JP2015063521A - Tablet with high drug content and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tablet with high drug content in which eliminated are tableting disorders, such as lamination and capping, causing a problem when increasing drug content.SOLUTION: A tablet with high drug content is obtained by performing compression molding of the granulated material obtained by wet granulation using a binding liquid containing microparticles of a substantially water-insoluble substance.

Description

  The present invention relates to a tablet having a high drug content and a method for producing the same.

  Considering the patient's ingestion regarding the size of the tablet, it is said that the smaller the tablet, the easier it is to drink. For example, it is reported that many patients feel that it is easy to take when the diameter of the tablet is 5 mm to 9 mm, but more patients feel that it is difficult to take when the diameter is 11 mm or more (Non-patent Document 1). ). However, if the size of the tablet is too small, handling properties such as difficulty in picking up the tablet from the PTP sheet or packaging container, difficulty in picking, etc. will become a problem. Furthermore, the tablet diameter is preferably in the range of 6 mm to 10 mm. In other words, the size of tablets not only affects patient compliance and quality of life, but also affects the ease of handling and handling of healthcare professionals, so it is extremely important in developing pharmaceuticals for oral administration. It becomes a point.

  When designing tablets containing drugs with a large single dose, the size of the tablets tends to increase, or the number of tablets to be taken at one time tends to increase. It is required to make it. In order to reduce the size of tablets, it is necessary to reduce the content of pharmaceutical additives added at the time of manufacture as much as possible and to increase the drug content of the tablets. However, the physical properties of the drugs are given to the tableting process. The impact will be greater. In fact, many of the drugs used as active ingredients for oral administration produce tablets that cause tableting problems called lamination and capping due to the physical properties of each drug as the drug content of the tablet increases. It becomes difficult.

  In the manufacture of tablets, since compression molding is performed, it is important that the mixed powder for tableting has compression moldability. For this reason, a method is generally employed in which a binder is used and granulated by a dry or wet granulation method to improve the binding force between the particles during tableting. The wet granulation method is a technique in which a solvent or a binding liquid is added to a powder mixture containing drugs and the like and granulated under wet conditions. Generally, hydroxypropylcellulose, polyvinylpyrrolidone, or the like is used as a binder. Yes.

  In the production of tablets having a high drug content, several means have been proposed as methods for suppressing tableting troubles such as lamination. For example, Patent Document 1 discloses a method for producing a tablet containing 95 w / w% of acetaminophen by wet granulation using a binding liquid containing polyvinylpyrrolidone as a binder and propylene glycol as a plasticizer. ing. It is said that the obtained tablet does not affect disintegration and can reduce friability.

  Patent Document 2 discloses a tablet containing 87 w / w% of clarithromycin. By adding purified water to the mixed powder of drug, sodium carboxymethyl starch as a disintegrant, and hydroxypropyl cellulose as a binder, wet granulation, and by producing tablets by compression molding using the resulting granulated product, It has been reported that tableting troubles such as capping can be suppressed.

  Patent Document 3 discloses a tablet containing 80 w / w% of acetaminophen, and a mixed powder for granulation containing a drug, crystalline cellulose, hydroxypropyl cellulose, and the like, and an aqueous solution of hydroxypropyl cellulose as a binding solution. It has been reported that tableting troubles such as capping can be suppressed by adding and performing wet granulation.

  Patent Document 4 discloses a tablet containing 91.4 w / w% of famciclovir. High content of famciclovir without lactose by adding water to the mixed powder of drug and hydroxypropyl cellulose and performing wet granulation, adding specific excipients to the resulting granulated product and compression molding It has been reported that tablets can be obtained.

  However, the means disclosed in these patent documents are means for improving the compression moldability of the granulated product by improving the kind and blending amount of the granulated product in wet granulation. It is not a means of making any improvements to the binding liquid used in the graining. The methods disclosed in these patent documents are methods for producing tablets having a high drug content for a specific drug, and versatility for producing tablets having a high drug content for various drugs. There is no way.

JP 58-32820 A JP 2002-173428 A JP 2010-106014 A JP 2000-50311A

Medical Pharmacy (Jpn. J. Pharm. Health Care Sci.), 34, 289-296, 2008

An object of the present invention is to provide a tablet having a high drug content. More specifically, an object of the present invention is to provide a tablet having a high drug content, which eliminates tableting troubles such as lamination and capping, which are problematic when the drug content is increased. is there.
Another object of the present invention is a method for producing a tablet having a high drug content, which can avoid tableting troubles such as lamination and capping which are problematic when the drug content is increased. Is to provide.

  As a result of intensive studies to solve such problems, the present inventors have found that fine particles of a substantially water-insoluble substance such as partially pregelatinized starch, anhydrous calcium hydrogen phosphate, or crospovidone as a binding liquid in wet granulation. It has been found that by using a binding solution containing, tableting troubles such as lamination and capping during tablet production are remarkably suppressed, and tablets having a high drug content can be produced efficiently. The present invention has been completed based on the above findings.

  That is, according to the present invention, a tablet having a high drug content, which is obtained by compression molding a granulated product obtained by wet granulation using a binding liquid containing fine particles of a substantially water-insoluble substance. A tablet is provided.

  In a preferred embodiment of the above invention, the tablet as described above, wherein the substantially water-insoluble substance is a substantially water-insoluble pharmaceutical additive; the substantially water-insoluble substance is partially pregelatinized starch, crospovidone, and phosphoric anhydride The above-mentioned tablet which is one or more kinds of pharmaceutical additives selected from the group consisting of calcium hydrogen; the above-mentioned tablet having fine particles having an average particle size of 5 μm or less, preferably 3 μm or less, more preferably 1 μm or less; and The above-mentioned tablet is provided in which the fine particles are fine particles obtained by wet grinding.

  In a more preferred embodiment, the above-mentioned tablet in which the content of fine particles in the granulated product is 3 w / w% or less, preferably 1 w / w% or less; and the content of the drug in the tablet is 80 w / w% or more, Preferably, the above tablet is provided with 90 w / w% or more, more preferably 92 w / w% or more, and even more preferably 95 w / w% or more.

  In another preferred embodiment, the above tablet wherein the maximum single dose of at least one of the one or more drugs contained in the tablet is 150 mg or more; acetaminophen, tramadol, probenecid, Ethambutol, levofloxacin, mesalazine, salazosulfapyridine, gabapentin, aliskiren, lanthanum, gefitinib, levocarnitine, efavirenz, erlotinib, acyclovir, ganciclovir, valganciclovir, famciclovir, raltegravir, telaprevir, darunavir, atbacon, spiramycin, spiramycin Flucytosine, inosine planovex, albendazole, cephalexin, erythromycin, azithromycin, moxifloxacin, sultamicillin, fosfomycin, Moxicillin, ciprofloxacin, sultiam, celecoxib, mefenamic acid, aluminum flufenamic acid, chloramphenicol, nabumetone, ascorbic acid, sodium valproate, quetiapine, cimetidine, theophylline, tranexamic acid, disopyramide, potassium citrate, sodium citrate A tablet containing one or more drugs selected from the group consisting of precipitated calcium carbonate, tolbutamide, metronidazole, probucol, levodopa, linezolid, galenoxacin, levetiracetam, capecitabine, and pirfenidone; acetaminophen, tramadol, The above tablet comprising one or more drugs selected from the group consisting of probenecid, ethambutol, famciclovir, and ascorbic acid; There is provided the above tablet comprising a combination of acetaminophen and tramadol as; and the above tablet comprising famciclovir as a drug.

  From another point of view, according to the present invention, there is provided a method for producing a tablet having a high drug content, wherein a granulated product is prepared by wet granulation using a binding liquid containing fine particles of a substantially water-insoluble substance. There is provided a method comprising a step and a step of compression molding the granulate.

  From yet another aspect, the present invention provides a granulated product that can be obtained by wet granulation using a binding liquid containing fine particles of a substantially water-insoluble substance. This granulated product can be suitably used for the production of tablets having a high drug content.

  Although the tablet of the present invention has a high drug content, since it does not cause tableting troubles such as lamination and capping during tablet compression, a desired tablet can be produced with good reproducibility. Production efficiency can be increased. Since the downsizing of the tablet is achieved by increasing the drug content, it is also useful for improving patient compliance. Moreover, since the tablet of the present invention has sufficient hardness and good disintegration, it has extremely excellent characteristics as a solid pharmaceutical product. Furthermore, by the method of the present invention, not only tableting troubles such as lamination and capping can be suppressed, but also the strength of the tablet can be improved.

2 is an electron micrograph of an acetaminophen granulated product containing partially pregelatinized starch fine particles in Example 1 (1) (magnification: 10,000 times). FIG. 3 is an electron micrograph of an acetaminophen granulated product containing anhydrous calcium hydrogenphosphate fine particles in Example 3 (1) (magnification: 10,000 times).

  The tablet of the present invention is a tablet having a high drug content, and is obtained by compression molding a granulated product obtained by wet granulation using a binding liquid containing fine particles of a substantially water-insoluble substance. It is characterized by being a tablet.

  The tablet of the present invention generally comprises a step of preparing a granulated product by wet granulation using a binding liquid containing fine particles of a substantially water-insoluble substance, and a step of compressing the granulated product. It can be manufactured by doing. More specifically, for example, (1) a substantially water-insoluble substance is wet-pulverized to prepare a suspension containing fine particles, and (2) a binding solution is prepared using the obtained suspension. And (3) granulation and drying while adding a binding solution to the drug using a granulator to obtain a granulated product, and (4) the obtained granulated product as necessary Although a tablet can be manufactured by adding an additive and compression-molding, the manufacturing method of the tablet of this invention is not limited to the manufacturing method containing said specific process.

  As the drug contained in the tablet of the present invention, any kind of drug may be used as long as it can be administered orally. Examples of the drug used in the present invention include nourishing tonics, antipyretic analgesics, antipsychotics, anxiolytics, antidepressants, hypnotic sedatives, antispasmodics, central nervous system agonists, brain metabolism improving agents, brain Circulation improving agent, antiepileptic agent, sympathomimetic agent, gastrointestinal agent, gastrointestinal agent, antacid, antiulcer agent, antitussive expectorant, antiemetic agent, respiratory accelerator, bronchodilator, allergic agent, dental oral Drugs, antihistamines, cardiotonic agents, arrhythmic agents, diuretics, antihypertensive agents, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia agents, diuretics, antibiotics, chemotherapeutic agents, diabetes One selected from an agent, an osteoporosis agent, an anti-rheumatic agent, a skeletal muscle relaxant, an antispasmodic agent, a hormone agent, an alkaloid narcotic, a sulfa drug, a gout therapeutic agent, a vascular coagulation inhibitor, an antineoplastic agent, or the like Two or more drugs are used, but limited to these It will not be.

  Specific examples of the drug are not particularly limited as long as they are intended for oral administration. For example, the maximum dose per dose is 150 mg or more, and a drug for which downsizing of the tablet is desired is preferably used. be able to. As drugs that can be suitably used in the present invention, more specifically, acetaminophen, tramadol, probenecid, ethambutol, levofloxacin, mesalazine, salazosulfapyridine, gabapentin, aliskiren, lanthanum, gefitinib, levocarnitine, efavirenz, erlotinib, Acyclovir, ganciclovir, valganciclovir, famciclovir, raltegravir, telaprevir, darunavir, atobacon, spiramycin, procainamide, flucytosine, inosine pranobex, albendazole, cephalexin, erythromycin, azithromycin, moxifloxacin, sultamicillin, fosfomycin, amoxicillin, amoxicillin Ciprofloxacin, sultiam, celecoxib, mefenamic acid, fu Aluminum fenamate, chloramphenicol, nabumetone, ascorbic acid, sodium valproate, quetiapine, cimetidine, theophylline, tranexamic acid, disopyramide, potassium citrate, sodium citrate, precipitated calcium carbonate, tolbutamide, metronidazole, probucol, levodopa, linezolid , Galenoxacin, levetiracetam, capecitabine, and one or more drugs selected from the group consisting of pirfenidone and the like. Furthermore, it is more preferable to use a combination of acetaminophen and tramadol or famciclovir as a drug.

  Moreover, the form of these drugs is not particularly limited, and any form such as a free form, a pharmaceutically acceptable salt form, or a hydrate or solvate form may be used. The drug may be used after being pulverized by a pulverizer or the like, if necessary, and may be used after further sizing treatment. The tablet of the present invention may contain two or more drugs and may be prepared as a so-called combination tablet.

  Although the kind of substantially water-insoluble substance is not particularly limited, it is generally preferable to select a substance that can be used as a pharmaceutical additive. It is preferable to use a substance that has good dispersibility in a solvent such as water in the form of fine particles and has a property of giving a uniform suspended state, and any substance having such a property can be used. . The substantially water-insoluble substance may have a water solubility of, for example, 1 mg / mL or less, preferably 0.1 mg / mL or less.

  As the substantially water-insoluble substance, for example, it is preferable to use one or more substances selected from the group consisting of starch-based polymer substances, crosslinked polymers of water-soluble polymers, or inorganic substances. However, it is not limited to these. For example, it is more preferable to use one or more substances selected from the group consisting of partially pregelatinized starch, crospovidone, and anhydrous calcium hydrogen phosphate, and it is more preferable to use partially pregelatinized starch.

  The fine particles of the substantially water-insoluble substance may be finely divided in advance, or may be finely divided by a pulverization process. The apparatus used for the pulverization treatment is not particularly limited, and any apparatus can be used as long as fine particles can be prepared. In the present specification, the term “fine particles” refers to a substance having an average particle size equal to or less than that obtained by a normal dry pulverization technique such as jet mill pulverization. Specifically, the average particle size is about 5 μm or less, more preferably 3 μm or less, and even more preferably 1 μm or less. The average particle diameter refers to a volume average particle diameter as measured by, for example, a laser diffraction / scattering particle size distribution analyzer. The average particle diameter can be measured using a known method and a measuring instrument, and can be easily measured by a method such as laser light scattering particle size distribution measurement or dynamic light scattering particle size distribution measurement.

  The pulverization method for obtaining fine particles is not particularly limited, and examples thereof include wet pulverization. As an apparatus that can be suitably used for wet pulverization, for example, a high-pressure homogenizer can be mentioned, but it is not limited thereto. The pulverization conditions can be appropriately changed depending on the type of substantially water-insoluble substance. For example, when a high-pressure homogenizer is used, the pulverization process is performed once or twice at a pressure of about 100 to 250 MPa, preferably about 200 MPa. It can be repeated ten or more times, preferably about 3 to 10 times, more preferably about 5 times. For example, in the case of wet pulverization of partially pregelatinized starch, anhydrous calcium hydrogen phosphate, or crospovidone, the wet pulverization may be repeated about 5 times at about 200 MPa using a high-pressure homogenizer, and the average particle size is 5 μm or less. Fine particles can be easily prepared.

  The type of medium used for wet pulverization is not particularly limited, but it is preferable to use a medium capable of uniformly suspending the fine particles obtained after the treatment, for example, a liquid having a viscosity that facilitates suspension. For example, water, methanol, ethanol, isopropanol, acetone, or a mixed solvent of two or more of these can be used, and water is more preferable. When wet pulverization is performed, a binder such as hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, methyl cellulose, carmellose sodium, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, sodium alginate and the like can be dissolved in the medium. As the binder, a water-soluble polymer binder is preferable, and hydroxypropylcellulose is more preferable. The concentration of fine particles in the suspension obtained by wet pulverization is not particularly limited. For example, the concentration is preferably about 1 to 30 w / w%, more preferably 2 to 15 w / w%.

  The suspension of fine particles to which a binder has been added in advance can be used as it is as a binding solution. However, if necessary, a new medium is added, and additionally hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, methylcellulose are added as a binder. , Carmellose sodium, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polyvinyl alcohol / polyethylene glycol / graft copolymer, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyethylene glycol, polyacrylic acid, sodium polyacrylate, ethyl cellulose, acrylic acid One or two selected from ethyl methyl methacrylate copolymer, aminoalkyl methacrylate copolymer RS and sodium alginate, etc. More than seeds can be added to form a binding solution. When a new medium is added, for example, water, methanol, ethanol, isopropanol, acetone, or a mixed solvent of two or more of these can be used. Alternatively, a suspension obtained by wet pulverization can be diluted by adding a pharmaceutically acceptable medium to obtain a binding solution. Furthermore, if necessary, the binding solution may be a saccharide such as lactose hydrate, a sugar alcohol such as D-mannitol, a plasticizer, a surfactant, a sweetener, a corrigent, a cooling agent, a colorant, a light-shielding agent, Alternatively, one or more arbitrary pharmaceutical additives such as a fragrance can be added. The content of the binder can be less than 10 w / w% with respect to the granulated product or tablet, and is preferably less than 5 w / w%, and less than 2 w / w% for tablet size reduction It is more preferable that it is less than 1.3 w / w%.

  As an apparatus for producing the granulated product, any apparatus widely used in the wet granulation method can be used. For example, a high speed stirring type mixing granulator, a stirring type kneader, a rolling granulator, a fluidized bed granulating coating apparatus, a centrifugal rolling type fluidized bed granulating coating apparatus, and the like can be mentioned. It is preferable to granulate using a mixing granulator. The granulated product can be prepared by, for example, a method in which a drug is put into a granulating apparatus and granulated while adding a binding liquid by a spray method or a batch addition method. Can be appropriately selected by those skilled in the art, and is not particularly limited. In order to increase the drug content in the granulated product, it is preferable to granulate using only the drug and the above binding solution. However, a pharmaceutically acceptable pharmaceutical additive is added to the drug and granulated as a mixture. It is also possible.

  The granulated product can contain a drug in a proportion of 80 w / w% or more, and the drug content in the granulated product is preferably 90 w / w% or more, more preferably 95 w / w% or more. Preferably, it is 98 w / w% or more. Here, when the granulated product contains two or more drugs, it means the ratio of the total amount of each drug to the granulated product. The particle size of the granulated product is not particularly limited, but it is generally preferable that the average particle size is in the range of 100 to 500 μm so as to have appropriate fluidity in the tableting process. The content of fine particles in the granulated product or tablet can be, for example, 3 w / w% or less, and more preferably 1 w / w% or less.

  In tableting, various pharmaceutically acceptable pharmaceuticals such as a surface modifying base, a fluidizing agent, a disintegrating agent, a lubricant, a sweetener, a corrigent, a refreshing agent, or a fragrance, as necessary. Additives can be added. The amount of disintegrant blended varies depending on the physicochemical properties of the drug to be applied, but conforms to the 16th revised Japanese Pharmacopeia, general test method, disintegration test method (within 30 minutes for uncoated tablets, within 60 minutes for coated tablets) Thus, it is preferable to select the blending amount. The content of the drug in the tablet obtained by compression molding the granulated product is, for example, 80 w / w% or more, preferably 90 w / w% or more, more preferably 92 w / w% or more, and still more preferably 95 w / w%. This can be done. Here, in the case of a so-called combination in which the tablet contains two or more drugs, the ratio of the total amount of each drug to the tablet mass is defined as the drug content. The size of the tablet of the present invention is not particularly limited, and can be appropriately selected according to the kind and content of the drug, the usage of the tablet, and the like. In the case of a round tablet, the diameter is preferably in the range of 6 to 10 mm in consideration of ingestion and handling properties. The shape of the tablet is not particularly limited, and can be selected from, for example, flat flat tablets, flat corner locks, single R-type and double R-type convex tablets, caplet-type deformed tablets, and the like. Note that tablets obtained by compression molding can be appropriately coated with a film by a conventional production method as needed to impart bitterness control, light shielding properties, enteric properties, or sustained release properties. is there.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited by the following Example.

Example 1
(1) Production of Acetaminophen Granules Containing Partially Pregelatinized Starch Fine Particles Hydroxypropylcellulose (HPC-M, Nippon Soda) 10.0 g was dissolved in about 1,000 mL of water to obtain a 1% HPC-M aqueous solution. 50.0 g of partially pregelatinized starch (PCS PC-10, Asahi Kasei Chemicals) is suspended in about 1,000 mL of 1% HPC-M aqueous solution, and it is repeated five times at about 200 MPa with a high-pressure homogenizer (LSU 2010P14, Advanced Nano Technology). Wet milled into a partially pregelatinized starch microparticle suspension.

  Hydroxypropylcellulose (HPC-M, Nippon Soda) 25.0 g and D-mannitol (Mannit P, Mitsubishi Corporation Foodtech) 10.0 g are dissolved in about 500 mL of partially pregelatinized starch microparticle suspension and about 500 mL of ethanol (99.5). And used as a binding solution. Put 2500.0g of acetaminophen into a high-speed agitation type mixing granulator (FM-VG-25, POWREC), spray pressure: approx. 0.1MPa, feeding speed: 15-25g / min. After granulating while adding by the method, it was blown and dried in a shelf-type stationary dryer at 40 ° C. for 4 hours to obtain a granulated product. The content of acetaminophen in the granulated product was 98.5 w / w%.

(2) Production of acetaminophen tablet 200 mg Crospovidone (Polyplastone XL, ISP Japan) 0.5 w / w%, Magnesium stearate (Pure Chemical) 1.0 w / w% was added and mixed to obtain a tableting mixture. Compressed with a rotary fully automatic tableting machine (HT-AP-15SS II, manufactured by Hata Seiko Co., Ltd.) under the conditions of a rotating disk rotation speed of 20 rpm and a pressure of 650 kgf, 8 mm in diameter containing 200 mg of acetaminophen A flat corner tablet having a mass of 206 mg was obtained. The content of acetaminophen in the tablet was 97.0 w / w%.

(3) Production of 400 mg of acetaminophen tablet In the same manner as the 200 mg tablet of (2), a flat corner tablet having a diameter of 10 mm and a mass of 412 mg containing 400 mg of acetaminophen was obtained. The content of acetaminophen in the tablet was 97.0 w / w%.

Example 2
(1) Production of acetaminophen granule containing crospovidone fine particles Crospovidone (Polyplastidone XL, ISP) instead of partially pregelatinized starch (PCS PC-10, Asahi Kasei Chemicals) used in Example 1 (1) A granulated product was obtained in the same manner except that (Japan) was used. The content of acetaminophen in the granulated product was 98.5 w / w%.
(2) Production of 400 mg of acetaminophen tablets Magnesium stearate (Pure Chemical) 1.0 w / w% was added to the granulated product obtained in (1) above and mixed to obtain a tableting mixture. Compressed with a rotary fully automatic tableting machine (HT-AP-15SS II, manufactured by Hata Plant) under the conditions of a rotating disk rotation speed of 20 rpm and a pressure of 700 kgf, and a diameter of 10 mm containing 400 mg of acetaminophen. A flat corner tablet having a mass of 410 mg was obtained. The content of acetaminophen in the tablet was 97.6 w / w%.

Example 3
(1) Production of acetaminophen granulate containing anhydrous calcium hydrogen phosphate fine particles Anhydrous calcium hydrogen phosphate (PCS PC-10, Asahi Kasei Chemicals) used in Example 1 (1) instead of partially pregelatinized starch A granulated product was obtained in the same manner except that L-Carica, Kyowa Chemical Industry Co., Ltd. was used. The content of acetaminophen in the granulated product was 98.5 w / w%.

(2) Manufacture of 400 mg of acetaminophen tablet A mixture for tableting was prepared in the same manner as in Example 1 (3), and the rotary type fully automatic tableting machine (HT-AP-15SS II, manufactured by Hatago Co., Ltd.) Then, the tablet was compressed under the conditions of a rotating disk rotation speed of 20 rpm and a pressure of 650 kgf to obtain a flat corner tablet having a diameter of 10 mm and a mass of 412 mg containing 400 mg of acetaminophen. The content of acetaminophen in the tablet was 97.0 w / w%.

Example 4
(1) Production of probenecid granule containing anhydrous calcium hydrogenphosphate fine particles A 1% HPC-M aqueous solution was prepared in the same manner as in Example 1 (1). After suspending 44.6 g of anhydrous calcium hydrogen phosphate (L-Carica, Kyowa Chemical Industry) in about 1,000 mL of 1% HPC-M aqueous solution, wet pulverization was performed in the same manner as in Example 1 (1), and anhydrous phosphorus A calcium oxyhydrogen fine particle suspension was prepared. Hydroxypropylcellulose (HPC-M, Nippon Soda) 25.0g, D-mannitol (Mannit P, Mitsubishi Foodtech) 7.4g in anhydrous calcium hydrogenphosphate fine particle suspension about 500mL and ethanol (99.5) about 500mL Dissolved and used as a binding solution. Granules were obtained by granulating and drying using 2,000.0 g of probenecid in the same manner as in Example 1 (1). The content of probenecid in the granulated product was 98.2 w / w%.

(2) Manufacture of probenecid tablets 250mg Crospovidone (Polyplastone XL, ISP Japan) 2.0w / w%, Magnesium stearate (Pure Chemical) 2.0w / w for the granulated product obtained in (1) above %, Talc (P-2, Matsumura Sangyo) 2.0 w / w% was added and mixed to obtain a tableting mixture. Compressed with a rotary fully automatic tableting machine (HT-AP-15SS II, manufactured by Hata Seiko Co., Ltd.) under the conditions of a rotating disk rotation speed of 20 rpm and a pressure of 500 kgf, 8 mm in diameter containing 250 mg of probenecid, mass 270 mg of flat corner tablets were obtained. The content of probenecid in the tablet was 92.7 w / w%.

Example 5
(1) Production of Ethambutol Hydrochloride Granules Containing Crospovidone Fine Particles A binding liquid containing crospovidone fine particles was prepared in the same manner as in Example 2 (1) except that D-mannitol was not used. Using 1,400.0 g of ethambutol hydrochloride, granulation and drying were performed in the same manner as in Example 1 (1) to obtain a granulated product. The content of ethambutol hydrochloride in the granulated product was 98.8 w / w%.

(2) Manufacture of ethambutol tablets 250mg Crospovidone (Polyplastone XL, ISP Japan) 0.5w / w%, Magnesium stearate (Pure Chemical) 1.0w / w for the granulated product obtained in (1) above %, Light anhydrous silicic acid (Aerosil 200, Nippon Aerosil) 0.5 w / w% was added and mixed to obtain a tableting mixture. Compressed with a rotary fully automatic tableting machine (HT-AP-15SS II, manufactured by Hata Seiko Co., Ltd.) under the conditions of a rotating disk rotation of 20 rpm and a pressure of 1200 kgf, a diameter of 9 mm containing 250 mg ethambutol hydrochloride A single R-type tablet having a mass of 258 mg was obtained. The content of ethambutol hydrochloride in the tablet was 96.8 w / w%.

Example 6
(1) Production of tramadol hydrochloride / acetaminophen granule containing partially pregelatinized starch fine particles A binding liquid containing partially pregelatinized starch fine particles was prepared in the same manner as in Example 1 (1). Using 206.9 g of tramadol hydrochloride and 1,793.1 g of acetaminophen, granulation and drying were performed in the same manner as in Example 1 (1) to obtain a granulated product. The content of the drug (total amount of tramadol hydrochloride and acetaminophen) in the granulated product was 99.0 w / w%.

(2) Manufacture of tramadol hydrochloride / acetaminophen combination tablets For the granulated product obtained in (1) above, crospovidone (Polyplastone XL, ISP Japan) 2.0 w / w%, magnesium stearate (genuine) Chemical) 1.0 w / w% was added and mixed to obtain a tableting mixture. Compressed with a rotary fully automatic tableting machine (HT-AP-15SS II, manufactured by Hata Plant) under the conditions of a rotating disk rotation of 20 rpm and a pressure of 900 kgf, 37.5 mg of tramadol hydrochloride and acetamino A single R-type tablet having a diameter of 9 mm and a mass of 377 mg containing 325 mg of phen was obtained. The content of the drug (total amount of tramadol hydrochloride and acetaminophen) in the tablet was 96.1 w / w%.

Example 7
(1) Production of Famciclovir Granules Containing Partially Pregelatinized Starch Fine Particles A partially pregelatinized starch fine particle suspension was prepared in the same manner as in Example 1 (1) except that D-mannitol was not used. . Hydroxypropylcellulose (HPC-M, Nippon Soda) 15.0 g was dissolved in about 500 mL of partially pregelatinized starch microparticle suspension and about 500 mL of ethanol (99.5) to obtain a binding solution. After putting 900.0g of famciclovir into a high-speed agitation type mixing granulator (LMA-10, Nara Machinery Co., Ltd.) and granulating while adding the binding solution in a batch addition system, shelves And dried by blowing at 40 ° C. for 4 hours to obtain a granulated product. The content of famciclovir in the granulated product was 98.8 w / w%.

(2) Manufacture of Famciclovir Tablets 250mg Crospovidone (Polyplastone XL, ISP Japan) 1.5w / w%, Magnesium Stearate (Pure Chemical) 1.5w / w% was added and mixed to obtain a tableting mixture. Compressed with a rotary fully automatic tableting machine (HT-AP-15SS II, manufactured by Hata Seiko Co., Ltd.) under the conditions of a rotating disk rotation speed of 20 rpm and a pressure of 200 kgf, a diameter containing 250.0 mg of famciclovir A single R-type tablet of 8.5 mm and a mass of 261 mg was obtained. The content of famciclovir in the tablet was 95.9 w / w%.

Example 8
(1) Production of Ascorbic Acid Granules Containing Partially Pregelatinized Starch Fine Particles 20.0 g of hypromellose (TC-5R, Shin-Etsu Chemical) was dissolved in about 1,000 mL of water to obtain a 2% TC-5R aqueous solution. Suspended 100.0 g of partially pregelatinized starch (PCS PC-10, Asahi Kasei Chemicals) in about 1,000 mL of 2% TC-5R aqueous solution, and repeated 5 times with high pressure homogenizer (LSU 2010P14, Advanced Nano Technology) at about 200 MPa. Wet milled into a partially pregelatinized starch microparticle suspension.

  40.0 g of hypromellose (TC-5R, Shin-Etsu Chemical) was dissolved in about 500 mL of partially pregelatinized starch microparticle suspension and about 500 mL of ethanol (99.5) to obtain a binding solution. Using ascorbic acid 2500.0g, granulation and drying were carried out in the same manner as in Example 1 (1) to obtain a granulated product. The content of ascorbic acid in the granulated product was 98.5 w / w%.

(2) Production of Ascorbic Acid Tablets 250mg For the granulated product obtained in (1) above, Crospovidone (Polyplastone XL, ISP Japan) 0.5w / w%, Magnesium Stearate (Pure Chemical) 1.5w / w% was added and mixed to obtain a tableting mixture. Compressed with a rotary fully automatic tableting machine (HT-AP-15SS II, manufactured by Hata Seiko Co., Ltd.) under the conditions of a rotating disk rotation speed of 20 rpm and a pressure of 650 kgf, a diameter of 9.0 containing 250.0 mg of ascorbic acid A flat corner tablet having a size of mm and a mass of 259 mg was obtained. The content of ascorbic acid in the tablet was 96.6 w / w%.

Comparative Example 1
(1) Production of acetaminophen granulated product In the same manner as in Example 1 (1), but without using a fine particle suspension and D-mannitol, a 3% HPC-M water / ethanol (99.5) mixture (1: 1) A solution was prepared as a binding solution. Acetaminophen 2,500.0 g was granulated and dried in the same manner as in Example 1 (1) to obtain a granulated product. The content of acetaminophen in the granulated product was 99.3 w / w%.

(2) Production of 200 mg of acetaminophen tablet A mixture for tableting was prepared in the same manner as in Example 2 (2), and the rotary type fully automatic tableting machine (HT-AP-15SS II, manufactured by Hatago Seiko) was used. Then, the tablet was compressed under the conditions of a rotating disk rotation speed of 20 rpm and a pressure of 650 kgf to obtain a flat corner tablet having a diameter of 8 mm and a mass of 203 mg containing 200 mg of acetaminophen. The content of acetaminophen in the tablet was 98.3 w / w%.

(3) Manufacture of 400 mg of acetaminophen tablets A tableting mixture was prepared in the same manner as in Example 2 (2), and the rotary type fully automatic tableting machine (HT-AP-15SS II, manufactured by Hatago Co., Ltd.) Then, the tablet was compressed under the conditions of a rotation speed of a rotating disk of 20 rpm and a pressure of 650 kgf to obtain a flat corner tablet having a diameter of 10 mm and a mass of 407 mg containing 400 mg of acetaminophen. The content of acetaminophen in the tablet was 98.3 w / w%.

Comparative Example 2
(1) Production of acetaminophen granulated product containing unpulverized partially pregelatinized starch In the same manner as in Example 1 (1), but without using a fine particle suspension, a 3% HPC-M water / ethanol mixture ( 1: 1) A solution was prepared. In about 1,000 mL of this solution, 25.0 g of partially pregelatinized starch (PCS PC-10, Asahi Kasei Chemicals) and 10.0 g of D-mannitol (Mannit P, Mitsubishi Corporation Foodtech) were suspended and dissolved to obtain a binding solution. Acetaminophen 2,500.0 g was granulated and dried in the same manner as in Example 1 (1) to obtain a granulated product. The content of acetaminophen in the granulated product was 98.5 w / w%.

(2) Production of 200 mg of acetaminophen tablet A mixture for tableting was prepared in the same manner as in Example 1 (2), and the rotary type fully automatic tableting machine (HT-AP-15SS II, manufactured by Hatago Seiko) was used. Then, the tablet was compressed under the conditions of a rotating disk rotation speed of 20 rpm and a pressure of 650 kgf to obtain a flat corner tablet having a diameter of 8 mm and a mass of 206 mg containing 200 mg of acetaminophen. The content of acetaminophen in the tablet was 97.0 w / w%.

Comparative Example 3
(1) Production of acetaminophen agglomerated product containing unpulverized anhydrous calcium hydrogen phosphate In the same manner as in Example 3 (1), but without using a fine particle suspension, 3% HPC-M water / ethanol mixture A (1: 1) solution was prepared. In about 1,000 mL of this solution, 25.0 g of anhydrous calcium hydrogen phosphate (L-Carica, Kyowa Chemical Industry) and 10.0 g of D-mannitol (Mannit P, Mitsubishi Corporation Foodtech) were suspended and dissolved to obtain a binding solution. Acetaminophen 2,500.0 g was granulated and dried in the same manner as in Example 1 (1) to obtain a granulated product. The content of acetaminophen in the granulated product was 98.5 w / w%.

(2) Manufacture of 400 mg of acetaminophen tablets A tableting mixture was prepared in the same manner as in Example 3 (2), and the rotary type fully automatic tableting machine (HT-AP-15SS II, manufactured by Hatago Co., Ltd.) Then, the tablet was compressed under the conditions of a rotating disk rotation speed of 20 rpm and a pressure of 650 kgf to obtain a flat corner tablet having a diameter of 10 mm and a mass of 412 mg containing 400 mg of acetaminophen. The content of acetaminophen in the tablet was 97.0 w / w%.

Comparative Example 4
(1) Manufacture of probenecid granulated material As in Example 4 (1), but without using fine particle suspension and D-mannitol, 3% HPC-M water / ethanol (99.5) mixture (1: 1) A solution was prepared and used as a binding solution. Granules were obtained by granulating and drying using 2,500.0 g of probenecid in the same manner as in Example 1 (1). The content of probenecid in the granulated product was 99.0 w / w%.

(2) Production of probenecid tablets 250 mg In the same manner as in Example 4 (2), a mixture for tableting was prepared, and a rotary fully automatic tableting machine (HT-AP-15SS II, manufactured by Hata Plant) The tablet was compressed under the conditions of a rotation speed of a rotating disk of 20 rpm and a pressure of 500 kgf to obtain a flat corner tablet having a diameter of 8 mm and a mass of 267 mg containing 250 mg of probenecid. The content of probenecid in the tablet was 93.5 w / w%.

Comparative Example 5
(1) Production of ethambutol hydrochloride granulated product containing cruspovidone unground product In the same manner as in Example 5 (1), but without using a fine particle suspension, 3% HPC-M water / ethanol (99.5) mixed solution A (1: 1) solution was prepared. In about 1,000 mL of this solution, 25.0 g of crospovidone (Polyplaston XL, ISP Japan) and 10.0 g of D-mannitol (Mannit P, Mitsubishi Corporation Foodtech) were suspended and dissolved to obtain a binding solution. Using 1400.0 g of ethambutol hydrochloride, granulation and drying were performed in the same manner as in Example 1 (1) to obtain a granulated product. The content of ethambutol hydrochloride in the granulated product was 98.8 w / w%.

(2) Manufacture of ethambutol hydrochloride tablets 250 mg A tableting mixture was prepared in the same manner as in Example 5 (2), and a rotary fully automatic tableting machine (HT-AP-15SS II, manufactured by Hata Coffee Factory) was used. Then, the tablet was compressed under the conditions of a rotation speed of a rotating disk of 20 rpm and a pressure of 1200 kgf to obtain a flat corner tablet having a diameter of 9 mm and a mass of 258 mg containing 250 mg of ethambutol hydrochloride. The content of ethambutol hydrochloride in the tablet was 96.8 w / w%.

Comparative Example 6
(1) Production of granule of tramadol hydrochloride / acetaminophen As in Example 6 (1), but without using a fine particle suspension, a 3% HPC-M water / ethanol (99.5) mixture (1: 1) A solution was prepared as a binding solution. Granules were obtained by granulating and drying 206.9 g of tramadol hydrochloride and 1,793.1 g of acetaminophen in the same manner as in Example 6 (1). The content of the drug (total amount of tramadol hydrochloride and acetaminophen) in the granulated product was 99.4 w / w%.

(2) Manufacture of tramadol hydrochloride / acetaminophen combination tablet A mixture for tableting was prepared in the same manner as in Example 6 (2), and a rotary fully automatic tableting machine (HT-AP-15SS II, Hata Koko) (Commercially available), compressed under the conditions of a rotating disk rotation speed of 20 rpm and a pressure of 900 kgf to obtain a single R-type tablet having a diameter of 9 mm and a mass of 376 mg containing 37.5 mg of tramadol hydrochloride and 325 mg of acetaminophen. . The content of the drug (total amount of tramadol hydrochloride and acetaminophen) in the tablet was 96.5 w / w%.

Comparative Example 7
(1) Production of granule of famciclovir In the same manner as in Example 7 (1), however, a 2% HPC-M water / ethanol (99.5) mixed solution (1: 1) solution was used without using a fine particle suspension. A binding solution was prepared. 900.0 g of famciclovir was granulated and dried in the same manner as in Example 7 (1) to obtain a granulated product. The content of famciclovir in the granulated product was 99.4 w / w%.

(2) Production of Famciclovir Tablets 250 mg A tableting mixture was prepared in the same manner as in Example 7 (2), and the rotary type fully automatic tableting machine (HT-AP-15SS II, manufactured by Hata Plant) The mixture was compressed under the conditions of a rotation speed of 20 rpm and a pressure of 200 kgf to obtain a single R-type tablet having a diameter of 8.5 mm and a mass of 259 mg containing 250 mg of famciclovir. The content of famciclovir in the tablet was 96.6 w / w%.

Comparative Example 8
(1) Manufacture of ascorbic acid granulated material As in Example 8 (1), but prepare a 5% TC-5R water / ethanol (99.5) mixed solution (1: 1) solution without using fine particle suspension. To obtain a binding solution. Granules were obtained by granulating and drying 2,500.0 g of ascorbic acid in the same manner as in Example 8 (1). The content of ascorbic acid in the granulated product was 99.3 w / w%.

(2) Manufacture of 250 mg of ascorbic acid tablets A mixture for tableting was prepared in the same manner as in Example 8 (2), using a rotary type fully automatic tableting machine (HT-AP-15SS II, manufactured by Hatago Seiko). Compressed under the conditions of a rotation speed of a rotating disk of 20 rpm and a pressure of 650 kgf, a flat corner tablet having a diameter of 9.0 mm and a mass of 257 mg containing 250 mg of ascorbic acid was obtained. The content of ascorbic acid in the tablet was 97.3 w / w%.

Test Example 1: Effect of suppressing tableting failure (lamination and capping) Using a tableting mixture described in Examples 1 to 8 and Comparative Examples 1 to 8, a rotary fully automatic tableting machine (HT-AP- 15SS II (manufactured by Hata Seiko Co., Ltd.) was used to continuously tablet 1000 tablets or more at a rotation speed of a rotating disk of 20 rpm, and the total number of tablets obtained was visually observed. As a result of the observation, when one occurrence of lamination and capping was observed, it was evaluated that there was a tableting failure, and when no tablet was observed, it was evaluated that there was no tableting failure. The presence or absence of the inhibitory effect was confirmed. The results are shown in Tables 1-7.

  The granulated product to which fine particles of partially pregelatinized starch, crospovidone, or anhydrous calcium hydrogen phosphate were added did not cause lamination or capping during tableting, and exhibited excellent compression moldability (Examples 1 to 8). . On the other hand, in a granulated product not added with fine particles of partially pregelatinized starch, crospovidone or anhydrous calcium hydrogen phosphate, or a granulated product added without pulverization, lamination and capping occurred during tableting (Comparative Example 1). ~ 8). Therefore, by wet granulation using a binding solution containing fine particles of partially pregelatinized starch, crospovidone, or anhydrous calcium hydrogen phosphate, the compression moldability of the granulated product is improved, and lamination during tableting It was confirmed that capping can be suppressed.

Test Example 2: Tablet disintegration Table 8 shows the results of the disintegration test of the tablets produced in Examples 1-8. The disintegration test was conducted according to the 16th revised Japanese Pharmacopoeia General Test Method disintegration test method using water as the test solution. The tablets produced in Comparative Examples 1 to 8 were excluded from the evaluation because of tableting failure of lamination and capping. Although the tablets produced in Examples 1 to 8 have a high drug content, they were disintegrated within 10 minutes in the disintegration test, and it was confirmed that all of them rapidly disintegrated.

Test Example 3: Tablet Hardness The tablet hardness was measured using a tablet hardness tester (HARDNESS TESTER, Kiya Seisakusho). Table 9 shows the hardness of the tablets produced in Examples 1-8. The tablets produced in Comparative Examples 1 to 8 were excluded from the evaluation because of tableting failure of lamination and capping. The tablets produced in Examples 1 to 8 had a hardness of 3.0 kgf or more, and it was confirmed that all the tablets had sufficient hardness.

Test Example 4: Average particle size before and after wet grinding treatment Partially pregelatinized starch, crospovidone, and anhydrous calcium hydrogen phosphate used in Example 1 (1), Example 2 (1) and Example 3 (1) The average particle size before and after the wet pulverization treatment was measured. The average particle size (μm) before wet pulverization is measured using a dry dispersion method (dispersion pressure: 0.2 MPa or more) using a laser light scattering particle size distribution analyzer (LDSA-1500A, Tohnichi Computer Applications Co., Ltd.). ). The average particle size (nm) after the wet pulverization treatment is 1% HPC-M for the suspension obtained by wet pulverization using a dynamic light scattering particle size distribution analyzer (NICOMP 380ZLS, PS Japan). After appropriately diluted with an aqueous solution and subjected to ultrasonic treatment for 5 minutes or longer with stirring, the average particle size of the fine particles in the suspension was measured.
As a result, it was confirmed that the partially pregelatinized starch, crospovidone, and anhydrous calcium hydrogen phosphate were finely divided by wet grinding, and the average particle size was 5 μm or less.

Test Example 5: Electron Microscopic Observation of Granules Containing Fine Particles Scanning electron micrographs of the acetaminophen granule obtained in Example 1 (1) and Example 3 (1) are shown in FIGS. 1 and 2, respectively. Shown in In the granulated product of Example 1 (1) and Example 3 (1), partially pregelatinized starch and anhydrous calcium hydrogen phosphate were finely divided to about 1 μm or less, respectively, on the surface of acetaminophen particles. It was confirmed to have an attached structural form.

  In the tablet of the present invention, tableting troubles such as lamination and capping are suppressed, and a tablet with an increased drug content can be efficiently produced with high reproducibility in an industrial process. In addition, miniaturization of tablets is achieved, which is useful for improving patient compliance.

Claims (18)

A tablet having a high drug content, which is obtained by compression-molding a granulated product obtained by wet granulation using a binding liquid containing fine particles of a substantially water-insoluble substance. The tablet according to claim 1, wherein the substantially water-insoluble substance is a substantially water-insoluble pharmaceutical additive. The tablet according to claim 1 or 2, wherein the substantially water-insoluble substance is one or more pharmaceutical additives selected from the group consisting of partially pregelatinized starch, crospovidone, and anhydrous calcium hydrogen phosphate. The tablet according to any one of claims 1 to 3, wherein the fine particles have an average particle diameter of 5 µm or less. The tablet according to any one of claims 1 to 4, wherein the fine particles have an average particle diameter of 3 µm or less. The tablet according to any one of claims 1 to 5, wherein the fine particles have an average particle diameter of 1 µm or less. The tablet according to any one of claims 1 to 3, wherein the fine particles are fine particles obtained by wet grinding. The tablet according to any one of claims 1 to 7, wherein the content of fine particles in the granulated product is 3 w / w% or less. The tablet according to any one of claims 1 to 8, wherein the content of fine particles in the granulated product is 1 w / w% or less. The tablet according to any one of claims 1 to 9, wherein the content of the drug in the tablet is 80 w / w% or more. The tablet according to any one of claims 1 to 10, wherein the content of the drug in the tablet is 90 w / w% or more. The tablet according to any one of claims 1 to 11, wherein the content of the drug in the tablet is 95 w / w% or more. The tablet according to any one of claims 1 to 12, comprising a drug having a maximum single dose of 150 mg or more. Acetaminophen, tramadol, probenecid, ethambutol, levofloxacin, mesalazine, salazosulfapyridine, gabapentin, aliskiren, lanthanum, gefitinib, levocarnitine, efavirenz, erlotinib, acyclovir, ganciclovir, valganciclovir, famciclovir, raltegravir, telaprevir , Atovacon, spiramycin, procainamide, flucytosine, inosine pranobex, albendazole, cephalexin, erythromycin, azithromycin, moxifloxacin, sultamicillin, fosfomycin, amoxicillin, ciprofloxacin, sultiam, celecoxib, mefenamic acid, flufenamic acid, Chloramphenicol, Nabmet , From ascorbic acid, sodium valproate, quetiapine, cimetidine, theophylline, tranexamic acid, disopyramide, potassium citrate, sodium citrate, precipitated calcium carbonate, tolbutamide, metronidazole, probucol, levodopa, linezolid, galenoxacin, levetiracetam, capecitadone, and pirfenitadone The tablet according to any one of claims 1 to 13, comprising one or more drugs selected from the group consisting of: The tablet according to any one of claims 1 to 13, comprising a combination of acetaminophen and tramadol as a drug. The tablet according to any one of claims 1 to 13, comprising famciclovir as a drug. A method for producing a tablet having a high drug content, comprising a step of preparing a granulated product by wet granulation using a binding liquid containing fine particles of a substantially water-insoluble substance, and compression molding the granulated product A method comprising the step of: A granulated product that can be obtained by wet granulation using a binding liquid containing fine particles of a substantially water-insoluble substance.