JP2017036214A - Composition, which contains carbonate, for intraorally disintegrating tablet, and intraorally disintegrating tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide intraorally disintegrating tablets and the like having excellent tablet hardness and disintegratability despite containing a high amount of a medical ingredient.SOLUTION: The present invention relates to a composition for intraorally disintegrating tablets containing hydrogen carbonate and a disintegrable particle composition produced by a granulation method comprising at least two steps, and further an intraorally disintegrating tablet containing a medical ingredient having a partition coefficient of -6.0 to 10.0, particularly, containing a disintegrable particle composition containing acid type carboxymethyl cellulose, wherein the tablet hardness is 30 to 150 N, and the disintegration time in water is 10 to 25 seconds.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a composition for an orally disintegrating tablet containing a bicarbonate, in particular, a disintegrating particle composition that contains acid-type carboxymethylcellulose and can be produced by a multistage granulation process, and the composition comprising a bicarbonate. And an orally disintegrating tablet containing a medicinal component having a distribution coefficient of −6.0 to 10.0.

  So far, orally disintegrating tablets have been developed as highly convenient forms that can be safely taken by patients, elderly people, children, etc. who have difficulty swallowing drugs, and can be taken easily without water. Orally disintegrating tablets have sufficient breaking strength (tablet hardness) that does not cause tablet chipping and powdering during tablet production or during transportation or opening, as in the case of ordinary tablets, and quickly in the oral cavity. It is important to have an excellent disintegration property (disintegration time) that disintegrates rapidly.

Also, excellent moldability is required during tablet production. The moldability here is the relationship between the tableting compression force and the tablet hardness obtained for this. Production methods that require high tableting compression force may cause problems such as restrictions on the performance of the tableting device, reduced productivity, and reduced function of the coating fine particles contained in the tablet. It is also important that the composition has excellent formability, i.e., the ability to obtain a higher tablet hardness with the same tablet compression force or to achieve the same tablet hardness with a lower tablet compression force. .

  Here, tablet hardness and disintegration are properties that are opposite to each other. Generally, increasing the molding pressure to increase the hardness increases the disintegration time, and decreasing the molding pressure to shorten the disintegration time decreases the hardness. Tend to be. For this reason, various techniques have been developed to achieve a balance between these two properties, or to achieve an optimal balance between the two properties.

Furthermore, particle components, granulation methods, and the like have been studied in order to impart excellent moldability to the particles or particle composition constituting the tablet.

  Acid-type carboxymethyl cellulose is another cellulose derivative called “carmellose”, which has the property of swelling when added with water but having almost no viscosity. As an excipient or disintegrant, it is used as a component of orally disintegrating tablets.

  For example, Patent Document 1 describes a disintegrating particle composition obtained by uniformly dispersing mannitol, xylitol, an inorganic excipient, a disintegrant, and carmellose in the presence of water and then drying. A characteristic of such a composition is that composite particles are formed by solidly dispersing xylitol in mannitol particles, and an inorganic excipient, a disintegrant and carmellose are dispersed in the composite particles. The disintegrating particle composition is produced by spray granulating a dispersion in which each of these components is dispersed in an aqueous medium, or spraying it on a carrier such as mannitol.

  Patent Document 2 describes an orally disintegrating tablet containing a medicinal component and 10% (w / w) or more of carboxymethyl cellulose based on the whole. The orally disintegrating tablet is prepared by a tableting machine after mixing each component.

  Furthermore, Patent Document 3 describes a method for producing an orally disintegrating tablet containing loratadine, which is a medicinal component. The production method includes a two-stage granulation process. In the first granulation process, loratadine and at least one additive such as a binder, an excipient, and a disintegrant are granulated to obtain a second granulation process. In the granulation step, the granulated product obtained in the first granulation step is further granulated together with at least one additive such as a binder, an excipient, and a disintegrant as in the first granulation step. Features. Carmellose is mentioned as an example of the disintegrant.

  Furthermore, Patent Document 4 describes a method for producing an orally disintegrating tablet. The production method comprises a step of spraying an aqueous suspension of a water-soluble but hydrophilic disintegrating component into a mixture of an excipient and a medicinal ingredient to obtain a granulated product A containing the medicinal ingredient; A step of spraying a similar aqueous suspension of a disintegrating component to obtain a granulated product B that does not contain a medicinal component, and a step of compression-molding the granulated product A and the granulated product B thus obtained.

International publication pamphlet WO2011 / 019045 JP 2008-285434 A JP 2012-31138 A Japanese Patent No. 4551627

  Conventionally, it has been required to increase the content of medicinal ingredients in orally disintegrating tablets. However, if the content is increased, it is difficult to obtain the desired tablet hardness, and the tableting pressure is increased to increase the hardness. And there was a problem that the collapse time was long.

  Accordingly, a further object of the present invention is to solve such problems and to provide an orally disintegrating tablet having excellent tablet hardness and disintegration even if the content of medicinal ingredients is high.

In order to solve the above problems, the present inventors have intensively studied, and in particular, disintegrating particles produced by at least a two-stage granulation method including a first disintegrant component composed of acid-type carboxymethylcellulose. It has been found that an orally disintegrating tablet composition can be produced by further adding a bicarbonate to the composition. Moreover, the orally disintegrating tablet containing the orally disintegrating tablet composition and the medicinal component having a distribution coefficient (logP) of 6.0 to 10.0 contains the medicinal component in a high content and is excellent. It discovered that it had tablet hardness and disintegration, and completed this invention.

That is, the present invention relates to the following aspects.
[Aspect 1]
An orally disintegrating tablet composition comprising a disintegrating particle composition produced by at least a two-stage granulation method and a bicarbonate.
[Aspect 2]
The composition for orally disintegrating tablets according to aspect 1, comprising acid-type carboxymethylcellulose.
[Aspect 3]
The composition for orally disintegrating tablets according to aspect 1 or 2, which does not contain an organic acid.
[Aspect 4]
The composition for orally disintegrating tablets according to any one of aspects 1 to 3, wherein the content of hydrogen carbonate is 0.1 to 20% by weight.
[Aspect 5]
An orally disintegrating tablet comprising the composition for orally disintegrating tablet according to any one of aspects 1 to 4 and a medicinal component having a distribution coefficient of -6.0 to 10.0.
[Aspect 6]
The orally disintegrating tablet according to aspect 5, which does not contain an organic acid.
[Aspect 7]
The orally disintegrating tablet according to aspect 5 or 6, wherein the distribution coefficient of the medicinal component is -5.0 to 6.0.
[Aspect 8]
The orally disintegrating tablet according to any one of embodiments 5 to 7, wherein the medicinal component is selected from the group consisting of ibubren, etenzamide, and famotidine.
[Aspect 9]
The orally disintegrating tablet according to any one of embodiments 5 to 8, wherein the content of the medicinal component is 30% by weight or more.
[Aspect 10]
The orally disintegrating tablet according to any one of aspects 5 to 9, wherein the bicarbonate content is 0.1 to 20% by weight.
[Aspect 11]
The orally disintegrating tablet according to any one of aspects 5 to 10, wherein the tablet hardness is 30 to 150 N and the disintegration time in water is 10 to 25 seconds.

  In the oral cavity, the disintegration time of the disintegrating tablet is shortened by carbon dioxide generated from the bicarbonate contained in the orally disintegrating tablet of the present invention, the content of medicinal components is high, and excellent tablet hardness and disintegration are achieved. It is possible to provide an orally disintegrating tablet or the like.

It is a figure which shows the correlation of the calculated value by CAChe, and the experimental value of the distribution coefficient of a medicinal ingredient. It is a figure which shows the correlation of the calculated value by KOWWIN, and the experimental value of the distribution coefficient of a medicinal ingredient.

The present invention relates to an orally disintegrating tablet composition comprising a disintegrating particle composition and a bicarbonate prepared by at least a two-stage granulation method, and an orally disintegrating tablet composition and a distribution coefficient of −6. It relates to an orally disintegrating tablet containing a medicinal component of 0.0 to 10.0.

Here, the distribution coefficient of the medicinal component is a numerical value representing the hydrophobicity of the whole compound. In the present invention, the distribution coefficient (logP) of the medicinal component is −6.0 to 10.0, preferably −5.0 to 6.0, and more preferably −1.0 to 6.0. In the present invention, the distribution coefficient of each medicinal ingredient is a value obtained by calculation as follows.
As the calculated value, the value obtained in principle (1) was adopted, and in the case of a chemical structure in which the medicinal component has a zwitterionic state like an amino acid, the value obtained in (2) was adopted.
(1) This is a logP calculation value by CAChe, and the following calculation formula was used.
LogP = Σn _i a _i
N _i in the formula represents the number of each atomic group. Further, a _i in the formula represents the contribution ratio of each atomic group. Refer to the following documents for numerical values of the contribution ratio of each atomic group.
(Reference: Journal of Computational Chemistry, Vol. 9, No. 1, 80-90 (1988))
(2) This is a logP calculation value by KOWWIN, and the following calculation formula was used.
log P = Σf _i n _i + Σc _j n _j +0.229
F _i in the formula represents the coefficient of each atomic group, and n _{i in} the formula represents the number of each atomic group. Further, c _j in the equation represents a coefficient of each correction factor, and n _{j in} the equation represents the number of each correction factor. For the numerical values of the coefficient of each atomic group and the coefficient of each correction factor, refer to the following documents.
(Reference: Journal of Pharmacological Sciences 84, 83-92 (1995))
In other words, a medicinal component having a high distribution coefficient is highly hydrophobic, and an orally disintegrating tablet containing the medicinal component may impair disintegration because it is assumed that it is difficult to conduct water to the inside of the tablet. . In addition, medicinal ingredients with a low distribution coefficient are highly hydrophilic and easily dissolved in water, while at the time of tableting compression, the medicinal ingredients can increase the binding properties inside the tablet and reduce the moldability and disintegration of the tablet. There is.

On the other hand, the measured value of the partition coefficient was calculated by an existing quantitative method such as absorptiometry, gas chromatography, or liquid chromatography when the medicinal component was dissolved in two phases of water and n-octanol. It calculated from the following formula using the concentration of the medicinal component in each phase.
LogP = Log [(Medical component concentration of n-octanol phase) / (Medical component concentration of aqueous phase)]
The relationship between the calculation formula and the actually measured value is shown in FIG. 1 and FIG.

The medicinal ingredient contained in the orally disintegrating tablet of the present invention is a nutritional ingredient in a pharmaceutical ingredient or food / health food. As the medicinal component, a medicinal component alone or a component obtained by coating or granulating the medicinal component for the purpose of slow release or bitterness masking can be added.

There are no particular restrictions on the use and type of the medicinal component contained in the orally disintegrating tablet of the present invention. Examples of the use and type of the medicinal component include those for central nervous system, drugs for peripheral nervous system, and sensory organs. Medicine, Cardiovascular medicine, Respiratory medicine, Gastrointestinal medicine, Hormonal agent, Urogenital medicine, Other individual organ system medicine, Vitamin, Nutrition tonic, Blood and body fluid medicine, Other metabolic Pharmaceuticals, cell-stimulating drugs, oncology drugs, radiopharmaceuticals, allergy drugs, other tissue cell functional drugs, crude drugs, traditional Chinese medicines, other crude drugs and medicines based on traditional Chinese medicines, antibiotics, chemotherapeutics, biological And pharmaceuticals for parasites, pharmaceuticals for other pathogenic organisms, pharmaceuticals for preparation, diagnostics, public health, and in vitro diagnostics.

Examples of medicinal ingredients having the above specific ranges of partition coefficients include clotrimazole, ibubrofen, etenzamide, acetaminophen, famotidine, ascorbic acid, glycine, loxoprofen, caffeine, loratadine, aldioxa, pipemidic acid, Mention may be made of medicinal ingredients selected from the group consisting of afroqualone, clofibrate and aspartic acid.
Table 1 below shows calculated values and experimental values of the distribution coefficient calculated by the above method for typical medicinal ingredients used in the present invention.

The content of the medicinal ingredient contained in the orally disintegrating tablet of the present invention is not particularly limited, but particularly by using the medicinal ingredient having the above distribution coefficient, the orally disintegrating tablet is preferably 30% by weight or more, More preferably, the medicinal component can be contained at a content of 40% by weight or more, more preferably 50% by weight or more.

Therefore, in the preferred orally disintegrating tablet of the present invention, for example, the content of the medicinal component having a distribution coefficient of 0.8 to 4.0 can be 60% by weight or more.

The bicarbonate used in the present invention generates carbon dioxide such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, rubidium bicarbonate and cesium bicarbonate, and is known to those skilled in the art as acceptable as a pharmaceutical ingredient. Any material can be used.

The amount of bicarbonate contained in the orally disintegrating tablet of the present invention can be appropriately determined by those skilled in the art depending on the amount and type of other ingredients such as medicinal ingredients and disintegrating particle compositions, but usually 0.1 to 20% by weight, preferably 0.5 to 15% by weight, and more preferably 0.5 to 10% by weight.

The orally disintegrating tablet of the present invention can be produced by any method known to those skilled in the art.

The composition for orally disintegrating tablets of the present invention is characterized by further containing a bicarbonate as a component in the following disintegrating particle composition produced by at least a two-step granulation method. When producing the composition, it is necessary to prevent carbon dioxide from being generated by contacting an acidic substance such as acid-type carboxymethyl cellulose with a hydrogen carbonate in the presence of water. For example, after producing a collapsible particle composition as an intermediate by the following wet granulation method, carbon dioxide is generated by appropriate means such as dry granulation and mixing such as compression granulation and crush granulation. The final composition for orally disintegrating tablets can be produced by mixing bicarbonate under such conditions.

The content of the bicarbonate contained in such an orally disintegrating tablet composition can be appropriately determined by those skilled in the art depending on the amount and type of other components of the disintegrating particle composition, It is 0.1 to 20% by weight, preferably 0.5 to 15% by weight, and more preferably 0.5 to 10% by weight.

There is no particular limitation on the specific mode of the two-stage granulation method for producing the disintegrating particle composition, and those skilled in the art can appropriately select specific conditions.
Examples of suitable two-stage granulation methods for disintegrating particle compositions include: a first disintegrant component comprising acid-type carboxymethylcellulose; a second disintegrant component other than acid-type carboxymethylcellulose; and an excipient A method for producing a disintegrating particle composition containing three components, the first wet granulation step using any two of the three components, and the granulated product obtained in the first wet granulation step And a second wet granulation step using at least the remaining one component not used in the first wet granulation step.

The granulation method may further include crystalline cellulose as a fourth component in addition to the above three components. In this method, the following two modes can be taken.
(1) The first wet granulation step using any two or three components of the four components, the granulated product obtained in the first wet granulation step, and the first wet granulation step of the four components A disintegrating particle composition comprising a second wet granulation step using at least the remaining one or two components not used in the step; and (2) any of the three components other than crystalline cellulose A first wet granulation step using two components, a second wet granulation step using at least the remaining one component not used in the first wet granulation step and the granulated product obtained in the first wet granulation step, And the disintegrating particle composition characterized by including the 3rd process which mixes crystalline cellulose with the granulated material obtained at the 2nd wet granulation process.

In the production method using the above four components, any of the components may be used only in one granulation step. For example, in the second wet granulation step, only the granulated product obtained in the first wet granulation step and the remaining components not used in the first wet granulation step can be used. Alternatively, one component can be used in a plurality of granulation steps. For example, it is also possible to use each component such as crystalline cellulose in both the first wet granulation step and the second wet granulation step.

  As disintegration mechanisms for tablets and the like, four "Wicking", "Swelling", "Deformation", and "Repulsion" have been proposed. Among these, Wicking is a disintegration mechanism in which moisture penetrates through components such as a disintegrant contained in a tablet, and as a result, the binding force between particles contained in the tablet weakens and proceeds. Acid type carboxymethyl cellulose is known as a representative example of such a disintegrant having a high effect of promoting wicking. Swelling is a disintegration mechanism in which the disintegrant itself swells and proceeds as a result of water permeating into the disintegrant.

Acid-type carboxymethylcellulose, which is the first disintegrant component contained in the disintegrating particle composition of the present invention, is a substance called carmellose and is used as a pharmaceutical additive. Similar to acid-type carboxymethylcellulose, for example, calcium salt of carboxymethylcellulose and a crosslinked product of sodium carboxymethylcellulose are both insoluble in water and used as a disintegrant in tablets and the like. On the other hand, sodium salt of carboxymethyl cellulose is water-soluble and is used for the purpose of a binder or the like. In addition, the salt of carboxymethylcellulose may be described as carmellose.

  As the second disintegrant component of the disintegrating particle composition of the present invention, any disintegrant known to those skilled in the art other than acid-type carboxymethylcellulose can be used. However, in order to obtain the combined effect of different disintegration mechanisms as described above, it is preferable to use a disintegrant excellent in the effect of promoting swelling as a second disintegrant component other than Wicking, for example. . Preferable examples of such disintegrants include crospovidone, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, hydroxypropyl starch, and starch. Crospovidone is a common name for a crosslinked polymer of 1-vinyl-2-pyrrolidone, and croscarmellose sodium is a common name for a crosslinked product of sodium carboxymethylcellulose.

Among these, one or two or more arbitrary combinations selected from crospovidone, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, or carboxymethylcellulose calcium are preferable.

The disintegrating particle composition of the present invention contains, as a third component, any compound known to those skilled in the art as an excipient. Typical examples include sugars or sugar alcohols such as mannitol, erythritol, sorbitol, D-glutitol (maltitol), xylitol, trehalose, lactose and maltose. Furthermore, preferred examples include mannitol, erythritol, trehalose, sorbitol, and D-glutitol (maltitol). As the excipient, two or more compounds appropriately selected from these can be used. Furthermore, when excipients are used in each of the first wet granulation step and the second wet granulation step of the present invention, they are of the same type (same combination) or different types (different combinations). There may be.

  The disintegrating particle composition produced by the method of the present invention can further contain crystalline cellulose known to those skilled in the art as the fourth component. Representative examples thereof include commercially available products such as Avicel (FMC Corporation), Theolas (Asahi Kasei Chemicals), and Viva Poor (Lettemeyer).

Furthermore, the disintegrating particle composition of the present invention contains, for example, various optional components known to those skilled in the art for the purpose of adjusting various properties such as disintegration power, binding power, and tablet ingestion. As long as the effects of the present invention by the four components are not impaired, they may be appropriately added and mixed. Examples of such components include fluidizing agents, inorganic excipients, sweeteners, fragrances, and coloring agents.

The amount of each component in the disintegrating particle composition of the present invention depends on the type of each component, the type and use of the medicinal component that is the target of use of the disintegrating particle composition, the use of the orally disintegrating tablet that is the final product, etc. Thus, those skilled in the art can appropriately determine. Usually, the first disintegrant component is 10 to 50% by weight, the second disintegrant component is 1 to 20% by weight, and the crystalline cellulose as the fourth component is 1 to 1% by weight based on the total weight of the disintegrating particle composition. 40% by weight and excipients range from 30 to 89% by weight.

The disintegrating particle composition of the present invention preferably has the following physical properties.
(1) Average particle size: 50 to 200 microns, for example, 50 to 150 microns, (2) Water content: 0.5 to 6% by weight, for example, 1 to 5% by weight.

These physical property values are measured under the following conditions and methods.
Average particle diameter: 2 g of the disintegrating particle composition is measured using a φ75 mm automatic shaking sieve (M-2 type, Tsutsui Riken Kikai Co., Ltd.). In the present specification, “R” means a radius of curvature.
Moisture: 5 g of disintegrating particle composition is measured using a halogen moisture meter (HB43 type, METTLER TOLEDO).

In each of the above methods, the first and second granulation steps are performed by a method of forming a composite by dispersing and drying each component in the presence of water, that is, a wet granulation method. Specific examples of the wet granulation method include spraying methods such as spray drying, tumbling granulation, stirring granulation, and fluidized bed granulation, freeze-drying methods, and kneading granulation. It can be produced by any method known to those skilled in the art.

Since disintegrants such as acid-type carboxymethylcellulose are hydrophilic, by performing an operation of applying physical force such as stirring in the presence of water by wet granulation, particles from the aggregated state at the time of dry powder Becomes more dispersed. Fluidized bed granulation for dispersion and drying by water spray, spray drying, tumbling granulation, stirring granulation, etc. can be performed most easily and the drying speed is fast, so these methods are preferable. .

Among them, the fluidized bed granulation method is a granulation method performed by spraying water or an aqueous solution containing a binder while blowing up the powder with warm air, and it is easy to adjust the spraying conditions and the like. Is the most preferred method.

In the first wet granulation step in the method of the present invention, which of the three components other than the crystalline cellulose to use is determined by a person skilled in the art depending on the type and amount thereof. I can do it. For example, the first wet granulation step can be performed using either the first disintegrant component or the second disintegrant component and an excipient.

For example, a specific disintegrating particle composition comprising a first disintegrant component composed of acid-type carboxymethylcellulose, a second disintegrant component other than acid-type carboxymethylcellulose, and three components of an excipient As an aspect, (1) In the first wet granulation step, two components of the first disintegrant component (or the second disintegrant component) and the excipient are used, and the second wet granulation step uses the second component. Method using disintegrant component (or first disintegrant component); (2) In the first wet granulation step, the first wet disintegrant component and the second disintegrant component are used, and the second wet structure A method of using an excipient in the granulation step; and (3) in the first wet granulation step, using the two components of the first disintegrant component (or the second disintegrant component) and the excipient; Second disintegrant component (or first disintegrant component) in wet granulation process And a method of using a two-component excipient.

Moreover, in the manufacturing method of the disintegrating particle composition containing the four components added with crystalline cellulose, the crystalline cellulose is mixed with other components in at least one of the first wet granulation step and the second wet granulation step. To produce a granulated product. For example, the first wet granulation step is performed using either the first disintegrant component or the second disintegrant component, the excipient, and the crystalline cellulose, and the other wet granulation step is performed. A disintegrant component can be added. Alternatively, the first wet granulation step is performed using either the first disintegrant component or the second disintegrant component and an excipient, and in the second wet granulation step, the crystalline cellulose and the other disintegration step are performed. An agent component can be added.

  Furthermore, in the first wet granulation step in another method for producing a collapsible particle composition containing four components, which two types of components other than the three components other than crystalline cellulose are used, the type A person skilled in the art can appropriately determine the amount according to the amount and the like. For example, the first wet granulation step can be performed using either the first disintegrant component or the second disintegrant component and an excipient.

Various optional components known to those skilled in the art other than the above four components, which can be appropriately included in the disintegrating particle composition of the present invention, are appropriately added in the first and / or second wet granulation step. I can do it. Alternatively, these optional components can be added and mixed in an appropriate granulation step after the third step.

Furthermore, in each of the first and second wet granulation processes, various conditions such as spraying speed, air supply temperature, exhaust temperature, air supply amount, etc. are determined according to the type and amount of each component. The contractor can decide as appropriate.

  In both the first wet granulation step and the second wet granulation step by the fluidized bed granulation method, as a spray liquid medium, for example, water, ethanol, methanol, acetone and other solvents acceptable for pharmaceuticals and foods are used. Can be mentioned. Alternatively, examples of the spray liquid include an aqueous solution in which the components of the collapsible particle composition are dissolved at less than 10%, and water or the aqueous solution is particularly preferable.

Furthermore, the orally disintegrating tablet of the present invention, in addition to the above-mentioned components, if necessary, excipients, surfactants, lubricants, acidulants, sweeteners, flavoring agents, fragrances, colorants, Any other pharmaceutically acceptable ingredient such as a stabilizer may be included as an aid. As these optional components, for example, the corresponding components described in the Pharmaceutical Additives Dictionary (Pharmaceutical Daily) and the Japanese Pharmacopoeia can be used. In addition, there is no restriction | limiting in particular in the kind of these adjuvants. Moreover, as long as the desired effect of this invention is show | played, there is no restriction | limiting in particular in the mixture ratio of arbitrary components, and those skilled in the art can determine suitably. Such orally disintegrating tablets can be formulated by any method known to those skilled in the art, such as tableting.

However, when acid-type carboxymethylcellulose is contained in the composition for orally disintegrating tablets or the orally disintegrating tablet of the present invention, carbon dioxide is generated by reacting with the hydrogen carbonate, and therefore these are organic acids. Need not be included.

By having the above configuration, the orally disintegrating tablet of the present invention has excellent tablet hardness and disintegration. Specifically, the hardness is 30 to 150 N, preferably 40 to 150 N, and the underwater disintegration time is 10 to 25 seconds, more preferably 10 to 20 seconds.

In addition, the description content of all the prior art documents referred in this specification is incorporated in this specification as a reference.

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

Reference Example (Production of disintegrating particle composition)
As a first wet granulation step, 280 g of mannitol (D-mannitol, Merck Ltd.) and 75 g of carmellose (NS-300, Gotoku Pharmaceutical Co., Ltd.) are charged into a fluidized bed granulator (LAB-1, Paulek Co., Ltd.). Then, 227 g of purified water is granulated by spraying at a rate of 24 g / min. Furthermore, as a second wet granulation step, 40 g of crospovidone (Polyplastidone INF-10, ISP Japan), crystalline cellulose (Theorus PH- 101, Asahi Kasei Chemicals) was added, and 300 g of purified water was sprayed at 10 g / min to obtain a disintegrating particle composition. 99.5 parts by weight of the resulting granulated product and 0.5 parts by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) are mixed and compressed using a simple tableting machine (HANDTAB-100, Ichibashi Seiki Co., Ltd.). Tableting was performed at a force of 6.0 kN to obtain a tablet (comparative example) having a diameter of 8.0 mm, a corner flat tablet, and a weight of 250 mg. The granulated product had the following physical property values. (1) Average particle diameter: 93 microns, (2) Water content: 1.8% by weight.

Example 1
98.5 parts by weight of the disintegrating particle composition obtained in Reference Example and 1 part by weight of sodium hydrogen carbonate (Wako Pure Chemical Industries) were mixed to obtain the composition for orally disintegrating tablets of the present invention. Furthermore, 0.5 parts by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) was mixed, and tableting was performed using a simple tablet molding machine (HANDTAB-100, Ichibashi Seiki Co., Ltd.) at a tableting compression force of 10.0 kN. A tablet having a diameter of 8.0 mm, a corner flat tablet, and a weight of 250 mg was obtained.

Example 2
94.5 parts by weight of the disintegrating particle composition obtained in Reference Example and 5 parts by weight of sodium hydrogen carbonate (Wako Pure Chemical Industries) were mixed to obtain the composition for orally disintegrating tablets of the present invention. Furthermore, 0.5 parts by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) was mixed, and tableting was performed using a simple tablet molding machine (HANDTAB-100, Ichibashi Seiki Co., Ltd.) at a tableting compression force of 10.0 kN. A tablet having a diameter of 8.0 mm, a corner flat tablet, and a weight of 250 mg was obtained.

Example 3-7 and Comparative Example 1-5
(Manufacture of orally disintegrating tablets)
The disintegrating particle composition obtained in the Reference Example and the bicarbonate of Table 2 were mixed to obtain the composition for orally disintegrating tablets of the present invention. Furthermore, the medicinal components shown in Table 2 and 0.5 parts by weight of magnesium stearate were mixed (100 parts by weight as a whole), and using a simple tableting machine (HANDTAB-100, Ichihashi Seiki Co., Ltd.), the hits shown in Table 3 were used. Tableting was performed with the tablet compression force to obtain a tablet having a diameter of 8.0 mm, a corner flat tablet, and a weight of 250 mg.

Comparative Example 6
(Production of disintegrating particle composition)
In the first wet granulation step, 285 g of mannitol (D-mannitol, Merck Ltd.), 75 g of corn starch (pharmacopoeia, Nippon Food Processing Co., Ltd.), and 100 g of crystalline cellulose (Theoras PH-101, Asahi Kasei Chemicals Corporation) It is put into a layer granulator (FL-LABO, Freund Sangyo Co., Ltd.), granulated by spraying 150 g of purified water at a rate of 5 to 15 g / min, and as a second wet granulation step, crospovidone (Polyplastidone INF-10, ISP Japan) 40 g was added, and 80 g of purified water was sprayed at 4 g / min to obtain a granulated product (disintegrating particle composition). The granulated product had the following physical property values. (1) Average particle size: 89 microns, (2) Water content: 3.4% by weight.

(Manufacture of orally disintegrating tablets)
36.5 parts by weight of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was mixed with 46.5 parts by weight of the disintegrating particle composition of Comparative Example 6 to obtain a composition for orally disintegrating tablets. Furthermore, 50 parts by weight of famotidine (Wako Pure Chemical Industries) and 0.5 part by weight of magnesium stearate (Taihei Chemical Industry Co., Ltd.) were added and mixed, and a simple tablet molding machine (HANDTAB-100, Ichihashi Seiki Co., Ltd.) was used. Tableting was performed at a tableting compression force of 6.0 kN to obtain a tablet having a diameter of 8.0 mm, a corner flat tablet, and a weight of 250 mg.

[Evaluation of hardness and disintegration test]
About each tablet obtained by the above Example and comparative example, hardness and disintegration time in water were measured with the following method. Table 3 shows the measurement results of hardness and disintegration time.

These physical property values were measured under the following conditions and methods.
Hardness: Hardness (N) was measured using a digital Kiya-type hardness meter (Fujiwara Manufacturing Co., Ltd.).
Disintegration time in water: The disintegration time in water was measured using a disintegration tester (NT-400, Toyama Sangyo Co., Ltd.) using an auxiliary cylinder described in the Japanese Pharmacopoeia (but without an auxiliary panel).
The hardness and the disintegration time were measured three times, and the average value was taken as the measurement result.

  From the results shown in Table 3, compared with Comparative Example 1 (without carbonate), the orally disintegrating tablet of Example 1-2 containing carbonate was more effective despite having equivalent tablet hardness. It has been demonstrated that it has rapid disintegration.

Similarly, similar results were obtained from comparison between Comparative Example 2 and Examples 3 and 5, Comparative Example 3 and Example 4, Comparative Example 4 and Example 6, and Comparative Example 5 and Example 7.

  Further, by comparing Comparative Example 6 and Example 4, the disintegrating particle composition contains acid-type carboxymethylcellulose (carmellose), so that an orally disintegrating tablet having excellent tablet hardness and disintegration is obtained. It turns out that it is obtained.

  The present invention greatly contributes to the research and development of orally disintegrating tablets having excellent tablet hardness and disintegration.

Claims (11)

An orally disintegrating tablet composition comprising a disintegrating particle composition produced by at least a two-stage granulation method and a bicarbonate. The composition for orally disintegrating tablets according to claim 1, comprising acid-type carboxymethylcellulose. The composition for orally disintegrating tablets according to claim 1 or 2, which does not contain an organic acid. The composition for an orally disintegrating tablet according to any one of claims 1 to 3, wherein the content of hydrogen carbonate is 0.1 to 20% by weight. An orally disintegrating tablet comprising the composition for orally disintegrating tablet according to any one of claims 1 to 4 and a medicinal component having a distribution coefficient of -6.0 to 10.0. The orally disintegrating tablet according to claim 5, which does not contain an organic acid. The orally disintegrating tablet according to claim 5 or 6, wherein the distribution coefficient of the medicinal component is -5.0 to 6.0. The orally disintegrating tablet according to any one of claims 5 to 7, wherein the medicinal component is selected from the group consisting of ibubren, etenzamide, and famotidine. The orally disintegrating tablet according to any one of claims 5 to 8, wherein the content of the medicinal component is 30% by weight or more. The orally disintegrating tablet according to claim 5, wherein the content of hydrogen carbonate is 0.1 to 20% by weight. The orally disintegrating tablet according to any one of claims 5 to 10, wherein the tablet hardness is 30 to 150 N and the disintegration time in water is 10 to 25 seconds.

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