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

Abstract

To provide a method for producing a granular composition with improved elution properties of an active ingredient; the granular composition; and a dissolution property improvement method for improving the dissolution properties of an active ingredient in a granular composition.SOLUTION: The present invention provides a production method for a granular composition containing the following compound (I), comprising a compression-molding step of compression-molding a mixture obtained by mixing the compound (I) 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 the dissolution 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) below, has an excellent prostaglandin I2 (also known as PGI2) receptor agonist activity and is known to exhibit various medicinal effects such as platelet aggregation inhibitory activity, vasodilatory activity, bronchial muscle dilating activity, lipid deposition inhibitory activity, and leukocyte activation inhibitory activity (e.g., Patent Document 1). Compound (I) is also formulated 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 make them easier to swallow, they are not necessarily easy to take for elderly people who produce less 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 allow greater freedom in changing the dosage.

[0007] Furthermore, when manufacturing pharmaceutical preparations, formulation techniques that enhance the dissolution of medicinal ingredients are usually used. Generally, the dissolution of medicinal ingredients from tablets depends on the time it takes for the tablet to disintegrate into granules or powder. Therefore, in the case of tablets, the medicinal ingredients cannot be expected to dissolve more quickly than in the case of granules or powder.

[0008] For these reasons, there is a demand for the formulation of a granular composition containing Compound (I). 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 studying the formulation of granules containing Compound (I), it was revealed that the dissolution rate of Compound (I) is low in granules obtained by a fluidized bed granulation method. In other words, it was revealed that in a granular composition containing Compound (I), simply attaching an excipient or the like to Compound (I) slows down the dissolution of Compound (I), resulting in low dissolution rate.

[0009] An object of the present invention is to provide a method for producing a granular composition that can improve the dissolution property of Compound (I). Another object of the present invention is to provide a method for improving dissolution property that can improve the dissolution property of Compound (I) in a granular composition. Another object of the present invention is to provide a granular composition that can improve 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 have 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 then 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] Furthermore, in the present invention, in the method for producing a granular composition having the above-mentioned configuration, it is preferable that the elution rate of compound (I) in the granular composition is higher than the elution rate of compound (I) in the mixture before the compression molding step.

[0013] Furthermore, in the method for producing a granular composition according to the present invention having the above-mentioned configuration, it is preferable that the porosity of the granular composition is 45% or less.

[0014] In the present invention, in the method for producing a granular composition having the above-mentioned configuration, the particle size of the granular composition is preferably smaller 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 roller compaction, tablet compression, briquetting, slugging, and extrusion granulation.

[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] Furthermore, in the present invention, the method for producing a granular composition having the above-mentioned configuration preferably further comprises a crushing step of crushing the compression-molded product.

[0018] Furthermore, in the method for producing a granular composition according to the present invention 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 provides a method for improving the dissolution of compound (I) in 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.

[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 method for improving dissolution property according to the present invention having the above-mentioned configuration, the compression molding step is preferably carried out by any one of roller compaction, tablet compression, briquetting, slugging, and extrusion granulation.

[0024] Furthermore, in the present invention, in the method for improving dissolution property 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.

[0025] Furthermore, in the method for improving dissolution property 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.

[0026] In the present invention, in the method for improving dissolution property having the above-mentioned configuration, the granular composition is preferably a granule, a powder, a capsule filling, a granular tablet, a 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, the particle size of the granular composition having the above-mentioned constitution is preferably smaller than 5 mm. [Effects of the Invention]

[0029] According to the method for producing a granular composition of the present invention, a granular composition having improved dissolution properties of compound (I) can be obtained. Furthermore, according to the method for improving dissolution properties of the present invention, the dissolution properties of compound (I) in the granular composition can be improved. Furthermore, according to the granular composition of the present invention, the dissolution properties of compound (I) can be improved. [Brief explanation 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 the granular composition of one embodiment of the present invention, where the vertical axis represents peak intensity (unit: cps) and the horizontal axis represents diffraction angle 2θ (unit: °). [Figure 2] 1 is a powder X-ray diffraction spectrum chart of the type II crystal of Compound (I) contained in a granular composition according to one embodiment of the present invention, where the vertical axis represents peak intensity (unit: cps) and the horizontal axis represents diffraction angle 2θ (unit: °). [Figure 3] 1 is a powder X-ray diffraction spectrum chart of the type III crystal of Compound (I) contained in the granular composition of one embodiment of the present invention, where the vertical axis represents peak intensity (unit: cps) and the horizontal axis represents diffraction angle 2θ (unit: °). [Figure 4] FIG. 1 is a process diagram showing a manufacturing process of a granular composition according to one embodiment of the present invention. [Figure 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 represents the dissolution rate (unit: %), and the horizontal axis represents time (unit: minutes). [Figure 6] 1 shows the time course of the dissolution rate of Compound (I) in Example 2 and Comparative Example 2. The vertical axis represents the dissolution rate (unit: %), and the horizontal axis represents time (unit: minutes). [Figure 7] 1 shows the time course of the dissolution rate of Compound (I) in Example 3 and Comparative Example 3. The vertical axis represents the dissolution rate (unit: %), and the horizontal axis represents time (unit: minutes). [Figure 8] 1 shows the time course of the dissolution rate of Compound (I) in Example 4 and Comparative Example 4. The vertical axis represents the dissolution rate (unit: %), and the horizontal axis represents time (unit: minutes). [Figure 9] 1 shows the time course of the dissolution rate of Compound (I) in Example 5 and Comparative Example 5. The vertical axis represents the dissolution rate (unit: %), and the horizontal axis represents time (unit: minutes). [Figure 10] 1 shows the time course of the dissolution rate of Compound (I) in Examples 6 to 8 and Comparative Example 6. The vertical axis represents the dissolution rate (unit: %), and the horizontal axis represents 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 represents the dissolution rate (unit: %), and the horizontal axis represents time (unit: minutes). DETAILED DESCRIPTION OF THE INVENTION

[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, which will be described later.

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

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

[0034] Figures 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 represents peak intensity (unit: cps), and the horizontal axis represents diffraction angle 2θ (unit: °). Powder X-ray diffraction spectra were measured using an X-ray diffractometer (RINT-Ultima III, manufactured by Rigaku Corporation). The target was Cu, the voltage was 40 kV, the current was 40 mA, and the scan speed was 4° / min.

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

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

[0037] The excipient contained in the granular composition may be at least one selected from the group consisting of sugar alcohols, starches, and sugars. The sugar alcohols, starches, and sugars 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 mixture of compound (I) and an excipient that has been 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, the dissolution of compound (I) can be further improved, which is preferable. The porosity will be described in detail later.

[0042] Furthermore, a particle size of the granular composition smaller than 5 mm is preferable because it is easier for the recipient to take and allows greater flexibility in adjusting the dosage. A particle size of the granular composition of 3 mm or less is even more preferable because it is easier for the recipient to take and allows greater flexibility in adjusting the dosage. Here, "particle size" means "average particle size" and is measured by microscopy (visual inspection) or image analysis.

[0043] The granular composition may contain various pharmaceutical additives in addition to the excipient. Pharmaceutical additives are not particularly limited as long as they are pharmaceutically and pharmacologically acceptable, and examples include binders, disintegrants, lubricants, fluidizing agents, colorants, coating agents, flavoring agents, foaming agents, sweeteners, flavoring agents, 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 appearance of the granular composition and ensure its distinctiveness. Furthermore, adding a colorant to the granular composition is preferable because it can improve the photostability of the granular composition and ensure its distinctiveness. Furthermore, 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, iron sesquioxide, yellow iron sesquioxide, 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, and DL-malic acid.

[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] Examples of antioxidants include sodium nitrite, ascorbic acid, natural vitamin E, and tocopherol.

[0056] Examples of surfactants 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 sucrose, 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 activity, 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 (e.g., chronic arteriosclerosis, 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 (e.g., systemic lupus erythematosus, scleroderma) (see, for example, Non-Patent Document 6). (see, for example, Non-Patent Document 11), mixed connective tissue disease, vasculitis syndrome, re-occlusion / restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute cerebral thrombosis, pulmonary embolism) (see, for example, Non-Patent Document 5 and Non-Patent Document 7), hypertension, pulmonary hypertension such as pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (see, for example, Non-Patent Document 8 and 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 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 organ or tissue fibrosis [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)], 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), urinary diseases (e.g., benign 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, psychotic 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 ulcer, ischemic eye disease (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular bone necrosis, administration of nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) The granular composition of the present invention is useful as a preventive or therapeutic agent for intestinal damage (for example, without particular limitation, as long as the damage occurs in the duodenum, small intestine, or large intestine, for example, mucosal damage such as erosion or ulcers occurring in the duodenum, small intestine, or large intestine) associated with spinal stenosis (for example, cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffuse spinal canal stenosis, and sacral stenosis) and symptoms (for example, paralysis, hypoesthesia, pain, numbness, and decreased walking ability) associated with spinal canal 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, a method for producing a granular composition will be described. Figure 4 is a process diagram showing the steps of producing a granular composition. The production process includes a mixing step, a compression molding step, a crushing step, a classification step, and an addition step. The dissolution improvement method for improving the dissolution of compound (I) in a granular composition is also carried out in the same manner as the production method.

[0061] <2-1. Mixing process> In the mixing step, a 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 compound (I) and an excipient are uniformly mixed together, and so-called "granulation" is performed, in which multiple small particles are allowed to adhere and aggregate to grow into larger particles.

[0062] The mixing step is carried out using a mixer. There are no particular limitations on the mixer, and for example, a container rotation 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 are no particular limitations 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 are no particular limitations on the compression molding method, and for example, roller compression, tablet compression, briquetting, slugging, or extrusion granulation is preferred.

[0064] The roller compaction method uses a roller compactor as the compression molding machine. The roller compactor has two rolls with their rotation axes arranged horizontally. The two rolls are positioned facing each other in a direction perpendicular to the rotation axis. A specified 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 results in a compression molding step using a roller compression method, 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 and improves 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 elution of Compound (I), and is preferably 0.5 N / mm 2 It is preferable that the resistance is 0.5 to 25 N / mm or more. 2 More preferably, it 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 the compression molding machine. Examples of tablet presses that can be used include single-punch tablet presses and rotary tablet presses. The tablet press has a cylindrical die 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 die from above and below to perform compression molding. This results in the compression molding process being 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 elution 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 briquetting method, a briquetting machine is used as the compression molding machine. The briquetting machine has two rolls with horizontally arranged rotation axes. The two rolls are arranged facing each other in a direction perpendicular to the rotation axes. A predetermined gap is provided between the two rolls, and the two rolls rotate in opposite directions. Multiple pockets are recessed into the surface of the rolls, aligned in the direction of rotation of the rolls. The pockets are the matrix of 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 briquettes (compressed molded products).

[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 elution 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 the 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 unit that presses the mixture in the storage chamber toward the multiple holes. Extrusion methods used in extrusion granulators include screw extrusion, plunger extrusion, and roller extrusion. The pressing units correspond to screws, plungers, and rollers, respectively. The holes are, for example, die holes or holes in a screen (perforated plate). The screw extrusion method is preferred 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 they are kneaded together. This gives a kneaded product (mixture). Examples of the solvent include water, ethanol, and various binder solutions (aqueous solutions or aqueous solutions containing ethanol). In the compression molding step, the kneaded product is placed in the 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 holes in the extrusion granulator is preferably 0.5 mm or less, and more preferably 0.2 to 0.5 mm. Since 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 holes, setting the diameter of the holes to 0.5 mm or less allows for more sufficient pressure to be applied to the kneaded product. When using an extrusion granulator (for example, a twin-screw type) that can apply a sufficiently large pressure to the kneaded product due to the configuration of its extrusion section, the diameter of the holes in 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 are no particular limitations 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 roller compression, tablet compression, briquetting, slugging, or extrusion granulation, a 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] After the compression molding step and before the crushing step, a crushing step of crushing the compression-molded product using a crusher may be performed, whereby the compression-molded product can be crushed stably 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 granulated material of the desired particle size. Note that crushed material 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-described manufacturing steps. The manufacturing method of this embodiment includes a compression molding step. This allows for the rapid dissolution of compound (I), making it possible to easily form a granular composition that can improve the dissolution properties of compound (I). Furthermore, the method for improving dissolution properties of this embodiment includes a compression molding step. This allows for the rapid dissolution of compound (I), making it possible to improve the dissolution properties of compound (I) in the granular composition.

[0082] Furthermore, the dissolution rate of Compound (I) in the granular composition is higher than the dissolution rate 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, pharmaceutical additives other than the excipients may be further added and mixed in addition to the excipients.

[0085] In addition, in the compression molding step, the pressure applied to the mixture may be gradually increased over time. Also, the pressure applied in the early stage of the compression molding step may be greater than the pressure applied in the later stage of the compression molding step. 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 explained in more detail below based on 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 used in the compression molding step of the method for producing the granular compositions of Examples 6 to 8. [Example]

[0090] The granular composition of Example 1 was prepared using the slug method. In the mixing step, 3 mg of Compound (I) and 297 mg of D-mannitol (Mannit P, manufactured by Mitsubishi Shoji Foodtech Co., Ltd.) were mixed to obtain 300 mg of a mixture. Next, in the compression molding step, a precision universal testing machine (AG-X, manufactured by Shimadzu Corporation) was used to apply a pressure of 130.1 N / mm 2 A pressure of 1000 psi 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 granules 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 of the crushed material passed through the sieve. [Example]

[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. [Example]

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

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

[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 preparation was the same as in Example 1. [Example]

[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 (Nissoku 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 kJ / cm 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 (granules). Thereafter, in the classification step, the crushed product 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 of 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 used in Example 6 were used. [Example]

[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 while mixing, a 10% aqueous solution of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) was sprayed. This resulted in granules (mixture) containing 50 mg of hydroxypropyl cellulose. The resulting granules were mixed with 15 mg of magnesium stearate (special magnesium stearate, 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 mixture of 780.9 N / mm 2 A pressure of 1000 kJ / cm was applied to the mixture to compress and mold it, thereby obtaining a plurality of disk-shaped granular compositions each having a diameter of about 2 mm and a mass of 5 mg as Example 7. [Example]

[0097] The granular composition of Example 8 was prepared using an 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 hydroxypropyl cellulose solution was added while mixing. This resulted in 1000 mg of a kneaded product (mixture) containing 20 mg of hydroxypropyl cellulose. The hydroxypropyl cellulose used was the same as 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 crushed in a crushing step to obtain a crushed product (granulated product). Thereafter, in a classification step, the crushed product passed through a sieve with an opening of 1700 μm to obtain 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] 20 mg of the mixture of Example 1 that had not undergone the compression molding process and subsequent steps was used as Comparative Example 1. The other steps were prepared in the same manner as in Example 1.

[0100] Comparative Example 2 The mixture of Example 2 and 20 mg that had not undergone the compression molding process and subsequent steps was used as Comparative Example 2. The other steps were prepared in the same manner as in Example 2.

[0101] Comparative Example 3 The mixture of Example 3 and Comparative Example 3 was prepared in the same manner as in Example 3 except for the above.

[0102] Comparative Example 4 The mixture of Example 4 and 20 mg that had not undergone the compression molding process was used as Comparative Example 4. The other steps were the same as those in Example 4.

[0103] Comparative Example 5 The mixture of Example 5 and 20 mg that had not undergone the compression molding process was used as Comparative Example 5. The other steps were the same as those in Example 5.

[0104] Comparative Example 6 A mixture that had not undergone the compression molding step or later in comparison with Example 7 was used as Comparative Example 6. The other steps were 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 other steps were the same as in Example 1.

[0106] [Comparative Example 8] The compound (I) that was not compression molded was used as Comparative Example 8. The other steps were the same as in Comparative Example 7.

[0107] Dissolution tests were conducted on 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.), dissolution tests were conducted by the paddle method using water as the dissolution test medium. The volume of the dissolution test medium was 900 mL, the temperature of the dissolution test medium was 37±0.5°C, and the paddle rotation speed was 50 rpm. The entire amount of each Example and Comparative Example was added to the dissolution test medium, and the dissolution test medium was sampled 5, 10, 15, 30, 45, 60, 90, and 120 minutes after the start of the test. The dissolution test medium was then filtered through 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 change over time in the dissolution rate of compound (I) from the granular compositions of Examples 1 to 5, respectively, and also show the change over time in the dissolution rate of compound (I) from Comparative Examples 1 to 5, respectively. Figure 10 shows the change over time in the dissolution rate of compound (I) from the granular compositions of Examples 6 to 8 and Comparative Example 6. Figure 11 shows the change over time in the dissolution rate of compound (I) from Comparative Examples 7 and 8. In Figures 5 to 11, the vertical axis represents the dissolution rate (unit: %), and the horizontal axis represents time (unit: minutes). Solid lines E1 to E8 represent the cases of Examples 1 to 8, respectively, and dashed lines C1 to C8 represent 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 to 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 Figure 10, the granular compositions of Examples 6 to 8 had improved dissolution rates of compound (I) compared to Comparative Example 6. Furthermore, 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 a compression molding step, 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 when the compression molding step is performed by roller compaction, tablet compression, or extrusion granulation.

[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 between 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, when they were mixed with excipients and then compression-molded as in the present embodiment, the dissolution rates were almost the same as those 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 compression molding a mixture of Compound (I) and an excipient is unclear, it is presumed that an interaction occurs between Compound (I) and the excipient during the compression molding process. However, the present invention is not limited to the above mechanism.

[0114] Next, an experiment was conducted 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 disc-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 of

[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 / mm) of the mixture itself (a granular composition not containing voids) in the granular composition was measured by a constant volume expansion method using a dry automatic density meter (AccuPyc II 1340, manufactured by Shimadzu Corporation). 3 ) was measured. Then, the porosity ε (unit: %) of the granular composition was calculated using 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 high, the porosity ε was small and the elution rate of compound (I) was high. Furthermore, it was found that when the porosity ε of the granular composition was 45% or less, the elution rate of compound (I) was sufficiently higher than the elution 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. However, the porosity ε may also be determined using, for example, a tap density measurement method. Specifically, a weighed sample (multiple granular compositions) is placed in, for example, a measuring cylinder, and the measuring cylinder is lightly tapped until no bulk loss is observed, thereby reducing the gaps between the individual granular compositions in the sample. The volume V (apparent volume) of the sample is then measured by reading the graduations on the measuring cylinder. The true density ρ of the sample is then measured using a dry automatic densimeter, and the porosity ε is calculated using the above formula (1). This method also makes it easy to determine the porosity ε of irregularly shaped granular compositions. [Industrial Applicability]

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

Claims

1. A method for producing a granular composition comprising the following compound (I): 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; The method for producing a granular composition, wherein the granular composition is a disk-shaped granular composition having a diameter of about 2 mm to 5 mm. 【Chemistry 1】

2. A method for producing a granular composition as described in claim 1, wherein the granular composition is a disk-shaped granular composition having a diameter of approximately 2 mm to 3 mm.

3. A method for producing a granular composition as described in claim 1, wherein the granular composition is a disk-shaped granular composition having a diameter of approximately 2 mm.

4. The method for producing a granular composition according to any one of claims 1 to 3, wherein the compression molding step is carried out by a tablet compression method.

5. A method for producing a granular composition described in any one of claims 1 to 4, wherein the granular composition has a higher elution rate of compound (I) than a granular composition that does not include the compression molding step.

6. 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, The granular composition has a diameter of about 2 mm to 5 mm, The compression molding step is carried out by a tablet compression method, A method for producing a granular composition, wherein the elution rate of compound (I) in the granular composition is higher than in a method not including the compression molding step. 【Chemistry 2】

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