JP6379884B2 - Orally disintegrating tablet and method for producing orally disintegrating tablet - Google Patents

Description

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

  Orally disintegrating tablets are easy to take for elderly people, children, and patients who have difficulty swallowing because the tablets disintegrate in the mouth and are easy to take even without water. As a method for producing an orally disintegrating tablet easily and at low cost, a production method described in Patent Document 1 is known.

International Publication No. 2013/125497

  Orally disintegrating tablets are easier to take as the disintegration time is shorter, but on the other hand, it is not preferable that wear occurs. Therefore, an orally disintegrating tablet with a desired disintegration time and low friability is desired.

  This invention is made | formed in view of the situation mentioned above, and aims at providing an orally disintegrating tablet with a short disintegration time and low friability.

  (1) The present invention relates to an orally disintegrating tablet having a bulging portion that bulges outward from each circular plane located above and below a cylindrical shape. Each of the planes is located at a peripheral edge adjacent to the cylindrical peripheral surface, and a length that is the shortest distance between the peripheral surface and the bulging portion in a cross section orthogonal to the plane is 0.01 to 0. 0.09 mm.

  (2) Preferably, the orally disintegrating tablet is tableted with particles containing a physiologically active substance, to which an aqueous sugar alcohol solution has been applied.

  (3) Preferably, the orally disintegrating tablet has a friability of 0.1% or less according to the friability test method of the tablet prescribed in the Japanese Pharmacopoeia.

  (4) Preferably, the orally disintegrating tablet has a disintegration time of 40 seconds measured using a Tricorp Tester (registered trademark) at a dropping speed of 6 mL / min, a dropping height of 8 cm, and a load of 40 g. It is as follows.

  (5) The method for producing an orally disintegrating tablet according to the present invention comprises a granulation step of granulating particles containing a physiologically active substance while applying an aqueous sugar alcohol solution, and particles obtained by the granulation step, A tableting step of tableting into a shape having a bulging portion that swells outward from each circular plane located above and below the columnar shape using a punch having a land width of 0.01 to 0.09 mm. .

  (6) Preferably, the sugar alcohol aqueous solution contains 18% (W / V) or more of sugar alcohol.

  (7) Preferably, the sugar alcohol aqueous solution is heated to 60 ° C. or higher.

  (8) Preferably, the application of the sugar alcohol aqueous solution is performed by spraying, dipping, or coating.

  According to the present invention, an orally disintegrating tablet with a short disintegration time and low friability is realized.

FIG. 1 is a plan view showing the structure of the orally disintegrating tablet 10. FIG. 2 is a front view showing the structure of the orally disintegrating tablet 10. FIG. 3 is a cross-sectional view showing the structure of the mortar 21, the upper punch 22, and the lower punch 23.

  Hereinafter, embodiments of the present invention will be described with appropriate reference to the drawings.

  A tablet refers to a solid preparation in which particles containing a physiologically active substance added with additives such as excipients and disintegrants are molded into a fixed shape by a method such as compression molding. An orally disintegrating tablet refers to a tablet prepared to disintegrate in the oral cavity without taking a liquid such as water together.

  As shown in FIGS. 1 and 2, the orally disintegrating tablet 10 has bulging portions 13 and 14 that swell in a vertical direction 7 from circular planes 11 and 12 positioned above and below a cylindrical shape.

  The planes 11 and 12 are perfect circles, but may be, for example, an ellipse, an egg shape, a rugby ball shape, or the like. The planes 11 and 12 are located on the periphery of the cylindrical shape adjacent to the peripheral surface 15 that is a curved surface, and are continuous in an annular shape. The planes 11 and 12 have the same shape. The peripheral surface 15 has a constant diameter in the up-down direction 7.

  The length in the radial direction of the planes 11 and 12, that is, the length that is the shortest distance between the peripheral surface 15 and the bulging portions 13 and 14 in the II-II cross section that is orthogonal to the planes 11 and 12 and passes through the center of the cylindrical shape. L is 0.01 to 0.09 mm, preferably 0.03 to 0.08 mm, and more preferably 0.04 to 0.06 mm. If the length L is short, the degree of wear will be low, but if the length L is too short, it will be difficult to continuously form the flat surfaces 11 and 12 adjacent to the peripheral surface by the saddle land.

  The bulging portions 13 and 14 have the same shape except that the position and orientation in the vertical direction 7 are different. To explain the bulging portion 13 as an example, the bulging portion 13 has an inclined surface 16 adjacent to the plane 11 and a circular plane 17 adjacent to the inclined surface 16. An angle θ at which the inclined surface 16 and the plane 11 intersect is about 30 °. The radial width when the inclined surface 16 is projected onto the plane 11 is about 10 to 20% with respect to the diameter of the plane 11. In addition, the outer surface of the bulging portion 13 does not necessarily need to be configured by the inclined surface 16 and the flat surface 17. For example, the outer surface of the bulging portion 13 may be a curved surface that swells in a dome shape as a whole. You may comprise combining.

The manufacturing method of the orally disintegrating tablet 10 includes the following steps.
(1) A granulation step of granulating particles containing a physiologically active substance while applying an aqueous sugar alcohol solution.
(2) The particles obtained by the granulation step are swelled outward from the planes 11 and 12 using the ridges (upper ridge 22 and lower ridge 23) having a land width of 0.01 to 0.09 mm. A tableting process for tableting into a cylindrical shape having portions 13 and 14.

  The physiologically active substance is not particularly limited, and includes any substance that has pharmacologically physiological activity. Examples of the physiologically active substance include candesartan cilexetil, aripiprazole, lansoprazole, omeprazole, rabeprazole, pantoprazole, leminoprazole, tenatoprazole, mevastatin, lovastatin, pravastatin, simvastatin, pitavastatin, atorvastatin, acarbose, furopropion, dilazep hydrochloride Salt hydrates, digitoxin, ubidecalenone, and nicorandil.

  The shape of the particle containing the physiologically active substance is not particularly limited, and examples thereof include powder, solid, and granule.

  The granulation step for obtaining particles containing a physiologically active substance is performed by mainly mixing excipients with the physiologically active substance. In addition to excipients, particles containing physiologically active substances may contain other additives such as disintegrants, fluidizers, stabilizers, colorants, lubricants, flavoring agents, and fragrances. Good. Additives such as physiologically active substances and excipients may be crushed as appropriate. The mixing amount and mixing method of various additives are appropriately selected. The mixing method is not particularly limited, and examples thereof include a method of mixing with a powder and a method of mixing after dissolving in a solvent such as water and evaporating the solvent. The granulating method is not particularly limited, and examples thereof include a method using a fluidized bed granulator / dryer, a stirring granulator, a cylindrical extrusion granulator, a rolling fluidized bed granulating / coating machine, a spray dryer and the like.

  A sugar alcohol aqueous solution, preferably a high-concentration sugar alcohol aqueous solution is formed on the outer surface of the particle containing the physiologically active substance in any of the granulation steps, that is, before granulation, during granulation, or after granulation. Is granted. Here, “applied to the outer surface of the particle” comprehensively represents a state in which the sugar alcohol aqueous solution is provided toward the outer surface of the particle containing the physiologically active substance. A state in which the inside of the particles is impregnated after the sugar alcohol aqueous solution is applied to the outer surface is also included.

  The sugar alcohol is not particularly limited, and examples thereof include mannitol, xylitol, sorbitol, erythritol, and mannitol is particularly preferable. It does not specifically limit as mannitol, For example, D-mannitol is mentioned. For example, the mannitol content of the high-concentration mannitol aqueous solution is 18% (w / v) or more, preferably 20% (w / v) or more, which is the saturated solubility of mannitol in water at 25 ° C. The preparation of the sugar alcohol aqueous solution is not particularly limited, but is preferably performed under heating. The set temperature under heating, that is, the heating temperature is not particularly limited, but is preferably 60 ° C. or higher.

  For the application of the sugar alcohol aqueous solution to the outer surface of the particle containing the physiologically active substance, various methods and means used in the art are used. For example, spraying, dipping, or application may be mentioned. Moreover, these methods may be combined as appropriate. In addition, the quantity and time which provide sugar alcohol aqueous solution are not specifically limited.

  The shape of the particles obtained by granulation is not particularly limited, and examples thereof include fine particles and granules. The size of the particle is not particularly limited as long as it can be tableted. The particles may be appropriately sized. The sizing method is not particularly limited, and examples thereof include a method using a sizing machine and a classifier.

  The particles containing the physiologically active substance to which the sugar alcohol aqueous solution has been applied are then tableted. Tableting is performed by mixing additives such as excipients, disintegrants, fluidizers, stabilizers, colorants, lubricants, flavoring agents, and fragrances as necessary. As a tableting method, a tableting mortar, a tableting upper punch and a lower punch are used, and a hydraulic hand press machine, a single-shot tableting machine, a rotary tableting machine or the like is used.

  As shown in FIG. 3, for example, in a rotary tableting machine, an upper punch 22 is provided above a mortar 21 having a cylindrical through hole 20 penetrating in the vertical direction 7, and a lower punch is provided below. 23 is provided. The leading end portion of the upper punch 22 and the leading end portion of the lower punch 23 can enter the through hole 20 of the mortar 21, respectively. A concave portion corresponding to the outer shape of the orally disintegrating tablet 10 is formed at the distal end of the upper collar 22 and the distal end of the lower collar 23. For example, the recess 24 has a curved surface 25 corresponding to the bulging portion 13 of the orally disintegrating tablet 10 and a land surface 26 corresponding to the flat surface 11. The width along the radial direction of the land surface 26, that is, the land width is 0.01 to 0.09 mm, and more preferably 0.04 to 0.08 mm. Although a detailed description of the concave portion of the lower collar 23 is omitted, the same curved surface and land surface as the concave portion 24 of the upper collar 22 are formed.

Tableting is performed by adjusting so that the resulting tablet has an appropriate hardness and can be rapidly disintegrated as an orally disintegrating tablet. The tableting pressure is appropriately adjusted according to the tableting method, the equipment used for tableting, the size of the tablet, the physiologically active substance, and the like. For example, when using the said apparatus, it is 5-30 kg / cm < ² > normally, Preferably it is 5-20 kg / cm < ² >. The obtained tablet may be further subjected to a predetermined coating using a coating agent.

  The size of the tablet is not particularly limited, and for example, the diameter is about 5 to 10 mm and the thickness is about 2 to 4 mm. The hardness is preferably 30N or more. As the friability, the friability according to the friability test method for tablets prescribed in the Japanese Pharmacopoeia is preferably 0.1% or less. The disintegration time is preferably within 60 seconds in the oral cavity when taken without water. As an objective criterion for the disintegration time, a disintegration time measured using a Tricorp Tester (registered trademark) under conditions of a dropping speed of 6 mL / min, a dropping height of 8 cm, and a load of 40 g is preferably 60 seconds or less. is there.

  The excipient is not particularly limited, and examples thereof include celluloses (crystalline cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose) and the like) and derivatives thereof, starch (corn starch) corn starch), potato starch. , Wheat starch, rice starch, partially pregelatinized starch, hydroxypropyl starch, etc. and derivatives thereof, sugar (glucose, lactose, sucrose (including purified sucrose)), powdered sugar, trehalose, dextran, dextrin, etc., sugar alcohol (mannitol) , Xylitol, sorbitol, erythritol, etc.), glycerin fatty acid ester, inorganic powder (magnesium aluminate metasilicate, synthetic hydrotalcite), soft anhydrous silicic acid, anhydrous phosphoric acid calcine Um, precipitated calcium carbonate, calcium silicate, calcium hydrogen hydrate phosphate, anhydrous calcium hydrogen phosphate, and inorganic salts such as sodium hydrogen carbonate. Preferred are mannitol, crystalline cellulose, and starch. These may be used alone or in combination of two or more.

  The disintegrant is not particularly limited, and for example, crospovidone, crystalline cellulose, carboxymethylcellulose (carmellose), croscarmellose sodium, carboxymethyl starch sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, starch, partially gelatinized Examples include starch, hydroxypropyl starch, calcium carbonate, precipitated calcium carbonate, calcium citrate, soft anhydrous silicic acid, and synthetic aluminum silicate. Preferred are crospovidone, carmellose, croscarmellose, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, starch, and hydroxypropyl starch. These may be used alone or in combination of two or more.

  The fluidizing agent is not particularly limited, and examples thereof include hydrous silicon dioxide, soft anhydrous silicic acid, talc, synthetic aluminum silicate, titanium oxide, stearic acid, magnesium stearate, calcium stearate, magnesium aluminate metasilicate. . These may be used alone or in combination of two or more.

  The stabilizer is appropriately selected according to the physiologically active substance. For example, if the physiologically active substance is an acid labile substance such as aripiprazole, lansoprazole, omeprazole, rabeprazole, pantoprazole, leminoprazole, tenatoprazole, mevastatin, lovastatin, pravastatin, simvastatin, pitavastatin, atorvastatin, As a stabilizer, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, sodium phosphate, sodium dihydrogen phosphate, magnesium oxide, magnesium hydroxide, Examples include basic additives such as L-arginine, L-lysine, meglumine, and magnesium aluminate metasilicate. In addition, if the physiologically active substance is an alkali labile substance such as acarbose, furopropion, dirazep hydrochloride hydrate, digitoxin, ubidecarenone, etc., as a stabilizer, citric acid, malic acid, succinic acid, Acid additives such as acid, maleic acid, fumaric acid, aspartic acid, glutamic acid and phosphoric acid can be mentioned. In addition, if the physiologically active substance is a substance that is easily decomposed during tableting, such as candesartan cilexetil, nicorandil, etc., as a stabilizer, fats and oils such as stearic acid, stearic alcohol, polyethylene glycol, glycerin, propylene glycol -Like additives.

  The coating agent is not particularly limited, and examples thereof include hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), aminoalkyl methacrylate copolymer, titanium oxide, and polyethylene glycol (Macrogol 6000). These may be used alone or in combination of two or more.

  The colorant is not particularly limited. For example, iron sesquioxide (red), yellow sesquioxide, yellow iron oxide, orange essence, brown iron oxide, caramel, soft anhydrous silicic acid, edible blue No. 1, edible blue 2 No. 4, Edible Yellow No. 4, Edible Yellow No. 5, Edible Red No. 2, Edible Red No. 3, Edible Red No. 102, Edible Blue No. 1 Aluminum Lake, Edible Blue No. 2 Aluminum Lake, Edible Yellow No. 4 Aluminum Lake, Edible Yellow No. 5 aluminum lake, food red No. 2 aluminum lake, food red No. 3 aluminum lake, food red No. 102 aluminum lake, talc, sodium fluorescein, green tea powder, vitamin C and the like. These may be used independently and 2 or more types may be used together.

  The lubricant is not particularly limited, and examples thereof include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, soft anhydrous silicic acid, hydrogenated oil, glycerin fatty acid ester, and talc. Can be mentioned. Preferred are magnesium stearate, sodium stearyl fumarate, calcium stearate, and sucrose fatty acid ester. These may be used independently and 2 or more types may be used together.

  The corrigent is not particularly limited, and examples include aspartame, stevia, sugar alcohol, saccharin sodium, dipotassium glycyrrhizin, thaumatin, acesulfame potassium, and sucralose. These may be used independently and 2 or more types may be used together.

  The fragrance is not particularly limited, and examples include orange corton and pineapple flavor. These may be used independently and 2 or more types may be used together.

  Examples of the present invention will be described below, but it goes without saying that the present invention is not limited to the following examples.

[Example]
300 g of aripiprazole, 5300 g of D-mannitol and 1000 g of low-substituted hydroxypropylcellulose were put into a fluidized bed granulator (MP-01 manufactured by POWREC Co., Ltd.), 1400 g of D-mannitol and 0.8 g of edible blue No. 2 at 60 ° C. Then, a high concentration mannitol aqueous solution (25% (w / v)) obtained by dissolving in 4200 g of purified water was sprayed and granulated. 1400 g of crystalline cellulose and 100 g of magnesium stearate are mixed with the obtained particles, and this mixture is put into a tableting machine (VIRGO512SS2AZ manufactured by Kikusui Seisakusho Co., Ltd.) and tableted using a punch having a diameter of 6 mm and a land width of 0.05 mm. Tableting was performed at a pressure of 6 kN to obtain an orally disintegrating tablet.

[Comparative example]
An orally disintegrating tablet was obtained in the same manner as in the Example except that a tablet having a diameter of 6 mm and a land width of 0.1 mm was used in the tableting machine.

[Hardness test]
Hardness was measured using a tablet hardness tester (Dr. Schleuniger Pharmatro Tablet Tester 8M). The results are shown in Table 1.

[Abrasion test]
According to the 16th revision Japanese Pharmacopoeia, page 2062, the friability test method described in Example and Comparative Example was used for the orally disintegrating tablets using a friability tester manufactured by Higaki Medical Science Co., Ltd. Degree test was conducted. The results are shown in Table 1.

[Disintegration time measurement test]
Using a tricoop tester (registered trademark (Nipro Corporation), manufactured by Okada Seiko Co., Ltd.), the measurement was performed under conditions of a dropping speed of 6 mL / min, a dropping height of 8 cm, and a load of 40 g. The results are shown in Table 1.

  As is clear from Table 1, the orally disintegrating tablet according to the example has a friability of 0.046%, which is significantly higher than the friability of the orally disintegrating tablet according to the comparative example of 0.340%. It was a small value. The disintegration time of the orally disintegrating tablet according to the example was 15.3 seconds, which was shorter than the disintegration time of the orally disintegrating tablet according to the comparative example.

DESCRIPTION OF SYMBOLS 10 Orally disintegrating tablet 11,12 Plane 13,14 Swelling part 15 Perimeter surface 22 Upper collar 23 Lower collar

Claims (8)

An orally disintegrating tablet having a bulging portion that swells outward from each circular plane located above and below the cylindrical shape,
Each of the planes is located at a peripheral edge adjacent to the cylindrical peripheral surface, and a length that is the shortest distance between the peripheral surface and the bulging portion in a cross section orthogonal to the plane is 0.01 to 0. Orally disintegrating tablet which is 0.09 mm.   The orally disintegrating tablet according to claim 1, wherein particles containing a physiologically active substance, to which an aqueous sugar alcohol solution is added, are tableted.   The orally disintegrating tablet according to claim 1 or 2, wherein the tablet has a friability of 0.1% or less according to the friability test method defined in the Japanese Pharmacopoeia.   The disintegration time measured using a Tricorp Tester (registered trademark) under the conditions of a dropping speed of 6 mL / min, a dropping height of 8 cm, and a load of 40 g is 40 seconds or less. Orally disintegrating tablets. A granulation step of granulating particles containing a physiologically active substance while providing an aqueous sugar alcohol solution;
The shape of the particles obtained by the granulation step is a shape having bulges that swell outward from each circular plane located above and below the columnar shape using a ridge having a land width of 0.01 to 0.09 mm. And a tableting step for tableting into a tablet.   The method for producing an orally disintegrating tablet according to claim 5, wherein the sugar alcohol aqueous solution contains 18% (W / V) or more of sugar alcohol.   The method for producing an orally disintegrating tablet according to claim 5 or 6, wherein the sugar alcohol aqueous solution is heated to 60 ° C or higher. The method for producing an orally disintegrating tablet according to any one of claims 5 to 7, wherein the application of the sugar alcohol aqueous solution is performed by spraying, dipping, or coating.

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