Tableting of thickness regulator for assisting deglutition of food and beverage

Abstract

To provide a tablet having both practically sufficient hardness and rapid disintegrability in order to omit labor to measure granule according to a thickness degree and to facilitate handling.SOLUTION: A method for producing tablets includes adding porous dextrin to the granule that a mixture of dextrin and thickener is granulated, and compressing the mixture. The tablets produced by the above method are also provided.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a thickening agent for aiding swallowing of food and beverages. [Background technology]

[0002] Japan is currently an aging society. As people get older, their swallowing ability declines. By thickening liquid foods and beverages with a thickening agent, it is possible to assist the swallowing of people with dysphagia (Patent Document 1). At home or in elderly care facilities, family members and staff adjust the degree of viscosity according to the degree of decline in the swallowing ability of each person with dysphagia. However, all commercially available products currently on the market are granular, and there is an issue that it is difficult to reproducibly adjust the degree of viscosity. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Patent 4694109 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a tablet having both practically sufficient hardness and rapid disintegrability, thereby eliminating the need to measure granules according to the degree of viscosity and facilitating handling. [Means for solving the problem]

[0005] As a result of extensive efforts, the inventors discovered that dextrin, a dispersant contained in commercially available viscosity control agents, melts when humidified and dried, forming interparticle crosslinks and increasing the strength of the compact. They then optimized the formulation and manufacturing method of thickening agent granules through granulation, added porous dextrin to the resulting granules, and compressed and molded them at low pressure to obtain a porous compact, which is then hardened by humidification and drying treatment as necessary, creating a new tableting method. The present invention was completed based on these findings. The gist of the present invention is as follows. (1) A method for producing tablets, comprising granulating a mixture of dextrin and a thickener, adding porous dextrin to the granules, and compressing the granules. (2) The method according to claim 1, wherein the tableting pressure during compression molding is 1 to 14 MPa. (3) A tablet manufactured by the method described in (1) or (2). (4) The tablet described in (3) having a hardness of 50 N or more. (5) The tablet according to (3) or (4) having a porosity of 57% or more. (6) The tablet according to any one of (3) to (5), which is used to thicken food. Effect of the Invention

[0006] According to the present invention, it has become possible to form a viscosity regulator into a tablet. By forming the viscosity regulator into a tablet, the time and effort required for measuring granules according to the degree of viscosity is eliminated, making the viscosity regulator easier to handle. [Brief description of the drawings]

[0007] [Figure 1] SEM images of the ingredients in thickening food. From the left: thickening agent (granules), dextrin, xanthan gum. [Diagram 2] Particle size distribution of granulated products made from each formulation. [Diagram 3] SEM photograph of the particle surface of the fluidized bed granulated material. [Figure 4] SEM photo of DEX added to granules for tableting during tablet formation. [Diagram 5]Particle size distribution of DEX added to granules for tableting during tablet formation. [Figure 6] Schematic diagram of compression molding. [Figure 7] Schematic diagram of dissolution test using electrical conductivity. [Figure 8] Schematic diagram of viscosity measurement method. [Figure 9] SEM images of modified tablet surfaces with post-added DEX. [Figure 10] Effect of type of post-added DEX on tablet hardness (before humidification). [Figure 11] Effect of type of post-added DEX on tablet porosity (before humidification). [Figure 12] Effect of tableting granule formulation on tablet hardness (before humidification). [Figure 13] Effect of tablet granule formulation on tablet porosity (before humidification). [Figure 14] SEM photographs of tablet surfaces with different humidification times (humidification 60°C, 75% RH). [Figure 15] SEM photographs of the cut surface of tablets with different humidification times (humidification 60°C, 75% RH). [Figure 16] Effect of humidification time on tablet hardness (Gr(20)-1). [Figure 17] Effect of humidification time on tablet porosity (Gr(20)-1). [Figure 18] Dissolution behavior of KCl from tablets with different tableting powders as a function of electrical conductivity. [Figure 19] Dissolution behavior of KCl from tablets with different humidification times as a function of electrical conductivity. A: 10 MPa, B: 12 ​​MPa, C: 14 MPa. [Figure 20] Effect of humidification time on tablet hardness. [Figure 21] Effect of humidification time on tablet porosity. [Figure 22] Dissolution behavior of KCl from tablets with different humidification times as a function of electrical conductivity. [Figure 23] Effect of humidification temperature on tablet hardness. [Figure 24] Effect of humidification temperature on tablet porosity. [Diagram 25] Dissolution behavior of KCl from tablets at different humidification temperatures as determined by electrical conductivity. [Figure 26] Effect of short-term humidification on tablet hardness. [Figure 27] Effect of short-term humidification on tablet porosity. [Figure 28] Dissolution behavior of KCl from tablets with different humidification times as a function of electrical conductivity. [Figure 29] Effect of humidification time on tablet hardness. [Diagram 30] Effect of humidification time on tablet porosity. [Diagram 31] Dissolution behavior of KCl from tablets with different humidification times as a function of electrical conductivity. [Diagram 32] Effect of humidification time on viscosity of dissolution solution after dissolution test. [Diagram 33] Effect of humidification temperature on viscosity of dissolution solution after dissolution test. [Diagram 34] Effect of short-term humidification on the viscosity of the dissolution solution after dissolution testing. [Diagram 35] Effect of short-term humidification on the viscosity of the dissolution solution after dissolution testing. [Diagram 36] 1 is a summary of the experimental data of Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Hereinafter, the embodiment of the present invention will be described in more detail.

[0009] The present invention provides a method for producing tablets, which comprises granulating a mixture of dextrin and a thickener, adding porous dextrin to the granules, and compressing the granules.

[0010] Thickeners are used to improve food texture for medical and nursing care purposes or for general food processing purposes, for example, to improve liquid foods to a sol or gel state. Examples of food texture improvement for medical and nursing care purposes include improving the texture of liquid foods that cause swallowing disorders or aspiration in the elderly, such as liquids for drinks, soups, and liquids contained in solid foods, to a sol or gel state. As a solubilizing agent that induces solization, thickening polysaccharides such as xanthan gum can be used, and as a thickening agent that induces gelation, xanthan gum, locust bean gum, carrageenan, gellan gum, agar, gelatin, etc. can be used alone or in combination. In one embodiment of the present invention, xanthan gum is preferably used as the thickening agent.

[0011] Xanthan gum is a polysaccharide made by fermenting starch such as corn with the bacterium Xanthomonas campestris. It consists of repeating units of two glucose molecules, two mannose molecules, and glucuronic acid. Potassium, sodium, and calcium salts are also included in xanthan gum. Xanthan gum is used in a wide range of applications as a thickening agent and thickening stabilizer because it becomes viscous when mixed with water. It is currently the most commonly used thickening agent in nursing and medical care. By adding xanthan gum to food (especially liquid food), the food can be made low-adhesive and high-cohesive, and the denaturation of the food caused by temperature changes can be reduced. In other words, by making the food low-adhesive, it is possible to prevent it from sticking to the oral cavity and pharynx, and by making the food highly cohesive, the food can be crushed once by tongue pressure and then re-attached to form a bolus without falling apart, allowing the food to be sent correctly to the esophagus. Furthermore, by lowering the temperature denaturation of food, it is possible to prevent gelatin from changing into a low-viscosity liquid that is likely to cause aspiration due to dissolution at the temperature in the oral cavity, which is likely to occur. In addition to the above characteristics, xanthan gum also has excellent features such as being less susceptible to the salt concentration, pH, potassium concentration, etc. of liquid foods. However, xanthan gum has extremely low dispersibility and solubility, and forms lumps when added to liquid foods, and it is extremely difficult to completely dissolve it even when stirred. In order to improve the dispersibility and solubility of xanthan gum, it is preferable to use xanthan gum as a granule. Furthermore, it is preferable to make it into porous particles that can improve the solubility, rather than simply granulating it. There is no particular limit to the granulation method of this xanthan gum, but a method used to form porous particles that can improve the solubility, such as a flow coating granulation method using a flow coater, can be suitably used. The particle size of the granules can be arbitrarily determined using the solubility and dispersibility in liquid foods as indicators, and can be, for example, 250 μm to 1000 μm in diameter.

[0012] Dextrin is a carbohydrate obtained by hydrolysis of starch, dextrin or glycogen. In the present invention, the DE (dextrose equivalent) of the dextrin mixed with the thickener is preferably 2 to 30, more preferably 5 to 30, and more preferably 7 to 13. DE can be measured by the SOMOGYI method. The weight-average molecular weight of the dextrin is preferably 4000 to 100000, and more preferably 17000 to 100000. The source material from which the dextrin is derived is not limited, and examples thereof include corn, sweet potato, potato, tapioca, wheat, and rice. In order to aid in the dispersibility and solubility of the thickener (e.g., xanthan gum) in the thickening agent for swallowing aid of food and beverages, dextrin is often mixed as a dispersant. By adding dextrin to the viscosity regulator, the particles of the thickener (e.g., xanthan gum) are prevented from adhering to each other in the liquid food to form agglomerates, improving the dispersibility of the thickener particles in the liquid food, and the improved dispersibility can increase the solubility. In order to mix dextrin homogeneously with the thickener particles, it is preferable to make it into a granule like the thickener particles. From the viewpoint of preventing separation after mixing the thickener (e.g., xanthan gum) particles and the dextrin particles, it is preferable that the particle size of the dextrin is the same as that of the thickener (e.g., xanthan gum) particles, and when the thickener is xanthan gum, it is preferable that the diameter of the dextrin is, for example, 250 μm to 1000 μm, like the xanthan gum particles.

[0013] In the method for producing tablets of the present invention, porous dextrin is added to granules obtained by granulating a mixture of dextrin and a thickener, and the mixture is compressed and molded. After mixing dextrin and a thickener, a granulation product is prepared by a granulator, the granulation product obtained is sieved, and granules of an appropriate particle size are used as granules for tableting. To prepare a granulation product, dextrin and a thickener are premixed, then charged into a granulator, and granulated while spraying an aqueous potassium chloride solution. The granulation method may be any method such as a rolling granulation method or a fluidized bed granulation method, and the fluidized bed granulation method is preferred. Potassium chloride may be added to improve the surface modification of xanthan gum and its dispersibility in water. Instead of potassium chloride, metal salts such as calcium chloride, sodium chloride, magnesium chloride, and sodium gluconate may be used. The mixing ratio of dextrin to a thickener is preferably 1:9 to 9:1, and more preferably 1:9 to 8:2. The mixing ratio of the thickener to potassium chloride is preferably 5:1 to 9:1, and more preferably 6:1 to 8:1.

[0014] The granulated product prepared by the granulator is passed through a 250 or 1000 μm sieve (for example, JIS Z 8801), and granules of 250 to 1000 μm are collected and used as granules for tableting.

[0015] After adding porous dextrin to the granules for tableting, tablets can be prepared by compression molding at low pressure. The molded body can also be hardened by humidifying and drying. By adding porous dextrin to the granules for tableting, tablets with high hardness and large porosity can be obtained. The pores in the tablet contribute to the disintegration and water conductivity of the tablet, and it is presumed that the larger the pores, the easier it is for water to be guided into the tablet, and the easier it is to disintegrate. In addition, dextrin melts when humidified and dried, forming interparticle crosslinks and increasing the physical strength of the tablet.

[0016] Porous dextrin is obtained by drying starch hydrolysate in a drum dryer, and is often plate-like in shape and has good dispersibility in water. Therefore, it is possible to more effectively prevent the formation of agglomerates before the thickener (e.g., xanthan gum) particles are dispersed. The DE value of the porous dextrin is preferably 5 to 30, and more preferably 7 to 13. The bulk density of the porous dextrin is g / cm 3 is 0.08 to 0.32 g / cm 3 It is preferable that the density is 0.09 to 0.16 g / cm 3 is preferred.

[0017] The mixing ratio of the granules for tableting to the porous dextrin (granules for tableting:porous dextrin) is preferably 1:2 to 3:1, and more preferably 1:2 to 2:1. The composition ratio in the tablet after the addition of the porous dextrin (dextrin:thickener:potassium chloride) is preferably 45-80:15-55:2-10, and more preferably 50-70:20-45:3-7.

[0018] The tableting pressure when compressing and molding after adding the porous dextrin to the granules for tableting is preferably 1 to 14 MPa, and preferably 4 to 12 MPa. As the compression means, a tablet press, a compression tensile tester, and the like can be used. A lubricant may be added during molding. Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, and sodium lauryl sulfate. Other compression molding conditions for the tablet include a diameter of 1 to 30 mm, preferably 10 to 25 mm, a charge amount of 200 to 3000 mg, preferably 400 to 2000 mg, and a thickness of 1 to 20 mm, preferably 2 to 15 mm.

[0019] The tablet may be further subjected to a humidification treatment. As a humidification method, a method of placing in a high humidity environment, a method of spraying water with a spray, a method of spraying steam, etc. can be used. In the method of placing in a high humidity environment, the humidification conditions are preferably a temperature of 50 to 85°C, preferably 55 to 80°C, a humidity of 60 to 95% RH, preferably 75 to 95% RH, and a time of 5 seconds to 5 minutes, preferably 5 seconds to 3 minutes. As the humidification time increases, an increase in hardness is confirmed.

[0020] After the humidification treatment, a drying treatment may be performed. Examples of the drying method include a method of placing the material under high temperature conditions and a method of contacting the material with high-temperature dry air. In the method of placing the material under high temperature conditions, the drying temperature is preferably 70 to 95°C, and more preferably 75 to 85°C, and the drying time is preferably 3 to 20 minutes, and more preferably 5 to 15 minutes.

[0021] The tablet production method of the present invention makes it possible to obtain tablets having both practically sufficient hardness and rapid disintegrability. The present invention also provides tablets produced by the above-mentioned method.

[0022] The hardness of the tablet is 50 N or more, and preferably 50 to 80 N. The hardness of the tablet can be measured by applying pressure in the diameter direction with a load cell type tablet hardness tester, and the load at which the tablet breaks is taken as the hardness (Hardness, N). A hardness of 50 N or more can be said to be sufficient for practical use.

[0023] For rapid disintegration of the tablet, the porosity of the tablet is preferably 57% or more, and more preferably 60% or more. When the porosity of the tablet is high, water can rapidly penetrate through the pores, resulting in rapid dissolution behavior.

[0024] The porosity of a tablet can be calculated using the following formula: JPEG2024179019000001.jpg21108

[0025] The true density of the tablet can be measured using a helium gas displacement type true density meter.

[0026] The disintegration property of the tablet can be examined by measuring the electrical conductivity of KCl dissolved due to disintegration after the tablet is put into water (dissolution test described in the Examples below). The electrical conductivity can be measured using an electrical conductivity meter. In the dissolution test, the shorter the time for the electrical conductivity value to reach the plateau, the faster the tablet disintegrates, and the higher the electrical conductivity plateau value, the easier the tablet disintegrates. It can be said that the closer the dissolution behavior is to that of the thickening agent (granules), the better the disintegration property of the tablet. In addition, the results of the viscosity measurement of the solution after the dissolution test show that the viscosity also increases in the order of the electrical conductivity plateau value in the dissolution behavior of each tablet, suggesting a proportional relationship between the dissolution of KCl and the development of viscosity. The viscosity of the solution after the dissolution test can be measured using a cone-plate type rotational viscometer and a B-type viscometer. An example of the viscosity measurement conditions is as described in the Examples below.

[0027] Examples of the shape of the tablet include a cylinder, an elliptical cylinder, a cube, a rectangular parallelepiped, a plate, a sphere, a polygonal prism, a polygonal pyramid, a polygonal truncated pyramid, and a polyhedron.

[0028] When the tablet has a cylindrical shape, the size of the tablet may be 1 to 30 mmφ, preferably 10 to 25 mmφ, and the thickness of the tablet may be 1 to 20 mm, preferably 2 to 15 mm.

[0029] The tablet of the present invention can be used to thicken food (particularly liquid food). "Thickening" is a concept that means a state in which a liquid has some viscosity, and "thickening" is classified into the following "three stages of thickening" in the "Swallowing Adjustment Food Classification 2021 (Thickening)" (Journal of the Japanese Society of Dysphagia Rehabilitation 25(2):135-149, 2021) of the Japanese Society of Dysphagia Rehabilitation. "Thin and thick": When you tilt the spoon, it flows down smoothly. Viscosity (mPa s) * 50-150 "Medium viscosity": When you tilt the spoon, it flows down smoothly. Viscosity (mPa·s) 150-300 "Thick and viscous": Even if you tilt the spoon, it will retain its shape to some extent and will not flow easily. Viscosity (mPa·s) 300-500 Viscosity (mPa s) * : A cone-plate type rotational viscometer was used, the measurement temperature was 20°C, and the shear rate was 50 s -1 The viscosity measurement results after 1 minute are shown in Fig.

[0030] The food may be any food or drink, and is particularly preferred if it is used for enteral nutrition such as liquid food (any of the following may be used: natural food type (using normal food), semi-digested type (using products that have been decomposed to a certain extent from food), or digested type (food that can be absorbed without being decomposed)) for patients who have difficulty swallowing food, patients with chronic intestinal diseases, the elderly, and other patients who have difficulty taking food orally. Other foods that may be used include thickened dishes, soups, stews, and other liquids, mitarashi, syrup, jam, pudding, mousse, and the like. EXAMPLES

[0031] The present invention will be specifically described below based on examples. [Introduction] Japan is currently an aging society. As people age, their swallowing ability declines. By thickening liquids with thickening foods, it is possible to assist people with dysphagia with swallowing difficulties. At home or in elderly care facilities, family members and staff adjust the degree of viscosity according to the degree of decline in swallowing ability of each person with dysphagia. However, all commercially available products currently on the market are granular, and there is an issue that it is difficult to reproducibly adjust the degree of viscosity.

[0032] Therefore, the inventors aimed to develop a tablet that combines sufficient hardness for practical use with rapid disintegration, in order to eliminate the need to measure granules according to the degree of viscosity and to make them easier to handle, and worked on creating a formulation and manufacturing method for it. During the development, they discovered that the dextrin contained in the thickening agent melts when humidified and heated, forming interparticle crosslinks and increasing the strength of the compact. They therefore optimized the formulation and manufacturing method of the thickening agent granules through granulation, added dextrin to the resulting granules, and compressed and molded them at low pressure to obtain a porous compact, which is then hardened by a humidification and drying process, creating a new tableting method. The following is a detailed description of the results of a study on tableting a thickening agent for swallowing assistance.

[0033] [Example 1] Preparation and evaluation of granules for tableting by granulation 1.1 Purpose It was shown that a fluidized bed granulation product (hereinafter referred to as "thickening agent") consisting of dextrin (hereinafter DEX) as a dispersant, thickening polysaccharides such as xanthan gum, and potassium chloride (hereinafter KCl) added to modify the surface of the thickening polysaccharides and improve their dispersibility in water, was compressed and molded, and hardened by humidification and drying. It was found that the hardening phenomenon was greatly affected by changes in humidification temperature, humidification humidity, and humidification time, and it was presumed that the increase in hardness was related to the cross-linking formation caused by the thermal melting of dextrin (DEX). However, when a tablet directly compressed with a thickening agent was placed in water, the xanthan gum (XG) on the tablet surface formed a gelling layer, which prevented water from reaching the inside of the tablet, and appropriate disintegration properties could not be obtained. Therefore, in this example, several recipes were examined in which the mixing ratio of the thickening agent components was changed, and granules for tableting were prepared.

[0034] 1.2 Method 1.2.1 Sample The composition of the thickening agent is shown in Table 1. SEM photographs of each sample are shown in Figure 1.

[0035] Table 1. Composition of thickening agent JPEG2024179019000002.jpg3169

[0036] 1.2.2 Preparation method and formulation design of granules for tableting 1.2.2.1 Preparation of granules for tableting In order to create tablets that have sufficient hardness and rapid disintegration for practical use, granulation was performed using a granulator to determine the optimal formulation.

[0037] [Preparation method] DEX and XG were mixed and then placed in a granulator, where they were granulated while spraying an aqueous KCl solution. The granulated material was sieved, and granules in the range of 250-1000 μm were used as granules for tableting.

[0038] 1.2.2.2 Formulation design of granules for tableting Several formulations with different thickening agent ratios were examined and a formulation was designed. Three formulations were examined, as shown in Table 2, in which the DEX content in the granules was varied with a standard XG:KCl=7:1 ratio. Each granule was designated Gr(DEX%), referring to the DEX composition ratio (%) in the granule.

[0039] Table 2. Granulated formulation JPEG2024179019000003.jpg62125

[0040] 1.2.3 Method for evaluating particle size of granules for tableting The particle size distribution of the granulated material was measured by two methods: sieving and laser diffraction / scattering. For particle size distribution by sieving, the granulated material was collected, the total amount collected was measured, and then it was passed through 250 and 1000 μm test sieves (JIS Z 8801), shaken for 10 minutes, and the granules remaining on the sieves were weighed, and the particle size distribution rate was calculated. In addition, the particle size distribution of only the granules in the range of 250 to 1000 μm determined by the sieving method was measured using a laser diffraction / scattering method (LMS-2000e, Seishin Enterprises) to evaluate the particles of the granulated product. The laser diffraction / scattering method was performed using dry dispersion, and the compressed air pressure was 0.4 MPa.

[0041] 1.2.4 Particle photograph of granules for tableting The particle state of the granulated material was observed using a scanning electron microscope (SEM, JSM-IT100LA, JEOL). The granulated material was placed on a sample stage with insulating double-sided adhesive tape attached, and platinum deposition (JFC-1600 Auto fine coater, JEOL) was performed at 3.0 Pa or less, 30 mA, and 180 s, and then observations were performed.

[0042] 1.3 Results and discussion 1.3.1 Particle size distribution by sieving The particle size fractions of the granulated material obtained, as determined by sieving, are shown in Table 3. In all formulations, the fraction of granules over 1000 μm was only about 5%, and the granules for tableting of 250 to 1000 μm accounted for more than 60%, indicating that granulation was progressing satisfactorily. On the other hand, the small particle fraction of 250 μm or less tended to increase as the DEX content in the granules increased.

[0043] Table 3. Particle size fractions of granulated materials as determined by sieving method JPEG2024179019000004.jpg41131

[0044] 1.3.2 Particle size distribution by laser diffraction / scattering method The D10, D50 (median diameter), and D90 measured by the laser diffraction and scattering method are shown in Table 4, and the particle size distribution is shown in Figure 2. The D50 of the thickening agent (granules) was 434.67 μm, and the D50 value was within the range of 430 to 560 μm for all formulations. Furthermore, comparing formulations, as the DEX content in the granules decreased (and the XG content in the granules increased), the particle size distribution in Figure 2 shifted to the right, and granules with larger particle sizes were obtained. From this, it was believed that the prepared granules were equivalent to or better than those produced by fluidized bed granulation using thickening agents. Furthermore, since the particle size increased as the XG content in the granules increased, it was inferred that as the XG content in the granules increases, the opportunities for the XG to come into contact with the KCl aqueous solution increase, promoting the growth of the granules.

[0045] Table 4 D of granulated material measured by laser diffraction / scattering method 10 ,D 50 ,D 90 JPEG2024179019000005.jpg42113

[0046] 1.3.3 Observation of the particle state of granules for tableting Figure 3 shows SEM photographs taken using a scanning electron microscope to observe the particle state of the granulated material. The thickening agent (granular product) is a composite of spherical DEX particles and block-shaped XG particles, and this composite particle was confirmed in each granulated product. It was presumed that the XG and DEX particles were combined to form granules.

[0047] 1.4 Summary It was confirmed from the particle size distribution measurement results and particle surface images of all formulations that granulation produced granules similar to those produced by fluidized bed granulation using thickening agents.

[0048] [Example 2] Study of viscosity-adjusting tablets using granules for tableting 2.1 Purpose In preliminary studies, we discovered a phenomenon in which the thickening agent (granules) was compressed and molded, and the molded body hardened through a humidification and drying process. We found that this phenomenon was greatly affected by changes in humidification temperature, humidity, and time, and we speculated that the increase in hardness was related to the formation of crosslinks due to the thermal melting and hardening of DEX (hereafter referred to as candy formation). We also developed a new tableting method in which DEX was added to the granules, and the porous molded body obtained by compression molding at low pressure was then hardened through a humidification and drying process; however, an issue arose in that an extremely strong stirring force was required to cause the product to disintegrate. Therefore, further studies were carried out with the aim of obtaining tablets that combine rapid disintegration and appropriate hardness by compressing the mixed powder prepared in Example 1 with various grades of DEX added at low pressure, humidifying the compact, and hardening it.

[0049] 2.2 Method 2.2.1 Sample 2.2.1.1 Granules for tabletting See Example 1, 1.2.1 Sample, 1.2.2 Preparation method and formulation design of granules for tableting.

[0050] 2.2.1.2 DEX added to granules for tableting during tableting Three grades of DEX with different manufacturing methods and shapes were used as DEX to be added to the granules for tableting. The DE values ​​of DEX selected were 7 to 12.

[0051] The physicochemical properties of each sample are shown in Table 5, and SEM photographs are shown in Figure 4. The D10, D50 (median diameter), and D90 of each sample measured by laser diffraction and scattering are shown in Table 6, and the particle size distribution is shown in Figure 5.

[0052] Table 5. Physicochemical properties of DEX added to granules for tableting during tableting JPEG2024179019000006.jpg48130

[0053] Table 6 D of granulated material measured by laser diffraction / scattering method 10 ,D 50 ,D90 JPEG2024179019000007.jpg3397

[0054] 2.2.2 Tablet preparation method and formulation design 2.2.2.1 Tablet formulation As the formulation for the tableting powder contains 60% DEX in the thickening agent (granules), the tableting granules DEX1-3 prepared in Example 1 were added and mixed in to make the tableting powder so that the DEX content in the tablet was 60%. In other words, the composition ratio in the tablets was unified so that all tablets had the same ratio as the thickening agent (granules). The mixing ratio of the granules used for tableting with DEX added later and the composition ratio in the tablet after the addition are shown in Table 7.

[0055] Table 7. Mixing ratio with DEX added later and composition ratio in tablet after adding later JPEG2024179019000008.jpg29148

[0056] 2.2.2.2 Tablet preparation method The mixed powder obtained above was filled into a circular flat die and compressed at various tableting pressures using a universal compression and tensile testing device (Autograph AG-X, Shimadzu Corporation). During molding, a 0.5 w / v% magnesium stearate EtOH (99.5) solution was applied to the circular flat punch and die as a lubricant. The number of tappings when filling the die was 5 times. A schematic diagram of the compression molding is shown in Figure 6, and the tableting conditions are shown in Table 8. Each tablet is indicated as (name of granules for tableting)-(post-added DEX number)-(tabletting pressure).

[0057] Table 8. Tablet compression molding conditions JPEG2024179019000009.jpg3078

[0058] 2.2.3 Moisturizing and drying treatment The tablets were arranged on a 500 μm sieve (Test sieves, JIS Z 8801) and humidified in a small environmental tester (SH-242, Espec) under the conditions shown in Table 9. The drying time was standardized to 80°C and 10 min using a small environmental tester (STH-120, Espec). Each tablet is indicated as (Name of granules for tableting)-(Post-added DEX number)-(Tableting pressure)-(humidification time).

[0059] Table 9. Humidification conditions for tablet hardening JPEG2024179019000010.jpg2466

[0060] 2.2.4 Tablet Evaluation 2.2.4.1 Hardness measurement Using a load cell type tablet hardness tester (PC-30, Okada Seiko), pressure was applied in the diametric direction, and the load at which the tablet broke was recorded as the hardness (Hardness, N).

[0061] 2.2.4.2 Observation of tablet surface The surface condition was observed using a scanning electron microscope (SEM, JSM-IT100LA, JEOL). The tablet was placed on a sample stage with an insulating adhesive double-sided tape attached, and platinum deposition (JFC-1600 Auto fine coater, JEOL) was performed at 4.5 Pa or less for 30 mA and 240 s, after which the upper surface of the tablet was photographed and observed. The preparation conditions of the molded bodies for SEM photography are shown in Table 10. Observation of the tablet surface that had been subjected to humidification treatment was performed only for Gr(20)-1-10.

[0062] Table 10. Compression molding and humidification / drying conditions for preparing tablets for SEM imaging JPEG2024179019000011.jpg41148

[0063] 2.2.4.3 Dissolution Test The electrical conductivity of KCl dissolved due to disintegration of the thickening agent (granules) or tablets was measured using an electrical conductivity meter (Seven Excellence, Mettler Toledo). A schematic diagram of the dissolution test is shown in Figure 7.

[0064] [Dissolution test method] 1) Prepare 200 mL of 20°C purified water in a 300 mL beaker. 2) 1) is stirred using a magnetic stirrer with a stir bar of 40 mm in length at a rotation speed of 400 rpm. 3) Place the electrode part of the electrical conductivity meter (Seven Excellence, Mettler Toledo) into the beaker and secure it in place. 4) Place 1,000 mg of thickening agent (granules) or one 1,000 mg tablet into a beaker and stir for 300 s. Measure the electrical conductivity over time at 2 s intervals.

[0065] 2.2.4.4 Viscosity measurement Using a touch panel type B-type viscometer DVNext (BROOKFIELD type viscometer, Eiko Seiki Co., Ltd.), the viscosity of the aqueous solution immediately after the dissolution test was measured in 2.2.4.3 Dissolution test. A schematic diagram of the viscosity measurement method is shown in Figure 8.

[0066] [Viscosity measurement method] 1) After the dissolution test, insert the viscometer probe into the eluate and measure the viscosity using a touch panel type B viscometer.

[0067] [Measurement conditions for B-type viscometer] Spindle: LV-02 - Revolution speed: 60.0 rpm Mode: Multipoint (2s interval) Measurement time: 1 min

[0068] 2.2.4.5 Tablet density and porosity Using a helium gas replacement type true density meter (Ultrapycnometer 1000, Quantachrome), the particle density was measured for each formulation of tableting granules and each grade of DEX, and the true density of the mixed powder after each DEX was added was calculated. The true density thus obtained and the thickness, diameter, and mass of the prepared tablets were used to calculate the porosity of the tablets using the following formula. JPEG2024179019000012.jpg21108

[0069] 2.3 Results and discussion 2.3.1 Effect of type of post-added DEX on tablet properties 2.3.1.1 Tablet surface photograph Figure 9 shows SEM photographs taken with a scanning electron microscope (SEM, JSM-IT100LA, JEOL) of the surface condition of tablets made by fixing the granules for tableting to Gr(20) and adding each DEX afterwards. From the SEM images of each tablet, it was observed that the tablets made with DEX1 had flat particles stacked on top of each other, while the tablets made with DEX2 and DEX3 had clumped aggregates.

[0070] 2.3.1.2 Changes in tablet hardness depending on the type of DEX added later The hardness of unmoisturized tablets made with granules fixed at Gr(20) and with DEX1, 2, and 3 added later is shown at each tableting pressure in Figure 10, and the calculated porosity is shown in Figure 11. It was confirmed that tablets made with DEX1 had higher hardness than tablets made with DEX2 and DEX3 at all compression pressures. Furthermore, among the tablets made with DEX1, those made with a compression pressure of 12 MPa or more achieved a hardness of 50 N or more, which is considered sufficient for practical use even for unhumidified tablets. From this, it was inferred that the post-addition of DEX, which has a very low bulk density (bulky), improved moldability by increasing the degree of compression, leading to an increase in hardness. Regarding porosity, DEX1 had the largest porosity at all tableting pressures, followed by DEX3 and DEX2, suggesting that the tablets made using DEX1, which has the largest porosity, were the most porous, and it is possible that these voids contribute to the disintegration and water conductivity of the tablets. From this, it is inferred that the bulk density of the DEX added later has a large effect on the porosity of the tablets after compression molding.

[0071] 2.3.2 Changes in tablet hardness due to granule formulation The amount of DEX added later was fixed at DEX1, and the results of hardness measurements at each compression pressure for unhumidified tablets made using each tableting granule are shown in Figure 12, and the calculated porosity is shown in Figure 13. It was confirmed that both tablet hardness and tablet porosity of tablets made using Gr(20) were greater than those made using other formulations at any tableting pressure. From this, it was inferred that the greater the mixing ratio of DEX added later, the greater the effect on the tablet produced by DEX added later to the granules for tableting during tableting.

[0072] 2.3.3 Effect of humidification time on tablet properties 2.3.3.1 Surface condition photograph The surface condition of Gr(20)-1-10 tablets with different humidification times was observed using a scanning electron microscope (SEM, JSM-IT100LA, JEOL Ltd.) in Figure 14, and the cut surface condition was observed in Figure 15. On the tablet surface, DEX did not candy in the unhumidified tablets, but it was confirmed that DEX candy was in all humidified tablets. It was observed that the more humidified the tablets, the more the fusion between particles progressed, and the stronger the interparticle cross-linking became. From this, it was inferred that the candying and thermal melting of DEX became greater with an increase in the humidification time, and that interparticle cross-linking also became more likely to occur. It was considered that the length of the humidification time affected the increase in hardness because the particles in the tablet were strongly bonded to each other as the degree of candying and interparticle cross-linking of DEX increased. Furthermore, from SEM photographs of the cut surfaces, it was observed that the hardened layer in which candy-like properties (interparticle cross-linking) had developed expanded slightly deeper as the humidification time was extended. However, candy-like properties were not observed inside the tablets, and it was inferred that the humidification treatment had little effect on the internal structure. However, it was inferred that the thicker the hardened layer became, the more disadvantageous it became during disintegration.

[0073] 2.3.3.2 Change in tablet hardness depending on humidification time The formulation of the granules for tableting was set to Gr(20), and the DEX added later was fixed at DEX1. The hardness of the tablets was measured at each tableting pressure when not humidified and when humidified for 2, 5, and 10 minutes, and the calculated porosity was shown in Figure 16, and Figure 17, respectively. It was confirmed that the harder the tablets were, the longer the humidification time was. The SEM photographs of the tablet surfaces mentioned above in 2.3.3.1 also showed that the melted proportion of the tablet surface increased with increasing humidification time. From this, it was inferred that the degree of interparticle cross-linking increased due to the candying and thermal melting of DEX, which caused the particles to bond more strongly together, resulting in an increase in hardness. It was suggested that the length of humidification time affects the hardness of the tablets. No change in porosity was observed with or without humidification or with increased humidification time. This supports the hypothesis mentioned above in 2.3.3.1 that the internal structure of the tablets does not change significantly due to humidification and drying treatments.

[0074] 2.3.4 Dissolution behavior and viscosity measurement results based on electrical conductivity 2.3.4.1 Dissolution behavior and viscosity measurement results of tablets with different tableting powders as a function of electrical conductivity The physical properties and post-disintegration viscosity measurements of tablets made with different tableting powders are shown in Table 11, and the dissolution behavior of KCl from tablets made with different tableting powders as a function of electrical conductivity is shown in Figure 18. Although noise was introduced due to localized non-uniformity in concentration, it was possible to measure the dissolution behavior of KCl using an electrical conductivity meter. From the results of the dissolution behavior, only the tablets made with the granule formulation for tableting of Gr(20) and DEX1 as the post-added DEX showed the same dissolution behavior as the thickening agent (granules), and although a slight delay in dissolution was observed, the tablets disintegrated rapidly. From this, as mentioned above in 2.3.1.2 and 2.3.2, by adding a large amount of bulky DEX1 to the granules and making tablets, a porous tablet with a large porosity was obtained. It was inferred that these pores contribute to the disintegration and water conductivity of the tablet, and that the larger the pores, the easier it is for water to be conducted into the tablet and the easier it is to disintegrate. As mentioned in 2.3.2, Gr(20) had the highest mixing ratio of post-added DEX in the formulation of the granules for tableting, which had a large effect on the hardness and rapid disintegration of the tablets. In addition, the mixing ratio of XG and KCl in the granules for tableting was higher than in the other granules for tableting, so the particles were close to each other, and the gelation of XG on the tablet surface was delayed. This is thought to contribute to the rapid disintegration not seen in the direct compression of the thickening agent (granules). Furthermore, compared to tablets that did not completely disintegrate, the plateau value of conductivity for tablets made using the new tableting method that completely disintegrated showed a plateau value equivalent to that of the thickening agent (granules), suggesting that the composition ratio within the tablet was equivalent to that of the thickening agent (granules). The results of viscosity measurements of the solutions after the disintegration test showed that the viscosity increased in the order of the plateau value of the conductivity in the dissolution behavior of each tablet, suggesting a proportional relationship between the dissolution of KCl and the development of viscosity. However, because the thickening agent (granules) used a thickening agent with a different strength from that used in this study, the viscosity was higher than that of the prepared tablets.

[0075] Table 11 Physical properties and viscosity measurement results after disintegration of tablets with different tableting powders JPEG2024179019000013.jpg88134

[0076] 2.3.4.2 Dissolution behavior and viscosity measurement results of tablets with different humidification times measured by electrical conductivity The physical properties of tablets with different moistening times and the results of viscosity measurements after disintegration are shown in Table 12, and the dissolution behavior of KCl from tablets with different moistening times as measured by electrical conductivity is shown in Figure 19. For the study, tablets were used that were prepared using a tableting powder in which DEX1 was added after adding Gr(20), which was the optimal formulation in 2.3.4.1. The results of the dissolution behavior showed that the tablets prepared under the conditions of a compression pressure of 14 MPa or less and a humidification time of 0 to 5 min showed the same dissolution behavior as the thickening agent (granules), and although a slight delay in dissolution was observed, the tablets were rapidly disintegrated. It was also shown that the dissolution of the tablets prepared under each compression pressure gradually delayed as the humidification time was extended to 0 min, 2 min, and 5 min. The tablets prepared under the humidification time of 10 min did not completely disintegrate, even though the compression pressure was low at 4 MPa, and the tablets had a lower hardness and a higher porosity than the other tablets. As mentioned above in 2.3.3.1, it was suggested that the tablets prepared under the humidification time of 10 min had a thick hardened layer, which was not destroyed and did not disintegrate. Therefore, it was suggested that the tablets prepared under the humidification time of 5 min had a thick hardened layer, which was not destroyed and did not disintegrate. It was found that tablets with rapid disintegration could be prepared by keeping the temperature at or below 100°C and by keeping the degree of candying (interparticle cross-linking) at an appropriate level. It was also hypothesized that by applying an appropriate humidification treatment, the interparticle cross-linking was limited to the surface and did not progress to the interior, thereby increasing the physical strength of the tablet while maintaining rapid disintegration. As described above, it is expected that tablets with an optimized formulation will disintegrate quickly even in drinking water, and it is considered that they can be commercialized as thickening tablets to be prepared just before use.

[0077] Table 12. Physical properties and viscosity measurement results after disintegration of tablets with different humidification times JPEG2024179019000014.jpg139152

[0078] 2.4 Summary The granules for tableting were granulated by increasing the compounding ratio of XG and KCl, and a large amount of DEX1, which is very bulky, has the highest compressibility, and has the highest tablet porosity after tableting, was added and mixed with Gr(20), which has a high coating efficiency for XG particles, as a post-addition DEX. Tablets made with the appropriate tableting pressure and humidification time achieved a practically sufficient hardness of 50 N or more and rapid disintegration equivalent to that of thickening agents (granules). By mixing the extremely bulky DEX1 in the same amount as the granules for tableting and compressing it at low pressure, tablets with high porosity were produced. Because of the high porosity, water can rapidly penetrate through the pores, and the prepared tablets can achieve rapid dissolution behavior equivalent to that of thickening agents (granules). In addition, the humidification treatment caused the thermal melting of the DEX added later, resulting in the formation of interparticle crosslinks, and tablets with sufficient hardness for practical use were obtained. Since the hardness increased with increasing humidification time, it was found that the candying and thermal melting of DEX progressed with increasing humidification time. Therefore, by carrying out the humidification treatment under mild conditions (60°C, 75% RH, short time), it became possible to form interparticle crosslinks while maintaining a high porosity, and we succeeded in increasing the physical strength while maintaining rapid water penetration. Furthermore, it was revealed that if the humidification conditions were too severe, the hardened layer became excessively thick, and even tablets with a high porosity and relatively low hardness would not disintegrate.

[0079] Summary In this study, we attempted to develop a formula and manufacturing method for a viscosity-adjusting tablet that has sufficient hardness and rapid disintegration for practical use, in order to eliminate the need to measure the amount of viscosity agent (granules) according to the desired degree of viscosity and to facilitate handling. In Example 1, granules for tableting were prepared using three recipes with different ingredient contents, and the particle size distribution was measured and the particle state was observed.

[0080] In Example 2, the compounding ratio of XG and KCl was increased as the formula for the granules for tableting, and granulation was performed. Gr(20), which has a high coating efficiency for XG particles, was added and mixed with a large amount of DEX1, which is very bulky as a post-addition DEX, has the highest compression degree, and also has the highest tablet porosity after tableting. The tablets made with the appropriate tableting pressure and humidification time achieved a practically sufficient hardness of 50 N or more and rapid disintegration equivalent to that of a thickening agent (granules). Furthermore, interparticle cross-linking was formed due to the thermal melting of the DEX added later by the humidification treatment, and tablets with sufficient hardness for practical use were obtained. Since an increase in hardness was observed with an increase in the humidification time, it was determined that the candying and thermal melting of DEX progresses with an increase in the humidification time. Therefore, by carrying out the humidification treatment under mild conditions (60°C, 75% RH, short time), it became possible to form interparticle cross-linking while maintaining a high porosity, and we succeeded in increasing the physical strength while maintaining rapid water penetration. In conclusion, it is expected that tablets prepared using the optimized formulation and tableting method will disintegrate quickly even in drinking water, and that they can be commercialized as thickening tablets to be prepared just before use.

[0081] [Example 3] Examination of preparation conditions for viscosity adjusting tablets -Effects of humidification and heating conditions- [Granulation] ● Sample (granules for tableting) See Example 1, 1.2.1 Sample, 1.2.2 Preparation method and formulation design of granules for tableting.

[0082] [Tablet compression] Sample [Example 2] See 2.2.2.1 Tablet formulation design and 2.2.2.2 Tablet preparation method.

[0083] Consider using Gr(20)-1.

[0084] [Humidification / drying] See Example 2, 2.2.3 Moistening and drying treatment. The effects of humidification and heating conditions were confirmed under the following conditions. Humidification conditions Experiment 1: Effects of humidification time [1] Unhumidified [2] 60℃, 75% RH for 2 min [3] 60℃, 75% RH for 5 min. [4] 10 min at 60℃ and 75% RH <Experiment 2: Effect of humidification temperature> [5] 60℃, 95% RH for 30 seconds [6] 70℃, 95% RH for 30 seconds [7] 80℃, 95% RH for 30 seconds [8] 90℃, 95% RH for 30 seconds <Experiment 3: Examination of short-term humidification conditions> [9] 80℃, 95% RH for 5 seconds

[10] 10 seconds at 80℃ and 95% RH

[11] 80℃, 95% RH for 20 seconds [7] 80℃, 95% RH for 30 seconds Experiment 4

[12] 10 seconds at 75℃ and 95% RH

[13] 75℃, 95%RH for 20 seconds

[14] 75℃, 95%RH for 30 seconds Drying conditions Temperature: 80℃ Time: 10 minutes

[0085] [Dissolution test] See Example 2, 2.2.4.3 Dissolution test. Experimental results Experiment 1: Effects of humidification time Figure 20 (tablet hardness), Figure 21 (tablet porosity), Figure 22 (dissolution behavior of KCl from tablets as a function of electrical conductivity). <Experiment 2: Effect of humidification temperature> Figure 23 (tablet hardness), Figure 24 (tablet porosity), Figure 25 (dissolution behavior of KCl from tablets as a function of electrical conductivity). <Experiment 3: Examination of short-term humidification conditions> Figure 26 (tablet hardness), Figure 27 (tablet porosity), Figure 28 (dissolution behavior of KCl from tablets as a function of electrical conductivity). Experiment 4 Figure 29 (tablet hardness), Figure 30 (tablet porosity), Figure 31 (dissolution behavior of KCl from tablets as a function of electrical conductivity).

[0086] ●Consideration Experiment 1: Effects of humidification time The results showed that the greater the compression pressure and the longer the humidification time, the higher the hardness. The porosity of the unhumidified tablet was the lowest. Humidification caused the tablet to expand, increasing the porosity. In addition, although the porosity decreased slightly with increasing humidification time, no significant change was observed. This suggests that the internal structure of the tablet did not change significantly with humidification, and that solid cross-linking deepened from the surface to the inside. It can be seen from the graph in Figure 22 that the disintegration and dissolution of unhumidified tablets is delayed compared to tablets humidified for 2 minutes. This correlates with the porosity shown in the results of the [humidification / drying] process, and it is believed that voids that allow water to flow inside the tablet are necessary for rapid disintegration and dissolution. Good conditions: 60℃, 75%RH, 2min, 4~10MPa <Experiment 2: Effect of humidification temperature> It was found that the higher the humidification temperature, the higher the hardness and the lower the porosity. At 90°C, the tablets shrunk, resulting in a smaller porosity. In the next experiment, experiment 3, in order to examine even shorter humidification times, we decided to narrow down the conditions to 80°C and 95% RH, at which all tablets achieved a hardness of 50N or more, which is sufficient for practical use, with a humidification time of 30 seconds, and to conduct a comparative study. At humidification temperatures of 80℃ and 90℃, disintegration and dissolution were delayed at all tableting pressures. It is believed that disintegration and dissolution are influenced not only by the porosity inside the tablet, but also by the thickness of the hardened layer on the tablet surface. When the humidification strength is high, the hardened layer becomes thicker and water is less likely to be absorbed. Good conditions: 70℃, 95%RH, 30sec, 6~8MPa <Experiment 3: Examination of short-term humidification conditions> Although the hardness increased with increasing humidification time, no significant change was observed in the porosity. To obtain tablets with a hardness of 50N or more, a tableting pressure of 8 MPa or more is required for 5 seconds of processing at 80°C and 95% RH, and 6 MPa or more is required for 10 to 20 seconds of processing (red circle). Good conditions: 80℃, 95%RH, 5sec, 10~12MPa 10sec, 8-10MPa 20sec or more, none Experiment 4 Although the hardness increased with increasing humidification time, no significant change was observed in the porosity. It was found that to obtain tablets with a hardness of 50N or more, a tableting pressure of 8MPa or more is required for 10 seconds of processing at 75°C and 95% RH, and 6MPa or more is required for 20 to 30 seconds of processing (red circle). Good conditions: 75℃, 95%RH, 10sec, 8~12MPa 20sec, 6-10MPa

[0087] [Viscosity test] Viscosity measurement [Example 2] See 2.2.4.4 Viscosity measurement. Experimental results Experiment 1: Effects of humidification time Figure 32 (Viscosity of the eluate after the elution test) <Experiment 2: Effect of humidification temperature> Figure 33 (Viscosity of the eluate after the elution test) <Experiment 3: Examination of short-term humidification conditions> Figure 34 (Viscosity of the eluate after the elution test) Experiment 4 Figure 35 (Viscosity of the eluate after dissolution test) ●Consideration Experiment 1: Effects of humidification time The tablets humidified for 2 minutes, which had excellent disintegration and dissolution properties, showed high viscosity. Even tablets that showed the same dissolution behavior as the thickening agent (granules) had a lower viscosity than the thickening agent (granules). This is thought to be because the thickening agent (granules) used a thickener with a different strength than that used in this study, resulting in a higher viscosity than the prepared tablets.

[0088] (Summary) Figure 36 Good conditions: 60℃, 75%RH, 2min, 4~10MPa 70℃, 95%RH, 30sec, 6~8MPa (80℃, 95%RH, 5sec, 10~12MPa: Backup when humidification time must be shortened) [Industrial Applicability]

[0089] The present invention can be used as a thickening agent to aid in the swallowing of food and beverages.

Claims

1. A method for producing tablets, comprising adding porous dextrin to granules obtained by granulating a mixture of dextrin and a thickening agent, and then compressing and molding them.

2. The method according to claim 1, wherein the tablet pressure during compression molding is 1 to 14 MPa.

3. A tablet manufactured by the method described in claim 1.

4. A tablet according to claim 3, having a hardness of 50 N or more.

5. The tablet according to claim 3, wherein the porosity is 57% or more.

6. A tablet according to claim 3, used to thicken food.

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