Effervescent tablet to be dissolved before use

Abstract

Provided is an effervescent tablet to be dissolved before use that reduces turbidity of an obtained solution. The effervescent tablet to be dissolved before use according to the present disclosure contains leucine and / or a salt thereof and cyclodextrin.

Description

Effervescent tablets that dissolve upon use

[0001] The present invention relates to effervescent tablets that dissolve upon use.

[0002] Conventionally, there have been dosage forms of preparations that dissolve upon use which are solid preparations during distribution and storage and can be dissolved in water or the like to prepare a liquid preparation during use (see, for example, Patent Document 1). Such preparations have the advantage of combining the high portability characteristic of solid preparations and the ease of administration characteristic of liquid preparations.

[0003] Japanese Patent Application Laid-Open "JP-A-2009-029711"

[0004] As in the technology disclosed in Patent Document 1, the dosage form of preparations that dissolve upon use is often a powder. However, in addition to powders, effervescent tablets that dissolve upon use have also been proposed. Effervescent tablets are tablets containing a foaming agent such as sodium hydrogen carbonate and foam and rapidly dissolve when put into water or the like. Since effervescent tablets are tablets, they have higher portability than powders. Also, effervescent tablets take less time to dissolve and are superior to powders in this regard.

[0005] Since effervescent tablets are tablets, a lubricant is required during production. However, according to the findings of the present inventors, depending on the type of lubricant, turbidity may occur in the resulting solution. A turbid solution has poor appearance, and there are also some users who feel a sense of repulsion, which is not desirable.

[0006] One aspect of the present invention aims to provide an effervescent tablet that dissolves upon use with reduced turbidity of the resulting solution.

[0007] The present invention includes the following embodiments: <1> A ready-to-use effervescent tablet comprising leucine and / or a salt thereof and cyclodextrin. <2> The effervescent tablet according to <1>, wherein the cyclodextrin is α-cyclodextrin and / or β-cyclodextrin. <3> The effervescent tablet according to <1> or <2>, wherein the total content of magnesium stearate, calcium stearate, sodium stearyl fumarate, and sucrose fatty acid ester contained in the effervescent tablet is 0.1% by weight or less, when the total amount of the effervescent tablet is 100% by weight. <4> A method for producing a ready-to-use effervescent tablet, comprising the step of compressing a raw material containing a lubricant and an excipient, wherein the lubricant contains leucine and / or a salt thereof, and the excipient contains cyclodextrin.

[0008] According to one aspect of the present invention, a ready-to-use effervescent tablet is provided that reduces the turbidity of the resulting solution.

[0009] This figure shows the solution obtained by dissolving the effervescent tablets according to Example 1A and Comparative Examples 1A and 1B. This figure shows the solution obtained by dissolving the effervescent tablets according to Example 5.

[0010] One embodiment of the present invention is described below. However, the present invention is not limited to the configurations described below. The present invention can be modified in various ways within the scope of the claims. The technical scope of the present invention also extends to embodiments or examples obtained by appropriately combining the multiple technical means disclosed herein. In this case, the multiple technical means may be disclosed across multiple embodiments or examples.

[0011] Unless otherwise specified in this specification, "A to B" representing a numerical range means "greater than or equal to A and less than or equal to B".

[0012] [1. Effervescent Tablets] An effervescent tablet that dissolves immediately upon use according to one aspect of the present invention contains leucine and / or a salt thereof. The solution obtained from such an effervescent tablet has reduced turbidity. An effervescent tablet according to another aspect of the present invention contains cyclodextrin. Such an effervescent tablet has a balance between tablet hardness and dissolution time.

[0013] Effervescent tablets are designed to be dissolved immediately before use. That is, the tablet is dissolved in water or another liquid before taking the solution. Note that this differs from tablets that are taken without dissolving (in such cases, cloudiness in the solution is usually not perceived as a sign of poor appearance). The solution obtained by dissolving a ready-to-use effervescent tablet may be taken immediately or stored for a certain period before consumption.

[0014] [1.1. Composition of effervescent tablets] In one embodiment, the effervescent tablet contains leucine and / or a salt thereof. In one embodiment, the effervescent tablet contains cyclodextrin. In one embodiment, the effervescent tablet contains both leucine and / or a salt thereof and cyclodextrin. Each of these components may be present in single form or in two or more forms.

[0015] [1.1.1. Leucine and Cyclodextrins] Leucine is (COOH)(NH ２ ) CH-CH ２ -CH(CH ３ ) - CH ３ Leucine is an amino acid represented by . Leucine is usually in its L-form. Leucine may form salts with any anion or cation. Examples of salts include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, maleate, fumarate, citrate, benzoate, methanesulfonate, and sodium salt. Salts of leucine esters or amides are also included in the salts of leucine. Examples of such salts include leucine methyl ester hydrochloride, leucine ethyl ester hydrochloride, and leucine β-naphthylamide hydrochloride.

[0016] Cyclodextrin is an oligosaccharide in which glucose molecules are linked cyclically by α-1,4 bonds. Depending on the number of glucose molecules contained, there are different types such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. In one embodiment, the cyclodextrin is α-cyclodextrin and / or β-cyclodextrin. The cyclodextrin may have substituents, or two or more cyclodextrin molecules may be polymerized.

[0017] In effervescent tablets, the lower limit of the total leucine and salt content may be 0.5% by weight or more, or 1% by weight or more, when converted to leucine and assuming the weight of the effervescent tablet is 100% by weight. In effervescent tablets, the upper limit of the total leucine and salt content may be 10% by weight or less, or 8% by weight or less, when converted to leucine and assuming the weight of the effervescent tablet is 100% by weight. If the total leucine and salt content is within the above range, the turbidity of the resulting solution can be reduced.

[0018] In effervescent tablets, the lower limit of the cyclodextrin content may be 20% or more, 25% or more, 30% or more, or 35% or more, when the weight of the effervescent tablet is considered to be 100% by weight. In effervescent tablets, the upper limit of the cyclodextrin content may be 70% or less, 65% or less, 60% or less, 55% or less, or 50% or less, when the weight of the effervescent tablet is considered to be 100% by weight. If the cyclodextrin content is within the above range, an effervescent tablet with sufficiently high tablet hardness and sufficiently short dissolution time can be obtained.

[0019] In one embodiment, leucine and / or its salts are included in the effervescent tablet as a lubricant. The preferred content described above may be the content of leucine and / or its salts included as a lubricant.

[0020] In one embodiment, cyclodextrin is included in the effervescent tablet as an excipient. The preferred content described above may be the content of cyclodextrin included as an excipient.

[0021] In one embodiment, the effervescent tablet contains little to no magnesium stearate, calcium stearate, sodium stearyl fumarate, or sucrose fatty acid ester. The total content of these components may be 0.1% by weight or less, 0.05% by weight or less, or 0.01% by weight or less, when the total amount of the effervescent tablet is considered to be 100% by weight. In another embodiment, the effervescent tablet contains none of magnesium stearate, calcium stearate, sodium stearyl fumarate, or sucrose fatty acid ester. By adopting such a composition, the turbidity of the resulting solution can be further reduced.

[0022] [1.1.2. Other Ingredients] In addition to the two ingredients mentioned above, effervescent tablets may also contain other ingredients such as additives. Examples of such ingredients include effervescent agents, excipients, disintegrants, binders, lubricants or fluidizers (anti-adhesion agents), colorants, flavorings, sweeteners, preservatives or antimicrobials. These ingredients may be present in single-ingredient or double-ingredient forms.

[0023] An example of a foaming agent is carbonate. Carbonates are composed of carbonate ions (CO2). ３ ２－ A carbonate is a salt of a sodium carbonate and any cation. Carbonates also include bicarbonates. Examples of carbonates include sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, magnesium carbonate, and their hydrates. In one embodiment, the carbonate is sodium bicarbonate.

[0024] Examples of excipients include sugars (lactose monohydrate, sucrose, maltose, fructose, glucose, trehalose, etc.), sugar alcohols (mannitol (especially D-mannitol), maltitol, sorbitol, xylitol, erythritol, lactitol, etc.), starches (starch, pregelatinized starch, partially pregelatinized starch, etc.), celluloses (crystalline cellulose, etc.), dextrin, dextran, glycerol fatty acid esters, and inorganic powders (magnesium aluminometasilicate, synthetic hydrotalcite, etc.).

[0025] Examples of binders include povidone, celluloses (methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (hypromellose), croscarmellose sodium, etc.), starch, gelatin, agar, thickening polysaccharides (alginic acid, sodium alginate, tragacanth, xanthan gum, acacia gum, pullulan, dextrin, etc.), polyvinyl alcohol-polyethylene glycol graft copolymer, carboxyvinyl polymer, polyethylene oxide, copolividone, polyoxyethylene hydrogenated castor oil, polymers including N-isopropylacrylamide and / or derivatives of acrylamide with a hydrophobic group introduced at the N position, polyoxyethylene-polyoxypropylene glycol, polyvinyl alcohol (including partially saponified polyvinyl alcohol), basic (meth)acrylate copolymer, and polyethylene glycol.

[0026] Examples of disintegrants include crospovidone, celluloses (carboxymethylcellulose (carmellose), carmellose sodium, carmellose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, crystalline cellulose, etc.), starches (starch, pregelatinized starch, partially pregelatinized starch, carboxymethyl starch sodium, carboxystarch sodium, hydroxypropyl starch, etc.), dextrin, calcium silicate, calcium citrate, and light anhydrous silicic acid.

[0027] Examples of lubricants or fluidizing agents (anti-adhesion agents) include stearic acid, stearates (magnesium stearate, calcium stearate, aluminum stearate, zinc stearate, etc.), sodium stearyl fumarate, glyceryl monostearate, glyceryl palmitostearate, sodium lauryl sulfate, polyethylene glycol, talc, glycerin fatty acid esters, sucrose fatty acid esters, potassium sodium tartrate, carnauba wax, hydrogenated oil, silicic acid compounds (light anhydrous silicic acid, magnesium aluminometasilicate, hydrated silicon dioxide, synthetic aluminum silicate, etc.), and titanium dioxide. However, from the viewpoint of reducing turbidity of the solution, it is preferable not to include too much of these components. In particular, with respect to magnesium stearate, calcium stearate, sodium stearyl fumarate, and sucrose fatty acid esters, it is preferable not to include them at all, or to include only very small amounts (the preferred amounts are as described above).

[0028] Examples of colorants include yellow ferric oxide, ferric oxide, titanium dioxide, black iron oxide, food tar dyes, and natural pigments (such as safflower yellow, beta-carotene, and riboflavin).

[0029] Examples of sweeteners include sucralose, mannitol, sorbitol, sucrose, aspartame, stevia, and acesulfame potassium.

[0030] Examples of flavorings include peppermint, L-menthol, dry-coated peach, lemon micron, strawberry micron, peppermint micron, peach micron, lychee micron, and pineapple micron.

[0031] Examples of preservatives or antimicrobials include ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, benzoic acid, and sodium benzoate.

[0032] [1.2. Characteristics of Effervescent Tablets] In this specification, the turbidity of the solution obtained by dissolving the effervescent tablet is measured in accordance with Method 180.01 specified by the U.S. Environmental Protection Agency (EPA). The standard substance is AMCO polymer solution. The measurement principle is 90° scattered light intensity (in accordance with Method 180.01). The turbidity value of the solution obtained by dissolving one effervescent tablet in 100 mL of deionized water may be 300 NTU or less, 200 NTU or less, 100 NTU or less, 50 NTU or less, or 25 NTU or less.

[0033] The lower limit of the tablet hardness of effervescent tablets may be 30 N or higher, 35 N or higher, or 40 N or higher. The upper limit of the tablet hardness may be 120 N or lower, or 150 N or lower. If the tablet hardness is within the above range, wear of the effervescent tablets can be reduced. In this specification, tablet hardness is measured using a tablet hardness tester (such as the TBH series from ERWEKA).

[0034] The upper limit of the dissolution time for effervescent tablets may be 240 seconds or less, 210 seconds or less, or 180 seconds or less. If the dissolution time is within the above range, the solution can be prepared in a sufficiently short time. In this specification, the dissolution time for effervescent tablets is measured based on the disintegration test method of the 18th edition of the Japanese Pharmacopoeia.

[0035] [2. Method for Manufacturing Effervescent Tablets] One aspect of the present invention provides a method for manufacturing effervescent tablets that dissolve immediately upon use, comprising the step of compressing a raw material containing leucine and / or a salt thereof as a lubricant. This manufacturing method can reduce the turbidity of the solution obtained by dissolving the effervescent tablets. Another aspect of the present invention provides a method for manufacturing effervescent tablets, comprising the step of compressing a raw material containing cyclodextrin as an excipient. This manufacturing method provides a balance between tablet hardness and dissolution time. Yet another aspect of the present invention provides a method for manufacturing effervescent tablets, comprising the step of compressing a raw material containing leucine and / or a salt thereof as a lubricant and cyclodextrin as an excipient.

[0036] Effervescent tablets can be manufactured by manufacturing methods known in the art. Examples of manufacturing methods include direct compression (direct compression or semi-direct compression) and granular compression (dry granular compression or wet granular compression).

[0037] The tableting pressure when tableting tablets can be appropriately adjusted according to the composition or shape of the effervescent tablets. The tableting pressure is, for example, about 3 to 16 kN.

[0038] Regarding the materials that can be used in the production of effervescent tablets, as described in section [1], the description will not be repeated here.

[0039] The preferred numerical ranges of the turbidity of the solution, the tablet hardness of the effervescent tablets, and the dissolution rate of the effervescent tablets are as exemplified in section [1].

[0040] [3. Method for reducing the turbidity of the solution obtained by dissolving the effervescent tablets] The method for reducing the turbidity of the solution obtained from the on-demand dissolution type effervescent tablets according to one aspect of the present invention includes a step of tableting a raw material containing leucine and / or its salt as a lubricant. The preferred numerical range of the turbidity of the solution is as exemplified in section [1].

[0041] Regarding the materials that can be contained in the effervescent tablets, as described in section [1], the description will not be repeated here. Regarding the methods that can be used in the production of effervescent tablets, as described in section [2], the description will not be repeated here.

[0042] [4. Method for achieving both tablet hardness and dissolution time of effervescent tablets] The method for increasing the tablet hardness and shortening the dissolution time of the on-demand dissolution type effervescent tablets according to one aspect of the present invention includes a step of tableting a raw material containing cyclodextrin as an excipient. The preferred numerical ranges of the tablet hardness and dissolution time of the effervescent tablets are as exemplified in section [1].

[0043] Regarding the materials that can be contained in the effervescent tablets, as described in section [1], the description will not be repeated here. Regarding the methods that can be used in the production of effervescent tablets, as described in section [2], the description will not be repeated here.

[0044] [Example 1] In this example, it is shown that by blending L-leucine, the turbidity of the solution obtained by dissolving the effervescent tablets is reduced.

[0045] [Materials] ● Active ingredient - Ascorbic Acid Fine Powder (DSM Co., Ltd.) ● Foaming agent - Sodium hydrogen carbonate (Sodium bicarbonate, AGC Co., Ltd.) ● Sweetener - Sucralose (Sucralose (P), San-Ei Gen F.F.I. Co., Ltd.) ● Excipient - Sorbitol (NEOSORB XTAB 290, Roquette) ● Lubricants - L-Leucine (Food additive L-Leucine, Phytopharm Co., Ltd.) - Magnesium stearate (Magnesium stearate, Taihei Chemical Industry Co., Ltd.) - Sucrose fatty acid ester (Surfhope J1816, Mitsubishi Chemical Corporation) ● Disintegrant - Calcium carmellose (E.C.G.-505, Gode Chemical Co., Ltd.) ● Flavor - Peach micron (Peach micron H-80450, Takasago Perfumery Co., Ltd.)

[0046] [Production Example] Effervescent tablets were produced according to the following procedure. The weight ratios of the materials used are as described in Table 1. 1. Materials other than the lubricant were mixed in a plastic bag to obtain a primary mixed powder. 2. The primary mixed powder and the lubricant were mixed to obtain a tableting powder. The types of lubricants to be blended are as described in Table 1. 3. The tableting powder was tableted using a single-shot tableting machine. Thus, effervescent tablets were produced.

[0047]

[0048] [Evaluation Method] The following procedure was followed. 1. One of the obtained effervescent tablets was dissolved in 100 mL of water. After the effervescent tablet was completely dissolved, the appearance of the obtained solution was visually observed to determine the presence or absence of suspended matter. 2. The solution was stirred using a stirrer for 1 minute. 3. The solution was added to a cell for turbidity measurement and mixed by inversion. At this time, the cell was not rinsed with the solution. 4. The turbidity of the solution was measured using a digital turbidimeter (TN420, APERA INSTRUMENTS). This turbidimeter complies with Method 180.01 defined by the United States Environmental Protection Agency (EPA).

[0049] [Results] The results are shown in Figure 1 and Table 2. In the example, L-leucine was used as a lubricant. In the comparative example, a lubricant other than L-leucine was used. As can be seen from Figure 1, a clear solution was obtained from the effervescent tablets of the example. On the other hand, the solution obtained from the effervescent tablets of the comparative example was generally cloudy, and in particular, film-like clumps were floating on the surface. Thus, the solution obtained from the effervescent tablets of the example can be said to have superior appearance. As can be seen from Table 2, the quantified turbidity value was very high for the solution obtained from the effervescent tablets of Comparative Example 1A, and slightly high for the solution obtained from the effervescent tablets of Comparative Example 1B. As shown in the same table, only the effervescent tablets of Example 1A yielded a solution with low turbidity and no suspended matter.

[0050] [Example 2] This example demonstrates that by incorporating cyclodextrin, it is possible to achieve a balance between the hardness of the effervescent tablet and the dissolution time.

[0051] [Ingredients] ● Active ingredient: Ascorbic acid (Ascorbic Acid Fine Powder, DSM Co., Ltd.) ● Foaming agent: Sodium bicarbonate (Sodium Bicarbonate, AGC Inc.) ● Sweeteners: Sucralose (Sucralose (P), San-Ei Gen F.F.I. Co., Ltd.) Sorbitol (NEOSORB XTAB 290, Roquette) ● Excipients: α-Cyclodextrin (Celldex A-100, Nippon Shokuhin Kako Co., Ltd.) β-Cyclodextrin (Celldex B-100H, Nippon Shokuhin Kako Co., Ltd.) Xylitol (Xylitol, Bussan Food Science Co., Ltd.) Amicol (Amicol No. 6-L, Nichiden Chemical Co., Ltd.) Dextrin (GLUCIDEX IT6, Roquette) Maltitol (Resis, Mitsubishi Corporation Life Sciences Co., Ltd.) Anhydrous lactose (SuperTab 21AN, DFE Pharma) • D-mannitol (PEARLITOL 50C, Roquette) • Erythritol (Erythritol Granules DC, Bussan Food Science Co., Ltd.) • Trehalose (Trehalose Hydrate P, Asahi Kasei Corporation) • Sorbitol (NEOSORB XTAB 290, Roquette) ● Lubricant: L-leucine (Food Additive L-leucine, Phytopharma Co., Ltd.) ● Flavoring: Peach Micron (Peach Micron H-80450, Takasago International Corporation)

[0052] [Manufacturing Example] Foaming tablets were manufactured according to the following procedure. The weight ratios of the materials used are as shown in Table 3. 1. The materials other than the lubricant were mixed in a plastic bag to obtain a primary mixed powder. The types of excipients used are as shown in Table 3. 2. The primary mixed powder and the lubricant were mixed to obtain a tablet powder. 3. The tablet powder was compressed using a single-shot tablet press. Foaming tablets were manufactured in this manner.

[0053] [Measurement Method] (Tablet Hardness) Measured using a tablet hardness tester (TBH 425, ERWEKA). (Dissolution Time) Measured according to the disintegration test method of the 18th edition of the Japanese Pharmacopoeia.

[0054] [Results] The results are shown in Table 3.

[0055] In the examples, cyclodextrin was used as an excipient. In the comparative examples, excipients other than cyclodextrin were used. As can be seen from Table 3, the effervescent tablets in the examples had high tablet hardness and a short dissolution time. On the other hand, the effervescent tablets in the comparative examples did not satisfy any of these conditions. Specifically, in Comparative Example 2A, no excipient was used, and therefore no tablet hardness was achieved. In Comparative Examples 2B to 2E, excipients were used, but still no tablet hardness was achieved. In Comparative Examples 2F to 2I, other types of excipients were used, and the tablet hardness increased somewhat, but it was insufficient. In Comparative Example 2J, yet another type of excipient was used, and a sufficiently high tablet hardness was achieved, but the dissolution time was extremely long. Thus, it can be said that the effervescent tablets in the examples achieve a balance between tablet hardness and dissolution time.

[0056] In particular, sorbitol and erythritol are known to be more soluble than cyclodextrin. However, the fact that the dissolution time could not be significantly shortened even when these substances were added was a surprising result that could not be predicted by those skilled in the art.

[0057] [Example 3] This example demonstrates that a balance between tablet hardness and dissolution time can be achieved in effervescent tablets regardless of the type and combination of cyclodextrins.

[0058] [Materials] The same materials as in Examples 1 and 2 were used.

[0059] [Manufacturing Example] Effervescent tablets were manufactured according to the following procedure. The weight ratios of the materials used are as shown in Table 4. 1. The materials other than the lubricant were mixed in a plastic bag to obtain a primary mixed powder. The types of excipients (cyclodextrins) used are as shown in Table 4. 2. The primary mixed powder and the lubricant were mixed to obtain a tablet powder. 3. The tablet powder was compressed using a single-shot tablet press. In this way, effervescent tablets were manufactured.

[0060] [Measurement Method] Tablet hardness and dissolution time were measured using the same method as in Example 2.

[0061] [Results] The results are shown in Table 4.

[0062] In all examples, effervescent tablets with sufficiently high tablet hardness and sufficiently short dissolution time were obtained. The higher the cyclodextrin content, the higher the tablet hardness and the longer the dissolution time tended to be.

[0063] [Example 4] This example demonstrates that a balance between tablet hardness and dissolution time can be achieved in effervescent tablets regardless of the type and combination of cyclodextrins. In this example, effervescent tablets with a different formulation from that of Example 3 were manufactured.

[0064] [Ingredients] ● Granulated powder: Ascorbic acid (Ascorbic Acid Fine Powder, DSM Co., Ltd.), α-cyclodextrin (CAVAMAX W6 Food, Cyclochem Co., Ltd.), Safflower yellow pigment (Powdered Sun Yellow No. 2 FU, San-Ei Gen F.F.I. Co., Ltd.), Riboflavin (Riboflavin K, Mitsubishi Chemical Corporation), Nicotinamide (Food additive nicotinamide, Arcsada Japan Co., Ltd.), Pyridoxine hydrochloride (Food additive vitamin B6, Konan Chemical Co., Ltd.), Purified water ● Tablet powder: Sodium bicarbonate (Sodium Bicarbonate, Tosoh Corporation), Sucralose (Sucralose (P), San-Ei Gen F.F.I. Co., Ltd.), Dry Coat Peach (Dry Coat Peach #20029, Takada Fragrance Co., Ltd.), α-cyclodextrin (CAVAMAX W6 Food, Cyclochem Co., Ltd.) • β-cyclodextrin (Celldex B-100H, Nippon Shokuhin Kako Co., Ltd.) • Carmellose calcium (ECG-FA, Nichirin Chemical Industry Co., Ltd.) • L-leucine (Food additive L-leucine, Phytopharma Co., Ltd.) • L-valine (Food additive L-valine, Phytopharma Co., Ltd.) • L-isoleucine (Food additive L-isoleucine, Phytopharma Co., Ltd.) • L-arginine (Food additive L-arginine, Phytopharma Co., Ltd.)

[0065] [Manufacturing Example] Effervescent tablets were manufactured according to the following procedure. The weight ratio of the materials used is as shown in Table 5. (Crushing of Materials) 1. L-leucine and sodium bicarbonate were crushed in a crusher. The average particle size after crushing was 5 μm for L-leucine and 3.5 μm for sodium bicarbonate. (Preparation of Granulated Powder) 2. Ascorbic acid was sieved through a 30-mesh sieve, and the sieved fraction was selected. 3. The sieved ascorbic acid was placed in a fluidized bed granulator and pre-fluidized. 4. Purified water and α-cyclodextrin were mixed, and safflower yellow pigment, riboflavin, nicotinamide, and pyridoxine hydrochloride were further dispersed to prepare a granulated solution. The granulated solution was sprayed onto the ascorbic acid to granulate it, and then dried. 5. The granules were sieved through a 30-mesh sieve, and the sieved fraction was obtained as granule powder. (Tabletization of effervescent tablets) 6. Sodium bicarbonate, sucralose, dry-coated peach, α-cyclodextrin and / or β-cyclodextrin, carmellose calcium, L-leucine, L-valine, L-isoleucine, and L-arginine were added to the granule powder and mixed. Tablet powder was obtained in this way. 7. Tablet powder was compressed using a rotary tablet press. The compression pressure was 6 kN, 8 kN, 10 kN, or 12 kN. Effervescent tablets were produced in this way.

[0066] [Measurement Method] Tablet hardness and dissolution time were measured using the same method as in Example 2.

[0067] [Results] The results are shown in Table 5.

[0068] Using α-cyclodextrin alone, β-cyclodextrin alone, or both as excipients resulted in effervescent tablets with sufficiently high hardness and sufficiently short dissolution time. Higher compression pressure tended to result in higher tablet hardness and longer dissolution time.

[0069] [Example 5] This example demonstrates that a balance between tablet hardness and dissolution time can be achieved by incorporating cyclodextrin, and that the turbidity of the solution obtained by dissolving the effervescent tablet is reduced by incorporating L-leucine. In this example, effervescent tablets with a different composition from Examples 1 to 4 were manufactured.

[0070] [Ingredients] ● Granulated powder - L-ascorbic acid (Vitamin C tablet granules, Fuso Chemical Industry Co., Ltd.) - Sodium bicarbonate (Sodium bicarbonate for food additive, Tosoh Corporation) - α-cyclodextrin (CAVAMAX W6 Food, Cyclochem Co., Ltd.) - Aspartame (PAL SWEET DIET, Ajinomoto Healthy Supply Co., Ltd.) - L-valine (Food additive L-valine, Phytopharma Co., Ltd.) - L-isoleucine (Food additive L-isoleucine, Phytopharma Co., Ltd.) - L-arginine (Food additive L-arginine, Phytopharma Co., Ltd.) - Safflower yellow pigment (Powdered Sun Yellow No. 2 FU, San-Ei Gen F.F.I. Co., Ltd.) - Riboflavin (Food additive Riboflavin K, Mitsubishi Chemical Corporation) - Nicotinamide (Nicotinamide, DSM Co., Ltd.) • Pyridoxine hydrochloride (Vitamin B6 for food additives, Taisho Technos Co., Ltd.) • Tablet powder • Dry Coat Peach (Dry Coat Peach #20029, Takada Fragrance Co., Ltd.) • Carboxymethylcellulose calcium (ECG-FA, Nichirin Chemical Industry Co., Ltd.) • L-leucine (Food additive L-leucine, Phytopharma Co., Ltd.)

[0071] [Manufacturing Example] Foaming tablets were manufactured according to the following procedure. The weight ratios of the materials used are as shown in Table 6. (Preparation of Granulated Powder) 1. Granulated liquid I and granulated liquid II were prepared by mixing the materials listed in the Granulated Liquid I and Granulated Liquid II columns, respectively. Purified water was also prepared to make granulated liquid III. 2. Sodium bicarbonate and aspartame from the materials listed in the Powder column were pre-mixed with an amount of α-cyclodextrin equal to or greater than the total amount of these materials. 3. The resulting mixture was sieved through a 32-mesh sieve. 4. The sieved mixture and the remaining materials listed in the Powder column were placed in a fluidized bed granulator and pre-fluidized. 5. Granulated liquid I was sprayed onto the powder in the fluidized bed granulator to granulate it. 6. After the spraying of granulated liquid I was completed, granulated liquid II was sprayed onto the powder. 7. After the spraying of granulated liquid II was completed, granulated liquid III was sprayed onto the powder to dry it. In this way, granules were obtained. 8. The granules were sieved through a 16-mesh sieve to obtain a fine powder. (Tableting of foaming tablets) 9. Four times or more of the granulated powder was added to L-leucine, one of the materials listed for the tableting powder, and pre-mixed. 10. The obtained mixture was sieved through a 32-mesh sieve. 11. The obtained mixture was mixed with the remainder of the materials listed in the tableting powder section. In this way, a tableting powder was obtained. 12. The tableting powder was compressed using a tablet press. The compression pressure was 12 kN. In this way, foaming tablets were manufactured.

[0072]

[0073] [Evaluation Method] The appearance of the solution obtained by dissolving the effervescent tablets was visually observed and the turbidity was measured, in the same manner as in Example 1. In addition, the tablet hardness and dissolution time were measured in the same manner as in Example 2.

[0074] [Results] The results are shown in Figure 2. As shown in the figure, a clear solution free of suspended matter was obtained from the effervescent tablets of Example 5. The turbidity of the solution was measured with a digital turbidimeter and was 21.3 NTU. The hardness of the obtained tablets was 64.7 N, and the dissolution time was 221.3 seconds, indicating that effervescent tablets with sufficiently high hardness and sufficiently short dissolution time were obtained.

[0075] [Example prescription] [Examples of ingredients] [Example of manufacturing method] (Grinding of materials) 1. Grind L-leucine and sodium bicarbonate in a grinder. The average particle size after grinding shall be L-leucine: 5 μm, sodium bicarbonate: 2.5 μm. (Preparation of granulated powder A-1) 2. Sieve the ascorbic acid with a 30-mesh sieve and select the sieved fraction. 3. Place the sieved ascorbic acid into a fluidized bed granulator and pre-flow it. 4. Mix purified water and α-cyclodextrin to prepare the granulation solution. Spray the granulation solution onto the ascorbic acid to granulate and dry it. 5. Sieve the granulated material with a 30-mesh sieve and select the sieved fraction as granulated powder A-1. (Preparation of granulated powder A-2) 6. Place granulated powder A-1 into a fluidized bed granulator and pre-flow it. 7. 10. Disperse safflower yellow pigment, riboflavin, nicotinamide, and pyridoxine hydrochloride in purified water to prepare a granulation solution. Spray the granulation solution onto granulation powder A-1 to form a coating layer and allow to dry. 8. Sieve the coated particles with a 30-mesh sieve and use the sieved fraction as granulation powder A-2. (Preparation of granulation powder B) 9. Sodium bicarbonate, sucralose, a portion of β-cyclodextrin, L-valine, L-isoleucine, and L-arginine with a 30-mesh sieve and select the sieved fraction. 11. Place the sieved powder and the remaining β-cyclodextrin into a fluidized bed granulator and pre-fluidize. 12. Mix purified water and α-cyclodextrin to prepare a granulation solution. 12. Granulation is performed by spraying the powder with granulation solution and drying. 13. The granulated material is sieved through a 30-mesh sieve, and the sieved fraction is designated as granulated powder B. (Tableting of effervescent tablets) 14. α-cyclodextrin, L-leucine, carmellose calcium, and peach micron are added to a portion of granulated powder B and dispersed. 15. The mixture obtained in step 13 is sieved through a 30-mesh sieve, and the sieved fraction is selected. 16. Granulated powder A-2 and the remainder of granulated powder B are added to the obtained mixture and mixed further. Tablet powder is obtained in this way. 17. Tablet powder is compressed using a rotary tablet press. Effervescent tablets are manufactured in this way.

[0076] This invention can be used in effervescent tablets and the like.

Claims

1. A ready-to-use effervescent tablet containing leucine and / or its salts and cyclodextrin.

2. The effervescent tablet according to claim 1, wherein the cyclodextrin is α-cyclodextrin and / or β-cyclodextrin.

3. The effervescent tablet according to claim 1 or 2, wherein the total content of magnesium stearate, calcium stearate, sodium stearyl fumarate, and sucrose fatty acid ester contained in the effervescent tablet is 0.1% by weight or less, when the total amount of the effervescent tablet is 100% by weight.

4. A method for producing a dissolvable effervescent tablet, comprising the step of compressing a raw material containing a lubricant and an excipient, wherein the lubricant contains leucine and / or a salt thereof, and the excipient contains cyclodextrin.

Images