JP2017052754A - Method for producing orally disintegrating tablet, and granules used for the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a technique of obtaining an orally disintegrating tablet having sufficient hardness and disintegratability.SOLUTION: A method for producing orally disintegrating tablet containing pharmaceutically active ingredients, low-substituted hydroxypropyl cellulose of fine powder grade, and binder has: a process of subjecting a powder composition containing low-substituted hydroxypropyl cellulose of fine powder grade to wet stirring granulation by using binding liquid containing water to obtain granules; and a process of tabletting a granule composition containing the granules.SELECTED DRAWING: None

Description

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

  Oral medicines include tablets, fine granules, capsules, jellies and the like, and some tablets are called orally disintegrating tablets. Orally disintegrating tablets are designed to disintegrate with a small amount of water or a small amount of water in the amount of saliva in the oral cavity of a patient, which can increase patient compliance. An orally disintegrating tablet is required to be easily disintegrated in the oral cavity, while being required to have sufficient tablet hardness.

  Orally disintegrating tablets are generally obtained by obtaining granules containing a disintegrant and tableting the granules together with a binder. Here, by making the disintegrant contained in the granules for the production of orally disintegrating tablets low-substituted hydroxypropylcellulose, there is a technique for achieving both improvement in hardness of the resulting tablet and improvement in disintegration. Have been reported (see Patent Document 1 and Non-Patent Document 1).

JP 2010-189384 A

Summary of the 27th Symposium on Formulation and Particle Design (2010) Page 150 Fast-disintegrating tablet in the oral cavity using L-HPC aqueous dispersion granulation method (Shin-Etsu Chemical Co., Ltd.)

  As described above, a technique for obtaining an orally disintegrating tablet having sufficient hardness and disintegration has been proposed. However, in these techniques, granules are often obtained by fluid bed granulation. This is because the granules obtained by the fluidized bed granulation method have a relatively low hardness, and thus the hardness of the tablets obtained by compressing them tends to be high. However, fluidized bed granulation requires a long time for granulation and has many production parameters, so that there are many problems such as differences in physical properties between lots and changes in physical properties when the production scale is changed.

  Then, this invention provides the technique which obtains the orally disintegrating tablet which has sufficient hardness and disintegration by tableting the granule composition containing the granule obtained by wet stirring granulation.

The present invention is as follows.
[1] A method for producing an orally disintegrating tablet comprising a pharmaceutically active ingredient, a fine powder grade low-substituted hydroxypropyl cellulose, and a binder,
A step of wet granulating a powder composition containing a fine powder grade low-substituted hydroxypropyl cellulose using a binding solution containing water to obtain granules; and a step of tableting the granule composition containing the granules; The manufacturing method containing.
[2] The production method according to claim 1, wherein the content of the low-substituted hydroxypropylcellulose in the powder composition is 6 to 30% by mass.
[3] The production method according to [1] or [2], wherein the binding liquid further contains a low-viscosity binder.
[4] Granules obtained by wet-stirring granulation of a powder composition containing fine powder grade low-substituted hydroxypropylcellulose with a binding liquid containing water.

  The orally disintegrating tablet of the present invention has sufficient disintegration property and high hardness despite being manufactured by tableting a granule composition containing granules obtained by wet stirring granulation.

It is a graph which shows the result of having measured the hardness of the tablet obtained in Example 1, 2, and 3. FIG. It is a conceptual diagram which shows the state of the tablet set to the measuring apparatus in the measurement of tablet hardness.

  The method for producing an orally disintegrating tablet of the present invention includes 1) a step of obtaining granules by wet-stir granulating a powder composition containing a fine powder grade low-substituted hydroxypropyl cellulose using a binding solution containing water ( And 2) a step of tableting the granule composition containing the granule (also referred to as a “tablet step”).

1) About granulation process The granulation process in this invention is a process of carrying out wet stirring granulation of the powder composition containing low substituted hydroxypropyl cellulose using a binding liquid.

  Wet stirring granulation is a method in which raw material granules are put into a granulation vessel, and agitation liquid such as water is added while stirring with a rotating blade to aggregate the raw material granules into spherical particles. It is. Although the apparatus which performs wet stirring granulation is divided roughly into a batch type stirring granulator and a continuous stirring granulator, the granulation process in this invention may be performed by any apparatus.

  Moreover, wet stirring granulation is classified into a low-speed rotation type and a high-speed rotation type according to the rotation speed of stirring. The low-speed rotation type wet agitation granulation can be performed with a Shinagawa kneader or the like. The rotation speed of the low-speed rotation blade is preferably set to 100 rpm or less. On the other hand, the high-speed rotation type wet stirring granulation can be performed with a high-speed mixer or the like. A high-speed rotating granulator may have two rotating blades, an agitator (stirring blade) and a chopper (breaking blade). Set the rotation speed of the agitator to 100 rpm or more and set the rotation speed of the chopper to 1000 rpm or more. Often set to.

  The granulation step in the production method of the present invention may be preferably performed by low-speed rotation type wet stirring granulation. This is because, by adopting the low-speed rotation type, a certain amount of voids can be provided in the obtained granules, and the hardness of the granules can be lowered. When tablets with low hardness are tableted, the compression rate of the resulting tablets increases and the tablet hardness increases. Moreover, since the granule with low hardness is easy to plastically deform, the moldability in tableting also increases.

  The granulated powder composition contains at least low-substituted hydroxypropyl cellulose (L-HPC). Low substituted hydroxypropylcellulose can act as a disintegrant. The low-substituted hydroxypropyl cellulose preferably has a fine powder grade particle size. The fine powder grade preferably has a D50 of 50 μm or less, and more preferably 30 μm or less. By making the low-substituted hydroxypropylcellulose a fine powder grade, the tablet hardness of the resulting orally disintegrating tablet is increased and the disintegration in the oral cavity of the resulting orally disintegrating tablet is smoothed (improving mouse feeling) )be able to. Fine powder grade low-substituted hydroxypropylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd. LH-31 (D50 = 20μm), LH-32 (D50 = 20μm), LH-21 (D50 = 45μm), LH-22 (D50) = 45 μm).

  The content of the low-substituted hydroxypropylcellulose in the powder composition is preferably 6 to 30% by mass, preferably 6 to 20% by mass, and more preferably 8 to 15% by mass. Moreover, it is preferable to set so that content of the low-substituted hydroxypropyl cellulose in the orally disintegrating tablet obtained is preferably 5 to 25% by weight, 5 to 19% by weight, and preferably 6 to 14% by weight.

  In general, a granulated product (granule) obtained by wet stirring granulation is a granule that is dense and hardly plastically deformed. When granules that are difficult to plastically deform are tableted, there is a problem that the hardness of the tablets (orally disintegrating tablets) obtained thereby is difficult to increase. In contrast, in the present invention, a relatively high amount of low-substituted hydroxypropyl cellulose is added to the powder composition, so that moisture can be easily taken into the granulated product in wet stirring granulation, and the granulated product is swollen. It is easy to do. When the swollen granulated product is dried, voids are generated in the dried granulated product, and as a result, low hardness granules can be obtained. As a result, the hardness of the orally disintegrating tablet obtained by tableting can be increased.

  The powder composition to be granulated may contain other components other than the low-substituted hydroxypropylcellulose. Specifically, a diluent and the like are included, and further, a pharmaceutically active ingredient (API), a disintegrating agent other than low-substituted hydroxypropylcellulose, a bulking agent, and the like can be included.

  Examples of diluents include sugar alcohols or sugars, specifically mannitol, sorbitol, erythritol, lactose, sucrose and the like. The content of the diluent in the powder composition is preferably 10 to 95% by mass, more preferably 40 to 95% by mass; the content of the diluent in the orally disintegrating tablet is preferably 5 to 90% by mass. More preferably, it is 50-85 mass%.

  Examples of active pharmaceutical ingredients include central nervous system drugs, antipyretic analgesics, cardiovascular drugs, respiratory drugs, digestive drugs, antibiotics and chemotherapeutic agents, metabolic drugs, urinary drugs, vitamin drugs Etc., but not particularly limited. Content of the pharmaceutical active ingredient in an orally disintegrating tablet is not specifically limited, What is necessary is just to set according to the effect and efficacy of the pharmaceutical active ingredient.

Examples of central nervous system drugs include olanzapine, aripiprazole, mirtazapine, diazepam, idebenone, lorazepam, nitrazepam, phenytoin, memantine, galantamine, eszopiclone, selegiline, escitalopram oxalate and the like.

  Examples of antipyretic analgesics include aspirin, ibuprofen, paracetamol, naproxen, piroxicam, diclofenac, indomethacin, sulindac, acetaminophen, etenzamid, ketoprofen and the like.

  Examples of circulatory drugs include olmesartan, molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedibin, atenolol, spironolactone, metoprolol, vindolol, captopril, izorbitan nitrate, eletriptan, cinacalcet, azilsartan, etc. It is.

  Examples of respiratory drugs include amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, guaifenesin and the like.

  Examples of gastrointestinal drugs include 2-[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl] penzimidazole and 5-methoxy-2-[( 4-methoxy-3,5-dimethyl-2-pyridyl) methylsulfinyl] benzimidazole drugs having anti-ulcer activity such as benzimidazole, cimetidine, ranitidine, pancreatin, bisacodyl, 5-aminosalicylic acid and the like.

  Examples of antibiotics and chemotherapeutic agents include cephalexin, cefaclor, cefradine, amoxicillin, pivampicillin, bacampicillin, dicloxacillin, erythromycin, erythromycin stearate, lincomycin, doxycycline, trimethoprim / sulfamethoxazole and the like.

  Examples of metabolic drugs include serrapeptase, lysozyme chloride, adenosine triphosphate, glibenclamide, potassium chloride, febuxostat and the like.

  Examples of urinary drugs include solifenacin and the like.

  Examples of vitamin drugs include vitamin B1, vitamin B2, vitamin B6, vitamin C and the like.

  Examples of disintegrants other than low-substituted hydroxypropylcellulose include corn starch, potato starch, partially pregelatinized starch, carboxymethyl starch sodium, carmellose, croscarmellose sodium, crystalline cellulose, crospovidone, and the like.

  Examples of the bulking agent include erythritol, mannitol, sorbitol, lactose, sucrose, calcium phosphate, calcium sulfate and the like.

  In the granulation step in the present invention, the powder composition is granulated with a binding liquid containing water. The binding liquid may contain only water, but preferably contains a binder together with water. The binder contained in the binding liquid is preferably a water-soluble low viscosity binder. By making the binder contained in the binding liquid for granulation a low viscosity type, the disintegration property of the orally disintegrating tablet obtained is improved. Examples of low-viscosity binders include dextrin, hydroxypropylcellulose, hypromellose, povidone, polyvinyl alcohol / polyethylene glycol graft copolymer (product name: Kollicoat IR), copolymer of polyvinyl alcohol and acrylic acid, methyl methacrylate (product) Name: POVA coat). The amount of the binder with respect to the orally disintegrating tablet is preferably 0.5 to 3% by mass.

  Various parameters in the granulation step (stirring granulation step) in the present invention include agitation speed, agitation time, amount of binding liquid, and the like. In agitation granulation, once these parameters are set appropriately, reproducibility is good. It is easy to obtain a granulated product (granule) of the same quality. In contrast, fluidized bed granulation has many types of parameters (intake air temperature, exhaust air temperature, supply air volume, spray flow rate, spray pressure, etc.), and while confirming the progress of the granulation process, The parameter needs to be adjusted. For this reason, the granules obtained by fluidized bed granulation are likely to cause problems such as differences in physical properties between lots or changes in physical properties when the production scale is changed. Thus, in this invention, the granule which has a desired characteristic can be obtained simply.

2) About tableting process The tableting process in the manufacturing method of this invention is a process of tableting the granule composition containing the granule obtained by the granulation process of said 1), and a binder.

  The binder contained in the granule composition is not particularly limited, but is preferably a disintegrant binder, and examples thereof include crystalline cellulose and hydroxypropyl cellulose, and crystalline cellulose is preferred. It is preferable that content of the binder in a granule composition or the orally disintegrating tablet obtained is 3-20 mass%.

  The granule composition may further contain a lubricant, a taste-masking ingredient, a fragrance and the like. Examples of lubricants include stearic acid, stearates (such as magnesium stearate), sucrose fatty acid esters and the like. Examples of taste masking ingredients include citric acid, tartaric acid, malic acid and the like. Examples of flavoring agents include menthol, mint oil, vanillin and the like.

Moreover, the granule composition may contain other granules in addition to the granules obtained in the granulation step of 1). Specifically, the following modes can be considered.
A. The granules containing the active pharmaceutical ingredient together with the granules not containing the active pharmaceutical ingredient obtained in the granulation step of 1) are combined and compressed.
B. Together with the granules containing the active pharmaceutical ingredient obtained in the granulation step of 1), the granules containing the other active pharmaceutical ingredients are combined and compressed (a combination tablet containing two or more active pharmaceutical ingredients is obtained).

  The tableting pressure of the granule composition may be set so that the obtained orally disintegrating tablet has appropriate tablet hardness and disintegration. Although not particularly limited, the tableting pressure may be about 300 kgf or more, usually 500 kgf or more, preferably 700 kgf or more, or 1000 kgf or more.

About Orally Disintegrating Tablet The orally disintegrating tablet of the present invention preferably has both improved disintegration and improved tablet hardness. Usually, the hardness of an orally disintegrating tablet is 2 kgf or more, usually 3 kgf or more, preferably 4 kgf or more, more preferably 5 kgf or more, and further preferably 6 kgf or more. Further, the disintegration property of the orally disintegrating tablet of the present invention is that the disintegration time measured by the orally disintegrating tablet test tenth, orally disintegrating tablet tester ODT-101 (manufactured by Toyama Sangyo Co., Ltd.) is 30 seconds or less. It is preferably 20 seconds or less.

  In general, granules obtained by wet stirring granulation have relatively high density, dense particles, and high hardness, so that the hardness of tablets obtained by tableting them tends to decrease. The orally disintegrating tablet of the present invention can have a sufficiently high tablet hardness despite the tableting of granules obtained by wet stirring granulation. For example, it may have a tablet hardness comparable to that of a tablet obtained by tableting granules obtained by a fluidized bed granulation method with relatively low hardness. This is because the granulated product (granules) in the present invention contains a relatively large amount of low-substituted hydroxypropylcellulose, so that moisture is taken in during the stirring granulation process and voids are generated in the dried granules. This is considered to be because the density decreased and the hardness decreased.

  Moreover, since the granulated product (granule) of the present invention is reduced in hardness, it becomes easy to be plastically deformed in the tableting process, and the moldability is improved. Therefore, the orally disintegrating tablet of the present invention can be produced efficiently with few tableting troubles.

  In addition, since the orally disintegrating tablet of the present invention is usually a naked tablet, it is often unnecessary to coat it.

  Examples 1-1 to 1-4 (olanzapine-containing orally disintegrating tablets)

Preparation method of Example 1-1 Olanzapine 100 g, D-mannitol 8.0328 kg, and low-substituted hydroxypropylcellulose (LH-32, D50 = 20 μm) 1.04 kg mixed stirring granulator (low-speed rotary stirring granulator, The mixture was put into a Shinagawa kneader (DALTON, 45 type, 26 rpm) and mixed for 10 minutes. Thereafter, an aqueous solution containing 104 g of dextrin was added and granulated. The granulated product was placed in a shelf dryer and dried. The granulated dried product was sized with a screen diameter of 0.8 mm. 9.2768 kg of the sized product, 1.04 kg of crystalline cellulose, and 4 g of fragrance were placed in a container rotating type mixer and mixed for 10 minutes. Thereafter, 83.2 g of magnesium stearate was added and further mixed for 1 minute. The mixed product was tableted using a rotary tableting machine to obtain an orally disintegrating tablet having a tablet mass of 130 mg.

  The hardness of the obtained tablets was measured using a tablet breaking strength meter TH-303MP (manufactured by Toyama Sangyo). As shown in FIG. 2, the tablet 3 was set between the jig 1 of the measuring instrument and the measuring table 2 so that pressure was applied in the radial direction of the tablet.

Preparation method of Examples 1-2 to 1-4 An oral disintegrating tablet was obtained in the same manner as in Example 1-1 except that the formulation composition and the tableting pressure were changed as shown in Table 1. Hardness was measured.

(2) Stability stability of tablet of Example 1-3 The tablet obtained in Example 1-3 and the tablet obtained by PTP packaging (transparent film material: polypropylene) were 25 ° C and 75%, respectively. Stored under RH conditions. Tablet hardness was measured during storage, 2 weeks, 4 weeks, and 6 weeks after storage. The tablet hardness was measured in the same manner as described above. The measurement results are shown in FIG. As shown in FIG. 1, in particular, the tablets with PTP packaging showed little decrease in hardness, and the tablet hardness was maintained.

Examples 1-5 to 1-10 (olanzapine)
A tablet having a tablet mass of 200 mg was obtained by the same preparation method as in Example 1-3, except that the formulation, the mixing method during granulation, and the tableting pressure were changed as shown in Table 2 below. . The disintegration time of the tablets was measured using an orally disintegrating tablet testing machine ODT-101 (Toyama Sangyo). Specifically, the tablet is fixed to the sample stage of the measuring device with a 15g / φ20mm load jig (weight), and 37 ° C purified water, which is the test solution, is supplied to the tablet while the load jig is used at 30rpm. Was rotated and the time until the tablet disintegrated was measured.
・ Low-speed agitation granulation: Universal mixing agitator (DALTON1, 5DMV-01-r) 70 rpm
・ High-speed agitation granulation: High-speed mixer l (Earth Technica, LFS-GS-2J)
Rotational speed agitator 400rpm, chopper 1200rpm

  As shown in Table 2, it can be seen that the tablet hardness is higher at any tableting pressure when the stirring speed of stirring granulation is set lower than when the speed is increased. This is considered to be because the hardness of the granules obtained is lowered when the stirring speed is lowered. In addition, it can be seen that the disintegration time antagonizes between the low speed and the high speed, and has approximately the same disintegration property. Thus, when the stirring speed of granulation is lowered, an orally disintegrating tablet having high tablet hardness and good disintegration can be obtained as compared with the case of increasing the speed.

Comparative Examples 1-1 to 1-3 (olanzapine)
Olanzapine 8g and D-mannitol 289.6g were put into a fluidized bed granulator / dryer (FLOUND, FLO-LABO) and mixed for 5 minutes. Thereafter, an aqueous solution containing 19.2 g of low-substituted hydroxypropylcellulose (LH-32, D50 = 20 μm) and 1.6 g of sucralose was sprayed and granulated at an intake air temperature of 70 ° C. The granulated product was dried until the exhaust temperature reached 40 ° C. The granulated dried product was sized with a 32 mesh sieve (aperture 0.5 mm). The granulated product 318.4 g and magnesium stearate 1.4 g were put into a container rotating type mixer and mixed for 1 minute. The mixed product was tableted using a rotary tableting machine to obtain tablets with a tablet mass of 200 mg. The tableting pressure was adjusted as shown in Table 3. The hardness of the obtained tablets was measured using a tablet breaking strength meter TH-303MP (manufactured by Toyama Sangyo).

造粒機：フローコーターLABO（FREUND製）
吸気温度：70℃

Granulator: Flow coater LABO (FREUND)
Intake air temperature: 70 ℃

  As can be seen from the comparison between Table 3 and Tables 1 and 2, the method of the present invention is similar to the comparative example in which the granules are obtained by fluidized bed granulation although the granules are obtained by wet stirring granulation. Orally disintegrating tablets with tablet hardness can be produced. In the comparative example, severe tableting troubles (sticking and binding) occurred in tableting, and high quality tablets could not be obtained.

  Examples 2-1 to 2-4 (aripiprazole)

Preparation Method of Example 2-1 420 g of aripiprazole, 1.12 kg of low-substituted hydroxypropylcellulose, and 8321.6 kg of D-mannitol were placed in a mixing stirrer and mixed for 10 minutes. Thereafter, an aqueous solution containing 16.8 g of sucralose and 112 g of dextrin was added and granulated for 10 minutes. The granulated product was dried in a shelf dryer. The granulated dried product was sized with a screen diameter of 0.8 mm. The sized product, 9.904 kg, crystalline cellulose, 1.12 kg, and fragrance were placed in a rotating container mixer and mixed for 10 minutes. Further, 89.6 g of magnesium stearate was added and mixed for 2 minutes. The mixed product was tableted with a rotary tableting machine to obtain tablets with a tablet mass of 80 mg. The hardness of the obtained tablets was measured using a tablet breaking strength meter TH-303MP (manufactured by Toyama Sangyo).

Preparation methods of Examples 2-2 to 2-4 Tablets were obtained in the same procedure as in Example 2-1, except that the formulation composition was changed as shown in Table 4, and the tablet hardness was measured.

  Examples 3-1 to 3-2 (olmesartan)

Preparation Method of Example 3-1 Olmesartan medoxomil 850 g, D-mannitol 7.4545 kg, low-substituted hydroxypropyl cellulose 1.071 kg was placed in a mixing stirrer and mixed for 10 minutes. Furthermore, an aqueous solution containing 51 g of dextrin was added and granulated, and further an aqueous solution containing 51 g of dextrin was added and granulated. The granulated product was put in a shelf dryer and dried. The granulated dried product was sized with a screen diameter of 0.8 mm. 9.4775 kg of the sized product, 637.5 g of crystalline cellulose, 4.25 g of 1-menthol, 10.2 g of sucralose, and 8.5 g of a fragrance were placed in a rotating container mixer and mixed for 10 minutes. Thereafter, 85 g of calcium stearate was added and mixed for 2 minutes. The mixed product was tableted using a tableting machine to obtain tablets with a tablet mass of 120 mg. The hardness of the obtained tablets was measured using a tablet breaking strength meter TH-303MP (manufactured by Toyama Sangyo).

Preparation method of Example 3-2 Tablets were obtained in the same procedure as in Example 3-1, except that the formulation and tableting pressure were changed as shown in Table 5, and the tablet hardness was measured.

  Examples 4-1 to 4-6 (Mirtazapine)

Preparation method of Example 4-1 1.05 kg of mirtazapine, 5.7134 kg of D-mannitol, 2.38 kg of low-substituted hydroxypropylcellulose, and 33.6 g of yellow iron sesquioxide were placed in a mixing stirrer and mixed for 5 minutes. Thereafter, an aqueous solution containing 245 g of dextrin was added and granulated for 5 minutes. The granulated product was dried in a shelf dryer. The granulated dried product was sized with a screen diameter of 0.8 mm. 9.42 kg of the sized product and 2.38 kg of crystalline cellulose were put into a rotating container mixer and mixed for 10 minutes. Further, 98 g of magnesium stearate was added and mixed for 1 minute. The mixed product was tableted with a rotary tableting machine to obtain tablets with a tablet mass of 170.0 mg. The hardness of the obtained tablets was measured using a tablet breaking strength meter TH-303MP (manufactured by Toyama Sangyo).

Adjustment method of Examples 4-2 to 4-3 Except that the tableting pressure was changed as shown in Table 6, tablets were obtained in the same procedure as in Example 4-1, and the tablet hardness was measured.

Preparation method of Examples 4-4 to 4-6 Except that the formulation and tableting pressure were changed as shown in Table 6, tablets were obtained in the same procedure as in Example 4-1, and the tablet hardness was adjusted. It was measured.

  Examples 5-1 to 5-2 (galantamine)

Preparation Method of Example 5-1 Galantamine hydrobromide 560 g, D-mannitol 6.433 kg, low-substituted hydroxypropylcellulose 1.40 kg, and a mixing stirrer were mixed for 10 minutes. Thereafter, an aqueous solution containing 196 g of dextrin was added and granulated for 10 minutes. The granulated product was dried in a shelf dryer. The granulated dried product was sized with a screen diameter of 0.8 mm. 6.74 kg of the sized product and 0.98 kg of crystalline cellulose were put into a container rotating type mixer and mixed for 10 minutes. Further, 70 g of magnesium stearate was added and mixed for 2 minutes. The mixed product was tableted with a rotary tableting machine to obtain tablets with a tablet mass of 140 mg. The hardness of the obtained tablets was measured using a tablet breaking strength meter TH-303MP (manufactured by Toyama Sangyo).

Adjustment method of Example 5-2 Except that the tableting pressure was changed as shown in Table 7, tablets were obtained in the same procedure as in Example 5-1, and the tablet hardness was measured.

  Examples 6-1 to 6-3 (memantine)

Preparation method of Example 6-1 Memantine 720 g, low-substituted hydroxypropylcellulose 1.440 kg, and D-mannitol 6.6204 kg were placed in a mixing stirrer and mixed for 10 minutes. An aqueous solution containing 201.6 g of dextrin was added and granulated for 10 minutes. The granulated product was dried in a shelf dryer. The granulated dried product was sized with a screen diameter of 0.8 mm. The granulated product (6.986 kg), crystalline cellulose (0.784 kg), and a fragrance were placed in a rotating container mixer and mixed for 10 minutes. Further, 70 g of magnesium stearate was added and mixed for 2 minutes. The mixed product was tableted with a rotary tableting machine to obtain tablets with a tablet mass of 280 mg. The hardness of the obtained tablets was measured using a tablet breaking strength meter TH-303MP (manufactured by Toyama Sangyo).

Adjustment method of Examples 6-2 to 6-3 Except that the tableting pressure was changed as shown in Table 8, tablets were obtained in the same procedure as Example 6-1 and the tablet hardness was measured.

  Example 7-1 (escitalopram oxalate)

Preparation method of Example 7-1 510.8 g of escitalopram oxalate, 1.04 kg of low-substituted hydroxypropylcellulose, and 7.62 kg of D-mannitol were placed in a mixing stirrer and mixed for 10 minutes. Thereafter, an aqueous solution containing 104 g of dextrin was added and granulated for 10 minutes. The granulated product was dried in a shelf dryer. The granulated dried product was sized with a screen diameter of 0.8 mm. 9.28 kg of the sized product and 1.04 kg of crystalline cellulose were placed in a rotating container mixer and mixed for 10 minutes. Further, 84 g of magnesium stearate was added and mixed for 2 minutes. The mixed product was tableted with a rotary tableting machine to obtain tablets with a tablet mass of 260 mg. The hardness of the obtained tablets was measured using a tablet breaking strength meter TH-303MP (manufactured by Toyama Sangyo).

  Although the orally disintegrating tablet of the present invention is produced by tableting a granule obtained by a stirring granulation method, it has good disintegration and high tablet hardness. Therefore, in the production method of the present invention, a uniform and high quality orally disintegrating tablet can be easily produced.

Claims (4)

A method for producing an orally disintegrating tablet comprising a pharmaceutically active ingredient, a fine powder grade low-substituted hydroxypropyl cellulose, and a binder,
A step of obtaining a granule by wet granulating a powder composition containing a fine powder grade low-substituted hydroxypropyl cellulose using a binding solution containing water; and
Tableting a granule composition comprising the granules;
Manufacturing method.   The manufacturing method of Claim 1 whose content of the said low substituted hydroxypropyl cellulose in the said powder composition is 6-30 mass%.   The manufacturing method according to claim 1 or 2, wherein the binding liquid further contains a low viscosity binder. Granules obtained by wet stirring granulation of a powder composition containing a fine powder grade low-substituted hydroxypropyl cellulose with a binding solution containing water.

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