JP2011513194A - Orally disintegrating tablets - Google Patents

Abstract

[PROBLEMS] To provide an excellent orally disintegrating tablet for patients to whom cilostazol is applied, particularly elderly patients and patients with dysphagia.
An orally disintegrating tablet comprising cilostazol, mannitol, a saccharide other than mannitol, an inorganic substance, and a disintegrating agent, and an organic excipient and a fluidizing agent.
[Selection figure] None

Description

  The present invention relates to cilostazol orally disintegrating tablets.

Cilostazol is 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril represented by the following formula (1) and exhibits high platelet aggregation inhibitory action. In addition, it has phosphodiesterase inhibitory action, anti-ulcer action, antihypertensive action, anti-inflammatory action, etc., so it is widely used clinically as a therapeutic agent for ischemic symptoms based on chronic arterial occlusion. It is a drug that has been additionally approved for the efficacy and effect of “suppression of recurrence after onset (excluding primary cerebral embolism)” (Patent Document 1). Already, 50 mg of pretal tablets, 100 mg of pretal tablets and 20% of pretal tablets (Otsuka Pharmaceutical Co., Ltd., both registered trademarks) are already on the market.

  In patients using cilostazol, the proportion of elderly people is high due to the indication disease. In general, it is said that the eating and swallowing function decreases with age. In addition, among cerebral infarction patients newly targeted for indication from 2003, it is known that patients exhibiting mild to moderate dysphagia as sequelae of cerebral infarction are known. Medications for these patients should be taken with jelly, pudding, sputum, etc., or with a liquid with a trolley instead of water if the disorder is mild to moderate (water aspiration, occasional aspiration) The actual situation is that it is administered orally with contrivances. It is known that patients with water aspiration and occasional aspiration are able to swallow saliva although it is difficult to drink water.

  The present inventors have previously conducted various studies to develop a novel cilostazol preparation that can be taken without water, and that it can be a preparation that can be disintegrated in the oral cavity by blending mannitol with a powder form. (Patent document 2).

  However, powders and granules have problems such as handling problems at the time of opening and adherence to the oral cavity, and are not always satisfactory for elderly people or patients who have difficulty swallowing. In order to solve such problems, development of an orally disintegrating tablet of cilostazol that can be easily taken without water and can be easily taken at any time has been desired.

  Patent Documents 3 to 5 report compositions containing certain saccharides, disintegrants, and inorganic excipients in specific ratios as compositions suitable for producing intraorally rapidly disintegrating tablets. . Further, Patent Document 6 discloses that by improving these compositions and further adding a lubricant, a disintegration aid, and a binder, a further excellent oral disintegrating tablet can be produced. ing. However, the active ingredients contained in these disclosed fast disintegrating tablets have been tested only with a limited number of compounds, and there are a variety of options for each vehicle composition excipient. In addition, their content was only limited to a certain range. The oral cavity disintegrating tablets of cilostazol can be produced by using these disclosed compositions, or a good oral disintegrating tablet of cilostazol can be prepared, or among various excipient options. It is unclear whether a suitable one can be selected. Actually, it was necessary to conduct a great deal of experimentation, and it was not considered easy to find a good composition from these ranges. In particular, cilostazol is difficult to dissolve in water and includes a factor that requires a large dose of tablets or a large tablet due to its large single dose. There are also problems such as poor taking feeling and it was considered that it was more difficult than the pharmaceutical ingredients actually tried in these documents.

JP 56-49378 A International Publication WO 2007/001086 Japanese Patent No. 3841804 International Publication WO2005 / 037254 International Publication WO2005 / 037319 International Publication No. WO2007 / 029376

  As mentioned above, cilostazol orally disintegrating oral preparations that can disintegrate in the oral cavity and can be taken without water for many patients to whom cilostazol is indicated, especially elderly patients and patients with dysphagia, especially handling Easy tablets were eagerly desired.

  As a result of intensive studies to solve the above problems, the present inventors have found that a tablet having good oral disintegration can be produced by applying cilostazol to the composition described in Patent Document 6. In the composition described in the heading and Patent Document 6, by selecting a specific excipient and its content ratio, it had superior oral disintegration property, formulation characteristics, manufacturing advantages, etc. A cilostazol orally disintegrating tablet was found and the present invention was completed.

  That is, the present invention relates to the following inventions.

  The present invention contains granulated particles in which inorganic substances and disintegrants are uniformly dispersed in a composite particle of cilostazol and two or more saccharides, has a good disintegration property, is excellent in taking feeling, and is sufficient An orally disintegrating tablet having a high hardness is provided.

  The present invention also provides an orally disintegrating tablet containing cilostazol, particles obtained by uniformly dispersing an inorganic substance and a disintegrant in composite particles of two or more saccharides, and a fluidizing agent. The present invention also provides an orally disintegrating tablet further containing an organic excipient.

  Furthermore, the present invention relates to particles obtained by uniformly dispersing cilostazol, two or more kinds of saccharides and an inorganic substance and a disintegrant, a fluidizing agent and an organic excipient, and if desired, a lubricant, sweetener, An orally disintegrating tablet containing one or more additives selected from the group consisting of an agent, a fragrance, a binder, and a colorant is provided.

  The present invention further relates to (1) particles obtained by sufficiently mixing a fluidizing agent with cilostazol, and (2) particles and organic excipients in which an inorganic substance and a disintegrant are uniformly dispersed in composite particles of two or more saccharides. Then, a lubricant and a sweetener are added, (3) after mixing, and (4) an orally disintegrating tablet that is compression-molded by an external lubricant tableting method is provided.

The composition of the preferred orally disintegrating agent of the present invention is:
(1) cilostazol,
(2) A composition in which mannitol and xylitol form composite particles by spray drying, and an inorganic substance and a disintegrant are homogeneously dispersed in the composite particles, and (a) a saccharide comprising a combination of mannitol and xylitol 40 to 90 parts by weight; (b) 1 to 30 parts by weight of an inorganic excipient; (c) 5 to 40 parts by weight of a disintegrant and the total amount of components (a), (b) and (c) A composition comprising components (a) to (c) such that the weight ratio of mannitol to xylitol is 98: 2 to 67:33, and (3) an organic additive. A group consisting of one or more selected from starches and celluloses as a form and one or more selected from hydrous silicon dioxide, light anhydrous silicic acid, and heavy anhydrous silicic acid as a fluidizing agent From At least one component barrel
Containing. More preferably, as the organic excipient, the starch is one or more selected from corn starch, rice starch, potato starch, partially pregelatinized starch, and hydroxypropyl starch, and the cellulose is crystalline cellulose. , One or more selected from carboxymethylcellulose. Most preferably, the starch is corn starch and the cellulose is crystalline cellulose.
Further, the more preferable fluidizing agent is one or more selected from hydrous silicon dioxide, light anhydrous silicic acid, and heavy anhydrous silicic acid, and most preferably hydrous silicon dioxide and / or light anhydrous Silicic acid.

  According to the present invention, for many patients to whom cilostazol is applied, particularly elderly patients and patients with dysphagia, it has rapid disintegration in the oral cavity, has a good feeling of taking, and has excellent hardness. An orally disintegrating tablet can be provided. The cilostazol orally disintegrating tablet provided by the present invention disintegrates rapidly in the oral cavity and has a good feeling of administration, and exhibits dissolution properties equivalent to those of a commercially available cilostazol tablet.

  The orally disintegrating tablet of the present invention comprises cilostazol blended with particles in which an inorganic substance and a disintegrant are uniformly dispersed in composite particles of two or more saccharides. Among them, in particular, an orally disintegrating tablet obtained by blending particles in which an inorganic substance and a disintegrant are uniformly dispersed in a composite particle of two or more saccharides in cilostazol, a fluidizing agent, and an organic excipient. .

  Cilostazol can be produced, for example, by the method of Patent Document 1.

  The “granulated particles in which an inorganic substance and a disintegrant are uniformly dispersed in a composite particle of two or more saccharides” (hereinafter referred to as “granulated particles”) used in the present invention are saccharides other than mannitol and mannitol, and disintegrants. The inorganic substance is dispersed in water and then spray-dried. Specifically, it is a composition for orally disintegrating tablets produced by the method described in Patent Document 4 or Patent Document 5. Two or more saccharides contained in the granulated particles are a combination of mannitol and a saccharide other than mannitol. Sugars refer to sugars and sugar alcohols. The saccharide other than mannitol is, for example, at least one selected from xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, maltose, trehalose, palatinit, palatinose, and the like. A combination of mannitol and xylitol is preferable. The weight ratio between mannitol and saccharides other than mannitol is mannitol: saccharides other than mannitol = 98: 2-67: 33, preferably mannitol: saccharides other than mannitol = 97: 3-87: 13, more preferably mannitol: Saccharides other than mannitol = 96: 4 to 89:11.

  The inorganic substance contained in the granulated particles of the present invention is preferably a pharmaceutically acceptable inorganic acid compound containing at least one of aluminum, magnesium and calcium, such as magnesium aluminate metasilicate and magnesium aluminate silicate. , Calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, hydrotalcite, aluminum silicate, calcium phosphate, calcium carbonate, calcium silicate, magnesium silicate, magnesium oxide, magnesium hydroxide, water It is at least one selected from alumina magnesium oxide, dry aluminum hydroxide gel, magnesium carbonate and the like. More preferably, magnesium aluminate metasilicate, magnesium aluminate silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granulation, hydrotalcite, calcium carbonate, calcium silicate and dry hydroxide At least one selected from aluminum gels, and more preferably at least one selected from magnesium aluminate metasilicate, hydrotalcite, anhydrous calcium hydrogen phosphate, and calcium carbonate. The average particle diameter of these inorganic substances is 0.1 to 100 μm, preferably 1 to 60 μm, and more preferably 1 to 40 μm. In order to obtain a desired average particle diameter, a pulverized product by a conventional method can be used.

  The disintegrant contained in the granulated particles of the present invention is preferably at least one selected from crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose and crystalline cellulose, and any one of these may be used alone. However, it is more preferable to use it as a mixture. Of these, crospovidone and crystalline cellulose are more preferably used. When crospovidone and crystalline cellulose are used, the weight ratio of crospovidone and crystalline cellulose is 5: 8 to 15:22, preferably 5:10 to 14:22, and more preferably 6:12 to 13:21. The disintegrant is preferably an average particle size of 0.1 to 100 μm, more preferably 1 to 60 μm, and still more preferably, in order to prevent homogeneous dispersibility in the composition of the present invention and roughness in the oral cavity. Is 1-40 μm. In order to obtain a desired average particle diameter, a pulverized product by a conventional method can be used.

  The amount of each component in the granulated particles is 40 to 90 parts by weight of saccharide, 1 to 30 parts by weight of an inorganic substance, and 5 to 40 parts by weight of a disintegrant, preferably 100 parts by weight of the entire granulated particle. It is 50-80 weight part of saccharides, 2-15 weight part of inorganic substance, and 10-36 weight part of disintegrant with respect to 100 weight part of the whole grain particle. More preferably, they are 62-78 weight part of saccharides, 3-8 weight part of inorganic substance, and 18-34 weight part of disintegrant with respect to 100 weight part of the whole granulated particle. The granulated particles can be produced by a commonly used method such as a spray granulation method, a fluidized bed granulation drying method, an agitation granulation method, or a wet granulation method such as a wet extrusion granulation method. 6 can be used. These granulated particles can be obtained as, for example, commercially available F-MELT (registered trademark, manufactured by Fuji Chemical Industry Co., Ltd.).

  The blended amount of the granulated particles is usually about 10 to 60% by weight, preferably about 20 to 40% by weight per 100% by weight of the orally disintegrating tablet.

  Examples of the “fluidizing agent” used in the present invention include hydrous silicon dioxide, light anhydrous silicic acid, heavy anhydrous silicic acid and the like. Light anhydrous silicic acid and hydrous silicon dioxide are preferred. More preferred is light anhydrous silicic acid. You may use 1 type, or 2 or more types of these components. The blending amount of the fluidizing agent per 100% by weight of the orally disintegrating tablet is about 0.2 to 2% by weight, preferably about 0.5 to 1.5% by weight.

  Examples of the “organic excipient” blended in the solid preparation of the present invention include celluloses and starches. Examples of celluloses include crystalline cellulose, carboxymethylcellulose, ethylcellulose, carboxymethylethylcellulose, carmellose sodium, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like. Crystalline cellulose and carboxymethyl cellulose are preferred. More preferred is crystalline cellulose. Examples of starches include corn starch, rice starch, potato starch, wheat starch, partially pregelatinized starch, and hydroxypropyl starch. Corn starch, rice starch, potato starch, partially pregelatinized starch, and hydroxypropyl starch are preferred. More preferred is corn starch. You may use 1 type, or 2 or more types of these components. Preferably, crystalline cellulose and corn starch are used. The blending amount of the organic excipient per 100% by weight of the orally disintegrating tablet is 5 to 60% by weight, preferably about 10 to 30% by weight.

  Moreover, as long as the disintegration property and moldability of the orally disintegrating tablet of the present invention are not impaired, various additives generally used for tablet production may be included. Examples of the additive include a lubricant, a sweetener, a corrigent, a fragrance, a binder, and a colorant.

  Examples of the lubricant include stearic acid, magnesium stearate, stearic acid metal salts such as calcium stearate, sodium stearyl fumarate, talc, colloidal silica, sucrose fatty acid ester, hydrogenated oil, polyethylene glycol and the like. Among these, stearic acid or a metal salt thereof is preferable, and magnesium stearate is more preferable. The blending amount of the lubricant is usually 0.01 to 1% by weight, preferably 0.1 to 0.6% by weight, per 100% by weight of the orally disintegrating tablet.

  Examples of the sweetening agent include acesulfame potassium, aspartame, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevia or a salt thereof, sucralose, thaumatin and the like.

  Examples of the corrigent include ascorbic acid or a salt thereof, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid or a salt thereof, anhydrous citric acid, L-glutamic acid or a salt thereof, succinic acid or a salt thereof, acetic acid, Examples thereof include tartaric acid or a salt thereof, sodium hydrogen carbonate, fumaric acid or a salt thereof, malic acid or a salt thereof, glacial acetic acid, disodium inosinate, and honey.

  The fragrance includes what is called a flavoring agent, such as orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, mint oil, vanilla flavor. , Bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, menthol, lemon powder, lemon oil, rose oil and the like.

  Examples of the binder include gum arabic, gum arabic powder, gelatin, agar, dextrin, pullulan, povidone, polyvinyl alcohol and the like.

  Examples of the colorant include food colors such as food red No. 3, food yellow No. 5, food blue No. 1, yellow ferric oxide, ferric oxide, brown iron oxide, black iron oxide, copper chlorophyll, copper chlorophyllin sodium, Examples include riboflavin and powdered green tea.

  These additive components can usually be used in any amount alone or as a mixture. As a specific method for producing an orally disintegrating tablet according to the present invention, cilostazol and other preparation raw materials are weighed and mixed with an appropriate mixer such as a V-type mixer, and then directly compressed into tablets. And a manufacturing method.

  In order to obtain a mixed powder for tablets, a method of strongly mixing with a stirring granulator or a method of mixing and pulverizing with a pulverizer may be used. Also, a method of compressing and granulating with a dry granulator, a method of performing wet granulation using water, acetone, ethyl alcohol, propyl alcohol or a mixture thereof in which a binder is dispersed or dissolved as necessary, A method of producing a mixed powder for tablets by dividing into two or more separate groups may be used. When producing a mixed powder for tablets, a lubricant, a sweetener, a corrigent, a fragrance, a binder, a colorant, and the like may be mixed as necessary.

  First, it is preferable that cilostazol and a fluidizing agent are thoroughly mixed, and then an organic excipient, granulated particles, a sweetening agent and a lubricant are added thereto, and further thoroughly mixed.

  The mixed powder for tablets thus obtained is compression-molded by applying a pressure of 200 kg to 600 kg / 杵 using, for example, a single tableting machine, a rotary tableting machine or the like. If the pressure is lower than this, the tablet hardness is insufficient and sufficient hardness for handling cannot be secured, and if the pressure is high, disintegration is delayed, which is not preferable.

  For compression molding, a normal tableting method can be used, but an external lubrication tableting method can also be used. By the external lubricant tableting method, the amount of lubricant added can be reduced, the disintegration rate can be increased, and the tablet hardness can be improved.

  Regarding the molding of the orally disintegrating tablet of the present invention, any shape can be adopted, for example, a round shape, an oval shape, a spherical shape, a rod shape, a donut shape, a laminated tablet, a dry-coated tablet, etc. Further, it may be coated by a coating method generally used in the production of a coated preparation. Further, marks for improving the identification, characters, etc., or dividing lines for division may be added.

  The orally disintegrating tablet of the present invention is rapidly disintegrated in the oral cavity with saliva and can be taken smoothly. Typically, the hardness (measured with a tablet hardness meter) is 30 N or more, and the oral disintegration time in healthy adults is usually within 90 seconds, preferably within 60 seconds, more preferably within 40 seconds. .

  Additives defined in the present invention, such as minerals, disintegrants, sugars, fluidizing agents, organic excipients, starch, cellulose, additives, lubricants, sweeteners, flavoring agents, fragrances, binders, coloring agents An agent or the like includes a single component, a plurality of components, and a mixture of a plurality of components, even if expressed as a single component or a plurality of components.

  EXAMPLES The present invention will be described more specifically with reference to the following examples and control examples, but the present invention is not limited to these examples.

Example 1
40 parts by weight of cilostazol powder, 39.2 parts by weight of granulated particles (F-melt, manufactured by Fuji Chemical Co., Ltd.), 20 parts by weight of carmellose (NS-300, manufactured by Gotoku Pharmaceutical Co., Ltd.), menthol (manufactured by Takasago Fragrance Co., Ltd.) 0 .2 parts by weight, 0.2 parts by weight of aspartame (manufactured by Ajinomoto Co., Inc.) and 0.4 parts by weight of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) are mixed, and then a rotary tableting machine (HT-AP18SSII type, manufactured by Hata Seiko, Tablets were obtained by tableting using a 9 mmφ ridge with a corner plane) so that each tablet had 250 mg and a tablet hardness of 50 N.

(Example 2)
40 parts by weight of cilostazol powder, 39.2 parts by weight of granulated particles (F-melt, manufactured by Fuji Chemical Industry Co., Ltd.), 10 parts by weight of crystalline cellulose (Theolas PH-101, manufactured by Asahi Kasei Chemicals Corporation), corn starch (eclipse corn starch ( XX16) W, manufactured by Nippon Shokuhin Kako Co., Ltd. 10 parts by weight, menthol (manufactured by Takasago Inc.) 0.2 part by weight, aspartame (manufactured by Ajinomoto Co.) 0.2 part by weight, and magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) 0.4 After mixing the parts by weight, using a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Kogyo, 9 mmφ, corner plane punch), tableting is performed so that one tablet is 250 mg and tablet hardness is 50N. To obtain tablets.

(Example 3)
40 parts by weight of cilostazol powder, 39.2 parts by weight of granulated particles (Fmelt, manufactured by Fuji Chemical Co., Ltd.), 20 parts by weight of rice starch (Micropearl, manufactured by Shimada Chemical Co., Ltd.), 0. 2 parts by weight, 0.2 parts by weight of aspartame (Ajinomoto Co., Inc.) and 0.4 parts by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) are mixed, and then a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Kogakusho) , 9 mmφ, corner plane plane)), tablets were tableted to give a tablet of 250 mg and a tablet hardness of 50 N to obtain tablets.

Example 4
After mixing 40 parts by weight of cilostazol powder and 0.5 parts by weight of hydrous silicon dioxide (Adsolider 102, manufactured by Freund Sangyo Co., Ltd.), 33.7 parts by weight of granulated particles (Fmelt, manufactured by Fuji Chemical Industry Co., Ltd.), crystalline cellulose (Theoras PH-101, manufactured by Asahi Kasei Chemicals Corporation) 15 parts by weight, corn starch (eclipse cornstarch (XX16) W, manufactured by Nippon Shokuhin Kako), 10 parts by weight, menthol (manufactured by Takasago Fragrance Co., Ltd.), 0.2 parts by weight, After mixing 0.2 parts by weight of aspartame (manufactured by Ajinomoto Co., Inc.) and 0.4 parts by weight of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), a rotary tableting machine (HT-AP18SS-II type, manufactured by Hata Plant, 9 mmφ, corner Tablets were obtained using a square-faced punch) so that one tablet was 250 mg and the tablet hardness was 50 N.

(Example 5)
After mixing 40 parts by weight of cilostazol powder and 0.5 parts by weight of light anhydrous silicic acid (ADSOLIDER 101, manufactured by Freund Corporation), 33.7 parts by weight of granulated particles (Fmelt, manufactured by Fuji Chemical Industry Co., Ltd.), crystals 15 parts by weight of cellulose (Theorus PH-101, manufactured by Asahi Kasei Chemicals Corporation), 10 parts by weight of corn starch (Niskan Corn Starch (XX16) W, manufactured by Nippon Shokuhin Kako), 0.2 parts by weight of menthol (manufactured by Takasago Fragrance Co., Ltd.) , 0.2 parts by weight of aspartame (manufactured by Ajinomoto Co., Inc.) and 0.4 parts by weight of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) were mixed, and then a rotary tableting machine (HT-AP18SS-II type, manufactured by Hata Plant, 9 mmφ, Tablets were obtained by tableting using a scissors with a corner plane so that each tablet had 250 mg and a tablet hardness of 50 N.

(Example 6)
After mixing 40 parts by weight of cilostazol powder and 0.5 parts by weight of light anhydrous silicic acid (Aerosil 380, manufactured by Nippon Aerosil Co., Ltd.), 33.7 parts by weight of granulated particles (Fmelt, manufactured by Fuji Chemical Industry Co., Ltd.), crystals 15 parts by weight of cellulose (Theorus PH-101, manufactured by Asahi Kasei Chemicals Corporation), 10 parts by weight of corn starch (Niskan Corn Starch (XX16) W, manufactured by Nippon Shokuhin Kako), 0.2 parts by weight of menthol (manufactured by Takasago Fragrance Co., Ltd.) , 0.2 parts by weight of aspartame (manufactured by Ajinomoto Co., Inc.) and 0.4 parts by weight of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) were mixed, and then a rotary tableting machine (HT-AP18SS-II type, manufactured by Hata Plant, 9 mmφ, Tablets were obtained by tableting using a scissors with a corner plane so that each tablet had 250 mg and a tablet hardness of 50 N.

(Example 7)
After mixing 40 parts by weight of cilostazol powder and 0.5 parts by weight of hydrous silicon dioxide (Adsolider 102, manufactured by Freund Sangyo Co., Ltd.), 33.7 parts by weight of granulated particles (Fmelt, manufactured by Fuji Chemical Industry Co., Ltd.), crystalline cellulose (Theoras PH-101, manufactured by Asahi Kasei Chemicals Corporation) 10 parts by weight, corn starch (eclipse corn starch (XX16) W, manufactured by Nippon Shokuhin Kako), 15 parts by weight, menthol (manufactured by Takasago Fragrance Co., Ltd.), 0.2 parts by weight, After mixing 0.2 parts by weight of aspartame (manufactured by Ajinomoto Co., Inc.) and 0.4 parts by weight of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), a rotary tableting machine (HT-AP18SS-II type, manufactured by Hata Plant, 9 mmφ, corner Tablets were obtained using a square-faced punch) so that one tablet was 250 mg and the tablet hardness was 50 N.

(Control 1)
Fluid flow casting of 192 g of erythritol (Niken Chemical Co., Ltd.), 100 g of corn starch (Nissan Corn Starch (XX16) W, manufactured by Nippon Shokuhin Kako), 8 g of hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) and 100 g of cilostazol powder The mixture was put into a drier (multiplex MP-1, manufactured by Pou Lec Co., Ltd.), granulated by spraying purified water as a binder, and dried as it was to obtain granules A. To 400 g of granule A, 40 g of PVP-XL (manufactured by ISP) as a disintegrant and 2 g of magnesium stearate as a lubricant were added, and tableted using a continuous tableting machine (812 HUK, manufactured by Kikusui Seisakusho), cilostazol A tablet having a total amount of 442 mg and a diameter of 12 mm containing 100 mg was obtained.

(Control 2)
94 g of corn starch (eclipse corn starch (XX16) W, manufactured by Nippon Shokuhin Kako), 6 g of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) and 100 g of cilostazol powder were fluidized and flow-dried (Multiplex MP-1, Paulek) Granulated by spraying purified water as a binding solution and drying as it was to obtain granules B. 0.5% by weight of magnesium stearate is added as a lubricant to Granule B, tableted using a continuous tableting machine (812HUK, manufactured by Kikusui Seisakusho), containing 100 mg of cilostazol, total amount 201 mg, diameter A 9 mm tablet was obtained.

(Test Example 1)
Cilostazol 100 mg tablets of Examples 1 to 7 and Control Examples 1 and 2 were included in the mouth, disintegrated on the tongue, and the time until complete disintegration was measured and compared as oral time. Further, for Examples 1 to 7, the local decay time and hardness were also measured. The hardness was measured using a Monsanto hardness tester (manufactured by Higaki Medical Science Co., Ltd.), and the collateral disintegration time was measured as time (seconds) until disintegration according to the disintegration test method described in Japanese Pharmacopoeia 15th revision. . The test solution was measured using water and without an auxiliary plate.

As shown in Table 1, in the orally disintegrating tablets of Examples 1 to 7 of the present invention, the shortening of the orally disintegrating time was recognized as compared with the tablets of Control Examples 1 and 2.
In particular, in the production of each tablet of Examples 1 to 7, the composition before tableting of Examples 4 to 7 to which a fluidizing agent was added was superior in fluidity to the same composition of Examples 1 to 3 and was compressed. Locking was easy. Moreover, about Example 4 and 7, it tested about the feeling of dosing. The feeling of dosing was good in both Examples 4 and 7, but was even better in Example 7 than in Example 4.

(Example 8)
40 parts by weight of cilostazol powder and 1.2 parts by weight of light anhydrous silicic acid (ADSOLIDER 101, manufactured by Freund Sangyo Co., Ltd.) are mixed with a high-speed stirring type mixing granulator (VG-10, manufactured by POWREC, main shaft blade: 400 rpm, granulated blade: The mixture was stirred and mixed at 1500 rpm) for 15 minutes. To this powder, 15 parts by weight of corn starch (eclipse corn starch (XX16) W, manufactured by Nippon Shokuhin Kako) was added and stirred and mixed for 15 minutes under the same conditions. To this mixed powder, 35.12 parts by weight of granulated particles (F-melt, manufactured by Fuji Chemical Industry Co., Ltd.) was added and stirred and mixed under the same conditions for 15 minutes. Further, 8 parts by weight of crystalline cellulose (Theorus KG802, manufactured by Asahi Kasei Chemicals Corporation) and 0.2 part by weight of aspartame (manufactured by Ajinomoto Co., Inc.) were added, and the mixture was stirred and mixed for 15 minutes under the same conditions to produce a powder for tablets. Next, using a rotary tableting machine (manufactured by Kikusui Seisakusho) equipped with an external lubrication device (manufactured by Kikusui Seisakusho), 250 mg tablets per tablet under the condition that 1.2 mg magnesium stearate adheres per tablet. Produced. At this time, the shape of the punch was round, the diameter was 9 mm, and the tableting pressure was 400-500 kg.

Example 9
40 parts by weight of cilostazol powder and 1.2 parts by weight of light anhydrous silicic acid (ADSOLIDER 101, manufactured by Freund Sangyo Co., Ltd.) are mixed with a high-speed agitation type mixing granulator (FM-VG-120P, manufactured by POWREC, spindle blade: 240 rpm, granulation The mixture was stirred and mixed at a blade of 1500 rpm for 15 minutes. As an organic excipient, 15 parts by weight of corn starch (eclipse corn starch (XX16) W, manufactured by Nippon Shokuhin Kako), 8 parts by weight of crystalline cellulose (Theoras KG802, manufactured by Asahi Kasei Chemicals), and aspartame as other additives are added to the powder. (Ajinomoto Co., Inc.) 0.2 parts by weight was added and stirred and mixed under the same conditions for 15 minutes. To this mixed powder, 35.12 parts by weight of granulated particles (Fmelt, manufactured by Fuji Chemical Industry Co., Ltd.) was added and mixed for 10 minutes with a drum type mixer (Ishihi Seisakusho, 12 rpm). To this mixed powder, 0.16 part by weight of magnesium stearate (manufactured by Taihei Chemical Industry) was added and mixed for 10 minutes under the same conditions to prepare a tablet powder. Next, using a rotary tableting machine (manufactured by Kikusui Seisakusho) equipped with an external lubrication device (manufactured by Kikusui Seisakusho), 250 mg tablets per tablet under the condition that 0.8 mg of magnesium stearate adheres per tablet. Produced. At this time, the shape of the punch was round, the diameter was 9 mm, and the tableting pressure was 400-500 kg.

(Test Example 2)
The characteristics of the tablets produced according to Examples 8 and 9 were examined, and the results shown in Table 2 were obtained.
The hardness was measured using a tablet hardness meter (manufactured by Schleunigel), and the pharmacopeial disintegration time was measured as the time (seconds) until disintegration according to the disintegration test method described in the Japanese Pharmacopoeia 15th revision. The test solution was measured using water and without an auxiliary plate. The test was conducted on 6 tablets and the average value was shown.
In addition, it was administered into the oral cavity of 6 healthy adult males, and the time until complete disintegration in the mouth with saliva alone was measured and the average value was shown.

実施例９に示した処方および製造方法により製造された口腔内崩壊錠においては、市販のシロスタゾール１００ｍｇ錠と同等の溶出プロファイルを示した。 (Test Example 3)
A dissolution test was conducted on the tablets of Examples 7 and 9 and a commercially available cilostazol 100 mg tablet, and the results are shown in Table 3.
The dissolution test was performed according to the dissolution test method described in the 15th revision of the Japanese Pharmacopoeia, 900 ml of sodium lauryl sulfate solution (3 → 1000) was used as the test solution, and the rotational speed was 50 rpm by the paddle method. The quantification method was performed by the UV-visible absorbance measurement method at 257 nm.
The test was carried out with 3 tablets for Example 7, 6 tablets for Example 9 and a commercially available cilostazol 100 mg tablet, and the average value was shown.

The orally disintegrating tablet produced by the formulation and production method shown in Example 9 showed an elution profile equivalent to that of a commercially available cilostazol 100 mg tablet.

Claims (20)

  An orally disintegrating tablet comprising granulated particles obtained by uniformly dispersing an inorganic substance and a disintegrant in a composite particle of cilostazol and two or more kinds of sugars.   The orally disintegrating tablet according to claim 1, further comprising a fluidizing agent.   The orally disintegrating tablet according to claim 2, comprising 0.2 to 2% by weight of a fluidizing agent.   The orally disintegrating tablet according to claim 3, wherein the fluidizing agent is one or more selected from hydrous silicon dioxide, light anhydrous silicic acid, and heavy anhydrous silicic acid.   The orally disintegrating tablet according to claim 4, wherein the fluidizing agent is hydrous silicon dioxide and / or light anhydrous silicic acid.   The orally disintegrating tablet according to any one of claims 1 to 5, further comprising an organic excipient.   The orally disintegrating tablet according to claim 6, wherein the organic excipient is one or more selected from starches and celluloses.   The orally disintegrating tablet according to claim 7, wherein the starch is one or more selected from corn starch, rice starch, potato starch, partially pregelatinized starch, and hydroxypropyl starch.   The orally disintegrating tablet according to claim 8, wherein the starch is corn starch.   The orally disintegrating tablet according to claim 7, wherein the cellulose is one or more selected from crystalline cellulose and carboxymethylcellulose.   The orally disintegrating tablet according to claim 10, wherein the cellulose is crystalline cellulose.   The orally disintegrating tablet according to claim 7, wherein the organic excipient is crystalline cellulose and corn starch.   Furthermore, if desired, one or more additives selected from the group consisting of lubricants, sweeteners, flavoring agents, fragrances, binders, and coloring agents may be included. The orally disintegrating tablet according to any one of 12 above.   The orally disintegrating tablet according to claim 13, wherein the sweetening agent is aspartame.   The orally disintegrating tablet according to any one of claims 1 to 14, which is compression-molded by an external lubricant tableting method.   (A) mixing cilostazol and fluidizing agent; (b) mixing organic excipients, granulated particles and other additives into the mixed powder prepared in step (a); and (c) step. A method for preparing an orally disintegrating tablet comprising the step of compressing the mixture of (b) into a tablet.   The preparation method according to claim 16, wherein the tablet compression method in step (c) is an external lubricant tableting method.   The saccharides in the granulated particles in which the inorganic substance and the disintegrant are uniformly dispersed in the composite particles of two or more saccharides are mannitol, xylitol, sorbitol, erythritol, maltitol, lactose, sucrose, glucose, fructose, The orally disintegrating tablet according to any one of claims 1 to 15, comprising a combination with one or more sugars other than mannitol selected from maltose, trehalose, palatinit and palatinose.   (A) 40 to 90 parts by weight of saccharide, (b) 1 to 30 parts by weight of inorganic substance, (c) 5 to 40 parts by weight of disintegrant, and the total amount of components (a), (b) and (c) The orally disintegrating tablet according to claim 18, comprising 100 parts by weight, wherein the saccharide of (a) is a granulated particle having a ratio of saccharide other than mannitol: mannitol = 98: 2-67: 33.   The orally disintegrating tablet according to claim 19, wherein the two or more sugars are mannitol and xylitol.