WO2006085497A1

WO2006085497A1 - Tablet disintegrating in the oral cavity

Info

Publication number: WO2006085497A1
Application number: PCT/JP2006/301951
Authority: WO
Inventors: Kazuki Mimura; Ken Kanada; Kiyohisa Ouchi
Original assignee: Kissei Pharmaceutical Co., Ltd.
Priority date: 2005-02-09
Filing date: 2006-02-06
Publication date: 2006-08-17
Also published as: JPWO2006085497A1; JP5004236B2; JP2012107049A; JP5342028B2; JP2014001233A

Abstract

It is intended to provide a tablet, which quickly disintegrates in the oral cavity, has an appropriate hardness and is suitable for the production on the industrial scale, and a method of producing the same. Namely, a tablet disintegrating in the oral cavity which comprises a) an active ingredient, b) a sugar or a sugar alcohol, c) a partly gelatinized starch containing from 10 to 20% by weight of matters soluble in cold water, and d) a disintegrating agent. The tablet disintegrating in the oral cavity as described above can be produced by blending the disintegrating agent with a granular mixture consisting of the active ingredient a), the sugar or the sugar alcohol b) and the partly gelatinized starch containing from 10 to 20% by weight of matters soluble in cold water c) followed by compression molding.

Description

Specification

Orally disintegrating tablets

Technical field

[0001] The present invention relates to a tablet that rapidly disintegrates in the oral cavity and a method for producing the same.

Background art

[0002] In recent years, development of solid preparations that rapidly disintegrate or dissolve in the oral cavity has been promoted as dosage forms that can be easily taken by elderly people, patients who have difficulty swallowing, or can be taken without water. Yes.

[0003] For example, an orally disintegrating tablet prepared by dispensing a suspension of an active ingredient into a bowl and freeze-drying is known (for example, see Patent Document 1). The orally disintegrating tablets that require equipment are inconvenient to handle because of their low hardness.

[0004] JP-A-8-291051 discloses the production of an orally disintegrating tablet prepared by compression-molding a granulated product containing an active ingredient, a water-soluble binder and a water-soluble excipient, followed by humidification and drying. Although a method has been disclosed, this method requires special manufacturing equipment (see, for example, Patent Document 2).

[0005] WO95 / 20380 discloses an orally disintegrating preparation that is prepared by combining granulated and compression-molded saccharides with low moldability and saccharides with high moldability, and then humidifying and drying to increase hardness. (For example, see Patent Document 3).

[0006] In addition, various orally disintegrating tablets in which a low moldability, sugar alcohol or saccharide and a disintegrant are combined as an excipient have been proposed.

[0007] For example, W097 / 47287 includes an orally disintegrating tablet comprising a combination of a sugar alcohol or saccharide having an average particle size of 30 μm or less, an active ingredient and a disintegrant, and having an appropriate hardness and disintegration. It is disclosed (for example, see Patent Document 4). However, the D-mannitol used here has a problem of causing tableting troubles such as binding and cabbing due to large friction with the metal wall during compression molding. There is a need for special manufacturing equipment such as applying tablets and tableting.

[0008] WO2000 / 57857 contains spray-dried D-mannitol and crospovidone. An orally disintegrating tablet having moderate hardness and disintegration prepared by directly tableting a mixture is disclosed (for example, see Patent Document 5). Japanese Patent Laid-Open No. 2001-163770 discloses an appropriate hardness and disintegration property obtained by directly compressing a tableting powder containing a co-ground product of a mixture containing a saccharide and a disintegrant and an unpowdered saccharide product. An orally disintegrating tablet having the above has been disclosed (for example, see Patent Document 6). However, when D-mannitol is used as an excipient and an orally disintegrating tablet is prepared according to these methods, there is a problem that tableting troubles such as binding still tend to occur during compression molding. I'm going.

Patent Document 1: U.S. Pat.No. 4,371,516

Patent Document 2: Japanese Patent Laid-Open No. 2001-163770

Patent Document 3: International Publication No. 95/20380 Pamphlet

Patent Document 4: International Publication No. 97/47287 Pamphlet

Patent Document 5: Pamphlet of International Publication No. 2000/57857

Patent Document 6: Japanese Patent Laid-Open No. 2001-163770

Disclosure of the invention

Problems to be solved by the invention

[0009] An object of the present invention is to provide an orally disintegrating tablet that has an appropriate hardness and quick disintegration, and can be industrially produced by a general production facility.

Means for solving the problem

[0010] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a partially alpha starch that has an active ingredient, sugar or sugar alcohol, and a disintegrant and a specific range of cold water soluble content. Orally disintegrating tablets containing a suitable hardness and rapid disintegration, and furthermore, the orally disintegrating tablets are generally used without unexpectedly causing tableting troubles during compression molding. Based on these findings, the present invention has been completed.

[0011] That is, the present invention provides:

[1] a) active ingredient, b) sugar or sugar alcohol, c) partially alpha-unified starch having a cold water soluble content of 10-20% by weight, and d) an orally disintegrating tablet containing a disintegrant;

[2] Sugar or sugar alcohol power At least selected from lactose and D_mannitol Orally disintegrating tablet according to [1], wherein

[3] Orally disintegrating tablet according to [1], which is sugar or sugar alcohol power S, D-mannitol; [4] The disintegrant is at least one selected from crospovidone and corn starch, [1] Orally disintegrating tablets;

[5] The orally disintegrating tablet according to [1], wherein the disintegrant is crospovidone;

[6] The orally disintegrating tablet according to [1], further comprising partially alpha-monified starch having a cold water soluble content of less than 10% by weight;

[7] Oral disintegration according to [1], wherein the content of partially alpha-monified starch having a cold water soluble content of 10 to 20% by weight is 0.5 to 30 parts by weight with respect to 100 parts by weight of the preparation [8] (I) a granulated product comprising a) active ingredient, b) sugar or sugar alcohol, and c) partially alpha-unified starch having a cold water soluble content of 10 to 20% by weight; II) Orally disintegrating tablets containing a disintegrant;

[9] Orally disintegrating tablet according to [8], which is at least one selected from sugar or sugar alcohol power S, lactose and D-mannitol;

[10] Orally disintegrating tablet according to [8], which is sugar or sugar alcohol power S, D-mannitol

[11] The orally disintegrating tablet according to [8], wherein the disintegrant is at least one selected from the group consisting of crospovidone and corn starch;

[12] The orally disintegrating tablet according to [8], wherein the disintegrant is crospovidone;

[13] The orally disintegrating tablet according to [8], wherein the granulated product further contains a partially alpha-ized starch having a cold water soluble content of less than 10% by weight;

[14] The orally disintegrating tablet according to [1] or [8], wherein the active ingredient is mitiglinide calcium hydrate;

[15] The orally disintegrating tablet according to [1] or [8], wherein the active ingredient is ritodrine hydrochloride; [16] a) active ingredient, b) sugar or sugar alcohol, and c) cold water soluble component A method for producing an orally disintegrating tablet comprising mixing a disintegrant with a granulated product containing partially alpha-ized starch of 10 to 20% by weight, followed by compression molding;

[17] The granulated product is further partially alpha-denidized with a cold water soluble content of less than 10% by weight. [16] The production method according to [16],

[18] Granulation of a mixture containing a) active ingredient and b) sugar or sugar alcohol while spraying partially alpha-monified starch having a cold water soluble content of 10 to 20% by weight. A method for producing an orally disintegrating tablet comprising mixing a disintegrant with a product and compression molding;

[19] The production method according to [18], wherein the mixture further contains partially alpha-monodenified starch having a cold water soluble content of less than 10% by weight;

[20] Granulate a mixture containing a) active ingredient, b) sugar or sugar alcohol, and c) partially alpha-gelatinized starch having a cold water soluble content of 10-20% by weight with the addition of water, A method for producing an orally disintegrating tablet, comprising mixing a disintegrant with the obtained granulated product and compression molding; and

[21] a) active ingredient, b) sugar or sugar alcohol, c) partially alpha-monified starch with cold water soluble content of 10-20% by weight, and d) portion with cold water soluble content of less than 10% by weight A method for producing an orally disintegrating tablet, comprising granulating a mixture containing alpha-monified starch while adding water, mixing the resulting granulated product with a disintegrant, and compressing the mixture; About.

As the active ingredient applied to the orally disintegrating tablet of the present invention, any active ingredient that can be administered orally without particular limitation can be used. Such active ingredients include, for example, antiparkinsonian drugs, antihyperlipidemic drugs, antidiabetic drugs, bronchial asthma drugs, allergic disease drugs, imminent flow premature birth drugs, dysuria drugs, etc. One or more selected components are used. Examples of the antiparkinsonian drug include L-dopa, strength belgorin and the like. Examples of the antihyperlipidemic agent include bezafibrate, furofibrate, symfibrate and the like. Examples of the antidiabetic agent include mitiglinide calcium hydrate, nateglinide and the like. Examples of the bronchial asthma therapeutic agent include ozadarel hydrochloride and the like. Examples of the allergic disease therapeutic agent include tranilast. For example, ritodrine hydrochloride is an example of the treatment for threatened premature birth. Examples of the urination disorder therapeutic agent include silodosin. In the orally disintegrating tablet of the present invention, the preferred active ingredient is mitiglinide Calcium hydrate, ritodrine hydrochloride, silodosin or strength bergolin.

[0013] In the orally disintegrating tablet of the present invention, the content of the active ingredient varies depending on the type of the tablet. Usually, about 0.01 to about 50 parts by weight, preferably about 0. 01 to about 20 parts by weight. When mitiglinide calcium hydrate is used as the active ingredient, the content of mitiglinide calcium hydrate is about 1 to about 20 parts by weight per tablet; L ₀₀ parts by weight.

, Preferably about 1 to about 10 parts by weight, more preferably about 2 to about 5 parts by weight.

[0014] As the sugar or sugar alcohol used in the orally disintegrating tablet of the present invention, those having high water solubility and low moldability are preferably used. Such sugars or sugar alcohols include, for example, sugars such as lactose, gnolecose, sucrose, and fructose; and sugar alcohols such as D-mannitol, xylitol, maltitol, sorbitol, and lactose or D_mannitol strength S, It is preferable because it has a good sweetness when taken, and D_mannito nore is particularly preferable because it has a refreshing feeling and easily obtains an appropriate hardness and quick disintegration.

These sugars or sugar alcohols can be used in combination of two or more as required. In addition, sugars and sugar alcohols can be used in combination.

[0015] In the orally disintegrating tablet of the present invention, the sugar or sugar alcohol content is about 10 to about 95 parts by weight, preferably about 30 to about 90 parts by weight, more preferably 100 parts by weight of the tablet. About 50 to about 90 parts by weight.

[0016] In the orally disintegrating tablet of the present invention, when sugar and sugar alcohol are used in combination, the content of sugar and sugar alcohol can be used in any ratio. Preferably, sugar: sugar alcohol power Used in the range of 0: 1 to about 9: about 1.

In the present invention, the “cold water soluble content (% by weight)” can be measured as follows.

Weigh accurately 3 g of sample (anhydrous conversion), add 297 mL of 25 ° C purified water, and stir at 1500 rpm for 2 minutes at high speed. Transfer the resulting suspension to a round bottom centrifuge tube and centrifuge at 2000 rpm for 15 minutes. Transfer 30mL of the supernatant to a weighing bottle and dry at 105 ° C until the weight is constant. Weighing the dry matter weight in the bottle by 1000 and dividing by the dry matter weight of the first sample is the cold water soluble content (% by weight).

[0018] In the present invention, "partially pregelatinized starch having a cold water soluble content of 10 to 20% by weight" `` Means partially alpha-ized dendron that is 10 to 20% by weight of the portion contained in the supernatant liquid when the cold water soluble component is measured according to the above measurement method. To do. Further, in the present invention, “partially partially modified starch having a cold water-soluble content of less than 10% by weight” means that when the cold water-soluble content is measured according to the above measurement method, the portion that dissolves in water is 10% by weight. Means less alpha alpha starch.

[0019] The partially alpha-ized starch used in the orally disintegrating tablet of the present invention is obtained by physically modifying cereal starches such as corn, wheat, and rice, and the kind thereof is not particularly limited. However, partially alpha-ized starch prepared from corn starch is preferred.

[0020] As a result of various investigations on starches having different degrees of alpha homogenization and different processing, the present inventors have determined that among partial alpha mono starches, "partial alpha having a cold water soluble content of 10 to 20% by weight". It has been found that, when blended with “monified starch”, the tableting trouble at the time of compression molding is unexpectedly improved. As shown in the test examples to be described later, this partially alpha-ized starch has a cold water soluble content of less than 10% by weight. In addition, starch soluble in water, such as alpha-monoized starch, did not show an effect of improving tableting trouble. In addition, dextrins that are readily soluble in water did not provide rapid disintegration as described later.

[0021] "Partially alpha-ized starch having a cold water soluble content of 10 to 20% by weight" used in the orally disintegrating tablet of the present invention is a commercially available partially alpha-ized starch such as Star chl500 ( Nippon Colorcon, cold water soluble component: 10 to 20% by weight) can be used.

In addition, “partially alpha-ized starch with a cold water-soluble content of less than 10% by weight” used in combination with “partially alpha-ized starch with a cold-water soluble content of 10 to 20% by weight” For example, PCS (manufactured by Asahi Kasei Kogyo Co., Ltd., cold water soluble content: less than 10% by weight), LYCATAB C (manufactured by Rocket) and the like can be used.

In addition, “partially alpha-ized starch having a cold water-soluble content of 10 to 20% by weight” and “partially alpha-ized starch having a cold water-soluble content of less than 10% by weight” are known methods, for example, Manufactured according to the method described in JP-B-59-47600, JP-A-4-318001, etc. I'll do it for you.

[0022] The cold water soluble content of the "partially pregelatinized starch having a cold water soluble content of 10 to 20% by weight" used in the orally disintegrating tablet of the present invention is preferably about 12 to about 18% by weight. More preferably about 14 to about 16% by weight. In addition, the cold water soluble content of the “partially alpha-monoized starch having a cold water soluble content of less than 10% by weight” used in the orally disintegrating tablet of the present invention is preferably about 1 to about 8% by weight, More preferably from about 1 to about 6% by weight, and even more preferably from about 1 to about 3% by weight.

[0023] In the orally disintegrating tablet of the present invention, the content of partially-alphatized starch having a cold water soluble content of 10 to 20% by weight is usually about 0.5 to about about 100 parts by weight of the tablet. If it is 30 parts by weight and less than 0.5 part by weight relative to 100 parts by weight of the tablet, a sufficient tableting failure improving effect cannot be obtained, and if it exceeds 30 parts by weight, rapid disintegration cannot be obtained. The preferred content of partially alpha-monified starch having a cold water soluble content of 10 to 20% by weight is about 1 to about 20 parts by weight, more preferably about 2 to about 15 parts by weight per 100 parts by weight of the tablet. Part.

[0024] Further, in the orally disintegrating tablet of the present invention, a partially alpha-ized starch having a cold water-soluble content of 10 to 20% by weight and a partially alpha-ized starch having a cold water-soluble content of less than 10% by weight. When used in combination, the ratio of partially pregelatinized starch having a cold water soluble content of 10 to 20% by weight to partially alpha-monified starch having a cold water soluble content of less than 10% by weight is 1: It is used in the range of 0 to about 1: about 9, preferably about 2: about 1 to about 1: about 9.

[0025] Examples of the disintegrant used in the orally disintegrating tablet of the present invention include crospovidone and corn starch, and crospovidone is preferred.

[0026] In the orally disintegrating tablet of the present invention, the content of the disintegrant varies depending on the type of disintegrating tablet, but is usually about 0.5 to about 30 parts by weight with respect to 100 parts by weight of the tablet. More specifically, the content of crospovidone is about 0.5 to about 10 parts by weight, preferably about 1 to about 7 parts by weight, based on 100 parts by weight of the tablet. The content of corn starch is about 3 to about 20 parts by weight, preferably about 5 to about 20 parts by weight per 100 parts by weight of the tablet.

[0027] In addition, the orally disintegrating tablet of the present invention has various additives, such as excipients, binders, lubricants, and sweeteners used in the preparation of the preparation, as long as the effects of the invention are not hindered. In addition, an appropriate amount of acidulant, foaming agent, fragrance, colorant, and the like can be contained. [0028] Examples of such excipients include rice starch, crystalline cellulose, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate, and ethyl cellulose. Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polybutyl pyrrolidone, methyl cellulose, polybutyl alcohol, sodium alginate, aminoalkyl methacrylate copolymer, polyethylene glycol and the like. As the lubricant, for example, magnesium stearate, calcium stearate, talc, light anhydrous key acid, sucrose fatty acid ester, sodium stearyl fumarate and the like can be mentioned. Examples of sweeteners include aspartame (registered trademark), saccharin sodium, dipotassium glycyrrhizin, stevia, thaumatin, and acesulfame K. Examples of the acidulant include citrate, tartaric acid, malic acid, ascorbic acid and the like. Examples of the foaming agent include sodium hydrogen carbonate, sodium carbonate, calcium carbonate and the like. Examples of the corrigent include L-aspartic acid, sodium chloride, magnesium chloride, sodium citrate, calcium citrate, sodium L-glutamate, and sodium bicarbonate. Examples of the fragrances include orange oil, lemon oil, menthol, and various fragrance powders. Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, yellow ferric oxide, ferric oxide, and caramel pigment.

[0029] Next, a method for producing the orally disintegrating tablet of the present invention will be described.

[0030] The orally disintegrating tablet of the present invention comprises: a) an active ingredient, b) a sugar or sugar alcohol, and c) cold water, a partially alpha-gelatinized starch having a soluble content of 10 to 20% by weight. In addition, a disintegrant may be added, mixed, and compression molded. As described above, the method for producing an orally disintegrating tablet of the present invention is characterized in that the granulated product contains partially pregelatinized starch having a cold water soluble content of 10 to 20% by weight. By coexisting with sugar or sugar alcohol in the product together with partially alpha-unified starch having a cold water soluble content of 10 to 20% by weight, it is possible to improve tableting troubles during compression molding.

[0031] Further, in the orally disintegrating tablet of the present invention, the active ingredient in the granulated product can be contained in any amount, and as long as the effect of the invention is not hindered, the sugar or sugar alcohol and the moiety. Add and mix active ingredients and disintegrant to granulated product made from alpha-ized starch However, it is also possible to manufacture by compression molding.

[0032] Further, the disintegrability can be enhanced by adding a partially alpha-integrated starch having a cold water-soluble content of less than 10% by weight to the granulated product. Adjust the disintegration time in the oral cavity to a preferred time by appropriately increasing or decreasing the amount of partially alpha-ized starch that is 20% by weight and the amount of partially alpha-ized starch that is soluble in cold water less than 10% by weight. Can do.

[0033] Examples of the granulation method used for the orally disintegrating tablet of the present invention include, for example, a fluidized bed granulation method, a high-speed stirring granulation method, an extrusion granulation method, a rolling granulation method, and a rolling fluid granulation method. The fluidized bed granulation method and the high-speed stirring granulation method are preferably used.

[0034] The orally disintegrating tablet of the present invention can be produced, for example, as follows.

[0035] Manufacturing method 1

The orally disintegrating tablet of the present invention comprises a mixture of a) an active ingredient and b) a sugar or a sugar alcohol while spraying partially alpha-monified starch having a cold water soluble content of 10 to 20% by weight. However, it is possible to manufacture by adding a disintegrant to the granulated product, mixing it, and compressing it. In the above granulation step, a part of the partially alpha-monified starch having a cold water soluble content of 10 to 20% by weight is mixed with the active ingredient and sugar or sugar alcohol, and the remaining partially alpha-ized starch is mixed. It can also be granulated while spraying.

[0036] Manufacturing method 2

Further, the orally disintegrating tablet of the present invention comprises a mixture containing a) an active ingredient, b) a sugar or sugar alcohol, and c) partially alpha-unified starch having a cold water soluble content of less than 10% by weight. It can be produced by granulating while partially spraying partially alpha-monified starch having a soluble content of 10 to 20% by weight, adding a disintegrant to the granulated product, mixing, and compression molding.

[0037] Manufacturing method 3

In addition, the orally disintegrating tablet of the present invention comprises a mixture containing a) an active ingredient, b) a sugar or sugar alcohol, and c) a partially alpha-monified starch having a cold water soluble content of 10 to 20% by weight. It is possible to produce the product by granulating it with the addition of, adding a disintegrant to the granulated product, mixing it, and compression molding. [0038] Manufacturing method 4

Also, the orally disintegrating tablet of the present invention comprises: a) an active ingredient, b) sugar or sugar alcohol, c) partially alpha-starch starch having a soluble content of 10 to 20% by weight of cold water, and d) less than 10% by weight The ability to produce a mixture containing partially alpha-monoized starch having a soluble content of cold water by adding water, adding a disintegrant to the granulated product, mixing, and compression-molding S can.

[0039] In the above production methods 1 to 4, when sugar and sugar alcohol are used in combination, both sugar and sugar alcohol may be mixed with the active ingredient and granulated, but either one is granulated. The other may be added and mixed after granulation. Preferably, a mixture containing an active ingredient and a sugar alcohol is granulated, and a sugar and a disintegrant are added to and mixed with the resulting granulated product, thereby preventing tableting troubles during compression molding. The orally disintegrating tablet of the invention can be prepared.

[0040] In the above production methods 1 to 4, after granulation, an appropriate amount of a lubricant, a sweetener, a foaming agent, a sour agent, a corrigent, a fragrance and the like may be mixed as necessary.

[0041] In the orally disintegrating tablet of the present invention, compression molding can be performed using a single-punch tableting machine, a rotary tableting machine, or the like. The pressure for tableting is usually ² to 60 kN / cm ² , preferably 6 to 30 kN / cm ² .

[0042] The orally disintegrating tablet of the present invention thus obtained exhibits moderate hardness and rapid or powerful disintegration or solubility in the oral cavity. The orally disintegrating time of the orally disintegrating tablet of the present invention is a force that varies depending on the size and thickness of the tablet, and is usually within 60 seconds, and preferably within 40 seconds. Further, the hardness of the orally disintegrating tablet of the present invention is usually 30 N or more, preferably 5

It is more than ON.

The invention's effect

[0043] Since the orally disintegrating tablet of the present invention rapidly disintegrates or dissolves in the oral cavity, it can be easily taken by elderly people and children who have difficulty swallowing. In addition, the orally disintegrating tablet of the present invention is easy to handle because it has sufficient hardness not to be damaged in the distribution process. Furthermore, since the orally disintegrating tablet of the present invention can be easily produced without causing problems such as tableting troubles in the production process, it is suitable for industrial production. BEST MODE FOR CARRYING OUT THE INVENTION

[0044] The contents of the present invention will be described in more detail with reference to the following examples, comparative examples and test examples. The contents of the present invention are not limited to these.

Example

[0045] Test Example 1

Measurement of cold water soluble content

As starches, corn starch, partially alpha-monified starch and alpha-monified starch, and cold water soluble content of dextrin were measured according to the following method.

[0046] 3 g (anhydrous equivalent) of the sample was precisely weighed, 297 mL of purified water at 25 ° C was added, and the mixture was stirred at 1500 rpm for 2 minutes at high speed. The resulting suspension was transferred to a round bottom centrifuge tube and centrifuged at 2000 rpm for 15 minutes. 30 mL of the supernatant was placed in a weighing bottle and dried at 105 ° C until the weight was constant. The value obtained by multiplying the dry matter weight in the weighing bottle by 1000 and dividing by the dry matter weight of the first sample was taken as the cold water soluble content (% by weight). The results are shown in Table 1.

[0047] [Table 1]

1 ； Alpha union cannot be measured because the whole is paste-like

[0048] Test Example 2

Hardness test

Example:! ~ 11 and comparative example:! ~ 8 The hardness of the tablets produced by! ~ 8 was measured with a hardness meter (TS-75N, Oka Measured by Tasei). The test was conducted with 3 tablets and the average value was determined. The results are shown in Table 2 and Table 3.

[0049] Test Example 3

Oral disintegration test

In 3 healthy men, 1 tablet containing 1 tablet prepared in Examples 1 to 11 and Comparative Examples 1 to 8 was measured in the mouth, and the time when the tablet disintegrated was measured while gently rolling with the tongue. The average value was obtained. The results are shown in Table 2 and Table 3.

[0050] Test Example 4

Tableting disorder

Examples 1 to 11: In the tableting process of 11 and Comparative Examples 1 to 8, the appearance of the tablet was determined from the appearance of the upper and lower surfaces of the tablet, the presence of binding was determined from the appearance of the tablet side surface, and the cabbage was removed from the occurrence of delamination of the tablet. The presence or absence was observed. In addition, if the powder adheres to the mortar wall or the frictional state (occurrence of abnormal noise) is severe, tableting is prohibited. The results are shown in Table 2 and Table 3.

[0051] Example 1

D-mannito nore 181.0 mg

Partially alpha starch (Starchl500) 6.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Magnesium stearate 2.0 mg

(Total 200.0 mg / tablet) D-Mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size) pulverized for 2 minutes using a high-speed mixing and agitation granulator (FM-VG-10, manufactured by Baurek) 45 xm) 633.5 g was charged into a fluidized bed granulator (LAB-1, manufactured by Paurek), and partially alpha-ized starch (Starchl500, manufactured by Nippon Colorcon, cold water soluble content: 15.8 wt%) 2 ^ dispersed in purified water 180 _8, and granulation was performed while spraying the dispersion in a spray nozzle. 374g of granulated material sieved with No. 18 sieve, 20g of crospovidone (Polyplasdone XL-10, made by ISP), light anhydrous key acid (Adsolidar 101, furo) 2 g of Into Sangyo) and 4 g of magnesium stearate (Taihei Chemical Industry) were mixed for 2 minutes using a V-type mixer (DV-1, Dalton). Using this tableting mixture, a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho Co., Ltd.) has a tablet weight of 200 mg, a round of 8 mm, a table rotation speed of 30 mm, a tableting pressure of 7.8, 11.7 mm. papermaking tablets in 15.61 ^ N 111 ² of the conditions.

[0052] Example 2

D-mannito nore 177.0 mg

Partially alpha starch (Starchl500) 10.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Magnesium stearate 2.0 mg

(Total 200.0 mg / 1 tablet)

D—Mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 / im) 619.5g and partially alpha-ized starch (Starchl500, manufactured by Nippon Colorcon, cold water soluble content: 15.8% by weight) 14g The mixture was mixed for 2 minutes using a stirring granulator (FM-VG-10, manufactured by Paurek). This mixture was put into a fluidized bed granulator / dryer (LAB-1, manufactured by Norrec), and 21 g of partially alpha-modified starch (Starchl500, manufactured by Nippon Colorcon, cold water soluble content: 15.8% by weight) was added to 180 g of purified water. Granulation was performed while spraying this dispersion with a spray nozzle. Granulated material sieved with No. 18 sieve 374g, crospovidone (Polyplasdone XL-10, ISP) 20g, light anhydrous anhydrous (Adsolidar 101, Freund Sangyo) 2g and magnesium stearate (made by Taihei Chemical Sangyo) 4g Was mixed for 2 minutes using a V-type mixer (DV-1, manufactured by Dalton). Using this tableting mixture, a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), tablet weight 200 mg, 8 φ Γηπι circular, table rotation speed 30 mm, tableting pressure 7.8, 11.7 press 15.61 Tablets were produced under the conditions of 111 ² .

[0053] Example 3

D-mannito nore 161.0 mg

Partially alpha starch (Starchl500) 26.0 mg

Crospovidone 10.0 mg Light anhydrous anhydrous 1.0 mg

Magnesium stearate 2.0 mg

(Total 200.0 mg / 1 tablet)

D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 zm) 563.5 g and partially alpha-unified starch (Starchl500, manufactured by Nippon Colorcon Co., Ltd., cold water soluble content: 15.8 wt%) 70 g are mixed at high speed. The mixture was mixed for 2 minutes using a granulator (FM-VG-10, manufactured by Paurek). This mixture was put into a fluidized bed granulator / dryer (LAB-1, manufactured by Norec), and 21 g of partially alpha-integrated starch (Starchl500, manufactured by Nippon Colorcon, cold water soluble content: 15.8% by weight) was added to 180 g of purified water. Granulation was performed while spraying this dispersion with a spray nozzle. 374g of granulated material sieved with No. 18 sieve, 20g of crospovidone (Polyplasdone XL_10, manufactured by ISP), 2g of light anhydrous anhydrous (Adsolidar 101, manufactured by Freund Corporation) and 4g of magnesium stearate (produced by Taihei Chemical Industry) The mixture was mixed for 2 minutes using a V-type mixer (DV-1, manufactured by Dalton). Using a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), the tableting mixture was mixed with a tablet weight of 200 mg, 8 φ ππη circle, table rotation speed 30 mm, tableting pressure 11.7, 15.6 and 19.5 kN / Tablets were made under conditions of cm ² .

Example 4

D-mannito nore 147.0 mg

Partially alpha-ized starch (Starchl500) 40.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Magnesium stearate 2.0 mg

(Total 200.0 mg / 1 tablet)

D—Mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 zm) 514.5 g and partially alpha-unified starch (Starchl500, manufactured by Nippon Colorcon, cold water soluble content: 15.8 wt%) 119§ The mixture was mixed for 2 minutes using an agitation granulator (FM-VG-10, manufactured by Paurek). This mixture is put into a fluidized bed granulator / dryer (LAB-1, manufactured by Paurek), and a partial alpha is added. 21 g of starch monified (Starchl500, manufactured by Nippon Colorcon, cold water soluble content: 15.8% by weight) was dispersed in 180 g of purified water, and granulation was performed while spraying this dispersion with a spray nozzle. Granulated material sieved with No. 18 sieve 374g, crospovidone (Polyplasdone XL-10, ISP) 20g, light anhydrous caustic acid (Adsolidar 101, Freund Sangyo) 2g and magnesium stearate (Taiwa Kagaku Sangyo) 4g Were mixed for 2 minutes using a V-type mixer (DV_1, manufactured by Dalton). Using a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), this tableting mixture was tablet weight 200 mg, 8 φ Γηπι circular, table rotation speed 30 mm, tableting pressure 11.7 and 15.6 kN m ² Tablets were made under the conditions of

[0055] Example 5

D-mannitol 152.0 mg

Partially alpha starch (Starchl500)

Corn starch 40.0 mg

Light anhydrous anhydrous 1.0 mg

Magnesium stearate 2.0 mg

(Total 200.0 mg / 1 tablet) D-Mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size) pulverized for 2 minutes using a high-speed mixing and agitation granulator (FM-VG-10, manufactured by Paurek) 45 im) 633.5 g was put into a fluidized bed granulator (LAB-1, manufactured by Paurek), and another partially alpha-gelatinized starch (Starchl500, manufactured by Nippon Colorcon, cold water soluble content: 15.8% by weight) 21 _§ Granulated while purifying purified water 18 (spread in ¾ and spraying this dispersion with a spray nozzle. 219.8 g of granulated product sieved with No. 18 sieve, 56 g of corn starch (manufactured by Nippon Shokuhin Kako), light anhydrous Caic acid (Adsolidar 101, manufactured by Freund Sangyo) 1.4g and magnesium stearate (produced by Taihei Chemical Sangyo) 2.8g were mixed for 2 minutes using a V-type mixer (DV_1, manufactured by Dalton). Using a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), tablet weight 200 mg, 8 φ mm round shape, Te one table rotating number 30卬m, tableting pressure 7.8, papermaking tablets with 11.7 Oyobi 15.61 ^ N 111 ² conditions.

[0056] Example 6

D-mannito nore 161.0 mg Partially alpha starch (Starchl500) 6.0 mg

Partially alpha starch (PCS) 20.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Magnesium stearate 2.0 mg

(Total 200.0 mg / 1 tablet)

D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 zm) 563.5 g and partially alpha-ized starch (PCS, manufactured by Asahi Kasei Kogyo Co., Ltd., cold water soluble content: 1.2% by weight) 70 ₈ are mixed at high speed. The mixture was mixed for 2 minutes using an agitation granulator (FM-VG-10, manufactured by Paurek). This mixture was put into a fluidized bed granulator / dryer (LAB-1, manufactured by Paurek). Separately, 21 g of partially alpha-ized dendron (Starchl 500, soluble in cold water: 15.8% by weight, manufactured by Nippon Colorcon) was added to 180 g of purified water. The mixture was dispersed and granulated while spraying this dispersion with a spray nozzle. Granulated material sieved with No. 18 sieve 374g, crospovidone (Polyplasdone XL-10, ISP) 20g, light anhydrous caustic acid (Ads olidar 101, Freund Sangyo) 2g and magnesium stearate (Taipei Sangyo Sangyo) 4 g was mixed for 2 minutes using a V-type mixer (DV-1, manufactured by Dalton). Using this tableting mixture, using a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), tablet weight 200 mg, 8 φ mm circle, table rotation speed 30 mm, tableting pressure 15.6, 19.5 mm 23.41 ^ papermaking a lock agent in N 111 ² of the conditions.

Comparative Example 1

D—Man 丄 ol.O mg

26.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

, Noic acid 2.0 mg

(Total 200.0 mg / 1 tablet)

D-mannitol (Mannit P, Towa Kasei Kogyo Co., Ltd., average particle size 45 zm) 563.5 g and partially-modified starch (PCS, Asahi Kasei Kogyo Co., Ltd., cold water soluble content: 1.2 wt%) 70 ₈ The mixture was mixed for 2 minutes using a mixing and stirring granulator (FM-VG-10, manufactured by Paurek). This mixture was put into a fluidized bed granulator / dryer (LAB-1, manufactured by Norec). Separately, partially alpha-ized dendron (PCS, manufactured by Asahi Kasei Kogyo Co., Ltd., cold water soluble content: 1.2% by weight) 21 _§ was added to purified water. The mixture was dispersed in 180 g and granulated while spraying this dispersion with a spray nozzle. Granulated material sieved with No. 18 sieve 3 74g, Crospovidone (Polyplasdone XL-10, ISP) 20g, Light anhydrous caustic acid (Adsolidar 101, Freund Sangyo) 2g and Magnesium stearate (Taipei Chemical Sangyo) 4 g was mixed for 2 minutes using a V-type mixer (DV_1, manufactured by Dalton). Using this rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), tablet weight 200 mg, 8 φ mm round, table rotation speed 30 mm, tableting pressure 15.6, 19.5 and 23.4 kN papermaking tablets under the condition of m ^2.

Comparative Example 2

D-mannitol 161.0 mg

Part: 26.0

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Acid 2.0 mg

(Total 200.0 mg / 1 tablet)

D—Mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 / im) 563.5 g and partially alpha-ized starch (LYCATAB C, manufactured by Rocket, cold water soluble content: 5.1 wt%) 70 _§ , high speed The mixture was mixed for 2 minutes using a mixing and stirring granulator (FM-VG-10, manufactured by Paurek). This mixture was put into a fluidized bed granulator / dryer (LAB-1, manufactured by Norrec), and a partially alpharized starch (LYCATAB C, manufactured by Rocket, cold water soluble content: 5.1% by weight) 2 ^ 18 (Dispersed in ^ and granulated while spraying this dispersion with a spray nozzle. 374 g of granulated product sieved with No. 18 sieve, 20 g of crospovidone (Polyplasdone XL-10, ISP), light anhydrous 2 g of caustic acid (Ads olidar 101, Freund Sangyo) and 4 g of magnesium stearate (Taipei Chemical Sangyo) were mixed for 2 minutes using a V-type mixer (DV_1, Dalton). Using a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), tablet weight 200mg, 8 Tablets were manufactured under the conditions of φ ιηπι circular, table rotation speed 30 mm, tableting pressure 15.6, 19.5 mm 23.41 ^ 111 ² .

[0059] Comparative Example 3

D-mannitol 187.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

, Noic acid 2.0 mg

(Total 200.0 mg / 1 tablet)

654.5 g of D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 zm) was pulverized for 2 minutes using a high-speed mixing and agitation granulator (FM-VG-10, manufactured by Paurek). This pulverized product was put into a fluidized bed granulator / dryer (LAB-1, manufactured by Norec), and granulated while spraying purified water with a spray nozzle. Granulated material sieved by No. 18 sieve 374g, Crospovidone (Polyplasdo ne XL-10, ISP) 20g, Light anhydrous caustic acid (Adsolidar 101, Freund Sangyo) 2g and Magnesium stearate (Taipei Chemical Sangyo) 4g Was mixed for 2 minutes using a V-type mixer (DV-1, manufactured by Dalton). Using a rotary tableting machine (Correct 12HUK, Kikusui Seisakusho), this tableting mixture is tablet weight 200mg, 8φππηcircle, table rotation speed 30mm, tableting pressure 15.6, 19.5 and 23.4kN m ² Tablets were produced under the following conditions.

[0060] Comparative Example 4

D-mannitol 161.0 mg

26.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

, Noic acid 2.0 mg

(Total 200.0 mg / 1 tablet)

D_Mannitol (Mannit P, Towa Kasei Kogyo Co., Ltd., average particle size 45 zm) 563.5 g and corn starch (Nihon Shokuhin Kako Co., Ltd., cold water soluble content: 0.1 wt%) 9 The mixture was mixed for 2 minutes using a stirring granulator (FM-VG-10, manufactured by Paurek). This mixture was put into a fluid bed granulator / dryer (LAB-1, Norec) and granulated while spraying purified water with a spray nozzle. 374g of granulated material sieved with No. 18 sieve, 20g of crospovidone (Polyplasdone XL-10, manufactured by ISP), 2g of light anhydrous caustic acid (Adsolidar 101, manufactured by Freund Industries) and 4g of magnesium stearate (Taipei Chemical Industry), The mixture was mixed for 2 minutes using a V-type mixer (DV_1, manufactured by Dalton). Using this tableting mixture, a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho) was used under the conditions of tablet weight 200 mg, 8 φ ππη circle, table rotation speed 30 mm, tableting pressure 11.7 kN m ² . Tablets were made.

[0061] Comparative Example 5

D-mannito nore 161.0 mg

Alpha-ized starch (UNI-PURE) 26.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Magnesium stearate 2.0 mg

(Total 200.0 mg / 1 tablet)

D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 / im) 563.5g and alpha starch (UNI-PURE, manufactured by National Starch & Chemical) 70g are mixed at high speed with agitation granulator (FM-VG-10) , Manufactured by Paurek) for 2 minutes. This mixture is put into a fluidized bed granulator / dryer (LAB-1, manufactured by Paurek), and 21 g of alpha-gelatinized starch (UNI-PURE, manufactured by National Starch & Chemical) is dispersed in 180 g of purified water, and this dispersion is sprayed. Granulation was carried out while spraying with sizzle. 374g of granulated material sieved with No. 18 sieve, 20g of crospovidone (Polyplasdone XL-10, manufactured by ISP), 2g of light anhydrous caustic acid (Adsolidar 101, manufactured by Freund Corporation) and magnesium stearate (produced by Taihei Chemical Industry) 4 g was mixed for 2 minutes using a V-type mixer (DV_1, manufactured by Dalton). Using this tableting mixture, using a rotary tableting machine (Correct 12 HUK, manufactured by Kikusui Seisakusho), tablet weight 200 mg, 8 φ ΐΜη circle, table rotation speed 30 rpm, tableting pressure 11.7 15 15.61 ^ 111 Tablets were produced under the conditions of ² .

[0062] Comparative Example 6 D-mannito nore 161.0 mg

Alpha-ized starch (Amicol C) 26.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Magnesium stearate 2.0 mg

(Total 200.0 mg / 1 tablet)

D_mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 μ πι) 563 / 5§ and alpha starch (Amcoll C, manufactured by Nissho Chemical Co., Ltd.) 80 g -V G-10, manufactured by Parek) for 2 minutes. This mixture is put into a fluidized bed granulator / dryer (LA B-1, manufactured by Baurek). Separately, 1 lg of alpha-monified starch (Amicol C, Nissho Chemical) is dispersed in 180 g of purified water, and this dispersion is sprayed. Granulation was carried out while spraying with Nozure. Granulated material sieved with No. 18 sieve 374g, crospovidone (Polyplasdone XL-10, IS) 20g, light anhydrous caustic acid (Adsolidar 101, Freund Sangyo) 2g and stearic acid magnesium (Taihei Chemical Sangyo) 4g Was mixed for 2 minutes using a V-type mixer (DV-1, manufactured by Dalton). Using a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), this tableting mixture was mixed with a tablet weight of 200 mg, 8 φ ππη circle, table rotation speed 30 mm, tableting pressure 15.6, 19.5 and 23.4 k ^ cm Tablets were produced under the conditions of ² .

Comparative Example 7

D-mannitol 161.0 mg

26.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

, Noic acid 2.0 mg

(Total 200.0 mg / 1 tablet)

D—Mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 zm) 563.5 g and dextrin (Amicol 10, manufactured by Nissui Chemical Co., Ltd., cold water soluble content: 100.0 wt%) 7 ^ mixture The mixture was mixed for 2 minutes using a stirring granulator (FM-VG-10, manufactured by Norrec). This mixture was put into a fluidized bed granulator (LAB-1, manufactured by Paurek), and 21 g of dextrin (Amicol 10, manufactured by Nissho Chemical Co., Ltd., cold water soluble component: 96.1%) was dispersed in 180 g of purified water. Granulation was performed while spraying the dispersion with a spray nozzle. 374g of granulated material sieved by No. 18 sieve, 20g of crospovidone (Polyplasdone XL_10, manufactured by ISP), 2g of light anhydrous caustic acid (Adsolidar 101, manufactured by Freund Corporation) and 4g of magnesium stearate (produced by Taihei Chemical Industry) The mixture was mixed for 2 minutes using a type mixer (DV-1, manufactured by Dalton). Using this tableting mixture, rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), tablet weight 200mg, 8φΐΜηcircle, table rotation speed 30 、 m, tableting pressure 11.7 ぉ 15.61 ^ 111 papermaking tablets in ^two conditions.

[Table 2]

Tableting pressure Tablet hardness Oral disintegration time

Sample Tableting disorder

(kN / cm ² ) (N) (seconds)

7.8 38 17 None Example 1 11.7 46 17 None

15.6 67 17 None

7.8 36 20 None Example 2 11.7 55 21 None

15.6 69 20 None

11.7 30 31 None Example 3 15.6 47 34 None

19.5 55 36 None

11.7 34 38 None Example 4

15.6 49 39 None

7.8 44 13 None Example 5 11.7 61 18 None

15.6 76 23 None

15.6 39 20 None Example 6 19.5 50 20 None

23.4 65 22 None

15.6 40 14 Binding Comparative Example 1 19.5 49 13 Pineding

23.4 54 12 Pineding

15.6 29 14 Binding Comparison 2 19.5 35 15 Binding

23.4 43 18 Pineding, caving

15.6 29 9 Binding Comparative Example 3 19.5 38 8 Binding

23.4 42 9 Binding [Table 2] continued

Example 8

Ritodrine hydrochloride 5.0 mg

D—mannito nore 156.0 mg

Partially alpha starch (Starchl500) 6.0 mg

Partially alpha starch (PCS) 20.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Sea bream 2.0 mg

(Total 200.0 mg / tablet) 17.5 g of ritodrine hydrochloride, D-mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 4 5 zm) 546 g and partially alpha-unified starch (PCS, manufactured by Asahi Kasei Kogyo Co., Ltd., soluble in cold water) Min: 1. 2 wt%) 7 (^ was mixed for 2 minutes using a high-speed mixing and agitation granulator (FM-VG-10, manufactured by Baurec). 1) (Norrec) and then partially alpha starch starch (Starchl500, Nippon Colorcon, cold water soluble content: 15.8% by weight) 21g is dispersed in 180g of purified water, and this dispersion is sprayed with spray nozzle. Granulated while sieving with No. 18 sieve 374g, crospovidone (Polyplasdone XL-10, made by ISP) 20g, light anhydrous caustic acid (Adsolidar 101, Freund Sangyo) 2g and stearic acid magnesium 4 g (Made by Taihei Chemical Industry) was mixed for 2 minutes using a V-type mixer (DV-1, Dalton). Using this rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), tablet weight 200 mg, 8 φ ππη circle, table rotation speed 30 mm, tableting pressure 11.7, 15.6 and 19.5 kN m Tablets were produced under the conditions of ² .

[0066] Example 9

Mitiglinide calcium hydrate 5.0 mg

D-mannito nore 155.0 mg

Partially alpha starch (Starchl500) 26.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Magnesium stearate 3.0 mg

(Total 200.0 mg / 1 tablet) mitiglinide calcium hydrate 17.5 g, D-mannitol (mannite P, Towa Chemical Industry Co., Ltd., average particle size 45 111) 542.5 _§ Oyobi partially Arufa starch (31 & 111 500, Colorcon Japan 70 _§ ) was mixed for 2 minutes using a high-speed mixing and agitation granulator (FM-VG-10, manufactured by Paurek). This mixture was put into a fluidized bed granulator / dryer (LAB-1, manufactured by Parec), and another partially alpha-ized starch (Starchl500, manufactured by Nippon Colorcon, cold water soluble content: 15.8 wt%) 21 _§ of purified water 18 (It was dispersed in ¾ and granulated while spraying this dispersion with a spray nozzle. 372 g of the granulated product sieved with No. 18 sieve, 20 g of crospovidone (Poly plasdone XL-10, ISP), light anhydrous Caic acid (Adsolidar 101, manufactured by Freund Industrial Co., Ltd.) 2 g and magnesium stearate (produced by Taihei Chemical Industrial Co., Ltd.) 6 g were mixed for 2 minutes using a V-type mixer (DV-1, manufactured by Dalton Co.). Using a rotary tableting machine (Correct 12 HUK, manufactured by Kikusui Seisakusho) under the conditions of tablet weight 200 mg, 8 φ ΐΜη circle, table rotation speed 30 rpm, tableting pressure 11.7, 15.6 and 19.5 kN m ² Made.

[0067] Example 10

Mitiglinide calcium hydrate 5.0 mg

D-mannito nore 155.0 mg Partially alpha starch (Starchl500) 6.0 mg

Partially alpha starch (PCS) 20.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Magnesium stearate 3.0 mg

(Total 200.0 mg / 1 tablet) Mitiglinide calcium hydrate 17.5g, D_mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 xm) and 542.5g of partially alpha-unified starch (PCS, manufactured by Asahi Kasei Kogyo, 70 ₈ was mixed for 2 minutes using a high-speed mixing and agitation granulator (FM-VG-10, manufactured by Paurek). This mixture was put into a fluidized bed granulator / dryer (LAB-1, Baurek). Separately alpha-starch starch (Starchl500, Nippon Colorcon, cold water soluble content: 15.8% by weight) 21 _§ of purified water 18 ( Then, the resulting dispersion was sprayed with a spray nozzle and granulated, and 372 g of the granulated product sieved with No. 18 sieve, 20 g of crospovidone (Polyplasdone X L-10, ISP), light anhydrous 2 g of caustic acid (Adsolidar 101, manufactured by Freund Corporation) and 6 g of magnesium stearate (produced by Taihei Chemical Industry) were mixed for 2 minutes using a V-type mixer (DV-1, Dalton). Using a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho), the tablet weight is 200 mg, 8 φ ππη circular, table rotation speed 30 mm, tableting pressure 11.7 and 15.6 kN m ² Made.

Example 11

Mitiglinide calcium hydrate 10.0 mg

D-mannito nore 50.0 mg

Lactose 114.2 mg

Partially alpha starch (Starchl500) 3.75 mg

Partially alpha starch (PCS) 11.25 mg

Crospovidone 6.0 mg

Aspartame 0.8 mg

Light anhydrous anhydrous 1.0 mg Magnesium stearate 3.0 mg

(Total 200.0 mg / tablet) Mitiglinide calcium hydrate 200g, D_mannitol (Mannit P, manufactured by Towa Kasei Kogyo Co., Ltd., average particle size 45 xm) 1000g, partially alpha-unified starch (PCS, manufactured by Asahi Kasei Kogyo Co., Ltd., cold water) (Soluble content: 1.2% by weight) 225 ₈ Sugar partially starched starch (5 & 111500, made by Nippon Colorcon, cold water soluble content: 15.8% by weight) 75 ₈ -10, manufactured by Paul Trek) for 3 minutes. In this state, 465 g of purified water was added to the mixture in a high-speed mixing and agitation granulator (FM-VG-10, manufactured by Pou Lec), granulated, and the wet granulated product was then fluidized-bed granulated dryer ( LAB-1, Paurek) and dried at an inlet temperature of 80 ° C. The dried granulated product was sized using a power mill (P_02S, manufactured by Dalton). Granulated granules 150g, lactose (Tablettose80, made by Megre, average particle size 145 μm) 228.4g, crospovidone (Polyplasdone XL-10, made by ISP) 12g and aspartame 1.6g, V type mixer (DV -1, manufactured by Danoleton) for 3 minutes. Further, 2 g of light anhydrous caustic acid (Adsolidar 101, manufactured by Freund Sangyo) and 6 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) were added and mixed for 2 minutes. This tableting mixture was tableted using a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho) under the conditions of tablet weight 200 mg, 8 φ ππη circle, table rotation speed 30 mm, tableting pressure 19.5 kN / cm ² Made.

Comparative Example 8

Mitiglinide calcium hydrate 5.0 mg

D-mannito nore 155.0 mg

Partially alpha starch (PCS) 26.0 mg

Crospovidone 10.0 mg

Light anhydrous anhydrous 1.0 mg

Magnesium stearate 3.0 mg

(Total 200.0 mg / 1 tablet) 17.5 g of mitiglinide calcium hydrate, D_mannitol (Mannit P, Towa Kasei Kogyo) , Average particle size 45 μΐη) 542.5g and partially alpha starch (PCS, manufactured by Asahi Kasei Kogyo Co., Ltd., cold water soluble content: 1.2% by weight) 70 _§ , high-speed mixing and agitation granulator (FM-VG-10, For 2 minutes. This mixture is put into a fluidized bed granulator / dryer (LAB-1, manufactured by Paurek), and 21 g of partially alpha-monoized starch (PCS, manufactured by Asahi Kasei Kogyo Co., Ltd., cold water soluble content: 1.2% by weight) is dispersed in 180 g of purified water. Then, this dispersion was granulated while spraying with a spray nozzle. 372g of granulated material sieved by No. 18 sieve, 20g of crospovidone (Polyplasdone XL_10, manufactured by ISP), 2g of light anhydrous caustic acid (Adsolidar 101, manufactured by Freund Industries) and 6g of magnesium stearate (produced by Taihei Chemical Sangyo), V Mix for 2 minutes using a type mixer (DV_1, manufactured by Dalton). Using this tableting mixture, a rotary tableting machine (Correct 12HUK, manufactured by Kikusui Seisakusho) was used under the conditions of tablet weight 200 mg, 8 φ ππη circle, table rotation speed 30 mm, tableting pressure 11.7 kN m ² . Tablets were made.

[Table 3]

Industrial applicability

The orally disintegrating tablet of the present invention has sufficient hardness not to be damaged in the distribution process and rapidly disintegrates or dissolves in the oral cavity, so that it is taken by elderly people and patients who have difficulty swallowing children. It is useful as an easy-to-use dosage form.

Claims

The scope of the claims

[I] An orally disintegrating tablet containing a) an active ingredient, b) a sugar or sugar alcohol, c) a partially alpha-ized starch having a cold water soluble content of 10 to 20% by weight, and d) a disintegrant.

[2] Sugar or sugar alcohol power The orally disintegrating tablet according to claim 1, which is at least one selected from lactose and D_mannitol.

[3] The orally disintegrating tablet according to claim 1, which is sugar or sugar alcohol power D_mannitol.

[4] The orally disintegrating tablet according to claim 1, wherein the disintegrant is at least one selected from crospovidone and corn starch.

[5] The orally disintegrating tablet according to claim 1, wherein the disintegrant is crospovidone.

[6] The orally disintegrating tablet according to claim 1, further comprising partially alpha-monified starch having a cold water soluble content of less than 10% by weight.

[7] Partially alpha-unified starch with a cold water soluble content of 10 to 20% by weight Formulation 1

The orally disintegrating tablet according to claim 1, wherein the amount is 0.5 to 30 parts by weight with respect to 00 parts by weight.

[8] Granules containing (I) a) active ingredient, b) sugar or sugar alcohol, and c) partially alpha-unified starch having a cold water soluble content of 10-20% by weight, and (ii) disintegration Orally disintegrating tablet containing the agent.

[9] The orally disintegrating tablet according to claim 8, which is at least one selected from sugar or sugar alcohol power and lactose and D_mannitol.

10. The orally disintegrating tablet according to claim 8, which is sugar or sugar alcohol power D-mannitol.

[II] The orally disintegrating tablet according to claim 8, wherein the disintegrant is at least one selected from the group consisting of crospovidone and corn starch.

12. The orally disintegrating tablet according to claim 8, wherein the disintegrant is crospovidone.

[13] The orally disintegrating tablet according to claim 8, wherein the granulated product further contains partially alpha-monified starch having a cold water-soluble content of less than 10% by weight.

[14] The orally disintegrating tablet according to claim 1 or 8, wherein the active ingredient is mitiglinide calcium hydrate.

[15] The orally disintegrating tablet according to claim 1 or 8, wherein the active ingredient is ritodrine hydrochloride.

[16] a) active ingredient, b) sugar or sugar alcohol, and c) 10% to 20% by weight soluble in cold water A method for producing an orally disintegrating tablet, comprising mixing a disintegrant with a granulated product containing partially alpha-ized starch.

17. The production method according to claim 16, wherein the granulated product further contains partially alpha-monified starch having a cold water soluble content of less than 10% by weight.

[18] Granulation obtained by granulating a mixture containing a) active ingredient and b) sugar or sugar alcohol while spraying partially pregelatinized starch having a cold water soluble content of 10 to 20% by weight. A method for producing an orally disintegrating tablet comprising mixing a disintegrant with a product and compression molding

[19] The production method according to claim 18, wherein the mixture further comprises partially pregelatinized starch having a cold water soluble content of less than 10% by weight.

[20] Granulate a mixture containing a) active ingredient, b) sugar or sugar alcohol, and c) partially pregelatinized starch having a cold water soluble content of 10-20% by weight with the addition of water. A method for producing an orally disintegrating tablet, wherein the obtained granulated product is mixed with a disintegrant and compression-molded.

[21] a) active ingredient, b) sugar or sugar alcohol, c) portion with 10-20% by weight of cold water soluble alpha alpha starch, and d) portion with less than 10% by weight of cold water soluble A method for producing an orally disintegrating tablet, comprising granulating a mixture containing alpha-ized starch while adding water, mixing a disintegrant with the obtained granulated product, and compressing the mixture.