 10 to 1500 N / mm 2 More preferably, it is 10 to 700 N / mm 2 It is even more preferable that:

[0072] In the extrusion granulation method, an extrusion granulator is used as a compression molding machine. The extrusion granulator has a storage chamber that stores the mixture prepared in the mixing step and has multiple circular holes, and a pressing part that presses the mixture in the storage chamber toward the multiple holes. The extrusion methods of the extrusion granulator include a screw extrusion method, a plunger extrusion method, and a roller extrusion method. The pressing parts correspond to a screw, a plunger, and a roller, respectively. The holes are, for example, die holes or holes in a screen (perforated plate). The screw extrusion method is preferable because it can easily improve the production efficiency of the granular composition.

[0073] When using the extrusion granulation method, in the mixing step, a solvent is added to compound (I) and an excipient, and the mixture is kneaded. This gives a kneaded product (mixture). The solvent can be, for example, water, ethanol, or various binder solutions (aqueous solutions or aqueous solutions containing ethanol). In the compression molding step, the kneaded product is stored in a storage chamber of an extrusion granulator, and the kneaded product is extruded from the hole to the outside of the extrusion granulator by the pressing part of the extrusion granulator. This gives a cylindrical compression molded product.

[0074] The diameter of the hole of the extrusion granulator is preferably 0.5 mm or less, more preferably 0.2 to 0.5 mm. The cross-sectional area of ​​the storage chamber of the extrusion granulator perpendicular to the extrusion direction is usually sufficiently larger than the area of ​​the hole, so if the diameter of the hole is 0.5 mm or less, more sufficient pressure can be applied to the kneaded material. When using an extrusion granulator (e.g., a twin-screw type) that can apply a sufficiently large pressure to the kneaded material due to the configuration of the extrusion part, the diameter of the hole of the extrusion granulator may be larger than 0.5 mm.

[0075] The slug method is a method in which the mixture prepared in the mixing step is pressed in a dry state to form a cylindrical powder compression molded mass (slug, compression molded product). There is no particular limitation on the size of the powder compression molded mass, and the diameter of the powder compression molded mass can be, for example, about 20 mm.

[0076] As described above, when the compression molding step is carried out by the roller compression method, tablet compression method, briquette method, slug method, or extrusion granulation method, the compression molded product can be easily formed.

[0077] <2-3. Crushing process> In the crushing process after the compression molding process, the compression molded product is crushed using a crusher or the like. In the crushing process, granular crushed material is formed from the compression molded product. In the following description, the "granular crushed material" may be referred to as "granular material".

[0078] In addition, a crushing step of crushing the compression molded product using a crusher may be performed after the compression molding step and before the crushing step, whereby the compression molded product can be stably crushed in the crushing step.

[0079] <2-4. Classification process> In the classification step after the crushing step, the crushed material is classified using an air classifier or a sieve. This makes it easy to obtain a granulated material of the desired particle size. Note that crushed material that is removed during the classification step due to insufficient crushing may be crushed again in the crushing step.

[0080] <2-5. Additional process> In the addition step after the classification step, the granulated material classified in the classification step is mixed with a pharmaceutical additive. The mixing method in the addition step is the same as the mixing method in the mixing step described above. In the addition step, the pharmaceutical additive is added to the granulated material.

[0081] A granular composition is formed by the above manufacturing steps. The manufacturing method of this embodiment includes a compression molding step. This makes it possible to easily form a granular composition that can quickly dissolve compound (I) and improve the dissolution property of compound (I). In addition, the dissolution improvement method of this embodiment includes a compression molding step. This makes it possible to quickly dissolve compound (I) and improve the dissolution property of compound (I) in the granular composition.

[0082] In addition, the dissolution property of compound (I) in the granular composition is higher than the dissolution property of compound (I) in the mixture before the compression molding step.

[0083] In this embodiment, the method for producing the granular composition is not particularly limited as long as it includes a compression molding step. For example, a general method described in a publication such as Powder Technology and Pharmaceutical Processes (D. Chulia et al., Elsevier Science Pub Co (December 1, 1993)) may be used.

[0084] In the mixing step, in addition to the excipient, pharmaceutical additives other than the excipient may be further added and mixed.

[0085] In addition, in the compression molding process, the pressure applied to the mixture may be gradually increased over time. Also, the pressure applied in the early stage of the compression molding process may be greater than the pressure applied in the later stage of the compression molding process. This prevents damage such as cracking of the compression molded product, and allows the compression molded product to be stably formed.

[0086] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0087] [Table 1]

[0088] [Table 2]

[0089] Table 1 shows the excipients contained in the granular compositions of Examples 1 to 5 and Comparative Examples 1 to 5. Table 2 shows the compression molding method in the compression molding step of the production method of the granular compositions of Examples 6 to 8. EXAMPLES

[0090] The granular composition of Example 1 was prepared using the slug method. In the mixing step, 3 mg of compound (I) was mixed with 297 mg of D-mannitol (Mannit P, manufactured by Mitsubishi Shoji Foodtech Co., Ltd.) to obtain a mixture of 300 mg. Next, in the compression molding step, the mixture was subjected to a pressure of 130.1 N / mm using a precision universal testing machine (AG-X, manufactured by Shimadzu Corporation). 2 A pressure of 1000 g was applied to obtain a compression molded product. In the crushing step, the compression molded product was crushed, and in the classification step, 20 mg of the granulated product that passed through a sieve with an opening of 1700 μm was used as the granular composition (granules) of Example 1. At this time, the compression molded product was crushed so that all the crushed product passed through the sieve. EXAMPLES

[0091] In the granular composition of Example 2, erythritol (Erythritol 50M, manufactured by Bussan Food Science Co., Ltd.) was used as an excipient. The rest of the composition was prepared in the same manner as in Example 1. EXAMPLES

[0092] In the granular composition of Example 3, isomalt (galenIQ 720, manufactured by BENEO-Palatinit) was used as an excipient. The rest of the composition was prepared in the same manner as in Example 1. EXAMPLES

[0093] In the granular composition of Example 4, corn starch (Nisshoku Corn Starch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) was used as an excipient. The rest of the composition was prepared in the same manner as in Example 1. EXAMPLES

[0094] In the granular composition of Example 5, lactose hydrate (Pharmatose (registered trademark) 200M, manufactured by DFE Pharma) was used as an excipient. The rest of the composition was prepared in the same manner as in Example 1. EXAMPLES

[0095] The granular composition of Example 6 was prepared using a roller compaction method. In the mixing step, 0.2 mg of compound (I), 900 mg of D-mannitol (Mannit P, manufactured by Mitsubishi Shoji Foodtech Co., Ltd.), and 99.8 mg of corn starch (Nisshoku Corn Starch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) were mixed to obtain a mixture of 1000 mg. Next, in the compression molding step, a roller compactor (TF-MINI, manufactured by Freund Corporation) was used to apply a pressure of 10 N / mm 2 A pressure of 1000 MPa was applied to obtain a thin plate-like compression molded product. Next, in the crushing step, the compression molded product was crushed to obtain a crushed product (granulated product). After that, in the classification step, the granulated product that passed through a sieve with an opening of 710 μm was used as the granular composition (granules) of Example 6. At this time, the compression molded product was crushed so that all the crushed product passed through the sieve. In the following Examples 7 and 8 and Comparative Example 6, the same compound (I), D-mannitol, and corn starch as those in Example 6 were used. EXAMPLES

[0096] The granular composition of Example 7 was prepared using a tablet compression method. In the mixing step, 0.2 mg of compound (I), 930 mg of D-mannitol, and 19.8 mg of corn starch were placed in a fluidized bed device (MP-01, manufactured by Powrex Corporation), and 10% hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) aqueous solution was sprayed while mixing. This resulted in granules (mixture) containing 50 mg of hydroxypropylcellulose. The resulting granules were mixed with 15 mg of magnesium stearate (special magnesium stearate product, manufactured by Taihei Chemical Industry Co., Ltd.) to obtain 1015 mg of a mixture. Next, in the compression molding step, a rotary tablet press (Collect, manufactured by Kikusui Seisakusho Co., Ltd.) was used to produce a granule with a pressure of 780.9 N / mm 2 A pressure of this order was applied to the mixture to perform compression molding, thereby obtaining a plurality of disk-shaped granular composition as Example 7, each having a diameter of about 2 mm and a mass of 5 mg. EXAMPLES

[0097] The granular composition of Example 8 was prepared using the extrusion granulation method. In the mixing step, 0.2 mg of compound (I), 960 mg of D-mannitol, and 19.8 mg of corn starch were placed in a stirring mixer granulator (VG-05, manufactured by Powrex Corporation), and a 10% aqueous hydroxypropylcellulose solution was added while mixing. This resulted in 1000 mg of a kneaded product (mixture) containing 20 mg of hydroxypropylcellulose. The hydroxypropylcellulose used was the same as that used in Example 7.

[0098] The obtained kneaded product was extruded through a screen with a hole diameter of 0.5 mm using a wet extrusion granulator (Multigran MG-55, manufactured by Dalton Co., Ltd.) to obtain a granulated product (compression molded product). The obtained granulated product was dried at 60°C, and then in a crushing process, the granulated product was crushed to obtain a crushed product (granulated product). After that, in a classification process, the granulated product that passed through a sieve with an opening of 1700 μm was used as the granular composition (granules) of Example 8. At this time, the compression molded product was crushed so that all the crushed product passed through the sieve.

[0099] [Comparative Example 1] The mixture of Example 1 (20 mg) that had not been subjected to the compression molding process and subsequent steps was used as Comparative Example 1. The rest of the preparation was the same as in Example 1.

[0100] [Comparative Example 2] The mixture of Example 2 (20 mg) that had not been subjected to the compression molding process and subsequent steps was used as Comparative Example 2. The rest of the composition was prepared in the same manner as in Example 2.

[0101] [Comparative Example 3] The mixture of Example 3 (20 mg) that had not been subjected to the compression molding process and subsequent steps was used as Comparative Example 3. The rest of the composition was prepared in the same manner as in Example 3.

[0102] [Comparative Example 4] The mixture of Example 4 (20 mg) that had not been subjected to the compression molding process and subsequent steps was used as Comparative Example 4. The rest of the preparation was the same as in Example 4.

[0103] [Comparative Example 5] Comparative Example 5 was prepared by using 20 mg of a mixture that had not been subjected to the compression molding process or subsequent steps in comparison with Example 5. The rest of the preparation was the same as in Example 5.

[0104] [Comparative Example 6] A mixture that had not been subjected to the compression molding process and subsequent steps in comparison with Example 7 was used as Comparative Example 6. The rest of the mixture was prepared in the same manner as in Example 7.

[0105] [Comparative Example 7] In Comparative Example 7, only Compound (I) was compression molded without using any excipient in the same manner as in Example 1. The rest of the preparation was the same as in Example 1.

[0106] [Comparative Example 8] Compound (I) that was not compression molded was used as Comparative Example 8. The rest was prepared in the same manner as in Comparative Example 7.

[0107] Dissolution tests were carried out for the granular compositions of Examples 1 to 8 and Comparative Examples 1 to 8 prepared as described above. The dissolution tests were conducted in accordance with the dissolution test method of the 17th edition of the Japanese Pharmacopoeia. Using a dissolution tester (NTR-6000 series, manufactured by Toyama Sangyo Co., Ltd.), the dissolution tests were carried out by the paddle method using water as the dissolution test liquid. At this time, the volume of the dissolution test liquid was 900 mL, the temperature of the dissolution test liquid was 37±0.5°C, and the rotation speed of the paddle was 50 rpm. The entire amount of each Example and Comparative Example was added to the dissolution test liquid, and the dissolution test liquid was collected 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the test, and the dissolution test liquid was filtered with a 0.45 μm filter (Whatman, manufactured by GE Healthcare), and the dissolution rate of compound (I) was measured using high performance liquid chromatography.

[0108] Figures 5 to 9 show the time course of the dissolution rate of compound (I) in the granular compositions of Examples 1 to 5, respectively, and also show the time course of the dissolution rate of compound (I) in Comparative Examples 1 to 5, respectively. Figure 10 shows the time course of the dissolution rate of compound (I) in the granular compositions of Examples 6 to 8 and Comparative Example 6. Figure 11 shows the time course of the dissolution rate of compound (I) in Comparative Examples 7 and 8. In Figures 5 to 11, the vertical axis shows the dissolution rate (unit: %), and the horizontal axis shows time (unit: minutes). Solid lines E1 to E8 show the cases of Examples 1 to 8, respectively, and dashed lines C1 to C8 show the cases of Comparative Examples 1 to 8, respectively.

[0109] 5 to 9, the granular compositions of Examples 1 to 5 had improved dissolution rates of compound (I) compared with Comparative Examples 1 to 5. From the above, it can be seen that the dissolution property of compound (I) is improved by compression molding a mixture of compound (I) and an excipient.

[0110] As shown in FIG. 10, the granular compositions of Examples 6 to 8 had improved dissolution rates of compound (I) compared to Comparative Example 6. In addition, in all of the granular compositions of Examples 6 to 8, the dissolution rate of compound (I) 120 minutes after the start of the test was 70% or more. On the other hand, in Comparative Example 6, which did not undergo the compression molding process, the dissolution rate of compound (I) 120 minutes after the start of the test was 41.2%. From the above, it can be seen that the dissolution property of compound (I) can be improved even if the compression molding process is performed by the roller compression method, tablet compression method, or extrusion granulation method.

[0111] 11, the dissolution rates of Comparative Examples 7 and 8 were less than 20% at 120 minutes from the start of the test, and there was no significant difference in the dissolution rates of Comparative Examples 7 and 8. From the above, it can be seen that an excipient selected from the group consisting of sugar alcohols, starches, and sugars is necessary to improve the dissolution of compound (I) in a granular composition.

[0112] Regarding acetaminophen, indomethacin, and celiprolol hydrochloride, the dissolution rates when they were mixed with excipients and then compression molded as in the present embodiment were almost the same as the dissolution rates when they were not compression molded.

[0113] Although the detailed mechanism by which the dissolution property of compound (I) in the granular composition is improved by compressing the mixture of compound (I) and excipient is unclear, it is presumed that the compression molding process causes an interaction between compound (I) and excipient. Note that the present invention is not limited to the above mechanism.

[0114] Next, an experiment was carried out to investigate the relationship between the porosity of the granular composition and the dissolution property of compound (I). In the mixing step, 0.2 mg of compound (I), D-mannitol, corn starch, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and magnesium stearate were mixed to obtain a mixture. Note that compound (I), D-mannitol, corn starch, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, and magnesium stearate were the same as those used in the above examples.

[0115] In the compression molding process, pressure was applied to the mixture using a tablet compression method to form disk-shaped granules. These granules were used as the granular composition used in this experiment. At this time, the pressure applied to the mixture was 0 to 509.6 N / mm 2 was variable within the range.

[0116] Next, the mass M (unit: g) per piece of the granular composition was measured, and the volume V (unit: mm 3 ) was calculated. Here, the volume V is the apparent volume including voids. In addition, the true density ρ (unit: g / mm2) of the mixture itself (a granular composition not including voids) in the granular composition was calculated by a constant volume expansion method using a dry automatic density meter (AccuPic II 1340, manufactured by Shimadzu Corporation). 3 ) was measured. The porosity ε (unit: %) of the granular composition was then calculated according to the following formula (1).

[0117] ε = 100 × (VM / ρ) / V (1)

[0118] After calculating the porosity ε, the granular composition was subjected to the same dissolution test as the above dissolution test.

[0119] As a result of this experiment, when the pressure applied to the mixture in the compression molding process was large, the porosity ε was small and the dissolution rate of compound (I) was large. It was also found that when the porosity ε of the granular composition was 45% or less, the dissolution rate of compound (I) was sufficiently larger than the dissolution rate when the compression molding process was not performed.

[0120] In this experiment, the volume V (apparent volume) of the granular composition was calculated based on the diameter and thickness to determine the porosity ε, but the porosity ε may also be determined using, for example, a tap density measurement method. Specifically, after weighing the sample (multiple granular compositions) into, for example, a graduated cylinder, the graduated cylinder is lightly tapped until there is no bulk loss, reducing the gaps between the granular compositions in the sample. Then, the graduations on the graduated cylinder are read to measure the volume V (apparent volume) of the sample. After that, the true density ρ of the sample is measured using a dry automatic density meter, and the porosity ε is calculated from the above formula (1). According to this method, the porosity ε of irregularly shaped granular compositions can also be easily determined. [Industrial Applicability]

[0121] The present invention can be utilized in a granular composition comprising Compound (I) and an excipient.

Claims

1. A method for producing a granular composition comprising the following compound (I): The method includes a compression molding step of compressing a mixture of the compound (I) and at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars to obtain a compression molded product, The method for producing a granular composition, wherein the granular composition is a granule, a powder or a fine granule. 【Chemistry 1】

2. The method for producing a granular composition according to claim 1 , further comprising a crushing step of crushing the compression-molded product to form a crushed product.

3. The method for producing a granular composition according to claim 2 , further comprising a classification step of classifying the crushed material.

4. A method for producing a granular composition as described in claim 3, wherein in the classification process, the granular composition passes through a sieve having a mesh size of 1700 μm.

5. A method for producing a granular composition as described in claim 3, wherein in the classification process, the granular composition passes through a sieve having a mesh size of 710 μm.

6. The method for producing a granular composition according to any one of claims 1 to 5, wherein the compression molding step is carried out by any one of a roller compaction method, a briquette method, a slug method, and an extrusion granulation method.

7. A method for producing a granular composition described in any one of claims 1 to 6, wherein the solubility of compound (I) in the granular composition is higher than when the compression molding step is not included.

8. A method for producing a granular composition as described in claim 1, wherein the granular composition is a granule.

9. A method for producing a capsule, comprising a step of filling a capsule with a granular composition produced by the method according to any one of claims 1 to 8.

10. A method for producing a dry syrup, comprising the method described in any one of claims 1 to 8, further comprising adding a sweetener in the mixing step and mixing.

11. A method for producing a granular composition comprising the following compound (I): a mixing step of mixing the compound (I) with at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars to obtain a mixture; A compression molding step of compression molding the mixture to obtain a compression molded product; A crushing step of crushing the compression molded product to form a crushed product, The granular composition is a granule, a powder or a fine granule, A method for producing a granular composition, in which the solubility of compound (I) in the granular composition is high, as compared with a method not including the compression molding step. 【Chemistry 2】

12. The method for producing a granular composition according to claim 11, further comprising a classification step of classifying the crushed material.

13. The method for producing a granular composition according to claim 12, wherein in the classification step, the granular composition is passed through a sieve having an opening of 1700 μm.

14. A method for producing a granular composition as described in Claim 12, wherein in the classification process, the granular composition passes through a sieve having a mesh size of 710 μm.

15. The method for producing a granular composition according to any one of claims 11 to 14, wherein the compression molding step is carried out by any one of a roller compaction method, a briquette method, a slug method, and an extrusion granulation method.

16. A method for producing a granular composition as described in claim 11, wherein the granular composition is a granule.

17. A method for producing a capsule, comprising a step of filling a capsule with a granular composition produced by the method according to any one of claims 11 to 16.

18. A method for producing a dry syrup preparation, comprising the step of: further adding a sweetener in the mixing step and performing mixing by using the method according to any one of claims 11 to 16.

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