JP3967767B1 - Method for producing intraoral rapidly disintegrating tablet - Google Patents

Abstract

[PROBLEMS] To produce a rapidly disintegrating intraoral tablet having excellent disintegration, sufficient hardness and wear resistance in normal handling, and having a good feeling of taking, using a conventional conventional pharmaceutical production equipment as it is. Providing a method.
[MEANS FOR SOLVING PROBLEMS] A 50% ethanol aqueous solution of polyvinylpyrrolidone K-30 is added to the crystal nucleus of crystalline lactose, and then silicic acid anhydride is added to etezamide in advance on the 50% ethanol aqueous solution of polyvinylpyrrolidone K-30. Mix and apply the poorly soluble drug ethenamide with modified powder properties of ethenamide to powder coat, then dry and size the powder-coated particles to powder-coated particles, Then, granulated lactose, crystalline cellulose, crospovidone and maltitol are added and mixed to form a mixture. Then, magnesium stearate is added to and mixed with this mixture, followed by tableting to obtain an orally rapidly disintegrating tablet.
[Selection figure] None

Description

  The present invention relates to a method for producing an excellent intraoral quick-disintegrating tablet with ordinary equipment. More specifically, it is obtained by using a solution or dispersion containing a water-soluble polymer and / or a water-insoluble polymer as a core, and further adding and mixing silicic anhydride in advance. The present invention relates to a method for producing an intraoral rapidly disintegrating tablet containing particles that are powder-coated with a modified poorly soluble drug or a powder containing the modified poorly soluble drug.

  Orally disintegrating preparations are described in “Silver Science Research, Ministry of Health and Welfare Science” by Sugihara et al. P. The introduction of Scherer's ZYDIS formulation was the beginning, and research and development became active. “Immediately useful particle design and processing technology (Jiho) 221 pages, 2003”.

  In recent years, active research has been conducted on tablets that dissolve or disintegrate rapidly in the oral cavity as dosage forms that can be easily taken by patients such as the elderly and children who are difficult to take ordinary oral preparations. There are also many commercialized products “Pharm.Tech.Japan, Vol. 14, No. 11, p. 111, 1998”.

As is well known, methods for producing orally disintegrating tablets are roughly divided into three. The first is a template formulation. This is a method in which a drug-dispersed or dissolved solution is filled in a pre-formed pocket such as a PTP seal and sealed after freeze-drying. This is a method in which the tablet is molded at a low pressure and dried to form a strong tablet. The third method is a general tablet type formulation. This can be divided into a porous molded body preparation, a preparation using an easily moldable additive and a preparation for disintegration mechanism. The porous molded body preparation is intended to improve tablet strength by molding a mixed granulated product such as drug and saccharide at low pressure, and then humidifying and drying, heating, and the like.
The preparation using an easily moldable additive is intended to improve moldability by miniaturization of an easily moldable additive such as crystalline cellulose and an additive such as sugar.
In addition, the disintegration mechanism devised formulation is intended to improve disintegration by using a super disintegrant, reducing the amount of lubricant (external lubricant), and using foaming action by acid-base reaction. Technology (Jiho), p.221, 2003 and Pharm.Tech.Japan, Vol. 14, No. 11, p.111, 1998 ”.

  Patent Document 1 discloses an intraoral quick-disintegrating tablet using aniseracem as a drug and containing a water-soluble polymer having a surface tension reducing ability.

  In Patent Document 1, for the purpose of providing a preparation having no stickiness or sliminess in the oral cavity, polyvinylpyrrolidone generally used as a binder and a water-soluble polymer having a surface tension reducing ability are used as hydroxypropylmethylcellulose. Etc. are also used in combination, and the surfactant dioctyl sodium sulfosuccinate is also blended. In the test examples, the state of disintegration is observed, but there is no description of the disintegration time. The combined use of water-soluble polymers in the range of 2.5 to 3.0% by weight results in a disintegrating effect, and the presence of 0.04% by weight of a surfactant that has a laxative action helps improve health. Is concerned about the impact of

  Patent Document 2 discloses a formulation method in which crystalline cellulose adsorbed with vitamin K is granulated with a solvent, dried, a saccharide is added thereto, an aqueous solution containing a binder is added, kneaded, and wet tableting is performed. It is disclosed.

  However, since this preparation method is a tablet using the wet tableting method, a special preparation device is required instead of a normal equipment.

  Patent Document 3 discloses a tablet in which the drug is substantially insoluble in water and is composed of an inorganic excipient, a disintegrant, a water-soluble excipient, and crystalline cellulose.

However, since the thing of this patent document 3 contains the inorganic excipient | filler insoluble in water, it is a problem at the point of taking feeling, such as roughness in an oral cavity.
Japanese Patent Laid-Open No. 11-130661 JP 2000-344664 A Special Table 2002-505269

  The problem to be solved by the present invention is that an intraoral quick-disintegrating tablet having excellent utility cannot be produced unless it is a special production facility, not a conventional facility existing in the past.

  Therefore, the object of the present invention is to provide excellent disintegration, sufficient hardness and wear resistance in ordinary handling by a conventional production facility that has been conventionally known, without requiring special new production facilities, and An object of the present invention is to provide a method capable of producing an intraoral rapidly disintegrating tablet having a good feeling of administration.

  The present inventors have disclosed a method for producing an intraoral quick-disintegrating tablet using the hydrophilic drug ascorbic acid in Japanese Patent No. 3884056 (Japanese Patent Application No. 2006-018342) already obtained. By using the pharmaceutical technology related to this patent, an orally fast-disintegrating tablet was produced using a sparingly soluble drug etenzamide, which is difficult to dissolve in water. The superior disintegration advantage compared to the conventional manufacturing method (wet tableting method) Could not be confirmed.

  Therefore, the production of an orally rapidly disintegrating tablet of the poorly soluble drug etenzamide was examined again.

  In advance, silicic anhydride was added to and mixed with etenzamide to improve the powder physical properties of etenzamide. This is referred to as modified etenzamid. An intraoral rapidly disintegrating tablet was produced using this modified etenzamid.

  First, using crystalline lactose as a core, an ethanol solution of polyvinylpyrrolidone K-30 is added, and then the modified ethenzamide is sprayed thereon to powder-coat the particle core. After repeating this powder coating operation, drying and drying are performed. The particles were sized to obtain powder-coated particles.

  The powder coated particles are then blended with granulated lactose, Kollidon-CL and maltitol and mixed uniformly. Further, magnesium stearate is added and secondarily mixed. This mixed powder was 8 mm in diameter and 200 mg in 1 tablet, and tableted by a rotary tableting machine to give tablets.

  However, as in the case of production with unmodified ethenzamid, the superiority of disintegration could not be confirmed as compared with the conventional production method (wet tableting method).

  Next, using a mixed solution of polyvinyl pyrrolidone K-30 in water ethanol instead of an ethanol solution of polyvinyl pyrrolidone K-30, an intraoral quick-disintegrating tablet containing modified ethenzamide was produced in the same manner. In addition, it was confirmed that an intraoral quick-disintegrating tablet having dramatically superior disintegration property can be produced as compared with the conventional manufacturing method (wet tableting method).

  In addition, whilst it is known that etenzamide generates whiskers on the tablet surface over time, whisker generation was not observed over time in the intraoral rapidly disintegrating tablets produced according to the present invention.

In the method for producing an intraoral rapidly disintegrating tablet according to claim 1 of the present invention, a 50% ethanol aqueous solution of polyvinylpyrrolidone K-30 is added to the particle core of crystalline lactose,
Next, silicic anhydride is added to and mixed with ethenamide in advance on a 50% ethanol aqueous solution of polyvinylpyrrolidone K-30, and the poorly soluble drug etenzamide with modified powder properties of ethenamide is applied to powder the particle core. Coated,
Next, the powder-coated particles are dried and sized to form powder-coated particles.
Next, granulated lactose, crystalline cellulose, crospovidone and maltitol are added to the powder coated particles and mixed to form a mixture.
Next, magnesium stearate is added to and mixed with this mixture, and then tableted to obtain an intraoral rapidly disintegrating tablet.

The method for producing an intraoral rapidly disintegrating tablet according to claim 2 comprises adding a 50% ethanol aqueous solution of polyvinylpyrrolidone K-30 to the particle core of crystalline lactose,
Next, silicic anhydride is added to and mixed with ethenzamide in advance on a 50% ethanol aqueous solution of polyvinylpyrrolidone K-30, and then the poorly soluble drug ethenzamide modified with the powder physical properties of ethenzamide is applied to powder the particle core. Coated,
Next, the powder-coated particles are dried and sized to form powder-coated particles.
Next, granulated lactose, crystalline cellulose, crospovidone and maltitol are added to the powder coated particles and mixed to form a mixture.
Next, this mixture is tableted by a tableting machine in which magnesium stearate is previously attached to the punch and mortar to obtain an intraoral rapidly disintegrating tablet.

  According to the present invention, without requiring a special new production facility, using a conventional conventional pharmaceutical production facility as it is, with excellent disintegration and sufficient hardness and wear resistance in normal handling, In addition, it is possible to produce an intraoral quick disintegrating tablet with a good feeling of taking.

  The method for producing an intraoral rapidly disintegrating tablet according to the present invention comprises a saccharide crystallized in a tablet or a particle containing 5 to 40% by weight of a granulated saccharide as a core, and a water-soluble polymer and / or water. Of powders coated with a sparingly soluble drug etenzamide using a solution containing a polymer insoluble in 1 to 30% by weight of crospovidone, carboxymethylcellulose, partially pregelatinized starch, low substituted hydroxypropylcellulose and corn starch The disintegrant is mixed with 0.1 to 5% by weight of magnesium stearate, sucrose fatty acid ester and talc lubricant, and tableted by the internal lubricant tableting method or the external lubricant tableting method.

  In addition, this invention is applicable also to fields, such as a quasi-drug and a foodstuff, including the pharmaceutical field | area.

  The particles (core) made of saccharides used in the present invention are sugars such as lactose, fructose and glucose, sugar alcohols such as maltitol, xylitol and mannitol, crystals thereof, or powders of sugar and sugar alcohol. Such as granulated particles.

  Examples of the water-soluble polymer used in the present invention include polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene glycol, gum arabic, sodium alginate, gelatin, pullulan and the like. These water-soluble polymers can be used alone or in combination of two or more.

  Moreover, you may mix | blend a fragrance | flavor, a stabilizer, etc. as needed.

  The content of the saccharide particles (core) used in the present invention is 5 to 40% by weight based on the whole tablet, but the content of the saccharide particles (core) is preferably 5 to 20% by weight.

  Moreover, although content of the disintegrating agent used for this invention is 1 to 30 weight%, Preferably it is 1 to 10 weight%.

  Further, the content of the lubricant used in the present invention is 0.1 to 5% by weight, but when the blending amount of magnesium stearate as the lubricant is 0% by weight, the flow of the tableting powder Since the disintegration tendency was delayed at 2.0% by weight, the lubricant content is preferably 0.1 to 1.0% by weight.

  The tableting pressure of the tablet in the production method of the present invention is 0.1 to 0.5 ton considering friability and disintegration, but 0.1, 0.2, 0.3, 0.4 and As a result of measuring the physical properties of the tablet with a tableting pressure of 0.5 ton, the disintegration degree is within 10 seconds, the tablet hardness is 30 N or more, and the degree of friability is 0.5% or less. It is preferable to form a tablet with a tableting pressure of ˜0.5 ton.

  The method of adding the lubricant in the present invention may be an internal lubricant tableting method in which the conventional tableting powder is blended and mixed, but preferably, the punch or die mounted on the tableting machine. This is an external lubricant tableting method in which a lubricant is applied to the skin.

Various ingredients can be blended in the tablet of the present invention depending on the application. In the pharmaceutical field, for example, antihistamines such as clemastine fumarate, hydroxyzine pamoate, diphenhydramine, cyproheptadine hydrochloride as poorly soluble pharmaceutical ingredients.
Antitussive expectorant such as dextromethorphan hydrobromide, guaifenesin, thiophylline.
Antihypertensive agents such as spironolactone, triamterene, methyldopa and reserpine.
Arrhythmic agents such as ajmaline and quinidine sulfate.
Diuretics such as hydrochlorothiazide and furosemide.
Antidiarrheal agents such as berberine chloride.
H2-receptor antagonists such as simeditine and famotidine.
Antipyretic analgesic and anti-inflammatory agents such as acetaminophen, ibubrofen, etenzamide.
Hypnotic sedatives such as diazepam, nitrazepam, and phenobarbital.

  Nutritional tonic health medicines are naturally derived substances such as herbal medicines and herbal medicines. Protein. amino acid. Vitamins such as vitamin A, vitamin B12, vitamin D, vitamin E, and vitamin K are included.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited by these descriptions.

  The method for producing an intraoral rapidly disintegrating tablet according to the present invention is characterized in that it uses a poorly soluble drug ethenamide in which the powder physical properties of ethenamide are modified.

  Thus, regarding the modification of etenzamide, the particle size distribution of ethenamide by the addition of light silicic anhydride will be described. Light silicic acid was added to ethenzamide and 9.9 g and 9.5 g of ethenzamide in advance, and the particle size distribution of each mixed ethenzamide was measured using a 30-200 mesh sieve. The results are shown in Table 1.

  Study Example 1 in Table 1 is the particle size distribution of etenzamide with the addition of 0.1% light anhydrous silicic acid, and Study Example 2 is the particle size distribution of etenzamide with the addition of 0.5% light anhydrous silicic acid. 1 is the particle size distribution of etenzamid.

注） ３０Ｍ ＯＮは、３０メッシュの篩を通過しない粉末の割合（％）
２００Ｍ ＰＡＳＳは、２００メッシュの篩を通過した粉末の割合（％）

Note) 30M ON is the percentage of powder that does not pass through a 30 mesh screen (%)
200M PASS is the percentage of powder that passed through a 200 mesh sieve (%)

  From the results in Table 1, in the etenzamide of Comparative Example 1, the proportion of powder that does not pass through the 30 mesh and 50 mesh sieves is large. It seems that etenzamide is aggregated.

  On the other hand, in Study Example 1 and Study Example 2 in which light anhydrous silicic acid was added, the proportion of powder that did not pass through the 30-mesh and 50-mesh screens was extremely small. In Study Example 1, powder that did not pass through the 140-mesh screen. The ratio accounts for 70%. In Study Example 2, the proportion of the powder that passed through the 200-mesh sieve was 35%, and it was considered that the aggregation of etezamide was improved.

  From the above examination results, the addition amount of light silicic acid 0.5% was determined as the optimum addition amount.

  Next, the particle size distribution of the etenzamide powder coating particles according to the binding liquid composition will be described. A binding solution of polyvinylpyrrolidone (PVP) K-30 (solid content 0.045 g) is added to 10 g of crystalline lactose. Here, 0.5 g of light anhydrous silicic acid is added to 9.5 g of ethenamide in advance, and the mixed modified etenzaamide is added. This operation was repeated 10 times, and after powder coating, drying and sizing were performed to obtain coated particles. About the coating particle made with each binding liquid composition, the particle size distribution was measured using a 30-200 mesh sieve. The results are shown in Table 2.

  In Examination Example 3 in Table 2, the composition of the binding solution is ethanol: water = 75: 25, Examination Example 4 is that the composition of the binding solution is ethanol: water = 50: 50, and Examination Example 5 is the binding. The liquid composition is ethanol: water = 25: 75, and Comparative Example 2 is ethanol 100%.

  From the results shown in Table 2, when the composition of the binding solution of Comparative Example 2 is 100% ethanol, the proportion of the powder that has passed through the 200 mesh sieve accounts for about 50%. This is probably because ethenzamide is dissolved in ethanol, and thus ethenzamide is dissolved by ethanol without being powder-coated and aggregated with ethenzamide.

  On the other hand, in Examination Examples 3 to 5 containing water in the binding liquid composition, the ratio of the powder that passed through the 200 mesh sieve was greatly reduced as compared with 100% of the binding liquid composition ethanol in Comparative Example 2.

  Therefore, it seems that ethenamide is powder-coated on crystalline lactose. When the composition of the binding solution in Study Example 4 is ethanol: water = 50: 50, the ratio of the powder that has passed through the 200 mesh sieve is 10% or less.

  From the above examination results, the binding solution composition was ethanol: water = 50: 50 as the optimum binding composition.

  Next, the Example of the manufacturing method of the intraoral quick-disintegrating tablet of this invention using the raw material component shown in the following Table 3 is demonstrated.

１）軽質無水ケイ酸（日本アエロジル（株） 商品名：アエロジル２００）
２）造粒乳糖（旭化成（株） 商品名：Ｓｕｐｅｒ Ｔａｂ）
３）結晶セルロース（旭化成（株） 商品名：アビセルＰＨ１０２）
４）クロスボビドン（ＢＡＳＦ武田ビタミン（株） 商品名：コリドンＣＬ）
５）マルチトール（東和化成工業(株) 商品名：粉末マルチトールＧ３）

1) Light anhydrous silicic acid (Nippon Aerosil Co., Ltd., trade name: Aerosil 200)
2) Granulated lactose (Asahi Kasei Corporation trade name: Super Tab)
3) Crystalline cellulose (Asahi Kasei Corporation trade name: Avicel PH102)
4) Crosbovidone (BASF Takeda Vitamin Co., Ltd., trade name: Kollidon CL)
5) Maltitol (Towa Kasei Kogyo Co., Ltd., trade name: powdered maltitol G3)

Example 1
10 g of crystalline lactose is put into a mixer, and a 50% ethanol aqueous solution of polyvinylpyrrolidone (PVP) -30 (solid component 0.045 g) is added thereto. Thereto, 0.5% light silicic anhydride is added in advance to 9.5 g of ethenzamide, and the mixed modified ethenzamide is added. This operation is repeated 10 times, powder-coated and then dried to form coated particles. 16.5 g of granulated lactose, 38.5 g of crystalline cellulose, 3 g of crosbovidone and 22 g of maltitol are added to the coated particles and mixed. To this mixture, 0.3 g of magnesium stearate as a lubricant was added and mixed, and a tableting machine was used to obtain an intraoral rapidly disintegrating tablet with a tableting pressure of 0.1 ton and a diameter of 8 mm and a tablet weight of 200 mg.

Example 2
The same procedure as in Example 1 was performed except that the raw material components shown in Example 1 in Table 3 were used, and the tableting pressure of the tableting machine was changed to 0.2 ton, and an intraoral rapidly disintegrating tablet having a diameter of 8 mm and a tablet weight of 200 mg. Got.

Example 3
The same procedure as in Example 1 was performed except that the tableting pressure of the tableting machine was changed to 0.3 ton using the raw material components shown in Example 1 of Table 3, and an intraoral rapidly disintegrating tablet having a diameter of 8 mm and a tablet weight of 200 mg. Got.

Example 4
Using the raw material components shown in Example 1 of Table 3, the same operation as in Example 1 was performed except that the tableting pressure of the tableting machine was changed to 0.4 ton, and an intraoral rapidly disintegrating tablet having a diameter of 8 mm and a tablet weight of 200 mg was obtained. Obtained.

Example 5
Using the raw material components shown in Example 1 of Table 3, the same operation as in Example 1 was performed except that the tableting pressure of the tableting machine was changed to 0.5 ton, and an intraoral rapidly disintegrating tablet having a diameter of 8 mm and a tablet weight of 200 mg. Got.

Example 6
10 g of crystalline lactose is put into a mixer, and a 50% ethanol aqueous solution of polyvinylpyrrolidone (PVP) -30 (solid component 0.045 g) is added thereto. Thereto, 0.5% light silicic anhydride is added in advance to 9.5 g of ethenzamide, and the mixed modified ethenzamide is added. This operation is repeated 10 times, powder-coated and then dried to form coated particles. 16.5 g of granulated lactose, 38.5 g of crystalline cellulose, 3 g of crosbovidone and 22 g of maltitol are added to the coated particles and mixed. Next, this mixture was tableted with a tableting machine in which 0.3 g of magnesium stearate, a lubricant, was previously attached to the punch and mortar with a tableting pressure of 0.1 ton, and the oral cavity having a diameter of 8 mm and a tablet weight of 200 mg. Internally disintegrating tablets were obtained.

Example 7
The same procedure as in Example 6 was performed except that the tableting pressure of the tableting machine was changed to 0.2 ton using the raw material components shown in Example 1 of Table 3, and an intraoral rapidly disintegrating tablet having a diameter of 8 mm and a tablet weight of 200 mg. Got.

Example 8
The same procedure as in Example 6 was carried out except that the raw material components shown in Example 1 in Table 3 were used and the tableting pressure of the tableting machine was changed to 0.3 ton, and an intraoral rapidly disintegrating tablet having a diameter of 8 mm and a tablet weight of 200 mg. Got.

Example 9
The same procedure as in Example 6 was performed except that the tableting pressure of the tableting machine was changed to 0.4 ton using the raw material components shown in Example 1 of Table 3, and an intraoral rapidly disintegrating tablet having a diameter of 8 mm and a tablet weight of 200 mg. Got.

Example 10
The same procedure as in Example 6 was performed except that the tableting pressure of the tableting machine was changed to 0.5 ton using the raw material components shown in Example 1 of Table 3, and an intraoral rapidly disintegrating tablet having a diameter of 8 mm and a tablet weight of 200 mg. Got.

Comparative Example 3
0.5% light silicic acid anhydride was added to ethenzamide 9.5 g in advance and mixed to each of modified etenzamide, crystalline lactose 10 g, granulated lactose 16.5 g, crystalline cellulose 38.5 g, crospovidone 3 g and maltitol 22 g. Is put into a mixer and mixed to obtain a uniform mixture. A 50% ethanol aqueous solution of polyvinylpyrrolidone (PVP) K-30 (solid content: 0.045 g) is added to this mixture and kneaded. This is granulated, dried, sized, and 0.3 g of magnesium stearate, a lubricant, is added to and mixed with this granulated product, and tableted with a tableting pressure of 0.3 ton using a tableting machine. An intraoral rapidly disintegrating tablet having a diameter of 8 mm and a tablet weight of 200 mg was obtained.

Test example 1
The physical properties of each of the tablets obtained by Examples 1 to 5 by the internal lubricant tableting method and the tablets obtained by Examples 6 to 10 by the external lubricant tableting method were measured. The results are shown in Table 4.

  From the results in Table 4, in the external lubricant tableting method of Example 6 to Example 10, the tablet disintegrated more quickly than the internal lubricant tableting method of Example 1 to Example 5 with respect to the disintegration degree of JP. . When the tableting pressure was 0.3 ton or higher, the tablet disintegration degree was within 10 seconds, the tablet hardness was about 30 N or more, and the friability was 0.5% or less. Therefore, the external lubricant tableting method is an excellent method for producing an intraoral quick disintegrating tablet.

Test example 2
The physical properties such as the disintegration degree of the tablets obtained in Example 3 and Comparative Example 3 were measured.

  In addition, according to the disintegration test method described in the Japanese Pharmacopoeia, the disintegration degree of tablets was measured using water as a test solution, and the average value of 6 tablets was calculated. The oral disintegration time was calculated by calculating the average value of three test results for each tablet for four healthy subjects. For the tablet hardness, a tablet hardness meter (TBH200 manufactured by Elbeca) was used to calculate the average value of 10 tablets. The tablet friability was measured by using a tablet friability tester described in Japanese Pharmacopoeia (TFT120 manufactured by Toyama Sangyo Co., Ltd.), rotating for 4 minutes at 25 rpm for 1 minute. The results are shown in Table 5.

  From the results of Table 5, in the conventional wet tableting method (Comparative Example 3), the JP disintegration degree was 6 times that of the production method of the present invention (Example 3). In addition, the oral disintegration time required 5 times as long as the wet tableting method (Comparative Example 3) of the production method of the present invention (Example 3).

  Therefore, the intraoral quick-disintegrating tablet obtained by the production method of the present invention has a disintegration degree of 10 seconds or less, a tablet hardness of 30 N or more and a friability of 0.5% or less, and the conventional wet compression. This method is superior to the tablet method.

  Next, observation of the whisker of the intraoral rapidly disintegrating tablet obtained by the manufacturing method according to the present invention will be described.

Study example 6
10 g of crystalline lactose is put into a mixer, and an ethanol solution of polyvinylpyrrolidone (PVP) K-30 (solid content: 0.045 g) is added thereto. There, 10 g of etenzamid is added. This operation is repeated 10 times, and after powder coating, it is dried and sized to obtain coated particles. Next, 16.5 g of granulated lactose, 38.5 g of crystalline cellulose, 3 g of crospovidone and 22 g of maltitol are added to the coating particles and mixed. Next, 0.3 g of magnesium stearate, which is a lubricant, was added to this mixture and mixed. Using a tableting machine, a rapidly disintegrating tablet with a tableting pressure of 0.3 ton and a diameter of 8 mm and a tablet weight of 200 mg was obtained. Obtained.

Study example 7
10 g of ethenzamide, 10 g of crystalline lactose, 16.5 g of granulated lactose, 38.5 g of crystalline cellulose, 3 g of crospovidone and 22 g of maltitol are introduced into a mixer and mixed to obtain a uniform mixed powder. Next, an ethanol solution of polyvinylpyrrolidone (PVP) K-30 (solid content: 0.045 g) is added to the mixed powder and kneaded. Next, the kneaded product is granulated, dried and then sized. Add 0.3 g of magnesium stearate, which is a lubricant, to this granulated product and mix. Using a tableting machine, rapidly compress tablets in the mouth with a tableting pressure of 0.3 ton and a diameter of 8 mm and a tablet weight of 200 mg. Obtained.

Test example 3
The etenzamide-containing tablet, the modified etenzamide-containing tablet, and each intraoral rapidly disintegrating tablet were placed in a glass container, and a plastic cap was applied. Furthermore, the cap and the glass container were wrapped and sealed using a synthetic resin sheet, and stored at 40 ° C. and 60 ° C. for 28 days. After storage, the appearance of each sample tablet and glass container was observed with a magnifying glass (magnification: 5 times). The results are shown in Table 6.

０：エテンザミド結晶の析出はみられない。
１：錠剤の表面およびガラス瓶表面・底部に、極めて僅かにエテンザミド結晶の析出がみられる。
２：錠剤の表面およびガラス瓶表面・底部に、僅かにエテンザミド結晶の析出がみられる。
３：錠剤の表面およびガラス瓶表面・底部に、エテンザミド結晶の析出がみられる。

0: No precipitation of ethenamide crystals is observed.
1: Very slight precipitation of ethenzamide crystals is observed on the surface of the tablet and the surface / bottom of the glass bottle.
2: Slight precipitation of ethenzamide crystals is observed on the surface of the tablet and the surface and bottom of the glass bottle.
3: Precipitation of ethenamide crystals is observed on the surface of the tablet and the surface and bottom of the glass bottle.

  From the results shown in Table 6, no difference was observed in the precipitation of ethenamide crystals under storage conditions of 40 ° C. and 60 ° C.

  In the modified etenzamide-containing tablet of Example 3, precipitation of ethenamide crystals was not observed, and the generation of whiskers was suppressed.

  On the other hand, in the tablet containing the coating particles of the ethenamide-containing tablet (Study Example 6), the degree of precipitation of ethenamide crystals was most frequently observed.

  Therefore, in the intraoral quick-disintegrating tablet of Example 3 produced by the method of the present invention, the occurrence of whiskers in the storage state at 40 ° C. and 60 ° C. could be suppressed.

Claims (2)

Add 50% ethanol aqueous solution of polyvinylpyrrolidone K-30 to the crystal nucleus of crystalline lactose,
Next, silicic anhydride is added to and mixed with ethenamide in advance on a 50% ethanol aqueous solution of polyvinylpyrrolidone K-30, and the poorly soluble drug etenzamide with modified powder properties of ethenamide is applied to powder the particle core. Coated,
Next, the powder-coated particles are dried and sized to form powder-coated particles.
Next, granulated lactose, crystalline cellulose, crospovidone and maltitol are added to the powder coated particles and mixed to form a mixture.
Subsequently, after adding and mixing magnesium stearate to this mixture, tableting is performed to obtain an intraoral rapidly disintegrating tablet. Add 50% ethanol aqueous solution of polyvinylpyrrolidone K-30 to the crystal nucleus of crystalline lactose,
Next, silicic anhydride is added to and mixed with ethenzamide in advance on a 50% ethanol aqueous solution of polyvinylpyrrolidone K-30, and then the poorly soluble drug ethenzamide modified with the powder physical properties of ethenzamide is applied to powder the particle core. Coated,
Next, the powder-coated particles are dried and sized to form powder-coated particles.
Next, granulated lactose, crystalline cellulose, crospovidone and maltitol are added to the powder coated particles and mixed to form a mixture.
Next, a method for producing an intraoral quick-disintegrating tablet is obtained by tableting this mixture with a tableting machine in which magnesium stearate is previously attached to a punch and a die to obtain an intraoral quick-disintegrating tablet.