TW201609193A - Carbonate-containing composition for intraorally disintegrating tablet, and intraorally disintegrating tablet - Google Patents

Abstract

The purpose of the present invention is to provide an intraorally disintegrating tablet that has excellent tablet hardness and disintegration properties even if containing a large amount of medicinal ingredient, and the like. A composition for an intraorally disintegrating tablet, said composition comprising a disintegrating granular composition that is produced by at least a two-step granulation method and a hydrogencarbonate; an intraorally disintegrating tablet containing a medicinal ingredient that has a partition coefficient of -6.0 to 10.0, in particular, the aforesaid intraorally disintegrating tablet wherein the disintegrating granular composition contains acid-type carboxymethylcellulose, the tablet hardness is 30 to 150 N, and the disintegration time in water is 10 to 25 sec; and the like.

Description

Composition for oral disintegration tablet containing carbonate and orally disintegrating tablet

The present invention relates to a composition for an orally disintegrating tablet containing bicarbonate, and more particularly to a disintegrating particle composition comprising a carboxymethylcellulose having an acid type which can be produced in a multistage granulation process and The composition of the hydrogencarbonate, and an orally disintegrating tablet containing the composition for the orally disintegrating tablet and the medicinal ingredient having a partition coefficient of -6.0 to 10.0.

In the past, an oral cavity disintegrating tablet has been developed as a form in which it is safe to take a patient, an elderly person, or a child who is difficult to ingest a drug, and can be easily taken without using water. In the case of an orally disintegrating tablet, it is important that, in the same manner as a usual tablet, it has a sufficient breaking strength (tablet hardness) such as a defect of the tablet or a powder in the middle of the production of the tablet or during the opening or opening, and has Excellent disintegration (disintegration time) which rapidly disintegrates in the oral cavity.

Further, in the production of a tablet, excellent formability is required. The formability described herein is the relationship between the compression force of the tablet and the hardness of the tablet to which it is obtained. The method for requiring high tablet compression force may have problems in performance limitations of the tableting device, reduction in productivity, and reduction in function of coated microparticles contained in the tablet, so that the particles or particle compositions constituting the tablet are excellent. The formability, that is, the higher tablet hardness can be obtained by the same tablet compression force, or the lower tablet compression force can be used to achieve the properties of the same tablet hardness.

Here, the hardness and the disintegration property of the tablet are opposite to each other. Generally, if the molding pressure is increased in order to increase the hardness, the disintegration time becomes long, and if the molding pressure is reduced in order to shorten the disintegration time, the hardness is increased. The tendency to become smaller. Therefore, various techniques have been developed in order to combine these two properties or to achieve an optimum balance between the two properties.

Further, in order to impart excellent formability to the particles or particle constituents constituting the tablet, the components of the particles, the granulation method, and the like are studied.

Further, the acid type carboxymethyl cellulose is a cellulose derivative of "carboxymethyl cellulose", and has a property of swelling when added with water, but has a substantially non-viscous suspension, and is used as a base, a binder, and a binder. An excipient or a disintegrant is used as a component of an orally disintegrating tablet.

For example, Patent Document 1 discloses a disintegrable particle composition in which mannitol, xylitol, an inorganic excipient, a disintegrant, and carboxymethylcellulose are uniformly dispersed in the presence of water and then dried. Things. The composition is characterized in that composite particles obtained by dispersing a xylitol solid in mannitol particles are formed, and an inorganic excipient, a disintegrant, and carboxymethylcellulose are dispersed in the composite particles. The disintegrable particle composition is produced by spray granulating a dispersion obtained by dispersing the components in an aqueous medium, or by spraying a carrier such as mannitol.

Further, Patent Document 2 describes an orally disintegrating ingot containing a medicinal ingredient and carboxymethylcellulose of 10% (w/w) or more in total. The orally disintegrating ingot was prepared by mixing the components and using a tableting machine.

Further, Patent Document 3 describes a method for producing an orally disintegrating ingot containing loratadine as a medicinal ingredient. This production method performs a two-stage granulation step in which loratadine and at least one additive such as a binder, an excipient, and a disintegrator are granulated in the first granulation step, and the second step is carried out. In the granulation step, the granules obtained in the first granulation step Further, at least one additive such as a binder, an excipient or a disintegrator which is the same as the first granulation step is further subjected to granulation. As an example of a disintegrating agent, carboxymethylcellulose is mentioned.

Further, Patent Document 4 describes a method for producing an orally disintegrating tablet. The production method comprises the steps of: spraying an aqueous suspension of a water-insoluble but hydrophilic disintegrating component on a mixture of an excipient and a medicinal ingredient to obtain a granule A containing a medicinal ingredient; and a pair of excipients The step of spraying the aqueous suspension of the same disintegrating component to obtain the granulated material B containing no medicinal ingredient; and the step of compression-molding the granulated product A and the granulated product B thus obtained.

[Patent Document 1] International Publication No. WO2011/019045

[Patent Document 2] Japanese Patent Laid-Open Publication No. 2008-285434

[Patent Document 3] Japanese Patent Laid-Open Publication No. 2012-31138

[Patent Document 4] Japanese Patent No. 4551627

Since the past, it has been required to increase the content of the medicinal ingredient in the orally disintegrating tablet, but if the content is increased, it is difficult to obtain the desired tablet hardness, and if the tableting pressure is increased in order to increase the hardness, Then the problem of the disintegration time becomes longer.

Therefore, a further object of the present invention is to solve such a problem, and to provide an orally disintegrating tablet or the like which has excellent tablet hardness and disintegration properties even when the content of the medicinal ingredient is high.

In order to solve the above problems, the inventors of the present invention have intensively studied and found that it is produced by a granulation method of at least two stages, in particular, by containing a first disintegrator component composed of acid carboxymethylcellulose or the like. The disintegrable particle composition is further added with bicarbonate to produce an oral cavity A composition for in-situ disintegration. Further, it has been found that an orally disintegrating tablet containing the composition for an orally disintegrating ingot and a medicinal ingredient having a partition coefficient (logP) of -6.0 to 10.0 contains the medicinal ingredient at a high content and has an excellent lozenge. The hardness and disintegratability are completed to complete the present invention.

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

[Scenario 1]

A composition for an orally disintegrating tablet comprising a disintegrable particle composition produced by at least two-stage granulation and a hydrogencarbonate.

[Surface 2]

The composition for an orally disintegrating tablet according to the aspect 1, which comprises an acid type carboxymethylcellulose.

[Surface 3]

A composition for an orally disintegrating tablet according to aspect 1 or 2 which does not contain an organic acid.

[Surface 4]

The composition for an orally disintegrating tablet according to any one of the aspects 1 to 3, wherein the content of the hydrogencarbonate is 0.1 to 20% by weight.

[Surface 5]

An orally disintegrating tablet comprising the composition for an orally disintegrating tablet according to any one of the aspects 1 to 4, and a medicinal component having a partition coefficient of -6.0 to 10.0.

[Figure 6]

An orally disintegrating tablet as described in the aspect 5, which does not contain an organic acid.

[Stage 7]

The oral disintegrating tablet according to the aspect 5 or 6, wherein the partition coefficient of the medicinal ingredient is -5.0 to 6.0.

[Surface 8]

The orally disintegrating tablet according to any one of aspects 5 to 7, wherein the medicinal component is selected from the group consisting of Ibuprofen, ethenzamide, and famotidine. .

[Surface 9]

The orally disintegrating tablet according to any one of the aspects 5 to 8, wherein the content of the medicinal ingredient is 30% by weight or more.

[Surface 10]

The orally disintegrating tablet according to any one of the aspects 5 to 9, wherein the content of the hydrogencarbonate is 0.1 to 20% by weight.

[Stage 11]

The orally disintegrating tablet according to any one of the aspects 5 to 10, wherein the tablet has a hardness of 30 to 150 N and a water disintegration time of 10 to 25 seconds.

The present invention provides a method for shortening the disintegration time of the disintegrating tablet by the carbon dioxide produced from the bicarbonate contained in the orally disintegrating tablet of the present invention in the oral cavity, and the content of the medicinal ingredient is high, and An orally disintegrating tablet or the like having excellent tablet hardness and disintegration properties.

Fig. 1 is a graph showing the relationship between the calculated value of CAChe and the experimental value of the partition coefficient of the medicinal ingredient.

Fig. 2 is a graph showing the relationship between the calculated value of KOWWIN and the experimental value of the partition coefficient of the medicinal ingredient.

The present invention relates to a composition for an intracavitary disintegrating tablet containing a disintegrable particle composition and a hydrogencarbonate produced by a granulation method of at least two stages, and a composition for containing the orally disintegrating tablet and An orally disintegrating lozenge of a medicinal ingredient having a partition coefficient of -6.0 to 10.0.

Here, the partition coefficient of the medicinal ingredient is a numerical value indicating the hydrophobicity of the entire compound. In the present invention, the partition coefficient (logP) of the medicinal ingredient 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 partition coefficient of each medicinal ingredient is a value calculated by calculation as follows.

In principle, the value obtained by (1) is used as the calculated value, and when the structure of the medicinal component is a chemical structure of a zwitterionic state such as an amino acid, the value obtained by (2) is used.

(1) In order to calculate the value based on the log of CAChe, the calculation formula shown below is used.

LogP=Σn _i a _i

Wherein n _i represents the number of each atomic group. Further, a _i in the formula represents the contribution ratio of each atomic group. For the numerical values of the contribution ratio of each atomic group, refer to the following documents.

(Reference: Journal of Computational Chemistry, Vol. 9, No. 1, 80-90 (1988))

(2) In order to calculate the value based on the logP of KOWWIN, the calculation formula shown below is used.

logP=Σ f _i n _i +Σ c _j n _j +0.229

Where f _i represents the coefficient of each atomic group, where n _i represents the number of each atomic group. And, wherein the coefficients c _j represents the correction factor, where n _j represents the number of each of the correction factor. The numerical values of the coefficients of the respective atomic groups and the coefficients of the respective correction factors are referred to the following documents.

(Reference: Journal of Pharmacological Sciences 84, 83-92 (1995))

In other words, the medicinal component having a high partition coefficient has high hydrophobicity, and the orally disintegrating tablet containing the medicinal component is presumably difficult to introduce water into the inside of the tablet, so that the disintegration property is impaired. Further, the medicinal component having a low partition coefficient has high hydrophilicity and is easily dissolved in water. On the other hand, when tableting is compressed, the medicinal components are improved in binding property inside the tablet, and the formability or disintegration of the tablet is lowered. The possibility of sex.

On the other hand, the measured value of the partition coefficient is calculated by the existing quantitative method such as absorption spectrophotometry, gas chromatography or liquid chromatography when the medicinal component is dissolved in water and n-octanol two phases. The concentration of the medicinal ingredient in the phase was calculated according to the following calculation formula.

LogP=Log[(concentration of the medicinal component of n-octanol phase) / (concentration of the medicinal component of the aqueous phase)]

Furthermore, the relationship between the calculation formula and the measured value is shown in FIGS. 1 and 2.

The medicinal component contained in the orally disintegrating tablet of the present invention is a nutrient component in a medicinal component or a food or a health food. Regarding the medicinal ingredient, the medicinal ingredient may be added alone or added for coating or granulating for the purpose of slow release of the medicinal ingredient or covering of bitterness.

The use and the type of the medicinal ingredient contained in the orally disintegrating tablet of the present invention are not particularly limited, and examples thereof include the use of the central nervous system, the drug for the peripheral nervous system, and the drug for the sensory organ. Circulating organ medication, respiratory organ medication, digestive organ medication, hormone, genitourinary medicine, other pharmaceuticals for various organ systems, vitamins, nutritional supplements, blood, body fluids, other metabolic drugs, cell activation drugs, Tumor medication, radiopharmaceutical, allergy medication, other tissue cell function medicines, natural medicines, Chinese herbal preparations, other medicines based on natural medicines and Chinese herbal medicines, antibiotics Agents, chemotherapeutic agents, biological preparations, drugs for parasitic animals, pharmaceuticals for other pathogenic organisms, preparations for administration, diagnostic drugs, public health drugs, pharmaceuticals for in vitro diagnostics, and the like.

Examples of the medicinal ingredient having the partition coefficient of the above specific range may be selected from the group consisting of chloramphenicol, ibuprofen, analgesic, acetaminophen, famotidine, ascorbic acid, glycine, and loxoprofen. A medicinal ingredient consisting of caffeine, loratadine, Aldioxa, pipemidic acid, Afloqualone, clofibrate, and aspartic acid.

Further, regarding the representative medicinal ingredients used in the present invention, the calculated values and experimental values of the partition coefficients calculated by the above method are shown in Table 1 below.

The content of the medicinal ingredient contained in the orally disintegrating tablet of the present invention is not particularly limited, and in particular, it is preferable to use 30 parts by weight in the orally disintegrating tablet by using the medicinal ingredient having the above partition coefficient. The content ratio of % or more, more preferably 40% by weight or more, and still more preferably 50% by weight or more contains a medicinal ingredient.

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

As the hydrogencarbonate used in the present invention, carbon dioxide can be produced by using sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydrogencarbonate, cesium hydrogencarbonate or cesium hydrogencarbonate, and any substance known as a pharmaceutical ingredient can be tolerated.

The amount of the bicarbonate contained in the orally disintegrating tablet of the present invention can be appropriately determined depending on the amount and type of other components such as the medicinal component and the disintegrable particle composition, and is usually 0.1 to 20% by weight. % is preferably from 0.5 to 15% by weight, more preferably from 0.5 to 10% by weight.

The orally disintegrating tablet of the present invention can be produced by any method known to the manufacturer.

The composition for an orally disintegrating tablet of the present invention is characterized in that the following disintegrable particle composition produced by at least two-stage granulation method further contains hydrogencarbonate as a component. In the production of the composition, it is necessary to contact an acidic substance such as acid type carboxymethyl cellulose with hydrogencarbonate in the presence of water without generating carbon dioxide. For example, the disintegrable particle composition as an intermediate can be produced by the following wet granulation method, and then, by means of dry granulation such as compression granulation, crush granulation, or the like, by appropriate means, without generating carbon dioxide. The bicarbonate is mixed to produce a final composition for the orally disintegrating ingot.

The content of the bicarbonate contained in the composition for the orally disintegrating ingot can be appropriately determined depending on the amount and type of other components of the disintegrable particle composition, and is usually 0.1 to 20% by weight, preferably It is 0.5 to 15% by weight, and more preferably 0.5 to 10% by weight.

The specific aspect of the granulation method for producing the two-stage disintegrating particle composition is not particularly limited, and the specific conditions can be appropriately selected by the manufacturer.

As an example of a preferred two-stage granulation method of the disintegrable particle composition, a production method comprising a first disintegrant component composed of acid carboxymethylcellulose and an acid carboxymethyl group is exemplified. A method for producing a disintegrable particle composition of a third disintegrant component other than cellulose and an excipient, comprising: first wet granulation using any two of the three components And a second wet granulation step of using at least one of the granules obtained in the first wet granulation step and one of the remaining components in the first wet granulation step.

The granulation method may further contain crystalline cellulose as a fourth component in addition to the above three components. Regarding this method, the following two aspects can be taken.

(1) A disintegrable particle composition comprising: a first wet granulation step using any two or three of the four components, and at least a first wet granulation step a second wet granulation step of granulating and one or two components remaining in the first wet granulation step of the four components; and

(2) A disintegrable particle composition comprising: a first wet granulation step using any two of the three components other than crystalline cellulose, at least using the first wet granulation step The obtained granules are mixed with the second wet granulation step which is not used in the first wet granulation step and the remaining components, and the granules obtained in the second wet granulation step are mixed and crystallized. The third step of cellulose.

Further, 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 granules obtained in the first wet granulation step and the components remaining unused in the first wet granulation step may be used. Alternatively, a component can be used in a plurality of granulation steps. For example, each component such as crystalline cellulose may be used in both the first wet granulation step and the second wet granulation step.

As a disintegration mechanism for tablets and the like, "Wicking", "Swelling", "Deformation" and "Repulsion" are advocated. In addition, the water absorption is a mechanism of disintegration in which the water permeates through a component such as a disintegrator contained in the tablet, and the binding force between the particles contained in the tablet is weakened. As a high effect of promoting such water absorption A representative example of the disintegrator is acid carboxymethylcellulose. Further, the swelling is a disintegration mechanism in which water permeates to the disintegrating agent, and the disintegrating agent swells by itself.

The acid type carboxymethyl cellulose which is a first disintegrator component contained in the disintegrable particle composition of the present invention is a substance called carboxymethyl cellulose and is used as a pharmaceutical additive. Similarly to the acid type carboxymethylcellulose, for example, a calcium salt of carboxymethylcellulose and a crosslinked product of sodium carboxymethylcellulose are insoluble in water, and are used as a disintegrating agent for a tablet or the like. On the other hand, the sodium salt of carboxymethylcellulose is water-soluble and is used for the purpose of a binder or the like. Further, the salt of carboxymethylcellulose is also described as carboxymethylcellulose.

Any disintegrator known to those skilled in the art other than the acid type carboxymethylcellulose can be used as the second disintegrator component of the disintegrable particle composition of the present invention. However, in order to obtain a composite effect of different disintegration mechanisms as described above, it is preferred to use a mechanism other than water absorption, for example, a disintegrant excellent in the effect of promoting swelling as a second disintegrant component. Preferred examples of such a disintegrator include crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and carboxymethylcellulose calcium. , hydroxypropyl starch and starch. Further, crospovidone is a general term for a crosslinked polymer of 1-vinyl-2-pyrrolidone, and croscarmellose sodium is a general term for a crosslinked product of sodium carboxymethylcellulose.

Among them, one selected from the group consisting of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose or carboxymethyl cellulose calcium, or both Any combination.

The disintegrable particle composition of the present invention contains any compound known as an excipient as a third component to the manufacturer. As representative examples thereof, mannitol, erythritol, sorbitol, D-glucitol (maltitol), xylitol, trehalose, lactose, and malt Sugar or sugar alcohol such as sugar. Further, preferred examples thereof include mannitol, erythritol, trehalose, sorbitol, and D-glucitol (maltitol). As the excipient, two or more kinds of compounds appropriately selected from the above may be used. Further, when the excipients are used in the first wet granulation step and the second wet granulation step of the present invention, respectively, the materials may be of the same kind (same combination), or may be different types. (different combinations).

The disintegrable particle composition produced by the method of the present invention may further contain crystalline cellulose known as a fourth component. Typical examples thereof include commercially available products such as Avicel (Fumansi), Ceolus (Asahi Kasei Chemical), and VIVAPUR (Rettenmaier).

Further, in the disintegrable particle composition of the present invention, for example, it is also possible to adjust various properties such as disintegration power, binding strength, and feeling of consumption of a tablet, without impairing the invention of the present invention produced by the above three or four components. Within the range of effects, various optional components known to the mixer are appropriately added. Examples of such a component include a plasticizer, an inorganic vehicle, a sweetener, a flavor, a coloring material, and the like.

The blending amount of each component in the disintegrable particle composition of the present invention can be used as the final product in accordance with the type of each component, the type and use of the medicinal component to be used as the disintegrable particle composition, and the use. The use of the aggregating tablet is appropriately determined. Usually, the first disintegrant component is in the range of 10 to 50% by weight, and the second disintegrant component is in the range of 1 to 20% by weight based on the total weight of the disintegrable particle composition, and the crystalline fiber as the fourth component The prime is in the range of 1 to 40% by weight, and the excipient is in the range of 30 to 89% by weight.

The disintegrable particle composition of the present invention preferably has the following physical properties.

(1) Average particle diameter: 50 to 200 μm, for example, 50 to 150 μm, (2) Moisture: 0.5 to 6% by weight, for example, 1 to 5% by weight.

Further, the physical property values were measured by the following conditions and methods.

Average particle size: use A 75 mm automatic oscillating sieve (M-2 type, Tsutsui Chemical Instruments Co., Ltd.) was used to measure 2 g of the disintegrable particle composition. Furthermore, in the present specification, "R" means the radius of curvature.

Moisture: 5 g of the disintegrable particle composition was measured using a halogen moisture meter (Model HB43, METTLER TOLEDO Co., Ltd.).

In each of the above methods, the first and second granulation steps are carried out by a wet granulation method in which a component is dispersed by drying in the presence of water and dried to form a composite. Specific examples of the wet granulation method include a spray method such as spray drying, rolling granulation, stirring granulation, and fluidized bed granulation, a freeze-drying method, and kneading granulation, and any method known to those skilled in the art can be used. Made for manufacturing.

Since a disintegrant such as an acid type carboxymethylcellulose is hydrophilic, by a wet granulation, a physical force is applied by stirring in the presence of water, and the aggregation state of the particles from the dry powder becomes More dispersed state. It is preferred that the flow layer granulation, spray drying, rolling granulation, and agitation granulation by dispersion and drying of water spray can be carried out most easily, and the drying speed is fast.

Among them, the fluidized bed granulation method is a granulation method in which a powder is blown up by a warm air, and an aqueous solution containing water or a binder is sprayed, and the spraying condition and the like are easily adjusted. .

In the first wet granulation step in the method of the present invention, the two components of the three components other than the crystalline cellulose can be appropriately determined depending on the type, amount, and the like. For example, any of the first disintegrant component or the second disintegrant component and the excipient may be used. A first wet granulation step is performed.

For example, it is a disintegrable particle composition containing a first disintegrant component composed of acid carboxymethylcellulose, a second disintegrant component other than acid carboxymethylcellulose, and an excipient. Specific examples of the production method include: (1) using the first disintegrant component (or the second disintegrant component) and the excipient two components in the first wet granulation step, in the second wet type a method of using a second disintegrant component (or a first disintegrant component) in the granulation step; (2) using a first disintegrant component and a second disintegrant component in the first wet granulation step a component, a method of using an excipient in the second wet granulation step; and (3) in the first wet granulation step, using the first disintegrant component (or the second disintegrant component) and The second component of the second component, the second disintegrator component (or the first disintegrant component) and the excipient component are used in the second wet granulation step.

Further, in the method for producing a disintegrable particle composition containing four components of crystalline cellulose, the crystalline cellulose is subjected to at least any of the first wet granulation step or the second wet granulation step. The other ingredients are mixed to produce granules. For example, the first wet granulation step may be carried out using any one of the first disintegrant component or the second disintegrant component, the excipient, and the crystalline cellulose, and further, in the second wet granulation step, Add another disintegrant ingredient. Alternatively, the first wet granulation step may be carried out using either the first disintegrant component or the second disintegrant component and the excipient, and the crystalline cellulose may be added in the second wet granulation step. Another disintegrant ingredient.

Further, in the first wet granulation step in another production method of the four-component disintegrable particle composition, the two components of the three components other than the crystalline cellulose can be used according to the The type, amount, and the like are appropriately determined. For example, the first wet granulation step can be carried out using either the first disintegrant component or the second disintegrant component and the excipient.

Furthermore, it can be suitably contained in the above-mentioned 40% of the disintegrable particle composition of the present invention. Any of various optional components known to those skilled in the art may be appropriately added in the first and/or second wet granulation step. Alternatively, the optional components may be added and mixed in a suitable granulation step after the third step.

Further, in the first and second wet granulation steps, various conditions such as a spray speed, an air supply temperature, an exhaust gas temperature, and an air supply amount may be appropriately selected depending on the type and amount of each component. Decide.

In the first wet granulation step and the second wet granulation step of the fluidized bed granulation method, examples of the medium for the spray liquid include pharmaceuticals or foods such as water, ethanol, methanol, and acetone. Allowable solvent. Alternatively, the spray liquid may be an aqueous solution obtained by dissolving a component of the disintegrable particle composition at less than 10%, and more preferably water or the aqueous solution.

Further, the orally disintegrating tablet of the present invention may contain an excipient, a surfactant, a lubricant, a sour material, a sweetener, a flavoring agent, a flavoring agent, a coloring agent, a stabilizer, etc., in addition to the above components. Any other ingredients that are pharmaceutically acceptable as an adjuvant. As such an arbitrary component, for example, a pharmaceutical additive list (Pharmacy Daily) and a compliant component described in the Japanese Pharmacopoeia can be used. Furthermore, the types of such auxiliary agents are not particularly limited. Further, as long as the effect required by the present invention is achieved, the blending ratio of the optional component is not particularly limited, and the manufacturer can appropriately determine it. Such an orally disintegrating tablet can be formulated by any method known to those skilled in the art of tableting.

In the case where the composition for an orally disintegrating tablet or the orally disintegrating tablet of the present invention contains an acid type carboxymethylcellulose, it reacts with hydrogencarbonate to generate carbon dioxide, so that it is not necessary in the case. Contains organic acids.

By having the above constitution, the orally disintegrating tablet of the present invention has excellent tablet hardness and disintegratability. Specifically, it is characterized by a hardness of 30 to 150 N, preferably 40 ~150N, and the water disintegration time is 10 to 25 seconds, more preferably 10 to 20 seconds.

In addition, the contents of all the prior art documents cited in the present specification are incorporated herein by reference.

Hereinafter, the present invention will be specifically described by examples, but the present invention is not limited by the examples.

[Examples]

Reference example

(Manufacture of disintegrating particle composition)

As the first wet granulation step, 280 g of mannitol (D-mannitol, Merck Co., Ltd.) and 75 g of carboxymethylcellulose (NS-300, Wude Pharmaceutical Co., Ltd.) were introduced into a fluidized layer granulator. (LAB-1, Powrex Co., Ltd.), 227 g of purified water was sprayed at a rate of 24 g/min to thereby granulate, and further, as a second wet granulation step, crospovidone (Polyplasdone INF-10, ISP Japan) 40 g of crystalline cellulose (Ceolus PH-101, Asahi Kasei Chemicals Co., Ltd.) was sprayed with 300 g of purified water at 10 g/min to obtain a disintegrable particle composition. 99.5 parts by weight of the obtained granules were mixed with 0.5 parts by weight of magnesium stearate (Taiping Chemical Industry Co., Ltd.), and a simple tablet molding machine (HANDTAB-100, Shiqiao Seiki Co., Ltd.) was used to compress the tablet. The ingot was subjected to ingoting at 6.0 kN to obtain a tablet having a diameter of 8.0 mm, a flat-angled ingot, and a weight of 250 mg (Comparative Example). Further, the granulated product has the following physical property values. (1) Average particle diameter: 93 μm, (2) Moisture: 1.8% by weight.

Example 1

98.5 parts by weight of the disintegrable particle composition obtained in the reference example and 1 part by weight of sodium hydrogencarbonate (Wako Pure Chemical Industries, Ltd.) were mixed to obtain a composition for an orally disintegrating ingot of the present invention. Further, mixing 0.5 parts by weight of magnesium stearate (Taiping Chemical Industry Co., Ltd.), using a simple tablet molding machine (HANDTAB-100, Shiqiao Seiki Co., Ltd.), ingots with a compression force of 10.0 kN, and a diameter of 8.0 mm. A flat-bottomed tablet with a weight of 250 mg.

Example 2

94.5 parts by weight of the disintegrable particle composition obtained in the reference example and 5 parts by weight of sodium hydrogencarbonate (Wako Pure Chemical Industries, Ltd.) were mixed to obtain a composition for an orally disintegrating ingot of the present invention. Furthermore, 0.5 parts by weight of magnesium stearate (Taiping Chemical Industry Co., Ltd.) was mixed, and a simple tablet molding machine (HANDTAB-100, Shiqiao Seiki Co., Ltd.) was used to perform ingot casting at a compression force of 10.0 kN to obtain a diameter. 8.0mm, enamel flat ingot, weight 250mg lozenge.

Examples 3-7 and Comparative Examples 1-5

(Manufacture of orally disintegrating tablets)

The disintegrable particle composition obtained in the reference example was mixed with the bicarbonate of Table 2 to obtain a composition for an orally disintegrating ingot of the present invention. Further, 0.5 parts by weight of the medicinal ingredient of Table 2 and magnesium stearate (100 parts by weight in total) were used, and a simple tablet molding machine (HANDTAB-100, Shiqiao Seiki Co., Ltd.) was used as shown in Table 3. The ingot was subjected to ingot compression to obtain a tablet having a diameter of 8.0 mm, a flat-angled ingot, and a weight of 250 mg.

Comparative Example 6

(Manufacture of disintegrating particle composition)

As the first wet granulation step, mannose (D-mannitol, Merck Co., Ltd.) 285 g, corn starch (Pharmaceutical Products, Japan Food Processing Co., Ltd.) 75 g, and crystalline cellulose (Ceolus PH-101, Asahi Kasei Chemical Co., Ltd.) 100 g of a fluidized layer granulator (FL-LABO, Freund, Inc.), sprayed 150 g of purified water at a rate of 5 to 15 g/min. By this, granulation was carried out, and as a second wet granulation step, 40 g of crospovidone (Polyplasdone INF-10, ISP Japan) was added, and 80 g of purified water was sprayed at 4 g/min, thereby obtaining granules (collapse). Decomposable particle composition). Further, the granulated product has the following physical property values. (1) Average particle diameter: 89 μm, (2) Moisture: 3.4% by weight.

(Manufacture of orally disintegrating tablets)

In 46.5 parts by weight of the disintegrable particle composition of Comparative Example 6, 3 parts by weight of sodium hydrogencarbonate (Wako Pure Chemical Industries, Ltd.) was mixed to obtain a composition for an orally disintegrating ingot. Further, 50 parts by weight of famotidine (Wako Pure Chemical Industries, Ltd.) and 0.5 parts by weight of magnesium stearate (Taiping Chemical Industry Co., Ltd.) were added and mixed, and a simple tablet molding machine (HANDTAB-100, Shiqiao Jingji Co., Ltd.) was used. The company) is ingots with a compression force of 6.0 kN, and obtains a tablet having a diameter of 8.0 mm, a flat-angled ingot, and a weight of 250 mg.

[Evaluation of hardness and disintegration test]

The respective tablets obtained in the above Examples and Comparative Examples were measured for hardness and water disintegration time by the following method. The measurement results of hardness and disintegration time are shown in Table 3.

Further, the physical property values were measured by the following conditions and methods.

Hardness: Hardness (N) was measured using a digital wooden house hardness tester (Fujiri Manufacturing Co., Ltd.).

Disintegration time in water: The disintegration time in water was measured using a disintegration tester (NT-400, Toyama Industries Co., Ltd.) using a method of using an auxiliary cylinder described in the Japanese Pharmacopoeia (without an auxiliary tray).

The hardness and the disintegration time were measured three times, and the average value of these was set as the measurement result.

According to the results shown in Table 3, it was confirmed that the orally disintegrating tablets of Examples 1 and 2 containing carbonates had the same tablet hardness as compared with Comparative Example 1 (without carbonate), but were faster. Disintegration.

Similarly, the same results can be obtained by comparing Comparative Example 2 with Examples 3 and 5, Comparative Example 3 with Example 4, Comparative Example 4, and Example 6 and Comparative Example 5 with Example 7.

Further, by comparing Comparative Example 6 with Example 4, it was found that the acid-containing carboxymethylcellulose (carboxymethylcellulose) was contained in the disintegrable particle composition, and it was found that the tablet hardness and the collapse were excellent. A solution to the disintegrating oral lozenge.

[Industrial availability]

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

Claims (11)

A composition for an orally disintegrating tablet comprising a disintegrable particle composition produced by at least two-stage granulation and a hydrogencarbonate. The composition for an orally disintegrating tablet of the invention of claim 1, which comprises an acid type carboxymethylcellulose. The composition for an orally disintegrating tablet of the invention of claim 1 or 2 which does not contain an organic acid. The composition for an orally disintegrating tablet of the first or second aspect of the invention, wherein the content of the hydrogencarbonate is 0.1 to 20% by weight. An orally disintegrating tablet containing the composition for an orally disintegrating tablet of any one of claims 1 to 4 and a medicinal ingredient having a partition coefficient of -6.0 to 10.0. An orally disintegrating tablet according to item 5 of the patent application, which does not contain an organic acid. For example, the oral disintegrating tablet in the scope of claim 5 or 6, wherein the partition coefficient of the medicinal ingredient is -5.0 to 6.0. The orally disintegrating lozenge of claim 5 or 6, wherein the medicinal ingredient is selected from the group consisting of Ibuprofen, ethenzamide, and famotidine. The orally disintegrating tablet according to claim 5 or 6, wherein the content of the medicinal ingredient is 30% by weight or more. The orally disintegrating tablet of the invention of claim 5 or 6, wherein the content of the bicarbonate is 0.1 to 20% by weight. Oral disintegrating lozenge according to claim 5 or 6, wherein the tablet hardness is 30 ~150N, the water disintegration time is 10~25 seconds.