JPWO2015046383A1 - Process for producing drug substance-containing nucleus, drug substance-containing nucleus, pharmaceutical composition, and orally disintegrating tablet - Google Patents

Abstract

With the contents in the fluidized bed granulator fluidized, the drug substance powder is intermittently or continuously added to the fluidized bed granulator while the binder solution is intermittently or continuously charged into the fluidized bed granulator. A method for producing a drug substance-containing nucleus having an average particle size of 100 μm to 500 μm, a drug substance-containing nucleus, a pharmaceutical composition, and an orally disintegrating tablet.

Description

  The present invention relates to a method for producing a drug substance-containing nucleus, a drug substance-containing nucleus, a pharmaceutical composition, and an orally disintegrating tablet.

In oral preparations, the drug substance or the pharmaceutical composition containing the drug substance is generally coated with a film, polymer, etc. to control the dissolution timing of the drug substance, mask the bitterness derived from the drug substance, etc. It has become.
In particular, since orally disintegrating tablets are oral preparations that dissolve or disintegrate in the oral cavity immediately after taking, preparation techniques such as inhibition of drug substance degradation, bitterness masking, and dissolution adjustment are more important than normal oral preparations. become.
In addition, it is important to improve the ease of tablet administration from the viewpoint of compliance, and not only the usual oral preparations but also the orally disintegrating tablets are smaller than the conventional preparations. Attempts have been made.

Japanese Patent Application Laid-Open No. 6-30975 discloses a granulation method for a drug substance that can reduce the size of a tablet by minimizing the addition amount of a component that has the effect of suppressing the adhesion and aggregation of the drug substance. Is described.
Japanese Patent Application Laid-Open No. 2006-131548 describes a method capable of efficiently producing highly stable particles when an unstable compound is used as a bulk powder.
Japanese Patent Application Laid-Open No. 2003-1091 describes a method in which drug substance-containing particles of 50 μm to 200 μm can be produced using a drug substance powder having an average particle diameter of 20 μm to 150 μm and the amount of spray liquid can be reduced. Yes.

Currently, orally disintegrating tablets generally have a structure containing fine granules containing the drug substance (hereinafter also simply referred to as “fine granules”) and excipients outside the granules. In general, fine granules contained in an orally disintegrating tablet include a plurality of layers such as a drug substance-containing nucleus including a drug substance layer, an intermediate layer, and an elution control layer.
Conventionally, there is no known method for producing a drug substance-containing nucleus that can improve the storage stability of a drug substance during and after production.
In addition, there is no known orally disintegrating tablet containing a drug substance-containing nucleus having a specific particle size of particulate clopidogrel sulfate or rabeprazole sodium as an active ingredient.

The present invention includes a method for producing a drug substance-containing nucleus that can improve the stability of the drug substance during and after the production of the drug substance-containing nucleus, the drug substance-containing nucleus obtained by this production method, and the drug substance-containing nucleus It is an object to provide a pharmaceutical composition.
The present invention also provides an orally disintegrating tablet containing clopidogrel sulfate or rabeprazole sodium as a drug substance, and containing a drug substance-containing nucleus that can improve the stability of the drug substance during and after the production of the drug substance-containing nucleus. This is the issue.

Means for solving the problems are as follows.
<1> Fluidized bed granulation of drug substance powder intermittently or continuously while the binder solution is intermittently or continuously charged into the fluidized bed granulator with the contents in the fluidized bed granulator fluidized. A method for producing a drug substance-containing nucleus having an average particle size of 100 μm to 500 μm, comprising granulating by putting into a granulator.
<2> The production method according to <1>, comprising granulating while maintaining the ratio of the drug substance powder in the fluidized bed granulator to 10% by mass or less with respect to the total solids in the fluidized bed granulator.
<3> The production method according to <1> or <2>, comprising setting the temperature in the fluidized bed granulator to 25 ° C to 80 ° C.
<4> The production method according to any one of <1> to <3>, wherein the drug substance-containing portion in the drug substance-containing nucleus contains 70% by mass to 100% by mass of the drug substance.
<5> The production method according to any one of <1> to <4>, wherein the drug substance-containing portion in the drug substance-containing nucleus contains 0% by mass to 10% by mass of a binder.
<6> The production method according to any one of <1> to <5>, wherein the drug substance powder has an average particle size of 0.1 μm to 20 μm.
<7> A drug substance-containing nucleus obtained by the production method according to any one of <1> to <6>.
<8> A pharmaceutical composition comprising the drug substance-containing nucleus according to <7>.
<9> An orally disintegrating tablet, wherein the drug substance-containing portion of the drug substance-containing nucleus contains particulate clopidogrel sulfate or particulate rabeprazole sodium, and the drug substance-containing nucleus has an average particle size of 100 μm to 500 μm.
<10> The orally disintegrating tablet according to <9>, wherein the drug substance-containing portion in the drug substance-containing nucleus contains 70% by mass to 100% by mass of clopidogrel sulfate or rabeprazole sodium.
<11> The orally disintegrating tablet according to <9> or <10>, wherein the drug substance-containing portion in the drug substance-containing nucleus contains 0% by mass to 10% by mass of a binder.
<12> The ratio (D90 / D10) of the particle size (D90) of 90% cumulative volume percentage to the particle size (D10) of 10% cumulative volume percent of the drug substance-containing nucleus is 4.0 or less <9> to < Oral disintegrating tablet as described in any one of 11>.
<13> The orally disintegrating tablet according to any one of <9> to <12>, wherein the water content is 1.0% by mass or less.

ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of the active ingredient containing nucleus which can improve the stability of the active ingredient at the time of manufacture of an active ingredient containing a drug substance and after manufacture, the active ingredient containing nucleus obtained by this manufacturing method, and this active ingredient containing nucleus Can be provided.
Further, according to the present invention, there is provided an orally disintegrating tablet containing clopidogrel sulfate or rabeprazole sodium as a drug substance, and containing a drug substance-containing nucleus that can improve the stability of the drug substance during and after the production of the drug substance-containing nucleus. Can be provided.

1 is a volume frequency distribution diagram showing a particle size distribution of drug substance powder according to Example 1. FIG. It is the volume frequency distribution figure which showed the particle size distribution of the drug substance powder concerning Example 2. 6 is a photograph of a drug substance-containing nucleus according to Example 3. 2 is a photograph of a drug substance-containing nucleus according to Comparative Example 1.

Hereinafter, the method for producing a drug substance-containing nucleus, drug substance-containing nucleus, pharmaceutical composition, and orally disintegrating tablet of the present invention will be described in detail.
In addition, the numerical value range shown using "to" in this specification shows the range which includes the numerical value described before and behind "to" as a minimum value and a maximum value, respectively.
In this specification, the amount of each component in the composition is the total amount of the plurality of substances present in the composition unless there is a specific indication when there are a plurality of substances corresponding to each component in the composition. Means.
In this specification, “(meth) acrylic acid” represents both or one of acrylic acid and methacrylic acid.
In this specification, the term “process” is not limited to an independent process, and is included in the term if the intended purpose of the process is achieved even when it cannot be clearly distinguished from other processes. .
In the present specification, the “average particle diameter” indicates a volume average particle diameter. As a measuring method of the average particle diameter, there is a laser diffraction particle size distribution measuring method, and a specific example is a method using a laser diffraction scattering particle size distribution measuring device (product name: LS 13 320, manufactured by Beckman Coulter, Inc.). It is done.

In general, particle granulation methods are roughly classified into wet granulation in which particles are formed by introducing a liquid such as a binding liquid and dry granulation in which no liquid is used.
Examples of wet granulation include fluidized bed granulation, stirring granulation, and spray drying.
Examples of dry granulation include compression granulation and pulverization granulation.
Examples of fluidized bed granulation include rolling fluidized bed granulation and spouted fluidized bed granulation.

≪Method for producing drug substance-containing core≫
In the method for producing a drug substance-containing nucleus of the present invention, while the contents in the fluid bed granulator are flowed, the drug substance powder is added while intermittently or continuously charging the binding liquid into the fluid bed granulator. It includes intermittently or continuously feeding into a fluidized bed granulator and granulating (hereinafter also referred to as “granulating step”).
By supplying the drug substance powder intermittently or continuously to the fluidized bed granulator, the storage stability of the drug substance during and after the production of the drug substance-containing nucleus can be improved.
The method for producing a drug substance-containing nucleus of the present invention may further include other steps as necessary.

<Granulation process>
In the granulation step, the drug substance powder is intermittently or continuously flowed while the binder solution is intermittently or continuously charged into the fluidized bed granulator while the contents in the fluidized bed granulator are flowing. It includes putting into a layer granulator and granulating.
In the granulation step, the drug substance powder may be added intermittently or continuously while charging the binding liquid into the fluidized bed granulator, or the charging of the binding liquid is stopped halfway and intermittently or continuously. Alternatively, the drug substance powder may be added and the binding solution may be charged again. In the granulation step, it is preferable to intermittently or continuously add the drug substance powder while putting the binding liquid into the fluidized bed granulator. It is more preferable to add while putting it in the fluidized bed granulator.
In the granulation step, the drug substance dissolved during the granulation step can be prevented from being decomposed.
Further, in the granulation step, the storage stability of the drug substance after the production of the drug substance-containing nucleus can be improved.
As the mechanism for improving the storage stability of the drug substance after the production of the drug substance-containing nucleus, the drug substance-containing core contains particulate drug substance, so that the drug substance and water, oxygen, binder, etc. It is believed that contact is reduced, but the scope of the present invention is not limited to this mechanism.

The method for charging the binding liquid into the fluidized bed granulator is not particularly limited, and may be a known method such as spraying or dropping, and it is preferable to spray the binding liquid into the fluidized bed granulator.
The input amount of the binding liquid may be adjusted according to the type and amount of the drug substance powder to be input to the fluidized bed granulator. For example, when clopidogrel sulfate is used as the drug substance powder, the input amount of the binding solution is 300% by mass to 30% by mass with respect to the total mass of the drug substance powder to be added to the fluidized bed granulator. Is more preferable, it is more preferable that it is 250 mass%-40 mass%, and it is still more preferable that it is 150 mass%-50 mass%.

  The temperature in the fluidized bed granulator is preferably 25 ° C to 80 ° C. It is preferable to set the temperature in the fluidized bed granulator to 25 ° C. or higher because decomposition due to moisture in the drug substance contained in the granulated product can be reduced. It is preferable to set the temperature in the fluidized bed granulator to 80 ° C. or lower because decomposition of the drug substance contained in the granulated product due to heat can be reduced. The temperature in the fluidized bed granulator is more preferably 30 ° C to 60 ° C, and further preferably 30 ° C to 40 ° C.

  The moisture in the granulated product can be measured with a heat-drying moisture meter (A & D Co., Ltd.), a Karl Fischer moisture meter (Mitsubishi Chemical Analytech Co., Ltd.) or the like. In the case of clopidogrel sulfate, the water content of the granulated material in the fluidized bed granulator is 1 to the total solid content of the granulated material in order to advance the granulation when measured with a heat drying moisture meter. It is desirable to maintain 0.0 mass% or more, and in order to suppress decomposition, it is more desirable to maintain 2.5 mass% or less with respect to the total solid content of the granulated product.

  The drug substance powder may be intermittently or continuously charged into the fluidized bed granulator. The method for charging the drug substance powder is not particularly limited, and may be a known method.

When the drug substance powder is intermittently or continuously charged into the fluidized bed granulator, in order to bind the charged drug substance powder to the granulated particles (granulated material) present in the fluidized bed granulator, The timing of loading the drug substance powder into the fluidized bed granulator is when the ratio of the drug substance powder in the fluidized bed granulator becomes 10% by mass or less with respect to the total solids in the fluidized bed granulator. Preferably, it is more preferably 5% by mass or less, and even more preferably 1% by mass or less.
The ratio of the drug substance powder in the fluidized bed granulator can be measured by sieving using a sieve, laser diffraction type particle size distribution measuring method or the like.
Specifically, a part of the solids in the fluidized bed granulator is extracted, and the mass% of the particles that have passed through the sieve is measured with respect to the total extraction amount using a sieve having an opening of about the maximum particle size of the drug substance powder. The measured value is defined as the ratio of the drug substance powder in the fluidized bed granulator.
It is preferable to use the dry mass excluding moisture as the total extraction amount and the mass of the particles that have passed through the sieve. The solid matter in the fluidized bed granulator is extracted and measured immediately, and is converted in advance. You may convert into the mass% at the time of drying using a type | formula.
In this specification, “ratio of drug substance powder in fluidized bed granulator” means a component of drug substance powder existing in fluidized bed granulator that can be a raw material of drug substance-containing core present in fluidized bed granulator Of the total solids.

  When the drug substance powder is intermittently or continuously charged into the fluidized bed granulator, the amount of the drug substance powder is controlled by suppressing the granulation of the drug substance powders that have been charged, Since it is desirable to bind to the granulated material in the bed granulator, it is preferably 10% by mass or less, more preferably 5% by mass or less, and still more preferably 1% by mass or less based on the total solids in the fluidized bed granulator. .

  When the drug substance powder is intermittently or continuously charged into the fluidized bed granulator, the drug substance powder feed rate is determined by the fluid bed granulator capacity, the type of drug substance, the particle diameter of the drug substance powder, the binding liquid. It can be set as appropriate depending on the type of the above.

In the granulation step, the ratio of the drug substance powder in the fluidized bed granulator is preferably maintained at 10% by mass or less with respect to the total solids in the fluidized bed granulator, and can be maintained at 5% by mass or less. More preferably, it is more preferably maintained at 1% by mass or less. By maintaining the ratio of the drug substance powder in the fluidized bed granulator to 10% by mass or less with respect to the total solids in the fluidized bed granulator, the granulation of the charged drug substance powders is suppressed and charged. The resulting drug substance powder binds to the granulated material present in the fluidized bed granulator, and the drug substance-containing core showing a sharp shape in the particle size distribution can be granulated.
In this specification, the “drug substance powder” refers to a drug substance whose surface is not wet with a binding liquid, or a free drug substance that is not bound to a core particle, a drug substance-containing nucleus, a fluidized bed granulator, etc., which will be described later. Means.

The ratio of the binding liquid and the drug substance powder charged into the fluidized bed granulator is preferably 3: 1 to 1: 3 on a mass basis (binding liquid: drug substance powder). By setting the ratio of the binding liquid and the drug substance powder in the range of 3: 1 to 1: 3, granulation of the charged drug substance powders is suppressed, and the drug substance powder that has been charged is contained in the fluidized bed granulator. It is possible to granulate a drug substance-containing nucleus that binds to a granulated product existing in the shape of the drug and has a shape with a sharp particle size distribution.
The ratio of the binding solution and the drug substance powder is more preferably 2.5: 1 to 1: 2.5 on a mass basis (binding solution: drug substance powder), and 2: 1 to 1: 2. Is more preferable.

  Examples of the fluidized bed granulator include, for example, a fluidized bed granulator (product name: FD-MP-01, manufactured by POWREC Co., Ltd.), a flow coater (product name: FL-1, manufactured by Freund Sangyo Co., Ltd.), and the like. Is mentioned.

The binding liquid is not particularly limited, and a known binding liquid used for fluidized bed granulation can be used.
As the binding liquid, for example, water or an organic solvent may be used as it is, or a binding liquid in which a binder is dissolved, dispersed, or suspended in water or an organic solvent may be used. In the case where the drug substance is a compound that is sticky when wetted with water, the binder may not be included.
The binding liquid may contain other components such as a component that can function as an excipient, a component that can function as a lubricant, and a fluidizing agent.
Examples of the organic solvent include methanol, ethanol, propanol, isopropanol and the like.
The binder is an additive used for imparting a binding force to a mixed granular material such as a main agent and a bulking agent and molding the mixture. Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, low-substituted hydroxypropylcellulose, carboxyvinyl polymer, carmellose sodium, pregelatinized starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, polyvinyl alcohol and the like. It is done.
Examples of the component that can function as an excipient include sugar, sugar alcohol, crystalline cellulose, starch and the like. Examples of the sugar include lactose, sucrose, maltose, trehalose, dextrin and the like. Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Examples of the starch include corn starch, potato starch, rice starch, wheat starch and the like.
Examples of components that can function as a lubricant and a fluidizing agent include talc and light anhydrous silicic acid.
The amount of the binder dissolved, dispersed, or suspended in the solvent can be appropriately set depending on the type of drug substance, the amount of drug substance, the particle diameter of the drug substance powder, and the like.
Examples of the binding liquid include a binding liquid in which 0% by mass to 10% by mass of a binder is added to the total mass of the solvent, a binding liquid in which 0% by mass to 5% by mass is added, and 0% by mass to 3% by mass. And the like.
When the drug substance is a compound that is unstable with respect to a binder such as clopidogrel, the binder content of the binding solution is preferably as small as possible in the range in which the drug substance can be granulated. For example, the binder content of the binding liquid is preferably 0% by mass to 5% by mass, and more preferably 0.01% by mass to 3% by mass.
The binder content of the drug substance-containing portion (in the drug substance layer) in the drug substance-containing nucleus is preferably 0% by mass to 10% by mass.

The drug substance (hereinafter also referred to as “active ingredient”) is not particularly limited, and is not limited to antiplatelet drugs, antiulcer drugs, antipsychotic drugs, bronchial asthma drugs, allergic rhinitis drugs, antihypertensive drugs, hypercholesterolemia Drugs, antidepressants, antihistamines, antibacterial agents, osteoporosis drugs, diabetes drugs, diuretics, antirheumatic drugs, and the like.
Examples of the antiplatelet drug include clopidogrel sulfate, ticlopidine, prosugrel hydrochloride, cilostazol and the like.
Examples of the anti-ulcer agent include proton pump inhibitors such as benzimidazole compounds such as rabeprazole, omeprazole, lansoprazole, pantoprazole or salts thereof; histamine H2 receptor antagonists such as famotidine, cimetidine, ranitidine hydrochloride, and the like.
Examples of antipsychotics include olanzapine, duloxetine, risperidone, quetiapine and the like.
Examples of bronchial asthma therapeutic agents or allergic rhinitis therapeutic agents include montelukast sodium and pranlukast.
Examples of antihypertensive agents include telmisartan, olmesartan medoxomil, valsartan, amlodipine besylate, and the like.
Examples of hypercholesterolemia include fluvastatin sodium and colestimide.
Examples of the antidepressant include imipramine, maprotiline hydrochloride, amphetamine and the like.
Examples of the antihistamine include diphenhydramine hydrochloride, promethazine, isothipentyl hydrochloride, dl-chlorpheniramine maleate, and the like.
Antibacterial agents include penicillin, ampicillin, erythromycin, clarithromycin, vancomycin and the like.
Examples of the osteoporosis agent include ipriflavone and the like.
Examples of the diabetes drug include tolbutamide, voglibose, pioglitazone hydrochloride, glibenclamide, troglitazone, rosiglitazone maleate, acarbose, miglitol, emiglitate, and the like.
Examples of diuretics include thiazide agents such as isosorbide, furosemide, and HCTZ (hydrochlorothiazide).
Examples of antirheumatic drugs include methotrexate and bucillamine.

Among them, clopidogrel sulfate or fluvastatin sodium is preferable as the drug substance from the viewpoint that it has bitterness and is unstable to water, so that the effects of the present invention can be fully exerted. Clopidogrel sulfate A salt is more preferred.
In addition, since it is easily decomposed into an acid, the drug substance is preferably a benzimidazole compound such as rabeprazole, lansoprazole, omeprazole, pantoprazole, or a salt thereof, from the viewpoint that the effects of the present invention can be fully exhibited, and rabeprazole sodium Is more preferable.

The average particle size of the drug substance powder is preferably 0.1 μm to 20 μm. By adjusting the average particle size of the drug substance powder to a range of 0.1 μm to 20 μm, the surface of the drug substance-containing core becomes smooth, the required coating film thickness can be reduced, and the tablet mass can be reduced.
The average particle size of the drug substance powder is more preferably 2 μm to 15 μm, still more preferably 5 μm to 10 μm.

  In the granulation step, other ingredients may be added as powder in addition to the drug substance powder. Moreover, you may add a core particle in a granulation process.

Examples of other components include excipients, binders, disintegrants, lubricants, fluidizing agents, and the like.
Disintegrants include starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low substituted hydroxypropylcellulose, crystalline cellulose, hydroxypropyl And starch.

In the granulation process, a granulated product with a sharp particle size distribution is obtained by using core particles with a sharp particle size distribution and a particle size larger than that of the drug substance powder. Can be obtained. In addition, by using core particles having a particle size larger than that of the drug substance powder, aggregation between particles can be suppressed, and a highly spherical granulated product can be obtained.
The core particles only need to contain at least one selected from the group consisting of the drug substance and other components. The core particles may contain only the drug substance, may contain the drug substance and other components, or may contain only other components. As the core particles, the raw powder (the drug substance powder) itself may be used, a granulated product may be used, or commercially available core particles may be used. Non-parrel (manufactured by Freund Sangyo Co., Ltd.), Selfia (manufactured by Asahi Kasei Chemicals Co., Ltd.) and the like are listed as commercially available core particles.

Preferably, the drug substance content of the drug substance-containing portion (in the drug substance layer) in the drug substance-containing nucleus is 70% by mass to 100% by mass.
If the drug substance content in the drug substance-containing core (in the drug substance layer) is lower than 70% by mass, it is not preferable because it may lead to a decrease in dosage due to an increase in tablet diameter.
The drug substance content in the drug substance-containing part (in the drug substance layer) of the drug substance-containing nucleus is more preferably 80% by mass to 100% by mass, and still more preferably 90% by mass to 100% by mass. .

The average particle diameter of the drug substance-containing nucleus is 100 μm to 500 μm. When preparing an orally disintegrating tablet containing a drug substance-containing nucleus, when the orally disintegrating tablet disintegrates in the oral cavity by adjusting the average particle size of the drug substance-containing nucleus to a range of 100 μm to 500 μm, The roughness in the inside can be reduced.
The average particle diameter of the drug substance-containing nucleus is preferably 100 μm to 350 μm, and more preferably 150 μm to 250 μm.
In addition, when preparing an orally disintegrating tablet containing a drug substance-containing nucleus, the drug substance content of the drug substance-containing part (in the drug substance layer) in the drug substance-containing nucleus is 70% by mass to 100% by mass, In addition, by setting the average particle size of the drug substance-containing nucleus to 100 μm to 350 μm, the size of the orally disintegrating tablet can be made smaller than that of the conventional orally disintegrating tablet.

The drug substance-containing nucleus obtained by the granulation process can be used for the preparation of a pharmaceutical composition. Examples of the pharmaceutical composition include tablets, capsules, powders, granules, fine granules, dry syrups, etc. Among them, tablets are preferable. The drug substance-containing nucleus can be particularly preferably used for the preparation of orally disintegrating tablets.
Specifically, an orally disintegrating tablet can be obtained by coating the drug substance-containing core with an intermediate layer and further coating the intermediate layer with an elution control layer.
A specific method for producing the orally disintegrating tablet may be in accordance with a known method, for example, according to the method described in JP2012-162502A.

≪Oral disintegrating tablet≫
The orally disintegrating tablet of the present invention contains particulate clopidogrel sulfate or particulate rabeprazole sodium in the drug substance-containing portion of the drug substance-containing nucleus, and the average particle diameter of the drug substance-containing nucleus is 100 μm to 500 μm. The thickness is preferably 100 μm to 350 μm, more preferably 150 μm to 250 μm.
The orally disintegrating tablet may contain other components or other layers as necessary.

The water content of the orally disintegrating tablet of the present invention is preferably 1.5% by mass or less. By setting the water content of the orally disintegrating tablet to 1.5% by mass or less, the storage stability of the orally disintegrating tablet is improved.
The water content of the orally disintegrating tablet is more preferably 1.0% by mass or less, and further preferably 0.5% by mass or less. The water content of the orally disintegrating tablet can be suppressed by drying the orally disintegrating tablet before packaging the orally disintegrating tablet.
The method for drying the orally disintegrating tablet is not particularly limited, and the orally disintegrating tablet can be dried by a method of supplying air dried to a relative humidity of 5% or less at a temperature of 25 ° C. for several hours. As a means for supplying dry air, a known dryer can be applied, and examples thereof include a dry dehumidifier (trade name: Honey Dry, (Daikin Co., Ltd.) and the like.

<Drug-containing nucleus>
The orally disintegrating tablet of the present invention contains a drug substance-containing nucleus. The drug substance-containing nucleus only needs to contain the drug substance-containing portion (the drug substance layer), and may contain nucleus particles.

The content ratio of clopidogrel sulfate or rabeprazole sodium contained in the drug substance layer is preferably in the range of 70% by mass to 100% by mass with respect to the total mass of the components forming the drug substance layer. By setting it as this range, the size of an orally disintegrating tablet can be made smaller than that of a conventional orally disintegrating tablet.
The content ratio of clopidogrel sulfate or rabeprazole sodium contained in the drug substance layer is more preferably 80% by mass to 100% by mass with respect to the total mass of the components forming the drug substance layer, and 90% by mass. More preferably, it is -100 mass%.

The orally disintegrating tablet of the present invention contains particulate clopidogrel sulfate or rabeprazole sodium in the drug substance layer.
By containing particulate clopidogrel sulfate or rabeprazole sodium in the drug substance layer, the storage stability of clopidogrel sulfate or rabeprazole sodium is improved.
The drug substance layer containing particulate clopidogrel sulfate or rabeprazole sodium is fluidized bed granulated using a binding solution not containing clopidogrel sulfate or rabeprazole sodium and a drug substance powder of clopidogrel sulfate or rabeprazole sodium. Can be obtained.
The presence of particulate drug substance in the drug substance-containing nucleus can be confirmed by observation of the drug substance-containing nucleus with an optical microscope. It is clear that the particulate drug substance is contained in fine granules or orally disintegrating tablets produced using a drug substance-containing core containing the particulate drug substance. The fact that the granular drug substance is contained in the fine granules or orally disintegrating tablets indicates that the cut surfaces of these fine granules or orally disintegrating tablets are observed by observation with a scanning electron microscope (SEM). It can also be confirmed by confirming the shape structure or by structural analysis by X-ray CT (Computed Tomography).

The particle diameter of the drug substance contained in the drug substance-containing nucleus is preferably 0.1 μm to 20 μm, more preferably 2 μm to 15 μm, and still more preferably 5 μm to 10 μm.
The drug substance layer may contain other components in addition to the drug substance. Examples of other components include excipients, binders, disintegrants, lubricants, fluidizing agents, and the like.
The content of the binder in the drug substance-containing portion (the drug substance layer) in the drug substance-containing nucleus is preferably 0% by mass to 10% by mass with respect to the total mass of the components forming the drug substance layer.

The drug substance-containing nucleus may contain nuclear particles.
The core particles only need to contain at least one selected from the group consisting of the drug substance and other components. The core particles may contain only the drug substance, may contain the drug substance and other components, or may contain only other components. As the core particles, the raw powder (the drug substance powder) itself may be used, a granulated product may be used, or commercially available core particles may be used. Non-parrel (manufactured by Freund Sangyo Co., Ltd.), Selfia (manufactured by Asahi Kasei Chemicals Co., Ltd.) and the like are listed as commercially available core particles.

The ratio (D90 / D10) of the 90% cumulative volume percentage (D90) to the 10% cumulative volume percentage (D10) of the drug substance-containing nucleus is preferably 4.0 or less. When D90 / D10 is 4.0 or less, roughness in the mouth can be suppressed and the feeling of dosing when an orally disintegrating tablet is contained in the mouth can be improved.
In this specification, the particle size at 10% of the cumulative volume percentage curve, that is, 10% of the total volume when accumulated from the smaller particle size, is obtained from the size distribution of the particle size obtained at the time of measuring the average particle size. The corresponding particle size is defined as “D10”.
Further, in the present specification, the particle size at 90% of the cumulative volume percentage curve, that is, 90% of the total volume when accumulated from the smaller particle size size, from the size distribution of the particle size obtained at the time of measuring the average particle size. The particle size corresponding to% is defined as “D90”.

  The orally disintegrating tablet of the present invention preferably contains a drug substance-containing nucleus obtained according to the above-described method for producing a drug substance-containing nucleus, but is not limited thereto.

  The orally disintegrating tablet preferably includes an intermediate layer and an elution control layer in addition to the drug substance-containing core.

<Intermediate layer>
The intermediate layer is a layer that covers the drug substance-containing nucleus and prevents contact between the release control layer and the drug substance-containing nucleus.
The orally disintegrating tablet preferably has at least one intermediate layer. The intermediate layer may be a multilayer of two or more layers.

  The form in which the intermediate layer covers the drug substance-containing nucleus may be in a state where the intermediate layer exists on at least a part of the surface of the drug substance-containing nucleus. The intermediate layer preferably covers 1/4 or more of the surface of the drug substance-containing nucleus, more preferably covers 1/2 or more, and most preferably covers the whole.

  The component forming the intermediate layer is not particularly limited, and known components can be used in the orally disintegrating tablet. Examples of components that can form the intermediate layer include water-soluble polymers and water-insoluble polymers. Examples of components that can form an intermediate layer other than these components include excipients, binders, disintegrants, lubricants, fluidizing agents, and the like.

Specific examples of the water-soluble polymer include water-soluble cellulose derivatives, water-soluble vinyl polymer derivatives, water-soluble acrylic acid copolymers, polyhydric alcohol polymers, and copolymers thereof (hereinafter referred to as “copolymer polymers”). Also called). Among them, the water-soluble polymer is preferably a water-soluble polymer selected from the group consisting of a water-soluble cellulose derivative and a water-soluble vinyl polymer derivative, and more preferably a water-soluble cellulose derivative.
More specifically, examples of the water-soluble cellulose derivative include methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose and the like. Examples of the water-soluble vinyl polymer derivative include polyvinyl alcohol and polyvinyl pyrrolidone. Examples of the water-soluble acrylic acid copolymer include polymers that contain acrylic acid, acrylic acid ester, methacrylic acid ester, and the like and that can be dissolved in any of acidic, neutral, and alkaline aqueous solutions. Examples of the polyhydric alcohol polymer include macrogol and polyglycerin. Examples of the copolymer include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyethylene glycol / polyvinyl alcohol graft copolymer, vinyl pyrrolidone / vinyl alcohol copolymer, and the like.
As the water-soluble polymer, a water-soluble cellulose derivative selected from the group consisting of hydroxypropylmethylcellulose and hydroxypropylcellulose is preferable from the viewpoint of viscosity and binding property suitable for fine particle coating.
A commercially available product may be used as the water-soluble polymer. Examples of commercially available water-soluble polymers include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (trade name: POVACOAT, manufactured by Daido Kasei Kogyo Co., Ltd.), polyethylene glycol / polyvinyl alcohol graft copolymer (product) Name: Kollicoat IR, manufactured by BASF), vinylpyrrolidone / vinyl alcohol copolymer (trade name: Kollicoat VA64, manufactured by BASF), and the like.
Any one water-soluble polymer may be used alone, or two or more water-soluble polymers may be used in combination.
The content of the water-soluble polymer contained in the intermediate layer can be appropriately determined in consideration of the type of the active ingredient, the content of the active ingredient, the daily dose of the active ingredient, the particle size of the fine particles, and the like. For example, the content of the water-soluble polymer is 0% by mass to 100% by mass, 15% by mass to 80% by mass, 30% by mass to 60% by mass, etc. with respect to the total mass of the film components forming the intermediate layer. be able to.

The water-insoluble polymer contained in the intermediate layer is not particularly limited as long as it is a component that does not depend on the pH value of the contacted aqueous solution and does not dissolve in any of the acidic, neutral, and alkaline aqueous solutions. Polymers can be used.
The water-insoluble polymer is preferably a polymer that controls the elution of the active ingredient, for example, by slowly releasing the coated active ingredient after the elution control layer covering the intermediate layer is dissolved in the stomach or intestine.
As used herein, “water-insoluble polymer” means a polymer having a solubility in water at 20 ° C. of less than 10 g / L.

Examples of the water-insoluble polymer include water-insoluble cellulose ether and water-insoluble acrylic acid copolymer. Examples of the water-insoluble cellulose ether include ethyl cellulose. Examples of the water-insoluble acrylic acid copolymer include ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer, ethyl acrylate / methyl methacrylate copolymer dispersion, and the like.
A commercially available product can also be used as the water-insoluble polymer. Examples of commercially available water-insoluble cellulose ethers include ethylcellulose aqueous dispersions (trade name: Aquacoat ECD, manufactured by FMC). Commercially available water-insoluble acrylic acid copolymers include ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer (trade name: Eudragit RS, Evonik Rohm GmbH), ethyl acrylate. / Methyl methacrylate copolymer dispersion (trade name: Eudragit NE30D, manufactured by Evonik).
As the water-insoluble polymer, any one of the water-insoluble polymers may be used alone, or two or more kinds thereof may be used in combination.
The content of the water-insoluble polymer contained in the intermediate layer can be appropriately determined in consideration of the type of the active ingredient, the content of the active ingredient, the daily dose of the active ingredient, the particle size of the fine particles, and the like. For example, the content of the water-insoluble polymer is 0% by mass to 100% by mass, 15% by mass to 80% by mass, 30% by mass to 60% by mass, etc. with respect to the total mass of the components forming the intermediate layer. Can do.

  The intermediate layer may contain other components in addition to the polymer as long as the effects of the present invention are not impaired. Examples of other components include excipients, binders, disintegrants, lubricants, fluidizing agents, and the like. These other components may be components in which one component assumes two or more functions.

The coating amount of the intermediate layer when coating the drug substance-containing nucleus with the intermediate layer is not particularly limited as long as it is an amount in which the drug substance-containing nucleus is covered with the intermediate layer. For example, the mass of the intermediate layer used for coating the drug substance-containing nucleus is 0.01 to 50 times, 0.1 to 5 times, or 0. The amount is 3 times to 1 time.
In the formation of the intermediate layer, 0.01 times to 50 times, 0.1 times to 5 times, or 0.3 times to 1 times the mass of the drug substance-containing nucleus in terms of mass. A component that forms an intermediate layer having a double mass may be dissolved or suspended in a pharmacologically acceptable solvent and sprayed onto the drug substance-containing nucleus.

  When two or more intermediate layers are provided, a plurality of intermediate layer coating solutions having different compositions may be sprayed onto the drug substance-containing core in a plurality of times for each intermediate layer coating solution.

<Elution control layer>
The elution control layer means a film that imparts timed release or sustained release to a preparation. Specifically, as an elution control layer, a gastric film and an enteric film that release the active ingredient at the target site by changing the solubility according to the pH of the liquid in contact, dissolved in water in a certain time In the meantime, water-soluble membranes that prevent the release of active ingredients, water-insoluble membranes that slowly release active ingredients due to low water solubility or water insolubility, and the functions of these membranes are combined Examples include membranes. The elution control layer may be formed of one or more layers, and may be a multilayer such as two layers.

The component that forms the elution control layer is not particularly limited, and known components can be used in the orally disintegrating tablet.
For example, the gastric film is not particularly limited as long as it is formed of components that dissolve in an acidic aqueous solution but do not dissolve in a basic aqueous solution. Examples of the gastric film include a film formed of components such as a gastric soluble polyvinyl derivative and a gastric soluble acrylic acid copolymer.
Examples of the gastric soluble polyvinyl derivative include polyvinyl acetal diethylaminoacetate. Examples of the gastric soluble acrylic acid copolymer include methyl (meth) acrylate / butyl (meth) acrylate / dimethylaminoethyl (meth) acrylate, methyl methacrylate / diethylaminoethyl methacrylate copolymer, etc. Is mentioned.
Commercially available products may be used as the gastric soluble polyvinyl derivative and the gastric soluble acrylic acid copolymer. Examples of commercially available gastric soluble polyvinyl derivatives include polyvinyl acetal diethylaminoacetate (trade name: AEA, manufactured by Mitsubishi Chemical Food Co., Ltd.). Commercially available gastric acrylic copolymers include, for example, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (trade names: Eudragit E100, Eudragit EPO, manufactured by Evonik), methyl methacrylate / Examples include diethylaminoethyl methacrylate copolymer (trade name: Kollicoat Smartseal 30D, manufactured by BASF).

Depending on the purpose, the gastric soluble membrane may be formed by using any one component alone, or by combining two or more components having similar properties or two or more components having different properties. May be formed. When using a combination of two or more components to form a gastric film, the gastric film can be formed to have a multilayer structure, for example.
The content of the gastric film can be 5% by mass to 70% by mass, 10% by mass to 60% by mass, 15% by mass to 50% by mass, etc. with respect to the total mass of the fine granules.

The enteric membrane is not particularly limited as long as it is formed of components that dissolve in a basic aqueous solution but do not dissolve in an acidic aqueous solution. The enteric membrane is preferably an enteric membrane containing an aqueous enteric polymer. Examples of the component that dissolves in the basic aqueous solution and does not dissolve in the acidic aqueous solution include enteric polymers such as enteric cellulose derivatives and enteric acrylic acid copolymers.
Examples of the enteric cellulose derivative include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, and the like.
Examples of the enteric acrylic copolymer include a methacrylic acid copolymer, and specifically, a methacrylic acid / methyl methacrylate copolymer, a methacrylic acid / ethyl acrylate copolymer, and a methyl acrylate / methacrylic acid. And methyl / methacrylic acid copolymer.
Among these, a methacrylic acid copolymer is preferable as a component for forming an enteric film from the viewpoint of easy coating of fine particles with a low viscosity even at a high concentration.
Commercially available products can be used as the enteric cellulose derivative and the enteric acrylic acid copolymer. Examples of commercially available enteric cellulose derivatives include hydroxypropyl methylcellulose acetate succinate (trade name: HPMCAS, manufactured by Shin-Etsu Chemical Co., Ltd.), hydroxypropyl methylcellulose phthalate (trade name: HPMCP, manufactured by Shin-Etsu Chemical Co., Ltd.). ), Carboxymethyl ethyl cellulose (trade name: CMEC, manufactured by Freund Sangyo Co., Ltd.) and the like. Examples of commercially available enteric acrylic acid copolymers include methacrylic acid / methyl methacrylate copolymers (trade names: Eudragit L100, Eudragit S, manufactured by Evonik), methacrylic acid / ethyl acrylate copolymers (commodities) Name: Eudragit L100-55, Eudragit L30D55, manufactured by Evonik), methyl acrylate / methyl methacrylate / methacrylic acid copolymer (trade name: Eudragit FS30D, manufactured by Evonik), and the like.

  The water-based enteric polymer refers to an enteric polymer that can be sprayed as an aqueous solution or an aqueous dispersion. Among the enteric polymers, examples of the aqueous enteric polymer include hydroxypropyl methylcellulose acetate succinate, methacrylic acid / ethyl acrylate copolymer, and methyl acrylate / methyl methacrylate / methacrylic acid copolymer.

An enteric membrane may be formed by using any one component alone depending on the purpose, and two or more components having similar properties or two or more components having different properties may be used in combination. May be formed. When two or more components are used in combination to form an enteric film, for example, the enteric film can be formed to have a multilayer structure.
Content of an enteric film | membrane can be 5 mass%-70 mass%, 10 mass%-60 mass%, 15 mass%-50 mass% etc. with respect to the total mass of a fine granule.

The water-soluble film is not particularly limited as long as it is a film formed of a water-soluble polymer that dissolves in water after a lapse of a certain time after the film is immersed in water at 20 ° C. The certain time can be appropriately set according to the dissolution time required for the water-soluble film. As fixed time, 0 hours-48 hours, 0 hours-24 hours, 0 hours-12 hours etc. are mentioned, for example.
Specific examples of the water-soluble polymer include water-soluble cellulose derivatives, water-soluble vinyl polymer derivatives, water-soluble acrylic acid copolymers, polyhydric alcohol polymers, and copolymers thereof (hereinafter referred to as “copolymer polymers”). ")"). Among these, the water-soluble polymer is preferably a water-soluble polymer selected from the group consisting of a water-soluble cellulose derivative and a water-soluble vinyl polymer derivative, and more preferably a water-soluble cellulose derivative.

  More specifically, examples of the water-soluble cellulose derivative include methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose and the like. Examples of the water-soluble vinyl polymer derivative include polyvinyl alcohol and polyvinyl pyrrolidone. Examples of the water-soluble acrylic acid copolymer include acrylic acid polymer, acrylic ester polymer, and methacrylic ester polymer. Examples of the polyhydric alcohol polymer include macrogol and polyglycerin. Examples of the copolymer include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyethylene glycol / polyvinyl alcohol graft copolymer, vinyl pyrrolidone / vinyl alcohol copolymer, and the like.

As the water-soluble polymer, a water-soluble cellulose derivative selected from the group consisting of hydroxypropylmethylcellulose and hydroxypropylcellulose is preferable from the viewpoint of viscosity and binding property suitable for fine particle coating.
A commercially available product may be used as the water-soluble polymer.
Examples of commercially available copolymer polymers include polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (trade name: POVACOAT, manufactured by Daido Kasei Kogyo Co., Ltd.), polyethylene glycol / polyvinyl alcohol graft copolymer ( Trade name: Kollicoat IR, manufactured by BASF), vinylpyrrolidone / vinyl alcohol copolymer (trade name: Kollicoat VA64, manufactured by BASF), and the like.

Examples of the water-insoluble film include films formed of components such as a water-insoluble cellulose ether and a water-insoluble acrylic acid copolymer. Examples of the water-insoluble cellulose ether include ethyl cellulose. Examples of the water-insoluble acrylic acid copolymer include ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer, ethyl acrylate / methyl methacrylate copolymer, and the like.
Commercially available products can also be used as the water-insoluble cellulose ether and the water-insoluble acrylic acid copolymer. Examples of commercially available water-insoluble cellulose ethers include ethylcellulose aqueous dispersions (trade name: Aquacoat ECD, manufactured by FMC). Examples of commercially available water-insoluble acrylic acid copolymers include ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer (trade name: Eudragit RS, manufactured by Evonik), ethyl acrylate / methacrylic acid. Examples thereof include a methyl copolymer dispersion (trade name: Eudragit NE30D, manufactured by Evonik).

Depending on the purpose, the water-insoluble film may be formed by using any one component alone, or a combination of two or more components having different properties or two or more components having different properties. May be formed. When a combination of two or more components is used to form a water-insoluble film, for example, the water-insoluble film can be formed to have a multilayer structure.
Content of a water-insoluble film | membrane can be 5 mass%-70 mass%, 10 mass%-60 mass%, 15 mass%-50 mass% etc. with respect to the total mass of a fine granule.

The elution control layer may be formed using a combination of two or more components having different properties from the membrane components according to the purpose. When two or more components are used in combination to form an elution control layer, for example, the elution control layer can be formed so as to have a multilayer structure.
When two or more elution control layers are provided, a plurality of elution control layer coating solutions with different compositions etc. are divided into a plurality of times for each elution control layer coating solution. What is necessary is just to spray on a composite component with this component.

The elution control layer may contain other components in addition to the polymer as long as the effects of the present invention are not impaired. Examples of other components include excipients, binders, lubricants, fluidizers, and plasticizers.
Specific examples of the excipient include sugar, sugar alcohol, crystalline cellulose, starch and the like. Examples of the sugar include lactose, sucrose, maltose, trehalose, dextrin and the like. Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Examples of the starch include corn starch, potato starch, rice starch, wheat starch and the like.
Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and the like.
Examples of the lubricant and the fluidizing agent include talc and light anhydrous silicic acid.

  Examples of the plasticizer include triethyl citrate, polyethylene glycol, polyoxyethylene sorbitan monooleate, acetyl triethyl citrate, tributyl citrate, and tributyl acetyl citrate.

  The form in which the elution control layer covers the intermediate layer may be in a state where the elution control layer exists on at least a part of the surface of the intermediate layer. The elution control layer preferably covers 1/4 or more of the surface of the intermediate layer, more preferably covers 1/2 or more, and most preferably covers the entire surface.

The coating amount of the elution control layer when the intermediate layer is coated with the elution control layer is not particularly limited as long as the intermediate layer is coated in the elution control layer. For example, the mass of the elution control layer used for coating the intermediate layer is 0.01 to 20 times, 0.1 to 15 times, or 0.3 times the total mass of the intermediate layer. It is mentioned that it is 10 times amount.
In the formation of the elution control layer, 0.01 times to 20 times, 0.1 times to 15 times, or 0.3 times to 10 times the mass based on the total mass of the intermediate layer. What is necessary is just to melt | dissolve or suspend the component which forms the elution control layer of the quantity of mass in a pharmacologically acceptable solvent, and to spray it on an intermediate | middle layer.

  When two or more elution control layers are provided, a plurality of elution control layer coating liquids having different compositions may be sprayed on the intermediate layer in a plurality of times for each elution control layer coating liquid.

More specifically, the orally disintegrating tablet includes fine granules containing a drug substance including a drug substance-containing nucleus, an intermediate layer and an elution control layer, and an excipient outside the fine granules.
In addition to the drug substance-containing nucleus, the intermediate layer and the elution control layer, the fine granules can contain other pharmacologically acceptable additives for pharmaceutical preparation. Other pharmaceutical additives include binders such as hydroxypropylcellulose and hydroxypropylmethylcellulose, excipients such as mannitol and lactose, lubricants such as talc and glyceryl monostearate, low-substituted hydroxypropylcellulose, partial In addition to disintegrants such as alpha starch, known ingredients can be used as additives for pharmaceutical preparations generally used in the manufacture of pharmaceuticals such as sweeteners, flavoring agents, fluidizing agents, flavoring agents, and coloring agents.
Ingredients known as pharmaceutical additives include ingredients that can function as binders, excipients, lubricants, disintegrants, etc. Even if one ingredient is responsible for two or more functions Good.
Any known excipient can be used as the extra-fine-grain excipient as long as it is a component that can function as an excipient. Examples of excipients other than fine granules include sugar, sugar alcohol, crystalline cellulose, anhydrous calcium phosphate, magnesium aluminate metasilicate, and the like.

Examples of the sugar include lactose, sucrose, maltose, trehalose, dextrin and the like.
Examples of the sugar alcohol include D-mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Among these, the sugar alcohol selected from the group consisting of D-mannitol and erythritol is preferable as the sugar alcohol from the solubility point of the orally disintegrating tablet.
A commercial item can also be used for crystalline cellulose. Examples of commercially available crystalline cellulose include Theolas (trade name, manufactured by Asahi Kasei Chemicals Corporation), Pharmacel (trade name, manufactured by DFE Pharma) and the like.
As the excipient, any one of the excipients may be used alone, or two or more kinds thereof may be used in combination.
The content of the excipient can be appropriately determined in consideration of the type of the active ingredient, the content of the active ingredient, the daily dose of the active ingredient, the particle size of the fine particles, and the like.
As the disintegrant, a known disintegrant can be used as long as it can function as a disintegrant. Examples of the disintegrant include starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, crystalline cellulose, Examples include hydroxypropyl starch.
Among these, from the viewpoint of disintegration, the disintegrant is more preferably a disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, and low-substituted hydroxypropylcellulose.

As the disintegrating agent, any one disintegrating agent may be used alone, or two or more disintegrating agents may be used in combination.
The content of the disintegrant can be appropriately determined in consideration of the type of the active ingredient, the content of the active ingredient, the daily dose of the active ingredient, the particle diameter of the fine particles, and the like.
As the lubricant, any known lubricant can be used as long as it can function as a lubricant. Examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate and the like. Sodium stearyl fumarate can be obtained as a commercial product from, for example, JRS PHARMA.
Any one lubricant may be used alone, or two or more lubricants may be used in combination.
The content of the lubricant can be appropriately determined in consideration of the type of the active ingredient, the content of the active ingredient, the daily dose of the active ingredient, the particle size of the fine particles, and the like.
Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, carboxyvinyl polymer, carmellose sodium, pregelatinized starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, polyvinyl alcohol and the like.
Any one binder may be used alone, or two or more binders may be used in combination.
The content of the binder can be appropriately determined in consideration of the type of the active ingredient, the content of the active ingredient, the daily dose of the active ingredient, the particle diameter of the fine particles, and the like.
The additive for formulation may be used individually by 1 type, and may use 2 or more types together.
The content of the formulation additive can be appropriately determined in consideration of the type of the active ingredient, the content of the active ingredient, the daily dose of the active ingredient, the particle size of the fine particles, and the like.

The average particle diameter of the fine particles is preferably 1 mm or less, more preferably 750 μm or less, and further preferably 500 μm or less.
The average particle diameter of the fine particles is preferably 50 μm or more, more preferably 150 μm or more, and further preferably 300 μm or more.

Fine granules can be prepared according to known methods such as granulating drug substance-containing nuclei, coating the granulated drug substance-containing nuclei with an intermediate layer, and covering the coated intermediate layer with an elution control layer. it can.
The method of granulating the drug substance-containing nuclei, the method of coating the granulated drug substance-containing nuclei with an intermediate layer, the method of coating the coated intermediate layer with an elution control layer, etc. are not particularly limited, and a known method is used. Can be used. Examples thereof include a fluidized bed granulation method, a stirring granulation method, a wet granulation method such as spray drying, a dry granulation method such as a compression granulation method, and a pulverization granulation method.
Examples of the granulator that can be used in the fluidized bed granulation method include a fluidized bed granulator (product name: FD-MP-01, manufactured by POWREC Co., Ltd.), a flow coater (product name: FL-1, Freund). Sangyo Co., Ltd.).

As described above, the orally disintegrating tablet of the present invention comprises fine granules containing the drug substance and excipients (excipients outside the fine granules).
Non-fine-grain excipients include disintegrants, lubricants, excipients, binders, sweeteners, flavoring agents, fluidizing agents, flavoring agents, coloring agents, and other preparations commonly used in the manufacture of pharmaceuticals. Known ingredients may be included as additives for use.

As the disintegrant, a known disintegrant can be used as long as it can function as a disintegrant. For example, starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, crystalline cellulose, hydroxypropyl starch, etc. Can be mentioned.
Among these, from the viewpoint of disintegration, the disintegrant is more preferably a disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, and low-substituted hydroxypropylcellulose.
As the disintegrating agent, any one disintegrating agent may be used alone, or two or more disintegrating agents may be used in combination.

As the lubricant, any known lubricant can be used as long as it can function as a lubricant. Examples of the lubricant include sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester and the like. Sodium stearyl fumarate can be obtained as a commercial product from, for example, JRS PHARMA.
Any one lubricant may be used alone, or two or more lubricants may be used in combination.

As the excipient, known excipients can be used as long as they can function as excipients. Examples of the excipient include sugar, sugar alcohol, crystalline cellulose, anhydrous calcium hydrogen phosphate, magnesium aluminate metasilicate, and the like.
Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Among these sugar alcohols, a sugar alcohol selected from the group consisting of mannitol and erythritol is preferable from the viewpoint of solubility of the orally disintegrating tablet.
A commercial item can also be used for crystalline cellulose. Examples of commercially available crystalline cellulose include Theolas (trade name, manufactured by Asahi Kasei Chemicals Corporation), Pharmacel (trade name, manufactured by DFE Pharma) and the like.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, carmellose sodium, pregelatinized starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, polyvinyl alcohol and the like.
The additive for formulation may be used individually by 1 type, and may use 2 or more types together.
The content of the formulation additive can be appropriately determined in consideration of the type of the active ingredient, the content of the active ingredient, the daily dose of the active ingredient, the particle size of the fine particles, and the like.

  The content of clopidogrel sulfate or rabeprazole sodium in one orally disintegrating tablet can be appropriately determined in consideration of the lower limit and upper limit of the daily dose of clopidogrel sulfate or rabeprazole sodium. For example, when clopidogrel sulfate is used, it is preferable to contain 32.6 mg to 97.9 mg of clopidogrel sulfate with respect to one orally disintegrating tablet.

The size and shape of the orally disintegrating tablet are not particularly limited as long as it is a pharmaceutically acceptable size and shape. In the case of a round tablet, the size of the orally disintegrating tablet includes a diameter of 7 mm to 12 mm, a thickness of 3.0 mm to 7.0 mm, preferably a diameter of 8 mm to 11 mm, and a thickness of 3.5 mm to 6.5 mm. . In the case of a deformed tablet, the size of the orally disintegrating tablet includes a minor axis of 4 mm to 8 mm, a major axis of 8 mm to 18 mm, preferably a minor axis of 4 mm to 6.5 mm, a major axis of 8 mm to 15 mm, and a thickness of 3.0 mm. To 7.0 mm, preferably 3.5 mm to 6.5 mm.
The hardness of the orally disintegrating tablet is not particularly limited. The hardness of the orally disintegrating tablet is preferably 20 N / m ² or more and 100 N / m ² or less, as measured with a tablet hardness meter, from the viewpoint of disintegration, transport stability, availability of an automatic packaging machine, and the like. / ^m is more preferably ² or more 70N / ^{m 2} or less. The hardness of the orally disintegrating tablet is measured using a tablet hardness tester Model 8M manufactured by Schleuniger.

In the present specification, the disintegration time is defined as the time during which it was confirmed that a part of the tablet disintegrated in the oral cavity. The disintegration time of the orally disintegrating tablet is preferably less than 30 seconds, and more preferably less than 20 seconds.
The method for producing the orally disintegrating tablet is not particularly limited, and a known method can be used. Orally disintegrating tablets, for example, enteric fine granules and pharmaceutical additives such as disintegrants, lubricants, excipients, binders, etc. are mixed to obtain a mixture, and the resulting mixture is obtained. It can be obtained by tableting with a tableting machine.
The method for mixing the fine particles and the excipient is not particularly limited. The fine granules and the excipient may be mixed using a known mixer such as a V-type mixer (made by Tsutsui Rika Kikai Co., Ltd.) or a fluidized bed granulator (made by Paulek Co., Ltd.). it can.
The method for tableting the obtained mixture is not particularly limited. The resulting mixture can be tableted using, for example, a known tableting machine such as a rotary tableting machine (product name HT-P18A, manufactured by Hata Seiko Co., Ltd.).

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist thereof. Unless otherwise specified, “part” is based on mass.
The mass of the granulated product taken out from the fluidized bed granulator and the granulated product that passed through the round sieve used the measured values as they were, but the mass ratio was substantial even when corrected with the moisture content. It was confirmed that it did not change.

Example 1
Preparation of drug substance-containing nucleus 390 g of spherical sphere granules of mannitol (manufactured by Freund Sangyo Co., Ltd.) and 65 g of clopidogrel sulfate are jetted fluidized bed granulator (trade name: FD-MP-01, manufactured by Powrec Co., Ltd.) ) (Hereinafter referred to as “fluidized bed granulator”), adjusted to a supply temperature of 60 ° C., an exhaust temperature of about 35 ° C., and a liquid speed of 2 g / min to 3 g / min. Granulation was performed by adding the bulk powder of clopidogrel sulfate while spraying the drug layer spray liquid into the fluidized bed granulator. The addition of the bulk powder of clopidogrel sulfate was performed 16 times in a total of 360 g at a pace of 4 g / min to 8 g / min from 25 minutes after the start of liquid feeding. Before adding, collect a part of the granulated material in the fluidized bed granulator and pass it through a round sieve (53 μm) of No. 280, and confirm that the proportion of the granulated material passed is 5% or less. did. In addition, granulation was performed so that the feed rate of the drug substance layer spray liquid during the addition of the bulk powder of clopidogrel sulfate was 344.1 g.
500 g of the granulated product obtained above was charged into a fluidized bed granulator, adjusted to an air supply temperature of 60 ° C., an exhaust temperature of about 35 ° C., and a liquid speed of 2 g / min to 3 g / min. Granulation was carried out again while spraying into the granulator and adding the bulk powder of clopidogrel sulfate.
The addition of the bulk powder of clopidogrel sulfate was performed in a total of 620 g divided into 31 times at a rate of 4 g / min from 10 minutes after the start of liquid feeding. Before adding, collect a part of the granulated material in the fluidized bed granulator and pass it through a round sieve (53 μm) of No. 280, and confirm that the proportion of the granulated material passed is 5% or less. did. In addition, granulation was performed so that the feed rate of the drug substance layer spray liquid during the addition of the bulk powder of clopidogrel sulfate was 593.1 g. The granulated product obtained above was passed through a round sieve (100 μm) of No. 149, and the granulated product that did not pass through was collected to obtain a drug substance-containing nucleus.

[Drug layer spray solution]
・ Hydroxypropylcellulose (Type L) (Nippon Soda Co., Ltd.)
25 parts ・ Mannitol 25 parts ・ Crown talc (Matsumura Sangyo Co., Ltd.) 20 parts ・ Purified water 930 parts

Preparation of intermediate layer coating particles 600 g of drug substance-containing nuclei are charged into a fluidized bed granulator, adjusted to an air supply temperature of 60 ° C., an exhaust temperature of about 35 ° C., and a liquid speed of 2 g / min to 3 g / min. 1387.5 g (specified amount) of the intermediate layer spray solution was spray coated to obtain intermediate layer coated particles.

[Interlayer spray]
・ 50 parts of mannitol ・ Hydroxypropylcellulose (type SSL) (manufactured by Nippon Soda Co., Ltd.)
50 parts ・ Talc (Matsumura Sangyo Co., Ltd.) 20 parts ・ Purified water 880 parts

Preparation of gastric fine granules 650g of intermediate layer coating particles are charged into a fluidized bed granulator, the supply temperature is set to room temperature, the liquid speed is adjusted to 2g / min to 3g / min, and the elution control layer spray having the following composition prepared in advance is prepared. At the time when 2232.1 g (specified amount) of liquid was sprayed into the fluidized bed granulator, the granulation was stopped and the granulated material was recovered. Subsequently, 650 g of the recovered granulated material is charged into a fluidized bed granulator and spray-coated with 665.0 g of a mannitol spray solution having the following composition prepared in advance to obtain gastric soluble granules (fine granules containing the drug substance). It was.

[Elution control layer spray]
・ Eudragit EPO
(Trade name, manufactured by Evonik Rohm Gmbh) 98.7 parts, glyceryl monostearate (manufactured by Riken Vitamin Co., Ltd.) 4.9 parts, polysorbate 80 2.0 parts, sodium lauryl sulfate 9.9 parts, stearic acid 14.8 Part ・ Yellow ferric oxide

[Mannitol spray solution]
・ 140 parts of mannitol ・ 860 parts of purified water

Preparation of orally disintegrating tablets D-mannitol / xylitol / crystalline cellulose / crospovidone / anhydrous calcium hydrogen phosphate mixture (Fuji Chemical Industry Co., Ltd .; Fmelt TypeC (trade name)) 299 parts, ethyl cellulose 25 parts, and cloth 52.5 parts of povidone (BASF; Kollidon CL-F (trade name)), 7.5 parts of sodium stearyl fumarate (JRS PHARMA; PRUV), 10 parts of calcium silicate, 5 parts of sucralose, 1 part of a fragrance and 600 parts of gastric soluble granules were mixed with a V-type mixer (manufactured by Tsutsui Riken Kikai Co., Ltd.) to obtain a tableting powder (mixed powder).
Using a tableting machine (RIVA SA; manufactured by PICCOLA NOVA B-10), this tableting powder (mixed powder) is 10.5 mmφ, two-step R-side punch so that 75 mg of clopidogrel per tablet is contained. Was tableted to obtain an orally disintegrating tablet. Tableting was performed with the pre-load thickness and the main-press thickness being constant.

Evaluation of Orally Disintegrating Tablets The mass of one orally disintegrating tablet obtained in Example 1 was 444 mg, and the content of clopidogrel was 75 mg. The orally disintegrating tablet obtained in Example 1 had an average particle diameter of the drug substance-containing nucleus of 197 μm, and the finished gastric fine granules had an average particle diameter of 251 μm. The tablet diameter of the orally disintegrating tablet obtained in Example 1 was 10.5 mmφ, and an orally disintegrating tablet with a good tablet size was obtained. When the orally disintegrating tablet obtained in Example 1 was actually contained in the mouth and the taste and feeling of taking were evaluated, the extremely strong bitterness of the drug substance was masked for 30 seconds or more, and when 30 seconds passed, It was confirmed that the tablet was disintegrated.

The content of clopidogrel sulfate in the drug substance layer of the orally disintegrating tablet obtained in Example 1 was 92.2% by mass, and 17.0% by mass in one tablet.
When the content rate per orally disintegrating tablet is maintained, the drug substance content rate decreases, so that both the tablet mass and the tablet diameter increase in calculation as shown in Table 1. Table 1 shows a trial calculation when the tablet diameter is assumed to be similar even when the tablet mass is increased, based on the same 10.5 mmφ as in Example 1 for the tablet diameter. The tablet diameter is set in increments of 0.5 mm. Since the feeling of administration decreases as the tablet diameter increases, the drug substance content in the drug substance layer (the drug substance layer drug substance content) is preferably higher. In the prescriptions of the examples, since the drug substance content is less than 70% by mass, the drug content tends to decrease due to the increase in tablet diameter, so the drug substance content in the drug substance layer is 70% by mass. % Or more is preferable.

(Example 2)
An orally disintegrating tablet was produced by the same production method as in Example 1 using clopidogrel sulfate having different average particle diameters of the drug substance powder.
The particle size distribution of the drug substance powder used in Example 1 and Example 2 is shown in FIGS.
1 and 2, the vertical axis represents the frequency volume ratio (%), and the horizontal axis represents the average particle diameter (μm) of the drug substance powder.

Evaluation of Stability In the orally disintegrating tablet obtained in Example 2, the average particle size of the drug substance-containing nucleus was 189 μm, and the average particle size of the finished fine granules was 253 μm. The tablet diameter of the orally disintegrating tablet obtained in Example 2 was 10.5 mmφ, and an orally disintegrating tablet with a good tablet size was obtained.
Moreover, when the orally disintegrating tablet obtained in Example 2 was actually included in the mouth and the taste and feeling of taking were evaluated, the extremely strong bitterness of the drug substance was masked for 30 seconds or more, and when 30 seconds had elapsed. It was confirmed that the tablet was disintegrated in the mouth.
Table 2 shows the stability evaluation results of the orally disintegrating tablets obtained in Example 1 and Example 2. As shown in Table 2, heat aging at 70 ° C. for 2 days has no effect on the stability of the drug substance in both examples, and even if the average particle size of the drug substance powder used is changed, good oral disintegration It was confirmed that the tablet could be produced.
The ratio (D90 / D10) of the particle diameter (D90) of 90% cumulative volume percentage to the particle diameter (D10) of 10% cumulative volume percentage of the drug substance-containing nuclei obtained in Example 1 and Example 2, respectively. 1.96 and 1.72.

Example 3
Preparation of drug substance-containing nucleus 390 g of spherical spheres of 50 to 150 μm mannitol and 65 g of clopidogrel sulfate are charged into a fluidized bed granulator, and the supply temperature is 60 ° C., the exhaust temperature is about 35 ° C., the liquid speed is 2 g / min to 3 g / Granulation was carried out by adding the bulk powder of clopidogrel sulfate while spraying a pre-prepared drug substance layer spray solution having the following composition into a fluid bed granulator. The addition of the bulk powder of clopidogrel sulfate was performed by dividing the total 360 g into 16 times at a pace of 4 g / min to 8 g / min 30 minutes after the start of liquid feeding. Before adding, collect a part of the granulated material in the fluidized bed granulator and pass it through a round sieve (53 μm) of No. 280, and confirm that the proportion of the granulated material passed is 5% or less. did. In addition, granulation was performed so that the feed rate of the drug substance layer spray liquid during the addition of the bulk powder of clopidogrel sulfate was 344.1 g to obtain a drug substance-containing nucleus.

[Drug layer spray solution]
・ Hydroxypropylcellulose (type L) 25 parts ・ Mannitol 25 parts ・ Crown talc 20 parts ・ Purified water 930 parts

(Comparative Example 1)
Preparation of drug substance-containing nuclei 10 g of spherical spherical granules of 50 μm to 150 μm of mannitol were charged into a micro fluidized bed granulator (Dalton Co., Ltd .; micro fluid bed / granulation / coating device (with draft tube)). The feed temperature is adjusted to 60 ° C., the exhaust temperature is about 35 ° C., and the liquid speed is adjusted to 0.1 g / min to 0.2 g / min. Obtained.

[Drug layer spray solution]
・ Clopidogrel sulfate 363.3 parts ・ Hydroxypropyl cellulose (type L) 7.3 parts ・ Mannitol 7.3 parts ・ Crown talc 6 parts ・ Purified water 616 parts

Optical microscope photographs of the drug substance-containing nuclei obtained in Example 3 and Comparative Example 1 are shown in FIGS. As shown in FIG. 3, since the drug substance-containing nucleus obtained in Example 3 has a rough surface, the drug substance adheres or aggregates to form a drug substance layer, and the drug substance layer is in the form of particles. It can be seen that it contains clopidogrel sulfate. Similarly, it can be confirmed that the drug substance-containing nuclei of Example 1, Example 2, and Example 4 described later contain particulate drug substances.
On the other hand, as shown in FIG. 4, it can be seen that the drug substance-containing nucleus obtained in Comparative Example 1 has a glossy surface and is smooth.

Example 4
Preparation of drug substance-containing core 252.7 g of granulated material of 150 μm to 250 μm of mannitol, talc, and hydroxypropylcellulose, 96.9 g of talc, and 100 g of rabeprazole sodium were charged into a fluidized bed granulator, and the air supply temperature was 60 ° C. The exhaust temperature was adjusted to about 30 ° C. and the liquid speed was adjusted to 2 g / min to 3 g / min. The addition of the raw powder of rabeprazole sodium was carried out in a total of 300 g divided into 10 times at a pace of 1 g / min to 2 g / min after 42 minutes from the start of liquid feeding. Before adding, collect a part of the granulated material in the fluidized bed granulator and pass it through a round sieve (53 μm) of No. 280, and confirm that the proportion of the granulated material passed is 5% or less. did.
In addition, granulation was performed so that the feed rate of the drug substance layer spray liquid during the addition of the raw powder of rabeprazole sodium was 669 g to obtain a drug substance-containing nucleus. Subsequently, 200 g (a prescribed amount) of the intermediate layer 1a spray liquid having the following composition prepared in advance was spray coated, and then dried at a supply air temperature of 80 ° C. for 30 minutes.

[Drug layer spray solution]
・ Sodium hydroxide 30 parts ・ Mannitol 50 parts ・ Crown talc 20 parts ・ Purified water 900 parts

[Intermediate layer 1a spray]
・ Sodium hydroxide 15 parts ・ Mannitol 50 parts ・ Crown talc 20 parts ・ Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 50 parts ・ Purified water 865 parts

G of prepared drug-containing nucleus total amount 387.5g of intermediate layer coated particles in a fluidized bed granulator, inlet air temperature 60 ° C., supply air volume ^{40m 3} / ^h~50m 3 / h, adjusted with a flow rate of about 5 g / min After spray-coating in order, 2084.4 g of the intermediate layer 1b spray solution having the following composition prepared in advance, 2406.4 g of the intermediate layer 2 spray solution, and 916.9 g of the intermediate layer 3 spray solution, Drying was performed for 75 minutes at a temperature of 80 ° C.
The obtained granulated product was sieved with a No. 42 round sieve (355 μm) and a No. 60 round sieve (250 μm) to obtain intermediate layer coated particles.

[Intermediate layer 1b spray]
・ Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 50 parts ・ Talc 20 parts ・ Mannitol 50 parts ・ Sodium hydroxide 12 parts ・ Purified water 868 parts

[Intermediate layer 2 spray]
・ Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 50 parts ・ Talc 20 parts ・ Mannitol 50 parts ・ Purified water 880 parts

[Intermediate layer 3 spray]
・ Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 50 parts ・ Talc 20 parts ・ Calcium chloride 50 parts ・ Light anhydrous silicic acid 50 parts ・ Purified water 830 parts

G of prepared intermediate layer coating particles 400g intestinal溶細grains in a fluidized bed granulator, inlet air temperature 40 to 60 ° C., supply air volume ^{50m 3} / ^h~70m 3 / h, a flow rate of 5g / min~10g / min 653 g of enteric layer 1 spray solution of the following composition prepared in advance, 5100 g of enteric layer 2 spray solution, and 519 g of mannitol solution were spray-coated in order, and the air supply temperature remained at 60 ° C. Drying was performed for 60 minutes, and drying was further performed at an air supply temperature of 80 ° C. for 60 minutes.
The obtained granulated product was passed through a No. 30 round sieve (500 μm) and a No. 42 round sieve (355 μm) to obtain enteric fine granules (fine granules containing the drug substance).

[Enteric layer 1 spray solution]
・ Methacrylic acid copolymer LD (30% by weight aqueous dispersion)
266.7 parts-Ethyl acrylate / methyl methacrylate copolymer dispersion (30% by weight aqueous dispersion) 66.7 parts-Macrogol 6000 10 parts-Glycerol monostearate 6 parts-Polysorbate 80 1.5 parts-Anhydrous citric acid 0.025 parts of acid, 422 parts of purified water

[Enteric layer 2 spray solution]
・ Methacrylic acid copolymer LD (30% by weight aqueous dispersion)
266.7 parts, ethyl acrylate / methyl methacrylate copolymer dispersion (30% by weight aqueous dispersion) 66.7 parts, triethyl citrate 10 parts, glyceryl monostearate 6 parts, polysorbate 80 1.5 parts, anhydrous citric acid Acid 0.025 parts, yellow iron sesquioxide 0.1 parts, purified water 422 parts

[Mannitol solution]
・ 140 parts of mannitol ・ 860 parts of purified water

Preparation of Orally Disintegrating Tablets 330 parts of D-mannitol / xylitol / crystalline cellulose / crospovidone / anhydrous calcium hydrogen phosphate mixture (Fuji Chemical Industry Co., Ltd .; Fmelt TypeC (trade name)) and crystalline cellulose (Asahi Kasei Chemicals ( 150 parts of Theolas KG-1000 (trade name), 60 parts of D-mannitol (Merck Corp .; Partec M100 (trade name)), low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.) L-HPC LH-31) 66 parts, 37.4 parts of the resulting granulated product, 0.4 part of sucralose, 0.08 part of fragrance, and magnesium aluminate metasilicate 1 .6 parts and 0.5 parts of sodium stearyl fumarate were mixed to obtain an excipient.
346.50 parts of the obtained excipient and 231.0 parts of fine granules were mixed to obtain a tableting powder (mixed powder).
The obtained tableting powder (mixed powder) was tableted with a tableting machine (RIVA SA, manufactured by PICCOLA NOVA B-10) with a 9.5 mmφ, two-stage R-side punch and disintegrated in the oral cavity. I got a tablet.

(Comparative Example 2)
Preparation of drug substance-containing nucleus 600 g of spherical granules (manufactured by Freund Sangyo Co., Ltd .; Non-Parel 108) of mannitol are charged into a fluidized bed granulator (manufactured by Paulek Co., Ltd .; MP-01 (SPC)) and supplied. air temperature of about 60 ° C., supply air volume ^{30m 3} / ^h~50m 3 / h, adjusted with a flow rate of about 5 g / min, and 1457g raw chemical pre-prepared following composition, and 652g of the intermediate layer 1a spray solution After sequentially spray-coating the spherical granules, drying was performed for 30 minutes at an air supply temperature of 80 ° C.
The resulting granulated product was sieved with a No. 50 round sieve (300 μm) and an No. 80 round sieve (180 μm) to obtain a drug substance-containing nucleus.

[Drug substance]
-269 parts of rabeprazole sodium-40.4 parts of hydroxypropyl cellulose (type SSL)-26.9 parts of sodium hydroxide-1457 parts of purified water

[Intermediate layer 1a spray]
・ Hydroxypropyl methylcellulose (type 2910, viscosity: 4.5 mPa · s) 35 parts ・ Talc 14 parts ・ Mannitol 35 parts ・ Sodium hydroxide 8.4 parts ・ Purified water 607.6 parts

G of prepared drug-containing nucleus 600g of the intermediate layer coated particles in a fluidized bed granulator, supply air temperature of about 60 ° C., supply air volume ^{40m 3} / ^h~50m 3 / h, adjusted with a flow rate of about 5 g / min, After spray-coating 419 g of the intermediate layer 1b spray solution having the following composition prepared in advance and 1115 g of the intermediate layer 2 spray solution in order on the drug substance-containing core, drying was performed at a supply temperature of 80 ° C. for 30 minutes.
The obtained granulated product was sieved with a round sieve of No. 42 (355 μm) and a round sieve of No. 60 (250 μm) to obtain intermediate layer coated particles (1).
G of intermediate layer-coated particles (1) 600 g to a fluidized bed granulator, to adjust the air supply temperature 60 ° C., supply air volume ^{40m 3} / ^h~50m 3 / h, at a flow rate of about 5 g / min, previously prepared following After spray coating the intermediate layer coating particles (1) with 353 g of the intermediate layer 2 spray liquid and 579 g of the intermediate layer 3 spray liquid in order, drying was performed at a supply air temperature of 80 ° C. for 30 minutes.
The obtained granulated product was sieved with a No. 42 round sieve (355 μm) and a No. 60 round sieve (250 μm) to obtain intermediate layer coated particles.

[Intermediate layer 1b spray]
・ Hydroxypropyl methylcellulose (type 2910, viscosity: 4.5 mPa · s) 25 parts ・ Talc 10 parts ・ Mannitol 25 parts ・ Sodium hydroxide 6 parts ・ Purified water 434 parts

[Intermediate layer 2 spray]
・ Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 60 parts ・ Talc 24 parts ・ Mannitol 60 parts ・ Purified water 1056 parts

[Intermediate layer 3 spray]
・ Hydroxypropyl methylcellulose (type 2910, viscosity 4.5 mPa · s) 30 parts ・ Talc 12 parts ・ Calcium chloride 30 parts ・ Light anhydrous silicic acid 30 parts ・ Purified water 498 parts

G of prepared intermediate layer coating particles 500g intestinal溶細grains in a fluidized bed granulator, inlet air temperature 40 to 60 ° C., supply air volume ^{50m 3} / ^h~70m 3 / h, a flow rate of 5g / min~10g / min 677 g of enteric layer 1 spray solution of the following composition prepared in advance, 5163 g of enteric layer 2 spray solution, and 504 g of mannitol solution were spray-coated on the intermediate layer coating particles in this order, and then the air supply temperature It dried for 60 minutes with 60 degreeC, and also dried for 60 minutes by making supply air temperature into 80 degreeC.
The obtained granulated product was passed through a No. 30 round sieve (500 μm) and a No. 42 round sieve (355 μm) to obtain enteric fine granules (fine granules containing the drug substance).

[Enteric layer 1 spray solution]
・ Methacrylic acid copolymer LD (30% by weight aqueous dispersion)
266.7 parts-Ethyl acrylate / methyl methacrylate copolymer dispersion (30% by weight aqueous dispersion) 66.7 parts-Macrogol 6000 10 parts-Glycerol monostearate 6 parts-Polysorbate 80 1.5 parts-Anhydrous citric acid 0.025 parts of acid, 422 parts of purified water

[Enteric layer 2 spray solution]
・ Methacrylic acid copolymer LD (30% by weight aqueous dispersion)
266.7 parts, ethyl acrylate / methyl methacrylate copolymer dispersion (30% by weight aqueous dispersion) 66.7 parts, triethyl citrate 10 parts, glyceryl monostearate 6 parts, polysorbate 80 1.5 parts, anhydrous citric acid Acid 0.025 parts, yellow iron sesquioxide 0.1 parts, purified water 422 parts

[Mannitol solution]
・ 140 parts of mannitol ・ 860 parts of purified water

Preparation of Orally Disintegrating Tablets 330 parts of D-mannitol / xylitol / crystalline cellulose / crospovidone / anhydrous calcium hydrogen phosphate mixture (Fuji Chemical Industry Co., Ltd .; Fmelt TypeC (trade name)) and crystalline cellulose (Asahi Kasei Chemicals ( 150 parts of Theolas KG-1000 (trade name), 60 parts of D-mannitol (Merck Corp .; Partec M100 (trade name)), low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.) L-HPC LH-31) 66 parts, 37.4 parts of the resulting granulated product, 0.4 part of sucralose, 0.08 part of fragrance, and magnesium aluminate metasilicate 1 .6 parts and 0.5 parts of sodium stearyl fumarate were mixed to obtain an excipient.
279.6 parts of the obtained excipient and 186.4 parts of fine granules were mixed to obtain a tableting powder (mixed powder).
The obtained tableting powder (mixed powder) was tableted with a tableting machine (RIVA SA, manufactured by PICCOLA NOVA B-10) with a 9.5 mmφ, two-stage R-side punch and disintegrated in the oral cavity. I got a tablet.

Evaluation of stability Decomposition product generation rate after thermal aging of Example 3 and Comparative Example 1 and Example 4 and Comparative Example 2, average particle diameter of drug substance-containing nuclei (measured by laser diffraction particle size distribution measurement method) Table 3 shows the drug substance content of the drug substance layer. The degradation product formation rate was determined by subtracting the peak area% of the drug substance after the lapse of time from the peak area% of the drug substance after manufacture by HPLC analysis.
The fine particles obtained in Comparative Example 1 had strong adhesion, and the average particle size could not be measured by the above method, so the average particle size was measured from a photomicrograph.
In Example 3 and Example 4 in which the drug substance was granulated as a solid, the degradation product generation rate was lower than in Comparative Example 1 and Comparative Example 2 in which the drug substance was dissolved and granulated. It is considered that the stability of the drug substance was improved by granulating the solid.

(Example 5)
Preparation of active ingredient-containing nucleus 300 g of spherical globules of 150 μm to 250 μm, 100 g of talc and 50 g of clopidogrel sulfate of mannitol (Freund Sangyo Co., Ltd.) are charged into a spouted fluidized bed granulator, supply temperature 60 ° C., exhaust temperature Adjust to about 35 ° C, liquid speed 1g / min to 2g / min, and add the bulk powder of clopidogrel sulfate while spraying the pre-prepared drug substance layer spray liquid in the fluidized bed granulator to granulate Went. Addition of the bulk powder of clopidogrel sulfate was carried out by dividing the total 640 g into 22 times at a pace of 4 g / min to 8 g / min from 30 minutes after the start of liquid feeding. Before adding, collect a part of the granulated material in the fluidized bed granulator and pass it through a round sieve (53 μm) of No. 280, and confirm that the proportion of the granulated material passed is 5% or less. did. In addition, granulation was performed so that the feed rate of the drug substance layer spray liquid during the addition of the bulk powder of clopidogrel sulfate was 241.6 g.
500 g of the granulated product obtained above is charged into a fluidized bed granulator, adjusted to an air supply temperature of 60 ° C., an exhaust temperature of about 35 ° C., and a liquid speed of 2 g / min to 4 g / min. Granulation was carried out again while spraying into the granulator and adding the bulk powder of clopidogrel sulfate.
The addition of the bulk powder of clopidogrel sulfate was carried out 24 times in a total of 960 g at a pace of 8 g / min from 10 minutes after the start of liquid feeding. Before adding, collect a part of the granulated material in the fluidized bed granulator and pass it through a round sieve (53 μm) of No. 280, and confirm that the proportion of the granulated material passed is 5% or less. did.
In addition, granulation was performed such that the feed rate of the drug substance layer spray liquid during the addition of the bulk powder of clopidogrel sulfate was 633.0 g. The obtained granulated product was passed through a round sieve (100 μm) of No. 149, and the granulated product that did not pass through was collected to obtain a drug substance-containing nucleus.

[Drug layer spray solution]
・ Mannitol 50 parts ・ Crown talc (Matsumura Sangyo Co., Ltd.) 20 parts ・ Purified water 950 parts

Preparation of intermediate layer coating particles 600 g of drug substance-containing nuclei are charged into a fluidized bed granulator, adjusted to an air supply temperature of 60 ° C., an exhaust temperature of about 35 ° C., and a liquid speed of 2 g / min to 3 g / min. The intermediate layer spray solution 617.0 g (specified amount) was spray coated to obtain intermediate layer coated particles.

[Interlayer spray]
・ 50 parts of mannitol ・ Hydroxypropylcellulose (type SSL) (manufactured by Nippon Soda Co., Ltd.)
50 parts ・ Talc (Matsumura Sangyo Co., Ltd.) 20 parts ・ Purified water 880 parts

Preparation of gastric fine granules 650g of intermediate layer coating particles are charged into a fluidized bed granulator, the supply temperature is set to room temperature, the liquid speed is adjusted to 2g / min to 3g / min, and the elution control layer spray having the following composition prepared in advance is prepared. When 613.8 g (specified amount) of the liquid was sprayed, the granulation was stopped to obtain a granulated product. Subsequently, 650 g of the recovered granulated material was charged into a fluidized bed granulator, and 417.9 g of mannitol spray liquid having the following composition prepared in advance was spray coated to obtain gastric soluble granules (fine granules containing the drug substance). It was.

[Elution control layer spray]
・ Eudragit EPO
(Trade name, manufactured by Evonik Rohm Gmbh) 98.7 parts, glyceryl monostearate (manufactured by Riken Vitamin Co., Ltd.) 4.9 parts, polysorbate 80 2.0 parts, sodium lauryl sulfate 9.9 parts, stearic acid 14.8 Part ・ Yellow ferric oxide

[Mannitol spray solution]
・ 140 parts of mannitol ・ 860 parts of purified water

Preparation of orally disintegrating tablets D-mannitol / xylitol / crystalline cellulose / crospovidone / anhydrous calcium hydrogen phosphate mixture (Fuji Chemical Industry Co., Ltd .; Fmelt TypeC (trade name)) 299 parts, ethyl cellulose 25 parts, and cloth 52.5 parts of povidone (BASF; Kollidon CL-F (trade name)), 7.5 parts of sodium stearyl fumarate (JRS PHARMA; PRUV), 10 parts of calcium silicate, 5 parts of sucralose, 1 part of a fragrance and 600 parts of gastric soluble granules were mixed with a V-type mixer (manufactured by Tsutsui Riken Kikai Co., Ltd.) to obtain a tableting powder (mixed powder).
Using a tableting machine (RIVA SA; manufactured by PICCOLA NOVA B-10), this tableting powder (mixed powder) is packed with 8.0 mmφ, two-stage R-side punch so that 75 mg of clopidogrel is contained per tablet. Was tableted to obtain an orally disintegrating tablet. Tableting was performed with the preload thickness and the main pressure thickness kept constant.

Evaluation of Orally Disintegrating Tablets The average particle size of the drug substance-containing core obtained in Example 5 was 404 μm, and the average particle size of the finished fine granules was 464 μm. The tablet diameter was 8.0 mmφ, and an orally disintegrating tablet with a good tablet size was obtained. Moreover, when the orally disintegrating tablet obtained in Example 5 was actually contained in the mouth and the taste and feeling of administration were evaluated, the extremely strong bitterness of the drug substance was masked for 30 seconds or more, and when 30 seconds had elapsed. It was confirmed that the tablet was disintegrated in the mouth. Moreover, there was little rough feeling by a fine granule and the oral disintegrating tablet with favorable mouthfeel was able to be obtained.

(Example 6)
The orally disintegrating tablet produced in the same manner as in Example 1 was subjected to PTP (Press Through Pack) packaging made of polypropylene without drying.

(Example 7)
The orally disintegrating tablet produced in the same manner as in Example 1 was placed in a sealed container together with silica gel, taken out after 8 hours, and subjected to PTP (Press Through Pack) packaging made of polypropylene.

(Example 8)
With respect to the orally disintegrating tablet produced in the same manner as in Example 1, dry air having a relative humidity of 5% or less at a temperature of 25 ° C. was dried with a dry dehumidifier (trade name: Honey Dry, Daikin Co., Ltd.). Air was supplied for 8 hours, and PTP (Press Through Pack) packaging made of polypropylene was applied in a room at a temperature of 25 ° C. and a relative humidity of 5% or less.

Evaluation of stability Using the Karl Fischer moisture meter (Mitsubishi Chemical Analytech Co., Ltd .; trace moisture measuring device CA-200 type, moisture vaporizer VA-200 type) of the tablets obtained in Examples 6-8. Table 4 shows the water content (% by mass) and the decomposition product generation rate (%) when heat-aging at 70 ° C. for 1 week. The degradation product formation rate was determined by subtracting the peak area% of the drug substance after the lapse of time from the peak area% of the drug substance after manufacture by HPLC analysis.
Compared to Example 6, in the tablet of Example 7 in which the moisture content decreased, the decomposition product generation rate was approximately halved, and in the dried Example 8, the decomposition product generation rate was further decreased by half.
From this result, the moisture content of the tablet at the time of packaging is preferably 1% by mass or less, and more preferably 0.5% by mass or less.

The disclosures of Japanese Patent Application No. 2013-205195 filed on September 30, 2013 and Japanese Patent Application No. 2014-055467 filed on March 18, 2014 are hereby incorporated by reference in their entirety. Is taken in.
All documents, patent applications, and technical standards described in this specification are specifically and individually incorporated by reference as if individual documents, patent applications, and technical standards were incorporated by reference. To the extent it is incorporated herein by reference.

Claims (13)

  With the contents in the fluidized bed granulator fluidized, the drug substance powder is intermittently or continuously added to the fluidized bed granulator while the binder solution is intermittently or continuously charged into the fluidized bed granulator. A method for producing a drug substance-containing nucleus having an average particle size of 100 μm to 500 μm, including charging and granulating.   The manufacturing method of Claim 1 including maintaining the ratio of the active ingredient powder in a fluid bed granulator at 10 mass% or less with respect to the total solid in a fluid bed granulator.   The manufacturing method of Claim 1 or Claim 2 including making the temperature in a fluid bed granulator into 25 to 80 degreeC.   The manufacturing method according to any one of claims 1 to 3, wherein the drug substance-containing portion in the drug substance-containing nucleus contains 70% by mass to 100% by mass of the drug substance.   The manufacturing method according to any one of claims 1 to 4, wherein the drug substance-containing portion in the drug substance-containing nucleus contains 0% by mass to 10% by mass of a binder.   The production method according to any one of claims 1 to 5, wherein the drug substance powder has an average particle size of 0.1 to 20 µm.   A drug substance-containing nucleus obtained by the production method according to any one of claims 1 to 6.   A pharmaceutical composition comprising the drug substance-containing nucleus according to claim 7.   An orally disintegrating tablet, wherein the drug substance-containing core contains particulate clopidogrel sulfate or particulate rabeprazole sodium, and the drug substance-containing nucleus has an average particle size of 100 μm to 500 μm.   The orally disintegrating tablet according to claim 9, wherein the drug substance-containing portion in the drug substance-containing nucleus contains 70% by mass to 100% by mass of clopidogrel sulfate or rabeprazole sodium.   The orally disintegrating tablet according to claim 9 or 10, wherein the drug substance-containing portion in the drug substance-containing nucleus contains 0% by mass to 10% by mass of a binder.   The orally disintegrating tablet according to any one of claims 9 to 11, wherein the ratio of the particle diameter of 90% cumulative volume percentage to the particle diameter of 10% cumulative volume percentage of the drug substance-containing nucleus is 4.0 or less. .   The orally disintegrating tablet according to any one of claims 9 to 12, having a water content of 1.0% by mass or less.