JP2005139086A - Quick-disintegration preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a quick-disintegration preparation quickly disintegrating in the oral cavity. <P>SOLUTION: This quick-disintegration preparation contains a drug component, a carbohydrate (sugar or sugar alcohol), crystalline cellulose and a disintegrating agent. Especially, the preparation is an excellent tablet quickly disintegrating with saliva or a small amount of water in the oral cavity or the stomach, the drug component is one or more compounds selected from epalrestat, limaprost, pranlukast hydrate and camostat mesylate and the carbohydrate is mannitol or erythritol. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a pharmaceutical preparation, in particular, an intraoral rapidly disintegrating preparation that has rapid disintegration or solubility even without water in the oral cavity.

  Usually, solid preparations such as tablets are intended to disintegrate and dissolve in the digestive tract by oral administration to absorb pharmaceutical components, and usually do not exhibit fast disintegration or solubility in the oral cavity. However, with the aging of the population and changes in the living environment, the elderly and children can easily take it without water while maintaining the convenience of handling, which is a feature of tablets. There is an urgent need for the development of an oral-dissolving solid preparation that can be taken at any time regardless of the location.

  For example, pranlukast hydrate is a compound described in Patent Document 1, epalrestat is a compound described in Patent Document 2, limaprost is a compound described in Patent Document 3, and camostat mesylate is a compound described in Patent Document 4. Although these drugs are supplied as tablets or capsules, they are not known as fast-disintegrating preparations at all, and preparations that can improve patient compliance have been desired.

  On the other hand, as a method for producing a rapidly disintegrating preparation in the oral cavity, for example, a drug that is difficult to compress is contained by compressing and molding the drug together with a melting binder and melting and solidifying the binder in the obtained tablet. To obtain a porous tablet that is soft, chewable, and rapidly disintegrates (see Patent Document 5), and tablets a mixture containing drug, saccharides, and water with a degree of moisture occupied by the particle surface of the saccharides It is known to obtain an orally-dissolving tablet having moderate strength and fast dissolution and disintegration in the oral cavity (see Patent Document 6).

Japanese Patent No. 1741466 Japanese Patent No. 14442337 Patent No. 1317845 Japanese Patent No. 1122708 Japanese National Patent Publication No. 7-503237 Japanese Patent Laid-Open No. 5-271054

  The present invention provides a preparation that can be easily taken without water, particularly a preparation that rapidly disintegrates and dissolves in the oral cavity.

  As a result of diligent studies, the inventors of the present invention quickly formulated a pharmaceutical composition containing three components, ie, saccharides represented by erythritol, crystalline cellulose, and a disintegrating agent, with saliva or a small amount of water in the oral cavity or stomach. It has been found that it has a disintegrating property, and the present invention has been completed.

  The present invention relates to an intraoral rapidly disintegrating preparation containing a pharmaceutical ingredient.

That is, the present invention is [1] a rapid composition comprising saccharide, crystalline cellulose, and a disintegrant as one or more selected from epalrestat, pranlukast hydrate, limaprost and camostat mesylate as a pharmaceutical ingredient. Disintegrating formulation,
[2] The preparation according to [1] above, which is an intraoral rapidly disintegrating preparation,
[3] The agent according to [1] above, wherein the saccharide is one or more selected from sugar alcohols and saccharides,
[4] The agent according to [3] above, wherein the sugar alcohol is one or more selected from sorbitol, mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, erythritol, palatinit and lactitol.
[5] Saccharose is sucrose, isomaltooligosaccharide, fructooligosaccharide, galactooligosaccharide, palatinose, coupling sugar, soybean oligosaccharide, maltooligosaccharide, dairy oligosaccharide, xylo-oligosaccharide, trehalose, glucose, fructose, galactose, maltose, lactose, The preparation according to [3] above, which is one or more selected from lactulose and sucrose,
[6] The preparation according to [1], wherein the disintegrant is one or more selected from crospovidone, croscarmellose sodium and carmellose calcium,
[7] The preparation according to [1] above, which is a tablet,
[8] The preparation described in [1] above, containing 5% to 60% by weight of epalrestat, pranlukast hydrate or camostat mesylate,
[9] The preparation described in [1] above, containing 0.0005% by weight to 0.04% by weight of limaprost,
[10] The preparation of the above-mentioned [4], wherein the sugar alcohol is erythritol or mannitol,
[11] The preparation according to [1] above, wherein (i) a pharmaceutical ingredient, (ii) erythritol, (iii) crystalline cellulose, and (iv) a disintegrant component are uniformly mixed.
[12] (i) a pharmaceutical ingredient, (ii) erythritol, (iii) crystalline cellulose, and (iv) a method for improving the oral disintegration of a preparation comprising a disintegrant,
[13] Use in the manufacture of a preparation with improved oral disintegration, comprising (i) a pharmaceutical ingredient, (ii) erythritol, (iii) crystalline cellulose, and (iv) a disintegrant.
[14] The preparation according to [1] above, having a hardness of 0.8 kgf to 10 kgf,
[15] The tablet of [7] above, which contains 25 mg, 50 mg or 100 mg of epalrestat per tablet,
[16] The tablet of [7] above, which contains 112.5 mg, 225 mg or 450 mg of pranlukast hydrate per tablet,
[17] The tablet of [7] above, which contains 2.5 μg, 5 μg, 10 μg, 15 μg or 30 μg of limaprost per tablet, and [18] 50 mg, 100 mg, 200 mg of camostat mesylate per tablet, It is related with the tablet of the preceding clause [7] characterized by containing 300 mg or 600 mg.

  The pharmaceutical ingredient used in the present invention may be in any form such as solid, powder, crystal, oily, solution, etc., for example, from epalrestat, pranlukast hydrate, limaprost, camostat mesylate, etc. One or more selected components are preferably used.

  The medicinal component may be diluted with a diluent or the like generally used in the medical or food fields. Moreover, you may use what was processed for the purpose of masking the bitterness of a pharmaceutical ingredient.

  Examples of the saccharide used in the present invention include saccharides (monosaccharides, disaccharides, oligosaccharides, polysaccharides), sugar alcohols, and the like, and these may include two or more of the same or different types at an appropriate ratio. You may mix and use.

  Examples of sugars include sucrose, isomaltooligosaccharide, fructooligosaccharide, galactooligosaccharide, palatinose, coupling sugar, soybean oligosaccharide, maltooligosaccharide, dairy oligosaccharide, xylo-oligosaccharide, trehalose, glucose, fructose, galactose, maltose, and lactose. , Lactulose or sucrose.

  Examples of the sugar alcohol include sorbitol, mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, erythritol, palatinit, or lactitol.

  The saccharide described above is preferably a water-soluble saccharide. Here, the water-soluble saccharide refers to a saccharide whose required amount of water is less than 30 ml when adding 1 g of saccharide to water and shaking it strongly every 5 minutes at 20 ° C. for 30 seconds to dissolve within about 30 minutes. means.

  In the present invention, the sugar alcohol is preferably mannitol, sorbitol, xylitol or erythritol. Preferred sugars are sucrose, lactose and trehalose.

  In order to obtain sufficient formulation strength and sufficient rapid disintegration, the saccharide content in the formulation is usually about 5% to about 97% by weight, preferably about 10% to about 90% by weight.

  Examples of the water-soluble polymer used in the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, sodium fibrin glycolate, fibrin glycol calcium, Examples include sodium starch glycolate, sodium starch phosphate ester, chitosan and chitin.

  The fast-disintegrating preparation of the present invention is preferably rapidly disintegrating (for example, any of oral disintegrating ability, fast disintegrating action in the stomach, and fast disintegrating action in the duodenum is preferred, and oral disintegrating action is particularly preferable) or strength of the preparation. As long as there is no hindrance, various additives used in the production of the general preparation may be included, and the addition amount is an amount used in the production of the general preparation. Examples of such additives include excipients, binders, disintegrants, lubricants, surfactants, swelling agents, swelling aids, stabilizers, solubilizers, flavoring agents, perfumes, and sour agents. And foaming agents.

  Examples of excipients include glucose, fructose, lactose, sucrose, D-mannitol, erythritol, maltitol, trehalose, sorbitol, corn starch, potato starch, wheat starch, rice starch, crystalline cellulose, anhydrous silicic acid, anhydrous calcium phosphate, Examples include precipitated calcium carbonate and calcium silicate. Preferred excipients are erythritol, trehalose, D-mannitol and crystalline cellulose.

  Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, sodium alginate, carboxymethylethylcellulose. , Dextrin, hydroxyethyl cellulose, polyvinyl alcohol, gelatin, crystalline cellulose, gum arabic powder and the like. Preferred binders are partially pregelatinized starch and hydroxypropylcellulose.

  Examples of the disintegrant include hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, hydroxypropyl starch and the like. Preferred disintegrants are crospovidone and carmellose calcium.

  Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, carnauba wax, honey beeswax, calcium stearate and the like. As the lubricant, magnesium stearate and stearic acid are preferable.

  Examples of the surfactant include polysorbate (polysorbate 80 and the like), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate, sucrose fatty acid ester, sorbitan monostearate and the like.

  Examples of the swelling agent include hydroxypropylcellulose, hydroxypropylmethylcellulose, carbopol, carboxymethylcellulose, polyvinyl alcohol, xanthan gum, and guar gum.

  Examples of the swelling aid include glucose, fructose, mannitol, xylitol, erythritol, maltose, trehalose, phosphate, citrate, silicate, glycine, glutamic acid, arginine and the like.

  Examples of the stabilizer include ascorbic acid, sodium sulfite, glycine, L-aspartic acid, tocopherol acetate, β-cyclodextrin, fumaric acid and the like.

  Examples of the solubilizer include polyethylene glycol, propylene glycol, glutamic acid, aspartic acid and the like.

  Examples of the corrigent include citric acid, ascorbic acid, lactic acid, acetic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharine, dipotassium glycyrrhizinate, sodium glutamate, 5′-sodium inosinate, and 5′-sodium guanylate. Etc.

  Examples of the fragrances include flavors such as orange, strawberry, mint, lemon and vanilla, lemon oil, orange oil, menthol and brackish oil.

  Examples of sour agents include citric acid.

  Examples of the foaming agent include baking soda.

  Further, antiseptics, antioxidants (for example, sodium ascorbate, L-cysteine, sodium sulfite, etc.) and colorants (for example, titanium oxide, edible yellow No. 5, edible blue No. 2, three, etc., which are commonly used as necessary) Add additives such as iron dioxide, yellow iron sesquioxide, edible red No. 2, edible lake pigment, bengara, etc.), masking agents (eg, titanium oxide), antistatic agents (eg, talc, titanium oxide, etc.) You can also.

  The rapidly disintegrating preparation of the present invention may be any preparation such as a tablet, capsule, pill, porous agent, granule, fine granule, etc., but a tablet and a capsule are particularly preferable.

  When the rapidly disintegrating preparation of the present invention is a tablet, the tablet may contain fine granules. The fine granules may contain pharmaceutical ingredients. These agents can be produced by known methods or similar methods. The fine granules may contain nuclei with or without pharmaceutical ingredients.

  Examples of such nuclei include: (1) spherical granulated product made of crystalline cellulose and lactose [eg, spherical granulated product of about 100 μm to about 200 μm made of crystalline cellulose (3 parts) and lactose (7 parts) (non-parrel 105 (Trade name, manufactured by Freund Corporation); spherical granulated product of about 150 μm to about 250 μm made of crystalline cellulose (3 parts) and lactose (7 parts) (nonparel NP-7: 3 (trade name), manufactured by Freund Corporation); Spherical granulated product of about 150 μm to about 250 μm in crystalline cellulose (5 parts) and lactose (5 parts) (Nonparel NP-5: 5 (trade name), manufactured by Freund Corporation), etc.], (2) About 150 μm of crystalline cellulose Or a spherical granulated product of about 250 μm [Avicel SP (trade name), manufactured by Asahi Kasei Co., Ltd., etc.]. In addition, sucrose, starch, lactose, and crystalline cellulose may be used in any combination. The core may be coated by a method known per se after coating with a pharmaceutical ingredient or the like for the purpose of further masking of taste and odor, enteric dissolution or sustained release.

  Examples of the coating agent in this case include enteric polymers (for example, cellulose acetate phthalate, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD (Eudragit L30D-55 (trade name: Laem Co., Ltd.)). ), Methacrylic acid copolymer S, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, Kollicoat MAE30DP (trade name; manufactured by BASF), Polykid PA30 (trade name: Sanyo Kasei) Etc.)], carboxymethyl ethyl cellulose, shellac, methacrylic acid copolymer [e.g. Eudragit NE30 (Trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.], triethyl citrate, polyethylene glycol, acetylated monoglyceride, triacetin, castor oil, etc.), gastric polymers (eg, polyvinyl acetal diethylaminoacetate, Aminoalkyl methacrylate copolymers, etc.), water-soluble polymers (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.), poorly soluble polymers (eg, ethylcellulose, aminoalkylmethacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer) Etc.), wax, etc. These may be used alone or in combination.

  The “fine granules” in the present invention can also be produced by a known granulation method. Examples of the “granulation method” include rolling granulation (eg, centrifugal rolling granulation), fluidized granulation (eg, rolling fluidized bed granulation, fluidized granulation, etc.), stirring granulation And extrusion granulation method. Of these, fluidized granulation and rolling fluidized bed granulation are preferred. Specific examples of the rolling granulation method include a method using a “CF apparatus” manufactured by Freund Corporation. Specific examples of the rolling fluidized bed granulation method include, for example, methods using “Spiraflow”, “Multiplex” manufactured by Paulek, “Nyumarume” manufactured by Fuji Paudal, and the like. The method of spraying the mixed liquid can be appropriately selected according to the type of granulator, and may be any of a top spray method, a bottom spray method, a tangential spray method, and the like. Of these, the tangential spray method is preferable.

  The “fine particles” in the present invention can be coated with components other than fine particles including pharmaceutical ingredients and the like using a method known per se or a similar method. For example, when the pharmaceutical ingredient is an acid labile physiologically active substance, a method of coating a nucleus containing crystalline cellulose and lactose with an acid labile physiologically active substance is used. For example, a core containing crystalline cellulose and lactose described in the production method (coating method) described in JP-A-5-092918, an acid-labile physiologically active substance, and, if necessary, a basic inorganic substance Examples thereof include a method of coating a salt, a binder, a lubricant, an excipient, a water-soluble polymer and the like (hereinafter sometimes abbreviated as a coating layer). For example, a method in which the core is coated with a physiologically active substance and a basic inorganic salt that are unstable to acid, and a binder, a lubricant, an excipient, a water-soluble polymer, or the like is used.

  The average particle diameter of the “nucleus” may be usually about 250 μm or less, preferably about 50 to about 250 μm, more preferably about 100 μm to about 250 μm, and particularly preferably about 100 μm to about 200 μm. As the core having such an average particle diameter, the entire size of the No. 50 (300 μm) sieve is passed through, and the particles remaining on the No. 60 (250 μm) sieve are about 5 w / w% or less of the whole, and No. 282 ( 53 μm) is included such that the particles are about 10 w / w% or less of the total. The specific volume of the “nucleus” is usually about 5 ml / g or less, preferably about 3 ml / g or less. Examples of the “core” include (1) spherical granulated product of crystalline cellulose and lactose, (2) spherical granulated product of crystalline cellulose having a size of about 150 μm to about 250 μm (Avicel SP manufactured by Asahi Kasei Corporation), ( 3) Stirring granulated product of about 50 to about 250 μm with lactose (9 parts) and pregelatinized starch (1 part), (4) About about the classification of microcrystalline cellulose spherical granules described in JP-A No. 61-213201 Fine particles of 250 μm or less, (5) processed products such as waxes formed into a spherical shape by spray chilling or melt granulation, (6) processed products such as gelatin beads of oil components, (7) calcium silicate, (8 ) Starch, (9) porous particles such as chitin, cellulose and chitosan, (10) bulk products such as granulated sugar, crystalline lactose, crystalline cellulose or sodium chloride and their Examples include processed pharmaceutical products. Further, these nuclei may be produced by a known pulverization method or granulation method, and sieved to prepare particles having a desired particle size.

  Examples of the “spherical granulated product of crystalline cellulose and lactose” include, for example, (i) a spherical granulated product of about 100 μm to about 200 μm (for example, non-parrel 105 ( 70-140) (particle diameter of about 100 μm to about 200 μm, manufactured by Freund Corporation), (ii) spherical granulated product of about 150 μm to about 250 μm (eg, non-parrel) made of crystalline cellulose (3 parts) and lactose (7 parts) NP-7: 3 (manufactured by Freund Corporation), (iii) spherical granulated product of about 100 μm to about 200 μm made of crystalline cellulose (4.5 parts) and lactose (5.5 parts) [e.g., nonpareil 105T (70- 140) (particle diameter of about 100 μm to about 200 μm, manufactured by Freund Corporation), etc.], (iv) about 150 μm to about 250 μm with crystalline cellulose (5 parts) and lactose (5 parts) Spherical granulated product [eg, Nonpareil NP-5: 5, manufactured by Freund], and the like. In order to produce a preparation excellent in solubility while maintaining an appropriate strength, the “core” is preferably a spherical granulated product of crystalline cellulose and lactose, more preferably a spherical granulated product of crystalline cellulose and lactose. And those containing about 50% by weight or more of lactose. Those containing about 40% to about 50% by weight of crystalline cellulose and about 50% to about 60% by weight of lactose are preferred. The core used in the present invention is preferably a spherical granulated product of crystalline cellulose and lactose, more preferably a spherical shape of about 100 μm to about 200 μm with crystalline cellulose (4.5 parts) and lactose (5.5 parts). It is a granulated product. The “nucleus” may contain a physiologically active substance such as the above-mentioned pharmaceutical component, but since the release layer of the physiologically active substance can be controlled by the coating layer containing the physiologically active substance, the nucleus is a physiologically active substance. May not be included. The “nuclei” may be fine particles, and preferably have a uniform spherical shape as much as possible in order to reduce the variation in coating.

  The ratio of the “coating layer” to the “core” can be selected within a range in which the elution property of the physiologically active substance and the particle size of the composition can be controlled, and for example, generally about 50 wt% to about 400 wt% with respect to the core It is. The “coating layer” may be formed of a plurality of layers as long as at least one of the plurality of coating layers contains a physiologically active substance. A combination of various coating layers such as a coating layer having no pharmaceutical ingredient, a coating layer for underlaying, an enteric coating layer, and the like, constituting a plurality of coating layers, can be appropriately selected. When coating the core, for example, the above-mentioned physiologically active substance and water-soluble polymer are used as a mixed solution. The mixed solution may be a solution or a dispersion, and can be prepared using water, an organic solvent such as ethanol, or a mixture thereof. The concentration of the water-soluble polymer in the mixed solution is determined depending on the ratio of the physiologically active substance and the additive in order to maintain the binding force of the physiologically active substance to the nucleus and maintain the viscosity of the mixed liquid to such an extent that the workability is not lowered. Usually, it is about 0.1% to about 50% by weight, preferably about 0.5 to about 10% by weight.

  When the coating layer is formed of a plurality of layers, select the blending ratio of water-soluble polymer and the grade of viscosity, or coat sequentially using a mixed liquid in which the ratio of physiologically active substances and other additives is changed, The physiologically active substance concentration in each layer may be changed continuously or stepwise. In that case, as long as the entire coating layer contains about 0.1 wt% to about 50 wt% of the water-soluble polymer, the coating layer may be coated with a mixed solution that is out of the blending ratio of about 0.1 wt% to about 50 wt%. Good. Furthermore, an inactive film may be formed by a known method, and a plurality of coating layers may be formed so as to block between layers containing a physiologically active substance. Moreover, when mix | blending 2 or more types of bioactive substances with bad compounding property, you may coat | cover a nucleus using each liquid mixture simultaneously or separately. After the coating is dried, a composition having a uniform particle size is obtained with a sieve. Since the shape of the composition usually corresponds to the core, a substantially spherical composition can be obtained. As the sieve, for example, a No. 50 (300 μm) round sieve can be used, and a composition can be obtained by selecting those passing through the No. 50 round sieve.

  The fast disintegrating preparation of the present invention is produced by a conventional method in the pharmaceutical field. Examples of such a method include a method in which a pharmaceutical ingredient, a saccharide, a crystalline cellulose, and a disintegrant are added with water as desired, mixed, molded, and further dried as desired. However, the rapidly disintegrating preparation of the present invention can be produced without using water.

For example, when the fast disintegrating preparation is a tablet (especially an orally disintegrating tablet), “molding” is performed using a single tablet machine (manufactured by Kikusui Seisakusho), a rotary tableting machine (manufactured by Kikusui Seisakusho), etc. It is performed by tableting at a pressure of about 3000 kg / cm ² , preferably about 1000 to about 2000 kg / cm ² . “Drying” is performed by a conventional drying method in the pharmaceutical field such as vacuum drying and fluidized bed drying. Mixing is performed by a commonly used mixing method, for example, mixing, kneading, granulation or the like. For example, a vertical granulator (manufactured by Paulek), a universal kneader (manufactured by Hata Iron Works), a fluidized bed granulator flow coater (manufactured by Freund), a rolling fluidized coating granulator NQ (manufactured by Dalton) ] Or the like.

  In the present specification, the term “coating” is used not only to cover the entire surface of an object to be coated (eg, core) but also to include a case where it is partially covered or adsorbed or absorbed. . The term “spherical” is not limited to a true spherical shape, but is used to mean a shape having a curved surface such as an elliptical cross section, an egg shape, or a droplet shape. The “average particle diameter” means a volume-based median diameter (median diameter: cumulative distribution 50% equivalent particle diameter) unless otherwise specified. Examples of the measurement method include a laser diffraction particle size distribution measurement method, and a specific example is a method using a laser diffraction scattering particle size distribution analyzer SALD-2100 (manufactured by Shimadzu Corporation).

  In addition, the “composition containing a physiologically active substance” may contain a water-soluble polymer, a binder, a lubricant, an excipient, and the like used in the production of the aforementioned general preparation. Examples of the “water-soluble polymer” include ethanol-soluble water-soluble polymers [eg, cellulose derivatives such as hydroxypropylcellulose (hereinafter sometimes referred to as HPC), polyvinylpyrrolidone, etc.], ethanol-insoluble water-soluble polymers [eg, , Hydroxypropylmethylcellulose (hereinafter sometimes referred to as HPMC), cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like]. When using a water-soluble polymer, a combination of an ethanol-soluble water-soluble polymer and an ethanol-insoluble water-soluble polymer, or a combination of water-soluble polymers with different viscosities can be used. ) Can be controlled.

  Preferred water-soluble polymers include cellulose derivatives such as HPC, HPMC and methylcellulose, polyvinyl alcohol, and more preferably cellulose derivatives such as HPC and HPMC. The HPC contains, for example, about 53.4% to about 77.5% by weight, preferably about 60% to about 70% by weight, of hydroxypropoxyl groups. The viscosity of a 2% by weight aqueous solution of HPC at 20 ° C. is usually from about 1 cps to about 150,000 cps (centipoise). As such HPC, JP hydroxypropylcellulose or the like is used (hereinafter, the viscosity of HPC is the value of a 2 wt% aqueous solution at 20 ° C.). The HPMC is a mixed ether in which a methoxy group and a hydroxypropoxy group are bonded. HPMC has a methoxy group content of, for example, about 19 wt% to about 30 wt%, and a hydroxypropoxy group content of, for example, about 4 wt% to about 12 wt%. The viscosity of a 2 wt% aqueous solution of HPMC at 20 ° C. is usually from about 1 centistokes to about 40000 centistokes. As such HPMC, JP hydroxypropyl methylcellulose 2208, JP hydroxypropyl methylcellulose 2906, JP hydroxypropylmethylcellulose 2910 and the like are used. Hydroxypropyl methylcellulose can be used alone or in combination. The content of the water-soluble polymer such as HPC and / or HPMC can usually control the elution of the physiologically active substance in the composition containing the physiologically active substance, and retain a high content of the physiologically active substance. About 0.1% to about 50% by weight, preferably about 1% to about 30% by weight.

  In the “orally disintegrating tablet” of the present invention, when the diameter of the tablet is usually about 5 mm to about 20 mm, preferably about 7 mm to about 15 mm, more preferably about 8 mm to about 13 mm, handling of the dosage becomes advantageous. Orally disintegrating tablets may not contain a lubricant inside the tablet.

  The fast disintegrating preparation of the present invention thus obtained exhibits rapid disintegration or solubility in the oral cavity, water and stomach, and moderate preparation strength. Furthermore, the quick disintegrating preparation of the present invention has improved powderiness and is palatable. The oral disintegration time of the fast disintegrating preparation of the present invention (the time until the preparation is completely disintegrated with saliva in the oral cavity of healthy adult boys and girls) is usually about 5 seconds to about 50 seconds, preferably about 5 seconds. Or about 40 seconds, more preferably about 5 seconds to about 35 seconds.

  The disintegration time in the stomach of the fast disintegrating preparation of the present invention (the time until the preparation is completely disintegrated with the saliva in the mouth of healthy adult boys and girls) is longer than the disintegration time of a normal dosage form such as a normal tablet. Also short. The disintegration time in water of the fast disintegrating preparation of the present invention is usually about 5 seconds to about 40 seconds, preferably about 5 seconds to about 30 seconds, more preferably about 5 seconds to about 25 seconds.

  The hardness (measured by a tablet hardness meter) of the fast disintegrating preparation of the present invention is usually about 0.8 kgf to about 10 kgf, preferably about 2 kgf to about 7 kgf. The fast disintegrating preparation of the present invention is particularly useful as an orally disintegrating tablet and is taken without water or with water. Examples of the method of taking include (1) a method of containing in the mouth and not swallowing a small amount of water, or a method of taking it by dissolving or disintegrating it with saliva in the oral cavity without water, or (2) a method of swallowing it with water and taking it as it is. It is done. Alternatively, tablets may be taken after dissolving or disintegrating with water. The “orally disintegrating tablet” of the present invention is (a) when it is often necessary to take without water, (b) when taken by a patient who has difficulty swallowing the tablet, or (c) if it is a normal tablet, the throat. It is advantageously used when elderly people or children who are likely to get clogged.

  Erythritol used as one of the raw materials for the preparation of the present invention is a kind of sugar alcohol, and is usually produced by fermentation with yeast using glucose as a raw material. In general, those having a particle size that can pass 50 mesh are used, which can be obtained as a commercial product (product of Nikken Chemical Co., Ltd.). The content of erythritol in the preparation is usually about 5% to about 90% by weight, preferably about 10% to about 80% by weight, more preferably about 20% to about 80% by weight. A content of about 50% to about 80% by weight is more preferred.

  The crystalline cellulose that can be used in the present invention includes what is called microcrystalline cellulose as long as α-cellulose is partially depolymerized and purified. Various grades such as Theolas KG801, Avicel PH101, Avicel PH102, Avicel PH301, Avicel PH302, Avicel RC-591 (crystalline cellulose / carmellose sodium) can be used. These crystalline celluloses may be used alone or in combination of two or more. Preferred is Theolas KG801, which is said to be a highly molded Avicel. These raw materials can be obtained as commercial products (Asahi Kasei Co., Ltd.). The content of crystalline cellulose in the preparation is usually about 3% to about 50% by weight, preferably about 5% to about 40% by weight. In particular, a content of about 5 wt% to about 25 wt% is preferable.

  As the disintegrant that can be used in the present invention, disintegrants commonly used in the pharmaceutical field can be used as long as the object of the present invention is not impaired. As preferred disintegrants, for example, disintegrants called super disintegrants such as crospovidone (ISP Inc., BASF), croscarmellose sodium (FMC-Asahi Kasei), carmellose calcium (Gotoku Pharmaceutical) are particularly preferred. Examples of other preferable disintegrants include sodium carboxymethyl starch (Matsutani Chemical Co., Ltd.), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.), corn starch and the like. These disintegrants can be used alone or in combination of two or more. For example, crospovidone alone or a combination of crospovidone and other disintegrants can be considered. In addition, crospovidone is cross-linked (crosslinked) popidone, Kollidon CL (manufactured by BASF), (polyplaston XL), polyplastone, XL-10, INF-10 (manufactured by ISP), polyvinylpolypyrrolidone, PVPP Any polymer that has a chemical name of 1-ethenyl-2-pyrrolidinone homopolymer and is cross-linked, including those referred to as 1-vinyl-2-pyrrolidinone homopolymer. Usually over 1,000,000 molecules. The content of such a disintegrant in the preparation is usually about 1% to about 20% by weight, preferably about 3% to about 15% by weight, more preferably about 5% to 10% by weight.

  The content of mannitol in the preparation of the present invention is preferably about 5% by weight to about 90% by weight. Mannitol can be obtained as a commercial product (Towa Kasei Co., Ltd.), and those having a particle size that can pass through 150 mesh are usually used. The preparation of the present invention is particularly useful as an intraoral rapidly disintegrating preparation, which is a solid, but is a preparation that is taken in by dissolving or disintegrating in the oral cavity without being swallowed as it is.

  The preparation of the present invention may contain various additives used for production of general preparations as long as the effects of the invention are not hindered. Examples of such additives include binders, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, and coloring agents.

  Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, pregelatinized starch, polyvinylpyrrolidone, gum arabic powder, gelatin, and pullulan.

  Examples of the acidulant include citric acid, tartaric acid, malic acid and the like.

  Examples of the foaming agent include sodium bicarbonate.

  Examples of artificial sweeteners include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, and thaumatin.

  As a fragrance | flavor, lemon, lemon lime, orange, menthol, etc. are mentioned, for example.

  Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.

  Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, edible lake pigments, and bengara.

  The preparation of the present invention preferably contains the above-described components uniformly. That is, it is preferable that each component is uniformly distributed throughout the preparation.

  The preparation of the present invention can be produced according to conventional techniques in the pharmaceutical preparation field. Usually, the pharmaceutical ingredients and other ingredients of the preparation are mixed, and if necessary, they are further kneaded or dried or formed through a molding process. In the case of a tablet, it is produced by further tableting the preparation thus obtained. The mixing of the pharmaceutical ingredient and the raw material ingredient of the preparation is performed by a commonly used mixing method such as mixing and kneading. Specifically, mixing can be performed using a vertical granulator (manufactured by Paulek), a universal kneader (manufactured by Hata Iron Works), a fluidized bed granulator flow coater (manufactured by Freund). A mixture containing a pharmaceutical ingredient and a raw material ingredient for preparation may be directly compressed, but is usually kneaded before tableting. For the kneading of the mixture containing moisture, a method generally used as a preparation means for the preparation can be used. For example, kneading can be performed using the above-described apparatus or the like used when mixing a pharmaceutical ingredient and a raw material ingredient. Drying may be performed by any method used for general preparations such as vacuum drying, freeze drying, natural drying, and fluidized bed drying.

For tableting for producing a tablet, an apparatus generally used for molding or granulating a tablet is used. For example, a single tablet machine (manufactured by Kikusui Seisakusho), a rotary tablet machine (manufactured by Kikusui Seisakusho), or the like can be used. The molding pressure for tableting is usually about 500 kg / cm ^{2 to} about 3000 kg / cm ² . The thus obtained solid pharmaceutical preparation of the present invention, particularly the oral dissolution tablet, exhibits rapid disintegration and solubility in the oral cavity. That is, the mouth dissolution time of the oral dissolving tablet of the present invention (the time until the tablet is completely dissolved in the saliva of the mouth of a healthy adult male) is usually about 0.1 to about 1.0 minute, preferably Is about 0.1 to about 0.8 minutes, more preferably about 0.1 to about 0.5 minutes. The hardness (measured by a tablet hardness meter) is usually about 0.8 kgf to about 10 kgf, preferably about 2 kgf to about 7 kgf. Therefore, the oral-dissolving tablet of the present invention is a tablet that is easy to take for the elderly and children, and is a safe preparation for emergencies of general adults, as well as conventional pharmaceutical preparations containing the respective pharmaceutical ingredients. In addition, it can be used for patients who need their treatment / prevention for the effective treatment and prevention of various illnesses of each pharmaceutical ingredient, and is excellent in long-term storage and stability. The preparation of the present invention does not need to be swallowed and can be easily dissolved in the oral cavity only with saliva, and can be administered in the same manner as conventional oral preparations except that it can be removed without water. The preparation of the present invention has low toxicity and can be safely administered to a wide range of people from children to the elderly. The dose is similar to that of conventional oral preparations, depending on the type of pharmaceutical ingredient, the severity of the patient, and the age.

  The pharmaceutical ingredient used in the present invention may be in any form such as solid, powder, crystalline, oily, solution, and the like, and particularly suitable for the present invention include, for example, pranlukast hydrate, Epalrestat, limaprost, camostat mesylate and the like.

  The pranlukast hydrate used in the present invention represents pranlukast ½ hydrate.

  In the preparation of the present invention, when the pharmaceutical ingredient is pranlukast hydrate, epalrestat, or camostat mesylate, the content of the pharmaceutical ingredient in the preparation is usually about 5 wt% to about 60 wt%, preferably about 5 wt%. % To about 50% by weight, more preferably about 8% to about 30% by weight.

  In the case of a preparation containing epalrestat, the content of epalrestat in the preparation is preferably about 20 mg to about 150 mg, more preferably about 25 mg, about 50 mg and about 100 mg.

  In the case of a preparation containing pranlukast hydrate, the content of pranlukast hydrate in the preparation is preferably about 100 mg to about 500 mg, more preferably about 112.5 mg, about 225 mg and about 450 mg. .

  In the case of a preparation containing camostat mesylate, the content of camostat mesylate in the preparation is preferably about 30 mg to about 800 mg, more preferably about 50 mg, about 100 mg, about 200 mg, about 300 mg and about 600 mg.

  Since prostaglandin derivatives such as limaprost are effective at low doses, the content of limaprost in the preparation is usually about 0.0005 wt% to about 0.04 wt%, preferably about 0.0005 wt% to About 0.02 wt%, more preferably about 0.0005 wt% to about 0.01 wt%.

  In the case of a preparation containing limaprost, the content of limaprost in the preparation is preferably about 1 μg to about 30 μg, more preferably about 2.5 μg, about 5 μg, about 10 μg, about 15 μg and about 30 μg.

  Limaprost is not particularly limited, but it is preferably formulated as a cyclodextrin inclusion compound, and more preferably formulated as an α-cyclodextrin inclusion compound (alphadex).

  The rapidly disintegrating preparation of the present invention is useful as a medicine. In this case, the preparation of the present invention can be administered orally in mammals (eg, humans, monkeys, sheep, horses, dogs, cats, rabbits, rats, mice, etc.).

  Examples of the packaging form of the solid preparation of the present invention include, but are not limited to, a form of PTP (press-through pack) packaging after tableting, SP (strip pack) packaging, or aluminum packaging.

  The pharmaceutical composition of the present invention has the property of rapidly disintegrating with saliva or a small amount of water in the oral cavity or stomach by combining three components of a saccharide such as erythritol, crystalline cellulose, and a disintegrating agent. .

Example 1
Epalrestat, erythritol, carmellose calcium, crystalline cellulose and partially pregelatinized starch were charged into a fluidized bed granulator (Freund Sangyo, flow coater) and granulated with purified water. After granulation, it was dried with the same machine, and it was sized with a sizing machine (Paurec, Comil). This granulated product was mixed with 0.5% magnesium stearate and tableted (1 tablet 500 mg, 11 mmφ) at a tableting pressure of 1000 kg / cm ² using a rotary tableting machine (manufactured by Kikusui Seisakusho).
Composition Epalrestat 50mg in tablets (500mg)
Erythritol 250mg
Carmellose calcium 47.5mg
Crystalline cellulose 100mg
Partially pregelatinized starch 50mg
Magnesium stearate 2.5mg
500mg total
Example 2
Pranlukast hydrate, erythritol, mannitol, crystalline cellulose and crospovidone were put into a high-speed stirring granulator (Paurek, vertical granulator) and granulated with a 55% ethanol solution. After granulation, it was dried with a fluidized bed granulator (Freund Sangyo, flow coater), and then sized with a granulator (Paurec, Comil). This granulated product was blended with 0.3% magnesium stearate and tableted (1 tablet 500 mg, 11 mmφ) at a tableting pressure of 1000 kg / cm ² using a rotary tableting machine (manufactured by Kikusui Seisakusho).
Composition pranlukast hydrate 112.5mg in tablets (500mg)
Erythritol 141mg
Mannitol 140mg
Crystalline cellulose 70mg
Crospovidone 35mg
Magnesium stearate 1.5mg
500mg total
Example 3
Camostat mesylate, erythritol, mannitol, crystalline cellulose and crospovidone were put into a high-speed stirring granulator (Paurek, vertical granulator) and granulated with a 55% ethanol solution. After granulation, it was dried with a fluidized bed granulator (Freund Sangyo, flow coater), and then sized with a granulator (Paurec, Comil). This granulated product was blended with 0.3% magnesium stearate and tableted (1 tablet 500 mg, 11 mmφ) at a tableting pressure of 1000 kg / cm ² using a rotary tableting machine (manufactured by Kikusui Seisakusho).
Composition in tablets (500mg) Camostat mesylate 100mg
Erythritol 148.5mg
Mannitol 145mg
Crystalline cellulose 70mg
Crospovidone 35mg
Magnesium stearate 1.5mg
500mg total
Example 4
Limaprost alphadex, erythritol, carmellose calcium, crystalline cellulose and partially pregelatinized starch were charged into a fluidized bed granulator (Freund Sangyo, flow coater) and granulated with purified water. After granulation, it was dried with the same machine, and it was sized with a sizing machine (Paurec, Comil). This granulated product was blended with 0.5% magnesium stearate and tableted (1 tablet 400 mg, 10 mmφ) at a tableting pressure of 1000 kg / cm ² using a rotary tableting machine (manufactured by Kikusui Seisakusho).
Composition Limaprost Alphadex 0.162mg (5μg as Limaprost) in tablets (400mg)
Erythritol 207.838mg
Carmellose calcium 40mg
Crystalline cellulose 100mg
Partially pregelatinized starch 50mg
Magnesium stearate 2.0mg
400mg total
Experimental example 1
About the tablet obtained in each Example, the disintegration property was measured. Disintegration was measured for each 6 tablets using a disintegration tester (Toyama Sangyo) according to the Japanese Pharmacopoeia Disintegration Test Method, and the average value was shown. Note that purified water was used as a solvent for the disintegration test.

Since the rapidly disintegrating preparation of the present invention has excellent disintegrating properties, it can be easily taken by elderly and children without water, particularly as a rapid disintegrating preparation in the oral cavity for the treatment and prevention of various diseases. Used for. In addition, disintegration in the stomach is also improved. Further, since the rapidly disintegrating preparation has an appropriate strength, it is excellent in long-term storage stability. Furthermore, the fast disintegrating preparation of the present invention has improved solubility and powderiness, and has a good palatability.

Claims (20)

A rapidly disintegrating preparation comprising a saccharide, crystalline cellulose and a disintegrating agent as one or more selected from epalrestat, pranlukast hydrate, limaprost and camostat mesylate as pharmaceutical ingredients. The preparation according to claim 1, which is an intraoral rapidly disintegrating preparation. The agent according to claim 1, wherein the saccharide is one or more selected from sugar alcohol and saccharide. The agent according to claim 3, wherein the sugar alcohol is one or more selected from sorbitol, mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, erythritol, palatinit and lactitol. Saccharose is sucrose, isomaltooligosaccharide, fructooligosaccharide, galactooligosaccharide, palatinose, coupling sugar, soybean oligosaccharide, maltooligosaccharide, dairy oligosaccharide, xylooligosaccharide, trehalose, glucose, fructose, galactose, maltose, lactose, lactulose and sucrose The preparation according to claim 3, which is one or more selected from sugars. The preparation according to claim 1, wherein the disintegrant is one or more selected from crospovidone, croscarmellose sodium and carmellose calcium. The preparation according to claim 1, which is a tablet. The preparation according to claim 1, wherein the content of epalrestat, pranlukast hydrate or camostat mesylate in the preparation is 5% by weight to 60% by weight. The preparation according to claim 1, wherein the content of limaprost in the preparation is 0.0005 wt% to 0.04 wt%. The preparation according to claim 4, wherein the sugar alcohol is erythritol or mannitol. The preparation according to claim 1, wherein the components of (i) a pharmaceutical ingredient, (ii) erythritol, (iii) crystalline cellulose, and (iv) a disintegrant are uniformly mixed. A method for improving the disintegration property in the oral cavity of a preparation comprising a combination of (i) a pharmaceutical ingredient, (ii) erythritol, (iii) crystalline cellulose and (iv) a disintegrant. Use in the manufacture of a preparation with improved oral disintegration, comprising (i) a pharmaceutical ingredient, (ii) erythritol, (iii) crystalline cellulose and (iv) a disintegrant. The preparation according to claim 1, which has a hardness of 0.8 kgf to 10 kgf. 8. The tablet according to claim 7, wherein 25 mg, 50 mg or 100 mg of epalrestat per tablet is contained. The tablet according to claim 7, which contains 112.5 mg, 225 mg or 450 mg of pranlukast hydrate per tablet. 8. The tablet according to claim 7, which contains 2.5 μg, 5 μg, 10 μg, 15 μg or 30 μg of limaprost per tablet. 8. The tablet according to claim 7, which contains 50 mg, 100 mg, 200 mg, 300 mg or 600 mg of camostat mesylate per tablet. The tablet according to claim 7, wherein the content of epalrestat, pranlukast hydrate or camostat mesylate in the tablet is from 5 wt% to about 60 wt%. The tablet according to claim 7, wherein the content of limaprost in the tablet is 0.0005 wt% to about 0.02 wt%.