JP5112619B2 - Solid pharmaceutical formulation - Google Patents

Description

  The present invention relates to solid pharmaceutical formulations. More specifically, the present invention relates to a solid pharmaceutical preparation having a high physical strength and excellent in drug release characteristics after administration and digestibility of excipients. Moreover, this invention relates to the manufacturing method of the said solid pharmaceutical formulation.

  In general, excipients are blended in solid pharmaceutical preparations, thereby improving drug ease of use, formulation moldability, and the like (for example, see Patent Document 1). Conventionally, starch is widely used as an excipient for solid preparations. In addition to being excellent in stability and safety, starch is used as an excipient for extruded granulated granules, which improves the plasticity of the granulated product by water retention and allows it to be used as an extrusion granulator screen. There is an advantage that the granulation process is facilitated.

  On the other hand, since starch has the physical characteristic that particles are round and hard in a dry state, when starch is used as an excipient for a solid preparation, there is a drawback that the strength of the solid preparation is reduced. The decrease in formulation strength of the solid formulation easily causes formulation breakage during the manufacturing process, and this causes a decrease in yield and efficiency of the packaging process. There is a need for improved formulation strength.

  Furthermore, solid preparations formulated with starch as an excipient may not be sufficient in terms of drug release characteristics after taking, and formulation measures are taken so that the drug is released more quickly in the digestive tract. Is required.

By the way, pregelatinized starch has a characteristic of becoming a paste when mixed with water, and is used by being incorporated in a small amount as a binder in a solid preparation by utilizing such characteristics. This pregelatinized starch is excellent in digestibility in the digestive tract as compared with starch, and is digested in the digestive tract, so that it is a suitable component to be blended in a pharmaceutical preparation. However, when a large amount of pregelatinized starch is blended as an excipient for a solid preparation, the mixture becomes paste-like during wet granulation, making it difficult to formulate. Moreover, even if the paste-like mixture of pregelatinized starch and drug is dried, it becomes a hard lump, and it is difficult to pulverize this lump and formulate it. As described above, there is no known technique for producing a formulation by hydro-granulation using pregelatinized starch, and a pharmaceutical formulation containing pregelatinized starch in a proportion of about 10% by weight or more and having a desired strength is produced. Currently, no technology has been established.
JP-A-11-286456

  The object of the present invention is to solve the problems of pharmaceutical preparations containing starch as an excipient. Specifically, an object of the present invention is to provide a solid pharmaceutical preparation that uses inexpensive and safe starch as a raw material, has high physical strength of the preparation, and has excellent drug release characteristics after administration. Another object of the present invention is to provide a method for producing a solid pharmaceutical preparation containing pregelatinized starch as an excipient.

  The inventors of the present invention have intensively studied to solve the above-mentioned problems. As a result, the solid pharmaceutical preparation obtained by mixing the drug and starch or by gelatinizing after mixing and molding has a physical strength of the preparation. It was found to be high and excellent in drug release characteristics after taking and digestibility of excipients. The present invention has been completed by further studies based on this finding.

That is, the present invention is a solid pharmaceutical preparation listed below:
Item 1. A solid pharmaceutical preparation comprising (a) a drug and (b) 10 to 90% by weight of pregelatinized starch.
Item 2. Item 3. The solid pharmaceutical preparation according to Item 1, obtained by a production method including the following steps (i) and (ii):
(i) preparing a raw material composition containing a drug and starch; and
(ii) a step of pregelatinizing the starch in the raw material composition;
Item 3. Item 3. The solid pharmaceutical preparation according to Item 2, wherein the raw material composition prepared in step (i) further contains crystalline cellulose and is formed by extrusion granulation.
Item 4. Item 4. The solid pharmaceutical preparation according to any one of Items 1 to 3, wherein the starch is corn starch.
Item 5. Item 5. The solid pharmaceutical preparation according to any one of Items 1 to 4, which is a granule or a powder.
Item 6. Item 6. The solid pharmaceutical preparation according to any one of Items 1 to 5, which is a sustained-release preparation.
Item 7. Item 7. The solid pharmaceutical preparation according to any one of Items 1 to 6, wherein the drug is poorly water-soluble.
Item 8. Item 8. The solid pharmaceutical preparation according to any one of Items 1 to 7, wherein the drug is classified into class II by a biopharmaceutical classification system.
Item 9. Item 9. The solid pharmaceutical preparation according to any one of Items 1 to 8, wherein the drug is cilostazol.
Item 10. Solid pharmaceutical preparation obtained by the production method including the following steps (i) and (ii):
(i) preparing a raw material composition containing a drug and starch; and
(ii) a step of pregelatinizing the starch in the raw material composition;
Item 11. Item 11. The solid pharmaceutical preparation according to Item 10, comprising pregelatinized starch in a proportion of 10 to 90% by weight.
Item 12. Item 12. The solid pharmaceutical preparation according to Item 10 or 11, wherein the raw material composition prepared in step (i) further contains crystalline cellulose and is formed by extrusion granulation.
Item 13. Item 13. The solid pharmaceutical preparation according to any one of Items 10 to 12, wherein the starch is corn starch.
Item 14. Item 14. The solid pharmaceutical preparation according to any one of Items 10 to 13, which is a granule or a powder.
Item 15. Item 15. The solid pharmaceutical preparation according to any one of Items 10 to 14, which is a sustained-release preparation.
Item 16. Item 16. The solid pharmaceutical preparation according to any one of Items 10 to 15, wherein the drug is poorly water-soluble.
Item 17. Item 18. The solid pharmaceutical preparation according to any one of Items 10 to 16, wherein the drug is classified into class II by a biopharmaceutical classification system.
Item 18. Item 18. The solid pharmaceutical preparation according to any one of Items 10 to 17, wherein the drug is cilostazol.

Furthermore, the present invention is a method for producing a solid pharmaceutical preparation listed below:
Item 19. A method for producing a solid pharmaceutical preparation comprising the following steps (i) and (ii):
(i) preparing a raw material composition containing a drug and starch; and
(ii) a step of pregelatinizing the starch in the raw material composition;
Item 20. Item 20. The production method according to Item 19, further comprising (iii) a drying step after step (ii).
Item 21. Item 21. The production method according to Item 19 or 20, wherein the step (i) is a step of preparing a raw material composition containing a drug, starch and crystalline cellulose and molded by extrusion granulation.
Item 22. Item 22. The production method according to any one of Items 19 to 21, wherein the solid pharmaceutical preparation contains 10 to 90% by weight of pregelatinized starch.
Item 23. Item 23. The method according to any one of Items 19 to 22, wherein the starch is corn starch.
Item 24. Item 24. The method according to any one of Items 19 to 23, wherein the solid pharmaceutical preparation is a granule or a powder.
Item 25. Item 25. The method according to any one of Items 19 to 24, wherein the solid pharmaceutical preparation is a sustained-release preparation.
Item 26. Item 26. The method according to any one of Items 19 to 25, wherein the drug is poorly water-soluble.
Item 27. Item 27. The production method according to any one of Items 19 to 26, wherein the drug is classified into class II by a biopharmaceutical classification system.
Item 28. Item 28. The method according to any one of Items 19 to 27, wherein the drug is cilostazol.

The present invention will be described in detail.
Solid pharmaceutical preparation The solid pharmaceutical preparation of the present invention comprises (a) a drug and (b) pregelatinized starch.

  The solid pharmaceutical preparation of the present invention contains pregelatinized starch in a proportion of usually 10 to 90% by weight, preferably 20 to 80% by weight, more preferably 30 to 70% by weight, based on the total weight of the preparation. By containing pregelatinized starch in such a ratio, the solid pharmaceutical preparation can be provided with the characteristics that the preparation strength is high and the drug is released in a continuous and efficient manner in the digestive tract after administration.

  The pregelatinized starch used in the present invention is not particularly limited as to its origin. Examples of pregelatinized starch include those obtained by pregelatinizing starch such as corn starch, wheat starch, potato starch, rice starch, cassava starch, and tapioca starch. These pregelatinized starches may be used alone or in any combination of two or more. The pregelatinized starch used in the present invention may be a partially pregelatinized starch.

  Among these pregelatinized starches, preferably pregelatinized corn starch, pregelatinized potato starch, and pregelatinized wheat starch. Since corn starch has a particle size of 10 to 30 μm, it is easy to mold, easy to handle after pregelatinization, and has low hygroscopicity compared to other starches. Particularly preferred is pregelatinized starch.

  In addition, as long as the drug used in the solid pharmaceutical preparation of the present invention is orally administrable, its medicinal effect and its type are not particularly limited, and any of a readily water-soluble drug or a poorly water-soluble drug can be used. May be. Examples of drugs include respiratory preparations, digestive organ preparations, cardiovascular preparations, central nervous system preparations, peripheral nerve preparations, antibiotic preparations, chemotherapeutic agents, antitumor agents, platelet aggregation inhibitors, antiallergic agents In addition, there can be mentioned ordinary drugs that are blended in various preparations such as vitamins and nutrients. The drug is preferably a poorly water-soluble drug. In addition, as the drug, “Waiver of in Vivo Bioavailability and Bioequivalents Studies for Immediate Release Solids Dosage Forms Containing Certain Active Moieties / Active Ingredients Based on Biopharmaceutics Classification System (FDA guidance)” (referred to herein as “Biopharmaceutical Classics”). In some cases, drugs classified as Class II (High Permeability, Low Solubility) can be used preferably. In this way, drugs that are sparingly soluble in water, when formulated as sustained-release preparations, have the property of releasing the drug continuously and effectively in the digestive tract, and are sufficient after taking. Can exhibit medicinal effects.

  In the present invention, drugs may be used alone or in any combination of two or more.

  Specific examples of the drug used in the solid pharmaceutical preparation of the present invention include, for example, theophylline, grepafloxacin, carteolol, procaterol, rebamipide, aripiprazole, cilostazol, acetaminophen, nifedipine, ketoprofen, naproxen, diclofenac, itraconazole, piroxicam , Phenytoin, verapamil and the like. In the present invention, these drugs may be used alone or in any combination of two or more. Among these drugs, preferably cilostazol, ketoprofen, naproxen, diclofenac, itraconazole, piroxicam, phenytoin, verapamil, and more preferably cilostazol. These drugs are particularly useful when a sustained-release preparation is used.

  The mixing ratio of the drug in the solid pharmaceutical preparation varies depending on the type and efficacy of the drug to be used, the sex and age of the administration subject, and is, for example, 0 with respect to the total amount (dry weight) of the composition. 0.01 to 60% by weight, preferably 0.1 to 50% by weight, and more preferably 1 to 50% by weight.

  In addition, solid pharmaceutical preparations are limited to other excipients, binders, pH adjusters, disintegrating agents, absorption promoters, lubricants, coloring agents, flavoring agents, and flavors, as long as they do not interfere with the effects of the present invention. An appropriate amount of various additives that can be blended in a solid pharmaceutical preparation such as the above can be contained.

  Specific examples of such additives include lactose, sucrose, mannitol, sodium chloride, glucose, calcium carbonate, kaolin, crystalline cellulose, silicate and other excipients; water, ethanol, simple syrup, glucose solution, starch solution , Gelatin solution, carboxymethylcellulose, carboxymethylcellulose Na, shellac, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinylalcohol, gelatin, dextrin, pullulan, etc .; citric acid, anhydrous citric acid, sodium citrate, PH adjusters such as sodium citrate dihydrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, sodium hydrogen phosphate; carmellose calcium, low-substituted hydroxypropyl acetate Disintegrants such as loin, carmellose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone; plasticizers such as polysorbate 80; absorption promoters such as quaternary ammonium base and sodium lauryl sulfate; purified talc, stearate, Lubricants such as polyethylene glycol, colloidal silicic acid, sucrose fatty acids; yellow iron oxide, yellow iron sesquioxide, iron sesquioxide, β-carotene, titanium oxide, food coloring (eg food blue No. 1 etc.), copper Examples include coloring agents such as chlorophyll and riboflavin; and flavoring agents such as ascorbic acid, aspartame, amateur, sodium chloride, fructose, saccharin, and powdered sugar.

  The solid pharmaceutical preparation of the present invention can take any solid form such as powder, powder, granule, tablet and the like. The solid pharmaceutical preparation of the present invention may be in the form of a coating preparation or a capsule. Of the various forms of the solid pharmaceutical preparation of the present invention, examples of preferred forms include granules and powders.

  In particular, when a granular form is used, it is desirable to incorporate crystalline cellulose in the solid pharmaceutical preparation. By blending crystalline cellulose, it becomes easy to spheroidize by spherical sizing, and an advantage that a granular preparation can be easily formed by extrusion granulation is obtained. In addition, the spheroidization has the advantage that the filling properties into capsules and the like are improved and the coating efficiency is improved. Thus, when crystalline cellulose is blended in a solid pharmaceutical preparation, the blending ratio of the crystalline cellulose is, for example, 5 to 90% by weight, preferably 10 to 80% by weight, further based on the total weight of the pharmaceutical preparation. Preferably 20 to 70 weight% is mentioned.

  In addition to being able to gradually elute the drug in the gastrointestinal tract, the solid pharmaceutical preparation of the present invention can efficiently release the drug by digestion and disintegration of the preparation itself by amylase in the small intestine. There is an advantage that it can be released sufficiently in the lower digestive tract. As described above, the solid pharmaceutical preparation of the present invention contains pregelatinized starch in the above-mentioned ratio, so that the drug is continuously released in the digestive tract after taking and the drug is efficiently released in the digestive tract. Since it has both characteristics, it is useful as a sustained-release preparation. That is, the solid pharmaceutical preparation of the present invention has the disadvantages of a normal sustained-release preparation, that is, the drug is designed to elute gradually, so that the lower gastrointestinal tract with less water (digestive fluid) to dissolve ( Since the drug is difficult to elute in the small intestine and later), the disadvantage that the compounded drug is discharged out of the body without being sufficiently dissolved and released has been eliminated.

Production Method The solid pharmaceutical preparation of the present invention is produced by pregelatinizing a composition containing a drug and starch (hereinafter referred to as a raw material composition). Specifically, the solid pharmaceutical preparation is produced through the following steps (i) and (ii).
(i) preparing a raw material composition containing a drug and starch; and
(ii) a step of pregelatinizing the starch in the raw material composition;

  The components contained in the raw material composition prepared in step (i) above are directly contained in the solid pharmaceutical preparation of the present invention except that starch is converted to pregelatinized starch. Therefore, in step (i), the ratio of the drug compounded in the solid pharmaceutical preparation of the present invention, starch used as a raw material for pregelatinized starch, and optional components (various additives) to the respective content ratios in the solid pharmaceutical preparation To prepare a raw material composition.

  The raw material composition preferably further contains water in addition to the above components. When water is included, the content of water in the raw material composition is not particularly limited, but for example, 30 to 80% by weight, preferably 40 to 80% by weight, and more preferably, based on the total amount of the raw material composition Preferably 40 to 70 weight% is illustrated. By containing water at such a ratio, the raw material composition can be easily molded, and further, the starch can be efficiently gelatinized in the next step.

  The form of the raw material composition may be any solid form such as powder, powder, granule, tablet and the like. The form of the raw material composition is retained even after the pregelatinization described later, and can be used as it is in the form of the solid pharmaceutical preparation of the present invention (pregelatinized starch-containing solid pharmaceutical preparation). It is desirable to adjust (mold) appropriately so as to correspond to the form to be performed.

  The method for preparing the form of the raw material composition is not particularly limited. As described above, if the solid pharmaceutical preparation of the present invention is granulated, in the step (i), the raw material composition is blended with crystalline cellulose so as to have the above ratio, and the raw material is formed by extrusion granulation. It is desirable to form the composition into granules.

  The raw material composition is subjected to the above step (ii) to gelatinize the starch in the raw material composition. The pregelatinization can be performed by a usual method used for pregelatinization of starch. For example, if the raw material composition contains water, the raw material composition may be heat-treated. For the heat treatment, known heat treatment means such as steam heat treatment, dry heat treatment, high-frequency dielectric heat treatment, microwave heat treatment and the like can be used. The heating temperature varies depending on the heat treatment means and the type of starch, but can usually be set to 75 to 100 ° C, preferably 80 to 100 ° C. The heating time can be appropriately set according to the heat treatment means. In addition, for example, if the raw material composition does not contain water, the raw material composition is subjected to steam heat treatment (for example, water is sprayed after spraying, steam microwave treatment, heat treatment using heated steam). Etc.), the starch in the raw material composition can be gelatinized. The conditions for the steam heat treatment are the same as described above.

  In particular, a granular raw material composition containing crystalline cellulose and formed by extrusion granulation has a uniform (high sphericity) spherical shape, and is therefore suitable for microwave heat treatment. . Normally, when a microwave raw material composition having a concavo-convex surface is subjected to microwave heat treatment, it is heated from the convex portions on the surface of the raw material composition, thereby causing moisture to evaporate from the surface and increasing the α conversion efficiency. It will decline. On the other hand, when microwave heat treatment is performed on a spherical raw material composition having a high degree of sphericity, the raw material composition is heated from the inside, so there is little evaporation of moisture from the surface, and during the heat treatment Since moisture is retained, efficient alpha conversion is possible.

  Thus, a preparation containing pregelatinized starch can be obtained by pregelatinizing starch in the raw material composition. Since the preparation obtained by performing the pregelatinization contains moisture, it is desirable to remove the moisture by subjecting it to a drying process. Drying can be performed according to a conventional method. For example, the drying temperature may be set to 50 to 90 ° C., preferably 60 to 80 ° C., and the drying time may be appropriately set according to the dosage form of the preparation, the drying temperature, and the like.

  The solid pharmaceutical preparation of the present invention may be a preparation (preparation after pregelatinization) itself obtained by subjecting it to the above steps (i), (ii) and, if necessary, a drying treatment, or as necessary. Accordingly, the pregelatinized preparation may be further processed by subjecting it to a known preparation step.

  For example, the solid pharmaceutical preparation of the present invention can be made into a tablet form by further tableting the granular preparation obtained by the pregelatinization treatment. Moreover, the solid pharmaceutical formulation of this invention can be made into the form of a coating formulation by coating the formulation after gelatinization processing, or the thing which shape-processed this. Moreover, the solid pharmaceutical formulation of this invention can also be made into the form of a capsule by accommodating the formulation after gelatinization processing, or the thing which shape-processed this in a capsule.

  The solid pharmaceutical preparation of the present invention has an advantage that it can be easily produced in a high yield since the physical strength of the preparation is high and the preparation is less likely to break or collapse during the production.

  In addition, the solid pharmaceutical preparation of the present invention has the property of releasing the drug continuously and efficiently in the digestive tract when taken, even though the physical strength of the preparation is high. It is excellent in that it can exhibit medicinal effects.

  Furthermore, since the solid pharmaceutical preparation of the present invention uses pregelatinized starch that is decomposed by the action of amylase in the digestive tract as an excipient, it is excellent in terms of digestibility.

  In addition, according to the production method of the present invention, a solid preparation containing pregelatinized starch as an excipient can be easily prepared, and a novel solid pharmaceutical preparation that has been difficult with conventional production methods can be provided.

  Hereinafter, the present invention will be described in detail based on examples, test examples, and the like, but the present invention is not limited thereto.

Example 1
210g of corn starch (trade name “Eclipse Corn Starch”, manufactured by Nippon Shokuhin Kako Co., Ltd.), 30 g of crystalline cellulose (trade name “Avicel PH301”, manufactured by Asahi Kasei Co., Ltd.) and 60 g of cilostazol (manufactured by Otsuka Pharmaceutical Co., Ltd.) are mixed. After being put into (Model No. NSK-150, manufactured by Okada Seiko Co., Ltd.), 160 g of purified water was added and mixed while stirring to prepare a raw material composition (raw material composition example 1). The raw material composition is subjected to extrusion granulation with an extrusion granulator (Dome Gran DG-L1, manufactured by Fuji Powder Co., Ltd.) equipped with a dome die with a diameter of 0.6 mm hole to obtain a hydrous granulated product, and then this hydrous granulation The granules were sized with a spherical sizer (Malmerizer QJ-400, manufactured by Fuji Powder Co., Ltd.) to obtain a water-containing granular raw material composition (raw material composition example 1). Using a steam microwave oven (model number NE-J630, manufactured by Matsushita Electric Industrial Co., Ltd.), the steam-containing raw material composition was steam-heated at 700 W for 6 minutes to make corn starch alpha. Next, the granules after steam heat treatment were dried for 6 hours in an air dryer set at 60 ° C. to obtain a granular solid pharmaceutical preparation (Example 1) containing 20% by weight of cilostazol.

Comparative production example 1
α kneaded corn starch (trade name “Amicol”, manufactured by Nissho Chemical Co., Ltd.) 210 g, crystalline cellulose (trade name “Avicel PH301”, manufactured by Asahi Kasei Co., Ltd.) 30 g, and cilostazol (manufactured by Otsuka Pharmaceutical Co., Ltd.) 60 g are mixed together, and a speed kneader is mixed. After being added to (Model No. NSK-150, manufactured by Okada Seiko Co., Ltd.), 160 g of purified water was added and mixed while stirring. As a result, the mixture became bowl-like in the kneader, and subsequent formulation work could not be performed.

Comparative Example 1
Granules containing 20% by weight of cilostazol by drying for 6 hours in a blow dryer set at 60 ° C. without subjecting to a water-containing granular raw material composition (raw material composition example 1) A solid pharmaceutical preparation (Comparative Example 1) was obtained.

Example 2-11
Starch, crystalline cellulose and drugs shown in Tables 1 and 2 are mixed, put into a speed kneader (model No. NSK-150, manufactured by Okada Seiko Co., Ltd.), mixed with 150 g to 220 g of purified water with stirring, and various raw material compositions A product (raw material composition example 2-11) was prepared. The raw material composition is subjected to extrusion granulation with an extrusion granulator (Dome Gran DG-L1, manufactured by Fuji Powder Co., Ltd.) equipped with a dome die with a diameter of 0.6 mm hole to obtain a hydrous granulated product, and then this hydrous granulation The granules were sized with a spherical sizing machine (Malmerizer QJ-400, manufactured by Fuji Powder Co., Ltd.) to obtain a water-containing granular raw material composition (raw material composition example 2-11). Using a steam microwave oven (model number NE-J630, manufactured by Matsushita Electric Industrial Co., Ltd.), the steam-containing raw material composition was steam-heated at 700 W for 6 minutes to make corn starch alpha. Next, the granules after the steam heat treatment were dried for 6 hours in an air dryer set at 60 ° C. to obtain a granular solid pharmaceutical preparation (Example 2-11).

Comparative Example 2-11
A granular solid medicine is obtained by drying each of the water-containing granular raw material composition (raw material composition example 2-11) for 6 hours in an air dryer set at 60 ° C. without performing pregelatinization. A preparation (Comparative Example 2-11) was obtained. Here, the granular solid pharmaceutical preparation of Comparative Example 2-11 corresponds to that prepared from Raw Material Composition Example 2-11, respectively.

Example 12
Corn starch (trade name “eclipse corn starch”, manufactured by Nippon Shokuhin Kako Co., Ltd.) 210 g, crystalline cellulose (trade name “Avicel PH301”, manufactured by Asahi Kasei Co., Ltd.) 30 g, and cilostazol (manufactured by Otsuka Pharmaceutical Co., Ltd.) 60 g are mixed together, and vertical granule is mixed. After putting into a lator (model number FM-VG-05P, manufactured by Paulek), granulated by adding 160 g of purified water while stirring to obtain hydrous granules (raw material composition example 8). Using a steam microwave oven (model number NE-J630, manufactured by Matsushita Electric Industrial Co., Ltd.), the water-containing granules were subjected to steam heat treatment at 700 W for 6 minutes to gelatinize the corn starch. Next, the granules after steam heat treatment were dried for 6 hours in an air dryer set at 60 ° C. to obtain a granular solid pharmaceutical preparation (Example 12) containing 20% by weight of cilostazol.

Example 13
20 g of the granule produced in Comparative Example 1 was taken and placed on a filter paper containing water having a diameter of about 11 cm, and the surface of the granule was wetted with a spray, and then a steam microwave oven (model number NE-J630, manufactured by Matsushita Electric Industrial Co., Ltd.) Was used for steam heating treatment at 700 W for 3 minutes to pregelatinize the corn starch in the granules. Next, the granules after the steam heat treatment were dried for 6 hours in an air dryer set at 60 ° C. to obtain a granular solid pharmaceutical preparation (Example 13) containing 20% by weight of cilostazol.

Examples 14 and 15
20 g of granules produced in Comparative Examples 3 and 7 were taken and processed in the same manner as in Example 13 to obtain granular solid pharmaceutical preparations (Examples 14 and 15) containing 20% by weight of cilostazol.

Examples 16-23
After mixing various components shown in Table 3 and adding them to a speed kneader (model number NSK-150, manufactured by Okada Seiko Co., Ltd.), 150 g to 220 g of purified water is added and mixed while stirring, and various raw material compositions (raw material composition examples) 16-23) was prepared. The raw material composition is subjected to extrusion granulation with an extrusion granulator (Dome Gran DG-L1, manufactured by Fuji Powder Co., Ltd.) equipped with a dome die with a diameter of 0.6 mm hole to obtain a hydrous granulated product, and then this hydrous granulation The granules were sized with a spherical sizing machine (Malmerizer QJ-400, manufactured by Fuji Powder Co., Ltd.) to obtain a hydrous granular raw material composition (raw material composition examples 16-23). Using a steam microwave oven (model number NE-J630, manufactured by Matsushita Electric Industrial Co., Ltd.), the steam-containing raw material composition was steam-heated at 700 W for 6 minutes to make corn starch alpha. Next, the granules after the steam heat treatment were dried for 6 hours in an air dryer set at 60 ° C. to obtain a granular solid pharmaceutical preparation (Examples 16-23).

Comparative Example 16-23
Granular solid medicine is obtained by drying each of the water-containing granular raw material compositions (raw raw material composition examples 16-23) for 6 hours in an air dryer set at 60 ° C. without performing pregelatinization. A formulation (Comparative Examples 16-23) was obtained. Here, the granular solid pharmaceutical preparations of Comparative Examples 16-23 correspond to those prepared from the raw material composition examples 16-23, respectively.

Test Example 1 Evaluation of Formulation Strength The formulation strength of one particle (particle size: about 0.6 mm) of the granular solid pharmaceutical formulation of Example 1-2 and Comparative Example 1-2 was calculated using Shimadzu Autograph (model number AG-I, Shimadzu). (N = 3). The results are shown in Table 4. In addition, the intensity | strength in a table | surface is a load (N) at the time of adding a load with respect to 1 particle | grains of a formulation, and a formulation (particle) fracture | ruptured. As a result, it is clear that the solid pharmaceutical preparations of Examples 1 and 2 have a preparation strength that is about 2 to 3 times as high as that of Comparative Examples 1 and 2. It turns out that it improves.

Test Example 2 Evaluation of Drug Release Characteristics Using the granular solid pharmaceutical preparations of Examples 3 and 14 and Comparative Example 3, drug release characteristics were evaluated. Specifically, 500 mg granular solid pharmaceutical preparations (Examples 3 and 14 and Comparative Example 3) were used, and 900 mL of 0.3 wt% aqueous sodium lauryl sulfate solution was used as the eluent. The test was conducted by the 2-method paddle method at 50 rpm, and the amount of cilostazol eluted in the eluate was measured over time to determine the ratio (dissolution rate) (%) of cilostazol eluted from the preparation. In this test, assuming the gastrointestinal tract, 0.18 g of amylase (activity 20 units / mg or more, trade name “α-amylase”, manufactured by Wako Pure Chemical Industries, Ltd.) was added to the eluate 4 hours after the start of the test. Added.

  The obtained results are shown in FIG. The preparations of Examples 3 and 14 and Comparative Example 3 showed similar drug dissolution behavior until amylase was added. On the other hand, after the addition of amylase, the drug elution rate significantly increased in the preparations of Examples 3 and 14. On the other hand, in the preparation of Comparative Example 3, even when amylase was added, no change was observed in the drug dissolution rate.

  From the above results, the solid pharmaceutical preparation of the present invention has the property of quickly eluting (releasing) a drug under the action of amylase when it is administered and reaches the digestive tract, particularly the digestive tract after the small intestine. It was confirmed that

Test Example 3 Evaluation of drug release characteristics (2)
Using the granular solid pharmaceutical preparations of Example 9 and Comparative Example 9, the drug release characteristics were evaluated. Specifically, 250 mg of a granular solid pharmaceutical preparation (Example 9 and Comparative Example 9) was used, and 0.09 g of amylase (activity 20 units / mg or more, trade name “α-amylase”, Wako Jun) as an eluent. Using a 0.5% by weight aqueous sodium lauryl sulfate solution (900 mL) containing Yakuhinsha Co., Ltd., the Japanese Pharmacopoeia Dissolution Test Method 2 Method Paddle Method was tested at 50 rpm and eluted in the eluate 4 hours after the start of the test. The amount of phenytoin was measured to determine the proportion (dissolution rate) (%) of phenytoin eluted from the preparation. For comparison, a test was conducted in the same manner as described above except that an eluate containing no amylase was used, and the ratio (elution rate) (%) of phenytoin was obtained.

  The results obtained are shown in Table 5. The elution rate of phenytoin in Comparative Example 9 was the same regardless of whether or not amylase was added to the elution test solution, whereas in Example 9, the elution test solution without amylase had the same value as Comparative Example 9. However, the dissolution rate is remarkably high in the test solution to which amylase is added, and when the solid pharmaceutical preparation of the present invention is administered and reaches the digestive tract, particularly the digestive tract after the small intestine, it receives the action of amylase. It was confirmed that it has the property of quickly eluting (releasing) the drug.

Test Example 4 Pharmacokinetic Evaluation (1)
500 mg of the granule containing 20% cilostazol produced in Example 3 or Comparative Example 3 (100 mg amount as cilostazol) was orally administered to four Beagle dogs on an empty stomach, blood was collected over time, and blood cilostazol concentration was measured. Similarly, commercially available pretal tablets (corresponding to 100 mg as cilostazol, containing crystalline cellulose, corn starch, carmellose calcium, hydroxypropylmethylcellulose, and magnesium stearate) (Comparative Example 13) were orally administered, and blood was collected over time. The blood cilostazol concentration (n = 4) was measured. Separately, 500 mg of the granule containing 20% cilostazol produced in Example 3 (100 mg as cilostazol) was administered to beagle dogs after meals, blood was collected in the same manner, and blood cilostazol concentration (n = 4) was obtained. It was measured. FIG. 2 shows the comparison of the blood concentration transition obtained, and Table 6 shows the calculated pharmacokinetic parameters (mean ± SD).

  From Table 6, in Comparative Example 3, although Cmax was suppressed as compared with Comparative Example 13 (commercially available pretal tablet), AUC was also decreased, and only the release was reduced, whereas In Example 3, AUC∞ was maintained at 94% while suppressing Cmax to 57% as compared with Comparative Example 13 (commercially available pretal tablet), indicating a good sustained release property. In addition, even when Example 3 was administered after meal, the blood concentration remained the same as when administered on an empty stomach, the pharmacokinetic parameters were not significantly changed, and the preparation had little influence on the pharmacokinetics. I can say that.

  As is clear from FIG. 2, in Comparative Example 3, the blood cilostazol concentration after 2 hours was lowered, and it can be said that the drug release in the gastrointestinal tract was clearly insufficient, whereas Example 3 In the gastrointestinal tract, the blood concentration is continuously maintained due to the sustained release of cilostazol.

  As described above, the preparation of the present invention can sufficiently release the drug in the gastrointestinal tract, and in particular for a poorly soluble drug that is insufficiently eluted at a portion of the lower part of the gastrointestinal tract, it is gradually released into the gastrointestinal tract. It was confirmed that the drug can be sufficiently released even after the transfer and is useful for preparation of a sustained-release preparation.

Test Example 5 Pharmacokinetic Evaluation (2)
Instead of the granule containing 20% cilostazol produced in Example 3 or Comparative Example 3, the granule containing 50% cilostazol produced in Example 23 or Comparative Example 23 was used in the same manner as in Test Example 5 above, and the drug was prepared. Kinetics were evaluated. FIG. 3 shows the comparison of the blood concentration transition obtained, and Table 7 shows the calculated pharmacokinetic parameters (mean ± SD).

  As can be seen from Table 7, in Example 23, AUC∞ was maintained at a high rate while suppressing Cmax to 66% as compared with Comparative Example 13 (commercially available pretal tablet), and excellent sustained release characteristics were exhibited. . As is clear from FIG. 3, in Example 23, the blood concentration was continuously maintained due to continuous cilostazol release in the gastrointestinal tract. From the above results, it was confirmed that in this test as well as Test Example 4, the preparation of the present invention can release the drug continuously and efficiently.

It is a figure which shows the elution characteristic of the solid pharmaceutical formulation (Examples 3 and 14 and Comparative Example 3) measured in Test Example 2. It is a figure which shows the time-dependent change of the average blood cilostazol concentration of the solid pharmaceutical formulation (Example 3, Comparative Examples 3 and 13) measured in Test Example 4. It is a figure which shows the time-dependent change of the average blood cilostazol concentration of the solid pharmaceutical formulation (Example 23, Comparative Examples 13 and 23) measured in Test Example 5.

Claims (4)

A sustained-release solid pharmaceutical preparation characterized by containing (a) cilostazol and (b) 10 to 90% by weight of pregelatinized starch and obtained by a production method including the following steps (i) and (ii):
(i) preparing a raw material composition containing cilostazol and starch, and
(ii) A step of gelatinizing the starch in the raw material composition by heat treatment . The sustained-release solid pharmaceutical preparation according to claim 1, wherein the starch is corn starch. The sustained-release solid pharmaceutical preparation according to claim 1 or 2, which is a granule or a powder. A method for producing a sustained-release solid pharmaceutical preparation comprising (a) cilostazol and (b) 10 to 90% by weight of pregelatinized starch, comprising the following steps (i) and (ii):
(i) preparing a raw material composition containing cilostazol and starch, and
(ii) A step of gelatinizing the starch in the raw material composition by heat treatment .

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