JP5159093B2 - Multi-layer solid preparation that controls the release of active ingredients to be sustained release - Google Patents

Description

  The present invention relates to a multilayer solid preparation in which the dissolution rate of an active ingredient is controlled to zero-order dissolution or sustained release at two or more stages (multi-stage dissolution).

  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 the active ingredients are uniformly dispersed together with the elution control base and compression-molded is developed due to the simple structure and manufacturing process in addition to stable elution control. Because of its high speed, it is often used for practical applications (matrix system).

Examples of the dissolution control base used in the matrix system include a hydrophilic dissolution control base, a lipophilic dissolution control base, and an inert dissolution control base (belonging to thermoplastic polymers).

  As hydrophilic elution control bases, cellulose derivatives such as methylcellulose (MC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC) are known as described in Patent Document 1 and the like. Patent Document 2 and the like describe a method for controlling elution of an active ingredient to zero-order elution by using glucose syrup in addition to an elution control base. These elution control bases have characteristics such that the active ingredient can be controlled to be sustained release without being affected by pH, and the stability over time is excellent. However, these cellulose derivatives have the property that they swell greatly in the compression direction as the gelation progresses in the elution solution, so that the diffusion distance of the active ingredient becomes longer and the elution rate decreases in the later stage of elution. On the other hand, the strength of the gelled solid preparation is weakened, and it has the disadvantage that it cannot withstand the load caused by the mechanical movement of the gastrointestinal tract and the erosion proceeds and the dissolution rate increases. Cellulose derivatives with different viscosities are commercially available. However, the higher the viscosity, the greater the swelling property in the compression direction, and thus problems such as a decrease in elution rate tend to be prominent.

  By the way, as a method for avoiding the problem of contraindication when a plurality of active ingredients are blended in one tablet, a method of blending active ingredients into different layers to form a multilayer solid preparation is known. By blending an elution control base in each layer, a multilayer solid preparation exhibiting sustained release can be obtained. By appropriately controlling the active ingredient content and elution rate of each layer, it is possible to control the elution of the active ingredient to the zero-order elution or two or more stages (Patent Documents 3 to 5, Non-Patent Document 1). .

  In a multilayer solid preparation, since each layer is composed of different compositions, generally the bonding strength between the layers tends to be weak and the layers tend to be separated. It is unavoidable that multilayer solid preparations comprising cellulose derivatives as a constituent component also have a weak bond strength between layers, especially when gelation progresses and swelling increases, so that the bond between layers becomes insufficient, and the type, content or composition of the active ingredient. In some cases, there is a drawback that rapid drug elution occurs due to interlayer separation. As a method for improving such delamination, Patent Document 6 discloses a method using crystalline cellulose in a specific bulk specific gravity range as a binder, and Patent Document 7 describes an average particle diameter of the powder constituting each layer. However, none of these methods are effective for multi-layer solid preparations having a highly swellable base as a constituent component.

  In addition, the cellulose derivative competes for hydration with a solute that creates ionic strength in a solution having a high ionic strength, so that gelation becomes insufficient, and the shape of the matrix cannot be maintained, and the cellulose derivative is disintegrated. 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 rises rapidly, and depending on the efficacy of the active ingredient with the lowest blood concentration and the narrower side effect concentration range, death occurs. There is a possibility. Since sustained release solid preparations in the pharmaceutical field need to provide accurate elution control even in the gastrointestinal environment where ionic strength varies, stable dissolution in solutions with varying ionic strength, especially in solutions with high ionic strength There is a need for controlled release solid formulations with controllability.

  Among cellulose derivatives, HPMC is one of the most frequently used elution control bases in the past, but in addition to the above-mentioned problems, it has a slightly yellowish color with poor fluidity. Improvements are desired in many respects in terms of powder physical properties such as inferiority and an irritating odor peculiar to synthetic glue.

  Patent Documents 8 to 12 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, since the use of fine particles according to Patent Documents 8 to 12 does not improve the swellability of the particles, the swellability of the processed starch and the swellability of the solid preparation cannot be improved. It also cannot solve problems such as separation.

  As hydrophilic elution control bases other than 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. However, these dissolution control bases have the property that they swell very much both in the direction perpendicular to the compression direction during tablet molding and in the compression direction. On the other hand, it has the disadvantage that the elution rate decreases because the gelled solid preparation has weakened strength and cannot withstand the load caused by the mechanical movement of the gastrointestinal tract. It was. Furthermore, since these solid preparations that are enlarged over time are likely to cause fluctuations in the residence time in the gastrointestinal tract, they are not always satisfactory in the pharmaceutical field where reproducibility and accurate dissolution control are required. It was not a slow-release solid preparation. In addition, the above-mentioned elution control base having a large swellability is unavoidable in the same manner as the cellulose derivative, the problem that the bonding force between the layers is weak, especially when the gelation progresses and the swelling becomes large, the bonding between the layers becomes insufficient, Depending on the type, content or composition of the active ingredient, there is a drawback that rapid drug elution occurs due to interlayer separation.

  Patent Document 13 discloses a modified starch having a water retention amount of 400% or more, a disintegration time of 5 hours or more, a gel indentation load of 200 g or more, and a sustained release solid preparation using the modified starch as an elution control base. Yes. The modified starch exhibits sufficient sustained release to have high resistance to α-amylase not found in conventional natural modified starch, and is not affected by ionic strength, resulting in dose dumping problems There is a description that it is possible to release the active ingredient relatively stably without any problem. In addition, since the naturally-derived starch raw material is produced only by physical processing, it can be safely ingested without problems such as chemical residue, and it has good fluidity and whiteness.

  However, the disclosed starch powder has a relatively large particle swellability, and in the case of a multi-layer solid preparation, the disadvantage that the layers are separated during the dissolution and the dissolution rate of the active ingredient are the compression molding pressure. It has the disadvantage that it fluctuates due to. Especially in the case of multi-layer solid preparations, the transmission of compression molding pressure is not constant in each layer, so the dissolution of the active ingredient varies greatly due to changes in compression molding pressure in the manufacturing process and changes in the formulation and blending amount. It was not possible to accurately control the elution without depending on.

  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 acids such as propylene glycol monostearate Esters and the like have been conventionally used in many cases, but they have many problems such as lack of storage stability and a large change in the elution of the active ingredient, or a decrease in the elution rate in the later stage of elution.

  As the inert elution control base, polyvinyl chloride, polyethylene, vinyl acetate / vinyl chloride copolymer, polymethyl methacrylate, polyamide, silicone, ethyl cellulose, polystyrene and the like have been conventionally used. However, sustained-release solid preparations using an inactive dissolution control base exhibit compression-release because the active ingredient diffuses through the pores formed by compression-molding water-insoluble particles. There was a problem that the pore size fluctuated by the pressure and the elution rate of the active ingredient also fluctuated. Especially in the case of multi-layer solid preparations, the compression molding pressure transmission is not constant in each layer, so the elution of the active ingredient varies greatly due to changes in the compression molding pressure in the manufacturing process and changes in the formulation and blending amount. It was not possible to accurately control elution without depending on pressure.

As described above, sustained-release multilayer solid preparations using a matrix system are useful preparations that can be designed to have an optimal dissolution pattern for the characteristics of the active ingredient, such as zero-order dissolution and multi-stage dissolution. Multi-layer solid preparations that are not affected by the in vivo environment such as pH and pH, and the compression force during compression molding, have little variation in gastrointestinal residence time, and have no variation in dissolution rate due to delamination are not found in the prior art However, such a sustained-release multilayer solid preparation has been desired.
US Pat. No. 6,296,873 Special Table 2002-525310 WO94 / 06416 pamphlet U.S. Pat. No. 4,839,177 US Pat. No. 5,422,123 JP 2003-144528 A JP 2000-336027 A 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 WO2005 / 005484 pamphlet U. Conte et al. , J .; Controlled. Rel. 26, pp 39-47 (1993)

  Under such circumstances, the present invention is less susceptible to interlayer separation, is less susceptible to in vivo environments such as ionic strength and pH, and compression force during compression molding, and has little fluctuation in gastrointestinal residence time. The object is to provide a multilayer solid preparation capable of accurate elution control such as elution and multistage elution.

  As a result of intensive investigations on the relationship between the swelling property of the multilayer solid preparation and the dissolution property of the active ingredient, and further on the relationship between the physical properties of the dissolution control base, the inventors have determined the degree of swelling of the multilayer solid formulation. Controlling within an appropriate range is effective in suppressing interlaminar separation during the elution process, and is best because it does not cause fluctuations in the residence time in the gastrointestinal tract. It discovered that the said subject could be solved by using for a control base, and completed this invention.

That is, the present invention is as follows.
(1) The water retention amount is 400% or more, the gel indentation load is 200 g or more, the amount of water-soluble components is 40 to 95% by weight, the particles passing through a sieve having an opening of 75 μm are 90% by weight or more, and the opening is 32 μm. The processed starch and the active ingredient in one or more layers containing a processed starch having a particle size of 20% by weight or more and an average particle size of 20 μm or more and less than 50 μm and one or more active ingredients. A multilayer solid preparation characterized in that one or more layers containing at least one of the above are laminated and have a sustained release property of the active ingredient. (2) The multi-layer solid preparation according to (1), wherein the sustained release property is controlled to a zero-order dissolution pattern. (3) The multilayer solid preparation according to (1), wherein the sustained release property is controlled in a multistage dissolution pattern. (4) Any of (1) to (3), 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. A solid preparation according to 1. (5) The sustained-release solid preparation according to (1) to (4), wherein the degree of swelling of the processed starch is 6 cm ³ / g or more and 10 cm ³ / g or less.

(6) The processed starch has an angle of repose of 45 ° or less and an apparent specific volume of 1.4 cm ³ / g or more and 3.6 cm ³ / g or less, according to any one of (1) to (5). Solid formulation. (7) The degree of swelling in the compression direction is 1.0 to 2.0, the degree of swelling is 0.5 to 1.5, the difference in elution rate due to ionic strength is 7% or less, and the elution rate due to compression molding pressure The multilayer solid preparation according to any one of (1) to (6), wherein the difference is 7% or less. (8) One or more types of active ingredients are pharmaceutical medicinal ingredients, The multilayer solid preparation according to any one of claims 1 to 7, (9) The content of the modified starch in the one or more layers is 5. It is 0-99.9 weight%, The multilayer solid formulation in any one of Claims 1-8 characterized by the above-mentioned. (10) At least one of the layers containing the modified starch and the one or more active ingredients has a water solubility of 0.1 g / cm ³ or more and 5.0 g / cm ³ or less at 20 ° C. And (1) to (9), comprising a hydrophilic polymer auxiliary agent that is a synthetic or natural polymer having a melting point of 50 ° C. or higher and an average molecular weight of 5000 or higher. Multi-layer solid formulation. (11) The multilayer solid preparation according to any one of (1) to (10), further comprising coated granules. (12) Further, any one of (1) to (11), further comprising a combination of at least one selected from sucrose fatty acid ester, talc and light anhydrous silicic acid and magnesium aluminate metasilicate as a lubricant. A solid preparation according to the above. (13) The multilayer solid preparation according to any one of (1) to (12), wherein the weight is greater than 0.20 g.

  The multi-layer solid preparation of the present invention is less susceptible to interlayer separation, is less susceptible to in vivo environments such as ionic strength and pH, and compression force during compression molding, and has a characteristic that fluctuations in the gastrointestinal tract residence time are small. Accurate elution control according to the tablet design such as next elution and multi-stage elution is possible.

Hereinafter, the present invention will be described in detail. The multilayer solid preparation of the present invention 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%, a particle passing through a sieve having an opening of 75 μm, 90% by weight or more, and an opening of 32 μm. Specific processed starch having a particle size of 20% by weight or more and an average particle size of 20 μm or more and less than 50 μm.
First, this specific processed starch will be described. A 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.

  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.

Also, certain modified starch is preferably degree of swelling is not more than 6 cm ³ / g or more 10 cm ³ / g. 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. (Cm ³ ) and dry weight (g) of processed starch 1.0 g are measured and defined as a 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)

When the degree of swelling of the processed starch is larger than 6 cm ³ / g, it becomes easy to control the elution of the active ingredient to be sustained release because it forms a gel by hydration. 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 or more and 10 cm ³ / g volume V or less, the active ingredient is preferably released stably and stably.

Further, the 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 volume of 1.4 cm ³ / g or more and 3.6 cm ³ / g or less. Processed starch with an angle of repose of 45 ° or less and an apparent specific volume in the range of 1.4 to 3.6 cm ³ / g is excellent in mixing and dispersibility with the active ingredient, and forms a uniform gel matrix. It is preferable because it is easy to achieve stable sustained release.

  Incidentally, Patent Document 13 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 13 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 inventors first manufactured a conventional processed starch C as described in the method according to Patent Document 13, specifically, Comparative 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 13 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 the 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, Natural starch, aging starch, cross-linked starch, etc. such as kuzu, yam, sweet potato, broad bean, kidney bean, sago, tapioca (cassava), bracken, lotus, and horse chestnut are exemplified, and it is not particularly limited as long as it contains 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. Furthermore, modified starch, it is preferable that the apparent specific volume is in the range of 1.4~3.6cm 3 / ^g, apparent specific volume of the processed starch is also affected by the magnitude of the liquid concentration in the drying step, Moreover, it is influenced also by the rotation speed of an atomizer in a spray dry drying process. Therefore, in order to make the apparent specific volume within the above preferable range, these may be appropriately adjusted.

  By using such a specific processed starch, solid formulations with different degrees of swelling in the compression direction of solid formulations, different elution rates when using test solutions with different ionic strength, and different pressures during compression molding Any difference in elution rate can be kept within the required range in order to be able to control to zero-order elution or multi-stage elution without being influenced by the ionic strength in the body and the compression pressure. Moreover, when it is set as a multilayer formulation, it is hard to produce interlayer separation, and also in a multilayer formulation, it becomes controllable to zero order elution or multistage elution.

  It is desirable to use this modified starch in each layer of the multilayer solid dosage form. Depending on the layer, a specific modified starch may not be included, but in order to obtain a desired sustained release pattern, it is desirable to use a specific modified starch in each layer as much as possible. In order to control the elution of the active ingredient from the layer containing the active ingredient to be controlled release by the specific processed starch, the content of the specific processed starch in the layer is 5.0 wt% or more and 99.9 wt% The following is preferable. More preferably, it is 10 to 99% by weight, and particularly preferably 20 to 99% by weight. In the layer containing no active ingredient, the specific processed starch may be 100%.

Other dissolution control bases may be used in combination with each layer of the multi-layer solid preparation as needed, as long as the effect is not impaired. Other elution control bases include hydrophilic elution control bases (eg, hydrophilic cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, non-cellulose polysaccharides such as xanthan gum and locust bean gum, polyethylene Synthetic polymers such as oxides and acrylic acid polymers), lipophilic elution control bases (for example, hydrogenated castor oil, glycerides such as stearin and palmitic acid, higher alcohols such as cetyl alcohol, and fatty acids such as stearic acid) Fatty acid esters such as propylene glycol monostearate), inert elution control bases (eg polyvinyl chloride, polyethylene, vinyl acetate / vinyl chloride copolymer, polymethyl methacrylate, polyamide, silica) Over emissions, ethyl cellulose, mention may be made of polystyrene, etc.), and the like.

Each layer of the multilayer solid preparation may contain 1 to 40% by weight of a hydrophilic polymer auxiliary agent in addition to the processed starch. Such hydrophilic polymer auxiliaries have a solubility in water of 0.1 to 5.0 g / cm ³ at 20 ° C., a melting point of 50 ° C. or higher, and an average molecular weight of 5000 or higher. The polymers are preferably. When the hydrophilic polymer auxiliary is included, the uptake of water into the layer of the multilayer solid preparation is promoted and the gelation of the elution control base is promoted. It is preferable because it is easy. The solubility in water is preferably 0.2 g / cm ³ or more, particularly preferably 0.4 mg / cm ³ or more. When the solubility in water is 0.1 or more, water is sufficiently taken into the solid preparation, and the elution of the active ingredient can be easily controlled to the zero-order elution or multi-stage elution. Solubility in water is 5.0 g / cm ³ or less, the amount of water absorption of the elution control base does not increase too much, and gelation is performed in a range where the gel density does not become rough, so that the strength of the solid preparation is less likely to become too weak, Since it can withstand the load caused by the mechanical movement of the gastrointestinal tract, erosion is unlikely to occur and the elution rate is likely to remain within an appropriate range.

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

  A multilayer solid preparation having a layer composed of these components is not easily affected by the ionic strength in the body or the compression pressure at the time of molding, and it is difficult to cause interlayer separation, so that the active ingredient contained in the multilayer solid component can be released slowly. Can be controlled. Specifically, depending on the formulation design, it is possible to accurately control the 0th-order elution pattern or to accurately control the multi-stage elution pattern.

  Here, the controlled release is controlled to the zero-order dissolution pattern when the active ingredient is gradually eluted from the solid preparation at a constant dissolution rate regardless of time, and more than 90% of the active ingredient is eluted. The characteristic that the time required is at least 3 hours or more. 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.

As a preferable elution pattern in which the elution of the active ingredient is controlled to the zero-order elution, the elution rate per unit time in the time zone in which the elution rate of the active ingredient is 20 to 40% (initial elution rate: M _20-40% ) And the ratio of elution rate per unit time (late elution rate: M _70-90% ) (M _70-90% / M _20-40% ) When evaluating the property, the ratio of the initial dissolution rate to the late dissolution rate is 0.5 to 1.2.

The initial dissolution rate and the late dissolution rate are defined as values obtained as follows. Dissolution test method first method (rotation) described in the 14th revision Japanese Pharmacopoeia using a solid preparation molded using a hydrostatic press under the conditions of weight 0.18 g, diameter 0.8 cm, compression molding pressure 120 MPa, and 300 MPa. Perform dissolution test in accordance with the basket method. The second liquid described in the Japanese Pharmacopoeia (with pH 6.8, ionic strength 0.14; hereinafter may be abbreviated as “second liquid”), and Mcilvine liquid (pH 7.2, ionic strength 0.40, Composition: disodium hydrogen phosphate 173.9 mM, citric acid 13.1 mM (hereinafter sometimes abbreviated as “Mc solution”), α-amylase was added to 5 μg / cm ³ respectively. Using any one of the solvents as a test solution, an elution test is performed under the conditions of any test solution 900 cm ³ , basket rotation speed 100 rpm, and test solution temperature 37 ± 0.5 ° C.

Sampling the test solution to determine the elution rate of the active ingredient at 30 minutes after the start of the test and every hour after the active ingredient is eluted at 90% or more, and the active ingredient is 20 and 40 from the obtained data, respectively. , 70, 90% to calculate the time required to elute. The time required for 20% elution of the active ingredient is plotted in a graph by plotting the sampling time before and after the elution rate of the active ingredient reaches 20% and the elution rate at that time, and the elution rate is equivalent to 20%. The time is calculated by dividing the time as a point on the straight line. Similarly, the time required to elute 40%, 70%, and 90% of the active ingredient is the sampling time before and after the elution rate of the active ingredient becomes 40%, 70%, and 90%, respectively, and the elution rate at that time. Each is plotted on a graph and connected with a straight line, and the elution times corresponding to the elution rates of 40%, 70%, and 90% are calculated as points on the straight line. Based on the data thus obtained, the initial elution rate: M _20-40% and the late elution rate: M _70-90% can be determined.

In addition, the sustained release follows a multi-stage dissolution pattern. The ratio M between the dissolution rate M _t per unit time at the elapsed time t after administration and the dissolution rate M _t-1 per unit time one hour before _t. When evaluating the dissolution property by _t / M _t−1, it means that the elapsed time t at which the ratio of dissolution rate is 1.2 or more is one or more.

Here, the elution rates M _t-1 and M _t / M _t-1 per unit time of the elapsed times t and t-1 are defined as values obtained as follows. Dissolution test first method (rotating basket) described in the 14th revised Japanese Pharmacopoeia using a solid preparation molded using a static pressure press under the conditions of weight 0.18 g, diameter 0.8 cm, compression molding pressure 120 MPa, and 300 MPa. The dissolution test is performed in accordance with the method. The test solution for the dissolution test includes the second solution (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia, or Mcilvine solution (pH 7.2, ionic strength 0.40, composition: disodium hydrogen phosphate 173 (9 mM, citric acid 13.1 mM) using a solvent in which α-amylase was added to 5 μg / cm ³ , under the conditions of 900 cm ^{3 of} the test solution, 100 rpm of the basket rotation speed, and 37 ± 0.5 ° C. of the test solution temperature. Perform a dissolution test. The test solution is sampled every hour until the active ingredient is eluted at 90% or more to obtain the active ingredient elution rate, and the value obtained by subtracting the elution rate at time t-1 from the elution rate at time t is the unit of time t Elution rate per time M _t (t = 0, 1, 2,...: Time until active ingredient is eluted 90% or more), and similarly, elution rate from time t-1 to elution time t-2 A value obtained by subtracting the rate is defined as an elution rate M _t-1 (t = 0, 1, 2,...: Time until elution of the active ingredient is 90% or more) per unit time at time t-1.

The degree of swelling in the compression direction in the multilayer solid preparation is preferably 1.0 or more and 2.0 or less. More preferably, it is 1.0 or more and 1.8 or less, Most preferably, it is 1.0 or more and 1.7 or less. The degree of swelling in the compression direction is defined as the ratio of swelling in the compression direction of the solid preparation in the test solvent determined as follows. Dissolution test method 1st method (rotating basket method) described in the 14th revision Japanese Pharmacopoeia using a solid preparation molded using a hydrostatic press under the conditions of weight 0.18g, diameter 0.8cm, compression molding pressure 120MPa Perform a dissolution test in accordance with the method. A solvent in which α-amylase is added to the second solution (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia so as to be 5 μg / cm ³ is used as the test solution, the test solution is 900 cm ³ , and the basket rotational speed is 100 rpm. The dissolution test is performed under the condition of the test solution temperature of 37 ± 0.5 ° C. The solid preparation was sampled before starting the test and at each time point 0.5, 1.0, 3.0, and 6.0 hours after the start of the test, the size in the compression direction was measured, and _Mai (i = 0) , 0.5, 1.0, 3.0, 6.0). The degree of swelling in the compression direction at each elapsed time is determined by dividing M _ai by M _a0 , and the maximum value {(M _ai / M _a0 ) _max } is defined as the degree of swelling in the compression direction.

  The minimum value of the degree of swelling in the compression direction is substantially 1.0 because the sustained-release solid preparation based on the dissolution control base commonly has the property of swelling by water absorption. By suppressing the degree of swelling in the compression direction to 2.0 or less, the bonding between the layers is sufficient and interlayer separation is less likely to occur. In addition, since the diffusion distance of the active ingredient remains in a short range, a phenomenon in which the dissolution rate decreases in the latter stage of elution is less likely to occur, and the zero-order dissolution tends to occur, and the strength of the gelled solid preparation remains in the strong range. Withstands the load caused by the mechanical movement of the gastrointestinal tract, it becomes easy to keep the dissolution rate constant. For this reason, it is possible to accurately control the elution of the active ingredient.

  Moreover, it is preferable that the swelling ratio obtained by dividing the swelling degree in the compression direction in the solid preparation by the swelling degree in the direction perpendicular to the compression direction is 0.5 to 1.5. When the swelling ratio is adjusted within this range, the solid preparation can swell substantially isotropically and uniformly. By swelling in this way, the diffusion distance of the active ingredient in the solid preparation is not too long, and the decrease in the strength of the swollen solid preparation remains in a certain range. An effect of suppressing the strength reduction of the tablet and suppressing the fluctuation of the residence time in the gastrointestinal tract can be produced. The swelling ratio is more preferably 0.5 to 1.4.

Here, the swelling degree ratio is defined by the ratio of the swelling degree with respect to different directions in the test solvent obtained as follows. Dissolution test method 1st method (rotating basket method) described in the 14th revision Japanese Pharmacopoeia using a solid preparation molded using a hydrostatic press under the conditions of weight 0.18g, diameter 0.8cm, compression molding pressure 120MPa Perform a dissolution test in accordance with the method. A solvent in which α-amylase is added to the second solution (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia so as to be 5 μg / cm ³ is used as the test solution, the test solution is 900 cm ³ , and the basket rotational speed is 100 rpm. The dissolution test is performed under the condition of the test solution temperature of 37 ± 0.5 ° C. Sample the solid preparation at each time point before starting the test, 0.5, 1.0, 3.0, and 6.0 hours after starting the test, and measure the size in the compression direction and the size in the direction perpendicular to the compression direction. The thickness is measured and set to M _ai and M _bi (i = 0, 0.5, 1.0, 3.0, 6.0), respectively. The swelling degree in the compression direction and the swelling degree perpendicular to the compression direction at each time are obtained by dividing M _ai by M _a0 and M _bi by M _b0 , respectively. Further, the degree of swelling (M _ai / M _a0 ) in the compression direction at each time point is divided by the degree of swelling (M _bi / M _b0 ) perpendicular to the compression direction, and the maximum value {( (M _ai / M _a0 ) / (M _bi / M _b0 )) _MAX } is defined as the swelling ratio.

  When the swelling ratio is within the above range, the solid formulation is almost isotropically and uniformly swelled, so that the residence time in the gastrointestinal tract is less likely to fluctuate, and the bonding between layers is sufficient, resulting in separation between layers. It becomes difficult to occur. In addition, since the diffusion distance of the active ingredient remains in a relatively short range, the elution rate is easily maintained even in the later stage of elution, and the zero-order elution tends to occur. In addition, the decrease in strength of the gelled solid preparation remains in a small range, and since it can withstand the load caused by the mechanical movement of the gastrointestinal tract, the elution rate is not easily increased, and accurate elution control of the active ingredient can be performed. .

  The multi-layer solid preparation preferably has a dissolution property of the active ingredient independent of the ionic strength, and the difference in dissolution rate depending on the ionic strength is preferably 7% or less. Within this range, so-called dose dumping is less likely to occur. Preferably it is 5% or less, More preferably, it is 4% or less. The difference in elution rate depending on ionic strength is determined as follows as the difference in elution rate between test solutions having different ionic strengths.

Dissolution test method described in the 14th revision Japanese Pharmacopoeia using a solid preparation containing acetaminophen molded using a hydrostatic press under the conditions of a weight of 0.18 g, a diameter of 0.8 cm and a compression molding pressure of 120 MPa. The dissolution test is performed in accordance with the first method (rotating basket method). First, a solvent obtained by adding α-amylase to the second solution described in the Japanese Pharmacopoeia so as to be 5 μg / cm ³ is used as a test solution, the test solution is 900 cm ³ , the basket rotation speed is 100 rpm, and the test solution temperature is 37 ± 0.5. Perform dissolution test under the condition of ℃. At each time point before the start of the test, 30 minutes after the start of the test, and every hour after the active ingredient was eluted over 90%, the dissolution rate of acetaminophen in each test solution: M _{2nd solution i} (I = 0, 0.5, 1.0, 2.0... Time until 90% or more of the active ingredient is eluted) is determined. This is defined as an elution rate of 1.

Also, a solvent in which α-amylase was added to Mcilvine solution so as to be 5 μg / cm ³ as described above was used as a test solution, and the dissolution rate at each time point: M _{mc solution i} (the meaning of i (Same as above), and this is defined as an elution rate of 2.

The difference between dissolution rate 1 and dissolution rate 2 at each time point is determined as the absolute value of the value obtained by subtracting _{Mmc solution i} from M _{second solution i} , and the maximum value {| M _{second solution i} -M _{mc solution i} | _MAX } is defined as the difference in dissolution rate between test solutions with different ionic strengths. Acetaminophen is used as the active ingredient because if the active ingredient is highly water-soluble, depending on the type and amount of the elution control base, the elution rate may be too high and the difference in elution rate may be overestimated, This is to prevent the elution rate from being too slow and underestimating the difference in elution rate if the property is small.

  The difference in dissolution rate between test solutions with different ionic strength is 7% or less, and the variation of the dissolution rate of the active ingredient due to the difference in ionic strength that varies under the influence of the region of the gastrointestinal tract and ingested food remains in a small range. Thus, it is possible to accurately control the elution of the active ingredient.

In addition, the multilayer solid preparation preferably has a dissolution property of the active ingredient independent of the compression force at the time of compression molding, and the difference in dissolution rate due to the compression molding pressure is preferably 7% or less. The difference in dissolution rate due to compression molding pressure is the difference between the dissolution rate obtained from the dissolution test of a solid preparation molded at a compression molding pressure of 120 MPa and the dissolution rate obtained from the dissolution test of a solid preparation molded at 300 MPa. Ask from. The difference in dissolution rate due to compression molding pressure is 7% or less, and the variation in dissolution characteristics due to fluctuations in conditions and variations during the production of the multilayer solid preparation remains within an acceptable range. Preferably it is 5% or less .

The difference in dissolution rate due to compression molding pressure is defined by the value obtained as follows. A solid preparation molded using a hydrostatic press under the conditions of a weight of 0.18 g, a diameter of 0.8 cm, and a compression molding pressure of 120 MPa, and a hydrostatic press using the same conditions except that the compression molding pressure was changed from 120 MPa to 300 MPa. Using the molded solid preparation, a dissolution test is performed by a method based on the dissolution test method first method (rotating basket method) described in the 14th revised Japanese Pharmacopoeia. A solvent prepared by adding α-amylase to the second liquid described in the Japanese Pharmacopoeia so as to be 5 μg / cm ³ is used as a test liquid. The test liquid is 900 cm ³ , the basket rotation speed is 100 rpm, and the test liquid temperature is 37 ± 0.5 ° C. Perform dissolution test under conditions. The dissolution rate M of the active ingredient in the dissolution test of the solid preparation of each compression molding pressure at each time point before the start of the test, 30 minutes after the start of the test, and every 1 hour until the active ingredient is eluted 90% or more. _120MPai , _M300MPai (i = ₀ , _0.5 , _1.0 , 2.0... Time until the active ingredient is eluted 90% or more) is determined. The difference in dissolution rate at each time point is obtained as an absolute value obtained by subtracting _M300MPai from _M120MPai , and the maximum value {| _M120MPai - _M300MPai | _MAX } among the solid preparations having different compression molding pressures. It is defined as the difference in dissolution rate.

  Even if the difference in dissolution rate between solid preparations with different compression molding pressures is 7% or less, fluctuations in compression molding pressure or changes in composition and blending amount occur during production of solid preparations or scale-up Fluctuation of the ingredient's dissolution tends to stay within an acceptable range, and the fluctuation of the active ingredient's dissolution tends to stay within an acceptable range even when the solid formulation changes over time, so that the active ingredient can be controlled accurately. It becomes possible.

  In addition to the above components, the multilayer solid preparation 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 granule, a more complex and accurate elution pattern of the active ingredient can be obtained as necessary.

  Examples of coating agents for coated granules include sustained-release coating agents and enteric coating agents. Specifically, a cellulose-based coating agent (for example, ethyl cellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate, etc.), an acrylic polymer-based coating agent (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. Examples of pharmaceutical medicinal ingredients that can be used in solid preparations are illustrated below, but are not limited thereto.

Analgesic and anti-inflammatory drugs (COX-2 inhibitors such as NSAID, fentanyl, indomethacin, ibuprofen, ketoprofen, nabumetone, paracetamol, piroxicam, tramadol, celecoxib and rofecoxib);
Antiarrhythmic agents (procainamide, quinidine, verapamil);
Antibacterial and antiprotozoal agents (amoxiline, ampicillin, benzathine penicillin, benzylpenicillin, cefaclor, cefadroxyl, cefprozil, cefuroxime axetil, cephaloxime, chloramphenicol, chloroquine, ciprofloxacin, claris Clarithromycin, clavulanic acid, clindamycin, doxyxyclin, erythromycin, flucloxacillin sodium, halofantrine, isoniazid, kanamycin sulfate, lincomycin, mefloquine, minocycline, naphthylline Sodium, nalidixic acid, neomycin, norfloxacin, ofloxacin, oxacillin, phenoxymethyl-penicillin potassium, pyrimethamine- Sulfadoxime, streptomycin);

Anticoagulant (warfarin);
Antidepressant (amitriptyline, amoxapine, buttriptyline, clomipramine, desipramine, dothiepin, doxepin, fluoxetine, reboxetine, amineptine, selegiline, gepirone, imipramine, lithium carbonate, mianserin, milplanin Nortriptyline, paroxetine, sertraline; 3- [2- [3,4-dihydrobenzofuran [3,2-c] pyridin-2 (1H) -yl] ethyl] -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one);
Anti-diabetic agents (glibenclamide, metformin);
Antiepileptics (carmabazepine, clonazepam, ethosuximide, gabapentin, lamotrigine, lavetiracetam, phenobarbitone, phenytoin, primidone, tiagabine, topiramate, valpromide, valpromid, valpromide ;

Antibacterial agents (amphotericin, clotrimazole, econazole, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole nitrate, nystatin, terbinafine, voriconazole);
Antihistamines (astemizole, cinnarizine, cyproheptadine, decarboethoxyloratadine, fexofenadine, flunarizine, levocabastine, loratadine, norastemole, noroxamidole Promethazine, terfenadine);
Antihypertensive agents (captopril enalapril, centarine, lizinopril, minoxidil, prazosin, ramipril, reserpine, terazosin);

Antimuscarinic agents (atropine sulfate, hyoscine);
Antitumor agents and antimetabolites (platinum compounds such as cisplatin and carboplatin; taxanes such as paclitaxel and docetaxel; taxanes such as camptothecin, irinotecan and topotecan (topotecan) tecan); Vinca alkaloids such as vinblastine, vindesine, vincristine, vinorelbine; derivatives of 5-fluorouracil, capecitabine, gemcitabine, mercaptopurine, thioguanine, cladribine, and methotrexate Folic acid antagonists; nitrogen mustards such as cyclophosphamide, chlorambucil, chlormethine, ifosphamide, meso Melphalan, or alkylating agents such as nitrosourea, eg carmustine, lomustine, or other alkylating agents such as busulfan, dalbazine, procarbazine, thiotepa; daunorubicin, doxorubicin, idarubicin, epirubicin, Antibiotics such as bleomycin, dactinomycin, mitomycin; HER 2 antibodies such as trastuzumab; podophyllotoxin derivatives such as etoposide and teniposide; farnesyl transferase inhibitors; anthraquinone derivatives such as mitozantrone) ;

Anti-migraine agents (alniditan, naratriptan, sumatriptan);
Antiparkinsonian agents (bromocryptine mesylate levotoba, selegiline);
Antipsychotic, hypnotic and sedative (alprazolam, buspirone, chlordiazepoxide, chlorpromazine chlorzapine, diazepam, flupetixol, fluphenazine, flurazepam, 9-hydroxyrisperidone, lorazepam mazapine, azapine (Olanzapine), oxazepam, pimozide, pipamperon, piracetam, promazine, risperidone, selfotel, seroquel, sertindole, sulpiride, temazepam, thiothixene, triazolam, trifluperi Dole, ziprasidone, zolpidem);

Anti-seizure agents (lubeluzole, lubeluzole oxide, riluzole, aptiganel, eliprodil, remacemide);
Antitussives (dextromethorphan, laevodropropizine);
Antiviral drugs (acyclovir, ganciclovir, loviride, chibirapin (tivirapine), zidovudine, lamivudine, zidovudine + lamivudine, didanosine, zalcitabine, stavudine, abacavir (aba) (Lopinavir), amprenavir, nevirapine, efavirenz, delavirdine, indinavir, nelfinavir, ritonavir, saquinavir, fo , Hydroxyurea);
Beta-adrenergic receptor agents (atenolol, carvedilol, metoprolol, nebivolol, propanol)

Cardiac inotropic agents (amrinone, digitoxin, digoxin, milrinone);
Corticosteroids (beclomethasone dipropionate, betamethasone, budesonide, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone);
Disinfectant (chlorhexidine);
Diuretics (acetazolamide, frusemide, hydrochlorothiazide, isosorbide);
enzyme;
Essential oils (Anethol, Anise oil, Caraway, Cardamom, Cassia oil, Cineol, Cinnamon oil, Clove oil, Coriander oil, Dementholised mint oil, Dill oil, Eucalyptus oil, Eugenol, Ginger, Lemon oil, Mustard Oil, neroli oil, nutmeg oil, orange oil, peppermint, sage, spearmint, terpineol, thyme);

Gastrointestinal drugs (cimetidine, cisapride, clebopride, diphenoxylate, domperidone, famotidine, lansoprazole, loperamide, loperamide oxide, mesalazine, metoclopramide (metoclopramide) , Mosapride, nizatidine, norcisapride, olsalazine, omeprazole, pantoprazole, perprazole, prucalopride, rabeprazole, ranitidine, reldogrel, ridogrel (Suphasalazine));
Hemostatic agent (aminocaproic acid);
Lipid regulators (atorvastine, sevastatin, pravastatin, probucol, simvastatin);
Local anesthetics (benzocaine, lignocaine);
Opioid analgesics (buprenorphine, codeine, dextromorphamide, dihydrocodeine, hydrocodone, oxycodone, morphine);

Parasympathomimetic and anti-dementia drugs (AIT-082, eptastigmine, galantamine, metriphonate, mirameline, neostigmine, physostigmine, tacrine, donepezil, rivastigmine, rivastigmine, subcomerine talsaclidine), xanomeline, memantine, lazabemide);
Peptides and proteins (antibodies, becaplermine, cyclosporine, erythropoietin, immunoglobulin, insulin);
Sex hormones (follicular hormones: conjugated follicular hormone, ethinyl estradiol, mestranol, estradiol, estriol, estrone; progesterone; chromadine acetate, cyproten acetate, 17-deacetyl norgestimate, desogestrel, dienogest, diedrogesterone , Etynodiol diacetate, gestodene, 3-keto desogestrel, levonorgestrel, linestrenol, methoxyprogesterone acetate, megesterol, norethindrone, norethindrone acetate, norethisterone acetate, norethisterol acetate , Norgestimate, norgestrel, norgestrienone, professional Suteron, acetate Kin Guess methanol);

Stimulant (sildenafil);
Vasodilators (amlodipine, buflomedil, amyl nitrite, diltiazem, dipyridamole, glyceryl trinitrate, isosorbide dinitrate, lidofrazine, molsidomine, nisaldipine, nifedipine, oxpentifylline, pentaerythritol trinitrate ;
N-oxides of the above substances, pharmaceutically acceptable acid or base addition salts of the above substances, and stereochemical isomers of the above substances.

  The content of the active ingredient is preferably 0.05% by weight or more and 70% by weight or less with respect to the multilayer solid preparation. If it is this range, the dispersion | variation in the elution rate by the difference in compression molding pressure or ionic strength is small, and it is possible to control to zero order elution etc. stably. A more preferable content is 0.1% by weight or more and 50% by weight or less.

  In addition to the active ingredient, the multilayer solid preparation may contain other components such as a disintegrant, a binder, a fluidizing agent, a lubricant, a corrigent, a fragrance, a colorant, and a sweetener as necessary. Be free. Other components can also be used freely 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, glucomannan , xanthan gum , Tamarind gum, pectin, sodium alginate, gum arabic, etc., water-soluble polysaccharides, crystalline cellulose (for example, “Theolas (registered trademark, the same shall apply hereinafter)” PH-101, PH-101D, PH-101L, manufactured by Asahi Kasei Chemicals Corporation 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 hydroxypropyl cellulose, 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.

  Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, talc, magnesium aluminate metasilicate, hydrous silicon dioxide, light anhydrous silicic acid and the like. One kind selected from the above may be used alone, or two or more kinds may be used in combination.

Here, an active ingredient having a solubility in water in the range of 0.0001 to 100 mg / cm ³ has little influence on the dissolution property, and can prevent the tableting powder from adhering to the mortar. It is preferable to use one or more selected from sugar fatty acid esters, talc and light anhydrous silicic acid. 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.

In addition, for an active ingredient having a solubility in water in the range of 100 to 100,000 mg / cm ³ , magnesium stearate, which has little influence on dissolution and can prevent tablet powder from adhering to the mortar, It is preferable to use one or more selected from calcium stearate, stearic acid, sucrose fatty acid ester, talc, and light anhydrous silicic acid. 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. Among them, when using a combination of at least one selected from magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, talc, and light anhydrous silicic acid, and magnesium aluminate metasilicate, the mortar of a tableting powder This is preferable because it can simultaneously prevent adhesion to the tablet, ensure fluidity of the tableting powder, and increase the breaking load of the compression molded product.

  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 chlorophyllin sodium , titanium oxide, riboflavin, 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 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 multilayer solid preparation of the present invention can be produced using any of the methods for producing a multilayer solid preparation usually performed in the pharmaceutical field. For example, two or more layers of the prescription powder can be simultaneously compression-molded, or a method of compressing and molding two or more layers that have been previously compression-molded can be used. The active ingredient and dissolution control base constituting the multilayer solid preparation can be granulated before compression molding as necessary. The dissolution control preparation may be granulated together with the active ingredient or added later to the granule, or both can be used. Granulation may be performed using a water-soluble binder (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc.), or it is solid at room temperature but becomes liquid at 40 ° C. or higher. A melt granulation method using a fat-soluble substance such as carnauba wax, hydrogenated castor oil, or polyglycerin, or a hydrophilic polymer such as polyethylene glycol 6000 can also be used. As the compression molding machine, for example, a compression molding machine usually used in the pharmaceutical field such as a static pressure press machine, a single punch tableting machine, a multilayer solid preparation molding machine or the like can be used.

  Moreover, as long as the effects of the present invention are not impaired, the multilayer solid preparation itself may be coated for the purpose of controlling the dissolution of the active ingredient, masking taste, preventing moisture, and the like. Examples of the coating agent include cellulose-based coating agents (ethylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate, etc.), acrylic polymer coating agents (Eudragit 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. 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 McCilvine solution (pH 7.2, ionic strength 0.40, composition: disodium hydrogen phosphate 173.9 mM, citric acid 13.0 mM, sometimes abbreviated as “second solution”) is used, and the test solution is 900 cm ^3. , Under conditions of basket rotation speed 100 rpm and test solution 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) The degree of swelling in the compression direction of the solid preparation

  0.18 g of the prescription powder is molded with a compressive force of 120 MPa using a static pressure press (MODEL-1321DW CREEP / manufactured by Aiko Engineering Co., Ltd.) to produce an R-shaped tablet having a diameter of 8 mmφ.

In accordance with the dissolution test method first method (rotating basket method) described in the 14th revised Japanese Pharmacopoeia, 5 μg of α-amylase was added to the second solution (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia. A solvent added so as to have an amount of / cm ³ is used as a test solution, and a dissolution test is performed under the conditions of a test solution of 900 cm ³ , a basket rotation speed of 100 rpm, and a test solution temperature of 37 ± 0.5 ° C. Prior to the start of the test, and at each time point after the start of the test after 0.5,1.0,3.0,6.0 hour, sampling the solid preparation, the magnitude of the compressive direction by measuring M _ai (i = 0, 0.5, 1.0, 3.0, 6.0). By dividing M _ai by M _a0 , the degree of swelling M _ai / M _a0 in the compression direction at each time is determined, and the one showing the maximum value is taken as the degree of swelling in the compression direction of the solid preparation.
(3) Swelling ratio

  0.18 g of the prescription powder is molded with a compressive force of 120 MPa using a static pressure press (MODEL-1321DW CREEP / manufactured by Aiko Engineering Co., Ltd.) to produce an R-shaped tablet having a diameter of 8 mmφ.

Α-amylase was added to the second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia by a method based on the dissolution test method first method (rotating basket method) described in the 14th revised Japanese Pharmacopoeia. A solvent added so as to have an amount of 5 μg / cm ³ is used as a test solution, and an elution test is performed under the conditions of 900 cm ^{3 of} the test solution, 100 rpm of the basket rotation speed, and 37 ± 0.5 ° C. of the test solution temperature. The solid preparation is sampled before starting the test and at each time point 0.5, 1.0, 3.0, and 6.0 hours after the start of the test, and the size in the compression direction and the size in the direction perpendicular to the compression direction. The thickness is measured and set to M _ai and M _bi (i = 0, 0.5, 1.0, 3.0, 6.0), respectively. The degree of swelling M _ai / M _a0 of the M _ai to the compression direction at each time obtained by dividing the M _a0, and the swelling degree M _bi / M _b0 to vertically M _bi in the compression direction at each time obtained by dividing the M _b0 Ask. By dividing the degree of swelling in the compression direction by the degree of swelling perpendicular to the compression direction, the ratio of swelling degree (M _ai / M _a0 ) / (M _bi / M _b0 ) at each time is obtained, and the maximum value is determined What is shown is the swelling ratio of the multilayer solid preparation.
(4) Difference in dissolution rate depending on ionic strength

  0.18 g of the prescription powder is molded with a compressive force of 120 MPa using a static pressure press (MODEL-1321DW CREP / manufactured by Aiko Engineering Co., Ltd.) to produce an R-shaped tablet having a diameter of 8 mmφ.

The second solution (pH 6.8, ionic strength) described in the Japanese Pharmacopoeia using acetaminophen as the active ingredient in a method based on the first method (rotating basket method) of the dissolution test method described in the 14th revised Japanese Pharmacopoeia. 0.14) and Mcilvaine solution (pH 7.2, ionic strength 0.40, composition: disodium hydrogen phosphate 173.9 mM, citric acid 13.1 mM) so that α-amylase is 5 μg / cm ³ respectively. Each added solvent is used as a test solution, and an elution test using each test solution is performed under the conditions of any one of the test solutions 900 cm ³ , basket rotation speed 100 rpm, and test solution temperature 37 ± 0.5 ° C. M _{2 solution i} , which is the dissolution rate of acetaminophen in each test solution, at each time point before the start of the test, 30 minutes after the start of the test, and every hour after the active ingredient is eluted 90% or more M _{mc solution i} (i = 0, 0.5, 1.0, 2.0... Time until active ingredient is eluted 90% or more) is determined. Calculated as the absolute value of the value of the difference in dissolution rate minus M _{mc solution i} from M _{2 solution i} at each time point, the maximum value among them | dissolution rate _MAX by ionic strength | M 2 _{solution i} -M _{mc solution i} Calculate as the difference between
(5) Dissolution rate difference due to compression molding pressure

  0.18 g of the prescription powder is molded with a compressive force of 120 MPa using a static pressure press (MODEL-1321DW CREEP / manufactured by Aiko Engineering Co., Ltd.) to produce an R-shaped tablet having a diameter of 8 mmφ. Similarly, it is molded with a compressive force of 300 MPa to produce an R-shaped tablet having a diameter of 8 mmφ.

Solvent obtained by adding α-amylase to 5 μg / cm ^{3 in} the second solution described in the Japanese Pharmacopoeia by a method based on the dissolution test method first method (rotating basket method) described in the 14th revised Japanese Pharmacopoeia Is used as a test solution, and a dissolution test is performed under the conditions of 900 cm ^{3 of} the test solution, 100 rpm of the basket rotation speed, and 37 ± 0.5 ° C of the test solution temperature. M _120MPai which is the dissolution rate of the active ingredient for each tablet with different compression molding pressure at each time point before the start of the test, 30 minutes after the start of the test, and every hour elapsed until the active ingredient is dissolved 90% or more. M _300MPai (i = 0, 0.5, 1.0, 2.0... Time until active ingredient is eluted 90% or more) is determined. The difference in dissolution rate at each time point is determined as an absolute value obtained by subtracting _M300MPai from _M120MPai , and the maximum value | _M120MPai − _M300MPai | _MAX is determined as the difference in dissolution rate due to compression molding pressure.
(6) Particle size distribution Number of particles smaller than 32 μm

Using a JIS sieve opening of 32 μm, when 3 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.
(7) 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 obtained from the weight percentage of the measurement sample that has passed through the sieve.
(8) 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 from the weight W (g) remaining in the lower layer (starch + the amount of pure water retained by the starch) by the following formula (A).
Water retention amount (%) = 100 × (W−W ₀ ) / W ₀ (i)
(9) 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.
(10) 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. When a rheometer (RHEONER, RE-33005, manufactured by YAMADEN) is used after being immersed in pure water for 4 hours to gel, and a cylindrical adapter with a diameter of 3 mm is pushed in at a speed of 0.1 mm / sec. Is defined as the maximum 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.
(11) Amount of water-soluble component (%)

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 (c) are defined as the amount of water-soluble components.
Water-soluble component (%) = (dry weight × 100 ÷ 30) ÷ absolute dry weight × 100 (c)
(12) 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 (D).
Swelling degree of processed starch (cm ³ / g) = V / dry weight of processed starch (D)
(13) 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 13). 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 C and the gel indentation load value under warm storage conditions were measured. Are shown in Table 1. Moreover, under the conditions for measuring the degree of swelling of the processed starch, the swelling state of the processed starch after being left for 16 hours was observed by 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. Moreover, the processed starch A is 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 whole processed starch, the degree of swelling of each fraction, and the gel indentation load value under warm storage conditions The results of measuring are shown in Table 1. Moreover, under the conditions for measuring the degree of swelling of the processed starch, the swelling state of the processed starch after being left for 16 hours was observed by an optical microscope after uniformly redispersing the upper and lower layers, and is shown in FIGS.

  The obtained modified starch A was used as an outer layer formulation, and modified starch A and crystalline cellulose ("Theorus" KG-802, manufactured by Asahi Kasei Chemicals Corporation), polyethylene glycol (Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.) Then, acetaminophen (manufactured by API Corporation) as an active ingredient was mixed at a weight ratio of 60/20/10/10 to obtain an inner layer prescription powder.

  Using a hydrostatic press (MODEL-1321DW CREEP / Eiko Engineering Co., Ltd.), compress the outer layer prescription powder 0.02 g at a pressure of 20 MPa, then stack the inner layer prescription powder 0.18 g and compress at a pressure of 20 MPa, Finally, 0.02 g of the outer layer formulated powder was stacked and compressed at a pressure of 120 MPa to obtain a multilayer tablet consisting of three layers with a diameter of 0.8 cm and a weight of 0.22 g. Separately, in the above tablet, a multilayer tablet having a diameter of 0.8 cm and a weight of 0.22 g was obtained in the same manner as above except that the outer layer prescription powder was compressed with a pressure of 300 MPa when it was finally stacked.

A multilayer tablet 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 degree of swelling, dissolution rate, dissolution rate, and indentation load value, and the dissolution pattern was also measured. In addition, various physical properties were also measured in the same manner except that the test solution was changed from the second solution described in the Japanese Pharmacopoeia to the Mcilvine solution (pH 7.2, ionic strength 0.40). Furthermore, various physical properties were measured in the same manner by adding tablets obtained at a compression molding pressure of 300 MPa using the second liquid described in the Japanese Pharmacopoeia and adding α-amylase to 5 μg / cm ³ . .

The degree of swelling of this multilayer tablet is shown in Table 3, the results of the dissolution test are shown in FIG. 7, and the ratio between the initial dissolution rate and the late dissolution rate is shown in Table 4. In addition, the result of the elution test of the comparative example 1 mentioned later was also shown in FIG. Multi-layer tablets prepared using processed starch A as an elution control agent (the outer layer is a barrier layer that does not contain an active ingredient) have an appropriate range for both the degree of swelling and the ratio of swelling in the compression direction. The 0th-order elution was stably shown without depending on. Moreover, the elution of the active ingredient at the initial stage of elution could be suppressed as compared with the tablet of Comparative Example 1 which was not a multi-layered tablet (the outer layer was not formed with a barrier layer), and showed more linear elution.
[Comparative Example 1]

Modified 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 acetaminophen (AP Corporation) The product is uniformly mixed to a weight ratio of 60/20/10/10, and compressed at a pressure of 120 MPa using a static pressure press (MODEL-1321DW CREEP / manufactured by Aiko Engineering Co., Ltd.). A monolayer tablet of 8 cm and a weight of 0.18 g was obtained. 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 be 5 μg / cm ^3, and a dissolution test was performed. Table 3 shows the degree of swelling of the tablets. The results of the dissolution test are shown in FIG. 7 together with the results of Example 1.
[Comparative Example 2]

  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. The 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 13). Table 2 shows the basic physical properties of the modified starch B.

Next, a multilayer tablet was prepared in the same manner as in Example 1 except that the modified starch A was changed to the modified starch B, and a dissolution test was performed. The swelling degree of the multilayer tablet is shown in Table 3, the result of the dissolution test is shown in FIG. 8, the difference in dissolution rate between different test solutions, the dissolution rate between tablets obtained at different compression molding pressures, the initial dissolution rate and the latter period. Table 4 shows the elution rate ratio. Multilayer tablets prepared using processed starch B as an elution control agent have a large swelling ratio, causing separation between layers when the compression molding pressure is 120 MPa, and the elution amount of the active ingredient increases after 6 hours. It was.
[Comparative Example 3]

  A multilayer tablet was prepared in the same manner as in Example 1 except that hydroxypropylmethylcellulose (Metroze 90SH-100SR, manufactured by Shin-Etsu Chemical Co., Ltd.) was used in place of the modified starch A, and a dissolution test was performed. The swelling degree of the multilayer tablet is shown in Table 3, the result of the dissolution test is shown in FIG. 9, the difference in dissolution rate between different test solutions, the dissolution rate between tablets obtained at different compression molding pressures, the initial dissolution rate and the latter period Table 4 shows the elution rate ratio.

Multilayer tablets prepared using hydroxypropylmethylcellulose as the dissolution control base (outer layer is a barrier layer containing no active ingredient) will disintegrate soon after the start of the test under high ionic strength conditions (ionic strength 0.14). The whole amount of the active ingredient was eluted.
[Comparative Example 4]

  A multilayer tablet was prepared in the same manner as in Example 1 except that Eudragit RSPO (manufactured by Degussa) was used in place of the modified starch A, and a dissolution test was performed. The swelling degree of the multilayer tablet is shown in Table 3, the results of the dissolution test are shown in FIG. 10, the difference in dissolution rate between different test solutions, the dissolution rate between tablets obtained at different compression molding pressures, the initial dissolution rate and the latter period. Table 4 shows the elution rate ratio.

Multilayer tablets prepared using Eudragit RSPO as an elution control base (the outer layer is a barrier layer not containing an active ingredient) had a varying dissolution rate depending on the compression molding pressure.
[Example 2]

  Modified starch A obtained in Example 1, crystalline cellulose ("Theorus" KG-802, manufactured by Asahi Kasei Chemicals Corporation), 100M lactose (Pharmacose 100M, manufactured by DMV) and acetaminophen (manufactured by API Corporation) Was mixed to a weight ratio of 30/15/45/10 to obtain an outer layer prescription powder, and processed starch A, crystalline cellulose and acetaminophen were mixed to a weight ratio of 60/30/10 to form an inner layer. A prescription powder was obtained.

  Using a hydrostatic press (MODEL-1321DW CREEP / Eiko Engineering Co., Ltd.), compress the outer layer prescription powder 0.02 g at a pressure of 20 MPa, then stack the inner layer prescription powder 0.18 g and compress at a pressure of 20 MPa, Finally, 0.02 g of the outer layer formulated powder was layered and compressed at a pressure of 120 MPa to obtain a multilayer tablet having a diameter of 0.8 cm and a weight of 0.22 g.

The resulting multilayer tablet was subjected to a dissolution test by adding α-amylase at 5 μg / cm ³ using a second solution (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia. The degree of swelling of the multilayer tablet is shown in Table 3, and the results of the dissolution test are shown in FIG. (FIG. 11 also shows the results of Example 1 when the same molding pressure and test solution were used, and the results of Examples 3 and 4 described later).

By using processed starch A as an elution control agent, making the outer layer immediate release and the inner layer sustained release, a large amount of active ingredient is eluted at the beginning of elution, and then the active ingredient is gradually eluted over a long period of time. Elution was shown.
[Example 3]

  An example of preparing a 5-layer tablet dissolution control preparation is shown. Modified starch A obtained in Example 1, crystalline cellulose ("Theorus" KG-802, manufactured by Asahi Kasei Chemicals Corporation), 100M lactose (Pharmacose 100M, manufactured by DMV) and acetaminophen (manufactured by API Corporation) Is mixed to a weight ratio of 30/15/45/10 to obtain an outer layer prescription powder (α), then processed starch A is used as an intermediate layer (β), and finally, processed starch, crystalline cellulose and polyethylene glycol Macrogol 6000 (manufactured by Sanyo Chemical Industries, Ltd.) and acetaminophen were mixed at a weight ratio of 60/20/10/10 to obtain an inner layer prescription powder (γ).

  The outer layer prescription powder (α) 0.02 g is compressed at a pressure of 20 MPa using a hydrostatic press (MODEL-1321DW CREEP / manufactured by Aiko Engineering Co., Ltd.), and then the intermediate prescription powder (β) 0.02 g is stacked to 20 MPa. Next, 0.14 g of the inner layer prescription powder (γ) is overlaid and compressed at a pressure of 20 MPa, then 0.02 g of the intermediate prescription powder (β) is overlaid and compressed at a pressure of 20 MPa, and finally The outer layer powder formulation (α) 0.20 g was stacked and compressed at a pressure of 120 MPa to obtain a multilayer tablet having a diameter of 0.8 cm and a weight of 0.22 g.

The resulting multilayer tablet was subjected to a dissolution test by adding α-amylase at 5 μg / cm ³ using a second solution (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia. The degree of swelling of the multilayer tablet is shown in Table 3, and the results of the dissolution test are shown in FIG.

Processed starch A is used as an elution control agent, and the outer layer has immediate release and the intermediate barrier layer has sustained release, so that a large amount of active ingredient is eluted at the beginning of elution. Over time.

  Modified 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 acetaminophen (AP Corporation) Co., Ltd.) is mixed to a weight ratio of 60/20/10/10 to form an outer layer powder, and processed starch A, crystalline cellulose, 100M lactose (Pharmacose 100M, manufactured by DMV) and acetaminophen 30 / 15/45/10 was mixed so as to have a weight ratio to obtain an inner layer prescription powder.

  Using a hydrostatic press (MODEL-1321DW CREEP / Eiko Engineering Co., Ltd.), compress the outer layer prescription powder 0.02 g at a pressure of 20 MPa, then stack the inner layer prescription powder 0.18 g and compress at a pressure of 20 MPa, Finally, 0.02 g of the outer layer formulated powder was layered and compressed at a pressure of 120 MPa to obtain a multilayer tablet having a diameter of 0.8 cm and a weight of 0.22 g.

The resulting multilayer tablet was subjected to a dissolution test by adding α-amylase at 5 μg / cm ³ using a second solution (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia. The degree of swelling of the multilayer tablet is shown in Table 3, and the results of the dissolution test are shown in FIG. By using processed starch A as an elution control agent, the outer layer was controlled to release slowly, and the inner layer was made to release quickly.
[Example 5]

  An outer layer prescription powder and an inner layer prescription powder having the same composition as in Example 1 were prepared. Using an external pressure press (MODEL-1321DW CREEP / Eiko Engineering Co., Ltd.), compressing 0.05 g of the outer layer prescription powder at a pressure of 20 MPa, and subsequently compressing 0.45 g of the inner layer prescription powder at a pressure of 20 MPa, Finally, 0.05 g of the outer layer formulated powder was stacked and compressed at 120 MPa pressure to obtain a multilayer tablet having a diameter of 11.3 cm and a weight of 0.55 g.

The resulting multilayer tablet was subjected to a dissolution test by adding α-amylase at 5 μg / cm ³ using a second solution (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia. The degree of swelling of the multilayer tablet is shown in Table 3, and the results of the dissolution test are shown in FIG. In addition, the results of the dissolution test using the second liquid of the tablet compression-molded at a pressure of 120 MPa in Example 1 are also shown in FIG. Multi-layer tablets using starch powder A as an elution control agent and having a tablet weight increased from 0.22 g to 0.55 g under the same prescription conditions could extend the elution time while maintaining elution.
[Comparative Example 5]

  An outer layer prescription powder and an inner layer prescription powder having the same composition as Comparative Example 3 were prepared. Using an external pressure press (MODEL-1321DW CREEP / Eiko Engineering Co., Ltd.), compressing 0.05 g of the outer layer prescription powder at a pressure of 20 MPa, and subsequently compressing 0.45 g of the inner layer prescription powder at a pressure of 20 MPa, Finally, 0.05 g of the outer layer formulated powder was stacked and compressed at 120 MPa pressure to obtain a multilayer tablet having a diameter of 11.3 cm and a weight of 0.55 g.

The resulting multilayer tablet was subjected to a dissolution test by adding α-amylase at 5 μg / cm ³ using a second solution (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia. The degree of swelling of the multilayer tablet is shown in Table 3, and the results of the dissolution test are shown in FIG. In addition, a dissolution test result using the second liquid of the tablet compression-molded at a pressure of 120 MPa in Comparative Example 3 is also shown in FIG. Multilayer tablets in which hydroxypropylmethylcellulose was used as an elution control agent and the tablet weight was increased from 0.22 g to 0.55 g under the same prescription conditions, the elution rate in the later stage of elution decreased.

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 time) of the swelling particle | grains of modified starch C (0-32 micrometer 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. 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. It is the graph which showed the elution test result of Examples 2-4. 6 is a graph showing the dissolution test results of Example 5 and Comparative Example 5.

Claims (12)

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, a particle passing through a sieve having a mesh opening of 75 μm, and a particle having a mesh opening of 32 μm. Contains processed starch having a particle size of 20% by weight or more, an average particle size of 20 μm or more and less than 50 μm, and a swelling degree of 6 cm ³ / g or more and 10 cm ³ / g or less, and one or more active ingredients One or more layers containing at least one of the modified starch and the active ingredient are laminated on one or more layers, and have a sustained release property of the active ingredient, and are manufactured by compression molding. A multilayer solid preparation characterized by that.   The multilayer solid preparation according to claim 1, wherein the sustained release property is controlled to a zero-order dissolution pattern.   The multi-layer solid preparation according to claim 1, wherein the sustained release property is controlled in a multistage dissolution pattern. 4. The multilayer solid 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. Formulation. The multilayer solid preparation according to any one of claims 1 to 4, wherein the processed starch has an angle of repose of 45 ° or less and an apparent specific volume of 1.4 cm ³ / g or more and 3.6 cm ³ / g or less.   The dissolution rate obtained from the dissolution test using the second solution listed in the Japanese Pharmacopoeia as the test solution, and the dissolution rate obtained from the dissolution test using the Mcilvine solution (pH 7.2, ionic strength 0.4) as the test solution; The dissolution rate obtained from the dissolution test of the solid preparation molded at 120 MPa and the dissolution test of the solid preparation molded at 300 MPa is 7% or less. And the swelling degree in the compression direction at the time of compression molding is 1.0 to 2.0, and the swelling degree in the compression direction is divided by the swelling degree in the direction perpendicular to the compression direction. The swelling degree ratio obtained by this is 0.5-1.5, The multilayer solid formulation in any one of Claims 1-5 characterized by the above-mentioned.   The multilayer solid preparation according to any one of claims 1 to 6, wherein the one or more active ingredients are pharmaceutical active ingredients.   The multilayer solid preparation according to any one of claims 1 to 7, wherein the content of the modified starch in the one or more layers is 5.0 to 99.9 wt%. At least one of the layers containing the modified starch and the one or more active ingredients has a water solubility at 20 ° C. of 0.1 g / cm ³ or more and 5.0 g / cm ³ or less, melting point The multi-layer solid preparation according to any one of claims 1 to 8, further comprising a hydrophilic polymer auxiliary agent which is a synthetic or natural polymer having an average molecular weight of 5000 or more.   The multilayer solid preparation according to any one of claims 1 to 9, further comprising a coated granule. Furthermore, the multilayer in any one of Claims 1-10 which contains the combination of 1 or more types selected from sucrose fatty acid ester, talc, and light silicic acid anhydride, and magnesium aluminate metasilicate as a lubricant. Solid formulation. The multilayer solid preparation according to any one of claims 1 to 11, wherein the weight per preparation is larger than 0.20 g.