JP5133514B2 - Solid formulation that elutes active ingredients in multiple stages - Google Patents

Description

  The present invention relates to a sustained-release solid preparation that elutes an active ingredient in multiple stages mainly for pharmaceutical use.

  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).

  Cellulose derivatives such as methylcellulose (MC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC) are known as elution control bases used in matrix systems as described in Patent Document 1 and the like. Yes. Patent Document 2 and the like describe a processed 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 processed starch as an elution control base. It is disclosed. These dissolution control bases swell when hydrated in an aqueous solution to form a gel layer on the surface of a solid preparation, thereby diffusing from the network structure of the gel layer, erosion of the gel layer, Either by dissolution or a combination thereof, the active ingredient is eluted continuously at a slow rate.

  Zero-order elution is reported as the dissolution property of a sustained-release preparation desirable for maintaining the blood concentration of the drug. If there is no difference in the absorption of the drug from the gastrointestinal tract depending on the site of absorption, the drug concentration in the plasma can be maintained by eluting the drug at a constant rate throughout the gastrointestinal tract (small and large intestine) after taking the solid preparation. It is based on the idea that it can be achieved. However, the gastrointestinal tract is not uniform, and the pH, the amount of digestive juice, the load applied to the solid preparation, the effective surface area, etc. differ depending on the site. For this reason, a preparation that exhibits zero-order dissolution in an in vitro dissolution test does not necessarily exhibit the same dissolution and absorption properties in the digestive tract. Therefore, depending on the type of drug used as the active ingredient, it may not be possible to maintain the blood concentration in the effective therapeutic range for a long time, and development of a sustained-release preparation that has dissolution properties according to the characteristics of the drug and the gastrointestinal environment Design is desired.

  For example, it is reported that the elution rate of the active ingredient is remarkably reduced because the amount of digestive fluid is reduced in the lower part of the digestive tract, so that the elution control base is insufficiently hydrated and gel formation is suppressed. In order to solve the above-described problem, Patent Document 3 discloses a sustained-release solid preparation that exhibits an elution pattern in which the elution rate becomes higher in the later stage of elution corresponding to the lower part of the digestive tract.

  As a method for eluting active ingredients in multiple stages, as described in Patent Documents 4 and 5, etc., a method is known in which a matrix having different active ingredient contents and dissolution rates is layered to form a solid preparation or a nucleated solid preparation. It has been. In multi-stage elution with a solid preparation or a nucleated solid preparation, it is necessary to appropriately control the active ingredient content and elution speed of each layer and to accurately compress and mold each layer. However, it is difficult to produce solid preparations and nucleated solid preparations with high accuracy in commercial-scale continuous production facilities, and it is difficult to obtain accurate dissolution controllability, and prescription powders are prepared for each layer. There was a drawback that the number of processes was increased. Sustained-release solid preparations that can be dissolved in multiple stages accurately by simply compression-molding uniform prescription granules without taking complicated structures and manufacturing processes such as solid preparations and nucleated solid preparations The current situation is that there is no technology, and such a sustained-release solid preparation has been desired.

In addition, as fatty acid metal salts, for example, magnesium stearate and calcium stearate are usually used for lubricants in the pharmaceutical field, and Patent Documents 6 and 7 report examples of application to sustained-release solid preparations. Has been. In these patent documents, a stearic acid metal salt is used as an elution retardant based on water repellency, and the elution of an active ingredient can be sustained-released by adding it to a solid preparation. It is described that the elution time is delayed as the content of the metal salt increases.
US Pat. No. 6,296,873 International Publication WO2005 / 005484 JP 2004-300149 A International Publication No. WO94 / 064146 JP 2003-146882 A JP-A-9-301872 JP 2003-146882 A

  Although the present invention can be produced simply by compression molding a uniform prescription granule without taking a complicated structure or production process such as a solid preparation or a nucleated solid preparation, an accurate multi-step elution It is another object of the present invention to provide a multistage sustained-release solid preparation in which dissolution characteristics are not affected by the in vivo environment such as ionic strength and pH, and the compression force at the time of compression molding.

  The inventors of the present invention have disclosed a gel formation mechanism and an active ingredient elution mechanism of a sustained-release solid preparation using a starch powder having a water retention amount of 400% or more, a disintegration time of 5 hours or more, and a gel indentation load of 200 g or more as an elution control base. As a result of intensive studies on the above, it is possible to control the processed starch so as to be in a specific particle size range, and to further control the active ingredient to multi-stage elution by adding a fatty acid metal salt. It was found that the elution start time after the second stage can be controlled by the amount of salt added, and the present invention was completed based on this finding.

That is, the present invention is as follows.
(1) A sustained-release solid preparation containing one or more active ingredients and an elution control base for controlling the elution of the active ingredients, wherein the elution control base has a water retention amount of 400% or more Thus, when the gel indentation load is 200 g or more, the amount of the water-soluble component is 40 to 95%, the particles passing through the sieve having an opening of 75 μm are 90 wt% or more, and the particles passing through the sieve having an opening of 32 μm are 20 wt%. A multistage sustained-release solid preparation comprising 50.0 to 99.9% by weight of the modified starch and 0.01 to 20% by weight of a fatty acid metal salt.
(2) The above-mentioned processed starch is characterized in that the particles passing through a sieve having an opening of 75 μm are 98% by weight or more and the particles passing through a sieve having an opening of 32 μm are 40% by weight or more ( The solid preparation according to 1).
(3) The solid preparation according to (1) or (2) above, wherein the active ingredient is a medicinal medicinal ingredient.
(4) The solid preparation according to any one of (1) to (3), wherein the fatty acid metal salt is a metal salt of stearic acid.
(5) The solid preparation according to any one of (1) to (4), further comprising coated granules.
(6) The solid preparation according to any one of (1) to (5) above, wherein the weight is greater than 0.20 g.

  Although the sustained-release solid preparation of the present invention can be produced only by compression molding a uniform prescription granular material without taking a complicated structure or production process such as a solid preparation or a nucleated solid preparation, Accurate multistage elution is possible without being affected by the in vivo environment such as ionic strength and pH, and the compression force during compression molding.

  Hereinafter, the present invention will be described in detail. The sustained-release solid preparation of the present invention contains one or more active ingredients and an elution control base that controls the elution of the active ingredients, and has multi-stage sustained-release properties that elute the active ingredients in multiple stages. This solid preparation only needs to constitute a so-called matrix system in which the active ingredient and the dissolution control base are simply mixed and uniformly dispersed. It is not necessary to have a more complex structure such as a multilayer solid formulation or a nucleated solid formulation, but doing so is optional.

  The elution control base has a function of controlling the elution of an active ingredient in multiple stages and imparting multistage sustained release to a solid preparation. The elution control base has a water retention amount of 400% or more, a gel indentation load of 200 g or more, a water-soluble component amount of 40 to 95%, and particles passing through a sieve having an opening of 75 μm of 90% by weight or more. It contains a specific processed starch having 20% by weight or more of particles passing through a sieve having an opening of 32 μm and a fatty acid metal salt. By including both of them, it is possible to impart accurate multistage sustained release properties to the solid preparation.

  First, the fatty acid metal salt will be described. By including a fatty acid metal salt in the elution control base, the reason is unknown, but it becomes possible to control the elution of the active ingredient in two or more stages. Although it does not specifically limit as a fatty acid, A thing with comparatively large molecular weight is preferable for elution control, and it is good to use a saturated fatty acid from a viewpoint of stability with respect to a time-dependent change of an elution characteristic. Examples thereof include lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid and the like. The metal ion species for forming the salt is not particularly limited, but is preferably divalent from the viewpoint of elution characteristics, and examples thereof include beryllium, magnesium, calcium, zinc, and strontium. In order to obtain excellent multistage sustained release properties, it is preferable to use a metal salt of stearic acid or palmitic acid, and more preferably selected from a magnesium salt of stearic acid or a calcium salt of stearic acid.

  The content of the fatty acid metal salt in the elution control base needs to be 0.01 to 20% by weight. When the fatty acid metal salt is 0.01% by weight or more, the sustained-release solid preparation can be controlled to multistage elution. As the amount of fatty acid metal salt increases, the elution start time after the second stage becomes faster. However, if the fatty acid metal salt is 20% by weight or less, the elution start time after the second stage in multi-stage elution remains in a moderately slow range. The difference from elution in the first stage becomes clear. The content of the fatty acid metal salt is preferably 0.05 to 15% by weight, more preferably 0.1 to 10% by weight.

  The elution control base has a water retention amount of 400% or more, a gel indentation load of 200 g or more, a water-soluble component amount of 40 to 95%, particles passing through a sieve having an opening of 75 μm, and 90% by weight or more and an opening of 32 μm. The particles passing through the sieve contain 20% by weight or more of specific processed starch. By using this specific processed starch as an elution control base for a solid preparation, an accurate multi-stage elution of the active ingredient from the solid preparation becomes possible.

  The elution control base needs to contain 50.0 to 99.9% by weight of a specific processed starch. The content of the specific processed starch is preferably 10.0 to 99.9% by weight, particularly preferably 20.0 to 99.9% by weight. When the content of the specific processed starch is 5.0% by weight or more, it becomes possible to control the elution of the active ingredient to be sustained release. The content of the specific processed starch can be appropriately selected depending on the type and amount of the active ingredient, but the content of the processed starch is 99.9% by weight or less, thereby containing the fatty acid metal salt. The amount is in a range where accurate multi-stage dissolution can be imparted.

  A specific modified starch will be described. The specific processed starch is required 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 of 200 g or more. The gel indentation load is 0 after a cylindrical shaped body having a diameter of 1.13 cm obtained by compressing 0.5 g of processed starch at 50 MPa is gelled by immersing it in pure water at 20 ° C. ± 5 ° C. for 4 hours. It is defined as the maximum load when a 3 mm diameter cylindrical adapter is pushed in at a speed of 1 mm / sec. Here, the maximum load is the load value at the time of rupture when there is a rupture of the gel layer, and the maximum load value shown until the adapter enters 5 mm into the gelled cylindrical molded body when there is no rupture. . When the gel indentation load is 200 g or more, 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 stronger the sustained release, 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 water-soluble component (% by weight) was determined by adding 99 g of pure water at 20 ° C. ± 5 ° C. to 1 g of processed starch and stirring the mixture with a magnetic stirrer for 2 hours to disperse 40 cm ³ of the obtained dispersion to 50 cm ³ . Transfer to a centrifuge tube, centrifuge at 5000 G for 15 minutes, put 30 cm ³ of this supernatant into a weighing bottle and dry at 110 ° C. until a constant weight is obtained to determine 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 (A).

  Water-soluble component amount = (dry weight × 100 ÷ 30) ÷ absolute dry weight of 1 g of starch × 100 (a)

  The amount of the water-soluble component is a value representing the amount of the paste component in which the processed starch is gelatinized by heat treatment and becomes water-soluble. When 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. On the other hand, a large amount of the active ingredient is eluted immediately after the sustained-release solid preparation comes into contact with the solvent. The phenomenon is less likely 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. Moreover, since it can withstand the load caused by the mechanical movement of the gastrointestinal tract, erosion is difficult to proceed and the elution rate is ensured within a certain range.

  The specific processed starch is required to have 90% by weight or more of particles passing through a sieve having an opening of 75 μm and 20% by weight or more of particles passing through a sieve having an opening of 32 μm. Preferably, the particles passing through a sieve having an opening of 75 μm are 95% by weight or more, the particles passing through a sieve having an opening of 32 μm are 30% by weight or more, and more preferably, the particles passing through a sieve having an opening of 75 μm are 98%. More than 40% by weight of the particles passing through a sieve having a mesh size of 32 μm. The specific processed starch has a smaller swellability and a stronger gel strength as the particles are smaller, so that 90% by weight or more of the particles passing through a sieve having a mesh opening of 75 μm and 20 particles passing through a sieve having a mesh opening of 32 μm are used. If it is more than% by weight, the swellability of the starch particles and the solid preparation comprising the starch particles remains in a relatively small range, and the density of the gel layer remains in a high and strong range, so that the active ingredient is eluted from the solid preparation. However, it becomes difficult to fluctuate by compression molding pressure. In addition, it is preferable that the elution start time after the second stage is not easily influenced by the compression molding pressure.

  By the way, Patent Document 2 discloses a method for producing processed starch having a water retention amount of 400% or more, a gel indentation load of 200 g or more, and a water-soluble component amount of 40 to 95% by weight. As a result of examining the processed starch obtained by the method described in Patent Document 2 in detail, the present inventors have different swelling properties depending on the particle size, and control the particle size and swelling properties of the processed starch within an appropriate range. Thus, for the first time, it has been found that an interlayer release in a solid preparation does not occur and a sustained release solid preparation independent of compression molding pressure can be obtained. The examination process will be described next.

  The inventors first manufactured a conventional processed starch C as described in the method of Patent Document 2, specifically as described in Comparative Production Example 1 described below, and obtained processed starch C was obtained. It fractionated for every particle size of 0-32, 32-75, 75-150, 150-500 micrometers, and compared the basic physical property. 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.

The degree of swelling of processed starch C shown in Table 1 is as follows: 1.0 g of processed starch C is dispersed in pure water at 20 ± 5 ° C., transferred to a 100 cm ³ sedimentation tube, the total amount is 100 cm ^3, and left for 16 hours. The value obtained by defining the volume of the lower layer divided into upper and lower. In addition, the gel indentation load under the warming storage condition was as follows: a cylindrical shaped body having a diameter of 1.13 cm obtained by compressing 0.5 g of processed starch at 50 MPa was placed in pure water at 37 ° C. ± 0.5 ° C. for 4 hours. After soaking and gelling, it was determined as a value that gave a peak first when a cylindrical adapter with a diameter of 3 mm was pushed in at a speed of 0.1 mm / sec.

  From the data of processed starch C in Table 1 and photographs of the processed starch C swollen particles in FIGS. 3 to 6, the particles having a fraction of 0 to 32 μm have a swelling degree of about 14 and a swollen particle size of about 100 μm. It can be seen that the gel indentation load value is small and large. On the other hand, 32 μm to 500 μm particles are uniform in any particle size fraction, have a swelling degree of 20 to 30, a swelling particle size of 200 to 300 μm, a large swelling property, and a small gel indentation load value. .

  From these facts, the processed starch obtained by the method described in Patent Document 2 has a particle group of 0 to 32 μm fraction having a shell structure of starch particles, a low swelling property and a large gel indentation load value, and a shell. It is composed of a particle group of 32 to 75 μm that has a structure and a large swellability and a small gel indentation load value, and a water-soluble paste component (which cannot be observed with an optical microscope because the contour disappears due to swelling and dissolution). It was clarified that these three components were granulated to form a processed starch having a particle size distribution of 0 to about 500 μm (because the surface of each particle is covered with a water-soluble component). These facts cannot be discriminated only by the appearance of the modified starch.)

  Furthermore, when the sustained release solid preparation is divided into a 0-32 μm fraction having a small swelling property and a large gel indentation load value and a 32-500 μm fraction having a large swelling property and a small gel indentation load value, the 0-32 μm fraction is Although it showed stable dissolution without fluctuation due to compression molding pressure, it became clear that the 32-500 μm fraction had larger swelling in the compression direction as the compression force was smaller, and the dissolution rate increased accordingly. . In order to obtain a sustained-release solid preparation that does not depend on the compression molding pressure, it was confirmed that the particle design should have a small swelling property and a large gel indentation load value.

  In view of the above-mentioned facts, the present inventors can suppress the swellability of the processed starch by destroying the primary particles having an outer shell structure of 32 to 75 μm present in the particles of 32 to 500 μm. As a result, it was considered that a sustained-release solid preparation independent of compressive force could be obtained. As a result of repeated examinations on various grinding conditions, the particle size distribution is controlled so that the particles passing through the sieve with 75 μm openings are 90% by weight or more and the particles passing through the 32 μm sieves are 20% by weight or more. As a result, it was found that processed starch having uniformly small swellability and a large gel indentation load value was obtained, and a solid preparation free from fluctuation due to interlayer separation or compression molding pressure was obtained.

  Here, the processed starch A obtained by Example 1, in which particles passing through a sieve having an opening of 75 μm are 90% by weight or more and particles passing through a sieve having an opening of 32 μm is 20% by weight or more, The basic physical properties of each fraction in the case of fractionation for each particle size of ˜32 and 32 to 75 μm were compared. Table 1 shows the entire processed starch A and the particle size distribution of each fraction, the degree of swelling, and the gel indentation load value under warmed storage conditions. 1 and 2 show optical micrographs of the swollen particles after the processed starch A 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 can also be confirmed that the swelling property of each particle size fraction is uniformly reduced, and the gel indentation load value shows a large value.

  Here, the sustained release means that the active ingredient is gradually eluted from the solid preparation at a constant elution rate regardless of time, and the time required for elution of 90% or more of the active ingredient is at least 3 hours or more. The characteristic which is 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 from the administration depending on the type of the active ingredient. Due to the limit, the upper limit is 72 hours at most.

This solid preparation having sustained release has the property that the elution of the active ingredient is controlled in multiple stages. The elution of the active ingredient is controlled in a multistage manner that the elution rate M _t per unit time at a certain elapsed time _t and the elution rate M _t-1 per unit time one hour before _t is M _t. When the dissolution property is evaluated by / M _t−1 , it means that there is one or more time t at which the ratio of dissolution rate is 1.2 or more. The elution rates M _t and M _t-1 per unit time at a certain elapsed time t and t-1 and the ratio M _t / M _t-1 are defined as values 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 is prepared. A solid preparation molded in the same manner except that the compression molding pressure is changed to 300 MPa is prepared.

Using these, the dissolution test is performed by a method based on the dissolution test first method (rotating basket method) described in the 14th revised Japanese Pharmacopoeia. As a test solution for the dissolution test, the second solution described in the Japanese Pharmacopoeia (pH 6.8, ionic strength 0.14. Hereinafter, sometimes referred to as “second solution”) or Mcilvine solution (pH 7.2). Ionic strength 0.40, composition: disodium hydrogen phosphate 173.9 mM, citric acid 13.1 mM (hereinafter sometimes referred to as “mc solution”), α-amylase is 5 μg / cm ³ respectively. The elution test is performed under the conditions of any of the test solutions of 900 cm ³ , basket rotation speed of 100 rpm, and test solution temperature of 37 ± 0.5 ° C. 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 rate from time t-2 The value obtained by subtracting is taken as the dissolution rate M _t-1 per unit time at time _t-1 (t = 0, 1, 2... Time until 90% or more of the active ingredient is eluted).

  The content of the dissolution control base in the solid preparation is preferably 5.0 to 99.9% by weight. If it is 5% by weight or more, it becomes possible to control the active ingredient to be sustained release in multiple stages, and if it is 99.9% by weight or less, the necessary active ingredient can be contained in the solid preparation. More preferably, it is 10.0-99.9 weight%, More preferably, it is 20.0-99.9 weight%.

  The manufacturing method of the above-mentioned specific modified 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 more and less 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 starch It is produced by a step of obtaining a powder of a mixture containing amylose and amylopectin existing outside the 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 material has a starchy content as described in, for example, JP-A-4-130102 and JP-A-7-25902. 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 manufacturing method in which the heating is performed at 80 ° C. or higher and for 5 minutes to 5 hours is disclosed, but any of these methods may be used.

  By these methods, starch obtained by subjecting the starch raw material to heat-moisture treatment under reduced pressure has a hollow interior and increased crystallinity of the outer shell of the particle, and can be seen in a polarization image of an optical microscope. The polarization cross pattern is weaker than raw starch and has a feature that 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 it has the feature that digestibility by α-amylase is increased compared to raw starch, and it can be used as a specific processed starch Is suitable.

  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 because the swelling property imparted to the starch particles can be stably adjusted 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 of the above, 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, etc. From the viewpoint of the heating time of the particles, a method of mixing steam with the starch 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, drying by solvent substitution, and the like. 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.

The particle size was adjusted so that the particles passing through the sieve having a mesh opening of 75 μm were 90% by weight or more, and the particles passing through the sieve having a mesh opening of 32 μm were 20% by weight or more, the water retention amount was 400% or more, and the gel indentation load was Processed starch having 200 g or more and a water-soluble component amount of 0 to 95% is characterized by a low degree of swelling and a high gel indentation load value as compared with an unadjusted particle size. In addition, it is preferable that the degree of swelling of the processed starch whose particle size has been adjusted is in the range of 5 to 20 cm ³ / g.

The processed starch used for the solid preparation preferably has a bulk density in the range of 0.1 to 0.7 g / cm ³ . More preferably from 0.15~0.7g / cm ^3, particularly preferably 0.2 to 0.7 g / cm ^3. Since the bulk density is 0.1 g / cm ³ or more and the fluidity is excellent, the weight distribution of the solid preparation is preferably difficult to spread. 0.7 g / cm ³ or less is preferable because compression moldability is ensured and appropriate practical hardness is obtained. The bulk density is affected by the liquid concentration in the drying process, and is also affected by the rotation speed of the atomizer in the spray dry drying process. Good.

  Other solid dissolution control bases may be used in combination with the 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.

  The solid preparation preferably further contains coated granules in addition to the above components. 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 preferably has a weight per grain 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 the swellability of the processed starch as an elution control base is adjusted to be small, so that the swelling of the solid preparation can be kept small, and the diffusion distance of the active ingredient is not greatly changed by the swelling of the solid preparation. . On the other hand, in an example where the swelling degree or swelling ratio in the compression direction is not within the scope of the present invention using a dissolution control base such as hydroxypropylmethylcellulose having a large swelling property, the dissolution rate in the later stage of dissolution when the weight of the solid preparation increases. Is not preferable because it decreases. One of the effects is that the elution time of the active ingredient can be extended by simply increasing the weight of the solid preparation while maintaining the elution of the active ingredient.

  Here, 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, for example, 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.

  A solid formulation has (a) 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) having a narrow therapeutic index, or (c) need to be well absorbed across the entire gastrointestinal tract, or (d) a therapeutically effective dose is relatively small, etc. Alternatively, it is particularly useful for formulating one or more medicinal active ingredients having two 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);
◇ Anti-arrhythmic agents (procainamide, quinidine, verapamil);
◇ Anti-bacterial and antigenic veterinary agents (amoxiline, ampicillin, benzathine penicillin, benzylpenicillin, cefaclor, cefadroxyl, cefprozil, cefuroxime axetil, cephaloxime, chloramphenicol, chloroquine, ciprofloxacin, Clarithromycin, clavulanic acid, clindamycin, doxyxyclin, erythromycin, flucloxacillin sodium, halofantrine, isoniazid, kanamycin sulfate, lincomycin, mefloquine, minocycline, Nafcillin Sodium, nalidixic acid, neomycin, norfloxacin, ofloxacin, oxacillin, phenoxymethyl-penicillin potassium, pyrimethami - Surufadokishimu, streptomycin);

◇ Anti-coagulant (warfarin);
◇ Antidepressants (amitriptyline, amoxapine, buttriptyline, clomipramine, desipramine, dothiepin, doxepin, fluoxetine, reboxetine, amineptine, selegiline, gepirone, imipramine, lithium carbonate, milan serine, milna serine , 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);
◇ Antidiabetic agents (glibenclamide, metformin);
◇ Antidepressants (carmabazepine, clonazepam, ethosuximide, gabapentin, lamotrigine, levetiracetam, phenobarbitone, phenytoin, primidone, tiagabine, topiramate, valpromid, topiramate, valpromid );
-Antibacterial agents (amphotericin, clotrimazole, econazole, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole nitrate, nystatin, terbinafine, voriconazole);

◇ Antihistamines (astemizole, cinnarizine, cyproheptadine, decarboethoxyloratadine, fexofenadine, flunarizine, levocabastine, loratadine, norastemazole (norastemizide) , Promethazine, terfenadine);
◇ Anti-hypertensive agents (captopril enalapril, centarine, lidinopril, minoxidil, prazosin, ramipril, reserpine, terazosin);
◇ Anti-muscarinic agent (atropine sulfate, hyoscine);

  ◇ Antineoplastic drugs and antimetabolites (platinum compounds such as cisplatin and carboplatin; taxanes such as paclitaxel and docetaxel; taxanes such as camptothecin, irinotecan and topotecan) (Tecan); Vinca alkaloids such as vinblastine, vindesine, vincristine, vinorelbine; derivatives such as 5-fluorouracil, capecitabine, gemcitabine, mercaptopurine, thioguanine, cladribine, methotrexate And folic acid antagonists; nitrogen mustards such as cyclophosphamide, chlorambucil, chlormethine, ifosphamide, meso Phalans, nitrosoureas, alkylating agents such as carmustine, lomustine, or other alkylating agents such as busulfan, dalbazine, procarbazine, thiotepa; daunorubicin, doxorubicin, idarubicin, epirubicin, Antibiotics such as bleomycin, dactinomycin and 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);
◇ Anti-parkinsonian (bromocryptine mesylate levotoba, selegiline);
◇ Antipsychotic, hypnotic and sedative (alprazolam, buspirone, chlordiazepoxide, chlorpromazine chlorzapine, diazepam, flupetixol, fluphenazine, flurazepam, 9-hydroxyrisperidone, lorazepam, zap Olanzapine, oxazepam, pimozide, pipamperon, piracetam, promazine, risperidone, selfotel, seroquel, sertindole, sulpiride, temazepam, triazolam, triazolam Peridol, ziprasidone, zolpidem);

◇ Anti-seizure agents (lubeluzole, lubeluzole oxide, riluzole, aptiganel, eliprodil, remacemide);
◇ Antitussives (dextromethorphan, leevodropropizine);
◇ Antiviral agents (acyclovir, ganciclovir, lobiride, chibirapin (tivirapine), zidovudine, lamivudine, zidovudine + lamivudine, didanosine, zalcitabine, stavudine, abacavir (aba), abacavir 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);
◇ fungicide (chlorhexidine);
◇ Diuretics (acetazolamide, frusemide, hydrochlorothiazide, isosorbide);
◇ Enzyme;
◇ From essential oils (Anethole, Anise oil, Caraway, Cardamom, Cassia oil, Cineol, Cinnamon oil, Clove oil, Coriander oil, Dementholised mint oil, Dill oil, Eucalyptus oil, Eugenol, Ginger, Lemon oil Coconut 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 Sulfasalazine);

◇ 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, subcomeline, abcomerine (Talsaclidine), xanomeline, memantine, lazabemide);

◇ Peptides and proteins (antibodies, becaplermine, cyclosporine, erythropoietin, immunoglobulin, insulin);
◇ Sex hormone (follicular hormone: conjugated follicular hormone, ethinyl estradiol, mestranol, estradiol, estriol, estrone; progesterone; chromadine acetate, cyproten acetate, 17-deacetyl norgestimate, desogestrel, dienogest, Didrogesterone, etynodiol diacetate, gestodene, 3-keto desogestrel, levonorgestrel, linestrenol, methoxyprogesterone acetate, megesterol, norethindrone, norethindrone acetate, norethisterone acetate, norethisterone acetate Norethinodrel, Norgestimate, Norgestrel, Norgestrienone, Pregest Gesuteron, acetate Kin Guess methanol);

◇ Stimulant (sildenafil);
Vasodilators (amlodipine, buflomedil, amyl nitrite, diltiazem, dipyridamole, glyceryl trinitrate, isosorbide dinitrate, ridofurazine, molsidomine, nisardipine, nifedipine, oxpentifylline, pentaerythritol trinitrate );
, Their N-oxides, their pharmaceutically acceptable acid or base addition salts and their stereochemical isomers.

  In addition to the active ingredient, solid preparations may contain other components such as disintegrants, binders, fluidizers, lubricants, corrigents, fragrances, colorants, and sweeteners as necessary. It is. 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, gluconannan, 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 that is excellent in compression moldability, it is possible to tablet with low compression pressure, so that it is possible to maintain the activity of the active ingredient that is inactivated by compression pressure. Therefore, tableting of bulky active ingredients and tableting of drugs containing many kinds of active ingredients is possible, and there are advantages such as miniaturization in some cases, excellent liquid component supportability, and suppression of tableting troubles. is there. As the crystalline cellulose that is commercially available and excellent in compression moldability, “Theolas” KG-801, KG-802 (manufactured by Asahi Kasei Chemicals Corporation) and the like can be used.

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

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

  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 selected from the above can be used alone. Even if it uses, it is also free to use 2 or more types together.

  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. However, it is also free to use two or more kinds in combination.

  Examples of the colorant include food colors such as Food Red No. 3, Food Yellow No. 5, Food Blue No. 1, etc., copper chlorofin sodium, titanium oxide, riboflavin, and the like. Even if it uses 2 or more types together, it is also free.

  Examples of the sweetening agent include aspartame, saccharin, dipotassium gilicyrrhizinate, stevia, maltose, maltitol, starch syrup, and amateur powder. Even if one kind selected from the above is used alone, two or more kinds can be used. They can also be used together.

  The solid preparation of the present invention can be produced using a method for producing a solid preparation usually performed in the pharmaceutical field. For example, the active ingredient, a specific processed starch, and a fatty acid metal salt are mixed with components such as a binder, a disintegrant, a fluidizing agent, a corrigent, a flavoring agent, a coloring agent, and a sweetening agent as necessary, and these are mixed uniformly. A direct powder compression method can be used in which tableting is performed. In other examples, wet granulation or dry granulation of active ingredients and specific processed starch, fatty acid metal salts, binders, disintegrants, fluidizers, corrigents, flavors, colorants, sweeteners, etc. In addition, if necessary, wet granulation is performed by adding a specific processed starch, fatty acid metal salt, binder, disintegrant, fluidizing agent, flavoring agent, flavoring agent, coloring agent, sweetening agent and the like to the obtained granules. It can be produced by a tableting method or a dry granulation tableting method.

  Alternatively, the active ingredient is solid at room temperature but becomes liquid at 40 ° C. or higher, for example, a fat-soluble substance such as carnauba wax, hydrogenated castor oil, or polyglycerin, or a hydrophilic polymer such as polyethylene glycol 6000 at 40 ° C. It is also possible to use a method in which the mixture is mixed so as to be uniform under the above temperature conditions and then cooled to form a solid and, if necessary, subjected to a pulverization process or the like to adjust the particle size and then compression molding. Furthermore, a solution was obtained using a solvent in which both the active ingredient and the specific processed starch were dissolved, or a uniform dispersion was obtained using an appropriate solvent, and the solution or dispersion was dried by a conventional method. It can also be produced by a method in which a fatty acid metal salt is mixed with a uniform dispersion of an active ingredient and a specific processed starch and compression molded. The solvent is selected from organic solvents such as methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, diethyl ether, ethyl acetate, n-butyl acetate, acetone, dioxane, toluene, cyclohexanone, cyclohexane, benzene, and water. One or more can be used.

  Examples of the compression molding machine used for compression molding a solid preparation include, for example, a rotary press machine such as a static pressure press machine, a briquetting roller type press machine, and a smooth roller type press machine, a single punch tableting machine, and a rotary machine. A tableting machine etc. can be mentioned.

  In addition, solid preparations may be coated for the purpose of controlling the dissolution of active ingredients, masking taste, preventing moisture, etc., but have complex structures and manufacturing processes such as multilayer solid preparations and nucleated solid preparations. Accurate multi-stage production that can be produced simply by compressing and molding uniform prescription powder without taking effect, and is not affected by the in vivo environment such as ionic strength and pH, and the compressive force during compression molding It can be used as long as it does not inhibit the effect of the present invention that elution is possible.

  Examples of the coating agent include cellulose-based coating agents (ethyl cellulose, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate, etc.), acrylic polymer coating agents ( Eudragit RS, Eudragit L, Eudragit NE, etc.), shellac, silicon resin and the like can be used. These coating agents may be used by dissolving the coating agent in an organic solvent or suspending it in water, and may be used by a known method of use.

  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, any test using Mcilvine solution (pH 7.2, ionic strength 0.39, composition: disodium hydrogen phosphate 173.9 mM, citric acid 13.0 mM, “second solution” may be abbreviated) The test is carried out under the conditions of 900 cm ^{3 of} solution, 100 rpm of basket rotation speed, and 37 ± 0.5 ° C. test solution temperature. In addition, 90 mg of α-amylase preparation (composition: α-amylase / calcium carbonate / corn starch = 5/5/90, AD “Amano” 1, Amano Enzyme Inc.) was added to each test solution, and the α-amylase content was determined. 5 μg / cm ³ .
(2) Particle size distribution Number of particles smaller than 32 μm

Using a JIS sieve opening of 32 μm, when 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.
(3) Particle size distribution Number of particles smaller than 75 μm

Using a JIS sieve opening of 75 μm, when 10 g of a measurement sample is sieved with an air jet sieve for 5 minutes, it is obtained from the weight percentage of the measurement sample that has passed through the sieve.
(4) Water retention amount

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

A cylindrical shaped body 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 / manufactured by Aiko Engineering Co., Ltd.) It is defined as the disintegration time in the test solution. The test solution is the second solution (pH 6.8) described in the 14th revised Japanese pharmacopoeia, and the disintegration test is performed using an auxiliary panel according to the disintegration test method of the 14th revised Japanese pharmacopoeia.
(6) Gel indentation load (g)

A cylindrical shaped 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 CREP / manufactured by Aiko Engineering Co., Ltd.) 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 defined as the maximum load at the time. The maximum load is the maximum load value at the time of breaking if the gel layer is broken, or the maximum load value until the adapter enters 5 mm into the gelled cylindrical molded body if there is no breaking. Calculate with an average value of five.
(7) Water-soluble component amount (%)

To 1 g of processed starch, add 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 15 minutes at 5000 G Centrifugation, 30 cm ³ of this supernatant is put into a weighing bottle, dried at 110 ° C. to a constant weight, and the dry weight (g) is measured. 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)
(8) Swelling degree of processed starch (cm ³ / g)

1.0 g of processed starch is dispersed in pure water at 20 ± 5 ° C. and transferred to a 100 cm ³ sedimentation tube. The total amount is 100 cm ^3, and after standing for 16 hours, the volume V (cm ³ ) of the lower layer divided into upper and lower parts The dry weight (g) of 1.0 g of the modified starch is measured and calculated from the following formula (D).

Swelling degree of processed starch (cm ³ / g) = V / dry weight of processed starch (D)
(9) Gel indentation load under warm storage conditions (g)

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

Potato starch was filled in a stainless bat (50 cm x 25 cm) with a layer thickness of 5 cm, decompressed in a pressure vessel for 5 minutes (600 mmHg), then treated with pressurized steam (120 ° C) for 20 minutes, and the raw material was solid. A starch emulsion having a partial concentration of 7.5% was prepared. This starch emulsion was heated and gelatinized at 20 L / hr with a jet cooker (exit temperature 100 ° C.), continuously passed through a residence tube (100 ° C.) of a 3 L container, and then spray-dried to obtain processed starch C. The basic physical properties of the modified starch C are shown in Table 2 (corresponding to Example 6 of Patent Document 2). Further, the processed starch C was fractionated for each particle size of 150 to 500 μm, 75 to 150 μm, 32 to 75 μm, and 0 to 32 μm, and the degree of swelling of the processed starch C and the gel indentation load value under warm storage conditions were measured. Are shown in Table 1. Further, under conditions for measuring the degree of swelling of the processed starch, the swelling state of the processed starch after standing for 16 hours was observed with an optical microscope after uniformly redispersing the upper and lower layers, and is shown in FIGS.
[Example 1]

  Potato starch was filled in a stainless bat (50 cm × 25 cm) with a layer thickness of 5 cm, and after being depressurized (600 mmHg) for 5 minutes in a pressure-resistant container, wet-heat treated with pressurized steam (120 ° C.) for 20 minutes as a raw material, A starch emulsion having a solid content of 7.5% was prepared. This starch emulsion is heated with a jet cooker at 20 L / hr, gelatinized (outlet temperature 100 ° C.), spray-dried, and then pulverized and classified using a pin-type mill with a built-in classifier to obtain processed starch A It was. Table 2 shows the basic physical properties of the modified starch A. 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 with an optical microscope after uniformly redispersing the upper and lower layers, and is shown in FIGS.

  The obtained modified starch A, crystalline cellulose ("Theorus" KG-802, manufactured by Asahi Kasei Chemicals Co., Ltd.), polyethylene glycol (Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.), and acetaminophen as an active ingredient ( API Corporation) and magnesium stearate (made by Taihei Chemical Sangyo Co., Ltd.), which is a fatty acid metal salt, are uniformly mixed so that the weight ratio is 50/30/10/10 / 0.3. It was compressed at a pressure of 120 MPa using a static pressure press (MODEL-1321DW CREP / manufactured by Aiko Engineering Co., Ltd.) to obtain a solid preparation having a diameter of 0.8 cm and a weight of 0.30 g. Further, a solid preparation having a diameter of 0.8 cm and a weight of 0.30 g was obtained in the same manner except that the molding pressure was changed to 300 MPa.

Test in which α-amylase was added to a second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia so as to be 5 μm / cm ³ using a solid preparation obtained at a compression molding pressure of 120 MPa. The dissolution test was performed using the solution. In addition, the elution test was performed in the same manner except that the test solution was changed from the second solution to the Mcilvine solution (pH 7.2, ionic strength 0.40). Furthermore, using a solid preparation obtained at a compression molding pressure of 300 MPa, a dissolution test was conducted using a solution obtained by adding α-amylase to the second solution described in the Japanese Pharmacopoeia to 5 μm / cm ³ as a test solution. It was. The results are shown in FIG. (FIG. 7 also shows the results of the dissolution test of Comparative Example 1 described later.)

It can be seen that the sustained-release solid preparation containing an elution control base composed of modified starch A and magnesium stearate can control the elution in two stages. In addition, the solid preparation showed stable dissolution without fluctuation in dissolution rate due to ionic strength or compression molding pressure.
[Comparative Example 1]

A tablet having a diameter of 0.8 cm and a weight of 0.30 g, which was compression-molded at 120 MPa, was obtained in the same manner as in Example 1 except that magnesium stearate was not contained. 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 μm / cm ^3, and a dissolution test was conducted. This is shown in FIG. 7 together with the result of Example 1. As a result, sustained release was controlled only in one stage.
[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 2). Table 2 shows the basic physical properties of the modified starch B.

Next, a tablet having a diameter of 0.8 cm and a weight of 0.30 g, which was compression-molded at 120 MPa, was obtained in the same manner as in Example 1 except that this modified starch B was used in place of the modified starch A. Using the second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia, α-amylase was added to the obtained tablet so as to be 5 μm / cm ^3, and a dissolution test was conducted. This is shown in FIG.

The sustained-release tablet using modified starch B was able to control dissolution in two stages by containing magnesium stearate, but the second stage dissolution start time fluctuated greatly depending on the compression molding pressure. I have.
[Example 2]

A solid preparation having a diameter of 0.8 cm and a weight of 0.30 g, which was compression-molded at 120 MPa, was obtained in the same manner as in Example 1 except that the composition ratio of magnesium stearate was changed from 0.3 to 0.1. Using the second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia, the resulting solid preparation was added with α-amylase to 5 μm / cm ³ and subjected to a dissolution test. 9 is shown in FIG. 9 together with the results of the same test solution at the same compression pressure in Examples 1, 3, and 4.

The sustained-release solid preparation using modified starch A has a relationship between the magnesium stearate content and the second stage elution start time, and the second stage elution start time increases as the magnesium stearate content increases. Became faster.
[Example 3]

A solid preparation having a diameter of 0.8 cm and a weight of 0.30 g, which was compression-molded at 120 MPa, was obtained in the same manner as in Example 1 except that the composition ratio of magnesium stearate was changed from 0.3 to 1.0. Using the second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia, the resulting solid preparation was added with α-amylase to 5 μm / cm ³ and subjected to a dissolution test. Is shown in FIG. 9 together with the results of Examples 1, 2, and 4. The elution start time of the second stage was earlier than that of Example 2.
[Example 4]

According to the same method as in Example 1 except that the composition ratio of magnesium stearate was changed from 0.3 to 5.0, a solid preparation having a diameter of 0.8 cm and a weight of 0.30 g, which was compression-molded at 120 MPa, was obtained. Using the second liquid (pH 6.8, ionic strength 0.14) described in the Japanese Pharmacopoeia, the resulting solid preparation was added with α-amylase to 5 μm / cm ³ and subjected to a dissolution test. Is shown in FIG. 9 together with the results of Examples 1 to 3. The elution start time of the second stage was earlier than that of Example 3.
[Comparative Example 3]

  In place of the modified starch A obtained in Production Example 1, hydroxypropylcellulose (Metroise 90SH-100SR, manufactured by Shin-Etsu Chemical Co., Ltd.) was used in the same manner as in Example 1, except that the diameter was 0. A tablet of 8 cm and a weight of 0.30 g was obtained. The obtained tablets were subjected to a dissolution test in the same manner as in Example 1, and the results are shown in FIG.

The sustained-release tablet using hydroxypropyl cellulose hardly changed the dissolution rate even when magnesium stearate was contained, and the dissolution could not be controlled in two stages. Moreover, in the sustained release tablet using hydroxypropylcellulose, in the Mcilvine solution having an ionic strength of 0.40, the disintegration of the tablet started immediately after the start of the test, and the entire amount of acetaminophen was eluted.
[Comparative Example 4]
A tablet was prepared in the same manner as in Comparative Example 1 except that hydroxypropylcellulose (Metroise 90SH-100SR, manufactured by Shin-Etsu Chemical Co., Ltd.) was used instead of the modified starch A obtained in Example 1, and the dissolution test was performed. went. The results of the dissolution test are shown in FIG. 10 together with the results of Comparative Example 3. No multi-stage elution occurred regardless of the presence or absence of magnesium stearate.

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. It is the graph which showed the elution test result of Examples 1-4. It is the graph which showed the dissolution test result of the comparative examples 3 and 4.

Claims (2)

A sustained-release solid preparation containing one or more pharmaceutical medicinal ingredients and an elution control base for controlling the elution of the medicinal medicinal ingredients, wherein the dissolution control base has a water retention amount of 400% or more. In addition, when the gel indentation load is 200 g or more, the amount of water-soluble components is 40 to 95%, the particles passing through a sieve having an opening of 75 μm are 90% by weight or more, and the particles passing through a sieve having an opening of 32 μm are 20% by weight or more. multistage controlled release solid preparation which is characterized in that the modified starch 50.0 to 99.9 wt%, is intended to include a metal salt 0.01-20 wt% of the stearate is.   The solid preparation according to claim 1, wherein the medicinal medicinal ingredient has solubility in water equal to or higher than that of acetaminophen.