JPH11310539A - Intraoral-disintegrative type composition and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an intraoral-disintegrative type composition having an appropriate strength necessary for handling medicinal preparations and promptly disintegrating in oral cavities, to provide a method for producing the composition, and to provide a medicinal preparation by using the composition. SOLUTION: This intraoral-disintegrative type composition is a hardened- molded composition and promptly disintegrable in oral cavities, and contains an organic acid, a carbonate salt, a network-maintaining agent forming a network with the organic acid and the carbonate salt, and a coloring inhibitor. The network-maintaining agent is a water-insoluble solid substance such as cornstarch, and the coloring inhibitor is a water-soluble saccharide such as erythritol. The network-maintaining agent and the coloring inhibitor are compounded in amounts of 25.0-625.0 pts.wt. and 25.0-937.5 pts.wt., respectively, per 100 pts.wt. of the mixture of the organic acid and the carbonate salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an orally disintegrating composition and a method for producing the same, and more particularly, to an orally disintegrating composition which has strength necessary for handling of a preparation and which rapidly disintegrates in the oral cavity. The present invention relates to a disintegrable composition, a method for producing the same, and an orally disintegrable preparation using the composition.

[0002]

2. Description of the Related Art With the advent of an aging society, various studies on aging have been actively conducted. One of the fields is a new formulation which is optimally administered to the elderly. Has been reported. This research report investigates whether self-administration of oral medicines is acceptable, the foods and drinks to be taken when taking the medicine, and the ingestibility of the dosage form, and is the most effective dosage form currently used. Patient preferences were also investigated for easy dosage forms, desired dosage forms in the future, and taste preferences of internal medicines.

[0003] Such research reports point out that the elderly have many problems in terms of dosage form when taking pharmaceuticals, and as a result, many of the dosage forms currently used are for general adults. It can be easily taken by physically handicapped elderly people who need assistance,
In addition, it has been desired to develop a dosage form that is easy to take even for elderly people who refuse to take the medicine due to the difficulty in taking it. A dosage form that can be easily taken by the elderly is also preferable for children and adults.

[0004] Further, according to this research report, oral dissolving-type preparations, as novel preparations preferable for the elderly,
Paste preparations and jelly preparations have been proposed,
In particular, oral dissolution-type preparations are considered to be the most realistic preparations in view of the stability during the distribution process and the like, and from this viewpoint, preparations of this type are being actively studied and developed.

In the background described above, Japanese Patent Publication No.
No. 50445 discloses gelatin, dextrin, hydrolyzed dextran or alginate, or a mixture of one or more of the above substances and polyvinyl alcohol, polyvinyl pyrrolidine or gum arabic, or a mixture of polyvinyl alcohol and polyvinyl pyrrolidine or gum arabic and polyvinyl pyrrolidine. Comprising a network of pharmaceutically acceptable water-soluble or water-dispersible polymer simple substance selected from the mixture of: and wherein the network comprises a unit dose of the drug substance and has a density of 10 to 200 mg / ml. Solid pharmaceutical dosage forms for administration have been described. However, since such preparations are prepared by freeze-drying, production equipment for freeze-drying is required,
The cost is high. In addition, since the preparation obtained by freeze-drying has low strength, there is a problem that handling is generally inconvenient.

[0006] WO 93/12769 discloses that the active ingredient and saccharides comprising lactose and / or mannitol, and the solid component, have a density of 0.1 to 1.2 w / w% agar containing 400 mg / agar. ml to 1000 mg /
An orally disintegrating solid preparation having sufficient strength for handling the preparation is described. However, this method for producing a solid preparation involves pouring a suspension into a mold and drying the suspension, which is problematic in that it is complicated, unlike the method for producing a general tablet.

[0007] International Publication WO95 / 20380 describes an orally dissolving, compression-molded product having rapid disintegration and dissolvability in the oral cavity, containing a sugar having low moldability and a saccharide having high moldability. Have been. However, in producing this compression-molded product, there is a problem that tableting trouble such as sticking occurs during tableting because saccharides having high moldability are present on the surface of the granulated product.

Japanese Patent Application Laid-Open No. 9-48726 discloses that a substance comprising a drug and a substance which is wettable to form by humidification and which maintains its shape by drying after molding is formed. A rapidly disintegrating oral preparation is described which is easily disintegrated. Also, Japanese Patent Application Laid-Open
Japanese Patent No. 291051 discloses that a tablet material in a dry state containing a drug, a water-soluble binder and a water-soluble excipient has a hardness capable of maintaining the shape when the material is transferred to the next manufacturing process as a tablet. In order to perform, a tableting step of press-molding at a minimum necessary low pressure, a humidifying step for absorbing moisture in the tablet molded in the tableting step, and a drying step of drying the tablet humidified in the humidifying step A method for producing a fast-dissolving tablet, comprising: However, any of the preparations or the production methods requires a step of humidifying the molded product, and the humidification step causes a problem that the tablet is bloated, the appearance of the tablet is impaired, and the commercial value is reduced.

Japanese Patent Application Laid-Open No. Hei 5-27054 describes a method for producing an orally dissolvable tablet in which a mixture containing a medicinal ingredient, a saccharide, and a water content such that the particle surface of the saccharide is moistened is used. However, this manufacturing method uses a wet tableting method in which water is forcibly added to a mixture for tableting and tableting is performed in a wet state, and the productivity is not sufficient due to tableting trouble. Is leaving. Similarly, as classified into the wet tableting method, European Patent Application Publication EP0590
Although there is a manufacturing method described in No. 963A1, in this manufacturing method, a very special manufacturing device is used in order to eliminate a tableting trouble at the time of wet-type tableting, so that there is a problem of manufacturing cost and productivity. I have. In addition, International Publication WO95 / 34290
And WO93 / 15724 are classified as wet tableting methods, but there is a problem that a special excipient is used or the productivity is low.

[0010] Japanese Patent Publication No. 58-24410 discloses that tablet contents are inactive at -30 ° C to +2
Mix with a solvent that freezes at 5 ° C., making the solvent 5 to 80% by weight of the total mixture, solidifying the mixture by placing it in an inert cooling medium, and compressing at a temperature below the freezing point of the solvent. A method for producing a porous tablet having good disintegration properties by forming a tablet and then volatilizing a solvent by freeze-drying or natural drying is described. Japanese Patent Application Laid-Open No. 3-86837 discloses that a composition comprising a water-soluble, hydratable gel or a foam material is used until substantially all water is removed.
Obtained by contacting an inorganic organic liquid desiccant such as anhydrous ethanol at a temperature of about 0 ° C. or less,
A readily dissolvable carrier material with sufficient strength is described. However, there is a problem that the manufacturing process is complicated in each of the manufacturing methods, and manufacturing equipment such as freeze-drying is required, which increases the cost.

[0011] WO 93/01805 and US Pat. No. 5,178,578 describe orally disintegrating preparations containing controlled release particles, which are merely tablets or mixtures. That is,
There is room for investigation on the rapid disintegration property in the oral cavity, which is a characteristic of orally disintegrating preparations. Also, JP-A-8-3
No. 01751 describes a rapidly dissolving edible unit in which an uncured shear matrix and a controlled release system are mixed, molded and cured. Such a saccharide must be used, and such an amorphization treatment is complicated.

JP-A-2-32014 discloses a solid preparation in the form of a wet tablet suitable for oral administration. A spray-drying step is followed by preparation of a wet mass with ethanol / water or water alone. However, since it is a method of obtaining a tablet by placing it in a mold and drying, it is expected that the production process is complicated and productivity is low.

JP-A-61-15830 discloses an antacid composition having a porous ultrafine crystal structure, which comprises a confectionery base containing an antacid and a confectionery sweetener and a plasticizer. Although described, the production method is complicated and there is a problem in productivity.

Further, as an effervescent tablet type, the one described in International Publication WO97 / 09037 is known, and this effervescent tablet is as large as about 5 g per tablet and is premised on disintegration in the oral cavity. Rather, it is intended to take a liquid preparation obtained by foaming in drinking water, and the technical field is different from the orally disintegrating preparation which can be taken as it is as intended by the present invention.

Further, as a similar effervescent tablet type,
Japanese Patent Publication No. 5-500956, Japanese Patent Publication No. 1-28321
9, US Pat. No. 7,107,744, U.S. Pat.
No. 004036 and No. 4265847, but since these are only tablets of mixtures or blends, there is room for investigation on rapid disintegration in the oral cavity, which is a characteristic of orally disintegrating preparations. There was a problem that remains.

The present invention has been made in view of the above-mentioned problems of the prior art, and has as its object to provide an appropriate strength required for handling a preparation, The present invention provides an orally disintegrating composition which rapidly disintegrates in the above, a method for producing the same, and an orally disintegrating preparation.

[0017]

Means for Solving the Problems In order to achieve the above object, the present inventors have conducted various studies to develop a novel orally disintegrating drug formulation, and found that organic acids, carbonates and specific networks have been developed. By molding a substantially dry mixture containing a maintenance agent and an anti-coloring agent and subjecting the obtained substantially dry molded body to a simple specific treatment, the manufacturing process, storage and distribution are unexpectedly performed. The present inventors have found that an appropriate strength that does not break in the process can be obtained, and that rapid disintegration in the oral cavity can be realized, and the present invention has been completed.

That is, the orally disintegrating composition of the present invention is an orally disintegrating cured molding composition which rapidly disintegrates in the oral cavity, and forms a network with an organic acid, a carbonate and these. A network maintainer and a color inhibitor, wherein the network maintainer is selected from the group consisting of corn starch, potato starch, sodium carboxymethyl starch, crystalline cellulose, low-substituted hydroxypropylcellulose and croscarmellose sodium. At least one water-soluble saccharide selected from the group consisting of erythritol, xylitol, mannitol and lactose, wherein the organic acid and the carbonate 25.0 to 625.0 based on 100 parts by weight of the mixture with The amount unit, the coloring preventing agent 2
It is characterized by comprising 5.0 to 937.5 parts by weight.

Further, a preferred embodiment of the orally disintegrating composition of the present invention is characterized in that the mixing ratio of the organic acid and the carbonate is 1: 1 to 9: 1 by weight.

Further, another preferred embodiment of the orally disintegrating composition of the present invention is characterized in that the carbonate is easily soluble in water.

Still another preferred embodiment of the orally disintegrating composition of the present invention has a porosity of 30 to 60%, a tablet strength of 1 to 10 kp, and a dissolution time in healthy adults of 1 to 10 kp. .5 minutes or less.

The orally disintegrating preparation of the present invention is characterized in that a pharmaceutically active ingredient is added to the orally disintegrating composition as described above.

The preferred form of the orally disintegrating preparation of the present invention is
The medicinal component is selected from the group consisting of drugs for central nervous system, drugs for allergies, drugs for circulatory organs, drugs for respiratory organs, drugs for digestive organs, hormonal drugs, drugs for tumors, antibiotics and bioactive peptides. Further, it is characterized by at least one kind.

Further, the method for producing an orally disintegrating composition of the present invention provides (1) 4.0 to 6 for producing an orally disintegrating cured molding composition which disintegrates rapidly in the oral cavity.
Consisting of 0.1% by weight of organic acid, 0.8 to 33.4% by weight of carbonate, corn starch, potato starch, sodium carboxymethyl starch, crystalline cellulose, low-substituted hydroxypropylcellulose and croscarmellose sodium Network maintainers 16.0 to 5 which are at least one poorly water-soluble solid substance selected from the group
0.0% by weight and at least one selected from the group consisting of erythritol, xylitol, mannitol and lactose
And 16.0 to 75.0% by weight of a coloring inhibitor, which is a kind of water-soluble saccharide, to obtain a molding mixture, and (2) 1 to 130 kg of the substantially dry molding mixture obtained. / C
molded at a molding pressure of m ^2, (3) Then, by heating the resulting molded body at 40 to 120 ° C., with the release of carbon dioxide and moisture from the molded body, the organic in the molded body Forming a network of acids, carbonates, network maintainers, color inhibitors and their reaction products,
Thereby, the molded body has a desired strength.

Further, a preferred embodiment of the method for producing the orally disintegrating composition of the present invention is that the above-mentioned organic acid, carbonate, network maintenance agent and coloring inhibitor are mixed after granulation, or these components are mixed. It is characterized in that the mixture for molding is granulated by mixing all and then granulating.

In a preferred embodiment of the method for producing the orally disintegrating composition of the present invention, the granulation is performed by a wet method, and the granulated molding mixture is dried before the molding.
The method is characterized in that the substantially dry molding mixture is obtained.

[0027]

The details of the mechanism by which the orally disintegrating composition of the present invention exhibits excellent orally disintegrating properties and appropriate strength as a pharmaceutical preparation are not clear, but are presumed as follows at present.

That is, the orally disintegrating composition of the present invention is obtained by molding a mixture containing an organic acid, a carbonate, a poorly water-soluble solid substance as a network maintainer, and a water-soluble saccharide as a coloring inhibitor at a considerably low molding pressure. Then, carbon dioxide gas and water are generated in the obtained molded body by a chemical reaction, and then the carbon dioxide gas and water are removed to obtain the molded product. Therefore, at the time of molding, the present composition has many voids inside due to a low molding pressure, and the strength should be insufficient as it is.

However, in the early stage of the generation and removal of carbon dioxide and water after molding, the water contained therein is released from all of the organic acids, carbonates, poorly water-soluble solid substances and water-soluble saccharides. Organic acids, carbonates and water-soluble saccharides are dissolved in the released water, and the dissolved organic acids and carbonates react to generate carbon dioxide gas and water. When the cycle is stopped, the composition is dried and solidified, a network of these raw materials is formed, and the composition is hardened, and the appropriate physical strength of the composition is realized. Note that the poorly water-soluble solid substance has a function of suppressing the expansion or contraction of the network when the network is formed, and contributes to maintaining the shape of the present composition.

As used herein, the term “network” refers to a connection between raw materials that gives the composition of the present invention an appropriate physical strength, and specifically, a connection between an organic acid and a carbonate. To a small amount of water generated locally by a chemical reaction,
A part of the raw material containing the organic acid and the carbonate, particularly the surface of the raw material particles is dissolved, and the raw material particles approach each other through the dissolved part, and as a raw material itself and a reaction product in the process of drying these. It refers to the interconnection of the raw materials and their reaction products, which are provided to the composition by curing in the amorphous or crystalline state.

On the other hand, the carbon dioxide gas and water generated with the progress of the above-mentioned phenomenon are scattered outside the present composition, so that an appropriate porosity can be obtained in combination with the above-mentioned low molding pressure (and networking). It is thought to promote rapid disintegration in the oral cavity. In addition, in the composition having voids therein as described above, in order to determine a delicate and good balance between the oral disintegration and tablet strength, the porosity and tablet strength defined in the present invention are used as a determination material. Is considered to be preferred.

[0032]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the orally disintegrating composition of the present invention will be described in detail. As described above, the orally disintegrating composition of the present invention contains an organic acid, a carbonate, a network maintenance agent and a coloring inhibitor, and the orally disintegrating formulation of the present invention contains The orally disintegrating composition is obtained by adding a medicinal ingredient to the orally disintegrating composition, and since both have almost common properties in disintegration and strength, both are described below.

Here, the active ingredient in the orally disintegrating preparation of the present invention is not limited by its shape or active area, and may be, for example, a central nervous system drug, a peripheral nervous system drug, a sensory organ drug. Medicine, allergy medicine, cardiovascular medicine, respiratory medicine, digestive medicine, hormonal medicine, urogenital and anal medicine, vitamin medicine, nutrient tonic altering medicine, blood and body fluid medicine, metabolic medicine, Cell stimulating drugs, tumor drugs, diagnostic drugs, drugs for physical disorders, antibiotics, chemotherapeutics, biological drugs, bioactive peptides, drugs for parasites, etc. One or more of these medicinal components can be used in combination.

The amount of the above-mentioned medicinal component depends on the nature thereof, but is not more than 80% by weight of the solid component, that is, the whole orally disintegrating composition of the present invention. Preferably 0.03 to
It is preferably 50% by weight, more preferably 0.03 to 20% by weight. If the compounding amount of the medicinal component exceeds 80% by weight, a favorable balance between the orally disintegrating property of the final product and the tablet strength cannot be obtained, which is not preferable.

The preparation of the present invention takes the form of a solid preparation, typically a tablet, but can be masked with a bitter mask or the like by a conventionally known method. Such masking can also be applied to the raw powder or granules of the medicinal ingredient and tableted.

The present composition contains, as essential components, an organic acid, a carbonate, a network maintaining agent and a coloring inhibitor, which will be described in detail below. The mixing ratio of these components is, by weight, a mixture of an organic acid and a carbonate. : Network maintainer: anti-coloring agent = 100: 2
5.0 to 625.0: 25.0 to 937.5. If the ratio is out of this range, the effects intended by the present invention may not be obtained, which is not preferable. Further, in the present composition, the mixing ratio between the organic acid and the carbonate is preferably set to an organic acid: carbonate = 1: 1 to 9: 1 by weight. Outside of this range, the effects intended by the present invention may not be obtained, which is not preferable.

First, preferred examples of the organic acid include L-tartaric acid, citric anhydride, lactic acid, dl-malic acid, fumaric acid, L-ascorbic acid and the like. -Tartaric acid and dl-malic acid and the like are particularly preferred. In the present invention, these organic acids can be used alone or in combination of two or more.
Such an organic acid performs a function of forming a network in addition to a function of generating water by reacting with a carbonate in the decarboxylation gas and dehydration step in the production of the present composition.

The content of the organic acid in the orally disintegrating composition of the present invention is sufficient as long as the obtained composition can achieve the intended orally disintegrating properties and tablet strength. It is 4.0 to 60.1% by weight, preferably 15.0 to 40.0% by weight. When the content of the organic acid is less than 4.0% by weight or more than 60.1% by weight, a good balance between the orally disintegrating property and the tablet strength in the final product cannot be obtained, which is not preferable.

Preferred examples of the carbonate include sodium bicarbonate, potassium bicarbonate and sodium carbonate. The water generated in the above-mentioned networking of the raw materials and the reaction with the organic acid may be used. From the viewpoint of rapid dissolution, a carbonate easily soluble in water can be particularly preferably used.

These carbonates may be used alone or in combination of two or more. The content of the carbonate in the present composition is not limited as long as the desired properties can be realized as described above. However, it is usually 0.8 to 33.4% by weight, preferably 2.5 to 15.0% by weight. When the content of the carbonate is less than 0.8% by weight or more than 33.4% by weight, a good balance between the orally disintegrating property and the tablet strength in the final product cannot be obtained, which is not preferable.

Next, corn starch, potato starch, sodium carboxymethyl starch, crystalline cellulose, low-substituted hydroxypropylcellulose or croscarmellose sodium are used as network maintainers.
And a poorly water-soluble solid substance according to any mixture thereof. This network maintaining agent has a function of suppressing deformation of the present composition (solid) due to expansion and contraction caused by expansion and shrinkage caused by the above-described decarbonation gas and dehydration step, and reduction of voids.
In addition, when this network maintenance agent is not added, the obtained orally disintegrating composition or the like shrinks and becomes too hard in a heating step described later, and dissolution in the mouth becomes poor.

The amount of the network maintainer is usually 16.0 to 50.0% by weight, preferably 25.0 to 5% by weight.
0.0% by weight. The amount of the network maintainer is 1
If the content is less than 6.0% by weight, the tablet shrinks and becomes too hard in the heating step described later, so that the dissolution in the mouth becomes poor, and 50.0% by weight.
If it exceeds, sufficient tablet strength cannot be obtained, which is not preferable.

On the other hand, water-soluble saccharides related to erythritol, xylitol, mannitol, lactose and any mixture thereof are used as the coloring inhibitor. As lactose, isomerized lactose, reduced lactose, and the like are used. In addition, if this coloring inhibitor is not added, the obtained orally disintegrating composition and preparation will have a poor taste at the time of ingestion, and the tablet will be discolored in the manufacturing process.

The content of the coloring inhibitor is usually 16.
It is 0 to 75.0% by weight, preferably 16.0 to 60.0% by weight. If the content of the coloring inhibitor is less than 16.0% by weight, the tablet will be discolored in the production process, and if it exceeds 75.0% by weight, sufficient tablet strength cannot be obtained, which is not preferable.

The orally disintegrating composition of the present invention has a suitable orally disintegrating property as described above, and a porosity suitable as an index thereof is 30 to 60%. The porosity of the orally disintegrating preparation of the present invention is in accordance with this. Here, the porosity is obtained by measuring the tablet volume and the total pore volume by a mercury intrusion method, and using the measured values, the following formula (1) porosity (%) = (total pore volume / tablet volume) ) × 100 (1). This porosity is 3
If it is less than 0%, it takes time to disintegrate in the oral cavity, and if it exceeds 60%, sufficient strength may not be obtained, which is not preferable.

As described above, the compositions and preparations of the present invention have excellent disintegration properties in the oral cavity and high physical strength (tablet strength). As described above, it is an advantage of the present invention to combine good disintegration in the oral cavity and appropriate strength in a formulation. For example, the tablet strength is usually 1 to 10 kp,
Preferably, it is about 1.5 to 7 kp. The dissolution in the mouth (the time required for the tablet to completely disintegrate with the saliva in the mouth of a healthy adult male) is usually within 1.5 minutes, preferably within 1 minute. Further, the disintegration time (measured by the disintegration test method described in the Japanese Pharmacopoeia 13th Edition) is usually within 1 minute, preferably within 30 seconds.

The essential components of the composition are the above-mentioned organic acids, carbonates, network maintainers and color inhibitors, but are generally used in the production of tablets as long as they do not adversely affect the disintegration and other properties described above. It is also possible to include additives of the type used. Such additives include, for example, binders, lubricants, sweeteners, flavors, coloring agents and the like.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and methylcellulose.

As the lubricant, for example, magnesium stearate, calcium stearate, stearic acid,
Examples include sucrose fatty acid esters, talc, polyethylene glycol and the like.

As sweeteners, erythritol, xylitol, mannitol, lactose, saccharin sodium,
Glycyrrhizin dipotassium, aspartame, stevia, thaumatin and the like can be mentioned. Examples of the flavor include lemon, lemon lime, orange, and menthol. As a coloring agent, for example, food yellow 5
No. 5, food red No. 5, food lake color, iron sesquioxide, yellow iron sesquioxide and the like.

The above-mentioned additives can be used alone or in combination of two or more. Further, these additives can be added at any stage of the production process. That is, these additives can be added in an appropriate amount at any time during the mixing of the organic acid, the carbonate, the network maintaining agent, and the coloring inhibitor, at the time of granulation or immediately before molding.

Next, a method for producing the orally disintegrating composition of the present invention will be described. As described above, in the present manufacturing method,
First, an organic acid, a carbonate, a network maintenance agent and a coloring inhibitor are mixed, and the molding mixture is mixed at 1 to 130 kg / c.
molding in a molding pressure of m ^2. Then, the obtained substantially dry molded body is heated at 40 to 120 ° C. to release carbon dioxide gas and moisture from the molded body and form a network of the above four components. An orally disintegrating composition in the form of a tablet having strength and disintegration properties can be obtained.

Here, the compounding amounts of the above four essential components are, as described above, 4.0 to 60.1% by weight of an organic acid and 0.1% of a carbonate.
8-33.4% by weight, network maintainer 16.0-5
0.0% by weight, and 16.0 to 75.0% by weight of a coloring inhibitor.

The method of mixing is not particularly limited, and the mixing can be performed as it is or after granulating the raw material such as the organic acid. In the present invention, the obtained molding mixture is substantially used. It is necessary that the molded body obtained in the next step be substantially dried. Here, the “substantially dry state” means that the moisture content measured by the Karl Fischer method is 5 w / w% or less. If the molding mixture is not in a substantially dry state, sticking is likely to occur at the time of tableting, and it may not be possible to continuously and quantitatively supply the raw material powder for molding.

The raw material can be granulated before or after mixing the raw materials, and the raw materials can be mixed in their entirety, individually or in any combination. It is preferable that this mixture can be smoothly supplied to a tablet molding machine in a subsequent molding step. Further, as the granulation method, it can be performed either dry or wet, but when wet granulation is performed, from the viewpoint of the above-mentioned reasons and the productivity during compression molding,
Before molding, it is necessary to remove water until it reaches a substantially dry state.

A single-shot tablet machine or a rotary tablet machine is generally used for molding the molding mixture. However, the present invention is not limited thereto, and a tablet machine with special specifications can be used. Molding pressure for tableting is usually 1 to 130k
g / cm ² , preferably 10 to 100 kg / cm
² , more preferably 20 to 80 kg / cm ² . If the molding pressure is less than 1 kg / cm ² , the molded product is easily damaged in the subsequent manufacturing process, and if it exceeds 130 kg / cm ² ,
The disintegration of the final product in the oral cavity is poor, which is not preferable.

When the orally disintegrating preparation of the present invention is prepared by adding a medicinal ingredient to the composition, the medicinal ingredient may be added before the above-mentioned molding. The amount of the above-mentioned organic acid and / or carbonate can be appropriately changed depending on the acidity / basicity of the target medicinal ingredient.

The molded body obtained as described above is in a substantially dry state, and then heated to release carbon dioxide and water from the molded body, and at the same time, the networking is performed. Is done. In addition, in the conventional method for manufacturing an orally disintegrating tablet, as described in JP-A-5-27054 and JP-A-8-291051, water is added to a molding mixture or a molded body itself. It is practiced that the molded body is wetted and then dried to obtain a tablet. However, in the present invention, such a water addition step is unnecessary, and the production cost is reduced by omitting one step. be able to.

Further, the above-mentioned heating to networking step is derived from the knowledge of the present inventors and shows the remarkableness of the present invention, and is unparalleled in other formulation techniques. Yes, it offers the opposite motivation.

That is, in the case of an effervescent tablet containing an organic acid and a carbonate, such heating has conventionally been regarded as a matter which must be strictly avoided since such effervescent tablet is deteriorated. In the case of effervescent tablets having a two-layer structure, by adopting such a layer structure, the area in which the carbonate and the organic acid are in direct contact with each other is reduced as much as possible to prevent the storage stability from deteriorating. ing. Furthermore, when a carbonate is coexisted with an organic acid and placed in a packaging container, a reaction occurs due to a small amount of moisture, so that the internal pressure of the packaging container increases due to the generation of carbon dioxide gas, and the container may swell, possibly causing damage. is there. It is known that when such a situation occurs, the commercial value is lost and the consumer's credibility is lost.

To avoid such a situation, Japanese Patent Application Laid-Open No.
No. 13714 discloses a method in which a double salt of a carbonate and a borate is prepared in advance, and an organic acid is added thereto. JP-A-58-105910 discloses a method in which polyethylene glycol (hereinafter abbreviated as "PEG") and another foaming component are blended and then heated and melted to embed the foaming component in the PEG. Have been. Further, JP-A-61-176519 discloses a method in which an organic acid which does not release water of crystallization at 50 ° C. or less and PEG are heated and melt-mixed, then cooled and powdered, and sodium bicarbonate and sodium carbonate are added thereto. It has been disclosed. These techniques are all proposed to prevent the composition from becoming unstable due to the coexistence of the carbonate and the organic acid, and are techniques devised so that the carbonate and the organic acid do not react.

On the other hand, in the present invention, in the manufacturing process, the organic acid and the carbonate are positively brought into contact with each other and heated to cause a part of them to react, whereby the strength of the obtained tablet is improved. And In addition, the storage stability of the present composition is improved by performing the heating to networking steps.

Although the details of this reason are not always clear at present, the carbon dioxide gas and water content of the organic acid particles and the carbonate particles adjacent or close to each other in the molded product by the predetermined heating-networking process of the present invention. In the process of forcibly performing the formation reaction, these are neutralized to form a network and harden, while the organic acid particles and the carbonate particles that did not participate in the carbon dioxide and water generation reaction are affected by such a reaction. It is isolated by the network to suppress direct contact and reaction with each other, thereby improving the storage stability of the tablet. In addition, in the tablet, the organic acid and carbonate in an amount required for rapid disintegration at the time of oral administration and a suitable mouthfeel remain in a well-balanced manner, so that the effects intended by the present invention are obtained. It is assumed that

The inventors of the present invention have confirmed that carbon dioxide gas and water are generated from the molded product by the chemical reaction between the organic acid and the carbonate in the above heating step.
It has been proved by an experiment using a fully automatic thermal desorption spectroscopy device (see FIGS. 1 and 2). That is, from the molded body having the same formulation as that of Example 2 described later, generation of carbon dioxide and water was detected when the temperature reached around 120 ° C. in about 10 minutes from the start of heating. In contrast, erythritol was replaced with mannitol in the formulation of Comparative Example 5 described later, that is, this formulation did not contain an organic acid, but generation of carbon dioxide and water due to a chemical reaction was not detected.

The carbon dioxide gas and water generated as the heating-to-networking process proceeds are scattered out of the present composition, so that the carbon dioxide gas and water can be combined with the above-mentioned low molding pressure (and networking) to give an appropriate amount. It is thought to promote porosity and achieve rapid disintegration in the oral cavity.However, organic acids and carbonates involved in the generation of carbon dioxide and water are not only rapidly formed in the oral cavity but also in the network. It is involved in the melting of the mouth and the appropriate mouthfeel, and not all of them are scattered. Therefore, in this respect, the idea of the present invention is completely different from the technology described in Japanese Patent No. 2640570 in which the volatile components such as ammonium bicarbonate are simply volatilized to realize a porous tablet.

The heating of the molded body can be performed using, for example, a microwave dryer or a ventilation dryer. The heating temperature is such that the obtained composition or preparation (particularly, tablet) has the above-mentioned porosity, tablet strength, etc., and the strength required in the manufacturing process, the packaging process, the distribution process, and the handling of the patient is excellent. Any temperature may be used as long as it can exhibit oral disintegration. Specifically, the heating temperature is 40 to 120 ° C, preferably 60 to 120 ° C. The upper limit of the heating temperature is preferably equal to or lower than the melting point of the added additive or medicinal component, but as long as the strength required for handling is obtained and the property of rapidly disintegrating in the oral cavity is obtained. However, the present invention is not limited to this.

Since the tablet according to the orally disintegrating composition of the present invention obtained as described above is supposed to be orally administered as it is, its weight and size naturally have an appropriate range. Typically, about 100-1000 mg,
Those having a range of about 6 to 12 mmφ × 2 to 6 mm (thickness) are preferable. If the weight and size deviate from the above range,
The physical volume ratio occupied in the oral cavity is high, making it difficult to take, which is not preferable.

[0068]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples. In addition, the following performance evaluation was performed about the composition and formulation obtained in each example.

[Porosity] Autopore 92 manufactured by Shimadzu Corporation
The mercury intrusion method was performed using Model 20 to measure the total pore volume and tablet volume, which were calculated from the above equation (1). The measurement was performed three times, and the average value was shown.

[Tablet strength] Tablet hardness tester (6D, Schl
(Euniger). The measurement was performed three times, and the average value was shown.

[Dissolution in the mouth] The time required for the tablet to completely disintegrate with saliva in the mouth of a healthy adult male was measured.
The measurement was performed three times, and the average value was shown.

Example 1 To a mortar, mannitol, corn starch, anhydrous citric acid, and sodium hydrogen carbonate were added in the respective formulations shown in Table 1, and mixed for about 3 minutes. Then, the mixture was molded by applying a pressure of about 10 kg / cm ² using a punch and a die having a diameter of 1 cm. This molded product is heated at 115 ° C. for 1 hour using a ventilation dryer.
After heating for 0 minutes and drying overnight in a closed container containing a desiccant, the orally disintegrating composition (tablet) of this example was obtained. The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0073]

[Table 1]

Example 2 The same operation as in Example 1 was repeated to obtain a mixture such as mannitol. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Thereafter, molding and heating were performed in the same manner as in Example 1, and the mixture was dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition of this example. The above-described performance evaluation was performed, and the obtained results are shown in Table 31.

(Example 3) Erythritol, corn starch, anhydrous citric acid, and sodium hydrogen carbonate were added to a mortar in the composition shown in Table 2, respectively, and mixed for about 3 minutes.
Next, about 0.6 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 10 kg / kg was added to this mixture using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of cm ² . The molded product was heated at 50 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition (tablet) of this example. . The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0076]

[Table 2]

(Example 4) Xylitol, corn starch, anhydrous citric acid, and sodium hydrogencarbonate were added to a mortar in the composition shown in Table 3, respectively, and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour.
The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 20 kg / cm was added to this mixture using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of ² . The molded product was heated at 50 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition (tablet) of this example. . The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0078]

[Table 3]

Example 5 In a mortar, mannitol, crystalline cellulose, anhydrous citric acid, and sodium hydrogen carbonate were added in the proportions shown in Table 4, respectively, and mixed for about 3 minutes. Next, about 0.3 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour.
The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 20 kg / cm was added to this mixture using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of ² . The molded product was heated at 110 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition (tablet) of this example. . The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0080]

[Table 4]

(Example 6) Erythritol, sodium carboxymethyl starch, anhydrous citric acid, and sodium hydrogen carbonate were added to a mortar in the composition shown in Table 5, respectively, and mixed for about 3 minutes. Then, about 0.2 ml of purified water was added to 6 g of the obtained mixture and mixed for about 2 minutes.
Dried at 50 ° C. for 1 hour. 500 ml of this dried mixture
The mixture was sized through a sieve having an opening of μm to obtain a granulated mixture for molding. Next, the mixture was molded by applying a pressure of about 20 kg / cm ² using a punch and a die having a diameter of 1 cm. This molded product is subjected to 6
After heating at 0 ° C. for 10 minutes, the mixture was dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition (tablet) of this example. The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0082]

[Table 5]

(Example 7) Erythritol, corn starch, anhydrous citric acid, and potassium hydrogen carbonate were added to a mortar in the composition shown in Table 6 and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour.
The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 20 kg / cm was added to this mixture using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of ² . The molded product was heated at 50 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition (tablet) of this example. . The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0084]

[Table 6]

Example 8 Erythritol, corn starch, anhydrous citric acid, and sodium hydrogencarbonate were added to a mortar in the proportions shown in Table 7 and mixed for about 3 minutes.
Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 20 kg / kg was added to this mixture using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of cm ² . The molded product was heated at 50 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition (tablet) of this example. . The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0086]

[Table 7]

Example 9 To a mortar, mannitol, corn starch, anhydrous citric acid, and sodium hydrogen carbonate were added in the respective formulations shown in Table 8, and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour.
The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 20 kg / cm was added to this mixture using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of ² . The molded product was heated at 110 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition (tablet) of this example. . The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0088]

[Table 8]

Example 10 Erythritol was placed in a mortar.
Corn starch, anhydrous citric acid and sodium bicarbonate were added in the respective formulations shown in Table 9 and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 600 μm to obtain a granulated mixture for molding. Then, about 20 kg was added to this mixture using a 1 cm diameter punch and die.
The molding was performed by applying a pressure of / cm ² . The molded product was heated at 50 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition (tablet) of this example. . The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0090]

[Table 9]

Example 11 Erythritol was placed in a mortar.
Corn starch, anhydrous citric acid and sodium bicarbonate were added in the respective formulations shown in Table 10 and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 20 kg was added to this mixture using a 1 cm diameter punch and die.
The molding was performed by applying a pressure of / cm ² . The molded product was heated at 60 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition (tablet) of this example. . The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0092]

[Table 10]

Example 12 Erythritol and mortar
Corn starch, anhydrous citric acid, and sodium hydrogen carbonate were added in the respective formulations shown in Table 11, and mixed for about 3 minutes. Next, about 0.4 ml of purified water was added to 12 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 600 μm to obtain a granulated mixture for molding. Then
About 30k using a 1cm diameter punch and mortar
The molding was performed by applying a pressure of g / cm ² .
The molded product was heated at 50 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating composition (tablet) of this example. . The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0094]

[Table 11]

(Example 13) Simvastatin was placed in a mortar.
Erythritol, corn starch, citric anhydride, and sodium hydrogen carbonate were added in the respective formulations shown in Table 12, and mixed for about 3 minutes. Then, about 0.2 ml of purified water was added to 6 g of the obtained mixture and mixed for about 2 minutes.
Dried at 50 ° C. for 1 hour. 500 ml of this dried mixture
The mixture was sized through a sieve having an opening of μm to obtain a granulated mixture for molding. Next, the mixture was molded by applying a pressure of about 60 kg / cm ² using a punch and a die having a diameter of 1 cm. This molded product is subjected to 7
After heating at 0 ° C. for 10 minutes, the product was dried overnight in a closed container containing a desiccant to obtain an orally disintegrating preparation (tablet) of this example. The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0096]

[Table 12]

(Example 14) In a mortar, rizatriptan,
Mannitol, corn starch, anhydrous citric acid, and sodium hydrogen carbonate were added in the formulations shown in Table 13, respectively.
Mix for about 3 minutes. Then, about 0.2 ml of purified water was added to 6 g of the obtained mixture and mixed for about 2 minutes.
Dry at 0 ° C. for 1 hour. 500 μl of this dried mixture
The mixture was sized through a sieve having a mesh size to obtain a granulated mixture for molding. Next, the mixture was molded by applying a pressure of about 60 kg / cm ² using a punch and a die having a diameter of 1 cm. This molded product is subjected to 11
After heating at 0 ° C. for 10 minutes, the product was dried overnight in a closed container containing a desiccant to obtain an orally disintegrating preparation (tablet) of this example. The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0098]

[Table 13]

Example 15 Losantan potassium, erythritol, corn starch, citric anhydride,
Sodium bicarbonate was added in the formulation shown in Table 14 and mixed for about 3 minutes. Then 6 g of the resulting mixture
Then, about 0.2 ml of purified water was added thereto, mixed for about 2 minutes, and then dried at 50 ° C. for 1 hour. This dried mixture is
The mixture was sized through a sieve having an opening of 00 μm to obtain a granulated mixture for molding. Next, the mixture was molded by applying a pressure of about 60 kg / cm ² using a punch and a die having a diameter of 1 cm. The molded product was heated at 70 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating preparation (tablet) of this example. The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0100]

[Table 14]

Example 16 In a mortar, an endothelin antagonist, Manyu Pharmaceutical Co., Ltd., compound code J-104,13
2. Mannitol, corn starch, citric anhydride, and sodium bicarbonate were added in the respective formulations shown in Table 15 and mixed for about 3 minutes. Then, about 0.2 ml of purified water was added to 6 g of the obtained mixture and mixed for about 2 minutes.
Dried at 50 ° C. for 1 hour. This dried mixture is mixed with 600
The mixture was sized through a sieve having an opening of μm to obtain a granulated mixture for molding. Next, the mixture was molded by applying a pressure of about 60 kg / cm ² using a punch and a die having a diameter of 1 cm. This molded product is subjected to 1
After heating at 15 ° C. for 10 minutes, the product was dried overnight in a closed container containing a desiccant to obtain an orally disintegrating preparation (tablet) of this example. The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0102]

[Table 15]

Example 17 To a mortar, Manyu Pharmaceutical Co., Ltd. compound code J-104, 135, erythritol, corn starch, anhydrous citric acid, and sodium hydrogen carbonate were added in the proportions shown in Table 16, respectively, and about 3 parts were added. Mix for minutes.
Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 600 μm to obtain a granulated mixture for molding. Then, about 60 kg / kg was added to this mixture using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of cm ² . The molded product was heated at 80 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating preparation (tablet) of this example. The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0104]

[Table 16]

Example 18 To a mortar, Manyu Pharmaceutical Co., Ltd. compound code J-112,534, erythritol, corn starch, anhydrous citric acid, and sodium hydrogencarbonate were added in the proportions shown in Table 17, respectively, and about 3 parts were added. Mix for minutes.
Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 600 μm to obtain a granulated mixture for molding. Then, about 60 kg / kg was added to this mixture using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of cm ² . The molded product was heated at 80 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain an orally disintegrating preparation (tablet) of this example. The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0106]

[Table 17]

Example 19 Erythritol was placed in a mortar.
Corn starch, anhydrous citric acid, and sodium bicarbonate were added in the formulations shown in Table 18 and mixed for about 3 minutes. Next, about 0.8 ml of purified water was added to 24 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 600 μm to obtain a granulated mixture for molding. Then
The mixture is added to the mixture using a 1 cm diameter punch and mortar for approximately 60 k.
The molding was performed by applying a pressure of g / cm ² .
This molded product is subjected to 2.6 using a microwave dryer (NE-A33, 2450 MHz, manufactured by Matsushita Electric Industrial Co., Ltd.).
After heating for one minute, the mixture was dried overnight in a closed container containing a desiccant to obtain an orally disintegrating preparation (tablet) of this example. The obtained tablets were evaluated for the performance described above, and the obtained results are shown in Table 31.

[0108]

[Table 18]

Comparative Example 1 In a mortar, mannitol, corn starch, anhydrous citric acid, and sodium hydrogen carbonate were added in the respective formulations shown in Table 19, and mixed for about 3 minutes.
Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 20 kg / kg was added to this mixture using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of cm ² . The molded product was heated at 130 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. The above tablets were evaluated for performance, and the results are shown in Table 32.

[0110]

[Table 19]

(Comparative Example 2) Erythritol, corn starch, anhydrous citric acid, and sodium hydrogen carbonate were added to a mortar according to the formulations shown in Table 20, and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 200 k was added to this mixture using a 1 cm diameter punch and die.
The molding was performed by applying a pressure of g / cm ² .
The molded product was heated at 50 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. The above tablets were evaluated for performance, and the results are shown in Table 32.

[0112]

[Table 20]

(Comparative Example 3) Erythritol, corn starch, anhydrous citric acid, and sodium hydrogen carbonate were added to a mortar in the proportions shown in Table 21 and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 20 kg was added to this mixture using a 1 cm diameter punch and die.
The molding was performed by applying a pressure of / cm ² . The molded product was heated at 50 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. The above tablets were evaluated for performance, and the results are shown in Table 32.

[0114]

[Table 21]

(Comparative Example 4) Mannitol, corn starch, and anhydrous citric acid were added to a mortar in the proportions shown in Table 22 and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Next, the mixture was molded by applying a pressure of about 20 kg / cm ² using a punch and a die having a diameter of 1 cm. The molded product was heated at 110 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. The above tablets were evaluated for performance, and the results are shown in Table 32.

[0116]

[Table 22]

(Comparative Example 5) Erythritol, corn starch, and sodium bicarbonate were added to a mortar according to the formulations shown in Table 23 and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture to give about 2 ml.
After mixing for 1 minute, the mixture was dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Next, the mixture was molded by applying a pressure of about 20 kg / cm ² using a punch and a die having a diameter of 1 cm. The molded product was heated at 70 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. For the obtained tablet, perform the above-described performance evaluation,
Table 32 shows the obtained results.

[0118]

[Table 23]

Comparative Example 6 Corn starch, anhydrous citric acid and sodium bicarbonate were added to a mortar in the proportions shown in Table 24 and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 600 μm to obtain a granulated mixture for molding. The mixture is then given a diameter of 1
Molding was performed by applying a pressure of about 10 kg / cm ² using a cm punch and die. The molded product was heated at 115 ° C. for 30 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. For the obtained tablet, perform the above-described performance evaluation,
Table 32 shows the obtained results.

[0120]

[Table 24]

Comparative Example 7 To a mortar, mannitol, anhydrous citric acid and sodium bicarbonate were added in the proportions shown in Table 25, respectively, and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 600 μm to obtain a granulated mixture for molding. Then, the mixture was added with a diameter of 1c.
Molding was performed by applying a pressure of about 20 kg / cm ² using a m-punch and a die. The molded product was heated at 115 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. The above tablets were evaluated for performance, and the results are shown in Table 32.

[0122]

[Table 25]

Comparative Example 8 Erythritol, corn starch, anhydrous citric acid, and sodium hydrogencarbonate were added to a mortar in the proportions shown in Table 26 and mixed for about 3 minutes. Next, about 0.2 ml of purified water was added to 6 g of the obtained mixture, mixed for about 2 minutes, and dried at 50 ° C. for 1 hour. The dried mixture was sized through a sieve having an opening of 500 μm to obtain a granulated mixture for molding. Then, about 400 k was added to this mixture using a 1 cm diameter punch and die.
The tablet of this example was obtained by applying a pressure of g / cm ² . The above tablets were evaluated for performance, and the results are shown in Table 32.

[0124]

[Table 26]

(Comparative Example 9) Erythritol was added with a diameter of 1c.
Molding was performed by applying a pressure of about 60 kg / cm ² using a m-punch and a die. The molded product was heated at 80 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. Table 27 shows the amounts of erythritol added. The above tablets were evaluated for performance, and the results are shown in Table 32.

[0126]

[Table 27]

(Comparative Example 10) Mannitol was added with a diameter of 1c.
Molding was performed by applying a pressure of about 60 kg / cm ² using a m-punch and a die. The molded product was heated at 115 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. Table 28 shows the amount of mannitol added. The above tablets were evaluated for performance, and the results are shown in Table 32.

[0128]

[Table 28]

(Comparative Example 11) About 1.0 ml of purified water was added to 6 g of erythritol and mixed for about 2 minutes.
Dry at 0 ° C. for 2 hours. The dried product was sized through a sieve having an opening of 600 μm and granulated. Then, about 60 kg / kg of this erythritol was added to the erythritol using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of cm ² . The molded product was heated at 80 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. Table 2 shows the amount of erythritol added.
It is shown in FIG. The above tablets were evaluated for performance, and the results are shown in Table 32.

[0130]

[Table 29]

(Comparative Example 12) About 6 mg of mannitol was added to about 1.
After adding 0 ml of purified water and mixing for about 2 minutes,
For 2 hours. The dried product was sized through a sieve having an opening of 600 μm and granulated. Next, about 60 kg / cm ² was applied to this mannitol using a 1 cm diameter punch and die.
Molding was performed by applying a pressure of The molded product was heated at 115 ° C. for 10 minutes using a ventilation dryer, and then dried overnight in a closed container containing a desiccant to obtain a tablet of this example. Table 30 shows the amount of mannitol added.
Shown in For the obtained tablet, perform the above-described performance evaluation,
Table 32 shows the obtained results.

[0132]

[Table 30]

[0133]

[Table 31]

[0134]

[Table 32]

The following can be understood from Tables 31 and 32. From Comparative Examples 9 to 12, it is not possible to obtain a tablet having the desired tablet strength and dissolution time in the mouth only with the water-soluble saccharide or the wet-granulated water-soluble saccharide. It is clear that salts and network maintainers are needed. Furthermore, from Comparative Examples 4 and 5, even when either the organic acid or the carbonate was not present,
The desired tablet strength was not obtained, which demonstrates that the neutralization reaction between the organic acid and the carbonate is responsible for the increase in tablet strength.

When no network maintaining agent is added as in Comparative Example 7, the tablet shrinks in the heating step, and the porosity decreases. As a result, although the tablet strength increases, the desired dissolution in the mouth cannot be obtained. On the other hand, in Comparative Example 6 in which the anti-coloring agent was removed, although the desired tablet strength and dissolution in the mouth were obtained, the taste at the time of ingestion was poor, and it was not preferable as an orally disintegrating tablet. Furthermore, coloring (discoloration) in the heating process
There is also a disadvantage of doing so. From the above, in the present invention, network formation, that is, increase in physical strength, is achieved between an organic acid, a carbonate, and a network maintainer. In this regard, a water-soluble saccharide is an essential component, and Many peripheral patents that obtain tablet strength by blending and the present invention have different technical ideas.

[0137]

As described above, according to the present invention, a substantially dry mixture containing an organic acid, a carbonate, a specific network maintaining agent, and a coloring inhibitor is molded, and the substantially obtained mixture is obtained. Orally disintegrating composition which has appropriate strength required for handling of preparations, and which rapidly disintegrates in the oral cavity, since the molded product in a dry state is subjected to a simple specific treatment, and its production Law can be provided.

As described above, since the orally disintegrating tablet of the present invention has excellent disintegration properties, it is easy to take.
Moreover, it has an appropriate strength and is easy to handle, and is excellent in long-term storage and stability. Therefore, it can be suitably used for treatment and prevention of diseases through improvement of patient compliance adapted according to the medicinal component to be contained.

[Brief description of the drawings]

FIG. 1 is a graph showing generation of carbon dioxide and water from a molded body.

FIG. 2 is a graph showing generation of water from a molded body.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 47/38 A61K 47/38 // A61K 9/46 9/46

Claims (11)

[Claims] Claims: 1. An orally disintegrating cured molding composition which rapidly disintegrates in the oral cavity, comprising an organic acid, a carbonate, a network maintaining agent and a color inhibitor which form a network with these. Wherein the network maintenance agent is at least one poorly water-soluble solid substance selected from the group consisting of corn starch, potato starch, sodium carboxymethyl starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, and croscarmellose sodium. Wherein the anti-coloring agent is at least one water-soluble saccharide selected from the group consisting of erythritol, xylitol, mannitol and lactose, and the network is based on 100 parts by weight of a mixture of the organic acid and the carbonate. 25.0 to 625.0 parts by weight of a maintenance agent,
An orally disintegrating composition comprising 25.0 to 937.5 parts by weight of the coloring inhibitor. 2. The orally disintegrating composition according to claim 1, wherein the mixing ratio of the organic acid and the carbonate is 1: 1 to 9: 1 by weight. 3. The orally disintegrating composition according to claim 1, wherein the carbonate is easily soluble in water. 4. The orally disintegrating composition according to any one of claims 1 to 3, wherein the porosity is 30 to 60%. 5. The orally disintegrating composition according to any one of claims 1 to 4, wherein the tablet strength is 1 to 10 kp. 6. The orally disintegrating composition according to any one of claims 1 to 5, wherein the dissolution time in the mouth of a healthy adult is 1.5 minutes or less. 7. An orally disintegrating preparation, comprising a pharmaceutically active ingredient added to the orally disintegrating composition according to any one of claims 1 to 6. 8. The medicinal component comprises a drug for central nervous system, a drug for allergies, a drug for circulatory organs, a drug for respiratory organs, a drug for digestive organs, a hormonal drug, a drug for tumors, an antibiotic and a bioactive peptide. The orally disintegrating preparation according to claim 7, which is at least one selected from the group consisting of: 9. In producing an orally disintegrating cured molded product composition which rapidly disintegrates in the oral cavity, (1) 4.0
６60.1% by weight of an organic acid and 0.8-33.4% by weight
And a network maintaining agent, which is at least one poorly water-soluble solid substance selected from the group consisting of corn starch, potato starch, sodium carboxymethyl starch, crystalline cellulose, low-substituted hydroxypropyl cellulose and croscarmellose sodium. 16.0
~ 50.0% by weight, erythritol, xylitol,
A coloring inhibitor of at least one water-soluble saccharide selected from the group consisting of mannitol and lactose;
And 0% by weight to obtain a molding mixture, and (2) 1 to 130 kg of the substantially dry molding mixture obtained.
/ Cm ^{2 at} a molding pressure of (3) Then, by heating the obtained molded body at 40 to 120 ° C., carbon dioxide gas and moisture are released from the molded body, and Forming a network of an organic acid, a carbonate, a network maintaining agent, a coloring inhibitor, and a reaction product thereof, whereby the molded body has a desired strength. Production method. 10. The molding mixture is formed by mixing each of the above-mentioned organic acids, carbonates, network maintainers, and coloring inhibitors after granulating them, or by mixing all of these components and then granulating them. The method for producing an orally disintegrating composition according to claim 9, wherein the composition is granulated. 11. The method according to claim 1, wherein the granulation is performed by a wet method, and the granulated molding mixture is dried before the molding to obtain the substantially dry molding mixture. 11. The method for producing the orally disintegrating composition according to item 10.