WO2005123040A1

WO2005123040A1 - Tablet rapidly disintegrating in mouth

Info

Publication number: WO2005123040A1
Application number: PCT/JP2005/011301
Authority: WO
Inventors: Chieko Kondou; Yoshitsugu Muguruma; Toshitada Toyoda; Tatsumori Yoshida
Original assignee: Shionogi & Co., Ltd.
Priority date: 2004-06-22
Filing date: 2005-06-21
Publication date: 2005-12-29
Also published as: JPWO2005123040A1; JP3996626B2

Abstract

A tablet rapidly disintegrating in the mouth which is obtained by directly compression-molding a powder consisting substantially of an active ingredient, crystalline cellulose, and an inorganic excipient. The tablet has satisfactory disintegrability, has a secure tablet hardness, and is pleasant to take.

Description

Specification

Oral quick disintegrating tablets

Technical field

The present invention relates to an orally rapidly disintegrating tablet. More specifically, the present invention relates to a rapidly disintegrating tablet in the oral cavity substantially comprising an active ingredient, crystalline cellulose and an inorganic excipient, wherein the weight ratio of crystalline cellulose to the inorganic excipient is 8: 2 to 2: 8. .

Background art

[0002] Elderly people and children have a low swallowing ability, making it difficult to take tablets. There is a need for a formulation that can be easily taken by the elderly and children and that can be swallowed quickly even in adults with the ability to swallow, and that can be taken smoothly without leaving any roughness. Some preparations are known!

[0003] In the production of rapidly disintegrating tablets in the oral cavity, disintegrants are generally used to ensure disintegration. Examples of documents that disclose a rapidly disintegrating tablet in the oral cavity containing a disintegrant include the following documents.

Patent Document 1 (Japanese Patent Application Laid-Open No. 10-182436) describes a rapidly disintegrating tablet in the oral cavity containing a pharmaceutical ingredient, erythritol, crystalline cellulose and a disintegrant. Comparative Example 1 discloses that a preparation containing no disintegrant had a poor oral disintegration time. Further, it was disclosed in Comparative Example 2 that the disintegration time of the preparation in the oral cavity was also poor when only crystalline cellulose was used as the tablet disintegrating component!

Patent Document 2 (Japanese Patent Application Laid-Open No. 2001-58944) describes a rapidly disintegrating tablet in the oral cavity containing a pharmaceutical ingredient, D-mantol, celluloses and a disintegrant. This document discloses that D-mantol having an average particle diameter of 30 to 300 μm is preferred! /. Patent Document 3 (Japanese Patent Application Laid-Open No. 2000-86537) discloses that a powdery product obtained by spray-drying a suspension in which an inorganic substance and a saccharide are uniformly dispersed is tableted together with crystalline cellulose and a disintegrant to rapidly disintegrate in the oral cavity. It is stated that tablets can be obtained. On the other hand, it is described that tablets obtained by directly compressing a simple mixture having the same composition power have poor hardness.

Patent Document 4 (WO00Z54752) discloses that a medicinal ingredient contains a surface modifying group such as light The surface-modified powder is mixed using a high-speed agitation granulator, etc., and a disintegrating agent is added to the surface-modified powder thus obtained, and the mixture is directly compressed into tablets. It states that it can be obtained. Disintegrants are described as being most suitable, partially alpha starch and crospovidone.

Patent Document 5 (Japanese Patent Application Laid-Open No. 2002-284679) describes a thyroid hormone-containing solid preparation substantially free of microcrystalline cellulose and containing 0.1 to 5.0% by weight of an inorganic stabilizer. ing. This formulation is not considered to be an orally rapidly disintegrating tablet. This is to stabilize thyroid hormone by adding an inorganic stabilizing agent, and does not use an inorganic compound as an excipient. In addition, each of the preparation examples contains a disintegrant. Patent Document 6 (Japanese Patent Application Laid-Open No. 2000-273038) describes a preparation containing an active ingredient, lactose, microcrystalline cellulose and light caffeic anhydride, but all preparations contain a disintegrant.

Patent Document 7 (Japanese Patent Application Laid-Open No. 2002-12540) discloses that granules containing a water-soluble drug are blended with a disintegrant, and cellulose powder and Z or inorganic additives are added. It is described that a perfect tablet can be obtained. This document states that "only cellulose powder and Z or an inorganic additive and without a disintegrant, tablet hardness is exhibited, but disintegration is not improved."

Non-patent document 1 (Kyowa Chemical Industry Co., Ltd.'s pamphlet (direct injection excipient anhydrous calcium hydrogen phosphate GS)) contains data on formulations containing crystalline cellulose and anhydrous calcium hydrogen phosphate. However, it is still a formulation containing a disintegrant.

Examples of the intraorally rapidly disintegrating tablet containing no disintegrant include the following.

Patent Document 8 (Japanese Patent Application Laid-Open No. 5-310558) describes a preparation containing mannitol and Z or lactose and containing a sorbitol powder having a bulk specific gravity of less than 60 gZml. This document also describes preparations that do not contain disintegrants such as carboxymethylcellulose and low-substituted hydroxypropylcellulose. In this document, by using a sorbitol powder having a bulk specific gravity of less than 60 gZ ml, the amount of other additives (eg, a cellulose compound, an acrylic acid compound, gelatin, etc.) can be reduced, It is stated that discomfort when contained in the mouth can be improved. Crystalline cellulose and Tablets containing inorganic excipients and no disintegrant are described, but those containing mannitol, lactose, and sorbitol, and the comparative examples without sorbitol show tableting problems and mouthfeel. It is described that it is evil.

Patent Document 9 (Japanese Patent Application Laid-Open No. 11-199517) describes a rapidly disintegrating buccal tablet containing a drug, crystalline cellulose, and sugar alcohol, and not containing a disintegrant. It is disclosed that by compressing and molding a mixture of crystalline cellulose and sugar alcohol at a specific ratio, a rapidly disintegrating oral tablet having sufficient disintegration properties can be obtained without adding a disintegrant. Literature 10 (Japanese Patent Application Laid-Open No. 2000-1428) discloses a magnesium oxide tablet, an excipient, and a talc, and a magnesium oxide tablet in which darkening is prevented by directly compressing magnesium stearate or calcium stearate. It states that it can be obtained. This preparation uses magnesium oxide as an active ingredient and has no description of disintegration time. All of the preparations with a disintegration time of less than 1 minute (Examples 2, 3, and 4) contain a disintegrant.

Patent Document 11 (WO98Z02185) describes an orally rapidly disintegrating tablet containing an excipient and erythritol. As a formulation containing no disintegrant, a formulation that also has erythritol and crystalline cellulose power (Example 2) and a formulation that also has erythritol and precipitated calcium carbonate power (Example 10) are disclosed. In the present invention, erythritol is essential, and there is no description of a preparation containing no erythritol. Examples of preparations containing the active ingredient include those containing a disintegrant (Example 13).

Patent Document 12 (Japanese Patent Application Laid-Open No. 8-143463) discloses a preparation containing useful enteric bacteria, which contains useful enteric bacteria and magnesium aluminate metasilicate, and further contains calcium citrate or anhydrous calcium hydrogen phosphate. Is described. It is stated that magnesium aluminate metasilicate is essential to increase the viable cell count in tablets. This preparation does not contain a disintegrant, but no description is given for a preparation using microcrystalline cellulose.

Patent Document 13 (Patent No. 2702325) discloses a method of obtaining granules capable of forming a calcium compound and polyvinylpyrrolidone, and then compressing the granules together with a disintegrant, a lubricant, a flavoring agent, and a flavoring agent. It is disclosed that tablets can be obtained. It is disclosed that the use of polyvinylpyrrolidone as a binder can reduce the powderiness felt when other binders are used. In Example 5, a pharmaceutical composition containing no disintegrant is described, but crystalline cellulose is not used. There is no description about the disintegration time.

The above documents describe a rapidly disintegrating tablet in the mouth using saccharides and Z or sugar alcohol as an excipient, and a rapidly disintegrating tablet in the mouth using a disintegrant. It is described and suggested that direct compression molding of a powder composed of microcrystalline cellulose and inorganic excipients can provide a fast-disintegrating oral tablet with good disintegration properties, tablet hardness and good mouth feel. Being,.

[0005] Patent Document 1: Japanese Patent Application Laid-Open No. H10-182436

Patent Document 2: JP 2001-58944A

Patent Document 3: JP 2000-86537

Patent document 4: WO00Z54752

Patent Document 5: JP-A-2002-284679

Patent Document 6: JP-A-2000-273038

Patent Document 7: JP 2002-12540

Patent Document 8: JP-A-5-310558

Patent Document 9: JP-A-11 199517

Patent Document 10: JP-A-2000-1428

Patent Document 11: WO98 / 02185

Patent Document 12: JP-A-8-143463

Patent Document 13: Patent 2702325

Non-Patent Document 1: Brochure of Kyowa Chemical Industry Co., Ltd. (Direct injection excipient anhydrous calcium phosphate anhydrous GS)

Disclosure of the invention

Problems to be solved by the invention

[0006] The present invention provides a palatable fast-disintegrating intraoral tablet exhibiting good disintegration properties and ensuring tablet hardness. Means for solving the problem

[0007] Practical direct compression molding of a powder comprising an active ingredient, microcrystalline cellulose and an inorganic excipient exhibits good disintegration and tablet hardness, and a pleasant oral speed. It has been found that disintegrating tablets can be obtained. In other words, a good oral disintegrating tablet with good oral disintegration and good tablet hardness can be obtained without using a saccharide or sugar alcohol as an excipient or using a disintegrant. I was able to.

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

[0008] (1) An orally rapidly disintegrating tablet substantially comprising an active ingredient, crystalline cellulose, and an inorganic excipient, wherein the weight ratio of the crystalline cellulose to the inorganic excipient is 8: 2 to 2: 8. .

(2) The orally rapidly disintegrating tablet according to (1), which contains 30 to 99.9% by weight of crystalline cellulose and an inorganic excipient based on the total weight of the tablet.

(3) The orally rapidly disintegrating tablet according to (1), which contains an additive in an amount of 0.1 to 30% by weight based on the total weight of the tablet.

(4) The intralumen fast-disintegrating tablet according to (1), wherein the weight ratio of the crystalline cellulose to the inorganic excipient is 5: 5 to 3: 7.

(5) By directly compression molding a powder consisting essentially of the active ingredient, crystalline cellulose and an inorganic excipient, wherein the weight ratio of crystalline cellulose to the inorganic excipient is 8: 2 to 2: 8. Obtained rapid collapse in the oral cavity.

(6) The inorganic excipient according to any one of (1) to (5), wherein the inorganic excipient is anhydrous calcium hydrogen phosphate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate and Z or magnesium carbonate. Oral quick disintegrating tablet.

(7) The orally rapidly disintegrating tablet according to (6), wherein the inorganic excipient is anhydrous calcium hydrogen phosphate.

(8) The intraorally rapidly disintegrating tablet according to (1), which is compression-molded by an external lubricating tablet method.

(9) The orally rapidly disintegrating tablet according to (3), wherein the additive is a sweetener, a flavoring agent, a flavor, a lubricant, a binder, a fluidizing agent, a coloring agent, and Z or a coating agent.

The invention's effect

[0009] The tablet of the present invention exhibits good disintegration, secures tablet hardness, and is palatable. Therefore, it can be used as an orally rapidly disintegrating tablet.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] The present invention substantially provides an orally rapidly disintegrating tablet comprising an active ingredient, crystalline cellulose, and an inorganic excipient. Hereinafter, the present invention will be described.

"Substantially, a preparation comprising an active ingredient, microcrystalline cellulose and an inorganic excipient" refers to the effect of the present invention (good disintegration of tablets, (Ensure appropriate hardness). Microcrystalline cellulose and an inorganic excipient may be essential components, and may contain other additives as long as the effects of the present invention are not affected.

Specific examples of the crystalline cellulose used in the orally rapidly disintegrating tablet of the present invention include Avicel PH101, Avicel PH102, Avicel PH301, Avicel PH302, Avicel PH-F20, Theoras KG801, Theoras KG802 (manufactured by Asahi Kasei Corporation) , VIVAPUR (grades 101, 301, 102, 12), ARBOCEL (grades, F120, A300), Prosolve SMCC50, and Prosolve SMCC90 (manufactured by JRS PHARMA). These crystalline celluloses may be used alone or in combination of two or more.

[0011] The inorganic excipient used in the orally rapidly disintegrating tablet of the present invention includes anhydrous calcium phosphate anhydrous, calcium carbonate, precipitated calcium carbonate, magnesium carbonate, magnesium aluminate metasilicate, synthetic hydrotalcite, Dry aluminum hydroxide gel, magnesium silicate aluminate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, alumina magnesium hydroxide, sodium hydroxide gel, sodium hydroxide sodium hydroxide Coprecipitated products, hydroxide aluminum hydroxide “magnesium carbonate” calcium carbonate coprecipitated products, magnesium hydroxide, sodium hydrogencarbonate, calcium silicate, and citric acid. Preferred are anhydrous calcium hydrogen phosphate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate and magnesium carbonate, and particularly preferred are anhydrous calcium hydrogen phosphate, magnesium metasilicate aluminate, and synthetic hydrotalcite. Lucite. One of these or a mixture of two or more thereof may be used. The above-mentioned inorganic excipients are not particularly limited as long as they are grades generally used in the field of formulation. Particularly preferred as anhydrous calcium hydrogen phosphate is anhydrous calcium hydrogen phosphate GS (manufactured by Kyowa Chemical Industry Co., Ltd.)! / ヽ. You can use Fujicalin (Fuji Chemical Co., Ltd.)! Neusilin (Fuji Chemical Industry Co., Ltd.) is preferable as the magnesium metasilicate aluminate. As the synthetic hydrotalcite, Alrik Mac (manufactured by Kyowa Chemical Industry Co., Ltd.) is preferable. The precipitated calcium carbonate preferably has an average particle size of 2 to 3 μm. Magnesium carbonate preferably has an average particle size of 9 to 12 μm.

[0012] In the orally rapidly disintegrating tablet of the present invention, the blending amounts of the crystalline cellulose and the inorganic excipient can be easily determined. For example, after appropriately mixing a desired amount of crystalline cellulose and an inorganic excipient with the active ingredient, compression molding is performed, and hardness and disintegration are confirmed, so that the suitability can be easily determined.

Since the amounts of the microcrystalline cellulose and the inorganic excipient also depend on the physical properties of the active ingredient, it is preferable to appropriately determine the amounts as described above. In particular, the total tablet weight relative preferable to use from 30 to 99.9 by weight ^_0/0 of crystalline cellulose and inorganic excipients. In particular,ヽpreferred to use crystalline cellulose and an inorganic excipient 50-99.9 by weight ^_0/0. At these loadings, the formulations of the present invention, which are less susceptible to the physical properties of the active ingredient, exhibit particularly good disintegration rates and tablet hardness.

Further, it is preferable that the mixing ratio between the crystalline cellulose and the inorganic excipient is appropriately determined as described above. The weight ratio between the crystalline cellulose and the inorganic excipient may be in the range of 8: 2 to 2: 8. Within the above range, an intraorally rapidly disintegrating tablet having a good disintegration rate and tablet hardness can be obtained. If the blending ratio of the crystalline cellulose is higher than this, the texture will decrease due to the roughness of the crystalline cellulose, and if the blending ratio of the crystalline cellulose is lower than S, the tablet hardness will decrease. Preferably, it is a preparation comprising microcrystalline cellulose and an inorganic excipient in a weight ratio of 5: 5 to 3: 7.

The weight of the active ingredient may be any amount, but when it is 0.1 to 70% by weight (particularly preferably 0.1 to 50% by weight) based on the total weight of the tablet, it is hardly affected by the physical properties of the active ingredient. The present formulation exhibits particularly good disintegration rates and tablet hardness.

[0013] As the active ingredient used in the orally rapidly disintegrating tablet of the present invention, any active ingredient can be used. There is no particular limitation as long as it is an orally administrable active ingredient. For example, Antibiotics, chemotherapeutics, sedative-hypnotics, antipsychotics, anxiolytics, antiepileptics, antipyretics analgesics and anti-inflammatory drugs, antiparkinson drugs, drugs for psychiatric nerves, skeletal muscle relaxants, drugs for autonomic nerves, sedatives , Cardiotonic, arrhythmic, diuretic, antihypertensive, vasodilator, vasoconstrictor, vasodilator, hyperlipidemic, antitussive, bronchodilator, antiperspirant, intestinal, Peptic ulcer, stomach digestive, antacid, bile, gastrointestinal, vitamin, nutrient tonic, liver disease, gout, diabetes, tumor, antihistamine, crude drug, Osteoporosis agents and the like.

The orally rapidly disintegrating tablet of the present invention may further contain, if necessary, various additives generally used for tablet production. For example, it may contain 0.1 to 30% by weight (preferably 0.1 to: LO% by weight, particularly preferably 0.1 to 5.0% by weight) based on the total weight of the tablet. . Further, these substances may be used alone or in a mixture at an arbitrary ratio. Examples of the additives include sweeteners, flavoring agents, flavors, lubricants, binders, fluidizers, coloring agents, coating agents, and the like.

Sweetening agents refer to carbohydrates, including sugars and sugar alcohols, and other non-sugars. Since the preparation of the present invention does not contain saccharides and sugar alcohols as excipients, it is difficult to obtain sufficient sweetness using saccharides and sugar alcohols. For this reason, in the orally rapidly disintegrating tablet of the present invention, non-saccharide natural sweeteners and synthetic sweeteners, which are preferable to those which have a strong sweetness in a small amount compared to sugars and sugar alcohols, are preferred. . Examples include acesulfame potassium, aspartame, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevia or a salt thereof, sucralose, thaumatin and the like.

Examples of the flavoring agent include ascorbic acid and its salts, glycine, sodium salt, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and its salts, citrate anhydride, L-glutamic acid and its salts, succinic acid and its salts Acetic acid, tartaric acid and its salts, sodium bicarbonate, fumaric acid and its salts, malic acid and its salts, glacial acetic acid, ninatrium inosinate, and honey.

Flavors include those referred to as flavoring agents, such as orange essence, orange oil, caramelole, camphor, keich oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, and nourishing oil. , Vanilla flavor, bi Examples include ter essence, fenolefreino, peno mint essence, mixfreino, mint flavor, menthol, lemon powder, lemon oil, and rose oil. Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester and the like.

As the binder, for example, gum arabic, gum arabic powder, partially alpha starch, gelatin, agar, dextrin, pullulan, povidone, polyvinyl alcohol, etinoresenorelose, canoleboximetinolethienoresenorelose, canolemelose, strength Examples include noremelose sodium, hydroxyethynoresenorelose, hydroxyethynolemethinoresenorelose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

Examples of the fluidizing agent include hydrated dicarboxylic acid anhydride, light calcium anhydride, heavy chemical anhydride, titanium oxide and the like.

Examples of coloring agents include food colors such as Food Red No. 3, Food Yellow No. 5, Food Blue No. 1, yellow iron trinitride, iron trinitride, brown iron oxide, black iron oxide, copper chlorophyll, and copper chlorophyll. E.g. sodium rinin, riboflavin, powdered green tea and the like.

Examples of the coating agent include polyvinyl alcohol, ethyl cellulose, carboxymethylenoretenoresenolerose, canolemelose, canolemelose sodium, hydroxyethynoresenolace mouth, hydroxyethynolemethinoresenololose, and hydroxypropinole. Senollose, hydroxypropyl methylcellulose, PVA copolymer, ethyl acrylate methacrylate methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer, oppadry, carnapalow, carboxyvinyl polymer, dry methacrylic acid copolymer, dimethylaminoethyl methacrylate Methionolemethaphthalate copolymer, stearyl alcohol, shellac, cetanol, hydroxypropyl methylcellulose acetate succinate, hydroxy Propyl methylcellulose phthalate, fumaric acid 'stearic acid' polybutylacetal getylaminoacetate / hydroxypropylmethylcellulose mixture, polybutylacetal getylaminoacetate, polybutyl alcohol, methacrylic acid copolymer, 2-methyl-5-bi- Rubiridin methyl acrylate, methacrylic acid copolymer, and the like.

These components can be usually used in an arbitrary amount alone or as a mixture as long as the disintegration and the moldability of the orally rapidly disintegrating tablet of the present invention are not impaired. Crystalline cellulose z anhydrous calcium hydrogen phosphate z magnesium stearate, crystalline cellulose z anhydrous calcium hydrogen phosphate z acesulfame potassium and z or stevia, aspartame, sucralose, sodium saccharin, thaumatin, dipotassium glycyrrhizinate z magnesium stearate,

Microcrystalline cellulose z anhydrous calcium hydrogen phosphate z acesulfame potassium and z or stevia z citrate and z or vanilla flavor, orange oil, lemon powder, ぺ pa mint powder, fruit flavor z magnesium stearate,

Microcrystalline cellulose Z anhydrous calcium hydrogen phosphate and Z or synthetic hydrotalcite, precipitated calcium carbonate, magnesium metasilicate aluminate, magnesium carbonate z acesulfame potassium and z or stevia Z citrate anhydride Z carplex Z magnesium stearate

And the like.

Generally, sugars and sugar alcohols are used as excipients in orally rapidly disintegrating tablets. Disintegrants are also used.

On the other hand, the orally rapidly disintegrating tablet of the present invention is substantially an orally rapidly disintegrating tablet comprising an active ingredient, crystalline cellulose, and an inorganic excipient. That is, the orally rapidly disintegrating tablet is characterized by not containing a saccharide as a commonly used excipient. In the orally rapidly disintegrating tablet of the present invention, saccharides such as sucrose, glucose, fructose, starch syrup, and lactose are not used as excipients.

Further, the orally rapidly disintegrating tablet of the present invention is characterized in that it does not contain a sugar alcohol as a commonly used excipient in the orally rapidly disintegrating tablet. In the orally rapidly disintegrating tablet of the present invention, erythritol, D-sorbitol, xylitol, D-mantol

Sugar alcohols such as maltitol are not used as excipients.

Further, the orally rapidly disintegrating tablet of the present invention is characterized in that it does not contain a commonly used disintegrating agent in the orally rapidly disintegrating tablet. Disintegrants are indispensable for ordinary orally rapidly disintegrating tablets to provide the desired disintegration properties. However, the present inventors surprisingly obtained a tablet showing sufficient disintegration without adding a disintegrant by compression-molding a mixture of crystalline cellulose and an inorganic excipient in a specific ratio. I found that. Disintegrant The tablet does not contain a disintegrant because it has the characteristics of deteriorating the tablet quality, such as lowering the tablet hardness or roughening the tablet surface due to moisture absorption, absorbing saliva, giving a feeling of quickness, and worsening the mouthfeel. The invention is superior.

Crospovidone, croscarmellose sodium, carmellose sodium, canolemellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, starch, partially alpha-monostarch, alginic acid, calcium alginate, tragacanth powder, agar powder, etc. Disintegrants are not included in the orally rapidly disintegrating tablets of the present invention.

Hereinafter, a method for preparing the orally rapidly disintegrating tablet of the present invention will be described.

As a specific manufacturing method, the active ingredient and the drug substance are weighed, and the mixed powder for tablets mixed with an appropriate mixer such as a V-type mixer is directly compressed and compressed using a tableting machine described later. Manufacturing method and the like. Also, in order to obtain a mixed powder for tablets, a method of mixing vigorously with a stirring granulator, a method of mixing and pulverizing with a pulverizer, a method of compressing and granulating with a dry granulator, or dispersing or dissolving a binder as necessary Wet granulation using water, acetone, ethyl alcohol, propyl alcohol, or a mixture thereof, or a method of producing mixed powder for tablets in two or more separate groups. Good. When producing the mixed powder for tablets, a binder, a flavoring agent, a fluidizing agent, a lubricant, a flavor, a sweetener, a coloring agent, and the like may be mixed as necessary.

Of the above, it is particularly preferable to directly compression-mold a powder consisting essentially of the active ingredient, crystalline cellulose and inorganic excipient. In particular, it is preferable to directly compression-mold a powder in which the weight ratio of crystalline cellulose to the inorganic excipient is 8: 2 to 2: 8.

In the present invention, the particle size of the active ingredient and the additive is not particularly limited, but the smaller the particle size, the better the feeling of taking.

[0017] The thus obtained mixed powder for tablets is compression-molded by applying a pressure of 200 kg to 1500 kg Z punch using, for example, a single tableting machine, a rotary tableting machine or the like. If the pressure is lower than this, the tablet hardness becomes insufficient and sufficient hardness for handling cannot be secured, and if the pressure is high, disintegration is delayed, which is not preferable.

For compression molding, a normal tableting method can be used, but an external lubricating tableting method can also be used. External lubricant tableting method reduces the amount of lubricant added and further disintegrates The speed can be increased and the tablet hardness can be improved. In the usual method of mixing a lubricant into a tablet mixture, 1 to 100 mg of a tablet is required .: The force that requires a lubricant of LOmg. Tableting with O.lmg or less in the external lubrication method. Is possible. As an external lubricating device, there is ELSP1-Type III manufactured by Kikusui Seisakusho.

Regarding the molding of the orally rapidly disintegrating tablet of the present invention, any shape can be adopted, for example, a round shape, an elliptical shape, a spherical shape, a rod shape, a donut shape, a laminated tablet, a dry coated tablet and the like. It can also be coated with a coating. Also, marks for improving the discrimination, markings such as characters, and dividing lines for division may be provided.

The intraorally rapidly disintegrating tablet of the present invention is rapidly disintegrated in the oral cavity by saliva, and can be taken smoothly without leaving roughness. The dissolution of the orally rapidly disintegrating tablet of the present invention in the mouth is usually about 1 to 60 seconds, preferably about 1 to 40 seconds, and more preferably about 1 to 20 seconds.

The hardness (measured by a tablet hardness tester) is known to be a problem-free value if it is generally about 35 to 70 N. The orally rapidly disintegrating tablet of the present invention has a strength of 10 to 200 N, preferably 30 to 70 N. It is about 150N.

It is recommended that this product be taken without disintegration in the oral cavity or taken with water.

Example

Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but these do not limit the present invention.

The tablets obtained in the examples and comparative examples were subjected to a sensory test by the following test methods for tablet hardness, disintegration time, and tablet.

(1) Hardness test

The hardness was measured using a dedicated machine for hardness measurement (manufactured by ERWEKA International AG). The test was performed with 10 tablets, and the average value is shown. (Based on 30N or more)

(2) Disintegration test Disintegration time of 6 tablets was measured according to the 14th Revised Japanese Pharmacopoeia Disintegration Test Method, and the average value is shown. (Based on within 60 seconds)

(3) Sensory test

Roughness due to crystalline cellulose in the oral cavity of the tablet It was measured by 5 healthy adults and evaluated according to the following criteria, and the average value is shown.

[table 1]

(Blending ratio of crystalline cellulose and inorganic excipient)

In Examples 1 to 7, the range of the mixing ratio of the crystalline cellulose of the present invention and the inorganic excipient was performed, and in Comparative Examples 1 to 4, the range of the mixing ratio of the present invention was out of the range.

[Table 2] Formulation amount (%)

(Examples 1 to 7)

In Examples 1 to 7, ethenzamide, crystalline cellulose, and anhydrous calcium hydrogen phosphate were weighed according to the amounts shown in Table 2 and mixed using a V-type mixer (manufactured by Dalton Co., Ltd.). Additional magnesium stearate was added to the mixed powder. After that, the powder mixed again with a V-type mixer was tableted at 100 mg per tablet using a single tablet press (Fuji Pharmaceutical Machinery Co., Ltd.). At this time, the shape of the punch was round, the diameter was 6.5 mm, and the tableting pressure was 3 kN. As ethenzamide, ethenzamide (average particle diameter: 11 m) pulverized by a sample mill (Dalton Co., Ltd.) was used. (Comparative Examples 1-4)

In Comparative Examples 1 to 4, tableting was performed under the same conditions as in Examples 1 to 7 according to the blending amounts in Table 2.

[Table 3] Tablet evaluation

Table 3 shows the results of evaluation of the hardness, disintegration time, roughness, and crispness of the tablets of Examples 1 to 7 and Comparative Examples 1 to 4 by the test method of the present invention. The ratio between the crystalline cellulose and the anhydrous calcium hydrogen phosphate in Examples 1 to 7 was 8: 2 to 2: 8, and both the hardness and the disintegration time were good. In Comparative Examples 1 and 2 in which the amount of microcrystalline cellulose was large, the disintegration time was delayed, and roughness in the oral cavity was strongly felt. In Comparative Examples 3 and 4, the tablet hardness was low. Among Examples 1 to 7, the ratio of crystalline cellulose having a disintegration time of 20 seconds or less and anhydrous calcium hydrogen phosphate was preferably 5: 5 to 3: 7. Furthermore, 4: 6 was good as the optimum ratio.

[0021] (Presence or absence of disintegrant)

(Comparative Examples 5 to 9)

In Comparative Examples 5 to 9, ethenzamide, crystalline cellulose, anhydrous calcium hydrogen phosphate, and a disintegrant (croscarmellose sodium, crospovidone, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose) were formulated in Table 4. The powder was weighed out according to the amount, mixed under the same conditions as in Example 5, added with magnesium stearate, and tableted.

[0022] Comparative Examples 5 to 9 were evaluated for the hardness, disintegration time, roughness, and crispness of the tablet by the test method of the present invention after being left for 4 days under the condition of opening the glass bottle at 40 ° C and 75% RH. did. Further, in Example 5, the same evaluation was performed after the tablets were placed under the same conditions. Table 5 shows the results of the evaluation.

When evaluated immediately after tableting, Comparative Examples 5 to 9 strongly felt quickness because the disintegrant absorbed saliva in the oral cavity. Further, Comparative Examples 5 to 9 were lower in hardness than Example 5 of the present invention. Further, in Comparative Examples 5 to 9, since the amount of water, that is, the amount of saliva in the oral cavity was limited, the disintegrant absorbed water first, and the disintegration time was prolonged vigorously.

Under the conditions of 40 ° C. and 75% RH, in Comparative Examples 5 to 9, the disintegrant absorbed water and the tablet surface was roughened, the hardness was significantly reduced, and the disintegration time was significantly extended. Example 5 of the present invention exhibited good appearance, hardness, and disintegration time even under conditions of 40 ° C. and 75% RH.

[Table 4]

Prescription amount (%)

[Table 5] Results of tablet evaluation

(Presence of sugar alcohol)

(Comparative Examples 10, 11) In Comparative Examples 10 and 11, the crystalline cellulose portion in Example 5 was replaced with sugar alcohol D-mantol or D-sorbitol, mixed under the same conditions as in Example 5, and magnesium stearate was added. Then, tableting was performed.

(Comparative Examples 12, 13)

In Comparative Examples 12 and 13, erythritol or xylitol, which is a sugar alcohol, was weighed out according to the blending amount shown in Table 6, charged into a fluidized bed granulator (Okawara Seisakusho), and granulated using water in which ethenzamide was suspended. Thoroughly dried. Next, the granulated product was weighed with anhydrous hydrogen phosphate anhydrous in accordance with the blending amount shown in Table 6, added to the mixture, mixed under the same conditions as in Example 5, added with magnesium stearate, and compressed into tablets. Was carried out.

[0027] Comparative Examples 10 to 13 were evaluated for the hardness, disintegration time, roughness, and crispness of the tablets by the test method of the present invention after being left for 4 days under the condition of opening the glass bottle at 40 ° C and 75% RH. did. In addition, the same evaluation was performed after leaving it for 4 days under the condition of sealed glass bottles at 60 ° C. Further, in Example 5, the same evaluation was performed after the tablets were placed under the same conditions. Table 7 shows the results of the evaluation.

Under the conditions of 40 ° C. and 75% RH, in Comparative Examples 10 to 13, some of the disintegration times were slightly extended. At 60 ° C, the hardness was significantly reduced and the disintegration time was significantly extended. On the other hand, in Example 5 of the present invention, both the hardness and the disintegration time were good under the conditions of 40 ° C 75% RH and 60 ° C.

[Table 6] Formulation amount (%)

[Table 7] Tablet evaluation

(Addition of sweetener)

An example in which a non-saccharide sweetener is added as a sweetener will be described.

(Examples 14 to 20)

In Examples 14 to 20, ethenzamide, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and non-sugar sweeteners (acesulfame potassium, aspartame, stevia, sucralose, sodium saccharin, thaumatin, dipotassium glycyrrhizinate) were added in the amounts shown in Table 8. And mixed under the same conditions as in Example 5, magnesium stearate was added, and tableting was performed.

[Table 8]

Prescription amount (%)

[Table 9]

Tablet evaluation

Table 9 shows the results of evaluation of the hardness, disintegration time, roughness, and crispness of the tablets of Examples 14 to 20 and Comparative Example 5 by the test method of the present invention. In Examples 14 to 20 in which the non-saccharide sweetener was added, the evaluation results were almost the same as those in Example 5 without the addition. The addition of sweetness improved mouthfeel, and the score in the sensory test was slightly higher than that of Example 5. [0031] (Addition of flavor and flavoring agent)

An example is shown in which vanilla flavor, orange oil, lemon powder, peppermint powder or fruit flavor is added as flavoring agent and citrate is added as a flavoring agent.

(Example 21)

In Example 21, since the fragrance was a liquid, the fragrance was mixed with the hydrated dioxygenated silicon in a ratio of 1: 2 as a pretreatment, and mixed in a plastic bag to give the hydrated dioxygenated silicon a liquid fragrance. Was adsorbed. Furthermore, sieving (80 mesh) was performed to prepare a vanilla flavor dispersion powder. Next, ethenzamide, crystalline cellulose, anhydrous calcium hydrogen phosphate, potassium acesulfame, and vanilla flavor dispersion powder were weighed according to the blending amounts shown in Table 10, mixed under the same conditions as in Example 5, and magnesium stearate was added. Tableting was performed.

(Example 22)

A dispersion powder similar to that of Example 21 was prepared using orange oil, and citric acid was further added according to the blending amounts shown in Table 10, mixed under the same conditions as in Example 5, and magnesium stearate was added. Tableting was performed.

(Examples 23 and 24)

Without preparing a dispersion powder, lemon powder or peppermint powder and citric acid were added according to the blending amounts shown in Table 10, mixed under the same conditions as in Example 5, magnesium stearate was added, and tableting was performed. did.

(Example 25)

The same dispersion powder as in Example 21 was prepared using a fruit flavor, and citric acid was added according to the compounding amounts shown in Table 10, mixed under the same conditions as in Example 5, and magnesium stearate was added. Tablets were implemented.

[Table 10] Prescription amount (%)

[Table 11] Tablet evaluation

Table 11 shows the results of evaluation of the hardness, disintegration time, roughness, and crispness of the tablets of Examples 21 to 25 and Comparative Example 5 by the present invention. In Examples 21 to 25 in which flavor and flavoring agent were added, do not add!評価 The evaluation result was almost the same as that of Example 5. The secretion of saliva was promoted, and the feeling of roughness and the feeling of swiftness were further suppressed. As compared with Example 5, the score in the sensory test was slightly higher.

(Addition of inorganic excipients other than anhydrous calcium hydrogen phosphate)

(Examples 26 to 29)

In Examples 26 to 29, as shown in Table 12, the portion of anhydrous calcium hydrogen phosphate of Example 5 was replaced with other inorganic excipients such as synthetic hydrotalcite, precipitated calcium carbonate, magnesium metasilicate and magnesium aluminate. The mixture was replaced with heavy magnesium carbonate, mixed under the same conditions as in Example 5, added with magnesium stearate, and tableted.

12] Prescription amount (%)

[Table 13]

Tablet evaluation

Table 13 shows the results of evaluation of the hardness, disintegration time, roughness, and crispness of the tablets of Examples 26 to 29 and Comparative Example 5 by the test method of the present invention. Good tablets were also obtained in Examples 26 to 29 in which an inorganic excipient other than anhydrous calcium hydrogen phosphate was added.

(Preparation of tablets by other production methods)

An example using a manufacturing method other than the manufacturing method shown in Example 5 will be described.

[0039] (1) A method of pulverizing a powder mixed with a main drug and additives and compressing the powder.

(Example 30)

In Example 30, ethenzamide, crystalline cellulose, and anhydrous calcium hydrogen phosphate were weighed according to the amounts shown in Table 14, mixed gently in a plastic bag, and ground by a sample mill to carry out mixing and grinding. Magnesium stearate was added thereto, and tableting was performed under the same conditions as in Example 5.

(2) Dry granule compression method

(Example 31)

In Example 31, ethenzamide, crystalline cellulose, and anhydrous calcium hydrogen phosphate were weighed according to the amounts shown in Table 14 and mixed using a V-type mixer (manufactured by Dalton Co., Ltd.), and the resulting mixed powder was subjected to a roller compactor (manufactured by Kurimoto Iron Works). Dry granulation with a power mill (16 mesh) It was sized. Magnesium stearate was added thereto, and tableting was performed under the same conditions as in Example 5.

(3) Wet granule compression method

(Example 32)

In Example 32, crystalline cellulose and anhydrous calcium hydrogen phosphate were weighed according to the blending amounts shown in Table 14 and charged in a fluidized bed granulating dryer (manufactured by Okawara Seisakusho), and granulated using water in which ethenzamide was suspended. And dried thoroughly. Next, magnesium stearate was added to the granules, and tableting was performed under the same conditions as in Example 5.

[Table 14]

Prescription amount (%)

[Table 15] Tablet evaluation

Table 15 shows the results of evaluation of the hardness, disintegration time, roughness, and crispness of the tablets of Examples 30 to 32 and Comparative Example 5 by the test method of the present invention. Good tablets were obtained by using a production method other than the production method shown in Example 5.

(Preparation of Tablet by External Lubricating Tablet Method)

Examples are shown in which magnesium stearate is mixed with powder and contained inside, and when tableting is performed, magnesium stearate is adhered to a punch and die and only the tablet surface is adhered.

(Example 33)

In Example 33, ethenzamide, crystalline cellulose, and anhydrous calcium hydrogen phosphate were weighed according to the amounts shown in Table 16, and mixed with a V-type mixer (Dalton Co., Ltd.) to produce a powder for tablets. Next, a rotary tableting machine equipped with an external lubrication device (manufactured by Kikusui Seisakusho) Using Kikusui Seisakusho), tablets of 100 mg per tablet were prepared under the condition that 0.1 mg of magnesium stearate per tablet adhered. At this time, the shape of the punch was round, the diameter was 6.5 mm, and the tableting pressure was 3 kN.

[Table 16] Formulation amount (%)

[Table 17]

Tablet evaluation

Table 17 shows the results of the evaluation of the hardness, disintegration time, roughness, and roughness of the tablet of Example 33 and Comparative Example 5 by the test method of the present invention. In Example 33 using the external lubricating tableting method, the hardness was significantly increased and the disintegration time was quicker than Example 5.

(Weight ratio of active ingredient)

Examples are shown in which the weight ratio of the active ingredient was changed to 0.1%, 10%, 30%, 50%, and 70%. The active ingredients used were ethenzamide, acetoaminophen, cefcapene pivoxil hydrochloride, rilmazaphon hydrochloride, and ketifen fumarate.

(Examples 34 to 38)

In Examples 34 to 38, ethenzamide, crystalline cellulose, and anhydrous calcium hydrogen phosphate were weighed out according to the amounts shown in Table 18, mixed with a V-type mixer (manufactured by Dalton Co., Ltd.), and magnesium stearate was added. The powder mixed with a V-type mixer was tableted at 100 mg per tablet using a static compression tester (manufactured by Tokyo Ikki Co., Ltd.). At this time, the shape of the punch was round, the diameter was 6.5 mm, and the tableting pressure was 6 kN.

[Table 18] Prescription amount (%)

[Table 19] Tablet evaluation

(Examples 39 to 43)

In Examples 39 to 43, as shown in Table 20, the ethenzamide portion in Examples 34 to 38 was replaced with acetoaminophen (average particle diameter 11 _m ), and mixed under the same conditions as in Examples 34 to 38 to obtain magnesium stearate. And tableting was performed.

[Table 20] Formulation amount (%)

[Table 21] Tablet evaluation

(Examples 44 to 48)

In Examples 44 to 48, as shown in Table 22, the ethenzamide portion of Examples 34 to 38 was replaced with cefcapene pivoxil hydrochloride, mixed under the same conditions as in Examples 34 to 38, and magnesium stearate was added. Tableting was performed.

[Table 22] Prescription amount (%)

[Table 23] Tablet evaluation

(Examples 49 to 53)

In Examples 49 to 53, as shown in Table 24, the ethenzamide portion of Examples 34 to 38 was replaced with rilmazaphone hydrochloride, mixed under the same conditions as in Examples 34 to 38, and magnesium stearate was added. Was carried out.

[Table 24] Formulation amount (%)

[Table 25] Tablet evaluation

(Examples 54 to 58)

In Examples 54 to 58, as shown in Table 26, the ethenzamide moiety of Examples 34 to 38 was replaced with ketotifen fumarate, mixed under the same conditions as in Examples 34 to 38, and magnesium stearate was added. Tableting was performed. Prescription amount (%)

[Table 27] Tablet evaluation

Tables 19, 21, 23, 25 and 27 show the results of the evaluation of the hardness and disintegration time of the tablets of Examples 34 to 58 by the test method of the present invention. In the case of ethenzamide having good compression moldability (Examples 34 to 38) and cefcapene pivoxil hydrochloride (Examples 44 to 48), good tablets were obtained even when the weight ratio of the active ingredient was 70%. Obtained. However, as the weight ratio of the active ingredient increases, the physical properties of the active ingredient greatly affect the properties of the tablet. Therefore, acetoaminophen (Examples 39 to 43), rilmazaphone hydrochloride (Examples 49 to 53), and ketotifen fumarate ( In Examples 54 to 58), the weight ratio of the active ingredient to obtain good tablets was up to 50%.

(Mask masking of active ingredient)

When the active ingredient has a bitter taste, it is difficult to take the active ingredient content due to the bitter taste. Cefcapene pivoxil hydrochloride is a drug having a bitter taste, and an example of suppressing the bitterness will be described.

(Example 59)

In Example 59, cefcapene pivoxil hydrochloride was charged into a composite fluidized bed granulation coating apparatus (manufactured by Freund Corporation) in the amounts shown in Table 28, and 30% coating was performed with an aqueous dispersion of ethyl cellulose. Microcrystalline cellulose and anhydrous hydrogen phosphate calcium were added thereto, mixed under the same conditions as in Examples 34 to 38, magnesium stearate was added, and tableting was performed.

(Example 60)

In Example 60, cefcapene pivoxil hydrochloride and crystalline cellulose were used in the amounts shown in Table 28. , Anhydrous calcium hydrogen phosphate, acesulfame potassium, aspartame, fragrance (lemon noda) and citric acid were added, mixed under the same conditions as in Example 59, and magnesium stearate was added, followed by tableting. .

(Example 61)

In Example 61, cefcapene pivoxil hydrochloride, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, acesulfame potassium, aspartame, fragrance (lemon powder), and citrate were coated in the same manner as in Example 59 with the blending amounts shown in Table 28. Was added, mixed under the same conditions as in Example 59, magnesium stearate was added, and tableting was performed.

[Table 28] Formulation amount (%)

[0059] Bitter taste masking was evaluated on average by five adults. (A sweetener or a flavoring agent was used without coating the active ingredient, and Example 27 was used as a comparison.) Table 29 shows the results. In Example 59 in which the active ingredient was coated and Example 60 in which acesulfame potassium, aspartame, cunic acid, and a fragrance were added, the bitter taste was reduced and the feeling of taking could be improved. In Example 61 in which acesulfame potassium, aspartame, citric acid, and a fragrance were added to the coating powder coated on the base drug, bitterness was further suppressed.

[Table 29] Tablet evaluation

X · · bitter △ · · a bit bitter 〇 · 'Do not feel bitter

Industrial applicability

The orally rapidly disintegrating tablet of the present invention is easy to produce, has both strength during production and storage, and has excellent long-term storage and stability. In addition, as it rapidly disintegrates in the oral cavity, it is used as an easy-to-take preparation for the elderly and children, and as a safe preparation for the general public, as well as conventional oral preparations containing the same drug. It can be used for treatment and prevention of illness.

Claims

The scope of the claims

[1] An orally rapidly disintegrating tablet in which the weight ratio of crystalline cellulose to an inorganic excipient is substantially 8: 2 to 2: 8.

[2] The orally rapidly disintegrating tablet according to claim 1, which contains 30 to 99.9% by weight of the total weight of the tablet of crystalline cellulose and an inorganic excipient.

3. The orally rapidly disintegrating tablet according to claim 1, wherein the tablet contains an additive in an amount of 0.1 to 30% by weight based on the total weight of the tablet.

4. The orally rapidly disintegrating tablet according to claim 1, wherein the weight ratio between the crystalline cellulose and the inorganic excipient is 5: 5 to 3: 7.

[5] Substantially by directly compressing a powder in which the active ingredient, crystalline cellulose and inorganic excipients have a weight ratio of crystalline cellulose to inorganic excipients of 8: 2 to 2: 8. The orally rapidly disintegrating tablet obtained.

[6] Any one of claims 1 to 5, wherein the inorganic excipient is anhydrous calcium hydrogen phosphate, magnesium metasilicate aluminate, synthetic hydrotalcite, precipitated calcium carbonate and Z or magnesium carbonate. 2. The rapidly disintegrating tablet in the oral cavity according to item 1.

7. The orally rapidly disintegrating tablet according to claim 6, wherein the inorganic excipient is anhydrous calcium hydrogen phosphate.

[8] The intraorally rapidly disintegrating tablet according to claim 1, which is compression-molded by an external lubricating tableting method.

[9] The orally rapidly disintegrating tablet according to claim 3, wherein the additive is a sweetener, a flavoring agent, a flavoring agent, a lubricant, a binder, a fluidizing agent, a coloring agent, or a Z agent or a coating agent.