JPWO2012091049A1 - Orally disintegrating tablets - Google Patents

Abstract

Needs special formulation technology that has rapid disintegration in the oral cavity, is not damaged in the distribution process, has an appropriate hardness that can withstand practical use even after moisture absorption, and does not cause a delay in disintegration time The present invention provides an orally disintegrating tablet that can be easily manufactured by general equipment. (1) Drug-containing particles having an average particle size of 150 to 300 μm, (2) spherical mannitol crystal particles, (3) partially pregelatinized starch having a viscosity of 5 to 45 mPa · s at 25 ° C., 10% by mass water suspension, And (4) an orally disintegrating tablet containing starch powder.

Description

  The present invention relates to a tablet having rapid disintegration even in a small amount of water or without water in the oral cavity.

  In today's aging society, as the number of elderly people who are forced to take many drugs on a daily basis due to the occurrence of various diseases has increased, `` the action of taking drugs '' due to the deterioration of swallowing function associated with aging The number of patients who are difficult to increase is also increasing. This situation contributes to a decrease in medication adherence. For patients with reduced swallowing function, rather than tablets and capsules, granules such as granules and fine granules, or orally disintegrating tablets that disintegrate rapidly with a small amount of water or saliva in the oral cavity are preferred. Liked.

  An orally disintegrating tablet is desired to have both rapid disintegration and high hardness. As an excipient for an orally disintegrating tablet, a sugar alcohol having an appropriate sweetness and coolness is suitable, and among them, D-mannitol having a low hygroscopic property is particularly suitable. However, ordinary powdered mannitol has low moldability, and in addition, tableting troubles such as binding and sticking often occur during tableting. In order to solve these problems, a method of blending granulated mannitol and starches has been proposed in the past, and an orally disintegrating tablet that has both rapid disintegration and high hardness and excellent productivity is proposed. Various developments have been made to obtain this.

  For example, Patent Document 1 discloses an orally disintegrating tablet further blended with granulated mannitol having excellent moldability but poor disintegration for the purpose of supplementing the moldability of powdered mannitol. By complementing each other's characteristics, the mechanical strength and disintegration of the orally disintegrating tablet are improved.

  Patent Document 2 discloses an orally disintegrating tablet obtained by blending processed starches having a specific degree of pregelatinization with powdered mannitol in addition to drugs and sugars, granulating with starch paste, and tableting. It is said that starches having a specific degree of pregelatinization are useful as an excipient for orally disintegrating tablets having both rapid disintegration and high hardness.

  On the other hand, in Patent Document 3, an orally disintegrating tablet having rapid disintegration and high hardness is obtained by improving mannitol itself and making it into spherical crystal particles using a spray drying method. It has been shown that

JP 2008-260709 A International Publication No. 2008/032767 International Publication No. 2010/021300

  However, when granulated mannitol as in Patent Document 1 is used together with powdered mannitol, in the tableting process, segregation occurs due to the difference in mutual average particle diameter, bulk density and fluidity, and the disintegration and hardness of each tablet It is likely to fluctuate. Further, as in Patent Document 2, if starches that are processed and exhibit a specific degree of pregelatinization are used as excipients, and starch starch is separately prepared and granulated, the number of starch processing steps increases, There is a risk that the manufacturing method becomes complicated. In addition, even if starches having the degree of pregelatinization are dispersed in the tablet, it may be considered that the disintegration property and hardness of the tablet may greatly vary depending on the form of the saccharide to be blended.

  On the other hand, Patent Document 3 describes that partially pregelatinized starch can be used in addition to hydroxypropylcellulose and the like as a binder, but any partially pregelatinized starch can be specifically selected. There has been no discussion about this. In particular, in the tableting process, when there is a risk of segregation of drugs and formed components, it is generally assumed that granulation using a binder is employed. The choice of binder used is very important because it can hinder disintegration. In addition, Patent Document 3 shows only a specific example of the drug content of 1 part by weight, and no consideration is given to the uniformity of the content. Therefore, it is still unclear whether sufficient disintegration and high hardness can be exhibited even when the drug content is increased in order to expand the application range as a tablet.

  Furthermore, none of the above documents pays attention to ensuring the physical stability of the tablet after moisture absorption, and it can withstand practical use even after moisture absorption while combining quick disintegration and high hardness. In order to obtain an orally disintegrating tablet having an appropriate hardness and sufficient disintegration property, there is still room for improvement.

  An object of the present invention is to provide an oral cavity that has rapid disintegration in the oral cavity, is not damaged in the distribution process, has an appropriate hardness that can withstand practical use even after moisture absorption, and does not cause a delay in disintegration time. It is to provide a disintegrating tablet.

  The inventor has prepared pharmaceutical properties and by producing orally disintegrating tablets using drug-containing particles having a specific average particle size, spherical mannitol crystal particles, partially pregelatinized starch having a specific viscosity, and starch powder. The present inventors have found that an orally disintegrating tablet excellent in production suitability can be obtained, and have completed the present invention.

That is, the present invention provides (1) drug-containing particles having an average particle size of 150 to 300 μm,
(2) Spherical mannitol crystal particles,
(3) A partially pregelatinized starch having a viscosity of 5 to 45 mPa · s at 25 ° C. and a 10% by mass water suspension, and (4) an orally disintegrating tablet containing starch powder.

  The orally disintegrating tablet of the present invention has a moderate strength that does not cause damage in the distribution process while providing a good feeling of taking while exhibiting rapid disintegration in the oral cavity. Further, even after moisture absorption, the disintegration time is not delayed while effectively maintaining the practical hardness, so that it can withstand equipment such as an automatic tablet packaging machine during dispensing. Furthermore, even when a drug with an unpleasant taste is contained, the unpleasant taste can be effectively shielded, and even when a drug-containing particle having a range of particle sizes is included, the content is uniform in a wide range of drug contents. It is possible to ensure the sex.

Hereinafter, the present invention will be described in detail.
In the present specification, the average particle diameter referred to in the drug-containing particles (1) and the spherical mannitol crystal particles (2) is generally referred to as a median diameter, and gives a particle diameter that gives 50% of the powder particle cumulative distribution. Means.

The drug-containing particles (1) used in the present invention have an average particle size of 150 to 300 μm, preferably 150 to 250 μm, more preferably 150 to 200 μm. In this way, by adopting finer particles than the conventional one, it is possible to greatly contribute to exerting excellent dosing feeling in the obtained tablet. In the present specification, the average particle diameter of the drug-containing particles (1) is determined by dry / one-shot measurement using a laser diffraction / scattering particle size distribution analyzer “LMS-30” (manufactured by Seishin Enterprise Co., Ltd.). Means the measured value.
As the drug-containing particles having such a particle size, for example, drug-containing particles produced according to the production method described in Japanese Patent No. 4019374, Japanese Patent No. 4277904, or Japanese Patent No. 3317444 can be considered. Examples thereof include drug-containing particles produced according to the same method.

  The drug contained in the drug-containing particles (1) is not particularly limited as long as it is effective as a pharmaceutically active ingredient for treating or preventing a disease when taken, and may be appropriately selected as desired. it can. Such drugs include central nervous system drugs, peripheral nervous system drugs, sensory organ drugs, circulatory organ drugs, respiratory organ drugs, gastrointestinal drugs, hormone drugs, urogenital and anal drugs, vitamin drugs , Nourishing tonics, blood and body fluids, other metabolic drugs, cell stimulants, oncology drugs, allergic drugs, herbal medicines, herbal medicines, antibiotic preparations, chemotherapeutic agents, parasitic animal drugs, alkaloids One or more components selected from narcotics, non-alkaloid narcotics and the like are used, but are not limited thereto. Among these drugs, it is desirable that the drug has an unpleasant taste from the viewpoint of utilizing the effect of the present invention that can effectively block an unpleasant taste such as a bitter taste in the oral cavity. Specifically, ranitidine hydrochloride Examples include drugs for digestive organs including anti-ulcer agents such as salt, cimetidine, famotidine, and lafutidine, among which lafutidine is preferable. Further, lafutidine is (±) -2- (furfurylsulfinyl) -N- [4- [4- (piperidinomethyl) -2-pyridyl] oxy- (Z) -2-butenyl] acetamide. In this case, it includes the stereoisomers and optical isomers, and also includes salts or derivatives that can be easily derived by those skilled in the art, and is synthesized, for example, according to the method described in JP-A-63-225371. .

  The content of the drug is preferably 40% by mass or less, more preferably 5 to 35% by mass, and still more preferably 10 to 30% by mass in 100% by mass of the total amount of the drug-containing particles (1). If the content is within the above range, even if the drug has an unpleasant taste, the desired medicinal effect can be effectively exhibited while sufficiently suppressing the unpleasant taste.

  The drug-containing particles (1) preferably include a membrane layer (A) containing a drug and a water-swellable polymer on the surface of the core particles (P) not containing the drug and the water-swellable polymer, A plurality of film layers including a film layer (B) containing an insoluble polymer, a water-soluble substance and an inorganic compound are preferably formed. Thus, a plurality of film layers are formed on the surface of the core particle (P), these layers cover the core particles, and at least one of the plurality of film layers contains a drug. In addition, it is preferable that the core particles (P) do not contain a drug and a water-swellable polymer. That is, the plurality of membrane layers include at least two of a membrane layer (A) containing a drug and a water-swellable polymer and a membrane layer (B) containing at least a water-insoluble polymer, a water-soluble substance and an inorganic compound. This means that a layer (A) containing a drug and a water-swellable polymer is formed on the surface of the core particle (P) as the innermost layer.

  By using the drug-containing particles (1) as coated particles having the above layer structure, combined with spherical mannitol crystal particles (2), specific partially pregelatinized starch (3) and starch powder (4) described later, In the case where the drug has an unpleasant taste while exhibiting excellent quick disintegration while having an appropriate hardness and disintegration time, the unpleasant taste can be effectively shielded.

The water-swellable polymer contained in the membrane layer (A) together with the drug is hardly soluble in water (solubility is water-swelling as stipulated in the 16th revised Japanese Pharmacopoeia. The water-swelling polymer 1g is evaluated by the degree of dissolution in 30 minutes when the water-soluble polymer is put in water at 25 ± 5 ° C. and shaken strongly every 5 minutes for 30 seconds. It means a case where the amount of water required for dissolution is 10,000 mL or more), and is a high-molecular substance that swells and contains water, and is not particularly limited as long as it is a high-molecular substance other than a water-insoluble polymer. Examples thereof include hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl cellulose or a salt thereof, croscarmellose sodium, and crospovidone. Of these, low-substituted hydroxypropylcellulose is preferable. Here, the low-substituted hydroxypropyl cellulose has a hydroxypropoxyl group substitution degree (mass%) of 5.0 to 16.0 mass%, more preferably 10 to 13 mass%. Those having a degree of substitution of the hydroxyproposyl group of less than 5.0% have poor swelling power, and those having a degree of substitution of more than 16.0% tend to become sticky when water is included, and thus it is easy to feel stickiness when taken. .
The degree of substitution of hydroxypropylcellulose means the amount (%) of hydroxypropoxyl group substituted with the hydroxyl group of cellulose's pyranose ring. Specifically, the degree of substitution is defined in the 16th revised Japanese Pharmacopoeia. It means a value measured using a gas chromatographic method in accordance with a quantitative method for low-substituted hydroxypropylcellulose.

  The content of the water-swellable polymer is preferably 13 to 30% by mass, more preferably 15 to 25% by mass, and still more preferably 17 to 22% by mass in 100% by mass of the total amount of the drug-containing particles (1). %. If the content is within the above range, the other film layer to be formed can be sufficiently broken, and the drug contained in the film layer (A) can be effectively released. Further, as will be described later, the water-swellable polymer is efficiently disposed on the surface of the core particle (P), so that the force necessary to break the membrane layer can be obtained even with a small addition amount. It is thought that If the content exceeds the desired value, the ratio of the other coating agent in the entire drug-containing particles (1) decreases, so that the dissolution becomes too fast, and the balance between the dissolution and the bitterness shielding effect may deteriorate. There is.

  The thickness of the film layer (A) is preferably 70 μm or less, and more preferably 20 to 50 μm. When the thickness is in the above range, the size of the drug-containing particles (1) can be reduced as much as possible, so that no roughness is felt during taking.

  The membrane layer (A) is hydroxypropylcellulose (hereinafter referred to as “hydroxypropylcellulose” unless otherwise referred to as “low-substituted hydroxypropylcellulose”. ), Binders such as hypromellose, polyvinyl alcohol and povidone, various flavors such as orange and lemon, l-menthol, mint oil, neotame, thaumatin, aspartame, stevia, sucralose, sodium saccharin, sodium glutamate, acesulfame A taste-masking agent such as potassium may be used alone or in combination of two or more as required.

  The core particle (P) means a particle serving as a core of the coating, and is not particularly limited as long as the film layer (A) can be formed as an innermost film layer on the surface thereof. Examples thereof include spherical granulated products and commercially available spray granulated products. Further, these core particles may be produced and used by a known pulverization method or granulation method. As these core particles, commercially available products may be used as they are, or particles having a desired particle diameter may be prepared by sieving. Examples of such core particles include core particles composed of one or a combination of two or more selected from mannitol, crystalline cellulose, lactose, purified sucrose, corn starch and the like. The core particles (P) do not contain drugs and water-swellable polymers.

  The shape of the core particle (P) is preferably a spherical particle from the viewpoint of obtaining particles having uniform physical properties and more effectively disposing the water-swellable polymer on the surface of the core particle (P). . If the shape is irregular, the thickness of the formed film layer tends to be non-uniform, especially if the drug has an unpleasant taste, the unpleasant taste shielding effect may be insufficient. . The average particle diameter of the core particles (P) may be any size that does not feel rough in the oral cavity when the drug-containing particles (1) are prepared using this. Specifically, the average particle size is preferably 10 to 200 μm, more preferably 50 to 170 μm, and still more preferably 100 to 150 μm. When the size is such, the size of the obtained drug-containing particles (1) is also sufficiently small and does not feel rough in the oral cavity.

As such core particles (P), commercially available products “Nonparel-108 (100)” (Freund Sangyo Co., Ltd.), “Selfia CP-102”, “Selfia SCP-100” (all manufactured by Asahi Kasei Chemicals Corporation) ), Etc., “FlowLac90”, “FlowLac100”, “Cellactose80”, “MicroceLac100”, “StarLac100” (all manufactured by Megre), “Super Tab 11SD”, “Super Tab 14SD” (all manufactured by DMV-Fontraent) Spray granulated products such as the above can be used.
The proportion of the mass of the core particles (P) is preferably 30% by mass or less, more preferably 14 to 20% by mass in 100% by mass of the total amount of the drug-containing particles (1).

  As the water-insoluble polymer contained in the membrane layer (B), the water-insoluble polymer hardly dissolves in water (the solubility is 25% as defined in the 16th revised Japanese Pharmacopoeia general rules). Put in water at ± 5 ° C and shake for 30 seconds strongly every 5 minutes. Evaluate from the degree of dissolution within 30 minutes. "It hardly dissolves in water" means water required to dissolve 1 g of water-insoluble polymer. And a polymer substance that does not swell even if it contains water, that is, a polymer substance other than a water-swellable polymer and generally used as an additive for pharmaceuticals There is no particular limitation, and those usually used as a coating agent can be mentioned. Examples of such water-insoluble polymers include ethyl cellulose, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer, and ethyl cellulose is preferred. The ethyl cellulose used in the present invention is in accordance with the Japanese Pharmaceutical Additives Standard, that is, the ethoxyl group content is 46.5 to 51.0%, and the viscosity of a 5% ethyl cellulose / toluene / ethanol solution at 25 ± 0.1 ° C. Is preferably about 4 to about 100 cps, more preferably about 7 to about 20 cps.

  The content of the water-insoluble polymer is preferably 7 to 11% by mass and more preferably 8 to 10% by mass in 100% by mass of the total amount of the drug-containing particles (1). When the drug has an unpleasant taste if it is less than the lower limit, the unpleasant taste may be insufficiently masked, and when the upper limit is exceeded, the release of the drug may be delayed more than necessary. is there.

  The water-soluble substance contained in the membrane layer (B) together with the water-insoluble polymer is soluble to some extent in water (the solubility is water-soluble as defined in the 16th revision of the Japanese Pharmacopoeia. When the polymer is put in water at 25 ± 5 ° C and shaken vigorously every 5 minutes for 30 seconds, it is evaluated from the degree to which it dissolves within 30 minutes. Equivalent to the property indicated by the terms “easy” or “easy to dissolve”, meaning that the amount of water required to dissolve 1 g of water-soluble substance is less than 10 mL), or a viscous colloidal dispersion Any of those generally used as an additive for pharmaceuticals is not particularly limited, and examples thereof include those usually used as a coating agent. Examples of such water-soluble substances include purified sucrose, D-sorbitol, D-mannitol, hydroxypropylcellulose, hypromellose, povidone, methylcellulose, and carmellose sodium.

  The content of the water-soluble substance contained in the membrane layer (B) based on 100% by mass of the drug-containing particles (1) is 100% by mass of the drug-containing particles (1). The content of the water-insoluble polymer is 0.4 to 0.6 times, preferably 0.45 to 0.55 times, and most preferably 0.5 times.

  As the inorganic compound further contained in the membrane layer (B), those effective for preventing aggregation and adhesion of the drug-containing particles (1) are preferable. Examples of such inorganic compounds include talc, titanium oxide, magnesium stearate, light anhydrous silicic acid and the like. Of these, titanium oxide is preferable.

  The content of the inorganic compound is preferably 25 to 35% by mass, more preferably 27 to 32% by mass, in 100% by mass of the membrane layer (B). If it is less than the above lower limit, there is a possibility that sufficient effects for aggregation and adhesion prevention of the resulting drug-containing particles (1) may not be obtained, and if it exceeds the above upper limit, film formation may be difficult. Further, when the amount is within the above range, even better storage stability can be imparted.

  Further, in 100% by mass of the membrane layer (B), the content of the water-insoluble polymer: the content of the water-soluble substance: the content of the inorganic compound is 1: 0.4 to 0.6: 0.5 by mass ratio. -0.7 is preferable, and 1: 0.5: 0.6 is more preferable. When the content is within the above range, the drug-containing particles (1) are effectively prevented from aggregating and adhering, and the drug has good dissolution properties and the drug has an unpleasant taste. It is possible to maintain an excellent balance between the unpleasant taste shielding effect and the drug dissolution.

  As a plurality of film layers formed on the surface of the core particle, an intermediate film layer may be further included. The intermediate film layer may be a single layer or a plurality of layers, and is preferably formed between the film layer (A) as the innermost film layer and the film layer (B). That is, the membrane layer (B) containing a water-insoluble polymer, a water-soluble substance and an inorganic compound is preferably the outermost membrane layer. Thus, by forming the intermediate film layer between the innermost film layer and the outermost film layer, it is possible to improve storage stability, taste, and the like.

  The component contained in the interlayer film is not limited as long as it does not interfere with the effect of the drug-containing particles (1). Specifically, purified sucrose, D-sorbitol, D-mannitol, hydroxypropylcellulose, Examples include, but are not limited to, hypromellose, povidone, methylcellulose, and carmellose sodium. These may be used alone or in combination of two or more. Of these components, D-mannitol and hypromellose are preferable, and hypromellose is more preferable from the viewpoint of easy coating. Furthermore, talc, titanium oxide, magnesium stearate, light anhydrous silicic acid, and the like may be added as necessary for the purpose of reducing adhesion when coating the intermediate film layer.

  The mass of the intermediate film layer is not limited as long as it does not interfere with the effect of the drug-containing particles (1), and may vary depending on the size of the core particles (P). 15-25 mass parts is preferable with respect to 100 mass parts of total amount with A), and 18-22 mass parts is more preferable.

  The content of the drug-containing particles (1) in the orally disintegrating tablet of the present invention is 100% by mass based on the total amount of the tablet from the viewpoint of sufficiently exhibiting a desired medicinal effect without inhibiting the compatibility between appropriate hardness and disintegration time. In the inside, Preferably it is 1-30 mass%, More preferably, it is 10-30 mass%.

  The drug-containing particles (1) may be adjusted to an average particle size of 150 to 300 μm by sieving according to a conventional method. Furthermore, in order to make the drug-containing particles (1) have a plurality of film layers including the film layer (A) and the film layer (B) formed on the surface of the core particles (P), What is necessary is just to manufacture by spraying the coating liquid containing a component on a core particle (P). Specifically, using a fluidized bed granulator or the like, (i) First, a spray prepared by dissolving or dispersing a drug and water-swellable polymer as innermost layer components in an organic solvent such as ethanol or methanol. Spray the liquid onto the core particles (P). The content of the film component in the spray liquid is preferably up to 30% by mass. If it exceeds 30% by mass, the spray gun may be blocked and spraying may be difficult.

  (Ii) Subsequently, when forming an intermediate film layer, a desired film component is dissolved in water or the like to prepare a spray solution, and sprayed on the particles obtained in (i). 5-15 mass% is preferable and, as for content of the film | membrane component in a spray liquid, 8-12 mass% is more preferable. If the content is less than the above lower limit, the film layer formation efficiency may deteriorate and the productivity may decrease, and if the content exceeds the upper limit, the drug-containing particles (1) aggregate to form aggregates. There is a fear.

  (Iii) Finally, a spray solution prepared by dissolving or dispersing a water-insoluble polymer, a water-soluble substance and an inorganic compound in a mixed solution of an organic solvent such as ethanol and methanol and water is added to the particles obtained in (ii). The desired drug-containing film-coated particles are obtained by spraying. 3-7 mass% is preferable and, as for content of the film | membrane component in a spray liquid, 4-6 mass% is more preferable. If the content is less than the above lower limit, the film layer formation efficiency may be deteriorated and the productivity may be lowered. If the content exceeds the upper limit, the drug-containing particles (1) aggregate, There is a risk.

  As a coating method, various methods such as an upper spray method, a side spray method, and a lower spray method can be selected. However, drug-containing particles having a narrow particle size distribution in which each film layer is densely formed and particles are not aggregated. From the viewpoint of efficiently obtaining (1), the side spray method is preferred.

  In 100% by mass of the above-mentioned drug-containing particles (1), the mass ratio of the core particles (P) is 30% by mass or less, the drug content is 40% by mass or less, and the water-swellable polymer content is 13 to 13%. 30% by mass, the content of the water-insoluble polymer is 7 to 11% by mass, and the content of the water-soluble substance contained in the membrane layer (B) is 0.4 to 0.6 of the content of the water-insoluble polymer. And the content of the inorganic compound is preferably 25 to 35% by mass in 100% by mass of the membrane layer (B). Furthermore, the content of the drug is 5 to 35% by mass, and the water swelling property The content of the polymer is 15 to 25% by mass, the content of the water-insoluble polymer is 8 to 10% by mass, and the content of the inorganic compound is 27 to 32 in 100% by mass of the membrane layer (B). What is mass% is more preferable.

  As the drug-containing particles (1) used for the orally disintegrating tablet of the present invention, a plurality of film layers including a film layer (A) and a film layer (B) are formed on the surface of the core particles (P) as described above. In the case of adopting such particles, the dissolution of the drug is suppressed as much as possible while staying in the oral cavity immediately after taking the tablet, and the particles in the tablet are in the stage of transferring from the oral cavity to the body while collapsing. Thus, when the drug is rapidly eluted, particularly when the drug has an unpleasant taste, a favorable elution profile excellent in the balance between the unpleasant taste shielding property and the drug elution property is exhibited. Therefore, it is possible to ensure bioavailability and bioequivalence to conventional preparations because the drug is released quickly as appropriate time passes without feeling unpleasant taste in the oral cavity when taken. It becomes. Specifically, the preferable dissolution profile was tested by the second method (50 rpm) using 900 mL of the dissolution test second solution described in the Japanese Pharmacopoeia General Test Methods Formulation Test Method Dissolution Test Method. The elution rate after 2 minutes is 5% or less, preferably 2% or less, and the elution rate after 30 minutes is 85% or more, preferably the elution rate after 15 minutes is 85% or more. Means.

  Further, the unpleasant taste shielding time in the drug-containing particles (1) may vary depending on the type of drug, but is preferably 30 to 300 seconds, more preferably 120 to 300 seconds.

  The orally disintegrating tablet of the present invention comprises drug-containing particles (1) prepared in advance as described above, spherical mannitol crystal particles (2) described later, specific partially pregelatinized starch (3), and starch powder (4). Containing.

  The spherical mannitol crystal particles (2) used in the present invention have a unique structure having a shape close to a true sphere and having voids therein. When the spherical mannitol crystal particles (2) are contained in the orally disintegrating tablet of the present invention, the tablet can be disintegrated in a short time while maintaining good tablet hardness. This is because the spherical mannitol crystal particles (2) are composed of very fine needle-like crystals, and when the spherical particles collapse due to tableting, the needle-like crystals are entangled with each other, thereby exhibiting high moldability. It is presumed that rapid disintegration is obtained by water permeating into the voids between the shaped crystals and the voids in the remaining spherical particles.

  In addition, when the spherical mannitol crystal particles (2) are granulated together with the drug-containing particles (1), the shape of the spherical mannitol crystal particles (2) is maintained in the granulated particles from observation in an electron micrograph. The characteristics are not lost by granulation.

  The spherical mannitol crystal particles (2) are preferably spherical particles having a small bulk density and a high sphericity. Specifically, the bulk density is preferably 0.3 to 0.7 g / mL, and more preferably 0.35 to 0.50 g / mL.

The bulk density of the spherical mannitol crystal particles (2) can be usually obtained by a known measurement method. For example, according to the method described in International Publication No. 2010/021300, spherical mannitol crystal particles (2) are lightly piled up into a 100 mL volume cup (mass Wa), and the weight Wb is measured by the following formula (I). What is necessary is just to measure the calculated | required value in multiple times and obtain | require the average value.
Bulk density (g / mL) = (Wb−Wa) / 100 (I)

  The sphericity of the spherical mannitol crystal particles (2) may be determined based on the aspect ratio (ratio between the major axis and the minor axis), and specifically, the aspect ratio is preferably 1.2 or less. 1.1 or less is more preferable. In the present specification, the aspect ratio is determined by taking a photograph of spherically placed spherical mannitol crystal particles (2) with a scanning electron microscope and measuring the length (major axis) and long axis of a plurality of spherical particles. The length (minor axis) of the minor axis perpendicularly drawn from the midpoint of the axis was measured, the ratio of the major axis to each minor axis was determined, and the average value of the ratios was obtained.

  The voids present in the spherical mannitol crystal particles (2) can be evaluated based on the oil absorption 1 and 2 by the test method A shown below, the oil absorption 1 is 25 to 60%, and the oil absorption 2 is 15 to 40%. It is preferable that

The oil absorption rate according to Test Method A can be determined by the following procedure. 30 g of medium-chain fatty acid triglyceride and 15 g of sample mannitol were put into a 100 mL glass beaker, and the oil and powder sample were gently mixed with a spatula so as not to damage the powder. Depressurize to 67 Pascals and impregnate with oil for 3 hours. Next, the tube is transferred to a centrifuge tube (having holes at the bottom) using a filter cloth having a mesh of 325 mesh (aperture 45 μm), and centrifuged at about 1300 G for 10 minutes using a centrifuge. From the measured values of the centrifuge tube containing the sample after centrifugation and the centrifuge tube tare mass, the mass (Wc) of the powder sample remaining in the centrifuge tube after centrifugation is obtained, and the value calculated by the following formula (II) is obtained. Oil absorption rate is 1.
Oil absorption 1 (%) = [(Wc-15) / 15] × 100 (II)

Further, the centrifuge tube containing the sample after centrifugation is placed in a 100 mL glass beaker, 20 g of n-hexane is added from above the powder sample, and the mixture is centrifuged at about 1300 G for 10 minutes using a centrifuge. Next, the mass (Wd) of the powder sample remaining in the centrifuge tube after centrifugation is obtained from the measured values of the centrifuge tube containing the sample after centrifugation and the centrifuge tube tare mass, and is calculated by the following formula (III). The oil absorption rate is 2.
Oil absorption 2 (%) = [(Wd-15) / 15] × 100 (III)

  The average particle diameter of the spherical mannitol crystal particles (2) is preferably 15 to 165 μm, more preferably 15 to 85 μm, and still more preferably 15 to 65 μm. In the present specification, the average particle diameter of the spherical mannitol crystal particles (2) is a laser diffraction / scattering particle size distribution measuring instrument “MT-3000” (manufactured by Nikkiso Co., Ltd.) and 2-propanol as a dispersion solvent. Means the measured value.

  The angle of repose of the spherical mannitol crystal particles (2) is preferably 30 to 50 degrees. Here, the angle of repose means the angle of a mountain formed in a state where powder is naturally dropped on a disc. The angle of repose can be obtained by a generally known measuring method, and is measured by the following method using, for example, an ABD powder characteristic measuring device. The sample put into the sample hopper is passed through a vibrating rod, net (mesh opening 1000 μm), discharge funnel, nozzle (inner diameter 1 cm), dropped on the disk of the angle of repose sample table to create a mountain, and in three different directions The angle of the mountain is measured with an angle meter, and the average value is obtained. The operation to obtain the angle of repose can be repeated three times, and the average value of these three times can be obtained.

  The spherical mannitol crystal particles (2) can be produced, for example, according to the methods described in International Publication No. 2010/021300, International Publication No. 2008/146590, and the like. Moreover, it can also manufacture by the manufacturing method shown below.

  As a manufacturing apparatus, a spray dryer “ODT-20 type” (manufactured by Okawara Chemical Co., Ltd.) is used. First, an atomizer equipped with a product recovery can at the bottom of the device and an M-pin type disk (φ84 mm disk, manufactured by Okawahara Koki Co., Ltd.) at the top of the device was installed, and two aqueous mannitol solutions were made from Teflon (registered trademark). It introduce | transduces in an atomizer through a tube (outer diameter 6mm, inner diameter 4mm). The hot air is a co-current type in which air is ejected in the same direction to the liquid to be sprayed to generate a vortex, and is introduced from the upper part of the apparatus and discharged from the lower part of the apparatus.

  Here, the mannitol aqueous solution is dissolved while heating until a solid solution is completely dissolved and becomes a clear solution by adding pure water to commercially available crystalline mannitol “Mannit P” (manufactured by Mitsubishi Corporation Foodtech Co., Ltd.). This is obtained by spray drying.

  That is, after introducing a preliminarily prepared mannitol aqueous solution into the apparatus, the powder accumulated in the product can at the bottom of the spray dryer is recovered, and using a fluidized bed dryer “FLO-5” (manufactured by Okawara Manufacturing Co., Ltd.). By drying this, spherical mannitol crystal particles (2) can be obtained.

  The content of the spherical mannitol crystal particles (2) in the orally disintegrating tablet of the present invention is the drug (1) in the drug-containing particles (1) from the viewpoint of imparting good tablet hardness while effectively preventing the disintegration time from being extended. It is preferably 40 to 80% by mass and more preferably 45 to 60% by mass in 100% by mass of the total components in the tablet excluding 1a).

  The partially pregelatinized starch (3) used in the present invention acts as a binder for the orally disintegrating tablet of the present invention, and the viscosity of a 10% by mass aqueous suspension at 25 ° C. is 5 to 45 mPa · s. Partially pregelatinized starch. Such a specific partially pregelatinized starch (3) does not hinder the disintegration of the tablet while exhibiting a sufficient effect as a binder. Simply mixing the drug-containing particles (1), the spherical mannitol crystal particles (2), and the starch powder (4) described later, a plurality of particles having a difference in average particle size, bulk density and fluidity are mixed together. Therefore, there is a possibility that segregation occurs in the tableting process, resulting in a decrease in granulation property even when granulating in advance before passing through the tableting process, and uniformity of drug content between tablets cannot be ensured. high. Therefore, in the present invention, the partially pregelatinized starch (3) is allowed to act as a binder to uniformly disperse these drug-containing particles (1), spherical mannitol crystal particles (2) and starch powder (4). Segregation in the tableting process can be effectively prevented, and good granulation can be exhibited even when granulating in advance before the tableting process, while maintaining sufficient tablet hardness. The uniformity of the drug content in can also be sufficiently ensured.

  The viscosity of the partially pregelatinized starch (3) at 25 ° C. and a 10% by mass aqueous suspension is preferably 8 to 35 mPa · s. The viscosity of the binding liquid can be measured using a rotational viscometer (R-type viscometer, manufactured by Toki Sangyo Co., Ltd.). If the viscosity of the 10% by mass aqueous suspension at 25 ° C. exceeds the upper limit, sufficient disintegration may not be obtained, and the disintegration time may be prolonged. If the viscosity of the liquid is less than the lower limit, granulation becomes difficult. In addition, the preferable pregelatinization degree in the partially pregelatinized starch (3) used by the said invention is 60 to 80%, More preferably, it is 70 to 80%. Here, the degree of pregelatinization of the partially pregelatinized starch (3) is the measurement method of the conventional glucoamylase method (edited by Jiro Nikoku, “Starch Chemistry Handbook”, Asakura Shoten, 1977, p.242). It means a value obtained by adoption, for example, according to the method described in International Publication No. 2008/032767.

  As such partially pregelatinized starch (3), commercially available “PCS (registered trademark)” (manufactured by Asahi Kasei Chemicals Corporation) can be used, and the degree of pregelatinization is 75.9% (International Publication No. 2008/032767). The content of the partially pregelatinized starch (3) is preferably 3 to 7.5% in the total amount of orally disintegrating tablets from the viewpoint of achieving both uniformity of drug content between tablets and disintegration of tablets. It is mass%, More preferably, it is 3-6 mass%. The partially pregelatinized starch (3) exhibits a sufficient effect as a binder and uses a suspension obtained by dispersing in purified water as a binder from the viewpoint of achieving uniformity in drug content among tablets. In addition, it is preferable to tablet after preparing a granulated material in advance, but the method of use is not particularly limited.

When a granulated product is prepared in advance using a suspension containing the partially pregelatinized starch (3) as a binding solution, it is possible to obtain a granulated product that exhibits good granulation properties and has a narrow particle size distribution width. . Specifically, the value of the ratio (D90 / D10) of the 90% cumulative particle size (D90) and the 10% cumulative particle size (D10) obtained from the cumulative particle size distribution curve is preferably 1 to 5, more Preferably it is 1-3.5.
In the present specification, the cumulative particle size distribution curve means that obtained using a laser diffraction / scattering particle size distribution measuring device “LMS-30” (manufactured by Seishin Enterprise Co., Ltd.).

  The starch powder (4) used in the present invention is a starch other than the partially pregelatinized starch (3) and has a powder form. Such starch powder (4) is not particularly limited as long as it is generally used as a pharmaceutical additive, and examples thereof include wheat starch, rice starch, corn starch, and potato starch. Among these, rice starch or corn starch is preferable from the viewpoint that there is little decrease in tablet hardness due to addition. The content (mass%) of the starch powder (4) is preferably 5 to 20 mass% in the total amount of the orally disintegrating tablet of 100 mass% from the viewpoint of achieving both disintegration and tablet hardness. % Is more preferred.

  In the present invention, the preferred orally disintegrating tablet is 1 to 30% by mass of the drug-containing particles (1), 3 to 7.5% by mass of partially pregelatinized starch (3), and starch in a total amount of 100% by mass. It is an orally disintegrating tablet containing 5 to 20% by mass of powder (4).

  In the orally disintegrating tablet of the present invention, in addition to the drug-containing particles (1), the spherical mannitol crystal particles (2), the partially pregelatinized starch (3), and the starch powder (4), a range that does not impede the effects of the present invention. Other additives can be used. Such additives are not particularly limited as long as they are additives for various preparations generally used in the production of orally disintegrating tablets. For example, excipients, binders, disintegrants, lubricants, coloring agents, wearing agents A fragrance | flavor, a corrigent, etc. can be mentioned.

  Examples of the excipient include monosaccharides such as xylose, glucose, and fructose; oligosaccharides such as sucrose, lactose, maltose, reduced maltose, and isomaltose, sugar alcohols such as xylitol, erythritol, and sorbitol, and light anhydrous silicic acid. And calcium silicate. These may be used alone or in combination of two or more.

  Examples of the binder include those other than the partially pregelatinized starch (3), such as hydroxypropylcellulose, hypromellose, polyvinyl alcohol, polyvinylpyrrolidone, magnesium aluminate metasilicate, and the like.

  Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, crystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, and the like. These disintegrants may be used alone or in combination of two or more.

  Examples of the lubricant include stearic acid metal salts such as magnesium stearate and calcium stearate; sodium stearyl fumarate, talc, hydrogenated oil, sucrose fatty acid ester and the like. Among these, magnesium stearate is preferable from the viewpoint that a sufficient lubrication effect can be obtained with a small amount of addition. These lubricants may be contained inside the tablet, or may be in a form localized on the tablet surface (external lubricant).

  Examples of flavoring agents include orange and lemon flavors.

  Examples of the corrigent include L-menthol, camphor, mint, neotame, thaumatin, aspartame, stevia, sucralose, sodium saccharin, sodium glutamate, potassium acesulfame and the like. These may be used alone or in combination of two or more.

  The orally disintegrating tablet of the present invention disintegrates rapidly by saliva when taken into the oral cavity, and the disintegration time is within 90 seconds, preferably within 60 seconds, more preferably within 30 seconds. .

  The tablet hardness of the orally disintegrating tablet of the present invention may be a level that can withstand normal handling and load such as dispensing by a fully automatic tablet packaging machine and extrusion from an extruding drug packaging machine (PTP), Specifically, the tablet hardness / tablet mass value is preferably 0.022 kgf / mg or more (in the case of a tablet mass of 180 mg, the tablet hardness is 3.96 kgf or more) (Medical Pharmacy Vol. 29, No. 3 (2003 ), 367-374). The tablet hardness of the orally disintegrating tablet of the present invention can be determined by a generally known measurement method. For example, the tablet hardness meter can be used to measure the hardness in the diameter direction and determine the average value of a plurality of tablets. .

  The orally disintegrating tablet of the present invention can be produced by a known tablet production method. For example, a drug-containing particle (1) is prepared in advance, and spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4), and optionally a component containing magnesium stearate. In addition, it can be obtained by mixing all together and then compression-molding the mixture, but is not limited to this method. In particular, from the viewpoint of sufficiently exerting the effect of the partially pregelatinized starch (3) as a binder to achieve good uniformity of the drug content between tablets, the drug-containing particles (1) prepared in advance are used. It is preferable to obtain an orally disintegrating tablet by a method in which spherical mannitol crystal particles (2) and starch powder (4) are blended and mixed, and then partially pregelatinized starch (3) is blended. That is, in this method, more specifically, drug-containing particles (1) are prepared in advance, and spherical mannitol crystal particles (2) and starch powder (4) are mixed therewith, and then partially pregelatinized starch (3 ) To prepare a granulated product by spraying, granulating and drying in advance, and adding the magnesium stearate-containing component to the resulting granulated product. After mixing, the mixture is compression-molded.

  As the granulation method, for example, a fluidized bed granulation method, a stirring granulation method, a rolling granulation method or the like can be selected, but the fluidized bed granulation method is preferable from the viewpoint of productivity. At this time, the supply temperature, the air volume, the amount of the binder liquid, the spraying air pressure, etc. are adjusted so that the product temperature of the granulated product is maintained at 35 to 50 ° C. and the moisture content of the granulated product is maintained at 5% or less. Is preferred. Moreover, it is preferable to perform granulation by intermittent spraying in order to prevent the granulated material from getting wet locally. Intermittent spraying is a spraying method that repeats liquid spraying and drying. The tableting method can be performed using a normal tableting machine such as a single tableting machine or a rotary tableting machine. Moreover, it can also be set as a tablet using an external lubrication tableting machine. Here, the pressure during compression molding is preferably 400 to 1000 kgf, more preferably 600 to 900 kgf, and even more preferably 700 to 850 kgf, from the viewpoint of imparting rapid disintegration while maintaining sufficient tablet hardness.

  The orally disintegrating tablet of the present invention is taken without water or with water. As a method of taking, there are a method in which it is taken into the mouth and not swallowed as it is, a small amount of water or a method in which it is taken up with saliva in the oral cavity without water, and a method in which it is swallowed with water and taken. Alternatively, the tablet may be taken after disintegrating with water. The orally disintegrating tablet of the present invention is often used without water, when it is taken by a patient who has difficulty swallowing the tablet, or when it is a normal tablet, an elderly person or child who may clog the throat It is advantageously used when taking the medicine.

The orally disintegrating tablet of the present invention is
[1] (1) Drug-containing particles having an average particle size of 150 to 300 μm,
(2) Spherical mannitol crystal particles,
(3) A partially pregelatinized starch having a viscosity of 5 to 45 mPa · s at 25 ° C. and a 10% by mass water suspension, and (4) an orally disintegrating tablet containing starch powder.

In the present invention, the following orally disintegrating tablets are preferred.
[2] In the total amount of the orally disintegrating tablet of 100% by mass, the drug-containing particles (1) are 1 to 30% by mass, preferably 10 to 30% by mass, and the partially pregelatinized starch (3) is 3 to 7.5% by mass. %, Preferably 3-6% by mass, and 5-20% by mass, preferably 10-15% by mass of starch powder (4), orally disintegrating tablet according to [1].
[3] The orally disintegrating tablet according to [1] or [2], wherein the drug contained in the drug-containing particles (1) is a drug with an unpleasant taste, and preferably an anti-ulcer agent.
[4] 40 to 80% by mass, preferably 45 to 60% by mass of the spherical mannitol crystal particles (2) in 100% by mass of the total amount of components in the orally disintegrating tablet excluding the drug in the drug-containing particles (1). Orally disintegrating tablets according to the above [1] to [3].
[5] Oral disintegration of [1] to [4] above, wherein the bulk density of the spherical mannitol crystal particles (2) is 0.3 to 0.7 g / mL, preferably 0.35 to 0.50 g / mL. tablet.
[6] The orally disintegrating tablet according to the above [1] to [5], wherein the partially pregelatinized starch (3) has a viscosity of 8 to 35 mPa · s at 25 ° C. and a 10 mass% aqueous suspension.
[7] The orally disintegrating tablet according to [1] to [6], wherein the partially pregelatinized starch (3) has a pregelatinization degree of 60 to 80%, preferably 70 to 80%.

[8] The drug-containing particle (1) has a film layer (A) containing the drug and the water-swellable polymer on the surface of the core particle (P) not containing the drug and the water-swellable polymer, and is water-insoluble. The orally disintegrating tablet according to the above [1] to [7], wherein a plurality of film layers including a film layer (B) containing a polymer, a water-soluble substance and an inorganic compound are formed.
[9] Of the plurality of film layers formed of the drug-containing particles (1), the film layer (A) is the innermost film layer, and the drug-containing particles (1) are 100% by mass in total, and the core particles The mass ratio of (P) is 30% by mass or less, the drug content is 40% by mass or less, the water-swellable polymer content is 13-30% by mass, and the water-insoluble polymer content is 7-11% by mass. %, And the content of the water-soluble substance contained in the membrane layer (B) is 0.4 to 0.6 times the content of the water-insoluble polymer, and in 100% by mass of the membrane layer (B), Orally disintegrating tablet of said [8] whose content of an inorganic compound is 25-35 mass%.
[10] The orally disintegrating tablet according to [8] or [9], wherein the membrane layer (B) is the outermost membrane layer among the plurality of membrane layers formed by forming the drug-containing particles (1).
[11] In the drug-containing particles (1) 100% by mass in total, the drug content is 5 to 35% by mass, the water-swellable polymer content is 15 to 25% by mass, and the water-insoluble polymer content is Orally disintegrating tablets according to [8] to [10], wherein the content of the inorganic compound is 27 to 32% by mass in 100% by mass of the membrane layer (B).
[12] The orally disintegrating tablet according to any one of [3] to [11], wherein the unpleasant tasting drug is one antiulcer agent selected from ranitidine hydrochloride, cimetidine, famotidine, and lafutidine, preferably lafutidine. .

The present invention is preferably the following production method.
[13] Spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4) are added to and mixed with drug-containing particles (1) prepared in advance, and the resulting mixture is compression molded. [1] to [12] A method for producing an orally disintegrating tablet.
[14] Spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4) are added to drug-containing particles (1) prepared in advance, and ingredients containing magnesium stearate are added and mixed. [13] The method for producing an orally disintegrating tablet according to [13].
[15] Suspension containing the partially pregelatinized starch (3) in the resulting mixture containing the drug-containing particles (1) prepared by adding spherical mannitol crystal particles (2) and starch powder (4) and mixing them. The method for producing an orally disintegrating tablet according to the above [1] to [12], wherein a granulated product is prepared by spraying and the resulting granulated product is compression molded.
[16] The method for producing an orally disintegrating tablet according to the above [16], wherein a component containing magnesium stearate is further added to and mixed with the obtained granulated product, followed by compression molding.

The present invention is preferably an orally disintegrating tablet obtained by the following method.
[17] Spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4) are added to and mixed with drug-containing particles (1) prepared in advance, and the resulting mixture is compression molded. Orally disintegrating tablets of the above-mentioned [1] to [12].
[18] Spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4) are added to drug-containing particles (1) prepared in advance, and ingredients containing magnesium stearate are added and mixed. The orally disintegrating tablet of [17] obtained by
[19] Spherical mannitol crystal particles (2) and starch powder (4) are added to and mixed with drug-containing particles (1) prepared in advance, and the resulting mixture contains a partially pregelatinized starch (3). The orally disintegrating tablet according to the above [1] to [12], which is obtained by spraying and preparing a granulated product and compression-molding the obtained granulated product.
[20] The orally disintegrating tablet according to [19], which is obtained by further adding and mixing a component containing magnesium stearate to the obtained granulated product, followed by compression molding.

  EXAMPLES Hereinafter, although this invention is demonstrated concretely based on an Example, this invention is not limited to these Examples.

[Reference Example 1]: Production of drug-containing particles (particle A) (1) Formation of drug-containing innermost layer 90 g hydroxypropylcellulose “HPC-SSL” (manufactured by Nippon Soda Co., Ltd.) was dissolved in 1610 g ethanol (95). Then, 300 g of lafutidine (manufactured by Central Glass Co., Ltd.) and 300 g of low-substituted hydroxypropyl cellulose “L-HPC (LH-31)” (manufactured by Shin-Etsu Chemical Co., Ltd.) were added to obtain a suspension (1) -1. As a core particle (P: a core particle not containing a drug and a water-swellable polymer), 250 g of Nonparel-108 (100) is applied to a fluidized bed granulation coating device (device name “Multiplex MP-01”, manufactured by POWREC Co., Ltd.). First, 1916.7 g of the suspension (1) -1 was sprayed at a set temperature of 60 to 65 ° C. and a spraying speed of 5.0 g / min, and after drying, the mixture was sieved with a sieve having an opening of 355 μm to obtain the lafutidine-containing particles. Obtained.
In addition, when measured by dry / one-shot measurement using a laser diffraction / scattering particle size distribution analyzer (LMS-30, manufactured by Seishin Enterprise Co., Ltd.), the average particle size of Non-Parallel-108 (100) was 100 μm. .
Further, the average particle size of the core particles described later and the average particle size of the obtained lafutidine-containing particles were determined in the same manner.

(2) Formation of intermediate layer membrane Hypromellose “TC-5E” (manufactured by Shin-Etsu Chemical Co., Ltd.) 50 g and talc “PKP-81” (manufactured by Fuji Talc Kogyo Co., Ltd.) 50 g are added to purified water, and a suspension ( 2) 1000 g of -1 was prepared. 350 g of lafutidine-containing particles prepared in (1) above were charged into a fluidized bed granulation coating apparatus “Multiplex MP-01”, and a suspension (2) -1 having a set temperature of 70 ° C. and a solid content of 20%. Was sprayed at a spray rate of 3.8 g / min, and after drying, 2.1 g of the above talc was added. This was passed through a sieve having an opening of 500 μm to obtain lafutidine-containing particles covering the intermediate layer.

(3) Formation of outermost membrane layer 60 g of hypromellose “TC-5E” was dissolved in a mixed solution consisting of 140 g of purified water and 400 g of ethanol (95) (referred to as solution A). 50 g of ethyl cellulose “ETHOCEL STD 7 Premium” (manufactured by The Dow Chemical Company) was dissolved in 950 g of ethanol (95), and 250 g of solution A was added (referred to as solution B). 32.2 g of titanium oxide “NA65” (manufactured by Toho Titanium Co., Ltd.) was dispersed in 200 g of purified water and added to the B solution to obtain a suspension (3) -1. 300 g of the lafutidine-containing particles prepared in (2) above were charged into a fluidized bed granulation coating apparatus “Multiplex MP-01”, and a suspension (3) -1 having a set temperature of 60 ° C. and a solid content of 30%. Was sprayed at a spray rate of 5.2 g / min, dried, and then passed through a sieve having an opening of 355 μm to obtain lafutidine-containing particles (particle A: average particle size 200 μm) covering the ethylcellulose-containing outermost layer.

[Reference Example 2]: Production of drug-containing particles (particle B) (1) Formation of drug-containing innermost membrane layer 920 g of hydroxypropylcellulose “HPC-SSL” was dissolved in 12.88 kg of ethanol (95), and 2.3 kg of lafutidine. Then, 2.3 kg of low-substituted hydroxypropylcellulose “L-HPC (LH-31)” was added to form a suspension (1) -2. Charge 2 kg of lactose “FlowLac90” (Meggle) (average particle size 120 μm) as core particles (P) to a fluidized granulation coating device (device name “Flowcoater NFLO-5 (2) SJ”, manufactured by Freund Corporation) Then, 16 kg of the suspension (1) -2 was sprayed at an intake air temperature of 54 to 67 ° C. and a spraying speed of 20.9 g / min, and after drying, it was sieved with a sieve having an opening of 355 μm to obtain lafutidine-containing particles.

(2) Formation of Intermediate Layer Film 700 g of hypromellose “TC-5E” and 700 g of talc “PKP-81” were added to purified water to prepare 14 kg of suspension (2) -2. 6.3 kg of lafutidine-containing particles prepared in (1) above were charged into a fluidized granulation coating apparatus “Flow Coater NFLO-5 (2) SJ” and suspended at an intake air temperature of 76-82 ° C. and a spray rate of 17.2 g / min. 12.6 kg of the liquid (2) -2 was sprayed, and after drying, 76 g of the talc was added. This was passed through a sieve having an opening of 500 μm to obtain lafutidine-containing particles covering the intermediate layer.

(3) Formation of outermost membrane layer 468 g of hypromellose “TC-5E” and 938.1 g of ethyl cellulose “ETHOCEL STD7 Premium” were dissolved in a mixed solution consisting of 2.145 kg of purified water and 33.69 kg of ethanol (95). ). 602.7 g of titanium oxide “NA65” was dispersed in 2.9472 kg of purified water and added to liquid C to obtain a suspension (3) -2. 7.2 kg of lafutidine-containing particles prepared in (2) above were charged into a fluidized bed granulation coating apparatus “Flow Coater NFLO-5 (2) SJ” and suspended at an intake air temperature of 62 to 68 ° C. and a spray rate of 24.0 g / min. 36 kg of the turbid liquid (3) -2 was sprayed, dried, and then passed through a sieve having an opening of 355 μm to obtain lafutidine-containing particles (particle B: average particle size 180 μm) covering the outermost layer containing ethylcellulose.

[Reference Example 3]: Production of drug-containing particles (particle C) (1) Formation of drug-containing innermost layer 57 g of hydroxypropylcellulose “HPC-SSL” was dissolved in 1019.7 g of ethanol (95), and 380 g of lafutidine was added. Suspension (1) -3 was obtained. As a core particle, 350 g of sodium carboxymethyl starch “Primojel” (average particle size 40 μm), which is a water-swellable polymer, is charged into a fluidized bed granulation coating apparatus “Multiplex MP-01”, a set temperature of 60 ° C., and a spraying speed of 5. 1341.7 g of the suspension (1) -3 was sprayed at 1 g / min, and after drying, it was sieved with a sieve having an opening of 355 μm to obtain luffidine-containing particles.

(2) Formation of intermediate layer film According to the same method as (2) of Reference Example 1, lafutidine-containing particles coated with the intermediate layer were obtained.

(3) Formation of Outermost Film Layer According to the same method as in (3) of Reference Example 1, lafutidine-containing particles (particle C: average particle size 210 μm) coated with the ethylcellulose-containing outermost layer were obtained.

[Reference Example 4]: Production of drug-containing particles (particle D) (1) Formation of drug-containing innermost membrane layer 64 g of hydroxypropylcellulose “HPC-SSL” was dissolved in 800 g of ethanol (95), 320 g of lafutidine, low substitution degree 160 g of hydroxypropylcellulose “L-HPC (LH-31)” was added to make a suspension (1) -4. As a core particle (P), 300 g of non-parrel-108 (100) is charged into a fluidized bed granulation coating apparatus “Multiplex MP-01”, and a suspension (1 ) -4 was sprayed with 1700 g, dried, and then sieved with a sieve having an opening of 355 μm to obtain lafutidine-containing particles.

(2) Formation of intermediate layer film According to the same method as (2) of Reference Example 1, lafutidine-containing particles coated with the intermediate layer were obtained.
(3) Formation of Outermost Film Layer According to the same method as in (3) of Reference Example 1, lafutidine-containing particles (particle D: average particle size 230 μm) covering the ethylcellulose-containing outermost layer were obtained.

[Reference Example 5]: Production of drug-containing particles (particle E) (1) Formation of drug-containing innermost membrane layer According to the same method as (1) of Reference Example 1, lafutidine-containing particles were obtained.
(2) Formation of intermediate layer film According to the same method as (2) of Reference Example 1, lafutidine-containing particles coated with the intermediate layer were obtained.

(3) Formation of outermost membrane layer 30 g of hypromellose “TC-5E” was dissolved in a mixed solution consisting of 70 g of purified water and 200 g of ethanol (95) (referred to as solution D). 78.4 g of ethyl cellulose “ETHOCEL STD 7 Premium” was dissolved in 1488.8 g of ethanol (95), and 196.2 g of D solution was added (referred to as E solution). Titanium oxide “NA65” (42 g) was dispersed in purified water (260.9 g) and added to solution E to obtain a suspension (3) -4. 300 g of lafutidine-containing particles prepared in (2) above were charged into a fluidized bed granulation coating apparatus “Multiplex MP-01”, and a suspension (3) -4 having a set temperature of 60 ° C. and a solid content of 30%. Was sprayed at a spraying rate of 5.4 g / min, and after drying, it was sieved with a sieve having an opening of 355 μm to obtain lafutidine-containing particles (particle E: average particle size 210 μm) covering the outermost layer containing ethylcellulose.

[Reference Example 6]: Production of drug-containing particles F (1) Formation of drug-containing innermost membrane layer According to the same method as (1) of Reference Example 1, lafutidine-containing particles were obtained.
(2) Formation of intermediate layer film According to the same method as (2) of Reference Example 1, lafutidine-containing particles coated with the intermediate layer were obtained.

(3) Formation of outermost membrane layer 40 g of hypromellose “TC-5E” was dissolved in a mixed solution consisting of 93.3 g of purified water and 266.7 g of ethanol (95) (referred to as “F solution”). 74.6 g of ethyl cellulose “ETHOCEL STD 7 Premium” was dissolved in 1417.4 g of ethanol (95), and 196.2 g of F solution was added (referred to as G solution). Titanium oxide “NA65” (28 g) was dispersed in purified water (173.9 g) and added to solution G to obtain a suspension (3) -5. 300 g of lafutidine-containing particles prepared in (2) above were charged into a fluidized bed granulation coating apparatus “Multiplex MP-01”, and a suspension (3) -5 having a set temperature of 60 ° C. and a solid content of 30%. Was sprayed at a spray rate of 5.3 g / min, dried, and then passed through a sieve having an opening of 355 μm to obtain lafutidine-containing particles (particle F: average particle size of 220 μm) covering the ethylcellulose-containing outermost layer.

[Reference Example 7]: Production of drug-containing particles G (1) Formation of drug-containing granulated core particles 82.4 g of hydroxypropylcellulose “HPC-SSL”, 205.9 g of lafutidine, low-substituted hydroxypropylcellulose “L-HPC” (LH-31) ”205.9 g and lactose hydrate“ Lactochem ”(manufactured by DOMO) 205.9 g were charged into a high-speed stirring granulator (device name“ vertical granulator VG-05 ”, manufactured by POWREC Co., Ltd.) After mixing for 2 minutes, 127.2 g of ethanol (95) was added and granulated. After drying using a fluidized bed granulation coating apparatus “Multiplex MP-01”, the mixture was sieved with a sieve having an opening of 355 μm to obtain luffidine-containing granulated core particles.

(2) Formation of Intermediate Layer Film According to the same method as (2) of Reference Example 1, lafutidine-containing film-coated particles coated with an intermediate layer (no innermost layer) were obtained. Thereafter, this lafutidine-containing granulated core particle was used in place of the lafutidine-containing film-coated particle obtained in (2) of Reference Example 1.

(3) Formation of outermost membrane layer According to the same method as in (3) of Reference Example 1 except that the spray amount of the suspension (3) -1 was set to 25% of the charged amount as a solid content, Lautidine-containing particles (particle G: average particle size 189 μm) coated with the outer layer were obtained.
These results are shown in Table 1.

[Test Example 1: Evaluation of dissolution rate]
Using the particles A to G obtained in Reference Examples 1 to 7, a sample was prepared according to the following method, and using the obtained sample, the Japanese Pharmacopoeia General Test Method, Preparation Test Method Dissolution Test Method, and the following measurement conditions The dissolution rate (%) was evaluated below. The results are shown in Table 2.

《Sample preparation》
Each drug-containing particle equivalent to 10 mg of lafutidine was weighed, and spherical mannitol crystal particles (hereinafter, spherical mannitol crystal particles) / low-substituted hydroxypropylcellulose “L-” produced according to the description of International Publication No. 2008/146590. HPC (LH-21) ”/ sodium stearyl fumarate“ PRUV (manufactured by JRS) ”= 160/8/1 was mixed with a mixture of 169 mg to obtain a prepared powder. This prepared powder was compression-molded at 250 kgf using a φ8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain each sample.

"Measurement condition"
Dissolution test method: Method 2 (50 rpm)
Test solution: Dissolution test second solution (900 mL)
Measurement wavelength: λ = 271 nm

  As is apparent from the results of Table 2, the drug-containing particles of Reference Examples 1 and 2 showed an elution rate of 85% or more after 15 minutes, even though the elution rate was 5% or less even after 2 minutes. It was. On the other hand, Reference Example 3 containing no water-swellable polymer in the drug layer and Reference Example 7 using drug-containing granulated core particles show an elution rate of 85% or more after 15 minutes, but elution after 2 minutes. The rate exceeded 5% and the unpleasant taste shielding was insufficient. Reference Example 4 in which the amount of water-swellable polymer in the total amount of particles is insufficient, Reference Example 5 in which the amount of water-soluble substance is small relative to the amount of water-insoluble polymer (ethyl cellulose), and inorganic in the outermost layer In all of Reference Examples 6 in which the amount of the compound is insufficient, the elution rate after 2 minutes is 5% or less, but the elution rate after 30 minutes is 85% or less. This was a result of concern about ensuring bioequivalence with the drug product.

[Reference Examples 8 to 16]
In accordance with the same method as in Reference Example 1, lafutidine-containing film-coated particles having an ethylcellulose-containing outermost layer coated with the formulation shown in Table 3 were obtained. Table 4 shows the predetermined content (mass%) and ratio values. In all of the reference examples, it was found that the elution rate after 2 minutes was as low as that of Reference Example 1, and that the unpleasant taste shielding was sufficient. After that, it showed rapid dissolution.

[Test Example 2: Evaluation of unpleasant taste shielding properties]
The drug-containing particles obtained in Reference Example 2 and Reference Example 3 and the taste of the luffidine raw powder were evaluated according to the following evaluation methods and evaluation criteria. The results are shown in Table 5.
"Evaluation method"
Three healthy adult males contained drug-containing particles equivalent to 10 mg of lafutidine or lafutidine bulk powder for 30 seconds and then vomited to evaluate unpleasant taste.
《Evaluation criteria for unpleasant taste》
-: Does not feel unpleasant taste
±: Slight taste but acceptable
+: Unpleasant taste
++: Strongly feel unpleasant taste

  As apparent from the results in Table 5, the raw material of lafutidine is a drug that strongly exhibits an unpleasant taste, but the coated particles of Reference Example 2 feel an unpleasant taste not only immediately after being put in the mouth but also after 1 minute. None or acceptable. On the other hand, the coated particles of Reference Example 3 felt an unpleasant taste.

[Reference Example 17: Production of tablet A]
0.1 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) is added to 9.9 g of spherical mannitol crystal particles (manufactured by Mitsubishi Corporation Foodtech Co., Ltd .; average particle size 44 μm), and mixed in a glass bottle for 1 minute to prepare the prepared powder. Obtained. This prepared powder was compression-molded at 250 kgf using a φ8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet A having a mass of 200 mg.

[Reference Example 18: Production of tablet B]
A tablet B was obtained in the same manner as in Reference Example 17 except that D-mannitol “PEARLITOL 50C” (manufactured by Rocket Japan Co., Ltd.) was used instead of the spherical mannitol crystal particles.

[Reference Example 19: Production of tablet C]
Tablet C was obtained according to the same method as in Reference Example 17, except that D-mannitol “PEARLITOL 200SD” (manufactured by Rocket Japan Co., Ltd.) was used instead of the spherical mannitol crystal particles.

[Test Example 3: Measurement of tablet hardness and disintegration time (1)]
About the tablet manufactured by Reference Examples 17-19, the hardness of a diameter direction was measured using the tablet hardness meter (6D, Schleuniger make), and tablet hardness was calculated | required from the average value of three tablets. The disintegration time was measured using an orally disintegrating tablet tester (ODT-101, manufactured by Toyama Sangyo Co., Ltd.) under the conditions of test solution: water (37 ± 1 ° C.), weight mass: 20 g, rotation speed: 75 rpm. did. The hardness and disintegration time were measured immediately after tableting (Initial) and after standing for 1 day at 40 ° C. and 75% relative humidity in an unwrapped state (40 ° C. and 75% RH (open)). The results are shown in Table 6.

  As is apparent from the results in Table 6, the tablets produced in Reference Examples 17 to 19 all exhibited a disintegration delay due to moisture absorption under the conditions of 40 ° C. and 75% RH (open).

[Example 1: Production of tablet D]
40 g of partially pregelatinized starch “PCS PC-10” (manufactured by Asahi Kasei Chemicals Corporation) was dispersed in 360 g of purified water to obtain a binding liquid (25 ° C., viscosity: 35 mPa · s). 200.64 g of drug-containing particles (particle B) produced in Reference Example 2 in a fluidized bed granulation coating apparatus “Multiplex MP-01”, spherical mannitol crystal particles (Mitsubishi Corporation Foodtech Co., Ltd .; average particle size 44 μm) 333 .12 g, 90 g of corn starch “Eclipse Corn Starch W” (manufactured by Nippon Shokuhin Kako Co., Ltd.) were charged and mixed, then 300 g of the above binding solution was sprayed and granulated, and dried to obtain a granulated product. . 0.1 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) was added to 9.9 g of the obtained granulated product, and mixed for 1 minute in a glass bottle to obtain a prepared powder. The prepared powder was compression molded at 1000 kgf using a φ8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet D having a mass of 200 mg.

[Example 2: Production of tablet E]
In 360 g of purified water, 40 g of corn starch “eclipse corn starch W” (manufactured by Nippon Shokuhin Kako Co., Ltd.) was dispersed and heated at 67 ° C. for 1 hour to obtain a binding solution (25 ° C., viscosity: 8 mPa · s). A tablet E was obtained in the same manner as in Example 1 except that this binding solution was used.

[Comparative Example 1: Production of tablet F]
In 360 g of purified water, 40 g of partially pregelatinized starch “Starch 1500G” (manufactured by Nippon Colorcon Co., Ltd.) was dispersed to obtain a binding liquid (25 ° C., viscosity: 50 mPa · s). A tablet F was obtained in the same manner as in Example 1 except that this binding solution was used.

[Comparative Example 2: Production of tablet G]
40 g of corn starch “eclipse corn starch W” (manufactured by Nippon Shokuhin Kako Co., Ltd.) was dispersed in 360 g of purified water to obtain a binding solution (25 ° C., viscosity: 2 mPa · s). A tablet G was obtained in the same manner as in Example 1 except that this binding solution was used.

[Comparative Example 3: Production of tablet H]
Hydroxypropyl cellulose “HPC-SSL” (manufactured by Nippon Soda Co., Ltd.) 40 g was dissolved in 360 g of purified water to obtain a binding solution. A tablet H was obtained in the same manner as in Example 1 except that this binding solution was used.

[Comparative Example 4: Production of Tablet I]
Povidone “Kollidon 30” (manufactured by BASF Japan Ltd.) 40 g was dissolved in 360 g of purified water to obtain a binding solution. A tablet I was obtained in the same manner as in Example 1 except that this binding solution was used.

[Test Example 4: Measurement of tablet hardness and disintegration time (2)]
About the tablet manufactured by Examples 1-2 and Comparative Examples 1-4, according to the method similar to Test Example 3, tablet hardness and disintegration time were measured. The results are shown in Table 7.

[Test Example 5: Measurement of granule particle size distribution]
About the granulated material obtained by Examples 1-2 and Comparative Examples 1-4, a laser diffraction and scattering type particle size distribution measuring apparatus "LMS-30" (made by Seishin Enterprise Co., Ltd.) is used for dry and one-shot measurement. The particle size distribution was measured by the above, and the ratio (D90 / D10) of the 90% cumulative particle size (D90) and the 10% cumulative particle size (D10) obtained from the cumulative particle size distribution curve was obtained. The results are shown in Table 7.

  As is apparent from the results in Table 7, in Examples 1 and 2 using partially pregelatinized starch having a viscosity of 5 to 45 mPa · s as a binder at 25 ° C. and a 10% by mass aqueous suspension, Granulation was obtained and disintegration was sufficient. Furthermore, even under severe conditions such as 40 ° C. and 75% RH (open), no significant delay in disintegration due to moisture absorption was observed, and sufficient tablet hardness was maintained. On the other hand, in Comparative Example 1 using partially pregelatinized starch in which the viscosity of a 10% by mass aqueous suspension at 25 ° C. is more than 45 mPa · s, sufficient disintegration property cannot be obtained, and further, 25 ° C., 10% by mass water. In Comparative Example 2 in which starch having a suspension viscosity of less than 5 mPa · s was used as a binder, good granulation properties could not be exhibited. In Comparative Example 3 using hydroxypropylcellulose as a binder and Comparative Example 4 using povidone as a binder, good granulation was obtained, but fast disintegration was not obtained.

[Example 3: Production of tablet J]
30 g of partially pregelatinized starch “PCS PC-10” (manufactured by Asahi Kasei Chemicals Corporation) was dispersed in 270 g of purified water to obtain a binding solution. 200.64 g of drug-containing particles (particle B) produced in Reference Example 2 in a fluidized bed granulation coating apparatus “Multiplex MP-01”, spherical mannitol crystal particles (manufactured by Mitsubishi Corporation Foodtech Co., Ltd .; average particle size 44 μm) 343 .12 g, 90 g of corn starch “Eclipse Corn Starch W” (manufactured by Nippon Shokuhin Kako Co., Ltd.) were charged and mixed, then 200 g of the above binding solution was sprayed and granulated, and dried to obtain a granulated product. . 0.1 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) was added to 9.9 g of the obtained granulated product, and mixed for 1 minute in a glass bottle to obtain a prepared powder. This prepared powder was compression-molded at 1000 kgf using a φ8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain tablet J having a mass of 200 mg.

[Example 4: Production of tablet K]
60 g of partially pregelatinized starch “PCS PC-10” (manufactured by Asahi Kasei Chemicals Corporation) was dispersed in 540 g of purified water to obtain a binding solution. 200.64 g of drug-containing particles (particle B) produced in Reference Example 2 in a fluidized bed granulation coating apparatus “Multiplex MP-01”, spherical mannitol crystal particles (manufactured by Mitsubishi Corporation Foodtech Co., Ltd .; average particle size 44 μm) 313 .52 g, 90 g of corn starch “Eclipse Corn Starch W” (manufactured by Nippon Shokuhin Kako Co., Ltd.) were charged and mixed, then 496 g of the above binding solution was sprayed and granulated, and dried to obtain a granulated product. . 0.1 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) was added to 9.9 g of the obtained granulated product, and mixed for 1 minute in a glass bottle to obtain a prepared powder. This prepared powder was compression-molded at 1000 kgf using a φ8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet K having a mass of 200 mg.

[Example 5: Production of tablet L]
3.0 g of drug-containing particles (particles B) produced in Reference Example 2, 5.9 g of spherical mannitol crystal particles (Mitsubishi Corporation Food Tech Co., Ltd .; average particle size 44 μm), corn starch “Eclipse Corn Starch W” (Japanese food) (Kako Co., Ltd.) 0.5g, partially pregelatinized starch "PCS PC-10" (Asahi Kasei Chemicals Co., Ltd.) 0.5g, 0.1 g of magnesium stearate (Taihei Chemical Industry Co., Ltd.) is added and placed in a glass bottle. Preparation powder was obtained by mixing for 1 minute. The prepared powder was compression-molded at 1000 kgf using a ８8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain tablets L having a mass of 200 mg.

[Example 6: Production of tablet M]
3.0 g of drug-containing particles (particles B) produced in Reference Example 2, 5.4 g of spherical mannitol crystal particles (Mitsubishi Corporation Food Tech Co., Ltd .; average particle size 44 μm), corn starch “Eclipse Corn Starch W” (Japanese food) Kagaku Co., Ltd.) 1.0 g, partially pregelatinized starch “PCS PC-10” (Asahi Kasei Chemicals Co., Ltd.) 0.5 g, magnesium stearate (Taihei Chemical Industrial Co., Ltd.) 0.1 g is added, and in a glass bottle. Preparation powder was obtained by mixing for 1 minute. This prepared powder was compression molded at 1000 kgf using a φ8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet M having a mass of 200 mg.

[Example 7: Production of tablet N]
3.0 g of drug-containing particles (particle B) produced in Reference Example 2, 4.4 g of spherical mannitol crystal particles (Mitsubishi Corporation Food Tech Co., Ltd .; average particle size 44 μm), corn starch “eclipse corn starch W” (Japanese food) Kagaku Co., Ltd.) 2.0 g, partially pregelatinized starch “PCS PC-10” (Asahi Kasei Chemicals Co., Ltd.) 0.5 g, magnesium stearate (Taihei Chemical Industrial Co., Ltd.) 0.1 g is added, and in a glass bottle. Preparation powder was obtained by mixing for 1 minute. This prepared powder was compression-molded at 1000 kgf using a φ8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet N having a mass of 200 mg.

[Test Example 6: Measurement of tablet hardness and disintegration time (3)]
About the tablet manufactured by Examples 3-7, according to the method similar to Test Example 3, tablet hardness and disintegration time were measured. The results are shown in Table 8.

[Test Example 7: Measurement of granule particle size distribution]
About the granulated material obtained by Examples 3-4, according to the method similar to Test Example 5, particle size distribution was measured and D90 / D10 was calculated | required. The results are shown in Table 8.

  As is clear from the results in Table 8, when the partially pregelatinized starch is 3 to 7.5% by mass in 100% by mass of the orally disintegrating tablet, sufficient granulation and sufficient disintegration can be obtained. found. Similarly, sufficient tablet hardness and sufficient disintegration are obtained when corn starch as starch powder is 5 to 20% by mass in 100% by mass of orally disintegrating tablet, and the condition is 40 ° C. and 75% RH (open). Below, it was found that there was no significant decay delay or hardness reduction due to moisture absorption.

[Example 8: Production of tablet O]
0.1 g of drug-containing particles (particle B) produced in Reference Example 2, 7.9 g of spherical mannitol crystal particles (Mitsubishi Corporation Food Tech Co., Ltd .; average particle size 44 μm), corn starch “Eclipse Corn Starch W” (Japanese food) 1.4 g of partially pregelatinized starch “PCS PC-10” (manufactured by Asahi Kasei Chemicals) 0.1 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) is added to the glass bottle. Preparation powder was obtained by mixing for 1 minute. This prepared powder was compression-molded at 1000 kgf using a φ8 mm, R12 mm punch and a hydraulic press (manufactured by Riken Seiki Co., Ltd.) to obtain a tablet O having a mass of 200 mg. The obtained tablet had sufficient tablet hardness and sufficient disintegration, and no significant disintegration delay or hardness decrease due to moisture absorption was observed under the conditions of 40 ° C. and 75% RH (open).

[Example 9: Production of tablet P]
Among the components shown in Table 9, partially pregelatinized starch “PCS PC-10” (manufactured by Asahi Kasei Chemicals Corporation) was dispersed in purified water, and this was used as a binding solution. The drug-containing particles (particles B), spherical mannitol crystal particles (manufactured by Mitsubishi Corporation Foodtech Co., Ltd .; average particle size 44 μm) produced in Reference Example 2 in the fluidized bed granulation coating apparatus “Multiplex MP-01”, corn starch “ After eclipse corn starch W "(manufactured by Nippon Shokuhin Kako Co., Ltd.) and mixing, the above binding solution was sprayed to granulate and dried to obtain a granulated product. Crospovidone “Kollidon CL-SF” (manufactured by BASF Japan), magnesium metasilicate aluminate “Neusilin UFL2” (manufactured by Fuji Chemical Industry Co., Ltd.), aspartame (manufactured by Ajinomoto Healthy Supply Co., Ltd.) , L-menthol (manufactured by Takasago International Corporation) and magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) were added and mixed to obtain a prepared powder. This prepared powder was compression molded at 800 kgf using a φ8 mm, R12 mm punch and a rotary tableting machine “12TU-AW” (manufactured by Kikusui Seisakusho) to obtain a tablet P having a mass of 180 mg.

[Example 10: Production of tablet Q]
All the components shown in Table 9 were mixed together to obtain a prepared powder. The prepared powder was compression molded at 900 kgf using a φ8 mm, R12 mm punch and a rotary tableting machine “12TU-AW” (manufactured by Kikusui Seisakusho) to obtain a tablet Q having a mass of 180 mg.

[Test Example 8: Measurement of tablet hardness and disintegration time (4)]
For the tablets produced in Examples 9 and 10, the tablet hardness immediately after tableting (Initial) was measured according to Test Example 3. The disintegration time was determined by measuring the time until a healthy adult male had a tablet in his mouth and the tablet completely disintegrated with saliva alone.
Furthermore, the variation in drug content (CV: unit =%) in the tablets was calculated by the following equation by measuring the individual contents of 30 tablets.
C. V. = Standard deviation of individual contents / average value of contents × 100
The results are shown in Table 9.

  As is clear from the results in Table 9, Examples 9 and 10 showed good results with respect to tablet hardness and disintegration time, but compared to Example 10, C.I. V. Since the value was low, it was more effective to mix the partially pregelatinized starch later than mixing all the ingredients at once, effectively suppressing variation in drug content between tablets. It has been shown that high quality tablets can be obtained.

Claims (10)

(1) Drug-containing particles having an average particle size of 150 to 300 μm,
(2) Spherical mannitol crystal particles,
(3) Partially pregelatinized starch having a viscosity of 5 to 45 mPa · s at 25 ° C. and a 10% by mass aqueous suspension, and (4) an orally disintegrating tablet containing starch powder.   1-100% by mass of the drug-containing particles (1), 3-7.5% by mass of partially pregelatinized starch (3), and 5-5% of starch powder (4) in 100% by mass of the orally disintegrating tablet The orally disintegrating tablet according to claim 1, containing 20% by mass.   The orally disintegrating tablet according to claim 1 or 2, wherein the drug contained in the drug-containing particles (1) is a drug having an unpleasant taste.   The drug-containing particle (1) comprises a film layer (A) containing a drug and a water-swellable polymer on the surface of the core particle (P) not containing the drug and the water-swellable polymer, a water-insoluble polymer, The orally disintegrating tablet according to any one of claims 1 to 3, wherein a plurality of film layers including a water-soluble substance and a film layer (B) containing an inorganic compound are formed.   Of the plurality of membrane layers formed by forming the drug-containing particles (1), the membrane layer (A) is the innermost membrane layer, and the total amount of the drug-containing particles (1) is 100% by mass, and the core particles (P) The proportion of the mass of 30% by mass or less, the content of the drug is 40% by mass or less, the content of the water-swellable polymer is 13 to 30% by mass, the content of the water-insoluble polymer is 7 to 11% by mass, and The content of the water-soluble substance contained in the membrane layer (B) is 0.4 to 0.6 times the content of the water-insoluble polymer, and 100% by mass of the membrane layer (B) contains an inorganic compound. The orally disintegrating tablet according to claim 4, wherein the content is 25 to 35% by mass.   The orally disintegrating tablet according to claim 4 or 5, wherein the membrane layer (B) is an outermost membrane layer among the plurality of membrane layers formed by forming the drug-containing particles (1).   In the total amount of the drug-containing particles (1) 100% by mass, the drug content is 5 to 35% by mass, the water-swellable polymer content is 15 to 25% by mass, and the water-insoluble polymer content is 8 to The orally disintegrating tablet according to any one of claims 4 to 6, wherein the content is 10% by mass and the content of the inorganic compound is 27 to 32% by mass in 100% by mass of the film layer (B).   The orally disintegrating tablet according to any one of claims 3 to 7, wherein the unpleasant-tasting drug is lafutidine.   Spherical mannitol crystal particles (2), partially pregelatinized starch (3) and starch powder (4) are added to and mixed with drug-containing particles (1) prepared in advance, and the resulting mixture is compression molded. A method for producing an orally disintegrating tablet.   Spherical mannitol crystal particles (2) and starch powder (4) are added to and mixed with drug-containing particles (1) prepared in advance, and the resulting mixture is sprayed with a suspension containing partially pregelatinized starch (3). The method for producing an orally disintegrating tablet according to claim 1, wherein the granulated product is prepared and the obtained granulated product is compression-molded.