Granules and method for producing same, and tablet

Abstract

The present invention provides granules containing at least a saccharide comprising a sugar and / or a sugar alcohol, two or more types of disintegrators, and a hydrophilic lubricant, wherein the ratio D90(μm) / loose bulk density (g / mL), which is the ratio of the 90% cumulative particle diameter D90 by volume to the loose bulk density of the granules is 220-320.

Description

Granules and their manufacturing method, and tablets

[0001] The present invention relates to granules suitably used for manufacturing pharmaceutical and food tablets, a method for manufacturing the same, and tablets using the granules.

[0002] There are two main methods for manufacturing tablets for pharmaceuticals and food products: one in which the raw materials are mixed and then compressed directly, and another in which the raw materials are granulated beforehand and then compressed. The method of pre-granulating the raw materials before compression has the advantage of producing tablets with uniform content, excellent fluidity during compression, and consistent performance. There are various granulation methods, including fluidized bed granulation, spray drying granulation, and dry granulation. Among these, spray drying granulation is advantageous in terms of productivity.

[0003] Furthermore, while the raw materials for tablets include not only the desired food ingredients and active ingredients, but also additives such as excipients, disintegrants, and lubricants, using a raw material that combines these additives into a single component can improve workability and increase the efficiency of tablet manufacturing.

[0004] To date, granules comprising sugars consisting of sugars and / or sugar alcohols, a disintegrant, and a hydrophilic lubricant have been proposed, which, when formed into tablets, satisfy predetermined physical properties of hardness, disintegration time, and in-oral disintegration time (see, for example, Patent Document 1).

[0005] Japanese Patent Publication No. 2023-173283

[0006] According to the technology described in Patent Document 1, it is possible to obtain granules that can be used to manufacture tablets with excellent moldability, hardness, disintegration, and storage stability. However, there is still a high demand for granules that have good disintegration when formed into tablets, excellent moldability, and can produce tablets with higher hardness when compressed at the same pressure.

[0007] The present invention aims to solve the aforementioned problems of the conventional method and achieve the following objectives. Specifically, the present invention aims to provide granules that have good disintegration properties when formed into tablets, excellent moldability, and can produce tablets with higher hardness when compressed with the same compression pressure, as well as tablets using the granules.

[0008] In order to solve the aforementioned problems, the inventors diligently conducted research and obtained the following findings. Specifically, a granule comprising at least a sugar consisting of sugars and / or sugar alcohols, two or more disintegrants, and a hydrophilic lubricant, wherein the granule has a 90% cumulative particle diameter D based on volume. ９０ And D is the ratio of the loose bulk density. ９０ We found that granules with a (μm) / loose bulk density (g / mL) of 220 to 320 exhibit excellent moldability, can produce tablets with higher hardness when compressed at the same compression pressure, and have good disintegration properties when formed into tablets.

[0009] The present invention is based on the aforementioned findings by the inventors, and the means for solving the aforementioned problems are as follows: <1> Granules comprising at least sugars consisting of sugars and / or sugar alcohols, two or more disintegrants, and a hydrophilic lubricant, wherein the 90% cumulative particle diameter D of the granules is based on volume. ９０ And D is the ratio of the loose bulk density. ９０The granules are characterized by having a (μm) / loose bulk density (g / mL) of 220 to 320. <2> The granules according to <1>, wherein the content of the sugar in the granules is 60 to 90% by mass. <3> The granules according to <1> or <2>, wherein the content of the disintegrant in the granules is 10 to 40% by mass. <4> The granules according to any one of <1> to <3>, wherein the disintegrant comprises croscarmellose sodium and crystalline cellulose, and the mass ratio of croscarmellose sodium to crystalline cellulose is 1:2 to 1:20. <5> The granules according to <4>, wherein the content of croscarmellose sodium in the granules is 1 to 4% by mass, and the content of crystalline cellulose in the granules is 10 to 39% by mass. <6> The granules according to any one of <1> to <5>, wherein the sugar is mannitol. <7> The granules according to any one of <1> to <6>, wherein the hydrophilic lubricant is sodium stearyl fumarate. <8> The granules according to <6>, wherein the mannitol content in the granules is 60 to 70% by mass. <9> The granules according to any one of <1> to <8>, wherein the disintegrant content in the granules is 25 to 40% by mass. <10> 90% cumulative particle size D on a volume basis ９０ The process includes a spray-drying liquid preparation step of mixing sugars consisting of sugars and / or sugar alcohols having a diameter of 15 to 23 μm with two or more disintegrants, a hydrophilic lubricant, and a solvent to prepare a spray-drying liquid, and a granule preparation step of spray-drying the spray-drying liquid to obtain granules, wherein the spray-drying liquid contains the sugars consisting of sugars and / or sugar alcohols in a suspended state, and the granules have a 90% cumulative particle diameter D based on volume. ９０ And D is the ratio of the loose bulk density. ９０A method for producing granules, characterized in that the (μm) / loose bulk density (g / mL) is 220 to 320. <11> A method for producing granules according to <10>, wherein the content of the sugar in the granules is 60 to 90% by mass. <12> A method for producing granules according to <10> or <11>, wherein the content of the disintegrant in the granules is 10 to 40% by mass. <13> A method for producing granules according to any one of <10> to <12>, wherein the disintegrant comprises croscarmellose sodium and crystalline cellulose, and the mass ratio of croscarmellose sodium to crystalline cellulose is 1:2 to 1:20. <14> A method for producing granules according to <13>, wherein the content of croscarmellose sodium in the granules is 1 to 4% by mass, and the content of crystalline cellulose in the granules is 10 to 39% by mass. <15> A method for producing granules according to any one of <10> to <14>, wherein the sugar is mannitol. <16> A method for producing granules according to any one of <10> to <15>, wherein the hydrophilic lubricant is sodium stearyl fumarate. <17> A method for producing granules according to <15>, wherein the mannitol content in the granules is 60 to 70% by mass. <18> A method for producing granules according to any one of <10> to <16>, wherein the disintegrant content in the granules is 25 to 40% by mass. <19> Granules characterized by being produced by the method for producing granules according to any one of <10> to <18>. <20> A tablet characterized by containing granules according to any one of <1> to <9> and <19>.

[0010] According to the present invention, it is possible to solve the aforementioned problems of the conventional method and achieve the aforementioned objectives, and to provide granules and a method for producing the same that have good disintegration properties when formed into tablets, excellent moldability, and can produce tablets with higher hardness when compressed with the same tableting pressure, as well as tablets using the granules.

[0011] Figure 1 is a diagram showing the results of measuring the tablet hardness in Test Example 1. Figure 2 is a diagram showing the results of measuring the disintegration time in Test Example 1. Figure 3 is a diagram showing the results of measuring the tablet hardness in Test Example 2. Figure 4 is a diagram showing the results of measuring the disintegration time in Test Example 2. Figure 5 is a diagram showing the results of measuring the tablet hardness in Test Example 3. Figure 6 is a diagram showing the results of measuring the tablet hardness in Test Example 3. Figure 7 is a diagram showing the results of measuring the tablet hardness in Test Example 3. Figure 8 is a diagram showing the results of measuring the disintegration time in Test Example 3. Figure 9 is a diagram showing the results of measuring the disintegration time in Test Example 3. Figure 10 is a diagram showing the results of measuring the disintegration time in Test Example 3.

[0012] (Granules and Method for Producing the Same) The granules of the present invention contain at least saccharides composed of sugar and / or sugar alcohol, two or more kinds of disintegrants, and a hydrophilic lubricant, and may further contain other components as necessary. As a method for producing the granules of the present invention, there is no particular limitation, and it can be appropriately selected according to the purpose, but it can be preferably produced by the method for producing the granules of the present invention. That is, the granules of the present invention are preferably granules obtained by spray drying granulation (hereinafter, may be referred to as "spray dried granules"). Hereinafter, the granules of the present invention will also be described together with the description of the method for producing the granules of the present invention.

[0013] <Method for Producing Granules> The method for producing the granules of the present invention includes at least a step of preparing a liquid for spray drying and a step of preparing granules, and may further include other steps as necessary.

[0014] <<Step of Preparing Liquid for Spray Drying>> The step of preparing a liquid for spray drying is a step of mixing saccharides composed of sugar and / or sugar alcohol having a 90% integrated particle diameter D ９０ of 15 to 23 μm on a volume basis, two or more kinds of disintegrants, a hydrophilic lubricant, and a solvent to prepare a liquid for spray drying.

[0015] - Liquid for Spray Drying - The liquid for spray drying has a 90% integrated particle diameter D ９０The material comprises at least a sugar and / or sugar alcohol having a particle size of 15 to 23 μm, two or more disintegrants, a hydrophilic lubricant, and a solvent, and optionally contains other components.

[0016] --Sugars consisting of sugars and / or sugar alcohols-- In the present invention, the sugars consisting of sugars and / or sugar alcohols are defined as the 90% cumulative particle size D on a volume basis. ９０ The 90% cumulative particle size D of the sugars and / or sugar alcohols to be blended into the spray-drying liquid is 15 to 23 μm. ９０ The fact that granules with excellent moldability can be produced by setting the particle size to 15-23 μm is a remarkable finding by the inventors.

[0017] 90% cumulative particle size D by volume of the sugars consisting of the aforementioned sugars and / or sugar alcohols ９０ As long as the particle size is between 15 and 23 μm, there are no particular restrictions, and it can be appropriately selected depending on the purpose. However, 15 to 20 μm is preferred in that it provides a better effect.

[0018] Volume-based 50% cumulative particle size D of the sugars consisting of the aforementioned sugars and / or sugar alcohols ５０ There are no particular restrictions on this, and it can be appropriately selected according to the purpose, but 8 to 12 μm is preferred, and 8 to 10 μm is more preferred in that it provides better effects.

[0019] Volume-based 10% cumulative particle size D of the sugars consisting of the aforementioned sugars and / or sugar alcohols １０ There are no particular restrictions on this, and it can be selected as appropriate depending on the purpose, but 3 to 5 μm is preferred in that it yields better results.

[0020] There are no particular limitations on the method for preparing the particle size of sugars consisting of sugars and / or sugar alcohols, and known methods can be appropriately selected. For example, a method may be used in which sugars consisting of sugars and / or sugar alcohols are crushed, classified as necessary, and then obtained to a predetermined particle size.

[0021] There are no particular restrictions on the method for measuring the particle size of sugars consisting of sugars and / or sugar alcohols, and known methods can be appropriately selected. For example, it can be measured using a laser diffraction / scattering particle size distribution analyzer (Microtrac MT3000II, manufactured by Microtrac Bell Co., Ltd.).

[0022] The type of sugars mentioned above is not particularly limited as long as they consist of sugars and / or sugar alcohols, and can be appropriately selected according to the purpose. Examples include sucrose, lactose, fructose, maltose, trehalose, mannitol, xylitol, erythritol, sorbitol, maltitol, isomalt, lactitol, sucrose, and glycerin. These may be used individually or in combination of two or more. Among these, sugar alcohols are preferred, and mannitol is more preferred, as they provide superior effects. Commercially available sugars can be used.

[0023] There are no particular restrictions on the content of the sugars in the spray-drying liquid, and it can be appropriately selected depending on the content in granules, the ease of spray-drying granulation, etc.

[0024] --Disintegrants-- In this invention, two or more types of disintegrants are used.

[0025] There are no particular restrictions on the type of disintegrant, and it can be appropriately selected depending on the purpose. Examples include croscarmellose sodium; crystalline cellulose; crospovidone; cellulose derivatives such as low-substituted hydroxypropyl cellulose (L-HPC) and carboxymethyl cellulose (carboxymethylcellulose sodium, carboxymethylcellulose calcium, etc.); and starches such as hydroxypropyl starch and corn starch.

[0026] The aforementioned disintegrant is not particularly limited as long as two or more types are used, and can be appropriately selected according to the purpose. However, it is preferable to include croscarmellose sodium and crystalline cellulose, and more preferably croscarmellose sodium and crystalline cellulose, in order to obtain a better effect.

[0027] The mass ratio of the crosscarmellose sodium to the crystalline cellulose (crosscarmellose sodium: crystalline cellulose) is not particularly limited and can be appropriately selected according to the purpose. However, in terms of obtaining more excellent effects, 1:2 to 1:20 is preferable, and 1:5 to 1:7.8 is more preferable.

[0028] Commercially available products can be used as the disintegrant.

[0029] The content of the disintegrant in the liquid for spray drying is not particularly limited and can be appropriately selected according to the content in the granules, the ease of spray drying granulation, etc.

[0030] - - Hydrophilic lubricant - - The hydrophilic lubricant is not particularly limited and can be appropriately selected according to the purpose. For example, sodium stearyl fumarate, sodium lauryl sulfate, sucrose fatty acid ester, etc. can be mentioned. These may be used alone or in combination of two or more.

[0031] Among these hydrophilic lubricants, sodium stearyl fumarate is preferable in terms of obtaining more excellent effects.

[0032] Commercially available products can be used as the hydrophilic lubricant.

[0033] The content of the hydrophilic lubricant in the liquid for spray drying is not particularly limited and can be appropriately selected according to the content in the granules, the ease of spray drying granulation, etc.

[0034] - - Other components - - The other components are not particularly limited as long as the effects of the present invention are not impaired and can be appropriately selected according to the purpose. For example, binders, inorganic additives, excipients other than the above saccharides, and other known pharmaceutical additives can be mentioned. These may be used alone or in combination of two or more. Commercially available products can be used as the other components. The content of the other components in the liquid for spray drying is not particularly limited and can be appropriately selected according to the content in the granules, the ease of spray drying granulation, etc.

[0035] The binder is not particularly limited and can be appropriately selected according to the purpose. For example, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, gelatin, partially pregelatinized starch, gum arabic, pullulan, dextrin, etc. may be mentioned. These may be used alone or in combination of two or more. The binder can be a commercially available product.

[0036] The content of the binder in the liquid for spray drying is not particularly limited and can be appropriately selected according to the content in the granules and the ease of spray drying granulation, etc.

[0037] The inorganic additive is not particularly limited and can be appropriately selected according to the purpose. For example, pharmaceutically acceptable inorganic compounds containing any of aluminum, magnesium, and calcium may be mentioned. More specific examples of the inorganic additive include magnesium aluminum metasilicate, magnesium aluminum silicate, calcium hydrogen phosphate, hydrotalcite, synthetic aluminum silicate, calcium phosphate, calcium carbonate, talc, magnesium silicate, magnesium oxide, aluminum magnesium hydroxide, dried aluminum hydroxide gel, magnesium carbonate, calcium silicate, etc. The inorganic additive may be used alone or in combination of two or more. The inorganic additive can be a commercially available product.

[0038] The content of the inorganic additive in the liquid for spray drying is not particularly limited and can be appropriately selected according to the content in the granules and the ease of spray drying granulation, etc.

[0039] Known additives for pharmaceuticals such as excipients other than the saccharides include, for example, excipients such as corn starch, fluidizing agents, sweeteners, moisture absorbents, dehumidifiers, coating agents, pigments, flavoring agents, solubilizing agents, etc. These may be used alone or in combination of two or more. Known additives for pharmaceuticals such as excipients other than the saccharides can be commercially available products.

[0040] There are no particular restrictions on the content of excipients other than sugars and other known pharmaceutical additives in the spray-drying liquid, and they can be appropriately selected depending on the content in granules and the ease of spray-drying granulation.

[0041] --Preparation-- There are no particular restrictions on the method for preparing the spray-drying liquid, and a suitable method can be selected depending on the purpose. For example, a method can be used to add and mix the above-mentioned components with a pharmaceutically acceptable solvent such as water, ethanol, or methanol. There are no particular restrictions on the order in which the components are added, and a suitable order can be selected depending on the purpose.

[0042] There are no particular restrictions on the mixing conditions; they can be selected as appropriate depending on the purpose.

[0043] The spray-drying liquid contains the sugars, consisting of the sugars and / or sugar alcohols, in a suspended state. In this specification, "suspended state" does not mean completely dissolved, but may mean partially dissolved.

[0044] The components other than sugars, which consist of the aforementioned sugars and / or sugar alcohols, may be in a dissolved state or in a suspended state.

[0045] <<Granule Preparation Process>> The granule preparation process is a process of spray-drying and granulating the spray-drying liquid to obtain granules (hereinafter sometimes referred to as the "spray-drying and granulation process").

[0046] --Spray drying granulation-- There are no particular restrictions on the method of spray drying granulation, and it can be carried out using known equipment.

[0047] There are no particular restrictions on the conditions for the spray drying granulation process, and they can be appropriately selected depending on the purpose.

[0048] For example, there are no particular restrictions on the outlet temperature during spray drying granulation, and it can be appropriately selected depending on the purpose, but 60 to 90°C is preferred. The inlet temperature during spray drying granulation can be appropriately selected depending on the size of the apparatus, etc.

[0049] The granules obtained by the spray-drying granulation method may be sieved if necessary.

[0050] <<Other Processes>> The other processes mentioned above are not particularly limited as long as they do not impair the effects of the present invention, and can be appropriately selected according to the purpose. For example, one example is a process of sieving the granules obtained by the spray drying granulation described above.

[0051] <Granules> The granules of the present invention have good disintegration properties when formed into tablets, and also have excellent moldability, allowing for the production of tablets with higher hardness when compressed at the same pressure. Furthermore, the addition of lubricants is unnecessary during tablet manufacturing, and the granules offer excellent mixing properties.

[0052] There are no particular restrictions on the content of the sugars in the granules, and it can be appropriately selected depending on the purpose, but in order to obtain a better effect, 60 to 90% by mass is preferred, 60 to 85% by mass is more preferred, and 60 to 70% by mass is particularly preferred.

[0053] There are no particular restrictions on the content of the disintegrant in the granules, and it can be appropriately selected depending on the purpose, but 10 to 40% by mass is preferred, and 25 to 40% by mass is more preferred in order to obtain a better effect.

[0054] There are no particular restrictions on the content of croscarmellose sodium in the granules, and it can be appropriately selected depending on the purpose, but 1 to 4% by mass is preferred, and 2 to 4% by mass is more preferred, in order to obtain a better effect.

[0055] There are no particular restrictions on the content of the crystalline cellulose in the granules, and it can be appropriately selected depending on the purpose. However, in order to obtain a better effect, 10 to 39% by mass is preferred, 20 to 39% by mass is more preferred, and 30 to 39% by mass is particularly preferred.

[0056] There are no particular restrictions on the content of the hydrophilic lubricant in the granules, and it can be appropriately selected depending on the purpose, but 0.1 to 3% by mass is preferred in that a better effect can be obtained.

[0057] There are no particular restrictions on the content of the other components in the granules, and they can be appropriately selected depending on the purpose.

[0058] The granules may consist only of the sugars, the disintegrant, and the hydrophilic lubricant.

[0059] The 90% cumulative particle diameter D of the aforementioned granules based on volume ９０ There are no particular restrictions on this, and it can be appropriately selected according to the purpose, but 90 to 130 μm is preferred in that it provides better effects.

[0060] The 50% cumulative particle size D of the aforementioned granules based on volume ５０ There are no particular restrictions, and it can be selected as appropriate depending on the purpose, but 50 to 80 μm is preferred in that it provides better results.

[0061] The 10% cumulative particle size D of the aforementioned granules based on volume １０ There are no particular restrictions on this, and it can be appropriately selected according to the purpose, but 15 to 30 μm is preferred, and 20 to 30 μm is more preferred in that it provides better effects.

[0062] There are no particular restrictions on the method for measuring the particle size of granules, and it can be appropriately selected depending on the purpose. For example, it can be measured in the same manner as the method for measuring the particle size of sugars consisting of sugars and / or sugar alcohols described above.

[0063] There are no particular restrictions on the bulk density of the loosened granules, and it can be appropriately selected depending on the purpose, but 0.40 to 0.50 g / mL is preferred in that it provides a better effect.

[0064] There are no particular restrictions on the method for measuring the loosened bulk density of granules, and any known method can be appropriately selected. For example, it can be measured using the A.B.D. Powder Properties Analyzer (manufactured by Tsutsui Chemical Instruments Co., Ltd.).

[0065] The 90% cumulative particle diameter D of the aforementioned granules based on volume ９０ And D is the ratio of the loose bulk density. ９０The ratio (μm) / loosening bulk density (g / mL) is not particularly limited as long as it is between 220 and 320, and can be appropriately selected depending on the purpose. However, 220 to 270 is preferred, and 220 to 250 is more preferred, in order to obtain a better effect.

[0066] The granules of the present invention can be suitably used as an excipient or the like in the manufacture of pharmaceutical and food tablets.

[0067] (Tablets) The tablets of the present invention contain at least the granules of the present invention, and also contain food materials or active ingredients and, if necessary, other ingredients.

[0068] <Granules> The granules mentioned above are the granules of the present invention as described above.

[0069] There are no particular restrictions on the content of the granules in the tablets, and it can be appropriately selected depending on the purpose, but 20 to 99.9% by mass is preferred, 50 to 99.9% by mass is more preferred, and 70 to 99.9% by mass is particularly preferred.

[0070] <Food Ingredients or Active Ingredients> -Food Ingredients- There are no particular restrictions on the food ingredients as long as they can be used in food, and they can be appropriately selected according to the purpose. Examples include glucosamine, amino acids, vitamins, chondroitin, minerals, collagen, turmeric, ginkgo biloba, blueberries, soy isoflavones, royal jelly, and chlorella. These may be used individually or in combination of two or more. Commercially available food ingredients may be used.

[0071] - Active Ingredients - There are no particular restrictions on the active ingredients, and they can be appropriately selected according to the purpose. Examples include antihypertensive drugs, angina pectoris drugs, bronchodilators, psychotropic drugs, anxiolytics, antidepressants, hypnotics and sedatives, antiparkinsonian drugs, anti-allergic drugs, dental and oral drugs, cardiac stimulants, antipyretic, analgesic and anti-inflammatory drugs, antihistamines, antitussives, antacids, herbal medicines, antihypertensive drugs, antibiotics, antibacterial agents, antiarrhythmic drugs, coronary vasodilators, peripheral vasodilators, and hyperlipidemia. Examples include active pharmaceutical ingredients used in orally toxic drugs, choleretics, hormone drugs, gout treatment drugs, anti-rheumatic drugs, chemotherapy drugs, diabetes drugs, antiemetics, antiepileptic drugs, sympathomimetic drugs, osteoporosis drugs, anti-cancer drugs, immunosuppressants, urological drugs, gastrointestinal drugs, cerebral metabolism improvers, cerebral circulation improvers, respiratory stimulants, vasoconstrictors, anti-vertigo drugs, expectorants, central nervous system agents, ulcer treatment drugs, gastric mucosal repair agents, analgesics, and antispasmodics. Specifically, ethenzamide, acetaminophen, temocapril hydrochloride, cabergoline, amlodipine besylate, omeprazole, lansoprazole, famotidine, lafutidine, ecabet sodium, mosapride citrate, rebamipide, voglibose, risperidone, imidapril hydrochloride, meloxicam, milnacipran hydrochloride, levofloxacin, clarithromycin, sarpogrelate hydrochloride, tosufloxacin tosylate, tamsulosin hydrochloride, mizoribine, tacrolimus hydrate, fluvoxamine maleate, glimepiride, ramosetron hydrochloride, nicorandil Examples include donepezil hydrochloride, zolpidem tartrate, pioglitazone hydrochloride, alendronate sodium hydrate, risedronate sodium hydrate, atorvastatin calcium hydrate, fluvastatin sodium, loratadine, losartan potassium, paroxetine hydrochloride hydrate, rabeprazole sodium, ribavirin, sumatriptan succinate, perospirone hydrochloride hydrate, quetiapine fumarate, olopatadine hydrochloride, fexofenadine hydrochloride, ebastine, cefditoren pivoxil, cefcapene pivoxil hydrochloride, valsartan, bicalutamide, and acarbose. The active ingredients may be used individually or in combination of two or more. Commercially available active ingredients may be used.

[0072] There are no particular restrictions on the content of the food material or active ingredient in the tablets, and it can be appropriately selected depending on the purpose, but 0.1 to 80% by mass is preferred, and 0.1 to 30% by mass is more preferred.

[0073] <Other Ingredients> The other ingredients mentioned above are not particularly limited as long as they do not impair the effects of the present invention and can be appropriately selected according to the purpose. Examples include those known as additives for the pharmaceuticals mentioned above. These may be used individually or in combination of two or more. The other ingredients may be used individually or in combination of two or more. Commercially available products may be used for the other ingredients. There are no particular restrictions on the content of the other ingredients in the tablets and can be appropriately selected according to the purpose.

[0074] There are no particular restrictions on the type of tablet, and they can be appropriately selected according to the purpose. Examples include uncoated tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, orally disintegrating tablets (OD tablets), sublingual tablets, and chewable tablets. The granules of the present invention can be suitably used in orally disintegrating tablets (sometimes referred to as "oral rapid disintegration tablets") among the tablets mentioned above.

[0075] There are no particular restrictions on the shape, structure, or size of the aforementioned tablets, and they can be appropriately selected according to the purpose.

[0076] The method for producing the tablets is not particularly limited except for using the granules of the present invention, and can be produced by known methods. For example, one method involves mixing the granules, the food material or active ingredient, and any other ingredients as needed, and then compressing the resulting powder into tablets using a tablet press.

[0077] The present invention will be explained below with reference to test examples, but the present invention is not limited in any way to these.

[0078] (Test Example 1) <Example 1, Comparative Examples 1-4> <<Preparation of Spray Drying Liquid>> 3,805 g of purified water and 1,800 g of mannitol with the particle size listed in Table 1 below were stirred and mixed to form a suspension. While stirring this suspension, 329.3 g of crystalline cellulose (manufactured by Asahi Kasei Corporation) and 43.9 g of croscarmellose sodium (manufactured by Asahi Kasei Corporation), which are disintegrants, and 22 g of stearyl fumarate sodium (manufactured by Nippon Soda Co., Ltd.), which is a hydrophilic lubricant, were added to prepare a uniform spray drying liquid.

[0079] <<Spray Drying>> Using a spray dryer (OC-16 model, manufactured by Okawara Chemical Machinery Co., Ltd.), spray drying was performed in a spray drying atmosphere with an outlet temperature of 70°C (inlet temperature of 105°C) while supplying the spray drying liquid with a disc atomizer (MC-65) to obtain spray-dried granules. The obtained spray-dried granules were sieved with a mesh opening of 250 μm to obtain granules with the particle sizes listed in Table 1 below.

[0080] The particle size of the mannitol used as a raw material and the resulting granules was measured using a laser diffraction / scattering particle size distribution analyzer (Microtrac MT3000II, manufactured by Microtrac Bell Co., Ltd.).

[0081] The loosened bulk density of the obtained granules was measured using the A.B.D. Powder Properties Analyzer (manufactured by Tsutsui Chemical Instruments Co., Ltd.).

[0082] Table 1 below shows the particle size of mannitol used as the raw material for each granule, the particle size of each granule, the loosened bulk density, and the D90 / loosened bulk density.

[0083]

[0084] As shown in Table 1, the 90% cumulative particle size D of the raw material mannitol based on volume ９０ Due to these differences, variations were observed in the bulk density of the spray-dried granules.

[0085] [Evaluation] Using the obtained granules, tablets were prepared as follows, and the physical properties of the tablets were evaluated.

[0086] <Preparation of Tablets> 500 g of the obtained granules were compressed into tablets using a rotary tablet press (VERGO, manufactured by Kikusui Seisakusho Co., Ltd.) at a rotation speed of 30 rpm (compression pressure: 6 kN, 8 kN, or 10 kN) to obtain placebo tablets with a diameter of 8 mm, a thickness of 4 mm, a curvature (R) of 10, and a mg content of 200 mg.

[0087] <Tablet Properties> - Tablet Hardness - The hardness of tablets immediately after manufacturing was measured using a tablet hardness measuring device (SmartTest 50, manufactured by SOTAX AG) (n=10). The results are shown in Figure 1. In Figure 1, the vertical axis represents tablet hardness (N), and the horizontal axis represents tablet compression pressure (kN). "●" represents the tablet using granules from Example 1, "○" represents the tablet using granules from Comparative Example 1, "△" represents the tablet using granules from Comparative Example 2, "□" represents the tablet using granules from Comparative Example 3, and "◇" represents the tablet using granules from Comparative Example 4.

[0088] - Disintegration Time (JP Disintegration Test) - Disintegration time of tablets immediately after manufacture was measured using a disintegration tablet measuring device (NT-400, manufactured by Toyama Sangyo Co., Ltd.) and purified water as the test solution under the conditions of the 18th Japanese Pharmacopoeia (n=6). The results are shown in Figure 2. In Figure 2, the vertical axis represents disintegration time (seconds), and the horizontal axis represents tablet hardness (N). "●" indicates the result for tablets using granules from Example 1, "○" indicates the result for tablets using granules from Comparative Example 1, "△" indicates the result for tablets using granules from Comparative Example 2, "□" indicates the result for tablets using granules from Comparative Example 3, and "◇" indicates the result for tablets using granules from Comparative Example 4.

[0089] As shown in Figures 1 and 2, the 90% cumulative particle diameter D on a volume basis ９０ The granules of Example 1, which use mannitol, an example of a sugar consisting of sugars and / or sugar alcohols with a diameter of 15-23 μm, were found to have excellent moldability and to produce tablets with higher hardness when compressed at the same compression pressure. Furthermore, the tablets made using the granules of Example 1 were also found to have good disintegration properties.

[0090] (Test Example 2) <Test Example 2-1> The granules produced in Example 1 of Test Example 1 were used as the granules for Test Example 2-1.

[0091] <Test Example 2-2> <<Preparation of Spray Drying Liquid>> 4,448 g of purified water and 2,450 g of mannitol (Pearlitol 50C, manufactured by ROQUETTE) were stirred and mixed to form a suspension. While stirring this suspension, 51.0 g of croscarmellose sodium (manufactured by Asahi Kasei Corporation) and 25.5 g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), which are disintegrants, and 25.5 g of stearyl fumarate sodium (manufactured by Nippon Soda Co., Ltd.), which is a hydrophilic lubricant, were added to prepare a homogeneous spray drying liquid.

[0092] <<Spray Drying>> Using a spray dryer (OC-16 model, manufactured by Okawara Chemical Machinery Co., Ltd.), spray drying was performed in a spray drying atmosphere with an outlet temperature of 100°C (inlet temperature of 146°C) while supplying the spray drying liquid with a disc atomizer (MC-65) to obtain spray-dried granules. The obtained spray-dried granules were sieved with a mesh size of 500 μm to obtain granules with the particle sizes listed in Table 2 below.

[0093] The particle size and loosened bulk density of the obtained granules were measured in the same manner as in Test Example 1.

[0094] Table 2 below shows the composition, particle size, loosened bulk density, and D90 / loosened bulk density of each granule.

[0095]

[0096] [Evaluation] Using the obtained granules, tablets were prepared as follows, and the physical properties of the tablets were evaluated.

[0097] <Preparation of Tablets> 700 g of the obtained granules and 300 g of ethenzamide (powder type, manufactured by Yamamoto Chemical Industry Co., Ltd.) as a model drug were mixed in a micro-type transparent V-type mixer (manufactured by Tsutsui Chemical Instruments Co., Ltd.). The resulting powder was compressed into tablets using a rotary tablet press (VERGO, manufactured by Kikusui Seisakusho Co., Ltd.) at a rotation speed of 30 rpm (compression pressure: 4 kN, 6 kN, 8 kN, or 10 kN) to obtain ethenzamide tablets with a diameter of 8 mm, a thickness of 4 mm, a curvature (R) of 10, and a dose of 200 mg.

[0098] <Tablet Physical Properties> - Tablet Hardness - The hardness of tablets immediately after manufacturing was measured in the same manner as in Test Example 1. The results are shown in Figure 3. In Figure 3, the vertical axis represents tablet hardness (N), and the horizontal axis represents tablet compression pressure (kN). "●" indicates the results for tablets using granules from Test Example 2-1, and "▲" indicates the results for tablets using granules from Test Example 2-2.

[0099] - Disintegration Time (JP Disintegration Test) - The disintegration time of tablets immediately after manufacturing was measured in the same manner as in Test Example 1. The results are shown in Figure 4. In Figure 4, the vertical axis represents disintegration time (seconds), and the horizontal axis represents tablet hardness (N). "●" indicates the results for tablets using granules from Test Example 2-1, and "▲" indicates the results for tablets using granules from Test Example 2-2.

[0100] As shown in Figures 3 and 4, D ９０ When using the granules of Test Example 2-1, which have a (μm) / loose bulk density (g / mL) of 220-320, the disintegration time of the tablets was similar to that of the granules of Test Example 2-2. This confirmed that moldability could be improved without extending the disintegration time.

[0101] (Test Example 3) <Example 2> <<Preparation of spray drying liquid>> 3,805 g of purified water and 1,537 g of mannitol with the same particle size as the mannitol used in Example 1 of Test Example 1 were stirred and mixed to form a suspension. While stirring this suspension, 592.8 g of crystalline cellulose (manufactured by Asahi Kasei Corporation) and 43.9 g of croscarmellose sodium (manufactured by Asahi Kasei Corporation), which are disintegrants, and 22 g of stearyl fumarate sodium (manufactured by Nippon Soda Co., Ltd.), which is a hydrophilic lubricant, were added to prepare a uniform spray drying liquid.

[0102] <<Spray Drying>> Except for using the spray drying liquid described above, spray drying was carried out in the same manner as in Example 1 of Test Example 1 to obtain spray-dried granules. The obtained spray-dried granules were sieved with a mesh opening of 250 μm to obtain granules with the particle sizes listed in Table 3 below.

[0103] <Example 3> <<Preparation of spray-drying liquid>> 3,805 g of purified water and 1,317 g of mannitol with the same particle size as the mannitol used in Example 1 of Test Example 1 were stirred and mixed to form a suspension. While stirring this suspension, 812.3 g of crystalline cellulose (manufactured by Asahi Kasei Corporation) and 43.9 g of croscarmellose sodium (manufactured by Asahi Kasei Corporation), which are disintegrants, and 22 g of stearyl fumarate sodium (manufactured by Nippon Soda Co., Ltd.), which is a hydrophilic lubricant, were added to prepare a uniform spray-drying liquid.

[0104] <<Spray Drying>> Except for using the spray drying liquid described above, spray drying was carried out in the same manner as in Example 1 of Test Example 1 to obtain spray-dried granules. The obtained spray-dried granules were sieved with a mesh opening of 250 μm to obtain granules with the particle sizes listed in Table 3 below.

[0105] <Example 4> <<Preparation of spray-drying liquid>> 3,805 g of purified water and 1,822 g of mannitol with the same particle size as the mannitol used in Example 1 of Test Example 1 were stirred and mixed to form a suspension. While stirring this suspension, 329.3 g of crystalline cellulose (manufactured by Asahi Kasei Corporation) and 22 g of croscarmellose sodium (manufactured by Asahi Kasei Corporation), which are disintegrants, and 22 g of stearyl fumarate sodium (manufactured by Nippon Soda Co., Ltd.), which is a hydrophilic lubricant, were added to prepare a uniform spray-drying liquid.

[0106] <<Spray Drying>> Except for using the spray drying liquid described above, spray drying was carried out in the same manner as in Example 1 of Test Example 1 to obtain spray-dried granules. The obtained spray-dried granules were sieved with a mesh opening of 250 μm to obtain granules with the particle sizes listed in Table 3 below.

[0107] <Example 5> <<Preparation of spray-drying liquid>> 3,805 g of purified water and 1,756 g of mannitol with the same particle size as the mannitol used in Example 1 of Test Example 1 were stirred and mixed to form a suspension. While stirring this suspension, 329.3 g of crystalline cellulose (manufactured by Asahi Kasei Corporation) and 87.8 g of croscarmellose sodium (manufactured by Asahi Kasei Corporation), which are disintegrants, and 22 g of stearyl fumarate sodium (manufactured by Nippon Soda Co., Ltd.), which is a hydrophilic lubricant, were added to prepare a uniform spray-drying liquid.

[0108] <<Spray Drying>> Except for using the spray drying liquid described above, spray drying was carried out in the same manner as in Example 1 of Test Example 1 to obtain spray-dried granules. The obtained spray-dried granules were sieved with a mesh opening of 250 μm to obtain granules with the particle sizes listed in Table 3 below.

[0109] <Example 6> <<Preparation of spray-drying liquid>> 3,805 g of purified water and 1,910 g of mannitol with the same particle size as the mannitol used in Example 1 of Test Example 1 were stirred and mixed to form a suspension. While stirring this suspension, 219.6 g of crystalline cellulose (manufactured by Asahi Kasei Corporation) and 43.9 g of croscarmellose sodium (manufactured by Asahi Kasei Corporation), which are disintegrants, and 22 g of stearyl fumarate sodium (manufactured by Nippon Soda Co., Ltd.), which is a hydrophilic lubricant, were added to prepare a uniform spray-drying liquid.

[0110] <<Spray Drying>> Except for using the spray drying liquid described above, spray drying was carried out in the same manner as in Example 1 of Test Example 1 to obtain spray-dried granules. The obtained spray-dried granules were sieved with a mesh opening of 250 μm to obtain granules with the particle sizes listed in Table 3 below.

[0111] <Example 7> <<Preparation of spray-drying liquid>> 3,805 g of purified water and 1,712 g of mannitol with the same particle size as the mannitol used in Example 1 of Test Example 1 were stirred and mixed to form a suspension. While stirring this suspension, 395.1 g of crystalline cellulose (manufactured by Asahi Kasei Corporation) and 65.9 g of croscarmellose sodium (manufactured by Asahi Kasei Corporation), which are disintegrants, and 22 g of stearyl fumarate sodium (manufactured by Nippon Soda Co., Ltd.), which is a hydrophilic lubricant, were added to prepare a uniform spray-drying liquid.

[0112] <<Spray Drying>> Except for using the spray drying liquid described above, spray drying was carried out in the same manner as in Example 1 of Test Example 1 to obtain spray-dried granules. The obtained spray-dried granules were sieved with a mesh opening of 250 μm to obtain granules with the particle sizes listed in Table 3 below.

[0113] The particle size and loosened bulk density of the granules obtained in Examples 2 to 7 were measured in the same manner as in Test Example 1.

[0114] Table 3 below shows the composition, particle size, loosened bulk density, and D90 / loosened bulk density of the granules obtained in Examples 2 to 7. The granules obtained in Example 1 of Test Example 1 are also shown.

[0115]

[0116] [Evaluation] Using the obtained granules, placebo tablets were prepared in the same manner as in Test Example 1, and the physical properties of the tablets were evaluated.

[0117] <Tablet Physical Properties> - Tablet Hardness - The hardness of the tablets immediately after manufacturing was measured in the same manner as in Test Example 1. The results are shown in Figures 5 to 7. In Figures 5 to 7, the vertical axis represents tablet hardness (N), and the horizontal axis represents tablet compression pressure (kN). "■, solid line" represents tablets using granules from Example 2, "◆, solid line" represents tablets using granules from Example 3, "▲, dotted line" represents tablets using granules from Example 4, "◇, dotted line" represents tablets using granules from Example 5, "○, dotted line" represents tablets using granules from Example 6, and "□, dotted line" represents tablets using granules from Example 7. The results for tablets using granules from Example 1 are also shown ("●, solid line").

[0118] - Disintegration Time (JP Disintegration Test) - The disintegration time of tablets immediately after manufacturing was measured in the same manner as in Test Example 1. The results are shown in Figures 8 to 10. In Figures 8 to 10, the vertical axis represents disintegration time (seconds), and the horizontal axis represents tablet hardness (N). "■, solid line" represents tablets using granules from Example 2, "◆, solid line" represents tablets using granules from Example 3, "▲, dotted line" represents tablets using granules from Example 4, "◇, dotted line" represents tablets using granules from Example 5, "○, dotted line" represents tablets using granules from Example 6, and "□, dotted line" represents tablets using granules from Example 7. The results for tablets using granules from Example 1 are also shown ("●, solid line").

[0119] As shown in Figures 5-10, D ９０ It was confirmed that even when using the granules of Examples 2 to 7, which have a (μm) / loose bulk density (g / mL) of 220 to 320, tablets with excellent moldability and good disintegration properties can be obtained. Furthermore, it was confirmed that moldability tends to improve as the amount of crystalline cellulose increases.

[0120] (Evaluation of granules from Examples 1-7 and Comparative Examples 1-4) Based on the results of the [Evaluation] for Examples 1 and 1-4 of Test Example 1, and the granules from Examples 2-7 of Test Example 3, the moldability and disintegration properties were evaluated according to the following evaluation criteria. The results are shown in Table 4 below.

[0121] <Evaluation Criteria> - Moldability - ◎: High hardness tablets are obtained, and moldability is excellent (the hardness of tablets obtained by compressing with a tableting pressure of 6 kN exceeds 100 N). ○: Tablets with sufficient hardness are obtained, and moldability is within an acceptable range (the hardness of tablets obtained by compressing with a tableting pressure of 6 kN is 80 to 100 N). ×: Tablets with sufficient hardness are not obtained, and moldability is poor (the hardness of tablets obtained by compressing with a tableting pressure of 6 kN is less than 80 N).

[0122] - Disintegration Properties - ◎: Short disintegration time and excellent disintegration properties (a tablet with a hardness of approximately 100N disintegrates in less than 30 seconds). ○: Disintegration properties are within an acceptable range (a tablet with a hardness of approximately 100N disintegrates in 30 to 1,800 seconds). ×: Long disintegration time and poor disintegration properties (a tablet with a hardness of approximately 100N disintegrates in more than 1,800 seconds).

[0123]

[0124] As shown in Table 4, D ９０ It was confirmed that when using the granules of Examples 1 to 7, which have a (μm) / loose bulk density (g / mL) of 220 to 320, tablets with excellent moldability and good disintegration properties can be obtained.

[0125] This application claims priority based on Japanese Patent Application No. 2024-224455, filed on 19 December 2024, and the entire contents of Japanese Patent Application No. 2024-224455 are incorporated herein by reference.

Claims

A granule comprising at least a sugar consisting of sugars and / or sugar alcohols, two or more disintegrants, and a hydrophilic lubricant, The 90% cumulative particle diameter D of the aforementioned granules based on volume ９０ And D is the ratio of the loose bulk density. ９０ Granules characterized by having a (μm) / loose bulk density (g / mL) of 220 to 320. 　 The granules according to claim 1, wherein the content of the sugar in the granules is 60 to 90% by mass. 　 The granules according to claim 1 or 2, wherein the content of the disintegrant in the granules is 10 to 40% by mass. 　 The disintegrant comprises croscarmellose sodium and crystalline cellulose. The granules according to claim 3, wherein the mass ratio of croscarmellose sodium to crystalline cellulose is 1:2 to 1:

20. The content of croscarmellose sodium in the granules is 1 to 4% by mass. The granules according to claim 4, wherein the content of the crystalline cellulose in the granules is 10 to 39% by mass. 　 The granules according to claim 1 or 2, wherein the sugar is mannitol. 　 The granules according to claim 1 or 2, wherein the hydrophilic lubricant is sodium stearyl fumarate. 　 The granules according to claim 6, wherein the mannitol content in the granules is 60 to 70% by mass. 　 The granules according to claim 1 or 2, wherein the content of the disintegrant in the granules is 25 to 40% by mass. 90% cumulative particle size D based on volume ９０ A spray drying liquid preparation step involves mixing sugars consisting of sugars and / or sugar alcohols having a particle size of 15 to 23 μm, two or more disintegrants, a hydrophilic lubricant, and a solvent to prepare a spray drying liquid. The process includes a granule preparation step of spray-drying the aforementioned spray-drying liquid to obtain granules, The spray-drying liquid contains sugars, which consist of the sugar and / or sugar alcohol, in a suspended state. The 90% cumulative particle diameter D of the aforementioned granules based on volume ９０ And D is the ratio of the loose bulk density. ９０ A method for producing granules characterized by having a (μm) / loose bulk density (g / mL) of 220 to 320. 　 The method for producing granules according to claim 10, wherein the content of the sugar in the granules is 60 to 90% by mass. 　 The method for producing granules according to claim 10 or 11, wherein the content of the disintegrant in the granules is 10 to 40% by mass. 　 The disintegrant comprises croscarmellose sodium and crystalline cellulose. The method for producing granules according to claim 12, wherein the mass ratio of croscarmellose sodium to crystalline cellulose is 1:2 to 1:

20. The content of croscarmellose sodium in the granules is 1 to 4% by mass. The method for producing granules according to claim 13, wherein the content of the crystalline cellulose in the granules is 10 to 39% by mass. 　 The method for producing granules according to claim 10 or 11, wherein the sugar is mannitol. 　 The method for producing granules according to claim 10 or 11, wherein the hydrophilic lubricant is sodium stearyl fumarate. 　 The method for producing granules according to claim 15, wherein the content of mannitol in the granules is 60 to 70% by mass. 　 The method for producing granules according to claim 10 or 11, wherein the content of the disintegrant in the granules is 25 to 40% by mass. 　 A tablet characterized by containing the granules described in claim 1 or 2.

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