Granular composition, method for producing a granular composition, and method for improving the elution properties of a granular composition.

Abstract

The present invention provides a method for producing a granular composition with improved dissolution of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, a method for improving dissolution, and a granular composition. [Solution] The method for producing the granular composition includes a compression molding step in which a mixture of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars is compressed and molded to obtain a compressed molded product.

Description

[Technical Field]

[0001] The present invention relates to a granular composition containing 2-{4-[N-(5,6-diphenylpyrazine-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). Furthermore, the present invention relates to a method for improving the elution properties of compound (I) in a granular composition containing compound (I). [Background technology]

[0002] The following structural formula: [ka] Compound (I), shown in [image / text], is known to have excellent prostaglandin I2 (also known as PGI2) receptor agonist activity and exhibit various pharmacological effects, including platelet aggregation inhibition, vasodilation, bronchomuscular dilation, lipid deposition inhibition, and leukocyte activation inhibition (see, for example, 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] Generally, it is difficult for children and the elderly with low swallowing ability to take tablets. Although OD tablets and chewable tablets have been developed as easily swallowable tablets, they are not necessarily easy to take for the elderly with little saliva secretion.

[0006] In contrast, granular preparations (granular compositions) such as powders, fine granules, granules, granulated tablets, and dry syrups are easy for the elderly to take, improve medication compliance, and are very useful because the degree of freedom in changing the dosage increases.

[0007] Also, when manufacturing a preparation, a preparation technique for enhancing the elution property of the medicinal ingredient is usually used. Generally, the elution property of the medicinal ingredient from a tablet depends on the time until the tablet disintegrates into granules or powder. Therefore, in the case of tablets, rapid elution of the medicinal ingredient cannot be expected as compared with the case of granules or powders.

[0008] From the above, a 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 elution property of compound (I) was low in the granules obtained by the fluidized bed granulation method. That is, in the granular composition containing compound (I), it was revealed that the elution of compound (I) becomes slow and the elution property is low only by attaching an excipient or the like to compound (I).

[0009] An object of the present invention is to provide a method for producing a granular composition capable of improving the elution property of compound (I). Another object of the present invention is to provide a method for improving elution property capable of improving the elution property of compound (I) in a granular composition. Another object of the present invention is to provide a granular composition capable of improving the elution property of compound (I).

Means for Solving the Problems

[0010] As a result of diligent research to solve the above problems, the inventors of the present invention have found that the elution properties 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 compression molding, thereby completing the present invention.

[0011] The present invention relates to a method for producing a granular composition containing compound (I), comprising a compression molding step of obtaining a compressed molded product by compression molding a mixture obtained by mixing compound (I) with at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars.

[0012] Furthermore, in the present invention, in a method for producing the granular composition having the above 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 the granular composition having the above configuration, it is preferable that the porosity of the granular composition is 45% or less.

[0014] Furthermore, in the method for producing the granular composition having the above configuration, it is preferable that the particle size of the granular composition is smaller than 5 mm.

[0015] Furthermore, in the present invention, in a method for producing the granular composition having the above configuration, it is preferable that the compression molding step is carried out by one of the following methods: roller compression, tablet compression, briquette, slug, and extrusion granulation.

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

[0017] Furthermore, in the method for producing the granular composition having the above configuration, it is preferable that the present invention further includes a crushing step of crushing the compressed molded product.

[0018] Furthermore, in the method for producing the granular composition having the above configuration, it is preferable that the granular composition is a granular preparation, a powder, a filling for a capsule, a granular tablet, a dry syrup, or a fine granule preparation.

[0019] The present invention relates to a method for improving the elution properties of compound (I) in a granular composition containing compound (I), comprising a compression molding step of obtaining a compressed molded product by compression molding a mixture of compound (I) and at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars.

[0020] Furthermore, in the method for improving elution properties according to the above configuration, it is preferable that the elution properties of compound (I) in the granular composition are higher than those of compound (I) in the mixture before the compression molding process.

[0021] Furthermore, in the method for improving dissolution properties with the above configuration, it is preferable that the porosity of the granular composition is 45% or less.

[0022] Furthermore, in the method for improving dissolution properties with the above configuration, it is preferable that the particle size of the granular composition is smaller than 5 mm.

[0023] Furthermore, in the method for improving dissolution properties with the above configuration, it is preferable that the compression molding step is carried out by one of the following methods: roller compression, tablet compression, briquette, slug, and extrusion granulation.

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

[0025] Furthermore, in the method for improving the elution properties of the present invention, it is preferable to further include a crushing step of crushing the compressed molded product.

[0026] Furthermore, in the method for improving dissolution properties of the above configuration, the granular composition is preferably a granular preparation, a powder, a filling for a capsule, 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, with a porosity of 45% or less.

[0028] Furthermore, in the granular composition having the above configuration, it is preferable that the particle size is smaller than 5 mm. [Effects of the Invention]

[0029] The method for producing the granular composition of the present invention makes it possible to obtain a granular composition with improved elution of compound (I). Furthermore, the method for improving elution of compound (I) in the granular composition makes it possible to improve the elution of compound (I). In addition, the granular composition of the present invention makes it possible to improve the elution of compound (I). [Brief explanation of the drawing]

[0030] [Figure 1] This is a powder X-ray diffraction spectrum chart of type I crystals of compound (I) contained in a granular composition according to one embodiment of the present invention. The vertical axis shows the peak intensity (unit: cps), and the horizontal axis shows the diffraction angle 2θ (unit: °). [Figure 2] This is a powder X-ray diffraction spectrum chart of type II crystals of compound (I) contained in a granular composition according to one embodiment of the present invention. The vertical axis shows the peak intensity (unit: cps), and the horizontal axis shows the diffraction angle 2θ (unit: °). [Figure 3] This is a powder X-ray diffraction spectrum chart of a type III crystal of compound (I) contained in a granular composition according to one embodiment of the present invention. The vertical axis shows the peak intensity (unit: cps), and the horizontal axis shows the diffraction angle 2θ (unit: °). [Figure 4] This is a process diagram showing the manufacturing process of a granular composition according to one embodiment of the present invention. [Figure 5]This figure shows the time course of the elution rate of compound (I) in Example 1 and Comparative Example 1. The vertical axis represents the elution rate (in %), and the horizontal axis represents time (in minutes). [Figure 6] This figure shows the time course of the elution rate of compound (I) in Example 2 and Comparative Example 2. The vertical axis represents the elution rate (in %), and the horizontal axis represents time (in minutes). [Figure 7] This figure shows the time course of the elution rate of compound (I) in Example 3 and Comparative Example 3. The vertical axis represents the elution rate (in %), and the horizontal axis represents time (in minutes). [Figure 8] This figure shows the time course of the elution rate of compound (I) in Example 4 and Comparative Example 4. The vertical axis represents the elution rate (in %), and the horizontal axis represents time (in minutes). [Figure 9] This figure shows the time course of the elution rate of compound (I) in Example 5 and Comparative Example 5. The vertical axis represents the elution rate (in %), and the horizontal axis represents time (in minutes). [Figure 10] This figure shows the time course of the elution rate of compound (I) in Examples 6-8 and Comparative Example 6. The vertical axis represents the elution rate (in %), and the horizontal axis represents time (in minutes). [Figure 11] This figure shows the time course of the elution rate of compound (I) in Comparative Examples 7 and 8. The vertical axis represents the elution rate (in %), and the horizontal axis represents time (in minutes). [Modes for carrying out the invention]

[0031] The following describes a granular composition according to one embodiment of the present invention. In this specification, "granular composition" means a material obtained by processing a powder raw material into granules larger than the powder raw material through a mixing step and a compression molding step described later.

[0032] <1. Composition of the granular composition> The granular composition of this embodiment includes, for example, granules, powders, fine granules, granular tablets, and dry syrups. Furthermore, the granular composition can be used, for example, as an oral solid preparation for direct internal administration. It can also be used as a suspension, dispersed in, for example, water or syrup. Additionally, the granular composition can be used by filling capsules; that is, it 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 crystalline forms (Type I crystal, Type II crystal, and Type III crystal).

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

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

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

[0037] The excipients included 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% by weight of compound (I).

[0038] Examples of sugar alcohols include D-mannitol, erythritol, xylitol, D-sorbitol, isomalt, maltitol, and lactitol. 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, and wheat starch. Corn starch and potato starch are preferred, with corn starch being more preferred.

[0040] Examples of sugars include maltose, trehalose, lactose, glucose, fructose, and sucrose. Maltose, trehalose, glucose, and lactose are preferred, with glucose and lactose being 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 improves the elution properties of compound (I) in the granular composition. Furthermore, it is preferable that the porosity of the granular composition is 45% or less, as this further improves the elution properties of compound (I). Details regarding porosity will be described later.

[0042] Furthermore, a particle size of less than 5 mm is preferable because it makes it easier for the user to take and increases the flexibility of adjusting the dosage. A particle size of 3 mm or less is even more preferable because it makes it easier for the user to take and increases the flexibility of adjusting the dosage. Here, "particle size" refers to the "average particle diameter," which is measured by microscopy (visual observation) or image analysis.

[0043] The granular composition may contain various pharmaceutical additives in addition to the excipients. The pharmaceutical additives are not particularly limited as long as they are pharmaceutically and pharmacologically acceptable, and examples include binders, disintegrants, lubricants, fluidizers, colorants, coatings, flavoring agents, foaming agents, sweeteners, fragrances, antioxidants, surfactants, plasticizers, and sugar coatings. These pharmaceutical additives may be used individually or in combination of two or more.

[0044] Coating the granular composition with a coating agent or sugar coating agent using a known method is preferable because it can improve the aesthetic appearance and ensure the identifiability of the granular composition. Furthermore, including a coloring agent in the granular composition is preferable because it can improve the photostability and ensure the identifiability of the granular composition. Furthermore, including a flavoring agent or fragrance in the granular composition is preferable because it can easily improve the flavor of the granular composition.

[0045] Examples of binders include gelatin, pullulan, hydroxypropylcellulose, methylcellulose, hypromellose, polyvinylpyrrolidone, macrogol, acacia gum, 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 fluidizing agents include light anhydrous silicic acid, hydrated silicon dioxide, synthetic aluminum silicate, magnesium aluminometasilicate, and calcium silicate.

[0049] Examples of coloring agents include titanium dioxide, talc, iron(III) oxide, yellow iron(III) oxide, food yellow No. 4, and food yellow No. 4 aluminum lake.

[0050] Examples of coating agents include hypromellose, hydroxypropylcellulose, polyvinyl alcohol, ethylcellulose, ethyl acrylate / methyl methacrylate copolymer, methacrylate copolymer LD, and hypromellose acetate succinate.

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

[0052] Examples of foaming agents include sodium bicarbonate, anhydrous sodium carbonate, and calcium carbonate.

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

[0054] Examples of fragrances 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 plasticizers 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 dioxide, macrogol, stearic acid, and ethylcellulose.

[0059] Compound (I) has excellent PGI2 receptor agonist activity and is effective in treating diseases involving PGI2, such as transient ischemic attacks (TIAs), diabetic neuropathy (see, for example, Non-Patent Document 1), diabetic gangrene (see, for example, Non-Patent Document 1), peripheral circulatory disorders (see, for example, 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 (see, for example, systemic lupus erythematosus, scleroderma) (see, for example, Non-Patent Document 6). (See also) Mixed connective tissue disease, vasculitis syndrome, reocclusion / restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute ischemic thrombosis, pulmonary embolism) (see, for example, Non-Patent Documents 5 and 7), hypertension, pulmonary hypertension such as pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (see, for example, Non-Patent Documents 8 and 9), ischemic disease (e.g., cerebral infarction, myocardial infarction (see, for example, Non-Patent Document 10)), angina pectoris (e.g., stable angina, unstable angina) (see, for example, Non-Patent Document 11), glomerulonephritis (see, for example, Non-Patent Document 12), diabetes Diseases involving organ or tissue fibrosis [e.g., kidney disease (e.g., see Non-Patent Literature 1), chronic renal failure, allergies, bronchial asthma (e.g., see Non-Patent Literature 13), ulcers, bedsores, restenosis after coronary interventions such as atherectomy and stent placement, thrombocytopenia due to dialysis, kidney disease (e.g., tubulointerstitial nephritis), respiratory disease (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease (e.g., see Non-Patent Literature 14)), digestive disease (e.g., cirrhosis, viral hepatitis, chronic pancreatitis, scirrhous gastric cancer), cardiovascular disease (e.g., myocardial cancer)] Physiology), 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 tract diseases (e.g., benign prostatic hyperplasia), other diseases (e.g., Alzheimer's disease, sclerotic peritonitis, type 1 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 prostatectomy, vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease,Intestinal tuberculosis, ischemic colitis, intestinal ulcers associated with Behçet's disease), gastritis, gastric ulcers, ischemic eye diseases (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular osteonecrosis, 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 symptoms associated with intestinal injuries (e.g., injuries occurring in the duodenum, small intestine, or large intestine, but not particularly limited to those occurring in the duodenum, small intestine, or large intestine, such as mucosal injuries or ulcers such as erosions in the duodenum, small intestine, or large intestine) and spinal stenosis (e.g., cervical spinal stenosis, thoracic spinal stenosis, lumbar spinal stenosis, extensive spinal stenosis, sacral stenosis) (e.g., paralysis, decreased sensation, pain, numbness, decreased walking ability). Furthermore, the granular composition of the present invention is also useful as a promoter of angiogenesis therapies such as gene therapy or autologous bone marrow transplantation, and as an angiogenesis promoter in peripheral vascular reconstruction or angiogenesis therapy.

[0060] <2. Method for producing the granular composition of this embodiment and method for improving the elution properties 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 step, a compression molding step, a crushing step, a classification step, and an addition step. A method for improving the elution properties of compound (I) in the granular composition is also performed in the same manner as the manufacturing process.

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

[0062] The mixing process is carried out using a mixer. There are no particular limitations on the mixer; for example, a rotary container mixer, a mechanical agitator mixer, an airflow mixer, or a kneading mixer can be used. Alternatively, a granulator may be used as the mixer for the mixing process. There are no particular limitations on the granulator; for example, a fluidized bed granulator, an agitator granulator, or a rotary granulator can be used.

[0063] <2-2. Compression molding process> In the compression molding process following the mixing process, the mixture prepared in the mixing process is compressed to obtain a compressed molded product. At this time, it is preferable that the porosity of the compressed molded product be 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, but for example, roller compression, tablet compression, briquette method, slug method, or extrusion granulation method are preferred.

[0064] In the roller compression method (roller compacting method), a roller compactor is used as the compression molding machine. The roller compactor has two rolls with their rotation axes positioned horizontally. The two rolls are positioned opposite each other in directions perpendicular to the rotation axis. A predetermined gap is provided between the two rolls, and the two rolls rotate in opposite directions.

[0065] The mixture obtained in the mixing process is supplied to the gap between two rotating rolls, and the mixture is compressed and molded by the two rolls. This performs the compression molding process using the roller compression method, forming a sheet-like (thin plate-like) or flake-like compressed molded product. The surface of the rolls may be smooth or may have multiple minute irregularities. Providing multiple minute irregularities on the surface of the rolls is preferable because it makes it easier to hold the mixture on the rolls and improves 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 large enough to improve the elution of compound (I), for example, 0.5 N / mm². 2 Preferably, it is 0.5 to 25 N / mm². 2 It is more preferable that the density is 0.5 to 10 N / mm². 2 It would be even more preferable if that were the case.

[0067] In the tabletting method, a tableting machine is used as the compression molding machine. As the tableting machine, for example, a single-shot tableting machine or a rotary tableting machine can be used. The tableting machine has a cylindrical mortar and a pair of upper and lower metal rods (upper pestle, lower pestle). In the compression molding process, the upper and lower pestles sandwich and compress the mixture filled in the mortar in the vertical direction. Thereby, the compression molding process is performed by the tabletting 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 can improve the elution property of the compound (I), and it is preferably 10 N / mm 2 or more. Also, the pressure applied to the mixture is more preferably 10 to 1500 N / mm 2 and even more preferably 10 to 700 N / mm 2

[0069] In the briquetting method, a briquetting machine is used as the compression molding machine. The briquetting machine has two rolls with horizontal rotating shafts. The two rolls are arranged opposite to each other in a direction perpendicular to the rotating shaft. A predetermined gap is provided between the two rolls, and the two rolls rotate in opposite directions. A plurality of pockets are recessed on the surface of the roll in the rotational direction of the roll. The pocket is a mold of the briquette, and the volume of the pocket is about 0.3 cm 3 to about 200 cm 3 and is preferably so.

[0070] In the compression molding process, the mixture prepared in the mixing process is supplied to the gap between the two rotating rolls, and the mixture is pressurized and compression molded by the two rolls. Thereby, the compression molding process is performed by the briquetting method, and a briquette (compression molded product) is formed.

[0071] At this time, the magnitude of the pressure applied to the mixture is not particularly limited as long as it can improve the elution property of the compound (I), and it is 10 N / mm 2 ​It is preferable that the pressure applied to the mixture be 10 to 1500 N / mm². 2 It is more preferable that the value is 10-700 N / mm 2 It would be even more preferable if that were the case.

[0072] In the extrusion granulation method, an extrusion granulator is used as the compression molding machine. The extrusion granulator has a storage chamber that houses the mixture prepared in the mixing process and opens multiple circular holes, and a pressing section that presses the mixture in the storage chamber toward the multiple holes. Extrusion methods for extrusion granulators include screw extrusion, plunger extrusion, and roller extrusion. The pressing section corresponds to a screw, plunger, and roller, 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 granular compositions.

[0073] In the extrusion granulation method, compound (I) and the excipient are mixed with a solvent during the mixing step. This yields a compound (mixture). Examples of solvents include water, ethanol, or various binder solutions (aqueous solutions or aqueous solutions containing ethanol). In the compression molding step, the compound is placed in the storage chamber of the extrusion granulator, and the pressing section of the extrusion granulator pushes the compound through the holes to the outside of the extrusion granulator. This yields a cylindrical compressed molded product.

[0074] The diameter of the holes in the extruder 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 extruder 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 compound. However, when using an extruder granulator that can apply sufficiently large pressure to the compound due to the configuration of the extrusion section (for example, a twin-screw type), the diameter of the holes in the extruder granulator may be larger than 0.5 mm.

[0075] The slug method is a method of forming a cylindrical powder compression molded mass (slug, compressed molded product) by applying pressure to the mixture prepared in the mixing process while it is still dry. There are no particular limitations on the size of the powder compression molded mass; for example, the diameter of the powder compression molded mass can be about 20 mm.

[0076] As described above, by performing the compression molding process using the roller compression method, tablet compression method, briquette method, slug method, or extrusion granulation method, compressed molded products can be easily formed.

[0077] <2-3. Crushing Process> In the crushing process following the compression molding process, the compressed molded product is crushed using a crusher or the like. This crushing process forms granular crushed material from the compressed molded product. In the following explanation, "granular crushed material" may be referred to as "finished granules."

[0078] Furthermore, a decompression process may be performed after the compression molding process and before the crushing process, in which the compressed molded material is loosened using a crusher. This allows the compressed molded material to be crushed stably during the crushing process.

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

[0080] <2-5. Additional Processes> In the addition step following the classification step, the granules classified in the classification step are mixed with pharmaceutical additives. The mixing method in the addition step is the same as the mixing method in the mixing step described above. Pharmaceutical additives are added to the granules through the addition step.

[0081] The granular composition is formed through the above manufacturing process. The manufacturing method of this embodiment includes a compression molding step. This allows for the rapid dissolution of compound (I) and the easy formation of a granular composition with improved dissolution properties of compound (I). Furthermore, the method for improving dissolution properties of this embodiment also includes a compression molding step. This allows for the rapid dissolution of compound (I) and the improved dissolution properties of compound (I) in the granular composition.

[0082] Furthermore, the elution rate of compound (I) in the granular composition is higher than that of compound (I) in the mixture before the compression molding process.

[0083] In this embodiment, the method for producing the granular composition only needs to include a compression molding step, and there are no particular restrictions on other steps. For example, general methods described in publications such as Powder Technology and Pharmaceutical Processes (D. Chulia et al., Elsevier Science Pub Co (December 1, 1993)) may be used.

[0084] Furthermore, in the mixing process, in addition to the excipients, pharmaceutical additives other than excipients may be added and mixed.

[0085] Furthermore, in the compression molding process, the pressure applied to the mixture may be gradually increased over time. Alternatively, the pressure applied in the early stages of the compression molding process may be greater than the pressure applied in the later stages. This prevents damage such as cracking of the compressed molded product and allows for the stable formation of the compressed molded product.

[0086] The present invention will be described 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 in the compression molding step of the manufacturing 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) and 297 mg of D-mannitol (Mannit P, manufactured by Mitsubishi Corporation Foodtech Co., Ltd.) were mixed to obtain a mixture of 300 mg. Next, in the compression molding step, a precision universal testing machine (AG-X, manufactured by Shimadzu Corporation) was used to compress the mixture to 130.1 N / mm². 2 A compressed molded product was obtained by applying pressure. In the crushing process, the compressed molded product was crushed, and in the classification process, 20 mg of the granules that passed through a sieve with a mesh size of 1700 μm was used as the granular composition (granules) of Example 1. At this time, the compressed molded product was crushed in such a way that all of the crushed material 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. Otherwise, it 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. Otherwise, it 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 Nippon Shokuhin Kako Co., Ltd.) was used as an excipient. The rest of the preparation was the same as in Example 1. [Examples]

[0094] In the granular composition of Example 5, lactose monohydrate (Pharmatose® 200M, manufactured by DFE Pharma) was used as an excipient. Otherwise, it was prepared in the same manner as in Example 1. [Examples]

[0095] The granular composition of Example 6 was prepared using the roller compression method. In the mixing step, 0.2 mg of compound (I), 900 mg of D-mannitol (Mannit P, manufactured by Mitsubishi Corporation Foodtech Co., Ltd.), and 99.8 mg of corn starch (Nisshoku Corn Starch W, manufactured by Nippon Shokuhin Kako Co., Ltd.) were mixed to obtain a 1000 mg mixture. Next, in the compression molding step, a roller compactor (TF-MINI, manufactured by Freund Industrial Co., Ltd.) was used to compress the mixture at a rate of 10 N / mm². 2 A thin, plate-shaped compressed molded product was obtained by applying pressure. Next, in the crushing process, the compressed molded product was crushed to obtain crushed material (granules). Subsequently, in the classification process, the granules that passed through a sieve with a mesh size of 710 μm were used as the granular composition (granules) of Example 6. At this time, the compressed molded product was crushed so that all of the crushed material passed through the sieve. In Examples 7 and 8 and Comparative Example 6 below, compound (I), D-mannitol, and corn starch were the same as in Example 6. [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 apparatus (MP-01, manufactured by Powrec Co., Ltd.), and a 10% hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) aqueous solution was sprayed while mixing. This yielded granules (mixture) containing 50 mg of hydroxypropyl cellulose. 15 mg of magnesium stearate (special magnesium stearate product, manufactured by Taihei Chemical Industry Co., Ltd.) was mixed with the obtained granules to obtain a mixture of 1015 mg. Next, in the compression molding step, a rotary tablet press (Collect, manufactured by Kikusui Seisakusho Co., Ltd.) was used to compress the mixture at 780.9 N / mm². 2 The mixture was compressed by applying pressure to it, and multiple disc-shaped granular compositions, each with a diameter of approximately 2 mm and a mass of 5 mg, were obtained as Example 7. [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 granulator (VG-05, manufactured by Powrec Co., Ltd.), and a 10% aqueous solution of hydroxypropyl cellulose was added while mixing. This yielded a 1000 mg paste (mixture) containing 20 mg of hydroxypropyl cellulose. The same hydroxypropyl cellulose used was the same as in Example 7.

[0098] The resulting mixture was extruded using a wet extrusion granulator (Multi-Gran MG-55, manufactured by Dalton Co., Ltd.) through a screen with a pore size of 0.5 mm to obtain granules (compressed molded product). The obtained granules were dried at 60°C, and then crushed in a crushing process to obtain crushed material (finished granules). Subsequently, in a classification process, the finished granules that passed through a sieve with a mesh size of 1700 μm were used as the granular composition (granules) of Example 8. At this time, the compressed molded product was crushed so that all of the crushed material passed through the sieve.

[0099] [Comparative Example 1] Comparative Example 1 consisted of 20 mg of the mixture from Example 1 that had not undergone the compression molding process. The rest of the preparation was the same as in Example 1.

[0100] [Comparative Example 2] Comparative Example 2 consisted of 20 mg of the mixture from Example 2 that had not undergone the compression molding process. The rest of the preparation was the same as in Example 2.

[0101] [Comparative Example 3] Comparative Example 3 consisted of 20 mg of the mixture from Example 3 that had not undergone the compression molding process. The rest of the preparation was the same as in Example 3.

[0102] [Comparative Example 4] Comparative Example 4 consisted of 20 mg of the mixture from Example 4 that had not undergone the compression molding process. The rest of the preparation was the same as in Example 4.

[0103] [Comparative Example 5] Comparative Example 5 consisted of 20 mg of the mixture from Example 5 that had not undergone the compression molding process. The rest of the preparation was the same as in Example 5.

[0104] [Comparative Example 6] Comparative Example 6 was prepared using a mixture that had not undergone the compression molding process or later, as opposed to Example 7. The rest of the preparation was the same as in Example 7.

[0105] [Comparative Example 7] As Comparative Example 7, compound (I) alone was compression-molded in the same manner as in Example 1, without the use of any excipients. All other preparations were carried out in the same manner as in Example 1.

[0106] [Comparative Example 8] Compound (I), which was not compression-molded, was designated as Comparative Example 8. The other compounds were prepared in the same manner as in Comparative Example 7.

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

[0108] Figures 5 to 9 show the time course of the elution rate of compound (I) in the granular compositions of Examples 1 to 5, and the time course of the elution rate of compound (I) in Comparative Examples 1 to 5, respectively. Figure 10 shows the time course of the elution rate of compound (I) in the granular compositions of Examples 6 to 8 and in Comparative Example 6. Figure 11 shows the time course of the elution rate of compound (I) in Comparative Examples 7 and 8. In Figures 5 to 11, the vertical axis represents the elution rate (in %), and the horizontal axis represents time (in 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] As shown in Figures 5 to 9, the granular compositions of Examples 1 to 5 showed an improved elution rate of compound (I) compared to Comparative Examples 1 to 5. Therefore, it can be seen that the elution properties of compound (I) are improved by compression molding of the mixture of compound (I) and the excipient.

[0110] As shown in Figure 10, the granular compositions of Examples 6 to 8 showed improved elution rates of compound (I) compared to Comparative Example 6. Furthermore, in all of the granular compositions of Examples 6 to 8, the elution rate of compound (I) at 120 minutes after the start of the test was 70% or higher. On the other hand, in Comparative Example 6, which did not undergo a compression molding process, the elution rate of compound (I) at 120 minutes after the start of the test was 41.2%. From the above, it can be seen that the elution properties of compound (I) can be improved even when a compression molding process is performed by roller compression, tablet compression, or extrusion granulation.

[0111] As shown in Figure 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 granular compositions.

[0112] Furthermore, when acetaminophen, indomethacin, and celiprolol hydrochloride were mixed with excipients and then compressed, as in this embodiment, the elution rates were approximately the same as those when not compressed.

[0113] The detailed mechanism by which the elution of compound (I) in the granular composition is improved by compression molding of a mixture of compound (I) and an excipient is unknown, but 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 elution properties 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. 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 the tablet compression method to form disc-shaped granules. These granules were used as the granular composition in this experiment. At this time, the pressure applied to the mixture ranged from 0 to 509.6 N / mm². 2 It varied within the range.

[0116] Next, the mass M (in g) of each granular composition is measured, and the volume V (in mm) of each granular composition is calculated based on the diameter and thickness of the granular composition. 3 The true density ρ (unit: g / mm³) of the mixture itself (granular composition without voids) in the granular composition was calculated using the constant volume expansion method with a dry automatic densimeter (Accupic II 1340, manufactured by Shimadzu Corporation). 3 The following parameters were 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 elution test as described above.

[0119] The results of this experiment showed that when the pressure applied to the mixture during 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 significantly 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 its diameter and thickness to determine the porosity ε. However, the porosity ε may also be determined using, for example, the tap density measurement method. Specifically, after placing the weighed sample (multiple granular compositions) into a graduated cylinder, for example, the graduated cylinder is lightly tapped until the volume reduction is eliminated, thereby reducing the gaps between each granular composition in the sample. Then, the volume V (apparent volume) of the sample is measured by reading the scale on the graduated cylinder. Subsequently, the true density ρ of the sample is measured using a dry automatic densimeter, and the porosity ε is determined from equation (1) above. Using this method, the porosity ε of irregularly shaped granular compositions can also be easily determined. [Industrial applicability]

[0121] The present invention can be used in granular compositions comprising compound (I) and an excipient.

Claims

1. A method for producing a granular composition containing the following compound (I): A method for producing a granular composition, comprising a compression molding step of obtaining a compressed molded product by compressing a mixture of the compound (I) and at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars. 【Chemistry 1】

2. A method for producing a granular composition according to claim 1, wherein the elution of compound (I) in the granular composition is higher than the elution of compound (I) in the mixture before the compression molding step.

3. A method for producing the granular composition according to claim 1 or claim 2, wherein the porosity of the granular composition is 45% or less.

4. A method for producing the granular composition according to any one of claims 1 to 3, wherein the particle size of the granular composition is less than 5 mm.

5. A method for producing a granular composition according to any one of claims 1 to 4, wherein the compression molding step is carried out by one of the following: roller compression, tablet compression, briquette, slug, and extrusion granulation.

6. In the compression molding process, The extrusion granulation method is performed using an extruder that extrudes the mixture through the holes. A method for producing the granular composition according to claim 5, wherein the diameter of the pore portion is 0.2 mm to 0.5 mm.

7. A method for producing a granular composition according to any one of claims 1 to 6, further comprising a crushing step of crushing the compressed molded product.

8. A method for producing a granular composition according to any one of claims 1 to 7, wherein the granular composition is a granule, a powder, a capsule filler, a granular tablet, a dry syrup, or fine granules.

9. A method for improving the elution properties of compound (I) in a granular composition containing the following compound (I), A method for improving elution properties, comprising a compression molding step of obtaining a compressed molded product by compression molding a mixture of the compound (I) and at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars. 【Chemistry 2】

10. The method for improving elution properties according to claim 9, wherein the elution properties of compound (I) in the granular composition are higher than those of compound (I) in the mixture before the compression molding step.

11. The method for improving elution properties according to claim 9 or claim 10, wherein the porosity of the granular composition is 45% or less.

12. The method for improving dissolution properties according to any one of claims 9 to 11, wherein the particle size of the granular composition is smaller than 5 mm.

13. The method for improving dissolution properties according to any one of claims 9 to 12, wherein the compression molding step is performed by one of the following: roller compression, tablet compression, briquette, slug, and extrusion granulation.

14. In the compression molding process, The extrusion granulation method is performed using an extruder that extrudes the mixture through the holes. The method for improving dissolution properties according to claim 13, wherein the diameter of the hole is 0.2 mm to 0.5 mm.

15. The method for improving dissolution properties according to any one of claims 9 to 14, further comprising a crushing step of crushing the compressed molded product.

16. The method for improving dissolution properties according to any one of claims 9 to 15, wherein the granular composition is a granular preparation, a powder, a filling for a capsule, a granular tablet, a dry syrup, or fine granules.

17. A granular composition having a void ratio of 45% or less, obtained by mixing the following compound (I) with at least one excipient selected from the group consisting of sugar alcohols, starches, and sugars. 【Transformation 3】

18. The granular composition according to claim 17, wherein the particle size is smaller than 5 mm.

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