JP2007153882A - Solid formulation to control elution of active ingredient to sustained-release - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a sustained-release solid formulation which is not affected by ion strength, pH, and compressive force during molding, and capable of controlling the elution of active ingredients which are small in water solubility to zero order elution etc. <P>SOLUTION: This sustained-release solid formulation contains at least an active ingredient and an elution controlling base, and the active ingredient has solubility in water of 0.0001-100 mg/cm<SP>3</SP>, and the elution controlling base is modified starch, having a water retaining capacity of not smaller than 400%, gel push-in load value of not lower than 200 g, water solubles content of 40-95 wt.%, and the passing particles through 75 μm sieve mesh of not smaller than 90 wt.%, the passing particles through 32 μm sieve mesh of not smaller than 20 wt.%, an average particle diameter of not smaller than 20 μm but smaller than 50 μm, and contains a hydrophilic auxiliary agent having solubility to water of 0.1-5.0 g/cm<SP>3</SP>at 20°C, and a molecular weight of not greater than 1,000, and the compounding ratio of the modified starch to the hydrophilic auxiliary agent is 5:40-99:1. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a solid preparation for controlling the elution of an active ingredient having a low solubility in water to a sustained release in uses such as pharmaceuticals, agricultural chemicals, fertilizers, feeds, foods, industry, and cosmetics. More specifically, elution of active ingredients that are not easily affected by the in vivo environment such as ionic strength and pH, and compression force during compression molding, have little fluctuation in gastrointestinal tract residence time, and have low solubility in water The present invention relates to a sustained-release solid preparation that can be controlled to be sustained-release.

  Sustained-release solid preparations for pharmaceutical use can be controlled by controlling the blood concentration of the active ingredient, thereby reducing the number of administrations and improving the ingestibility, improving the sustainability of the active ingredient with a short elimination half-life in vivo, It is a highly useful preparation because it can reduce the side effects of active ingredients with a minimum blood concentration and a narrow range of concentration of side effects.

  As a method for controlling the elution of active ingredients to be controlled release, a method in which active ingredients are uniformly dispersed together with an elution control base and compression-molded has been developed because of its simple structure and manufacturing process in addition to stable elution control. Because of its high speed, it is widely used for practical applications (matrix system). For elution control bases, hydrophilic elution control bases, lipophilic elution control bases, and inert elution control bases ( Belonging to thermoplastic polymers).

  Examples of hydrophilic elution control bases include cellulose derivatives such as methylcellulose (MC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC) as described in Patent Document 1 and the like. Yes. These have characteristics such that the active ingredient can be controlled to be sustained-released without being affected by pH, and the stability over time is excellent. However, since the cellulose derivative has a property of being greatly swollen by hydration, the solid preparation swells greatly in the compression direction as gelation proceeds in the elution solution. As a result, in the later stage of elution, the diffusion distance for elution of the active ingredient becomes longer and the elution rate is lowered. For this reason, it is difficult to accurately control the zero-order elution and the like. Cellulose derivatives are generally available in grades with different viscosities, and higher viscosity grades are more excellent in the ability to release active ingredients. However, on the other hand, the higher the viscosity grade, the greater the degree of swelling in the compression direction, and it was difficult to accurately control the zero-order elution.

  Patent Documents 2, 3 and the like describe a method of blending a water-soluble component as a method for adjusting the dissolution property of the cellulose derivative. Patent Document 2 describes the use of sorbitol, polyethylene glycol, or the like as an elution regulator for controlling release more slowly or faster in a sustained release solid preparation having a gel-forming polymer such as HPMC as an elution control base. Has been. However, there is no example using an elution control agent, and the effect of the elution control agent is not specifically disclosed. In addition, as is known among those skilled in the art, these elution regulators are expected to have the effect of slowing down or increasing the elution rate of the active ingredient as a whole, but the elution rate decreases later in the elution. It was not possible to improve the problem. Patent Document 3 discloses a sustained-release solid preparation containing a cellulose polymer compound such as HPMC as an elution control base and containing glucose syrup, and discloses that the active ingredient is eluted linearly. However, the dissolution test results actually disclosed in the examples show that the dissolution rate is reduced in the later stage of dissolution, which is insufficient to improve the speed reduction in the later stage of dissolution.

  Patent Document 4 discloses a method of using a multilayer tablet comprising a swellable layer containing an active ingredient and an erodible and / or soluble layer for the purpose of improving the rate reduction in the later stage of dissolution due to swelling of the cellulose derivative. Has been. In this method, the erodible and / or soluble layer is reduced in the later stage of elution to increase the surface area of the swollen layer containing the active ingredient, thereby preventing a decrease in elution rate in the later stage of elution. However, in this way, it was necessary to take a complicated formulation design in order to improve the problem of speed reduction in the late stage of elution of the cellulose derivative.

  Cellulose derivatives compete for hydration with solutes that produce ionic strength in a solution having a large ionic strength value. For this reason, gelation becomes insufficient, and the shape of the matrix cannot be maintained, and it has a property of collapsing. It is known that the ionic strength value in the gastrointestinal tract varies depending on not only the region but also the ingested food and varies in the range of about 0.01 to about 0.2. For this reason, the cellulose derivative also has a problem that in a ionic strength environment where the gastrointestinal tract fluctuates, hydration is suppressed at a moderate or higher ionic strength and the matrix collapses. When so-called dose dumping occurs due to the rapid dissolution of the remaining active ingredients due to the collapse of the matrix, the blood concentration increases rapidly. As a result, there is a possibility of dying depending on the efficacy of the active ingredient having a narrow blood concentration and a narrow side effect concentration range. The sustained-release solid preparation in the pharmaceutical field needs to provide accurate elution control even in the gastrointestinal tract environment where the ionic strength varies. Therefore, there is a demand for a sustained-release solid preparation having stable dissolution controllability in a solution with varying ionic strength, particularly in a solution with high ionic strength.

  Patent Documents 5 to 9 disclose methods for improving the elution controllability of HPC and HPMC. In these documents, for example, particles passing through a 100 mesh (opening of about 150 μm) sieve are 50 wt% or more in HPC, and particles passing through a 100 mesh (opening of about 150 μm) sieve are 95 wt% or more in HPMC. A method for miniaturizing particles is disclosed. According to these methods, the hydration rate is accelerated by refining the particles of HPC and HPMC, and a gel layer can be rapidly formed, and the disintegration of the tablet that occurs at the early stage of dissolution of the active ingredient is suppressed. And excessive elution can be prevented. However, the use of fine particles according to Patent Documents 5 to 9 does not improve the swellability of the particles, so it cannot solve the problem of speed reduction in the later stage of elution, and in a solution with high ionic strength. It was not possible to solve the collapse of the.

  Among cellulose derivatives, HPMC is one of the most frequently used elution control bases. However, in addition to the above-mentioned problems, improvements in many aspects of powder properties such as poor fluidity, slightly yellowish color and poor whiteness, and an irritating odor peculiar to synthetic glue are desired. The current situation is rare.

  As other hydrophilic elution control bases of cellulose derivatives, non-cellulose polysaccharides such as xanthan gum and locust bean gum, and synthetic polymers such as polyethylene oxide and acrylic acid polymers are known. These elution control bases generally have a swelling property larger than that of a cellulose derivative, and have a property of swelling not only in the compression direction but also in the direction perpendicular to the compression direction and becoming enlarged as time passes. As a result, there is a drawback that the elution rate is reduced in the later stage of elution. In addition, there is a high possibility that the residence time will vary in the gastrointestinal tract. Therefore, it is not always a satisfactory sustained release solid preparation in the pharmaceutical field where accurate elution is required with high reproducibility.

  Patent Documents 10 to 12 describe a method for adjusting the elution property by blending a non-cellulose polysaccharide or a synthetic polymer with a water-soluble component. Patent Document 10 describes that a sustained-release solid preparation containing a heteropolysaccharide gum and a homopolysaccharide gum that can be crosslinked with the heteropolysaccharide gum contains monosaccharides, disaccharides, and polyhydric alcohols as inert diluents. . However, there is no description about the effect of the inert diluent on the dissolution of the active ingredient.

  Patent Document 11 describes a sustained release solid preparation comprising a sustained release carrier such as a mixture of sodium alginate and xanthan gum and a gel hydration accelerator. There is a description that the gel hydration accelerator is preferably a mixture of HPMC and propylene glycol alginate. In addition, it is disclosed that since non-gelled core is not formed by fast gel hydration, the elution is not affected by the speed of movement of the gastrointestinal tract, and there is a description of zero-order elution. However, all of the sustained-release preparations disclosed in the Examples have almost no elution of the active ingredient until 2 hours after the start of the test, and are special ones having different elution properties from the zero-order elution generally required for pharmaceutical applications. there were.

  In Patent Document 12, a polymer that forms a hydrogel such as polyethylene oxide (PEO) and the amount of water required to dissolve 1 g are contained in one or more preparations having a solubility of 5 ml or less. There is a description of a sustained-release solid preparation containing an additive for infiltrating water. It is disclosed that since the gelation of the solid preparation is promoted, the active ingredient can be continuously released even in the lower part of the digestive tract where the amount of water is small. The additive used in Patent Document 12 needs to have a certain solubility or more in water. However, there is no description on the influence of differences in molecular weight or the like on the strength and dissolution property after gelation of a sustained-release solid preparation. In addition, the dissolution test results disclosed in the examples show that the speed is lowered in the late stage of elution, and the problem that the polymer forming the hydrogel is slowed down in the late stage of elution cannot be improved.

  Lipophilic elution control bases include hydrogenated castor oil, glycerides such as stearin and palmitic acid, higher alcohols such as cetyl alcohol, fatty acids such as stearic acid, and fatty acid esters such as propylene glycol monostearate However, they have many problems such as lack of storage stability, large changes in the dissolution of active ingredients, and a decrease in the dissolution rate in the later stage of dissolution.

  As the inert dissolution control base, polyvinyl chloride, polyethylene, vinyl acetate / vinyl chloride copolymer, polymethyl methacrylate, polyamide, silicone, ethyl cellulose, polystyrene and the like are known. Sustained release solid preparations using an inert elution control base exhibit sustained release properties as the active ingredient diffuses through pores formed by compression molding water-insoluble particles. Therefore, there has been a problem that when the pore size varies due to compression molding pressure, the elution rate of the active ingredient also varies. Further, in the latter half of the elution, there was a disadvantage that the elution rate was slow because the diffusion distance of the active ingredient was long.

  Patent Documents 13 and 14 and the like describe a method of adjusting the dissolution property by blending an inert dissolution control base with a water-soluble component. Patent Document 13 and the like describe a sustained-release solid preparation containing a methacrylic acid copolymer which is an elution control base and excipients such as D-sorbitol, powdered reduced maltose starch syrup and anhydrous calcium phosphate. It is disclosed that by using the solid preparation, the elution of the active ingredient is proportional to time and does not depend on the compressive force. However, in the dissolution test results disclosed in the examples, the dissolution rate decreased in the later stage of dissolution, and the problem that the methacrylic acid copolymer decreased in the later stage of dissolution was not improved. Moreover, it did not suppress the fluctuation of the dissolution rate due to the compression molding pressure. The methacrylic acid copolymer marketed as a pharmaceutical additive tends to generate static electricity and has a strong unpleasant odor peculiar to a chemically synthesized product, and has a problem in handling.

  Patent Document 14 discloses a water-soluble, water-soluble highly swellable or lipophilic shaping agent such as polyethylene glycol for modifying the release to a sustained release solid preparation containing a mixture of polyvinyl acetate and polyvinylpyrrolidone as an elution control base. Methods for formulating agents to increase or delay the release rate are described. This controls the water permeability of pores formed by compression molding of polyvinyl acetate to control the elution of the active ingredient as a whole. However, it has not been able to improve the problem of speed reduction in the late stage of elution. Moreover, since gel is formed on the tablet surface and initial elution is suppressed, there is a description that elution is linear. However, the problem of speed reduction in the later stage of elution cannot be improved, and in the examples, the use of polyethylene glycol or the like or linear elution was not specifically disclosed. Further, a mixture of polyvinyl acetate and polyvinyl pyrrolidone marketed as a pharmaceutical additive is strongly yellowish and has a strong unpleasant odor peculiar to chemically synthesized products.

  Patent Document 15 discloses a processed starch having a water retention amount of 400% or more, a disintegration time of 5 hours or more, and a gel indentation load of 200 g or more, and a sustained-release solid preparation using the processed starch as an elution control base. Yes. The processed starch has sufficient resistance to α-amylase not found in conventional natural processed starch, and thus exhibits sufficient sustained release and is not affected by ionic strength. Therefore, there is a description that the active ingredient can be released relatively stably without causing a problem of dose dumping. In addition, naturally occurring starchy raw materials are produced only by physical processing. Therefore, there is no problem of chemical residue and the like, and it can be taken in with peace of mind, and fluidity and whiteness are both good. However, the disclosed processed starch has relatively large particle swellability, and the disadvantage that the strength of the gelled solid preparation becomes weak and the elution rate of the active ingredient fluctuates due to the compression molding pressure. have. Moreover, the elution property of the active ingredient largely fluctuates due to a change in compression molding pressure and a change in formulation and blending amount in the manufacturing process. Therefore, it was not always possible to accurately control elution. Furthermore, when an active ingredient having a low solubility in water is used as the active ingredient, the solid preparation cracks in an unspecified time zone during elution, particularly when the compression force during compression molding is low, or two or more And the elution rate was primarily increased. As described above, the processed starch described in Patent Document 15 has an elution rate depending on the compression molding pressure even though accurate elution control is possible without depending on the in vivo environment such as ionic strength and pH. Depending on the type of the active ingredient, there is a problem that a large amount of the active ingredient is eluted suddenly at an unspecified time zone.

  The use of starch as an elution control base is described in Patent Documents 16 to 22 and the like. Patent Document 16 describes a pharmaceutical composition containing a pregelatinized starch having a low viscosity and a multimodal particle size for the purpose of improving variation in dissolution rate of an active ingredient. There is a description that this composition can be in many forms, including sustained release. However, in the examples, only preparations with a high dissolution rate in which 75% or more is eluted in 45 minutes are disclosed, and there is no specific disclosure showing sustained release. Further, it differs from the present invention in that there is no description that starch itself has a sustained release function.

Patent Document 17 describes a sustained-release preparation using a pregelatinized starch as a matrix base. However, as a preferred embodiment, the use of a pregelatinized corn starch having a soluble fraction of 10 to 20% is described, and the processed starch used in the present invention has a water-soluble component amount of 40 to 95% by weight. Different. The elution rate of the active ingredient is not specifically disclosed. However, starch having a small amount of cold water-soluble components as in Patent Document 17 has an insufficient sustained release function, and it is difficult to control an active ingredient having a particularly high water solubility to be sustained release.
Patent Document 18 discloses a matrix sustained-release preparation containing one or more of a water-soluble polymer and a lower water-soluble polymer. Patent Document 19 discloses a matrix sustained-release preparation containing both a water-soluble polymer and a less water-soluble polymer. Patent Documents 18 and 19 describe starch as a water-soluble polymer. However, the modified starch used in the present invention is different in that the amount of the water-soluble component is in the range of 40 to 95% and is only partially dissolved in water.

  Patent Document 20 describes the use of modified corn starch as a natural polysaccharide in a matrix sustained-release preparation containing a natural polysaccharide. However, the modified corn starch described is a water-soluble pregelatinized starch, and is different in that the processed starch used in the present invention has a water-soluble component amount of 40 to 95%. Further, as reported in Non-Patent Document 1, the pregelatinized starch mainly used in food applications as a thickener, a sericulture feed, etc. breaks the gel formed by starch in the presence of α-amylase. Therefore, there has been a problem that the sustained release performance is lowered.

  Patent Document 21 describes a sustained-release preparation using a starch obtained by subjecting a mixture of water containing 5-95% starch to water at a temperature of 130 to 160 ° C. as a matrix base. Patent Document 22 describes a sustained-release preparation using starch in which the crystallinity of the crystalline starch is partially or substantially completely lost. However, Patent Documents 21 and 22 were not able to control the elution of the active ingredient to zero-order elution or the like. Moreover, the pregelatinized starch has not solved the problem that the gel formed by starch in the presence of α-amylase is broken and the sustained release performance is lowered.

  Moreover, although patent documents 23-25 have description of the sustained release formulation which uses amylose as a matrix base, the processed starch used for this invention differs in the point containing amylose and amylopectin. Patent documents 26 to 28 and the like describe a sustained-release solid preparation using crosslinked amylose as a matrix base. However, cross-linked amylose is obtained by subjecting amylose obtained by removing amylopectin from natural starch to chemical treatment in the presence of alkali and through complicated steps. Furthermore, α-amylase is added as an elution rate adjusting agent to improve elution controllability (Patent Document 27), or HPMC is used to reduce dependency on α-amylase present in the intestinal environment. It was necessary to use (Patent Document 28).

  Patent Document 29 is a sustained release preparation using starch acetate as a matrix base, Patent Document 30 is a sustained release preparation using a substituted amylose substituted with an epoxy group or a halogen compound as a matrix base, There is a description of a sustained-release preparation using starch modified with acid or sulfate as a matrix base. Patent Documents 29 to 31 require chemical treatment in order to impart a sustained release function to starch, and the processed starch used in the present invention is obtained by processing natural starch only by physical treatment. It is different.

As described above, elution of an active ingredient having little fluctuation in the gastrointestinal residence time and low solubility in water is not affected by the in vivo environment such as ionic strength and pH, and the compression force at the time of compression molding. In the current state, there is no sustained-release solid preparation that can be controlled to the next dissolution or the like, and such a sustained-release solid preparation has been desired.
US Pat. No. 6,296,873 JP 2005-504052 gazette Special Table 2002-525310 Japanese Laid-Open Patent Publication No. 2004-107351 Japanese Patent Publication No. 7-515156 Japanese Patent Publication No. 7-8809 Japanese Examined Patent Publication No. 62-149632 JP-A-6-172161 JP-A-6-305982 Special table 2003-510265 gazette JP 2004-143175 A JP 2001-10951 A JP-A-11-5739 JP 2002-20319 A WO2005 / 005484 International Publication JP-T-2006-514687 JP-A-5-262649 JP 63-54319 A Japanese Patent Laid-Open No. 2-2038 JP 63-503225 A WO92 / 15285 International Publication Japanese Patent Laid-Open No. 61-5027 Special Table 2000-517351 WO99 / 009066 International Publication JP 2002-363106 A US Pat. No. 5,456,921 Japanese National Patent Publication No. 8-502036 Special table 2000-507561 Japanese National Patent Publication No. 10-502056 JP-T-2001-502700 WO2005-74976 International Publication Chem. Pharm. Bull. , 35 (10), 4346-4350 (1987).

  Under such circumstances, the present invention is not affected by the in vivo environment such as ionic strength and pH, compression force at the time of compression molding, the fluctuation of gastrointestinal residence time is small, and the active ingredient with low solubility in water An object of the present invention is to provide a sustained-release solid preparation capable of accurately controlling elution of lysine to zero-order elution or the like.

The present inventors have intensively studied the gel formation mechanism and the active ingredient elution mechanism in a solution of a sustained release solid preparation containing an active ingredient having low solubility in water. As a result, an activity with low solubility in water is obtained by using a specific processed starch as an elution control base and using a water-soluble auxiliary having a water solubility of 0.1 to 5.0 g / cm ³ in combination. The inventors have found that elution of components can be accurately controlled to zero-order elution and the like, and have completed the present invention based on this finding. That is, the present invention is as follows.

(1) A sustained-release solid preparation containing at least one active ingredient and an elution control base, wherein the active ingredient has a water solubility of 0.0001 to 100 mg / cm ³ . The elution control base has a water retention amount of 400% or more, a gel indentation load of 200 g or more, a water-soluble component amount of 40 to 95% by weight, and 90% by weight of particles passing through a sieve having an opening of 75 μm. The above is a processed starch having a particle size of 20% by weight or more passing through a sieve having an opening of 32 μm and an average particle size of 20 μm or more and less than 50 μm, and further has a solubility in water of 0.1 to 5.0 g at 20 ° C. / Cm ³ and having a molecular weight of 1000 or less, and the weight blending ratio of the processed starch and the hydrophilic assistant is within the range of 50:50 to 99: 1. Characteristic solid preparation. (2) The solid preparation according to (1), wherein the processed starch contains 98% by weight or more of particles passing through a sieve having an opening of 75 μm and 40% by weight or more of particles passing through a sieve having an opening of 32 μm. . (3) The solid preparation according to (1) or (2), wherein the degree of swelling of the processed starch is 6 cm ³ / g or more and 10 cm ³ / g or less. (4) The processed starch has an angle of repose of 45 ° or less and an apparent specific gravity of 1.4 cm ³ / g or more and 3.6 cm ³ / g or less, according to any one of (1) to (3) The solid preparation described.
(5) The hydrophilic auxiliary is at least one selected from the group consisting of sugar alcohols, saccharides, surfactants, salts, organic acids, amino acids, and amino sugars (1) to (4) The solid formulation in any one of. (6) The solid preparation according to (5), wherein the hydrophilic auxiliary is sorbitol and / or sucrose. (7) The elution control base further has a solubility in water at 20 ° C. of 0.1 g / cm ³ or more and 5.0 g / cm ³ or less, a melting point of 50 ° C. or more, and an average molecular weight of 5000 or more. Or the solid formulation in any one of (1)-(6) containing the hydrophilic polymer adjuvant which is natural polymers. (8) The solid preparation according to (7), wherein the hydrophilic polymer auxiliary is polyethylene glycol. (9) The solid preparation according to any one of (1) to (8), wherein the one or more active ingredients are pharmaceutical medicinal ingredients. (10) The solid preparation according to any one of (1) to (9), further comprising coated granules. (11) Furthermore, it contains at least one selected from sucrose fatty acid ester, talc and light anhydrous silicic acid, and magnesium aluminate metasilicate as a lubricant. The solid preparation described. (12) The solid preparation according to any one of (1) to (11), wherein the weight is greater than 0.2 g.

  According to the present invention, even when an active ingredient having low solubility in water is used, it is not affected by the in vivo environment such as ionic strength and pH after administration, or the compression force at the time of compression molding during production. In addition, accurate sustained release such as zero-order elution can be realized.

The present invention will be described in detail below. The sustained-release solid preparation of the present invention contains one or more active ingredients, and includes an insoluble active ingredient having a solubility in water of 0.0001 to 100 mg / cm ³ . The solubility of such an active ingredient in water is 0.0001 mg / cm ³ or more, the elution rate of the active ingredient from the solid preparation is ensured, and the active ingredient is in the time zone where the solid preparation stays in the gastrointestinal tract. Almost the entire amount can be eluted, and bioability is secured, which is preferable. If the solubility of the active ingredient in water is 100 g / cm ³ or less, the elution control base hydrates before the active ingredient and forms a gel layer on the surface of the solid preparation. This is preferable because the phenomenon that the active ingredient does not easily occur and the active ingredient can be easily controlled to be released in a controlled manner. The solubility of the active ingredient in water is preferably 0.0001~30mg / cm ^3, more preferably 0.0001~10mg / cm ^3.

As an active ingredient having a solubility in water of 0.0001 to 100 mg / cm ³ , for example, in the pharmaceutical field, a drug that is slightly soluble in water (dissolves 1 g of solute) described in the 14th revised Japanese Pharmacopoeia. The amount of solvent required is 10 to 30 cm ³ ), the drug slightly soluble in water (the amount of solvent required to dissolve 1 g of solute is 30 to 100 cm ³ ), the drug not soluble in water (the amount of solvent required to dissolve 1 g of solute is 100 to 1000 cm) ³ ) Drugs that are extremely insoluble in water (the amount of solvent required to dissolve 1 g of solute is 1000 to 1000 cm ³ ), drugs that are hardly soluble in water (the amount of solvent required to dissolve 1 g of solute is 10,000 cm ³ or more), and the like. it can.

Next, the solid preparation needs to contain a hydrophilic auxiliary having a solubility in water of 0.1 to 5.0 g / cm ^{3 at} 20 ° C. and a molecular weight of 1000 or less. The weight blending ratio of the processed starch and the hydrophilic auxiliary agent needs to be in the range of 50:50 to 99: 1. When the hydrophilic auxiliary is contained, water can penetrate into the solid preparation, promote hydration of a specific processed starch, which will be described later, and form a dense gel layer. The solubility of the hydrophilic auxiliary in water is preferably 0.2 to 5.0 g / cm ³ , more preferably 0.4 to 5.0 mg / cm ³ .

Despite the action of the active ingredient whose solubility in water of the hydrophilic auxiliary is 0.1 g / cm ³ or more and the solubility in water uniformly dispersed in the matrix is small, Infiltration is possible, a dense gel layer is formed, and cracks and division due to the swelling force of the solid preparation itself are less likely to occur. Further, the solubility of the hydrophilic auxiliary in water is 5.0 g / cm ³ or less, the water absorption amount remains in an appropriate range, and the gel density remains in a dense range without excessive water absorption. Therefore, the strength of the solid preparation is ensured and it can withstand the load caused by the mechanical movement of the gastrointestinal tract. Therefore, it is difficult to cause excessive erosion of the solid preparation, and the elution rate is easily kept stable.

Examples of hydrophilic auxiliaries having a solubility in water of 0.1 to 5.0 g / cm ³ and a molecular weight of 1000 or less include sugar alcohols such as sorbitol and mannitol, sucrose, anhydrous maltose, sucrose, fructose, dextran, and butter sugar. Saccharides such as, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, surfactants such as polyoxyethylene sorbitan higher fatty acid esters, salts such as sodium chloride and magnesium chloride, organic acids such as citric acid and tartaric acid, glycine Or one or more amino acids such as alanine and aminosaccharides such as meglumine can be used. Particularly preferred as hydrophilic aids include sorbitol and sucrose.

Also, solid preparation, in addition to the hydrophilic auxiliary agents described above, the solubility in water at the 20 ℃ 0.1g / cm ³ or more 5.0 g / cm ³ or less, a melting point of 50 ° C. or higher, an average molecular weight of 5000 or more synthetic Or it is preferable that the hydrophilic polymer auxiliary agent which is natural polymers is included. In that case, it is preferable that the compounding quantity of this hydrophilic polymer adjuvant is 0.1 to 40 weight%. When the hydrophilic polymer is contained, gelation of the dissolution control base dispersed on the solid preparation surface is promoted, so that the active ingredient dispersed on the solid preparation surface dissolves and dissolves faster than it dissolves. It is preferable because a gel layer can be formed on the surface of the preparation, and it is easy to control a large amount of active ingredient at the beginning of elution and control to zero order elution. The lower limit of the solubility of the hydrophilic polymer in water is preferably 0.2 g / cm ³ , more preferably 0.4 g / cm ³ . The upper limit of the solubility of the hydrophilic polymer in water is preferably 4.5 g / cm ³ , more preferably 4.0 g / cm ³ .

The hydrophilic polymer having a solubility in water of 0.1 to 5.0 g / cm ³ is preferably a hydrophilic synthetic polymer having a relatively high molecular weight, specifically, polyethylene. Glycol, polyvinyl pyrrolidone, polyvinyl alcohol, pullulan and the like can be mentioned, and polyethylene glycol is particularly preferred.

  Next, the solid preparation has a water retention amount of 400% or more, a gel indentation load of 200 g or more, a water-soluble component amount of 40 to 95% by weight, and particles passing through a sieve having an opening of 75 μm as an elution control base. It is necessary to contain a specific processed starch having a particle size of 90% by weight or more, 20% by weight of particles passing through a sieve having an opening of 32 μm, and an average particle size of 20 μm or more and less than 50 μm. This specific modified starch functions as an elution control base for ensuring sustained release of the active ingredient. Here, the modified starch as used in the field of this invention is the starch which improved the physical property only by physical processing using the natural starch raw material.

  The content of such specific processed starch in the solid preparation needs to be 5.0 to 99.9% by weight. When the content of the modified starch is 5% by weight or more, it becomes easy to control the elution of the active ingredient to be sustained release. The content of the modified starch can be appropriately selected depending on the type and amount of the active ingredient. However, if the content of the modified starch is 99.9% by weight or more, the content of the active ingredient is sufficiently reduced. The upper limit should be at most 99.9% by weight because it is difficult to impart a medicinal effect. More preferably, it is 10-99.9 weight%, Most preferably, it is 20-99.9 weight%.

  Such a specific processed starch needs to have a water retention amount of 400% or more. More preferably, it is 500% or more, and particularly preferably 700% or more. Here, the water retention amount is defined as the amount of pure water retained by starch after 1 g of dried processed starch is dispersed in pure water at 20 ° C. ± 5 ° C. and centrifuged (2000 G, 10 minutes). When the water retention amount is 400% or more, the processed starch is hydrated to form a gel, so that the solid preparation is not easily disintegrated, and the diffusion rate of the active ingredient is maintained, and sufficient sustained release is easily developed. The higher the water retention amount, the higher the gel-forming ability, and the gel is not broken even under high ionic strength. This is preferable, but the maximum value is at most 3000% depending on the properties of the starch raw material.

  Further, the specific processed starch needs to have a gel indentation load value of 200 g or more. The gel indentation load value is obtained by gelling a cylindrical molded body having a diameter of 1.13 cm obtained by compressing 0.5 g of processed starch at 50 MPa for 4 hours in pure water at 20 ° C. ± 5 ° C. This is defined as the maximum load when a 3 mm diameter cylindrical adapter is pushed in at a speed of 0.1 mm / sec. Here, the maximum load is the load value at the time of rupture when the gel layer is broken, and the maximum load value before the adapter enters 5 mm into the gelled cylindrical molded body when there is no rupture. When the gel indentation load value is 200 g or more, the diffusion of the active ingredient in the gel layer formed by the processed starch does not become too fast, and sufficient sustained release property is easily developed. The higher the gel indentation load value, the higher the sustained release ability, which is preferable, but it is about 3000 g at most.

Further, the specific processed starch needs to have a water-soluble component amount in the range of 40 to 95% by weight. The amount of the water-soluble component is defined as a value obtained by the following calculation. That is, 99 g of pure water at 20 ° C. ± 5 ° C. was added to 1 g of the processed starch and dispersed by stirring for 2 hours with a magnetic stirrer, and 40 cm ³ of the obtained dispersion was transferred to a 50 cm ³ centrifuge tube and 15 g at 5000 G. Centrifugation is performed for 30 minutes, and 30 cm ³ of this supernatant is placed in a weighing bottle and dried at 110 ° C. until a constant weight is obtained to obtain the dry weight (g) of the water-soluble component. Also, 1 g of the processed starch is dried at 110 ° C. until a constant weight is obtained, and the absolute dry weight (g) of the processed starch is determined. These values are defined by the values obtained by the following formula (1).
Water-soluble component amount (% by weight) = (dry weight (g) × 100 ÷ 30) ÷ absolute dry weight of 1 g of starch (g) × 100 (1)

  The amount of the water-soluble component is a value representing the amount of the paste component that has been processed into starch and becomes water-soluble. There is a phenomenon in which the amount of the water-soluble component is 40% by weight or more, the hydration rate is ensured and it does not become too slow, and a large amount of the active ingredient is eluted immediately after the sustained-release solid preparation comes into contact with the solvent. Hard to occur. When the amount of the water-soluble component is 95% by weight or less, the strength of the solid preparation is ensured, and sufficient sustained release is easily obtained. Further, since it can withstand the load caused by the mechanical movement of the gastrointestinal tract, the dissolution rate is ensured within a certain range without excessive erosion.

  Further, the specific processed starch has 90% or more of particles passing through a sieve having an opening of 75 μm, 20% or more of particles passing through a sieve having an opening of 32 μm, and an average particle size of 20 μm or more and less than 50 μm. There is a need. Preferably, 95% or more of the particles passing through the sieve having an opening of 75 μm, and 30% by weight or more of the particles passing through the sieve having an opening of 32 μm, and particularly preferably 98 particles passing through the sieve having an opening of 75 μm. More than 40% by weight of the particles passing through a sieve having a mesh size of 32 μm. The specific processed starch has smaller swellability and smaller gel strength when the particles are smaller. Therefore, if the particles passing through the sieve having an opening of 75 μm are 90% by weight or more, the particles passing through the sieve having an opening of 32 μm are 20% by weight or more, and the average particle size is less than 50 μm, the starch particles and the starch The swelling property of the solid preparation composed of particles remains within a relatively small range. Therefore, the elution of the active ingredient from the solid preparation is less likely to fluctuate due to the compression molding pressure.

The specific processed starch preferably has a degree of swelling of 6 cm ³ / g or more and 10 cm ³ / g or less. The degree of swelling of the processed starch was determined by dispersing 1.0 g of the processed starch in pure water at 20 ± 5 ° C., transferring it to a 100 cm ³ sedimentation tube, making the total amount 100 cm ^3, and letting it stand for 16 hours. The volume V (cm ³ ) and the dry weight (g) of the modified starch 1.0 g are measured and defined as the value obtained from the following formula (2).
Swelling degree of processed starch (cm ³ / g) = V (cm ³ ) / Dry weight of processed starch (g) (2)

Since the degree of swelling of the processed starch is 6 cm ³ / g or more and hydrates to form a gel, the elution of the active ingredient can be easily controlled to be sustained release. On the other hand, when the degree of swelling of the processed starch is greater than 10 cm ³ / g, the solid preparation swells greatly due to the swelling of the processed starch. As a result, the elution rate of the active ingredient is delayed, or the solid preparation is not able to withstand the swelling force, and the dosage form is undesirably collapsed. When the degree of swelling of the processed starch is in the range of 6 cm ³ / g to 10 cm ³ / g, the active ingredient is preferably released stably and stably.

This specific processed starch preferably has an angle of repose of 45 ° or less. The angle of repose is preferably 43 ° or less. The specific processed starch preferably has an apparent specific gravity of 1.4 cm ³ / g or more and 3.6 cm ³ / g or less. Processed starch having an angle of repose of 45 ° or less and an apparent specific gravity in the range of 1.4 to 3.6 cm ³ / g is excellent in mixing and dispersibility with the active ingredient, and thus forms a uniform gel matrix. This is preferable because it is easy to achieve stable sustained release.
Incidentally, Patent Document 15 discloses a method for producing processed starch having a water retention amount of 400% or more, a gel indentation load value of 200 g or more, and a water-soluble component amount of 40 to 95% by weight. The present inventors examined the modified starch obtained by the method described in Patent Document 15 in detail. As a result, the present inventors depended on the compression molding pressure for the first time by specifically varying the swellability and gel indentation load value depending on the particle size, and controlling the particle size and swellability of the processed starch within an appropriate range. It was found that a sustained-release solid preparation was obtained. The examination process will be described next.

  The present inventors first produced a conventional processed starch C as described in the method of Patent Document 15, specifically, as described in Comparative Production Example 1 described later. The obtained processed starch C was fractionated for each particle size of 0 to 32, 32 to 75, 75 to 150, and 150 to 500 μm, and the basic physical properties were compared. Table 1 shows the particle size distribution of the processed starch C obtained, the degree of swelling of the processed starch, and the gel indentation load value under warmed storage conditions. FIGS. 3 to 6 show optical micrographs of the particles after the processed starch C swells. Indicated.

  Here, the gel indentation load value under the warming storage conditions shown in Table 1 is that a cylindrical shaped product having a diameter of 1.13 cm obtained by compressing 0.5 g of processed starch at 50 MPa is 37 ° C. ± 0.5 ° C. It is a value obtained as a value that gave a peak first when a cylindrical adapter having a diameter of 3 mm was pushed in at a speed of 0.1 mm / sec after being immersed in pure water for 4 hours to be gelled. Moreover, the swelling degree of the modified starch shown in Table 1 is a value obtained by the same method as described above.

  From the data of processed starch C in Table 1 and photographs of the swollen particles in FIGS. 3 to 6, the processed starch particles having a fraction of 0 to 32 μm have a swelling degree of about 14 and a swelling particle size of about 100 μm. It can be seen that the gel indentation load value is as large as about 300. On the other hand, processed starch particles having a particle size fraction of 32 to 75, 75 to 150, and 150 to 500 μm are uniform and have a swelling degree of 20 to 30 and a swelling particle size of 200 to 300 μm. It can be seen that the gel indentation load value is as small as about 200. In addition, the swollen particles of the 32-75 μm fraction and the 75-150 μm and 150-500 μm fractions have the same size, and the swelling property of the processed starch particles correlates with the size of the particles before swelling. Therefore, the swellable starch particles having an outer shell structure contained in the processed starch particles in the range of 75 to 500 μm have the same constituent components as the swellable starch particles having an outer shell structure of the 32-75 μm fraction. It can be seen that the starch particles are granulated with a water-soluble paste component (swelled and dissolved so that the contour disappears and is not observed with an optical microscope) to form large processed starch particles of 75 to 500 μm.

  From these facts, the processed starch obtained by the method described in Patent Document 15 has a starch particle group of 0-32 μm fraction having a shell structure of starch particles, a low swelling property and a large gel indentation load value, It is composed of a starch particle group of 32 to 75 μm having a shell structure, a large swelling property and a small gel indentation load value, and three components of a water-soluble paste component, and these three components are granulated to 0 It was revealed that processed starch having a particle size distribution of ˜about 500 μm was formed. In addition, since the surface of each particle is covered with a water-soluble component, these facts cannot be determined only by the appearance of the processed starch.

  Furthermore, it is divided into a 0-32 μm fraction having a small swellability and a large gel indentation load value and a 32-500 μm fraction having a large swellability and a small gel indentation load value. Manufactured. Then, the solid preparation obtained from the 0-32 μm fraction showed an accurate and stable dissolution property independent of the compression force. On the other hand, in the solid preparation obtained from the 32-500 μm fraction, the smaller the compression force, the greater the swelling in the compression direction, and the faster the elution rate of the active ingredient, the weaker the strength of the gelled solid preparation. It became clear that That is, it was found that the characteristics of the obtained solid preparation greatly change at the particle size of 32 μm as a boundary. In order to obtain a sustained-release solid preparation that does not depend on the compression molding pressure, it was confirmed that it is preferable to use particles having low swelling properties and strong gel strength, such as the 0-32 μm fraction particles. It is considered that the disintegration force from the inside of the solid preparation can be suppressed by the small swelling property of the processed starch particles.

  In view of the above-mentioned facts, the present inventors can reduce the swelling property of the processed starch by crushing the starch particles having a 32-75 μm outer shell structure present in the 32-500 μm particles. As a result, it was thought that a sustained-release solid preparation independent of compressive force could be obtained. As a result of repeated studies on various grinding conditions, 90% by weight or more of particles passing through a sieve having an opening of 75 μm, 20% by weight or more of particles passing through a sieve having an opening of 32 μm, and an average particle size of 20 to 50 μm. It was found that by controlling the particle size distribution so as to obtain a processed starch having a small swellability and a large gel indentation load value. In this way, by controlling the particle size of the processed starch, a sustained-release solid preparation that does not fluctuate due to compression molding pressure has been obtained.

  Here, the particles obtained by Example 1 passing through a sieve having an opening of 75 μm are 90% by weight or more, the particles passing through a sieve having an opening of 32 μm are 20% by weight, and the average particle size is from 20 μm to 50 μm. The basic physical properties of each fractionated particle when the processed starch A was fractionated for each particle size of 0 to 32 and 32 to 75 μm were compared. Table 1 shows the entire processed starch A and the particle size distribution, swelling degree, and gel indentation load value of each fractionated particle under warmed storage conditions. 1 and 2 show optical micrographs of the swollen particles after each fractionated particle swells. It can be confirmed from the optical microscope image of the swollen particles that the primary particles having the outer shell structure of the processed starch are broken. Moreover, it was confirmed that any fraction particles of 0 to 32 μm and 32 to 75 μm have low swellability and a large gel indentation load value.

  Next, the manufacturing method of the above-mentioned specific processed starch is demonstrated. The specific processed starch is, for example, a step of heating a starch raw material in the presence of water at 60 ° C. or higher and lower than 100 ° C. to swell the starch particles of the starch raw material, and then drying the swollen starch particles to obtain the starch particles and the It is produced by a step of obtaining a powder of a mixture containing amylose and amylopectin existing outside the starch particles, a step of adjusting the particle size by pulverizing the obtained dry powder, and the like. Alternatively, the starch raw material heated at 100 to 130 ° C. under reduced pressure is further heated at 60 to 150 ° C. in the presence of water to swell the starch particles of the starch raw material, and then the swollen particles are dried. And a step of obtaining a powder of a mixture containing starch particles and amylose and amylopectin existing outside the starch particles, a step of adjusting the particle size by pulverizing the obtained dry powder, and the like. The amylose and amylopectin existing outside the starch particles are amylose and amylopectin eluted from the starch particles and derived from the starch whose outer shell structure is destroyed by swelling due to heat treatment. Moreover, the presence of water for the starch raw material refers to a state where the starch raw material and water are present and the water content is 40% by weight or more.

  Starch raw materials that can be used for production are rice, glutinous rice, corn, waxy corn, amylo corn, sorghum, wheat, barley, taro, mung bean, potato, lily, bonito, tulip, canna, pea, wrinkled pea, chestnut, Examples include natural starch such as kuzu, yam, sweet potato, broad bean, kidney bean, sago, tapioca (cassava), bracken, lotus, and horsetail, aging starch, cross-linked starch, etc., as long as they contain starchy substances. However, potato is preferred from the viewpoint of high particle swellability and easy control of water retention. As the starch raw material, one of the above may be used, or a mixture of two or more may be used. In addition, the size of the starchy raw material particles is preferably as large as possible from the viewpoint of easy swelling.

  From the viewpoint of increasing the gelatinization start temperature and increasing the swellability of the particles, the starchy raw material is, for example, as described in JP-A-4-130102 and JP-A-7-25902, as described in JP-A-4-130902. It is even better if it has been subjected to wet heat treatment such as heat treatment at 100 to 130 ° C. under reduced pressure.

  For example, in Japanese Patent Laid-Open No. 4-130102, (1) both a decompression line and a pressurized steam line are attached, and starch is placed in a container that can be sealed with pressure resistance for both internal and external pressures. In addition to the wet heat treatment method in which the starch is heated for a predetermined time and then cooled by performing pressure heating by introduction or by repeating this operation; Thus, when the aqueous suspension is heated, the starch particles are swollen but show substantially no viscosity, and the hydrothermal treatment method for producing starch having a remarkably high α-amylase adsorption ability, (3) (1 In addition to the method of (2) or (2), a wet heat treatment method is disclosed in which the pressure is reduced after heating to cool, but any of these wet heat treatment methods may be used.

  JP-A-7-25902 discloses (4) a starch-based grain filled in a pressure-resistant vessel in a wet-heat-treated starch-based grain production method obtained by wet-heat-treating starch-based grain. A method of producing a wet heat-treated starchy grain, wherein the first step of depressurizing and the second step of heating and pressurizing by introducing steam after depressurization are repeated at least once, (5) of the production method of (4) In the second step, a production method is disclosed in which heating is performed at 80 ° C. or higher and for 5 minutes to 5 hours. Any of these methods may be used.

  By these methods, starch obtained by subjecting a starch raw material to heat-moisture treatment under reduced pressure is obtained by heating at high temperature so that the inside of the particle is hollow and the crystallinity of the outer shell portion of the particle is increased. Such starch has the characteristic that the polarization cross pattern seen in the polarization image of an optical microscope is weaker than raw starch, and non-birefringent particles are reduced. In addition, the hollow part seems to have a structure in which the crystalline state of amylose and amylopectin is loosened, and has a feature that digestibility by α-amylase is increased as compared with raw starch. Therefore, it is suitable for using as a specific starchy raw material.

  In addition, when the starch raw material is wet-heat treated, the viscosity of the starch emulsion in the process of heating the starch emulsion to 50 to 95 ° C. is a value of 400 Brabender units (BU) or less when the viscosity is adjusted to 5%. It is preferable that the maximum viscosity when held at 95 ° C. for 30 minutes is 1000 BU or less. This is because it is easy to adjust the degree of swelling of the starch particles by heat treatment.

  The method for heating the starch raw material is not particularly limited as long as it is a known method. For example, a method in which starch raw material in the presence of water is introduced into a jacketed reactor and steam is introduced into the jacket to heat, in the presence of water. A method of mixing steam with the starch raw material, a method of heating in a liquid reservoir of a drum dryer, a method of simultaneously performing gelatinization and spraying while supplying steam to the starch slurry during spray drying, and the like. From the viewpoint of the heating time of the starch particles, a method of mixing steam with the starchy raw material in the presence of water is preferable. The heating temperature should just be the liquid temperature after gelatinizing starch by said various methods, 90-150 degreeC, Preferably it is 90-130 degreeC, More preferably, it is 95-130 degreeC.

  The drying method is not particularly limited, and examples include freeze drying, spray drying, drum drying, shelf drying, airflow drying, vacuum drying, and solvent replacement. Industrially, spray drying and drum drying are preferable. Moreover, it is preferable that liquid solid content at the time of drying shall be about 0.5 to 60 weight%. A productivity of 0.5% by weight or more is preferable, and a viscosity of 60% by weight or less is preferable because the viscosity does not become too high and a yield is secured. Furthermore, 1 to 30% by weight is more preferable, and 1 to 20% by weight is more preferable.

  There are no particular restrictions on the pulverization method, but examples include corn crusher, double roll crusher, hammer mill, ball mill, rod mill, pin type mill, and jet type mill. It is preferable to adopt a closed circuit pulverization method that combines both a machine and a classifier.

Water retention amount adjusted so that particles passing through a sieve having a mesh opening of 75 μm are 90% by weight or more, particles passing through a sieve having a mesh opening of 32 μm are 20% by weight or more, and the average particle size is 20 μm or more and less than 50 μm. Processed starch having a gel indentation load of 200 g or more and a water-soluble component amount of 40 to 95% by weight is characterized by having a lower degree of swelling and a higher gel indentation load value than those having no adjusted particle size. is there. The modified starch preferably has an apparent specific gravity in the range of 1.4 to 3.6 cm ³ / g, but the apparent specific gravity of the modified starch is also affected by the liquid concentration in the drying step, It is also affected by the rotation speed of the atomizer in the spray drying process. Therefore, in order to make the apparent specific gravity within the above preferable range, these may be appropriately adjusted.

  As long as the elution control base used in the solid preparation of the present invention does not impair the effect of the above-mentioned specific processed starch, another elution control base may be used in combination as necessary. Other elution control bases include hydrophilic elution control bases (eg, cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, non-cellulose polysaccharides such as xanthan gum and locust bean gum, polyethylene oxide and acrylics). Synthetic polymers such as acid polymers), lipophilic elution control bases (eg hydrogenated castor oil, glycerides such as stearin and palmitic acid, higher alcohols such as cetyl alcohol, fatty acids such as stearic acid, propylene glycol Fatty acid esters such as monostearate), inert elution control bases (eg polyvinyl chloride, polyethylene, vinyl acetate / vinyl chloride copolymer, polymethyl methacrylate, polyamide, silicone, Mention may be made of a chill cellulose, polystyrene, etc.) and the like.

  A solid preparation using such a specific processed starch as an elution control base is hardly affected by the ionic strength and compression molding pressure in the body, and the swellability of the solid preparation can be kept small within a certain range. Therefore, when such processed starch is used, it is preferable to easily control the active ingredient to zero-order elution and the like.

  Here, sustained release means that at least 3 hours or more is required for the active ingredient to be gradually eluted from the solid preparation at a constant dissolution rate regardless of time and to dissolve 90% or more of the active ingredient. A certain characteristic shall be said. The time required to elute 90% or more of the active ingredient can be appropriately selected, for example, 8 hours, 12 hours or 24 hours after administration depending on the type and purpose of the active ingredient. Due to the time limit, the upper limit is at most 72 hours. For example, when 90% or more of the active ingredient is eluted in 8 hours, the dissolution of the active ingredient after 1 hour is measured according to the dissolution test method method 1 (rotating basket method) described in the 14th revised Japanese Pharmacopoeia. It is preferable that the rate is 10 to 30%, the elution rate after 4 hours is 40 to 60%, and the elution rate after 6 hours is 70% or more. For example, when 90% or more of the active ingredient is eluted in 24 hours, the dissolution rate after 1 hour is 10 to 30%, the dissolution rate after 10 hours is 40 to 60%, and the dissolution rate after 18 hours is It is preferable to control to 70% or more. It is possible to control the time interval by changing the time interval according to the time for which the active ingredient is eluted.

  In addition to the above components, the solid preparation of the present invention preferably further contains coated granules. The term “coated granules” as used herein refers to granules obtained by subjecting granules containing one or more active ingredients to film coating. By including the coated granules, a more complex and precise release pattern of the active ingredient can be obtained as required.

  Examples of coating agents for coated granules include sustained-release coating agents and enteric coating agents. Specifically, cellulose-based coating agents (for example, ethyl cellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate, etc.), acrylic polymer-based coating agents (for example, Eudragit RS, Eudragit L, Eudragit NE, etc.), or one or more selected from shellac, silicon resin and the like can be used.

  A water-soluble substance, a plasticizer and the like for adjusting the dissolution rate may be added to the coating agent as necessary. Examples of water-soluble substances include water-soluble polymers such as hydroxypropylmethylcellulose, sugar alcohols such as mannitol, saccharides such as sucrose and anhydrous maltose, sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol, polysorbate, sodium lauryl sulfate, etc. One or more selected from the above surfactants and the like can be used. Plasticizers include acetylated monoglycerides, triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium chain triglycerides, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, dibutyl adipate, oleic acid, oleinol, etc. One or more selected from can be used.

  A coating agent such as these may be dissolved in an organic solvent and then coated on the granules, or after being suspended in water and coated on the granules. As the organic solvent, one or more selected from methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, diethyl ether, ethyl acetate, n-butyl acetate, acetone, dioxane, toluene, cyclohexanone, cyclohexane, benzene and the like are used. It can also be used, and it can also be used by further containing water.

  The granules containing the active ingredient may be granules of the active ingredient, a granulated product obtained by adding a binder or the like to the active ingredient, or a medicinal ingredient may be added to the elementary granule not containing the medicinal ingredient. Granules obtained by laminating may be used. As the binder, one or more selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and the like can be used. The granules containing active ingredients are preferably granules obtained by laminating medicinal ingredients on elementary granules with high mechanical strength in that the strength of the coated granules is increased and damage to the coating film due to compression molding can be suppressed. Is good. Commercially available elementary granules with high mechanical strength include core particles “Selfia (registered trademark)” SCP-100, CP-203, CP-305, CP-507 (Asahi Kasei) having crystalline cellulose as a constituent component. Chemicals Co., Ltd.) can be used.

  The solid preparation of the present invention preferably has a weight per preparation of 0.20 g or more. This makes it possible to easily extend the elution time without reducing the elution rate in the later stage of elution. This is because when the degree of swelling in the compression direction of the solid preparation and the swelling ratio are within a certain range, the dissolution of the active ingredient is not affected even if the shape of the solid preparation is increased. By the way, in the case where the elution control base such as hydroxypropylmethylcellulose is used and the swelling degree or swelling ratio in the compression direction is not within the above preferred range, the elution rate in the later stage of elution decreases as the weight of the solid preparation increases. This is not preferable. If the swelling degree and the swelling ratio of the solid preparation are within a certain range, the dissolution time of the active ingredient can be increased by simply increasing the weight of the solid preparation while maintaining the dissolution of the active ingredient. It can be extended.

  Next, the active ingredient refers to an ingredient that has a desirable chemical or biological effect on the surrounding environment such as the body to which the solid preparation is administered, such as a medicinal medicinal ingredient, an agrochemical ingredient, a fertilizer ingredient, It refers to feed ingredients, food ingredients, cosmetic ingredients, pigments, fragrances, metals, ceramics, catalysts, surfactants, and the like. The active ingredient may be in any form such as powder, crystal, oil, liquid, semi-solid, or any form such as powder, fine granules, granules and the like. The active ingredients may be used alone or in combination of two or more. As an active ingredient, it is most preferable to use a medicinal medicinal ingredient having strict performance requirements for sustained release.

  Anti-pyretic analgesics, antihypnotics, drowsiness preventives, antipruritics, pediatric analgesics, stomachic drugs, antacids, digestives, cardiotonic drugs, arrhythmic drugs, antihypertensives, vasodilators, For oral administration such as diuretics, anti-ulcer drugs, intestinal adjusters, osteoporosis drugs, antitussive expectorants, anti-asthma drugs, antibacterial agents, frequent urination agents, nourishing tonics, vitamins, etc. Become. The medicinal component can be used alone or in combination of two or more.

  Does the solid dosage form of the invention (a) have a short half-life on the order of 4-8 hours or less and must be taken in several divided doses per day when administered in a regular preparation? Or (b) has a narrow therapeutic index, (c) needs to be well absorbed across the entire gastrointestinal tract, or (d) has a relatively small therapeutically effective dose, etc. It is particularly useful for formulating one or more medicinal active ingredients having one or more characteristics.

  In addition to the active ingredient, the solid preparation in the present invention contains other components such as a disintegrant, a binder, a fluidizing agent, a lubricant, a corrigent, a fragrance, a colorant, and a sweetener as necessary. It doesn't matter. Moreover, you may use another component as a diluent.

  As binders, sugars such as sucrose, glucose, lactose, fructose, trehalose, sugar alcohols such as mannitol, xylitol, maltitol, erythritol, sorbitol, gelatin, pullulan, carrageenan, locust bean gum, agar, gluconannan, xanthan gum , Tamarind gum, pectin, sodium alginate, gum arabic, etc., water-soluble polysaccharides, crystalline cellulose (for example, “Seolas (registered trademark, the same applies hereinafter)” PH-101, PH-101D, PH-101L, manufactured by Asahi Kasei Chemicals PH-102, PH-301, PH-301Z, PH-302, PH-F20, PH-M06, M15, M25, KG-801, KG-802, etc.), powdered cellulose, hydroxypropyl cellulose, methylcellulose, etc. , Starches such as pregelatinized starch, starch paste, synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl alcohol, calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, magnesium aluminate silicate, etc. An inorganic compound etc. can be mentioned, Even if it uses individually by 1 type chosen from the above, it is also free to use 2 or more types together.

  As the crystalline cellulose that can be used as the binder, those excellent in compression moldability are preferable. By using crystalline cellulose with excellent compression moldability, the tablet can be tableted with a low compression pressure, so that it is possible to maintain the activity of the active ingredient that is deactivated by the compression pressure, and it can be made into a granule-containing tablet. Can be granted. Therefore, tableting of bulky active ingredients and tableting of drugs containing many kinds of active ingredients are possible. Therefore, in some cases, there are advantages such as miniaturization, excellent liquid component supportability, and suppression of tableting troubles. As the crystalline cellulose that is commercially available and excellent in compression moldability, “Theolas” KG-801, KG-802 (manufactured by Asahi Kasei Chemicals Corporation) and the like can be used.

  Disintegrants include croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, celluloses such as low-substituted hydroxypropylcellulose, carboxymethyl starch sodium, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato Examples thereof include starches such as starch and partially pregelatinized starch, celluloses such as crystalline cellulose and powdered cellulose, and synthetic polymers such as crospovidone and crospovidone copolymer. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

  Examples of the fluidizing agent include silicon compounds such as hydrous silicon dioxide and light anhydrous silicic acid. It may be used alone or in combination of two or more.

  As the lubricant, it is preferable to use at least one selected from sucrose fatty acid ester, talc and light anhydrous silicic acid in that it has little influence on the dissolution property and can prevent the tableting powder from adhering to the mortar. . In addition, one kind selected from magnesium aluminate metasilicate, hydrous silicon dioxide, and light anhydrous silicic acid in that it has little influence on the dissolution property and can secure the fluidity of the tableting powder and enhance the breaking load of the compression molded product. It is preferable to use the above. In particular, when a combination of one or more selected from sucrose fatty acid ester, talc, and light anhydrous silicic acid and magnesium aluminate metasilicate is used, the tableting powder is prevented from adhering to the mortar and the flow of the tableting powder. It is preferable because it can satisfy the securing of the property and the enhancement of the breaking load of the compression molded product at the same time.

  Examples of the corrigent include glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol and the like. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

  Examples of the fragrances include oils such as orange, vanilla, strawberry, yogurt, menthol, fennel oil, cinnamon oil, spruce oil, mint oil, green tea powder and the like, and one kind selected from the above is used alone. Or you may use 2 or more types together.

  Examples of the colorant include food colors such as food red No. 3, food yellow No. 5, and food blue No. 1, copper chlorofin sodium, titanium oxide, and riboflavin. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

  Examples of the sweetening agent include aspartame, saccharin, dipotassium gilicyrrhizinate, stevia, maltose, maltitol, starch syrup, and amateur powder. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

  The solid preparation of the present invention can be produced by any of the production methods by compression molding of a solid preparation usually performed in the pharmaceutical field. For example, a direct powder compression method in which an active ingredient, an elution control base, and if necessary, a binder, a disintegrant, a fluidizing agent, a corrigent, a fragrance, a colorant, a sweetener, and the like are uniformly mixed and then tableted. Can be used. In other examples, the active ingredient and, if necessary, an elution control preparation, a binder, a disintegrant, a fluidizing agent, a corrigent, a fragrance, a colorant, a sweetener, etc. are wet-granulated or dry-granulated. Wet granulation tableting method or dry granulation in which components such as elution control base, binder, disintegrant, fluidizing agent, flavoring agent, flavoring agent, coloring agent, sweetening agent and the like are added to the granules as necessary. It can be produced by a tableting method.

  Other examples of the method for producing a solid preparation include an active ingredient and a fat-soluble substance such as carnauba wax, hydrogenated castor oil, polyglycerin, and the like which are solid at room temperature but become liquid at 40 ° C. or higher, polyethylene glycol 6000, etc. A method in which a hydrophilic polymer is mixed uniformly at a temperature of 40 ° C. or higher, then cooled to a solid, and if necessary, pulverized to adjust the particle size and then compression molded is used. Can do. Furthermore, a solution was prepared using a solvent in which both the active ingredient and the elution control base were dissolved, or a uniform dispersion was prepared using an appropriate solvent, and the solution or dispersion was dried by a conventional method. It can also be produced by a method of compression molding a uniform dispersion of an active ingredient and an elution control base. The solvent is selected from organic solvents such as methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, diethyl ether, ethyl acetate, n-butyl acetate, acetone, dioxane, toluene, cyclohexanone, cyclohexane, benzene, and water. One or more can be used.

  As the compression molding machine for preparing a solid preparation, for example, a compression machine such as a static pressure press machine, a single punch tableting machine, a rotary tableting machine, a multilayer tablet molding machine, and a nucleated tableting machine can be used, and there is no particular limitation. .

  Further, as long as the effects of the present invention are not impaired, the solid preparation itself may be coated for the purpose of controlling the dissolution of the active ingredient, masking the taste, preventing moisture, and the like. Examples of the coating agent include cellulose-based coating agents (ethyl cellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate, etc.), acrylic polymer coating agents (eudragit) One or more selected from RS, Eudragit L, Eudragit NE, etc.), shellac, silicon resin and the like can be used. A known method can be used as a method of using these coating agents. The coating agent may be dissolved in an organic solvent or suspended in water.

EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, these do not limit the scope of the present invention. In addition, each test method in an Example and a comparative example and the measuring method of a physical property are as follows.
(1) Dissolution test

In accordance with the first method (rotating basket method) of the dissolution test method described in the 14th revised Japanese Pharmacopoeia, the second solution described in Japanese Pharmacopoeia (pH 6.8, ionic strength 0.14), Alternatively, a test solution using Mcilvine solution (pH 7.2, ionic strength 0.40, composition: disodium hydrogen phosphate 173.9 mM, citric acid 13.0 mM, hereinafter may be abbreviated as “second solution”) is used. The test is performed under the conditions of 900 cm ³ , basket rotation speed 100 rpm, test liquid temperature 37 ± 0.5 ° C. In addition, 90 mg of α-amylase preparation (composition: α-amylase / calcium carbonate / corn starch = 5/5/90, AD “Amano” 1, Amano Enzyme Inc.) was added to each test solution, and the α-amylase content was determined. 5 μg / cm ³ .
(2) Particle size distribution Number of particles smaller than 32 μm

Using a JIS sieve opening of 32 μm, when 5 g of a measurement sample is sieved with an air jet sieve for 5 minutes, it is obtained from the weight percentage of the measurement sample that has passed through the sieve.
(3) Particle size distribution Number of particles smaller than 75 μm

Using a JIS sieve opening of 75 μm, when 10 g of a measurement sample is sieved with an air jet sieve for 5 minutes, it is determined from the weight percentage of the measurement sample passing through the sieve.
(4) Particle size distribution Average particle size (μm)

Using a JIS sieve opening of 500 μm, 300 μm, 250 μm, 212 μm, and 150 μm, 20 g of the measurement sample is sieved for 15 minutes with a low-tap type sieve shaker (Sieve Shaker A type manufactured by Hira Kogakusho). Next, 5 g of a measurement sample obtained by sieving a 150 μm sieve is sieved with an air jet sieve for 5 minutes using a JIS sieve opening of 75 μm. Further, 5 g of a measurement sample obtained by sieving a 150 μm sieve is sieved with an air jet sieve for 5 minutes using a JIS sieve opening of 32 μm. The weight percentage [%] on the sieve of each sieve is obtained, and the particle diameter is obtained when the cumulative weight percentage is 50%.
(5) Angle of repose (°)

Obtained using a Sugihara-type angle of repose measuring instrument (Pharmacology 27, p.260, 1965).
(6) Apparent specific gravity (g / cm ³ )

Measured using a Scott volume meter (Tsutsui Rikenki Co., Ltd.). The powder sample is allowed to flow down for 2-3 minutes using a quantitative feeder until the powder overflows into the measurement container. Next, an excessive amount of powder deposited on the top of the container is scraped off, and the sample adhering to the side surface of the container is removed. Thereafter, the weight of the powder loosely filled in the container is measured. The apparent specific gravity is obtained by dividing the volume of the measurement container by the weight of the powder loosely packed in the container.
(4) Water retention amount

Dried processed starch W ₀ (g) (about 1 g) is gradually put into a 50 cm ³ centrifuge tube containing about 15 cm ³ of pure water at 20 ° C. ± 5 ° C. and stirred until it becomes transparent to translucent pure water. To disperse. Add pure water at 20 ° C. ± 5 ° C. and centrifuge (2000 G, 10 minutes) so that it becomes about 70% of the 50 cm ³ sedimentation tube. The upper layer separated immediately after the end of the centrifugation is discarded, and the water retention amount is determined by the following formula (3) from the weight W (g) remaining in the lower layer (starch + the amount of pure water retained by the starch).
Water retention amount (%) = 100 × (W−W ₀ ) / W ₀ (3)
(5) Collapse time (hr)

Disintegration in a test liquid of a cylindrical shaped product having a diameter of 0.8 cm obtained by molding 0.2 g of the prescription powder with a compressive force of 50 MPa using a static pressure press (MODEL-1321DW CREEP / Eiko Engineering Co., Ltd.) Defined in time. The test solution is the second solution (pH 6.8) described in the 14th revised Japanese pharmacopoeia, and the disintegration test is performed using an auxiliary panel according to the disintegration test method of the 14th revised Japanese pharmacopoeia.
(6) Gel indentation load (g)

A cylindrical molded body having a diameter of 1.13 cm obtained by molding 0.5 g of the prescription powder with a compressive force of 50 MPa using a static pressure press (MODEL-1321DW CREEP / manufactured by Aiko Engineering Co., Ltd.) is 20 ° C. ± 5 ° C. The maximum when a rheometer (RHEONER, RE-33005, manufactured by YAMADEN) is used and the 3 mm cylindrical adapter is pushed in at a speed of 0.1 mm / sec after gelling in pure water for 4 hours. Define as load. The maximum load is the maximum load value at the time of breaking if the gel layer is broken, or the maximum load value until the adapter enters 5 mm into the gelled cylindrical molded body if there is no breaking. Calculate with an average value of five.
(7) Water-soluble component amount of processed starch (%)

Add 1 g of processed starch to 99 g of pure water at 20 ° C ± 5 ° C and stir with a magnetic stirrer for 2 hours to disperse. Transfer 40 cm ³ of the resulting dispersion to a 50 cm ³ centrifuge tube and centrifuge at 5000 G for 15 minutes. Separate and put 30 cm ³ of this supernatant into a weighing bottle, dry at 110 ° C. to a constant weight and measure the dry weight (g). Further, 1 g of starch is dried at 110 ° C. to a constant weight, and the absolute dry weight (g) is measured. These measured values and the value obtained by the following formula (4) are defined as the amount of the water-soluble component.
Water-soluble component (%) = (dry weight × 100 ÷ 30) ÷ absolute dry weight × 100 (4)
(8) Swelling degree of processed starch (cm ³ / g)

1.0 g of processed starch is dispersed in pure water at 20 ± 5 ° C. and transferred to a 100 cm ³ sedimentation tube. The total amount is 100 cm ^3, and after standing for 16 hours, the volume V (cm ³ ) of the lower layer divided into upper and lower parts The dry weight (g) of 1.0 g of the modified starch is measured and calculated from the following formula (5).
Swelling degree of modified starch (cm ³ / g) = V / Dry weight of modified starch (5)
(9) Gel indentation load under warm storage conditions (g)

A cylindrical shaped product having a diameter of 1.13 cm obtained by molding 0.5 g of processed starch with a compressive force of 50 MPa using a static pressure press (MODEL-1321DW CREEP / manufactured by Aiko Engineering Co., Ltd.) is 37 ° C. ± 0.5. After gelling for 4 hours in pure water at ℃, use a rheometer (RHEONER, RE-33005, manufactured by YAMADEN) and push in a cylindrical adapter with a diameter of 3 mm at a speed of 0.1 mm / sec. It is determined by defining it as the value that gives the peak first. Calculate with an average value of five.
[Comparative Production Example 1]

  Potato starch was filled in a stainless bat (50 cm x 25 cm) with a layer thickness of 5 cm, decompressed in a pressure vessel for 5 minutes (600 mmHg), then treated with pressurized steam (120 ° C) for 20 minutes, and the raw material was solid. A starch emulsion having a partial concentration of 7.5% was prepared. This starch emulsion was heated and gelatinized at 20 L / hr with a jet cooker (exit temperature 100 ° C.), continuously passed through a residence tube (100 ° C.) of a 3 L container, and then spray-dried to obtain processed starch C. The basic physical properties of the modified starch C are shown in Table 2 (corresponding to Example 6 of Patent Document 2).

Further, the processed starch C was fractionated for each particle size of 150 to 500 μm, 75 to 150 μm, 32 to 75 μm, and 0 to 32 μm, and the degree of swelling of the processed starch and the gel indentation load value under warmed storage conditions were measured. Is shown in Table 1. Further, under the conditions for measuring the degree of swelling of the processed starch, the swelling state of the processed starch after 16 hours was observed with an optical microscope after uniformly redispersing the upper and lower layers, and is shown in FIGS.
[Example 1]

  Potato starch was filled in a stainless bat (50 cm × 25 cm) with a layer thickness of 5 cm, and after being depressurized (600 mmHg) for 5 minutes in a pressure-resistant container, wet-heat treated with pressurized steam (120 ° C.) for 20 minutes as a raw material, A starch emulsion having a solid content of 7.5% was prepared. This starch emulsion is heated with a jet cooker at 20 L / hr, gelatinized (outlet temperature 100 ° C.), spray-dried, and then pulverized and classified using a pin-type mill with a built-in classifier to obtain processed starch A It was. Table 2 shows the basic physical properties of the modified starch A. In addition, the processed starch A was fractionated into particle sizes of 150 to 500 μm, 75 to 150 μm, 32 to 75 μm, and 0 to 32 μm, and the degree of swelling of the processed starch and the gel indentation load value under warmed storage conditions were measured. Is shown in Table 1. Further, under the conditions for measuring the degree of swelling of the processed starch, the swelling state of the processed starch after 16 hours was observed with an optical microscope after uniformly redispersing the upper and lower layers, and is shown in FIGS.

  Processed starch A as an elution control base, crystalline cellulose as a binder ("Theolas" KG-802, manufactured by Asahi Kasei Chemicals Corporation), and sorbitol as a hydrophilic auxiliary (manufactured by Wako Pure Chemical Industries, Ltd.) Polyethylene glycol (Macrogol 6000, manufactured by Sanyo Kasei Kogyo Co., Ltd.), which is a hydrophilic polymer auxiliary, and etenzamide (ethoxybenzamide P, manufactured by API Corporation) as a sparingly soluble active ingredient Mix uniformly to a weight ratio of 10/10/10, and compress at a pressure of 120 MPa and 300 MPa using a static pressure press (MODEL-1321DW CREEP / manufactured by Aiko Engineering Co., Ltd.). A solid preparation weighing 0.18 g was obtained.

A solid preparation obtained at a compression molding pressure of 120 MPa, and a test solution obtained by adding α-amylase to 5 μg / cm ³ to the second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia Was used to measure the elution pattern of etenzamide. Further, the ethenamide elution pattern was measured in the same manner except that the test solution was changed from the second solution described in the Japanese Pharmacopoeia to the McCilvine solution (pH 7.2, ionic strength 0.40). Furthermore, using a second liquid described in the Japanese Pharmacopoeia, tablets obtained at a compression molding pressure of 300 MPa were added so that α-amylase was 5 μg / cm ^3, and the elution pattern of etezamide was measured.

The results of the dissolution test are shown in FIG. 7 together with the results of the dissolution test of Comparative Example 1. The sustained-release solid preparation of etenzamide using processed starch A as the dissolution control base, sorbitol as the water-soluble auxiliary agent, and polyethylene glycol as the water-soluble polymer is stable with no change in dissolution rate due to ionic strength or compression molding pressure. Of zero order elution.
[Comparative Example 1]

  Processed starch A obtained in Example 1, crystalline cellulose ("Theorus" KG-802, manufactured by Asahi Kasei Chemicals Co., Ltd.), polyethylene glycol (Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.) and etenzamide (ethoxybenzamide P, API Corporation) and 60/20/10/10 in a weight ratio, and compressed at a pressure of 120 MPa using a static pressure press (MODEL-1321DW CREEP / Aiko Engineering Co., Ltd.). As a result, a tablet having a diameter of 0.8 cm and a weight of 0.18 g was obtained (prescription containing no sorbitol as compared with Example 1).

Using the second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia, α-amylase was added to the obtained tablet so as to have a concentration of 5 μg / cm ^3, and a dissolution test was performed. The results are shown in FIG. 7 together with the results of Example 1.

Although the modified starch A was used as an elution control base, the ethenzamid sustained-release tablet of Comparative Example 1 which did not contain a water-soluble auxiliary agent caused tablet fragmentation within about 5 hours after the start of the dissolution test, and the dissolution of ethenamide. The amount has increased temporarily.
[Comparative Example 2]

  Potato starch was filled in a stainless bat (50 cm x 25 cm) with a layer thickness of 5 cm, decompressed in a pressure vessel for 5 minutes (600 mmHg), then treated with pressurized steam (120 ° C) for 20 minutes, and the raw material was solid. A starch emulsion having a partial concentration of 7.5% was prepared. This starch emulsion was heated with a jet cooker at 20 L / hr and gelatinized (exit temperature 115 ° C.) and then spray-dried to obtain processed starch B (corresponding to Example 5 of Patent Document 2). Table 2 shows the basic physical properties of the modified starch B.

A tablet having a diameter of 0.8 cm and a weight of 0.12 g obtained by compression molding at 120 MPa and 300 MPa was obtained in the same manner as in Example 1 except that the modified starch B was used instead of the modified starch A. Using the second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia, α-amylase was added to the obtained tablets so as to be 5 μg / cm ^3, and a dissolution test was conducted. This is shown in FIG.

Tablets using processed starch B as an elution control base showed stable zero-order dissolution at a compression force as high as 300 MPa. However, at a compression force of 120 MPa, the tablets were split about 6 hours after the start of the dissolution test. The elution amount of etezamide temporarily increased.
[Example 2]

  Instead of the sorbitol of Example 1, mannitol (manufactured by Wako Pure Chemical Industries, Ltd.) is used, and the composition ratio of processed starch A, crystalline cellulose, mannitol, polyethylene glycol, and etenzaamide is 45/5/35/5/10. Except for the above, it was carried out in the same manner as in Example 1 and compressed with a pressure of 120 MP to obtain a tablet having a diameter of 0.8 cm and a weight of 0.18 g.

Using the second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia, α-amylase was added to the obtained tablets so as to be 5 μg / cm ^3, and a dissolution test was conducted. The results are shown in FIG. 9 together with the results of the dissolution test under the same conditions in Examples 1 and 3. The sustained-release tablets of ethenamide using processed starch A as the dissolution control base, mannitol as the water-soluble auxiliary agent, and polyethylene glycol as the water-soluble polymer showed stable zero-order dissolution.
[Example 3]

  Example 1 except that polyvinylpyrrolidone K30 is used instead of polyethylene glycol in Example 1 and the composition ratio of modified starch A, crystalline cellulose, sorbitol, polyvinylpyrrolidone K30, and etenzaamide is 60/15/5/10/10. And compressed with a pressure of 120 MP to obtain a tablet having a diameter of 0.8 cm and a weight of 0.18 g.

Using the second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia, α-amylase was added to the obtained tablets so as to be 5 μg / cm ^3, and a dissolution test was conducted. The results are shown in FIG. 9 together with the results of the dissolution test under the same conditions in Examples 1 and 2. The sustained release tablet of etenzamide using processed starch A as the dissolution control base, sorbitol as the water-soluble auxiliary agent, and polyvinylpyrrolidone as the water-soluble polymer showed stable zero-order dissolution.
[Comparative Example 3]

  A tablet was prepared and dissolved in the same manner as in Example 1 except that hydroxypropyl methylcellulose (Metroise 90SH-100SR, manufactured by Shin-Etsu Chemical Co., Ltd.) was used instead of the modified starch A in Example 1. The results are shown in FIG.

Etensamide sustained-release tablets using hydroxypropylmethylcellulose as the dissolution control base showed stable dissolution with two liquids with ionic strength of 0.14, but dissolution tests with Mcilvine liquid with a high ionic strength of 0.40. Immediately after the start, the tablet disintegrated and the total amount of etenzamide was eluted.
[Comparative Example 4]

  A tablet was prepared and a dissolution test was performed in the same manner as in Example 1 except that Eudragit RSPO (manufactured by Degussa) was used in place of the modified starch A of Example 1, and the results of the dissolution test are shown in FIG.

In the sustained release tablets of etenzamide using Eudragit RSPO as the dissolution control base, the dissolution rate fluctuated greatly depending on the compression molding pressure.
[Example 4]

  Modified starch A obtained in Example 1, crystalline cellulose (“Theorus” KG-802, manufactured by Asahi Kasei Chemicals Corporation), sorbitol (manufactured by Nikken Chemical Co., Ltd.), polyethylene glycol (Macrogol 6000 (trade name), Sanyo 46.5 / 9.5 / 9.5 of Kasei Kogyo Co., Ltd., Etenzamid (manufactured by API Corporation), talc (Talcane Hayashi Co., Ltd., Hayashi Kasei Co., Ltd.) and Neusilin (Fuji Chemical Industry Co., Ltd.) The mixture was uniformly mixed so that the weight ratio was /0.5/30/3/1. This mixture was compressed with a pressure of 150 MPa using a rotary tableting machine (Clean Press Collect 12HUK / manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a tablet having a diameter of 8.0 mm and a weight of 0.2 g.

A dissolution test was performed on tablets obtained using a test solution in which α-amylase was added to a second solution (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia so as to have a concentration of 5 μg / cm ^3. The elution pattern of was measured. The dissolution test results are shown in FIG.
A controlled release tablet of etenzamide prepared using processed starch A as the dissolution control base, polyethylene glycol as the water-soluble polymer auxiliary, sorbitol as the water-soluble auxiliary, and talc and neucillin as the lubricant is stable. Next elution was shown.

It is an optical microscope photograph (100 time) of the swelling particle | grains of modified starch A (0-32 micrometer fraction). It is an optical microscope photograph (100 time) of the swelling particle | grains of modified starch A (32-75 micrometer fraction). It is an optical microscope photograph (100 times) of swollen particles of starch powder C (0-32 μm fraction). It is an optical microscope photograph (100 time) of the swelling particle | grains of modified starch C (32-75 micrometer fraction). It is an optical microscope photograph (100 time) of the swelling particle | grains of modified starch C (75-150 micrometer fraction). It is an optical microscope photograph (100 times) of the swelling particle | grains of modified starch C (150 micrometers-500 micrometers fraction). 2 is a graph showing the results of dissolution tests in Example 1 and Comparative Example 1. 6 is a graph showing the dissolution test results of Comparative Example 2. It is the graph which showed the elution test result of Examples 1-3. 6 is a graph showing the dissolution test results of Comparative Example 3. 10 is a graph showing the dissolution test results of Comparative Example 4. 6 is a graph showing the dissolution test results of Example 4.

Claims (12)

A sustained-release solid preparation containing one or more active ingredients and an elution control base, wherein the active ingredient has a solubility in water of 0.0001 to 100 mg / cm ³ , The elution control base has a water retention amount of 400% or more, a gel indentation load of 200 g or more, a water-soluble component amount of 40 to 95% by weight, and particles passing through a sieve having an opening of 75 μm of 90% by weight or more. It is a processed starch having a particle size of 20% by weight or more passing through a sieve having an opening of 32 μm and an average particle size of 20 μm or more and less than 50 μm, and further has a solubility in water of 0.1 to 5.0 g / cm ^{3 at} 20 ° C. In addition, it contains a hydrophilic auxiliary having a molecular weight of 1000 or less, and the weight blending ratio of the processed starch and the hydrophilic auxiliary is in the range of 50:50 to 99: 1. Solid formulation.   The solid preparation according to claim 1, wherein the processed starch has 98% by weight or more of particles passing through a sieve having an opening of 75 μm and 40% by weight or more of particles passing through a sieve having an opening of 32 μm. The swelling degree of modified starch is not more than 6 cm ³ / g or more 10 cm ³ / g, solid preparation according to claim 1 or 2. The solid preparation according to any one of claims 1 to 3, wherein the processed starch has an angle of repose of 45 ° or less and an apparent specific gravity of 1.4 cm ³ / g or more and 3.6 cm ³ / g or less.   The said hydrophilic auxiliary agent is at least 1 sort (s) selected from the group which consists of sugar alcohols, saccharides, surfactant, salts, organic acid, amino acids, and amino saccharides in any one of Claims 1-4. Solid formulation.   The solid preparation according to claim 5, wherein the hydrophilic auxiliary is sorbitol and / or sucrose. The elution control base further has a solubility in water at 20 ° C. of 0.1 g / cm ³ or more and 5.0 g / cm ³ or less, a melting point of 50 ° C. or more, and an average molecular weight of 5000 or more. The solid formulation in any one of Claims 1-6 containing the hydrophilic polymer adjuvant which is polymers.   The solid preparation according to claim 7, wherein the hydrophilic polymer auxiliary is polyethylene glycol.   The solid formulation in any one of Claims 1-8 whose said 1 or more types of active ingredient is a pharmaceutical active ingredient.   Furthermore, the solid formulation in any one of Claims 1-9 containing a coated granule.   Furthermore, the solid formulation in any one of Claims 1-10 which contains 1 or more types selected from a sucrose fatty acid ester, a talc, and a light silicic acid anhydride, and magnesium aluminate metasilicate as a lubricant.   The solid preparation according to any one of claims 1 to 11, having a weight of more than 0.2 g.