JP2021167306A - Method for producing disintegrative particle - Google Patents

Abstract

To provide a method for producing disintegrative particles that can control the particle size of the disintegrative particles.SOLUTION: A method for producing disintegrative particles for the production of an orally disintegrating tablet includes the step in which an excipient and/or disintegrator and a pharmaceutically acceptable solvent are mixed and granulated while transported in axial direction with a screw rotating in a blending case.SELECTED DRAWING: None

Description

The present invention relates to a method for producing disintegrating particles and a method for producing an orally disintegrating tablet containing the disintegrating particles.

Orally disintegrating tablets are tablets designed so that the entire tablet is disintegrated by saliva in a very short time when it is contained in the mouth, and has been developed as a dosage form that is easy for the elderly and children to take.

Orally disintegrating tablets, like ordinary tablets, have sufficient hardness so that the tablets do not chip or powder during tablet manufacturing, transportation, or opening, and they disintegrate rapidly in the oral cavity. It is required to have excellent disintegration property.

Here, the tablet hardness and the disintegration property are opposite to each other. Generally, when the molding pressure is increased in order to increase the hardness, the disintegration time becomes longer, and in order to shorten the disintegration time, the hardness tends to decrease when the molding pressure is decreased. There is.

Patent Document 1 describes granules having a specific range of compositions (rapid disintegrating granules) designed to give tablets having sufficient hardness and extremely rapid disintegration when tableted by themselves, and a medicinal ingredient. It is described that an orally disintegrating tablet having sufficient hardness and disintegration rate can be obtained by mixing and tableting itself or its composition (granule containing a medicinal ingredient, etc.).

Japanese Patent No. 6496085

The particle size of the medicinal ingredient-containing granules and the like changes according to the content of the medicinal ingredient itself, the particle size, and the function required for the tablet. In order to ensure the uniformity of the content of the tablets, it is desirable that the particle size of the rapidly disintegrating granules (hereinafter, also referred to as disintegrating particles) can be controlled in accordance with the particle size of the granules containing the medicinal ingredient.

In Patent Document 1, a fluidized bed granulation method is used in the production of rapidly disintegrating granules. In general, the fluidized bed granulation method is a granulation method that promotes particle growth by spraying a liquid containing a binder (see Pharmaceutics (Revised 7th Edition), p. 198). Here, if a binder is used to increase the particle size of the granules, there is a problem that the disintegration time is delayed.

An object of the present invention is to provide a method for producing disintegrating particles whose particle size can be controlled.

As a result of diligent studies, the present inventors kneaded and granulated a predetermined additive and solvent by a device equipped with a screw mechanism rotating in a kneading case, thereby causing disintegration having a desired particle size. We have found that it is possible to design and manufacture sex particles. It was also found that by using the disintegrating particles, an orally disintegrating tablet having excellent hardness, disintegration rate and content uniformity can be produced without depending on the composition and properties of the medicinal component-containing particles and the like. , The present invention has been completed.

That is, the present invention
[1] Orally disintegrating tablets comprising a step of mixing and granulating an excipient and / or a disintegrant and a pharmaceutically acceptable solvent while transporting them axially by a screw rotating in a kneading case. Manufacturing method of disintegrating particles for manufacturing,
[2] The method for producing disintegrating particles according to the above [1], wherein the average particle size (D50) of the disintegrating particles is 70 to 400 μm.
[3] The method for producing disintegrating particles according to the above [1] or [2], wherein the disintegrating particles contain an excipient containing sugar and / or a sugar alcohol.
[4] The method for producing disintegrating particles according to any one of [1] to [3] above, wherein the disintegrating particles further contain a hydrophilic and water-insoluble inorganic additive.
[5] The method for producing disintegrating particles according to any one of [1] to [4] above, wherein the disintegrating particles further contain a water-insoluble binder other than crystalline cellulose.
[6] The method for producing disintegrating particles according to any one of [1] to [5] above, wherein the content of the water-soluble binder in the disintegrating particles is less than 3.0% by weight.
[7] The method for producing disintegrating particles according to any one of [1] to [6] above, wherein the content of crystalline cellulose in the disintegrating particles is less than 10.0% by weight.
[8] The step of obtaining disintegrating particles by the production method according to any one of the above [1] to [7], and the above-mentioned disintegrating particles, a powder of a medicinal ingredient, a composition containing the medicinal ingredient, or a composition thereof. A method for producing an orally disintegrating tablet, which comprises a step of compression-molding a mixture of a granulated product and an additive that can be used for tableting.
[9] The present invention relates to an orally disintegrating lock produced by the production method according to the above [8].

According to the present invention, it is possible to design and manufacture disintegrating particles having a desired particle size. Further, according to the present invention, an orally disintegrating tablet having excellent hardness, disintegration rate and content uniformity can be produced without depending on the composition and properties of the medicinal ingredient-containing particles and the like.

The orally disintegrating tablet according to the present embodiment contains particles containing a medicinal ingredient and the like and disintegrating particles. Further, the disintegrating particles contain at least an excipient or a disintegrant, and each component constituting the disintegrating particles is mixed and granulated while being transported in the axial direction by a screw rotating in a kneading case. It is manufactured by a device (hereinafter, also referred to as an extruder device).

It is a schematic diagram which shows the structure of the extruder device.

As used herein, the term "participant-containing particles, etc." comprehensively means the medicinal ingredient itself for a disease to be treated or prevented, the composition containing the medicinal ingredient, and the granulated products thereof. .. The medicinal ingredient may be appropriately selected depending on the subject of treatment or prevention, and is not limited to a specific specific drug. This is because the essence of the present invention lies in the composition and function of other particles (disintegrating particles) that are mixed upon tableting to secure such particles in the form of tablets.

In the present invention, the "disintegrating particle" means a particle having a characteristic of rapidly disintegrating in the presence of water even when tableted into a tablet having a sufficiently high hardness.

In the present embodiment, the "average particle size" refers to the cumulative 50% particle size (D50) obtained by volume-based measurement when measured with a commercially available laser diffraction type particle size distribution measuring device, or a sonic vibration type sieving measuring device. It means the cumulative 50% particle size (D50) obtained based on the existing mass.

In the present embodiment, the degree of compression representing the fluidity of particles is determined by the following formula from the specific volume ((loose (mL / g), tap (mL / g)) measured using a 100 mL stainless steel cup.
(Compression degree (%)) = ((loose (mL / g))-(tap (mL / g)) / (loose (mL / g)) × 100

The procedure for producing an orally disintegrating tablet including the procedure for producing disintegrating particles according to an embodiment of the present invention will be described in detail below. However, the following description is an example for explaining the present invention, and does not mean that the technical scope of the present invention is limited to this description range. In this specification, when a numerical range is indicated by using "~", the numerical values at both ends thereof are included.

<Disintegrating particles and their manufacturing method>
The disintegrating particles according to the present embodiment preferably contain at least an excipient or a disintegrant and an inorganic additive. In addition, components other than the above components (other components) may be contained as long as the effects of the present invention are not impaired.

(Excipient)
Excipients are not particularly limited, and examples thereof include sugars, sugar alcohols, starches and the like, and sugars and sugar alcohols are preferred embodiments. Sugars and sugar alcohols disintegrate additional amounts of water around the tablet through hydrophilic and water-insoluble disintegrants by creating a local high osmotic pressure when dissolved in a small amount of water. It is convenient to drive inward. The sugar and sugar alcohol are preferably at least one selected from the group consisting of mannitol, erythritol, xylitol, trehalose, lactose, maltose, maltitol, and sorbitol; one selected from the group consisting of mannitol, trehalose, and lactose. The above is more preferable; mannitol is further preferable.

The total content of the disintegrating particles with respect to the total weight of the disintegrating particles when sugar and / or sugar alcohol is contained is not particularly limited, but is preferably 55% by weight or more, more preferably 60% by weight or more, still more preferably 65% by weight or more. The content is preferably 85% by weight or less, more preferably 80% by weight or less, and even more preferably 75% by weight or less.

The average particle size of the sugar and / or sugar alcohol is preferably 100 μm or less, more preferably 80 μm or less, still more preferably 60 μm or less, from the viewpoint of ensuring the disintegration rate. On the other hand, the lower limit of the average particle size is not particularly limited, but may be, for example, 1 μm or more, 3 μm or more, 5 μm or more, 10 μm or more, and 20 μm or more.

(Disintegrant)
The disintegrant is not particularly limited, but a hydrophilic and water-insoluble disintegrant is a preferred embodiment. Examples of such disintegrants include crospovidone, low-substituted hydroxypropyl cellulose, starches (corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, modified pregelatinized starch, hydroxypropyl starch, starch glycolic acid). (Sodium, etc.) and carmellose (carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, etc.) are mentioned, and it is preferable that one or more of these is contained. Among them, it is preferable to contain at least one selected from the group consisting of crospovidone, corn starch, and carmellose. Also preferred embodiments include disintegrants containing starches (preferably corn starch) and / or carmelloses (preferably carmellose) and crospovidone.

The total content of the disintegrating particles with respect to the total weight of the disintegrating particles is not particularly limited, but is preferably 10% by weight or more, more preferably 15% by weight or more, still more preferably 18% by weight or more. The content is preferably 40% by weight or less, more preferably 35% by weight or less, and even more preferably 32% by weight or less.

When starches (preferably corn starch) and / or carmellose (preferably carmellose) are contained, the total content with respect to the total weight of the disintegrating particles is not particularly limited, but is preferably 5.0% by weight or more, preferably 10% by weight. % Or more is more preferable, and 15% by weight or more is further preferable. The content is preferably 39% by weight or less, more preferably 34% by weight or less, and even more preferably 31% by weight or less.

The content of crospovidone with respect to the total weight of the disintegrating particles is not particularly limited, but is preferably 1.0% by weight or more, more preferably 3.0% by weight or more, still more preferably 5.0% by weight or more. .. The content is preferably 20% by weight or less, more preferably 15% by weight or less, still more preferably 10% by weight or less.

(Inorganic additive)
The disintegrating particles according to the present embodiment preferably contain an inorganic additive. As the inorganic additive, a hydrophilic and water-insoluble inorganic additive is mentioned as a preferable embodiment. It is considered that the water-conducting effect of such an inorganic additive improves the permeability of water in the granulated particles and immediately disintegrates the granulated particles when they come into contact with water. Inorganic additives include magnesium carbonate, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, magnesium aluminometasilicate, magnesium silicate aluminate, hydrotalcite, Includes aluminum silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, silicon dioxide, magnesium oxide, magnesium hydroxide, alumina magnesium hydroxide, dry aluminum hydroxide gel, and talc, one or more of these. Is more preferred; one or more selected from the group consisting of light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, and magnesium aluminometasilicate; is more preferred; light anhydrous silicic acid is even more preferred.

The content of the disintegrating particles with respect to the total weight of the disintegrating particles when the inorganic additive is contained is not particularly limited, but is preferably 0.1% by weight or more, more preferably 0.3% by weight or more, still more preferably 0.5% by weight or more. , 0.7% by weight or more is particularly preferable. The content is preferably 5.0% by weight or less, more preferably 3.0% by weight or less, still more preferably 1.5% by weight or less.

(Other additives)
The disintegrating particles according to the present embodiment may contain components (other components) other than the above-mentioned components as long as the effects of the present invention are not impaired. The other ingredients are not particularly limited, and examples thereof include binders, lubricants, sweeteners, fragrances, coating agents, colorants, solubilizing agents, medicinal ingredients and the like.

The binder is not particularly limited, but is a water-soluble binder such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone (povidone), or water such as crystalline cellulose, low-substituted hydroxypropyl cellulose, ethyl cellulose, and soy lecithin. Examples include insoluble binders. Water-soluble binders become viscous when dissolved in water, and this property tends to delay the disintegration time of tablets. For this reason, when a binder is contained, a water-insoluble binder is preferably used. Of these, water-insoluble binders other than crystalline cellulose are preferable, and ethyl cellulose is more preferable.

The content of the disintegrant particles with respect to the total weight of the disintegrating particles when the water-soluble binder is contained is preferably less than 3.0% by weight, more preferably less than 2.0% by weight, and 1.0% by weight from the viewpoint of ensuring the disintegration rate. Less than% is more preferred, less than 0.5% by weight is even more preferred, and less than 0.1% by weight is particularly preferred. Further, it may be a disintegrating particle that does not contain a water-soluble binder.

When a water-insoluble binder (preferably a water-insoluble binder other than crystalline cellulose; more preferably ethyl cellulose) is contained, the content based on the total weight of the disintegrating particles is preferably 0.1% by weight or more, preferably 0.5% by weight. The above is more preferable, 1.0% by weight or more is further preferable, 1.5% by weight or more is further preferable, and 2.0% by weight or more is particularly preferable. When a water-insoluble binder (preferably a water-insoluble binder other than crystalline cellulose; more preferably ethyl cellulose) is contained, the content based on the total weight of the disintegrating particles is preferably 10.0% by weight or less, preferably 5.0. By weight% or less is more preferable, and 3.0% by weight or less is further preferable.

When crystalline cellulose is contained, the content based on the total weight of the disintegrating particles is preferably less than 10.0% by weight, more preferably less than 5.0% by weight, and less than 3.0% by weight from the viewpoint of ensuring the disintegration rate. Is even more preferable, less than 1.0% by weight is further preferable, and less than 0.1% by weight is particularly preferable. Further, it may be a disintegrating particle that does not contain crystalline cellulose.

The medicinal ingredient is not particularly limited, and can be used regardless of properties such as basic, acidic, amphoteric, and neutral, and solubility. In addition, these medicinal ingredients may be used alone or in combination of two or more.

The content with respect to the total weight of the disintegrating particles when the medicinal ingredient is contained is not particularly limited, and is, for example, 30% by weight or less, 20% by weight or less, 10% by weight or less, 5.0% by weight or less, 3.0% by weight. % Or less, 1.0% by weight or less, 0.5% by mass or less, 0.1% by weight or less. Further, it may be a disintegrating particle that does not contain a medicinal ingredient.

The lubricant is not particularly limited, and examples thereof include talc, magnesium stearate, stearic acid, sucrose fatty acid ester, and stearyl alcohol. Magnesium stearate is particularly preferable.

The sweetener is not particularly limited, and examples thereof include aspartame, saccharin, and sucralose.

The fragrance is not particularly limited, and examples thereof include peppermint and l-menthol.

The coating agent is not particularly limited, and examples thereof include ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, and titanium oxide.

The colorant is not particularly limited, and examples thereof include yellow iron sesquioxide, iron sesquioxide, and black iron oxide.

The solubilizing agent is not particularly limited, and examples thereof include polysorbate and macrogol.

The method for producing disintegrating particles according to the present embodiment includes a step of mixing and granulating the excipient and / or the disintegrant and the liquid while transporting the excipient and / or the disintegrant and the liquid in the kneading case in the axial direction by a rotating screw. It is a feature.

The apparatus used for producing the disintegrating particles according to the present embodiment mixes and granulates while transporting each component constituting the disintegrating particles and the liquid in the kneading case (paddle) in the axial direction by a screw rotating in the kneading case (paddle). The device is not particularly limited as long as it is a device (extruder device) provided with a mechanism for performing the function. Typical examples of the extruder device include an extrusion granulation device, a continuous granulation device, and the like.

FIG. 1 is a schematic view showing the configuration of an extruder device. As shown in FIG. 1, the extruder device 1 includes a screw 4 rotationally driven by a motor and a kneading case (paddle) 2 in which the screw is housed, and the powder is powdered in the kneading case 2 by the screw 4. The raw materials are kneaded to form granules.

Above the kneading case 2, a raw material supply unit 3 for supplying raw materials into the kneading case 2 is attached. From the raw material supply unit 3, a fixed amount of the raw material mixture is supplied into the kneading case 2. In the kneading case 2, the supplied raw materials are kneaded and transported in the axial direction as the screw 4 rotates. At this time, a pharmaceutically acceptable solvent, a binder solution, or the like is appropriately added. A screen 5 is provided at one end of the kneading case 2. Further, the kneading case 2 preferably includes a solvent supply unit, a heating device, a cooling device, and the like (not shown).

The shape of the screen 5 is not particularly limited, and may be, for example, a flat plate, a hemisphere, a dome shape, a mortar shape, or the like, and may not be attached.

The mesh diameter and the pore size of the screen 5 can be appropriately set according to the desired particle size and extrusion speed of the granulated product. The mesh diameter can be, for example, in the range of 0.5 to 5.0 mm, 0.7 to 4.0 mm, and 1.0 to 3.0 mm. The opening rate can be, for example, in the range of 5 to 50% and 10 to 40%.

Pharmaceutically acceptable solvents include, for example, water; alcohol solvents such as methanol, ethanol, n-propanol and isopropanol; ketone solvents such as acetone and methyl ethyl ketone; ester solvents such as ethyl acetate and mixtures thereof. Examples include a solvent. Of these, water, alcoholic solvents and mixed solvents thereof are preferable; water, ethanol and mixed solvents thereof are more preferable; water is particularly preferable.

The amount of the solvent used can be appropriately designed to obtain disintegrating particles having a desired particle size, and for example, 2 to 100 parts by weight with respect to 100 parts by weight of the total amount of each component constituting the disintegrating particles. , 5 to 80 parts by weight, 10 to 60 parts by weight, and 15 to 40 parts by weight.

The number of screws 4 installed in the kneading case 2 is not particularly limited, and may be a uniaxial screw or a biaxial screw. A twin-screw screw is preferable from the viewpoint of excellent transportability of the kneaded product. In the case of a biaxial screw, the rotation direction may be the same direction or different directions.

The shape of the screw is not particularly limited, but a paddle type screw is preferable. Kneading can be easily controlled by appropriately changing the number and angles of paddles.

The extruder device 1 may be a continuous granulation device provided with a sizing unit, a drying device, or the like in the subsequent stage of the kneading case 2. In this case, the screen 5 may be installed at the outlet of the sizing portion.

An extruder device having the above mechanism is described in, for example, Japanese Patent Application Laid-Open No. 11-57452, Japanese Patent No. 6234166, and the like. In addition, granulators commercially available from Dalton Co., Ltd., Fuji Paudal Co., Ltd., Thermo Fisher Scientific Co., Ltd., Freund Sangyo Co., Ltd., etc. can also be used.

The average particle size (D50) of the disintegrating particles is arbitrary and can be appropriately designed according to the particle size and the degree of compression of the medicinal component-containing particles, for example, 5 to 500 μm, 10 to 500 μm, 50 to 450 μm. , 70-400 μm, 100-400 μm, 150-400 μm, 200-400 μm. According to the method for producing disintegrating particles according to the present experimental embodiment, disintegrating particles having various particle diameters can be obtained by appropriately varying the amount of solvent (particularly water) added during granulation and the mesh diameter of the screen. be able to. Further, according to the method for producing disintegrating particles according to the present experimental embodiment, disintegrating particles having an average particle diameter of 100 μm or more can be produced even if the amount of the water-soluble binder used is very small or not used at all as described above. Can be manufactured. Further, as the amount of the binder used is reduced, the disintegration property of the orally disintegrating tablet containing the disintegrating particles can be further improved.

The degree of compression of the disintegrating particles according to this experimental embodiment is preferably 20% or less, preferably 15% or less, and even more preferably 10% or less. By having such a degree of compression, the disintegrating particles show good fluidity, are easily mixed with other components, and are easily filled at the time of tablet molding, so that the formulation process can be performed smoothly, and the tablet can be made. It can exhibit excellent tableting property that it is uniformly compressed.

<Drug-containing particles, etc. and their manufacturing method>
The drug-containing particles and the like according to the present embodiment may be any of powders of medicinal ingredients, compositions containing medicinal ingredients, and granulated products thereof.

The drug contained in the drug-containing particles and the like is not particularly limited, and can be used regardless of properties such as basic, acidic, amphoteric, and neutral, and solubility. In addition, these drugs may be used alone or in combination of two or more.

The particles of the composition containing the medicinal ingredient (drug-containing particles) are produced by granulating by mixing the medicinal ingredient with a pharmaceutically acceptable additive by a conventional method. The pharmaceutically acceptable additive is not particularly limited, and for example, an excipient, a disintegrant, an inorganic additive, a binder, a lubricant, a sweetener, etc. used in the production of the disintegrating particles. Fragrances, coating agents, colorants, solubilizing agents and the like can be used in the same manner. Among them, excipients and / or disintegrants are preferably used, and excipients and / or disintegrants and binders are particularly preferably used.

The apparatus used for granulating a composition containing a medicinal ingredient is not particularly limited, and is a fluidized bed granulation apparatus, an extrusion granulation apparatus, a rolling granulation apparatus, a rolling fluidized bed granulation apparatus, and a high-speed stirring granulation apparatus. Equipment, high-speed mixing and stirring granulation equipment, high-speed stirring and mixing equipment, continuous direct granulation equipment, composite fluidized bed granulation equipment, dry composite equipment and the like can be used.

<Orally disintegrating lock and its manufacturing method>
High hardness is obtained by mixing the above-mentioned drug-containing particles and the like and the disintegrating particles produced by the above-mentioned method with an additive that can be used for tableting, if desired, and then compression-molding by a conventional method. It is possible to obtain an orally disintegrating tablet having an excellent disintegration rate while ensuring the above. Such an orally disintegrating tablet contains a medicinal ingredient in which disintegrating particles in a compressed state in the tablet physically bind to the entire tablet (that is, intervening particles and are compressed integrally) in the presence of water. Disintegrate very quickly (including particles). As a result, the function as an orally disintegrating tablet is fully exhibited, so that there is no particular limitation on the specific composition of the medicinal ingredient or additive in the particles containing the medicinal ingredient and the content ratio thereof.

In a preferred embodiment of the present embodiment, the reason why the orally disintegrating tablet has excellent disintegrating property is not intended to be bound by theory, but is considered as follows. Adjacent components by the hydrophilic and water-insoluble additives that make up each disintegrating particle, which quickly guides the water into contact with the water and places it on the surface of its fine particles. It forms an extremely thin layer of water at the interface with (disintegrating particles, medicinal component-containing particles, etc.), which breaks the bond between their adjacent components, and at the same time water directly from around the tablet into such a layer of water. It is considered that the influx of water rapidly loses the integrity of the tablet containing the disintegrating particles, the medicinal component-containing particles, and the like (the tablet disintegrates).

The additives that can be used for tableting are not particularly limited, and for example, excipients, disintegrants, inorganic additives, binders, lubricants, sweeteners, and fragrances used in the production of the disintegrating particles. , Coating agents, colorants, solubilizing agents and the like can be used in the same manner. Among them, it is preferable to contain at least one selected from the group consisting of a lubricant, an inorganic additive, a sweetener, a coating agent, and a colorant, and it is more preferable to include a lubricant.

The ratio of the disintegrating particles to the total amount of the drug-containing particles and the like and the disintegrating particles is preferably 40 to 90% by weight, more preferably 50 to 85% by weight, still more preferably 60 to 80% by weight.

The compression molding is preferably performed by a direct tableting method, and the tableting pressure at that time varies depending on the size of the tablet, but is usually 2 to 20 kN, preferably 3 to 16 kN, and more preferably 4 to 12 kN.

If the diameter of the orally disintegrating tablet is too large, it will be difficult to swallow, and if it is too small, it will be difficult to grasp and handle. The tablet diameter of the orally disintegrating tablet according to the present embodiment is, for example, 3 to 20 mm, preferably 6 to 12 mm.

The practical hardness of the orally disintegrating tablet according to the present embodiment is preferably 20 N or more, more preferably 25 N or more, still more preferably 30 N or more when the diameter is 4 to 6 mm. With a diameter of 6 to 9 mm, it is preferably 40 N or more, more preferably 45 N or more, still more preferably 50 N or more. With a diameter of 9 to 11 mm, it is preferably 50 N or more, more preferably 60 N or more, still more preferably 70 N or more. With a diameter of 11 to 15 mm, it is preferably 70 N or more, more preferably 85 N or more, and further preferably 100 N or more. When the diameter is 15 mm or more, it is preferably 100 N or more, more preferably 125 N or more, and further preferably 150 N or more. Tablets exceeding the above practical hardness will not be damaged during manufacturing or transportation. In the present embodiment, the hardness of the orally disintegrating tablet is the time when the tablet is cracked by using a tablet hardness tester (TBH-425, manufactured by ERWEKA), sandwiching the tablet from the lateral direction with the jig, and gradually applying pressure. It is obtained by the load (N) of.

As a method for producing an orally disintegrating tablet according to the present embodiment, an additive that can be used for tableting is further added and mixed with the above-mentioned medicinal ingredient-containing particles and the like and the disintegrating particles produced by the above method, if desired. After that, any method may be used as long as it is compression-molded by a conventional method, and a conventional method can be used.

The higher the tablet hardness, the lower the risk of breakage, but it has a contradictory relationship with the disintegration time, and it is preferable to set the disintegration time within a range not exceeding 30 seconds. The disintegration time of the orally disintegrating lock according to the present embodiment is preferably 30 seconds or less, more preferably 27 seconds or less, still more preferably 25 seconds or less. In this embodiment, the disintegration time of the orally disintegrating tablet can be measured by a method according to the Japanese Pharmacopoeia.

Although the present invention will be described based on examples, the present invention is not limited to the examples.

<Measurement of particle size (D50) of drug substance, additive and drug-containing particles>
The particle size (D50) of the drug substance, the additive and the obtained drug-containing particles can be measured by a volume standard with a laser diffraction type particle size distribution measuring device (Malvern Panasonic, MASTERSIZER 3000).

<Measurement of particle size (D50) of disintegrating particles>
The particle size (D50) of the disintegrating particles was measured on a mass basis with a sonic vibration type sieving measuring instrument (Seishin Enterprise Co., Ltd., Robot Shifter RPS-205).

<Measurement of specific volume and degree of compression>
The specific volume is expressed by the volume per unit weight (mL / g) of the powder. The drug-containing particles are naturally dropped into a 100 mL stainless steel cup, the sample raised from the stainless steel cup is scraped off with a flat metal plate, and then the mass of the stainless steel cup containing the sample is measured to loose (mL / g). ) Was calculated. Next, the stainless steel cup was vibrated and the drug-containing particles were added again until the volume change disappeared. The tap (mL / g) was calculated by measuring the mass of the stainless steel cup containing the sample after scraping off the sample raised from the stainless steel cup with a flat metal plate. From the values of loose (mL / g) and tap (mL / g), the degree of compression (%) of the powder was calculated by the following formula. The results are shown in Table 1. The smaller the degree of compression, the better the fluidity of the particles. The specific volume and the degree of compression of the disintegrating particles can also be calculated by the same method.
(Compression degree (%)) = ((loose (mL / g))-(tap (mL / g)) / (loose (mL / g)) × 100

<Hardness measurement>
Using a tablet hardness tester (ERWEKA, TBH425), the load (N) at the time when the tablet was cracked was measured by sandwiching the tablet from the lateral direction with the jig and gradually applying pressure.

<Collapse test>
A disintegration tester (based on the Japanese Pharmacopoeia) was used. 900 mL of water at 37 ° C. was placed in a glass container, and the basket containing the tablets (the bottom was reticulated) was moved up and down in the water of the container, and the time until the tablets collapsed (disintegration time) was measured.

Hereinafter, various APIs used in Examples and Comparative Examples are shown.
Compound A: Cilostazol (Cas No .: 73963-72-1, crushed jet mill)
Compound B: Olmesartan (Cas No .: 144689-24-7, pulverized product)

<Manufacturing of drug (compound A) -containing particles>
According to the amount charged in the table below, a rolling fluidized bed granulator (Paurec Co., Ltd., Multiplex MP-01) was used to prepare a 30% ethanol aqueous solution in which hydroxypropylmethyl cellulose was dissolved under the production conditions shown in Table 2. Layering was performed for 500 minutes while spraying the solution in which compound A was dispersed (Note that the amount in parentheses in the table below indicates the amount when the total amount of the charge other than the 30% ethanol aqueous solution is 100. There is). It was dried to an exhaust temperature of 40 ° C. using a rolling fluidized bed granulator (Paurek Co., Ltd., Multiplex MP-01) and sieved with 42 mesh to obtain drug-containing particles 1.

<Manufacture of disintegrating particles using a fluidized bed granulator>
In Production Examples 1-1, 1-2, and 1-3, a mixture of mannitol, ethyl cellulose, and light anhydrous silicic acid was mixed with a fluidized bed granulator (Paurec Co., Ltd., Multiplex MP-01) according to the charges in the table below. ), And the aqueous dispersion of corn starch and crospovidone was sprayed at the dispersion spraying rate shown in the table below to granulate. In Production Examples 1-4, a mixture of mannitol, ethyl cellulose, and light anhydrous silicic acid was charged into a fluidized bed granulator (Paurec Co., Ltd., Multiplex MP-01) according to the amount charged in the table below. A solution in which corn starch and crospovidone were dispersed in a hydroxypropyl cellulose solution was sprayed at the water dispersion spray rate shown in the table below to granulate (note that the amount in parentheses in the table below indicates the amount of charge other than water. The amount when the total is 100) is displayed). In Production Examples 1-3, the flow of powder during the process stopped, and granulation could not be performed. The obtained wet granulated product was dried and then sieved with 30 mesh to obtain disintegrant particles of Production Examples 1-1, 1-2 and 1-4.

<Manufacturing of disintegrating particles using an extruder device (extrusion granulation device)>
According to the amount charged in the table below, the mixture of each additive was put into a screw type extrusion granulator (Dalton Co., Ltd., Multigran MG-55), and kneaded and granulated under the condition of screw rotation speed of 50 rpm (Note that , The amount in parentheses of the amount charged in the table below indicates the amount with the total amount of additives other than water as 100). The obtained wet granulated product was passed through a wet dry granulator and then dried using a fluidized bed granulator. The dried granulated product was sieved with 22 mesh to obtain disintegrating particles of Production Examples 2-1 to 2-5.

<Manufacturing of tablets>
Using the drug-containing particles 1 and the obtained disintegrating particles, the beating powder was prepared according to the charged amount in the table below, and the tablets were tableted at a tableting pressure of 5 kN so that the tablet mass was 197.4 mg. Reference Example 1 , Comparative Examples 1 and 2, and Examples 1 to 5 tablets (diameter 10.0 mm) were obtained. Locking was performed using a rotary locking machine (Kikusui Seisakusho Co., Ltd., VELA). The hardness and disintegration time of the obtained tablets were measured. The target hardness is 50 N or more and the decay time is 30 seconds or less.

Even if the dispersion liquid was sprayed at a liquid rate setting twice that of Production Example 1-1 by the fluidized bed granulation method, no growth of the particle size of the disintegrating particles was observed (Production Example 1-2), and the liquid was further formed. When the speed was increased, poor flow occurred (Production Example 1-3). On the other hand, the disintegrating particles of Production Example 1-4 produced by adding hydroxypropyl cellulose to the formulation by the fluidized bed granulation method were confirmed to have particle size growth, but were produced using these disintegrating particles. The tablets showed a delay in disintegration time (Comparative Example 2). As described above, in the fluidized bed granulation method, it is difficult to produce disintegrating particles having a large particle size and ensuring a good disintegration time of the tablet when blended in the tablet.

On the other hand, when the extrusion granulation method is used, disintegrating particles having various particle sizes can be obtained by appropriately varying the amount of water added during granulation and the mesh diameter of the screen (Production Example). 2-1 to 2-5). Furthermore, it can be seen that the physical characteristics of the tablets containing these disintegrating particles are also good (Examples 1 to 5).

<Manufacturing of drug (compound B) -containing particles>
Hydroxypropyl cellulose was dissolved in water according to the amount charged in the table below, and a liquid (dispersion liquid A) in which lactose hydrate for dispersion was dispersed in this liquid was prepared. Compound B and lactose hydrate (for preparation) were charged into the fluidized bed granulator, and the dispersion liquid A was sprayed for 40 minutes under the production conditions shown in Table 7 for granulation. After completion of the spray, the mixture was dried using a fluidized bed granulator until the exhaust temperature reached 40 ° C., and sieved with 30 mesh to obtain drug-containing particles 2.

<Manufacturing of disintegrating particles using an extruder device (extrusion granulation device)>
Disintegrating particles of Production Example 2-6 were obtained in the same manner as in Production Example 2-1 according to the charges in the table below. The amount in parentheses in the table below indicates the amount with the total amount of additives other than water as 100.

<Manufacturing of tablets>
Using the drug-containing particles 2 and the obtained disintegrating particles, the beating powder was prepared according to the charged amount in the table below, and tableting was performed at a tableting pressure of 11 kN so that the tablet mass was 360 mg. Tablets of Example 6 and Example 7 (diameter 10.0 mm) were obtained. Locking was performed using a rotary locking machine (Kikusui Seisakusho Co., Ltd., VELA). The hardness and disintegration time of the obtained tablets were measured. The target hardness is 50 N or more and the decay time is 30 seconds or less.

From the results of Production Examples 2-6 and Example 7, even if the disintegrant was changed to carmellose in the extrusion granulation method, disintegrating particles having a particle size of 100 μm or more were obtained, and the disintegrating particles were blended. It can be seen that the physical properties of the tablets are also good.

<Manufacture of disintegrating particles using an extruder device (continuous granulation device)>
According to the amount charged in the table below, the mixture of each additive was put into a continuous granulator (Freund Sangyo Co., Ltd., Granulator) and kneaded and granulated under the condition of screw rotation speed of 20 rpm (Note that the table below). The amount in parentheses of the amount charged in is indicated by the total amount of additives other than water as 100). A screw was inserted in which 20 paddles were arranged so as to be offset by 60 °. The obtained wet granulated product was dried to an exhaust temperature of 74 ° C. and then sieved with 30 mesh to obtain disintegrating particles of Production Example 3-1.

<Manufacturing of tablets>
Using the drug-containing particles 2 and the obtained disintegrating particles, the beating powder was prepared according to the charged amount in the table below, and the tableting pressure was 9.0 kN so that the tablet mass was 180 mg. Reference Example 3, Tablets of Example 8 and Example 9 (8.0 mm in diameter) were obtained. Locking was performed using a rotary locking machine (Kikusui Seisakusho Co., Ltd., VELA). The hardness and disintegration time of the obtained tablets were measured. The target hardness is 40 N or more and the decay time is 30 seconds or less.

From the results of Production Examples 2-7 and Example 9, even when the continuous granulation method is used, disintegrating particles having a particle size of 100 μm or more can be obtained as in the extrusion granulation method, and the disintegrating particles can be obtained. It can be seen that the physical properties of the blended tablets are also good.

From the above results, it can be seen that the extrusion granulation method or the continuous granulation method can produce disintegrating particles having a large particle size and ensuring a good disintegration time of the tablet when blended in the tablet.

According to the present invention, it is possible to design and manufacture disintegrating particles having a desired particle size. Further, according to the present invention, various orally disintegrating tablets having excellent hardness, disintegration rate and content uniformity can be produced without depending on the composition and properties of the medicinal component-containing particles and the like. It can be used to manufacture disintegrating tablets.

1 Extruder device 2 Kneading case (paddle)
3 Raw material supply unit 4 Screw 5 Screen

Claims (9)

Disintegration for the manufacture of orally disintegrating tablets, comprising mixing and granulating the excipient and / or disintegrant with a pharmaceutically acceptable solvent while axially transporting them with a rotating screw in a kneading case. Method for producing sex particles. The method for producing disintegrating particles according to claim 1, wherein the average particle size (D50) of the disintegrating particles is 70 to 400 μm. The method for producing disintegrating particles according to claim 1 or 2, wherein the disintegrating particles contain an excipient containing sugar and / or a sugar alcohol. The method for producing disintegrating particles according to any one of claims 1 to 3, wherein the disintegrating particles further contain a hydrophilic and water-insoluble inorganic additive. The method for producing disintegrating particles according to any one of claims 1 to 4, wherein the disintegrating particles further contain a water-insoluble binder other than crystalline cellulose. The method for producing disintegrating particles according to any one of claims 1 to 5, wherein the content of the water-soluble binder in the disintegrating particles is less than 3.0% by weight. The method for producing disintegrating particles according to any one of claims 1 to 6, wherein the content of crystalline cellulose in the disintegrating particles is less than 10.0% by weight. The step of obtaining disintegrating particles by the production method according to any one of claims 1 to 7, and the disintegrating particles, a powder of a medicinal ingredient, a composition containing the medicinal ingredient, or a granulated product thereof. A method for producing an orally disintegrating tablet, which comprises a step of compression-molding a mixture with an additive that can be used for tableting. An orally disintegrating tablet produced by the production method according to claim 8.

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