JP6040218B2 - Direct compression excipient for orally disintegrating tablet, method for producing the same, and orally disintegrating tablet - Google Patents

Description

  The present invention relates to a direct compression excipient for orally disintegrating tablets, a method for producing the same, and an orally disintegrating tablet.

  In recent years, the use of orally disintegrating tablets (OD tablets) that disintegrated in the oral cavity and facilitated swallowing has increased year by year, not only for patients with reduced swallowing ability or patients who require restriction on water intake, but also for general patients. However, its usefulness as a preparation is becoming clear.

  As a method for producing the orally disintegrating tablet, various methods such as wet tableting and humidification drying after tableting have been proposed. However, since the wet tablets have low hardness, they cannot be provided in PTP packaging (packaging for extruding tablets or capsules), cannot be packaged, and require special manufacturing equipment. There is a problem that it becomes complicated.

  Moreover, although the method of using a hydroxypropyl cellulose is known as a coupling | bonding liquid at the time of granulating the said excipient | filler for orally disintegrating tablets, there exists a problem that the orally disintegrating property of the tablet obtained becomes slow. Thus, in order to obtain desirable orally disintegrating properties as the orally disintegrating tablet, a method of granulating an orally disintegrating tablet excipient using an aqueous disintegrant dispersion as the binding liquid has been proposed (for example, , See Patent Document 1). However, the OD tablet obtained by this method has a problem of high hygroscopicity, reduced tablet hardness, and changes in the appearance of the tablet.

  Therefore, while maintaining the properties required for tablets, such as tablet formability, tablet storage, wear resistance, and drug content uniformity, the oral cavity is excellent in hardness and stability of oral disintegration even when stored for a long period of time. Currently, there is a strong demand for technology that can provide disintegrating tablets.

JP 2010-189384 A

  An object of the present invention is to solve the conventional problems and achieve the following objects. That is, the present invention maintains hardness and stability of oral disintegration even when stored for a long period of time while maintaining the performance required for tablets, such as tablet moldability, disintegration in the oral cavity, friability, and drug content uniformity. An object of the present invention is to provide an orally disintegrating tablet direct injection excipient for producing an orally disintegrating tablet having excellent properties, a method for producing the same, and an orally disintegrating tablet.

  In order to solve the above-mentioned problems, the present inventors have made extensive studies and as a result, obtained the following findings. That is, it is obtained by spraying and granulating a mixture containing at least one of sugar and sugar alcohol on a mixture containing at least one of sugar and sugar alcohol and a disintegrant. The tablet formability, buccal disintegration, friability, and drug content uniformity required as a tablet simply by mixing the tablet directly into the orally disintegrating tablet and the drug component and compressing the tablet. It was found that an orally disintegrating tablet having excellent hardness and stability of disintegration in the oral cavity can be provided even when stored for a long period of time while maintaining the performance of the above.

The present invention is based on the above findings by the present inventors, and means for solving the above problems are as follows. That is,
<1> It is obtained by spraying a mixture containing at least one of sugar and sugar alcohol onto a mixture containing at least one of sugar and sugar alcohol and a disintegrant and granulating the mixture. This is a direct compression excipient for orally disintegrating tablets.
<2> The direct compression excipient for orally disintegrating tablets according to <1>, wherein the sugar is lactose and the sugar alcohol is at least one of mannitol, xylitol, erythritol, and lactitol.
<3> Direct disintegration for orally disintegrating tablets according to any one of <1> to <2>, wherein the disintegrant is at least one of crospovidone and low-substituted hydroxypropylcellulose (L-HPC). It is a dosage form.
<4> The direct compression excipient for orally disintegrating tablets according to any one of <1> to <3>, wherein the disintegrant has a volume average particle size of 50 μm or less.
<5> Spray and granulate a binding liquid containing at least one of sugar and sugar alcohol while flowing a mixture containing at least one of sugar and sugar alcohol and a disintegrant. Is a method for producing a direct compression excipient for orally disintegrating tablets.
<6> The method for producing a direct compression excipient for orally disintegrating tablets according to <5>, wherein the mixture is granulated by spraying 30% to 200% by mass of the binding liquid as a solid content.
<7> An orally disintegrating tablet obtained by tableting the direct compression excipient for orally disintegrating tablet according to any one of <1> to <4> and a drug component. .

  According to the present invention, it is possible to solve the above-mentioned conventional problems, and while maintaining the performance required for tablets, such as tablet formability, oral disintegration, friability, and drug content uniformity, for a long period of time. It is possible to provide an orally disintegrating tablet direct injection excipient for producing an orally disintegrating tablet which is excellent in hardness and stability of orally disintegrating even when stored, a method for producing the same, and an orally disintegrating tablet.

1A is a graph showing the results of tablet moldability in Test Example 1. FIG. FIG. 1B is a graph showing the results of hardness stability in Test Example 1. 2A is a graph showing the results of hardness stability of Test Example 2. FIG. FIG. 2B is a graph showing the results of hardness stability in Test Example 2. FIG. 2C is a graph showing the results of hardness stability in Test Example 2. FIG. 3A is a photograph showing the results of the powder physical properties of Test Example 3. FIG. 3B is a photograph showing the results of the powder physical properties of Test Example 3. FIG. 3C is a graph showing the results of tablet moldability in Test Example 3. FIG. 3D is a graph showing the results of tablet moldability in Test Example 3. FIG. 3E is a graph showing the results of hardness stability in Test Example 3. FIG. 3F is a graph showing the results of hardness stability in Test Example 3. FIG. 4A is a graph showing the results of tablet moldability of Test Example 4. FIG. 4B is a graph showing the results of friability of Test Example 4. FIG. 4C is a graph showing the results of orally disintegrating in Test Example 4. FIG. 4D is a graph showing the results of hardness stability in Test Example 4. 4E is a graph showing the results of oral disintegration time stability in Test Example 4. FIG.

(Orally disintegrating excipient for orally disintegrating tablets and production method thereof)
The direct compression excipient for orally disintegrating tablets of the present invention is a granulated product containing a saccharide, a disintegrant, and, if necessary, other additives. The granulated product is obtained by granulating a mixture containing at least the saccharide and the disintegrant while spraying a binding solution.
The method for producing a direct-extinguishing excipient for orally disintegrating tablets according to the present invention comprises at least a sugar and a sugar alcohol while flowing a mixture containing a sugar containing at least one of a sugar and a sugar alcohol and a disintegrant. This is a method for producing by spraying a binding liquid containing any of them.

  Since the surface of the mixture obtained by mixing the saccharide and the disintegrant is coated with the binding liquid, the direct compression excipient for the orally disintegrating tablet has a binding force between the saccharide and the disintegrant. Not only increases, but also the hygroscopicity of the disintegrant decreases. Thereby, even if the direct compression excipient | filler for orally disintegrating tablets of this invention is preserve | saved under high humidity for a long period of time, hardness does not fall and it is excellent in hardness stability. Moreover, since the expansion | swelling of the disintegrant by moisture absorption is suppressed, there are few changes of the tablet surface.

<Mixture>
The mixture includes the saccharide and the disintegrant, and further includes other additives as necessary.

<< saccharides >>
The sugar in the mixture is not particularly limited as long as it is a powder of at least one of sugar and sugar alcohol, and can be appropriately selected according to the purpose. For example, sucrose, lactose, fructose, mannitol, xylitol, erythritol , Powders of sorbitol, maltitol, isomalt, lactitol, sucrose, glycerin and the like. These may be used alone or in combination of two or more. Among these, lactose, mannitol, xylitol, erythritol, and lactitol powder are preferable, and mannitol powder is particularly preferable because an orally disintegrating tablet excellent in hardness stability and orally disintegrating property can be produced.

  The content of saccharides in the mixture is not particularly limited and may be appropriately selected depending on the intended purpose.However, the oral cavity disintegrates in that it can produce an orally disintegrating tablet excellent in hardness stability and oral disintegration. The saccharide content in the direct compression excipient for disintegrating tablets is preferably 70% by mass to 99% by mass.

  There is no restriction | limiting in particular as said saccharides, You may use a commercial item. Examples of the commercially available products include lactose (manufactured by DFE, trade name “Pharmacato”), mannitol (manufactured by ROQUETTE, trade name “Pearlitol 50C”; trade name “Mannit” manufactured by Mitsubishi Corporation Foodtech Co., Ltd.), erythritol ( (Mitsubishi Chemical Foods Co., Ltd., trade name “Erythritol”), Xylitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name “Xylit”), Sorbitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name “Sorbit”), Maltitol (Mitsubishi Corporation Foodtech Co., Ltd., trade names “Amarti”, “Resis”), Lactitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name “Milhen”) and the like.

<< Disintegrant >>
There is no restriction | limiting in particular as said disintegrating agent, According to the objective, it can select suitably, For example, crospovidone, low substituted hydroxypropyl cellulose (L-HPC), carboxymethylcellulose (carboxymethylcellulose Na, carboxymethylcellulose Ca etc.) ) And the like, and starches such as crystalline cellulose, hydroxypropyl starch, and corn starch.
These may be used alone or in combination of two or more. Among these, crospovidone and low-substituted hydroxypropylcellulose (L-HPC) are preferable in terms of producing an orally disintegrating tablet excellent in hardness stability and oral disintegration, and the combined use of crospovidone and corn starch is preferred. It is preferable in that it can further prevent a decrease in tablet hardness during moisture absorption.

  The volume average particle size of the disintegrant is not particularly limited and may be appropriately selected depending on the intended purpose, but is 100 μm or less in terms of producing an orally disintegrating tablet having excellent hardness stability and orally disintegrating properties. Is preferable, 50 μm or less is more preferable, and 20 μm or more and 50 μm or less is particularly preferable.

  The content of the disintegrant in the mixture is not particularly limited and can be appropriately selected depending on the purpose. However, the oral cavity disintegrates in terms of hardness stability and oral disintegration, so that the oral cavity can be produced. The content of the disintegrant in the directly collapsible excipient for the internally disintegrating tablet is preferably 1% by mass to 30% by mass.

  There is no restriction | limiting in particular as said disintegrating agent, What was synthesize | combined suitably may be used and a commercial item may be used. As the above-mentioned commercially available products, crospovidone [(trade name “Polyplastidone XL”, “Polyplastidone XL-10”, manufactured by ISP Co., Ltd.), (trade name “Collidon CL”, “Collidon CL-F”, manufactured by BASF) , “Collidon CL-SF”)], low-substituted hydroxypropyl cellulose (trade name “L-HPC” manufactured by Shin-Etsu Chemical Co., Ltd.), corn starch (trade name “Corn Starch W” manufactured by Nippon Shokuhin Kako Co., Ltd.), etc. Is mentioned.

<< Other additives >>
Other additives in the mixture are not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include fluidizers, sweeteners, lubricants, hygroscopic agents, dehumidifiers, coating agents, dyes, Examples include flavoring agents and solubilizing agents. These may be used alone or in combination of two or more.
Other additives in the mixture may be used by dissolving or suspending in a binding solution described later.
There is no restriction | limiting in particular as content in the said direct compression excipient | filler for orally disintegrating tablets of the said other additive, According to the objective, it can select suitably.

<Binding liquid>
The binding liquid contains at least one of sugar and sugar alcohol, and further contains other additives as necessary.
The binding liquid preferably does not contain a disintegrant.
The binding solution is not particularly limited as long as it is a solution containing at least one of sugar and sugar alcohol, and can be appropriately selected according to the purpose. For example, sucrose, lactose, fructose, mannitol, xylitol, Examples include erythritol, sorbitol, maltitol, isomalt, lactitol, sucrose, glycerin and the like. These may be used alone or in combination of two or more. Among these, a lactose, mannitol, xylitol, erythritol, and lactitol solution is preferable, and a mannitol solution is more preferable because an orally disintegrating tablet excellent in hardness stability and orally disintegrating property can be produced.

  The method for preparing the binding liquid is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a method for preparing by dissolving at least one powder of the sugar and sugar alcohol in a solvent. It is done. There is no restriction | limiting in particular as said solvent, Although it can select suitably according to the objective, Water is preferable at the point from which the solubility of at least any one of the said sugar and sugar alcohol becomes favorable.

  The concentration of at least one of the sugar and sugar alcohol in the binding solution is not particularly limited and can be appropriately selected according to the purpose. However, an orally disintegrating tablet excellent in hardness stability and oral disintegration is obtained. In the case of mannitol, 40 mass%-60 mass% are preferable at the point which can be manufactured.

  There is no particular limitation on the amount of spray solid content with respect to the mixture (a mixture containing at least the sugar and the disintegrant) of the binding liquid, and it can be appropriately selected according to the purpose. 30 mass%-200 mass% are preferable at the point which can manufacture the orally disintegrating tablet excellent in property.

  There is no restriction | limiting in particular as said binding liquid, You may use a commercial item. Examples of the commercially available products include lactose (manufactured by DFE, trade name “Pharmacato”), mannitol (manufactured by ROQUETTE, trade name “Pearlitol 50C”; trade name “Mannit” manufactured by Mitsubishi Corporation Foodtech Co., Ltd.), erythritol ( (Mitsubishi Chemical Foods Co., Ltd., trade name “Erythritol”), Xylitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name “Xylit”), Sorbitol (Mitsubishi Corporation Foodtech Co., Ltd., trade name “Sorbit”), Maltitol (Mitsubishi Corporation Food Tech Co., Ltd., trade names “Amarti”, “Resis”), Lactitol (Mitsubishi Corporation Food Tech Co., Ltd., trade name “Miruhen”) and the like. Use a solution prepared by using a hydrophilic solvent, etc. Door can be.

  The combination of the saccharide and the binding liquid is not particularly limited and may be appropriately selected depending on the intended purpose. However, the sugar can be produced in that an orally disintegrating tablet having excellent hardness stability and oral disintegration property can be produced. The alcohols are preferably the same, and a combination of mannitol powder as the saccharide and a mannitol solution as the binding liquid is more preferable.

<Powder Physical Properties of Oral Disintegrating Tablet Direct Injection Excipient (Granulated Product)>
The particle size in the cumulative distribution diagram of the direct compression excipient (granulated product) for the orally disintegrating tablet is not particularly limited and may be appropriately selected depending on the intended purpose. The D ₁₀ value is preferably 30 μm to ₉₀ μm, the D ₅₀ value is preferably 70 μm to 150 μm, and the D ₉₀ value is preferably 160 μm to 250 μm in that an orally disintegrating tablet having excellent properties can be produced. Incidentally, the D ₅₀ value corresponds to the volume average particle diameter of the orally disintegrating tablet for direct compression excipient (granules).
The particle size can be measured by, for example, a laser diffraction / scattering particle size distribution measuring device (Microtrack HRA (manufactured by Nikkiso Co., Ltd.)).

  There is no restriction | limiting in particular as the passage rate of the 75 micrometers sieve mesh of the said direct-disintegrating tablet for oral disintegrating tablets (granulated material), Although it can select suitably according to the objective, Hardness stability and oral disintegration 5% -50% is preferable at the point which can manufacture the orally disintegrating tablet excellent in property.

The bulk density (loose) of the direct compression excipient (granulated product) for the orally disintegrating tablet is not particularly limited and may be appropriately selected depending on the intended purpose. In terms of being able to produce an orally disintegrating tablet that is superior to the above, 0.4 g / mL to 0.6 g / mL is preferable.
There is no restriction | limiting in particular as a bulk density (tap) of the said direct compression excipient | filler (granulated material) for orally disintegrating tablets, Although it can select suitably according to the objective, Hardness stability and orally disintegrating property In terms of being able to produce an orally disintegrating tablet that is superior to the above, 0.5 g / mL to 0.7 g / mL is preferable.
The bulk density (loose) and the bulk density (tap) are, for example, A. B. It can be measured by a D powder characteristic measuring instrument (manufactured by Tsutsui Riken Kikai Co., Ltd.).

The angle of repose of the direct compression excipient (granulated product) for the orally disintegrating tablet is not particularly limited and may be appropriately selected depending on the intended purpose, but it is excellent in hardness stability and oral disintegration property. 30 to 40 degrees is preferable at the point which can manufacture an internally disintegrating tablet.
The angle of repose can be measured by, for example, the Nogami / Sugihara method described in JP-A-6-205959.

<Method for Producing Direct Excipient for Orally Disintegrating Tablet>
As a method for producing the direct-disintegrating excipient for orally disintegrating tablets, there is no particular limitation as long as it is a method obtained by fluidized bed granulation while spraying a liquid containing the binding liquid on the saccharide and the disintegrant. And can be appropriately selected according to the purpose.

-Fluidized bed granulation-
The fluidized bed granulation is a method of granulating by causing aggregation of liquid crosslinking between particles of the saccharide and the disintegrant by spraying the binding liquid, and can be performed by a fluidized bed granulation apparatus. it can.

  The fluidized bed granulator sprays the binding liquid onto a fluidized (floating fluid) powder (a mixture containing the saccharide and the disintegrant), and coats the powder with the binding liquid. And granulate.

  There is no restriction | limiting in particular as a commercially available apparatus of the said fluidized bed granulation apparatus, According to the objective, it can select suitably, For example, a flow coater, Spiraflow, Granurex (all are the Freund Sangyo Co., Ltd. product) etc. Can be mentioned.

<Effect of direct compression excipient for orally disintegrating tablets>
The direct compression excipient for orally disintegrating tablets of the present invention is required as a tablet only by mixing with a pharmaceutical ingredient and tableting, tablet formability, orally disintegrating property, friability, drug content uniformity It is possible to provide an orally disintegrating tablet that is excellent in hardness and stability of disintegration in the oral cavity even when stored for a long period of time while maintaining the performance of the above. Moreover, since the compounding quantity of the chemical | medical component in an orally disintegrating tablet can be easily adjusted by using the direct compression excipient | filler for orally disintegrating tablets of this invention, compared with the former, an orally disintegrating tablet Formulation design becomes easy.

(Orally disintegrating tablets)
The orally disintegrating tablet of the present invention contains the above-described direct compression excipient for orally disintegrating tablet and a drug component, and further contains other components as necessary.

<Direct compression excipient for orally disintegrating tablets>
The above-mentioned direct compression excipient for orally disintegrating tablets is used as the direct compression excipient for orally disintegrating tablets.
As content in the said orally disintegrating tablet of the said direct compression excipient | filler for orally disintegrating tablets, 20 mass%-99.9 mass% are preferable.

<Drug component>
The drug component is not particularly limited and may be appropriately selected depending on the purpose. For example, the drug component is a hypertension drug, angina drug, bronchodilator drug, psychotropic drug, anxiolytic drug, antidepressant drug, hypnotic sedative drug. , Antiparkinson, allergy, dental, oral, cardiotonic, antipyretic analgesic, antihistamine, antitussive, antacid, herbal medicine, antihypertensive, antibiotic, antibacterial, arrhythmia, coronary Dilators, peripheral vasodilators, hyperlipidemic drugs, antibacterial drugs, hormonal drugs, gout drugs, antirheumatic drugs, chemotherapy drugs, antidiabetic drugs, antiemetics, antiepileptic drugs, sympathomimetic drugs, Osteoporosis drugs, antineoplastic drugs, immunosuppressive drugs, urological drugs, gastrointestinal drugs, cerebral metabolism improving drugs, cerebral circulation improving drugs, respiratory stimulants, vasoconstrictors, antipruritic drugs, expectorants, drugs for central nervous system action , Drug components used for ulcer treatment, gastric mucosa repair drug, analgesic antispasmodic drug, etc. Specific examples include temocapril hydrochloride, cabergoline, amlodipine besylate, omeprazole, lansoprazole, famotidine, lafutidine, ecabet sodium, mosapride citrate, rebamipide, voglibose, risperidone, imidapril hydrochloride, meloxicam, milnacipran hydrochloride Salt, levofloxacin, clarithromycin, sarpogrelate hydrochloride, tosufloxacin tosylate, tamsulosin hydrochloride, mizoribine, tacrolimus hydrate, fluvoxamine maleate, glimepiride, ramosetron hydrochloride, nicorandil, donepezil hydrochloride, zolpidem tartrate, pioglitazone hydrochloride Salt, sodium alendronate hydrate, sodium risedronate hydrate, atorvastatin calcium hydrate, fluvastatin nato Um, loratadine, losartan potassium, paroxetine hydrochloride hydrate, rabeprazole sodium, ribavirin, sumatriptan succinate, perospirone hydrochloride hydrate, quetiapine fumarate, olopatadine hydrochloride, fexofenadine hydrochloride, ebastine, cefditoren pivoxil, Examples include cefcapene hydrochloride, valsartan, bicalutamide, and acarbose.

<Other ingredients>
The other component is not particularly limited as long as it is a component used in the orally disintegrating tablet and can be appropriately selected depending on the purpose, but a lubricant, a fluidizing agent, a sweetening agent, and the like are preferable. In addition, moisture absorption, a dehumidifying agent, a coating agent, a pigment, a flavoring agent, a solubilizing agent, and the like can be given. These may be used alone or in combination of two or more.

  The lubricant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include magnesium stearate, stearic acid, calcium stearate, talc, and hardened oil.

  The fluidizing agent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, hydrophilic silica, hydrophobic silica, calcium silicate, alkyl phosphate (PAP), water-soluble polymer compound, Anhydrous calcium hydrogen phosphate, magnesium silicate, calcium silicate, light anhydrous silicic acid, hydrous silicon dioxide, magnesium oxide and the like can be mentioned.

  The sweetener is not particularly limited and may be appropriately selected depending on the intended purpose.For example, aspartame, glucose, galactose, mannose, ribose, arabinose, maltose, lactose, isomaltose, cellobiose, gentiobiose, palatinose Can be mentioned.

<Method for producing orally disintegrating tablet>
The method for producing the orally disintegrating tablet is not particularly limited and may be appropriately selected depending on the purpose.For example, after mixing the direct-disintegrating excipient for the orally disintegrating tablet and the drug component, Examples thereof include a method of producing by tableting into tablets. At this time, generally used mixers and tableting machines can be used.

<Usage form of orally disintegrating tablet>
There is no restriction | limiting in particular as a usage form of the said orally disintegrating tablet, According to the objective, it can select suitably, For example, the method of oral administration without water, the method of oral administration with water, etc. are mentioned.

<Effects of orally disintegrating tablets>
The orally disintegrating tablet of the present invention maintains hardness and oral cavity even when stored for a long period of time while maintaining the performance required for tablets, such as tablet moldability, orally disintegrating property, friability, and drug content uniformity. Excellent collapse stability. Moreover, since the compounding amount of the drug component and the disintegrant in the orally disintegrating tablet can be easily adjusted by using the direct compression excipient for the orally disintegrating tablet of the present invention, The formulation design of disintegrating tablets becomes easy.

  Examples of the present invention will be described below, but the present invention is not limited to these Examples.

(Test Example 1: Comparative test with different granulation methods)
In Test Example 1, when producing a direct compression excipient for orally disintegrating tablets, the obtained direct compression excipient for orally disintegrating tablets was obtained due to the difference in granulation method (difference in timing of adding disintegrant). The differences in the physical properties of the oral cavity and how the hardness stability and oral disintegration property of the orally disintegrating placebo tablets produced using the direct-dissolving excipient for orally disintegrating tablets are evaluated.

-Manufacture of direct compression excipient for orally disintegrating tablets-
The direct compression excipient for orally disintegrating tablets was produced by subjecting a saccharide and a disintegrant to fluid bed granulation while spraying a binding liquid in a flow coater (FLO-5, manufactured by Freund Corporation). The used material is shown in Table (1-1), the composition of the used material is shown in Table (1-2), and the powder physical properties of the obtained direct hitting excipient are shown in Table (1-3) and FIG. 1A. It was shown to.

-Production of direct injection excipient for comparative orally disintegrating tablets-
The direct compression excipient for comparative orally disintegrating tablets was prepared by adding saccharides into a granulator (flow coater (FLO-5, manufactured by Freund Sangyo Co., Ltd.)) and spraying 4 kg of the binding solution, A fluidizing agent was added to the granulator as necessary, and the remaining binder solution was sprayed to produce fluidized bed granulation (post-addition). The materials used are shown in Table (1-1), the composition is shown in Table (1-2), and the powder physical properties of the obtained direct hitting excipient are shown in Table (1-3).

-Manufacture of orally disintegrating placebo tablets-
The orally disintegrating tablet was prepared by mixing the direct hitting excipient and lubricant listed in Table (1-4) under the conditions described in Table (1-4), and obtaining the resulting mixture (500 g) in the table ( It was manufactured by tableting under the conditions described in 1-4).

-Production of comparative orally disintegrating placebo tablets-
The comparative orally disintegrating tablet was prepared by mixing the direct hit excipient and lubricant described in Table (1-4) under the conditions described in Table (1-4), and expressing the resulting mixture (500 g). It was manufactured by tableting under the conditions described in (1-4).

(Evaluation of Test Example 1)
-Tablet formability-
Evaluation of tablet moldability was performed by measuring the hardness of the obtained “orally disintegrating placebo tablets” and “comparing orally disintegrating placebo tablets”. As a measuring machine, a Schleunigel tablet hardness tester 8M (manufactured by Freund Corporation) was used. The results are shown in FIG. 1A.

-Hardness stability-
Hardness stability was evaluated by storing each placebo tablet (use a product with a hardness of around 50 N) in an open state at 25 ° C. and 80% RH (constant humidity salt: KBr) for 1 week, and hardness (n = 3 ). The results are shown in FIG. 1B.

-Result-
From FIG. 1A and FIG. 1B, it was found that [Oral Disintegration (OD) Placebo Tablet 1] has high moldability and hardly decreases in hardness even under high humidity. On the other hand, [Comparative Oral Disintegration (OD) Placebo Tablet 1] and [Comparative Oral Disintegration (OD) Placebo Tablet 2] were found to have a large decrease in hardness under high humidity. Therefore, in order to maintain good hardness stability and disintegration in the oral cavity, it is necessary to spray 20% by mass or more of the binding liquid as a solid content on the mixture obtained by mixing the saccharide and the disintegrant. I found out.

(Test Example 2: Comparison test with simple mixed product)
In Test Example 2, manufactured using “orally disintegrating tablet” manufactured using “orally-disintegrating tablet for orally disintegrating tablet” of the present invention and “direct-compressing excipient for comparative orally disintegrating tablet”. The difference in hardness stability and drug content uniformity of the “comparable orally disintegrating tablets” was evaluated.

-Production of orally disintegrating tablets-
Orally disintegrating tablets were produced by mixing the materials described in Table (2-1) under the conditions described in Table (2-2) and tableting. In addition, the direct compression excipient | filler for OD tablets in Table (2-1) is what was manufactured in Test Example 1, ie, "sugar (sugar alcohol (D-mannitol))" and "disintegrating agent (crospovitone). Was produced by fluidized bed granulation while spraying the binding liquid in a granulator.

-Production of comparative orally disintegrating tablets-
The comparative orally disintegrating tablet was produced by mixing the materials described in Table (2-1) under the conditions described in Table (2-2) and tableting. The direct compression excipient for comparative OD tablets in Table (2-1) is a mixture of “saccharide (sugar alcohol (D-mannitol))” and “disintegrant (crospovitone)” at 9: 1 ( It was obtained by hand mixing (3 minutes).

(Evaluation of Test Example 2)
-Hardness stability-
The evaluation of hardness stability was carried out by subjecting the obtained “oral disintegration (OD) tablet” and “comparative oral disintegration (OD) tablet” to an open state at 25 ° C. in an environment with different humidity (55% RH (constant Store for 7 days in wet salt: Mg (NO ₃ ) ₂ ), 70% RH (constant humidity salt: KI), 80% RH (constant humidity salt: KBr)) and confirm the change in hardness (n = 3) It was done by doing. The results are shown in FIGS. 2A to 2C.

-Uniformity of drug content-
Evaluation of drug content uniformity of orally disintegrating tablets is based on the fifteenth revised JP on the obtained “orally disintegrating tablets” and “comparing orally disintegrating tablets”, and a determination value (n = 10) is calculated. Was done. The results are shown in Table (2-3).

-Result-
2A to 2C show that [Oral Disintegration (OD) Tablet 1] is most excellent in hardness stability. Moreover, from Table (2-3), it was found that [Oral Disintegration (OD) Tablet 1] has the most excellent drug content uniformity. [Oral Disintegration (OD) Tablet Direct Injection Excipient 1] used in [Oral Disintegration (OD) Tablet 1] has a surface obtained by mixing a saccharide and a disintegrant with a binding solution. Since it was coated, it was found that not only the binding force between the saccharide and the disintegrant was increased, but also the hygroscopicity of the disintegrant was decreased. As a result, it was found that the [Oral Disintegration (OD) Tablet 1] of the present invention is excellent in hardness stability without decreasing the hardness even when stored under high humidity for a long time.

(Test Example 3: Comparison test with disintegrant aqueous dispersion)
In Test Example 3, the “orally disintegrating tablet” produced by using the “direct compression excipient for orally disintegrating tablet” of the present invention and “Comparative Orally Disintegrating Tablet” disclosed in JP 2010-189384 A The difference in hardness stability of “Comparative Orally Disintegrating Tablets” produced using a disintegrant aqueous dispersion was evaluated with reference to “Directly Extruded Excipient”.

-Manufacture of direct compression excipient for orally disintegrating tablets-
The direct compression excipient for orally disintegrating tablets was produced by subjecting a saccharide and a disintegrant to fluid bed granulation while spraying the binding liquid in a granulator. The materials used are shown in Table (3-1), the production conditions are shown in Table (3-2), and the powder physical properties of the obtained direct hitting excipient are shown in Table (3-3) and FIGS. 3A to 3B. It was shown to.

-Production of direct injection excipient for comparative orally disintegrating tablets-
The direct compression excipient for comparative orally disintegrating tablets was produced by fluidized bed granulation while spraying saccharides in an agglomerator using an aqueous dispersion containing a disintegrant as a binder. The materials used are shown in Table (3-1), the prescription is shown in Table (3-2), and the powder physical properties of the obtained direct hitting excipient are shown in Table (3-3) and FIGS. 3A to 3B. Indicated.

-Manufacture of orally disintegrating placebo tablets-
The orally disintegrating tablet was prepared by mixing the direct hitting excipient and lubricant described in Table (3-4) under the conditions described in Table (3-4), and obtaining the resulting mixture (500 g) in the table ( It was manufactured by tableting under the conditions described in 3-4).

-Production of comparative orally disintegrating placebo tablets-
The comparative orally disintegrating tablet was prepared by mixing the direct hitting excipient and lubricant described in Table (3-4) under the conditions described in Table (3-4), and representing the resulting mixture (500 g). It was manufactured by tableting under the conditions described in (3-4).

(Evaluation of Test Example 3)
-Tablet formability-
Evaluation of tablet moldability was performed by measuring the hardness of the obtained “orally disintegrating (OD) placebo tablet” and “comparing orally disintegrating (OD) placebo tablet”. As a measuring machine, a Schleunigel tablet hardness tester 8M (manufactured by Freund Corporation) was used. The results are shown in Tables (3-5) and (3-6) and FIGS. 3C to 3D.

-Hardness stability-
The hardness stability was evaluated using the obtained “orally disintegrating placebo tablets” and “comparing orally disintegrating placebo tablets” having a hardness of 50 N to 60 N, and the placebo tablets in an open state at 25 ° C. under humidity. (55% RH (constant humidity salt: Mg (NO ₃ ) ₂ )) and 75% RH (constant humidity salt: NaCl) for 7 days and confirming the change in hardness. Is shown in FIGS. 3E to 3F.

-Result-
From Tables (3-5), (3-6), and FIGS. 3C to 3D, it was found that the placebo tablet using sugar alcohol (mannitol) as the binding solution was excellent in moldability. As can be seen from FIGS. 3A to 3B, the placebo tablet using sugar alcohol (mannitol) as the binding solution has a surface of saccharides and disintegrant as compared with the placebo tablet using other binding solution. It was suggested that coating with sugar alcohol (mannitol) increased the binding force between the saccharide and the disintegrant, resulting in excellent moldability.
3E to 3F show that placebo tablets using sugar alcohol (mannitol) as a binding solution stably have a certain hardness even in a high humidity environment. It was also found that the tablet surface was not uneven as compared with the placebo tablets using other binding solutions, and the tablet surface change due to moisture absorption was low. From these results, it was found that the placebo tablet using sugar alcohol (mannitol) as the binding solution is excellent in hardness stability. Furthermore, FIG. 3F shows that the OD placebo tablet 4 using crospovidone and corn starch as disintegrants can prevent a decrease in hardness during moisture absorption more than the OD placebo tablet 3 using only crospovidone. It was.

(Test Example 4: Superiority test based on particle size of disintegrant)
In Test Example 4, the superiority of tablet stability and hardness stability due to the difference in the particle size of the disintegrant among “direct compression excipients for orally disintegrating tablets” of the present invention was evaluated.

-Manufacture of direct compression excipient for orally disintegrating tablets-
The direct compression excipient for orally disintegrating tablets was produced by subjecting a saccharide and a disintegrant to fluid bed granulation while spraying the binding liquid in a granulator. The materials used are shown in Table (4-1), the composition is shown in Table (4-2), and the results of the powder physical properties of the obtained direct hitting excipient are shown in Table (4-3).

-Production of orally disintegrating tablets-
Orally disintegrating tablets were produced by mixing the materials described in Table (4-4) under the conditions described in Table (4-5) and tableting.

(Evaluation of Test Example 4)
-Tablet formability-
Evaluation of tablet moldability was performed by measuring the hardness (n = 20) of the tablets obtained under the production conditions described in Table (4-5). As a measuring machine, a Schleunigel tablet hardness tester 8M (manufactured by Freund Corporation) was used. The results are shown in FIG. 4A.

-Abrasion-
The friability was evaluated by measuring the friability of the tablets obtained under the production conditions described in Table (4-5). The results are shown in FIG. 4B.
The friability was measured by a tablet friability tester (Higaki Medical Science Co., Ltd.).

-Oral disintegration-
The evaluation of oral disintegration was performed by measuring the oral disintegration time (n = 1) of the tablets obtained under the production conditions described in Table (4-5). The results are shown in FIG. 4C.

-Hardness stability and oral disintegration time stability-
Evaluation of hardness stability and orally disintegrating time stability is based on each orally disintegrating tablet (having a hardness of around 50 N) in an environment of 55% RH at 25 ° C. (constant humidity salt: Mg (NO ₃ ) ₂ ). , Stored for 1 week in an open condition in an environment of 75% RH (constant humidity salt: NaCl) at 25 ° C., and confirming changes in hardness (n = 5) and disintegration time in the oral cavity (n = 5) It was. The results are shown in FIGS. 4D to 4E.

-Result-
From FIG. 4A to FIG. 4E, by using a disintegrant having a volume average particle diameter of 50 μm or less, more preferably a disintegrant having a volume average particle diameter in the range of 25 μm to 35 μm as a disintegrant (crospovidone), It was found to be excellent in internal disintegration and hardness stability.

  The direct compression excipient for orally disintegrating tablets of the present invention is required as a tablet only by mixing with a pharmaceutical ingredient and tableting, tablet formability, orally disintegrating property, friability, drug content uniformity While maintaining the performance of the above, it is possible to provide an orally disintegrating tablet that is excellent in hardness and stability of disintegration in the oral cavity even when stored for a long period of time, and thus can be suitably used for the production of orally disintegrating tablets. .

Claims (6)

The surface of a mixture containing a saccharide containing at least one of sugar and sugar alcohol and a disintegrant is a granulated product coated with at least one of sugar and sugar alcohol,
Wherein to a mixture, said mixture coated sugar and at least one of an amount of 30 mass% to 200% by mass orally disintegrating tablet for direct compression excipient, wherein Rukoto sugar alcohols. The sugar is lactose,
The direct compression excipient for orally disintegrating tablets according to claim 1, wherein the sugar alcohol is at least one of mannitol, xylitol, erythritol, and lactitol.   The direct compression excipient for orally disintegrating tablets according to any one of claims 1 to 2, wherein the disintegrant is at least one of crospovidone and low-substituted hydroxypropylcellulose.   4. The direct compression excipient for orally disintegrating tablets according to any one of claims 1 to 3, wherein the disintegrant has a volume average particle size of 50 µm or less. An orally disintegrating tablet that is granulated by spraying a binding liquid containing at least one of sugar and sugar alcohol while flowing a mixture containing a sugar containing at least one of sugar and sugar alcohol and a disintegrant. A method for producing a direct hitting excipient for use,
The mixture is granulated by spraying 30% to 200% by weight of the binding liquid as a solid content,
The solid content is at least one of sugar and sugar alcohol, The manufacturing method of the direct compression excipient | filler for orally disintegrating tablets characterized by the above-mentioned . Orally disintegrating tablet of the orally disintegrating tablet for direct compression excipient according to any one of claims 1 to 4, characterized in that it comprises a pharmaceutical ingredient.