Enteric-coated solid dosage forms

Abstract

To provide an enteric-coated solid preparation that has excellent gastric juice resistance and also has high intestinal juice leachability even after a passage of time.SOLUTION: An enteric-coated solid preparation contains (A) lactoferrin, (B) lactic acid bacteria, and (C) dextrin with a dextrose equivalent (DE) of 30 or less.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an enteric coated solid preparation. [Background technology]

[0002] In recent years, commercially available enteric-coated solid formulations commonly contain lactoferrin and lactic acid bacteria as active ingredients. Lactoferrin is known to exert various physiological functions, including improving bowel movements, improving intestinal flora, and maintaining immunity, and various products, including functional food and health foods, are already on the market. Lactic acid bacteria (e.g., Lacticaseibacillus casei) are also known to exert physiological functions, such as improving bowel movements and preventing and alleviating allergic symptoms, such as atopic dermatitis and hay fever. The physiological functions shared by lactoferrin and lactic acid bacteria often have different mechanisms of action, so combining the two components can simultaneously exert the desired physiological functions and synergistically promote health. Furthermore, because lactoferrin and lactic acid bacteria are easily degraded by digestive enzymes such as gastric acid and pepsin, enteric-coated solid formulations that dissolve in the intestine without dissolving in the stomach have been developed to maximize their physiological functions.

[0003] In order to obtain a superior effect of improving the intestinal environment, an intestinal environment improving agent containing lactoferrin and killed Lactobacillus brevis cells as active ingredients has been proposed (see, for example, Patent Document 1). However, the intestinal environment improving agent in Patent Document 1 suffers from the problem that, when stored in a high-temperature environment, it undergoes changes over time, resulting in a decrease in the intestinal fluid elution ability of lactoferrin. In addition, when lactic acid bacteria coated with peptidoglycan, an insoluble polymer, are used in combination with lactoferrin, the intestinal fluid elution ability of lactoferrin further decreases over time.

[0004] Furthermore, the intestinal environment-improving agent in Patent Document 1 has problems with gastric juice resistance, such as elution of the active ingredient from pores in the enteric coating in acidic solutions such as gastric juice, and holes due to non-uniformity in the enteric coating that lead to formulation disintegration. These problems are thought to be exacerbated by the deterioration of the enteric coating components during storage in a high-temperature environment.

[0005] Therefore, an enteric coated solid preparation that has excellent gastric juice resistance and high intestinal juice elution even after aging has not yet been provided, and there is currently a strong demand for its prompt development. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] JP 2014-111668 A Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention aims to solve the above-mentioned problems of the prior art and to achieve the following object: to provide an enteric coated solid preparation that has excellent resistance to gastric juice and high dissolution property in intestinal juice even after aging. [Means for solving the problem]

[0008] As a result of extensive research into achieving the above-mentioned object, the present inventors have found that the enteric coated solid preparation of the present invention contains (A) lactoferrin, (B) lactic acid bacteria, and (C) dextrin having a dextrose equivalent (DE) of 30 or less, and thereby has excellent resistance to gastric juice and high intestinal juice dissolution properties even after aging.

[0009] The present invention is based on the above findings of the present inventors, and the means for solving the above problems are as follows. <1> The enteric coated solid preparation contains (A) lactoferrin, (B) lactic acid bacteria, and (C) dextrin having a dextrose equivalent (DE) of 30 or less. <2> (C) the dextrose equivalent (DE) is 10 or more and 30 or less; <1> The enteric coated solid preparation is described in 1. <3> the mass ratio of the content of the component (C) to the content of the component (A) [(C) / (A)] is 0.05 or more and 0.6 or less; <1> The enteric coated solid preparation is described in 1. <4> The component (B) contains 100 million to 300 billion bacterial cells per tablet. <1> ~ <3> The enteric coated solid preparation according to any one of the above items. <5> The above-mentioned composition contains, as an excipient, one or more selected from cellulose or a cellulose derivative, a sugar or a sugar alcohol. <1> ~ <4> The enteric coated solid preparation according to any one of the above items. [Effects of the Invention]

[0010] According to the present invention, the above-mentioned conventional problems can be solved, the above-mentioned objects can be achieved, and an enteric coated solid preparation having excellent resistance to gastric juice and high intestinal juice elution even after aging can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0011] (enteric coated solid dosage form) The enteric coated solid preparation of the present invention contains (A) lactoferrin, (B) lactic acid bacteria, and (C) dextrin having a dextrose equivalent (DE) of 30 or less, and may further contain other ingredients as necessary. In this specification, (A) lactoferrin may be referred to as "(A) component," (B) lactic acid bacteria may be referred to as "(B) component," and (C) dextrin with a dextrose equivalent (DE) of 30 or less may be referred to as "(C) component" or "(C) dextrin."

[0012] <(A) Lactoferrin> The (A) lactoferrin is contained to exhibit physiological functions such as improving lipid metabolism, alleviating constipation, improving intestinal flora, improving sleep, promoting growth hormone secretion, improving dry eye and corneal epithelial abrasion, improving eye disorders caused by dry eye and corneal epithelial abrasion, lowering blood pressure, improving allergies, maintaining immune function, improving immune function, improving immune function, and improving liver function. In particular, the (A) lactoferrin is useful for reducing visceral fat and BMI as a lipid metabolism improving function, and for exhibiting the functions of maintaining, improving, and improving immune function.

[0013] The lactoferrin (A) is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include lactoferrin isolated from mammalian colostrum, transitional milk, normal milk, terminal milk, etc., lactoferrin isolated from processed mammalian milk products such as skim milk and whey, lactoferrin produced from plants, lactoferrin obtained by genetic recombination, etc. Among these, lactoferrin concentrates containing 50% by mass or more of lactoferrin monomer are preferred. The mammal is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include humans, cows, sheep, goats, and horses. The plant is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include rice.

[0014] The method for separating lactoferrin is not particularly limited and can be appropriately selected depending on the purpose. For example, ion exchange chromatography can be used. The lactoferrin to be used may be a commercially available product, or may be prepared by a known method.

[0015] From the viewpoint of the expression of physiological functions, the content of (A) lactoferrin in the enteric solid preparation is preferably 1% by mass or more and 60% by mass or less, more preferably 4% by mass or more and 60% by mass or less, even more preferably 15% by mass or more and 56% by mass or less, and particularly preferably 18% by mass or more and 50% by mass or less. When the content of (A) lactoferrin in the enteric-coated solid preparation is 1% by mass or more, physiological functions are exhibited, tableting problems (binding) are suppressed, the number of tablets to be taken can be kept within an appropriate range, and ease of administration is improved, which is preferable. When the content of the (A) lactoferrin in the enteric coated solid preparation is 60% by mass or less, the initial dissolution rate and disintegration rate of the lactoferrin, the retention rate of dissolution rate of lactoferrin, the retention rate of disintegration rate, the resistance to gastric juice after aging, and the moldability of the uncoated tablet are improved, which is preferable. Note that the "retention rate of disintegration rate" in the present invention indicates the degree to which the disintegration rate of the tablet after aging is maintained compared to the tablet immediately after production.

[0016] The daily intake of the (A) lactoferrin is not particularly limited and can be selected appropriately depending on the purpose, but from the viewpoint of the expression of physiological functions, it is preferably 50 mg or more and 1000 mg or less, more preferably 100 mg or more and 500 mg or less, and even more preferably 200 mg or more and 400 mg or less.

[0017] The method for producing the lactoferrin is not particularly limited, and lactoferrin produced by a conventional method can be used, which may include a drying step, for example. Examples of drying steps in the lactoferrin production method include freeze-drying and spray-drying. The lactoferrin obtained by the drying step is preferably contained in the dried product at a purity of 85% or more. Furthermore, the loss on drying in the drying step is preferably 6% by mass or less. The method for producing lactoferrin may further include processing steps such as granulation, particle coating, and pulverization.

[0018] The average particle size of the (A) lactoferrin is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 20 μm or more and 300 μm or less, and more preferably 20 μm or more and 100 μm or less. In the present invention, the average particle size refers to the 50% diameter (median diameter, volume basis) in the particle size distribution by laser diffraction scattering.

[0019] <(B) Lactic acid bacteria> The (B) lactic acid bacteria are contained to exhibit functions such as improving bowel movements, improving intestinal flora, maintaining skin moisture, protecting skin from dryness, maintaining skin barrier function, improving skin texture, preventing rough skin, maintaining skin flexibility, protecting skin from UV rays, giving skin firmness, giving skin luster, smoothing skin, improving sleep quality, improving immunity, preventing allergic symptoms such as atopic dermatitis and hay fever, alleviating allergic symptoms, improving blood flow, lowering blood pressure, preventing periodontal disease, and preventing bad breath. In particular, ingesting the (B) lactic acid bacteria prevents moisture loss from the skin, and is therefore useful for exhibiting the functions of protecting skin from dryness, maintaining skin barrier function, and improving bowel movements.

[0020] The (B) lactic acid bacteria are not particularly limited and can be selected appropriately depending on the purpose. Examples include lactic acid bacteria belonging to the genus Lactobacillus, Lacticaseibacillus, Lactiprantibacillus, Lactilactobacillus, Rigilactobacillus, Leviractobacillus, Rimosilactobacillus, Enterococcus, Lactococcus, Streptococcus, Staphylococcus, and Bifidobacterium. Examples of lactic acid bacteria belonging to the genus Lactobacillus include Lactobacillus gasseri, Lactobacillus paragasseri, Lactobacillus crispatus, and Lactobacillus helveticus. Examples of the lactic acid bacteria belonging to the genus Lacticaseibacillus include Lacticaseibacillus casei, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, and Lacticaseibacillus curvatus. Examples of the lactic acid bacteria belonging to the genus Lactiplantibacillus include Lactiplantibacillus plantarum and Lactiplantibacillus pentosus. Examples of the lactic acid bacteria belonging to the genus Lactilactobacillus include Latilactobacillus sakei. Examples of the lactic acid bacteria belonging to the genus Ligilactobacillus include Ligilactobacillus salivarius. Examples of the lactic acid bacteria belonging to the genus Levilactobacillus include Levilactobacillus brevis. Examples of the lactic acid bacteria belonging to the genus Limosilactobacillus include Limosilactobacillus reuteri. Examples of the lactic acid bacteria belonging to the genus Enterococcus include Enterococcus faecalis and Enterococcus faecium. Examples of the lactic acid bacteria belonging to the genus Lactococcus include Lactococcus lactis and Lactococcus cremoris. Examples of the lactic acid bacteria belonging to the genus Streptococcus include Streptococcus thermophilus. Examples of the lactic acid bacteria belonging to the genus Staphylococcus include Staphylococcus xylosus and Staphylococcus carnosus. Examples of lactic acid bacteria belonging to the genus Bifidobacterium include Bifidobacterium animalis lactis, Bifidobacterium animalis longum, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium adolescentis, Bifidobacterium infantis, etc. Lactic acid bacteria belonging to the genus Bifidobacterium are sometimes referred to as bifidobacteria. In 2020, Zheng et al. reclassified the Lactobacillus genus into a total of 25 genera. For example, Lactobacillus casei was renamed Lacticaseibacillus casei. (Int. J. Sys. Evol. Microbiol., 2020;70:2782-2858) These may be used alone or in combination of two or more.

[0021] The (B) lactic acid bacteria are not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include those derived from the human intestinal tract, dairy products, and plants (plant-derived products including processed foods such as miso, soy sauce, pickles, bran, grass, rice, wheat, and malt). Among these, those isolated from rice or processed rice foods are preferred. The (B) lactic acid bacteria may be viable cells or sterilized cells that have been subjected to a sterilization process. The (B) lactic acid bacteria may be a dispersion with an additive such as an excipient, which will be described later. Details of the case where the (B) lactic acid bacteria is a dispersion with an additive will be described later.

[0022] The content of the (B) lactic acid bacteria in the enteric coated solid preparation of the present invention is not particularly limited and can be appropriately selected depending on the dosage form, administration mode, and recipient. However, the content is preferably such that the number of bacteria per day ingested by an adult is 1 billion to 1 trillion, more preferably 2 billion to 500 billion, and even more preferably 5 billion to 100 billion. It is preferable to contain the (B) lactic acid bacteria in an amount that allows an adult to ingest 1 billion or more per day, as this will allow physiological functions to be expressed and improve gastric juice resistance over time. The (B) lactic acid bacteria content is preferably such that one adult can ingest 1 trillion or less per day, as this improves the initial disintegration property and disintegration property over time, the initial dissolution rate, the maintenance rate of dissolution over time, and moldability of the formulation.

[0023] The number of cells of the (B) lactic acid bacteria per tablet is preferably between 100 million and 300 billion, more preferably between 500 million and 160 billion, and particularly preferably between 1 billion and 100 billion. The number of cells of the (B) lactic acid bacteria is preferably 100 million or more per tablet, as this allows physiological functions to be expressed and improves gastric juice resistance over time. The number of cells of the (B) lactic acid bacteria per tablet is preferably 300 billion or less, since this improves the initial disintegration property and disintegration property over time, the initial dissolution rate, the retention rate of dissolution over time, and the moldability of the formulation.

[0024] The content of the (B) lactic acid bacteria in the enteric solid preparation is preferably 0.05% by mass or more and 35% by mass or less, more preferably 0.1% by mass or more and 30% by mass or less, even more preferably 0.2% by mass or more and 25% by mass or less, and particularly preferably 3% by mass or more and 20% by mass or less. If the content of the (B) lactic acid bacteria in the enteric coated solid preparation is 0.05% by mass or more, physiological functions are expressed and resistance to gastric juice is improved, which is preferable. When the content of the (B) lactic acid bacteria in the enteric coated solid preparation is 35% by mass or less, the initial disintegration property, disintegration property over time, initial dissolution rate, dissolution retention rate over time, and moldability of the preparation are improved, which is preferable. Note that when the (B) component is a triturated product containing additives such as excipients described below, the content of the (B) lactic acid bacteria does not include the additives.

[0025] The method for measuring the number of lactic acid bacteria contained in the raw material powder or solid preparation is not particularly limited and can be appropriately selected depending on the purpose, and examples include hemocytometer measurement, DAPI staining, etc. Among these, measurement of the number of bacterial cells by DAPI staining is preferred.

[0026] A specific example of the method for measuring the number of bacteria by the DAPI staining method is as follows. Weigh 0.1 g of sample into a 15 ml centrifuge tube and add phosphate buffered saline (34 g of anhydrous potassium dihydrogen phosphate dissolved in purified water, then add 1 M sodium hydroxide to adjust the pH to 7.2, and bring the total volume to 1000 mL) to a 100-fold dilution and mix. Homogenize using a vortex mixer and ultrasonic treatment to obtain the stock sample solution. Further dilute the stock sample solution appropriately to obtain the test sample solution. The sample solution for measurement is filtered through a membrane filter with a pore size of 0.20 μm, then reacted with DAPI solution (reagent) for about 1 minute and filtered through a filtration device. The cells captured on the membrane filter are photographed using an epifluorescence microscope. The number of cells in the photographed image and the average number of cells per image are counted, and the total number of bacteria per gram of sample is calculated using the following formula. Total number of bacteria (cells / g) = average number of cells per image × effective filtration area ÷ area of ​​one image ÷ filtration volume For the effective filtration area, check the specifications of the filtration device to be used.

[0027] The (B) lactic acid bacteria may be commercially available products or those prepared by known methods. The method for preparing the (B) lactic acid bacteria is not particularly limited and can be appropriately selected depending on the purpose, and can be obtained, for example, by freeze-drying a bacterial cell liquid containing live lactic acid bacteria. Furthermore, before freeze-drying, additives such as excipients, dispersants, and protective agents may be added as necessary to obtain a lactic acid bacteria dilution product. In the method for preparing lactic acid bacteria (B) above, when sterilized lactic acid bacteria are used as a raw material, a bacterial cell liquid containing live lactic acid bacteria may be sterilized by, for example, a heat method such as moist heat sterilization, dry heat sterilization, or high-frequency sterilization; a gas method such as ethylene oxide gas sterilization or hydrogen peroxide sterilization; or a radiation method such as gamma ray irradiation sterilization or electron beam irradiation sterilization. The (B) lactic acid bacteria may be stored frozen.

[0028] The additives are not particularly limited and can be appropriately selected depending on the purpose. Examples include saccharides such as dextrin, trehalose, potato starch, sucrose, and oligosaccharides; proteins such as milk protein; and lipids. When dextrin is used as the additive, it is preferable to use dextrin having a dextrose equivalent (DE) of 30 or less, as described below. When dextrin is used as the additive, the additive may be the entire amount of dextrin contained in the enteric coated solid preparation of the present invention, or may be a combination of dextrin and other optional ingredients.

[0029] When the (B) lactic acid bacteria are dispersed with the additive, the content of the (B) lactic acid bacteria in the dispersion is not particularly limited and can be selected appropriately depending on the purpose, but it is preferably contained in an amount of 1% by mass or more and 90% by mass or less, and more preferably contained in an amount of 10% by mass or more and 60% by mass or less. By setting the content of the (B) lactic acid bacteria in the diluted product to 1% by mass or more, physiological functions are easily expressed, which is preferable. By setting the content of the (B) lactic acid bacteria in the diluted product to 90% by mass or less, sufficient hardness is obtained and disintegration properties are improved.

[0030] The lactic acid bacteria used for preparing the (B) lactic acid bacteria can be obtained, for example, from organizations such as ATCC (registered trademark) or IFO, the Japan Bifidobacteria Center, and the Patent Microorganisms Deposit Center of the National Institute of Technology and Evaluation.

[0031] <(C) Dextrin> The dextrin of the component (C) is contained for the purpose of serving as an excipient, binder, etc. in solid preparations, and in the present invention, improves the retention rate of intestinal fluid dissolution and gastric juice resistance. Dextrins are obtained by hydrolyzing starch and are classified according to their dextrose equivalent (saccharification rate). The dextrose equivalent (saccharification rate) can be expressed as a DE value (Dextrose Equivalent Value). For example, a DE value closer to 0 indicates that the dextrose has properties closer to starch, and a DE value closer to 100 indicates that the starch has been hydrolyzed to a greater extent. In the present invention, the "maintenance rate of intestinal fluid dissolution" indicates the degree to which the intestinal fluid dissolution property of a tablet is maintained after aging compared to that of the tablet immediately after production.

[0032] The dextrin in the enteric coated solid preparation of the present invention has a dextrose equivalent (DE value) of 30 or less. The dextrose equivalent (DE value) of the component (C) is preferably 10 or more and 30 or less, and more preferably 10 or more and 20 or less. If the dextrose equivalent (DE value) of the component (C) is 10 or more, the retention rate of dissolution into intestinal fluid is improved, which is preferable. If the dextrose equivalent (DE value) of the component (C) is 30 or less, the retention rate of intestinal fluid elution and resistance to gastric juice over time are improved, which is preferable. In addition, as long as the final DE value measured in the enteric coated solid preparation of the present invention is 30 or less, a combination of dextrins having different DE values ​​may be used.

[0033] The method for measuring the dextrose equivalent (DE value) of the component (C) is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include the following methods (I) to (III). Among these, measurement by the method (II) is preferred. The DE value is not limited to dextrin alone, but can also be measured by the same method for dextrin in a formulation mixed with excipients or functional ingredients, and for dextrin in a lactic acid bacteria raw material produced by adding dextrin as a dispersion medium. However, when the formulation contains modified milk powder, it is preferable to measure it by the measurement method (III). (I) Consumer Affairs Agency, "Specifications and Standards for the Specified Health Foods (Standards and Standards Type) System," 2014. The measurement method for indigestible dextrin in the "(Attachment) Ingredient Standards" (measurement temperature: 15-30°C) (II) The measurement method described in the Central Customs Analysis Laboratory, "Quantitative Analysis Method for Reducing Sugars in Dextrin" (measurement temperature: 15-30°C) (III) The measurement method described in the Central Customs Analysis Laboratory Report (33), "Measurement of DE of Dextrin in Formulated Milk Powder," Central Customs Analysis Laboratory, 1994, pp. 23-28 (measurement temperature: 15-30°C).

[0034] A specific method for measuring (II) above is as follows. (II-1) The analytical sample to be analyzed is prepared as follows, depending on the properties of the sample. If the sample to be analyzed is a solid, it should be in powder or crystalline form, and any lumps present should be crushed and mixed thoroughly. If the sample to be analyzed is a liquid, and crystals or lumps have precipitated in the liquid, place it in a sealed container, immerse it in a water bath at 60-70°C to dissolve, shake well, mix, and then cool to room temperature. (II-2) Quantify the moisture content M (%). If the sample prepared in (II-1) above is a solid sample, accurately weigh out approximately 2 g into a weighing bottle adjusted to a constant weight in advance and dry in a vacuum oven for 4 hours at 70°C. Next, allow to cool to room temperature in a desiccator, weigh it, and then repeat the vacuum drying for 1 hour at a time. When the weight loss is 2 mg or less, it is considered to have reached a constant weight. If the sample prepared in (II-1) above is a liquid, place approximately 15 g of sea sand (or 5 g of Celite) in a weighing bottle as a drying aid. Then, along with a glass rod large enough to fit in the weighing bottle, place the sample in a 105°C oven and dry it to obtain a constant mass. Next, accurately weigh out an amount of the homogenized sample prepared in (II-1) above equivalent to approximately 2 g of solids. If necessary, add a small amount of water until the sample is completely submerged. Heat the sample in a water bath, stirring occasionally with the glass rod, to evaporate most of the water. Stir occasionally in a 105°C oven until the sample is nearly dry. Then, transfer the sample to a vacuum oven and dry at 70°C for 4 hours. Allow the sample to cool to room temperature in a desiccator and weigh it. Repeat the vacuum drying for one hour at a time; the sample is considered to have reached constant mass when the weight loss is less than 2 mg. When W0 is the amount of sample (g) and W0 is the weight (g) of the sample after drying, the moisture content M (%) can be calculated using the following formula (1). Moisture M(%)={(W0-W1) / W0}×100...Equation (1) (II-3) Prepare Fehling's solution. Dissolve 34.639 g of copper sulfate (CuSO4·5H2O) in water to make 500 mL, leave for two days, and then filter to prepare Fehling's solution A. Dissolve 173 g of potassium sodium tartrate (KNaC4H4O6·4H2O) and 50 g of sodium hydroxide in water to make 500 mL, leave for two days, and then filter to prepare Fehling's solution B. 5.0 mL of Fehling's solution A and 5 mL of Fehling's solution B are placed in a 200 mL Erlenmeyer flask, and 19.5 mL of standard invert sugar solution is added using a 50 mL burette. After boiling for 2 minutes on an electric heater, 4 drops of methylene blue solution are added, and while boiling, standard invert sugar solution is added dropwise. The endpoint is when the blue color disappears. The titration should be completed within 3 minutes after boiling begins. If A is the amount (mL) of standard invert sugar solution consumed, the titer of Fehling's solution can be calculated using the following formula (2). Titer = 20.36 / A (2) The standard invert sugar solution was prepared by accurately weighing 4.75 g of sucrose (reagent) and transferring it to a 500 mL volumetric flask using 90 mL of water, adding 5 mL of hydrochloric acid (specific gravity 1.18), leaving it at 20-30°C for 3 days, then adding water to the constant volume, and storing it in a cool, dark place. 50 mL of the solution was then transferred to a 200 mL volumetric flask, neutralized with 1 mol / L sodium hydroxide solution using phenolphthalein as an indicator, and added water to the constant volume. (II-4) Quantify reducing sugars. Approximately 10 g of the sample prepared in (II-1) above was accurately weighed, dissolved in water, transferred to a 500 mL volumetric flask, and water was added to the flask to make the volume constant, which was used as the test solution. Place 5.0 mL of Fehling's solution A and 5 mL of Fehling's solution B in a 200 mL Erlenmeyer flask and add 15 mL of test solution using a 50 mL burette. After boiling for 2 minutes on an electric heater, add 4 drops of methylene blue solution. While boiling, add the test solution dropwise. The endpoint is when the blue color disappears. The titration should be completed within 3 minutes after boiling begins, and this is considered a preliminary titration. Add an additional amount of test solution approximately 1 mL less than the titer obtained in the preliminary titration and titrate in the same manner. Multiply the amount of test solution consumed by the titer of Fehling's solution, and use this value to calculate the reducing sugar concentration (mg / 100 mg) in terms of glucose using the rhein-enoin sugar table (glucose) shown in Table 1 below.

[0035] [Table 1]

[0036] (II-5) The reducing sugar content of the sample in its dry state, calculated as glucose, can be calculated using the following formula (3): DE (%) is the reducing sugar content (%) of the sample in its dry state, Ds is the amount of glucose (mg) in 100 mL of test solution obtained using Table 1, M is the moisture content of the sample (%), and S is the amount of sample collected (g). DE(%)=[Ds / {2(100-M)S}]×100...(3) formula

[0037] When measuring the DE value of dextrin in a lactic acid bacteria raw material produced by adding dextrin as a dispersion medium, it is preferable to measure the DE value of the test solution from which insoluble matter such as lactic acid bacteria has been removed by filtering the sample through filter paper after dissolving the sample as described above in (II-4) and then filtering the sample again through a membrane filter of 1 μm or less. When the DE value is not measured for dextrin alone, it can be calculated using the following formula (4), which takes into account the mass ratio of dextrin in the sample, instead of formula (3) in (II-5) above, where R is the mass ratio (%) of dextrin in the sample. DE(%)=[Ds / {2(100-M)S×R / 100}]×100···(4) formula

[0038] The content of the (C) dextrin in the enteric coated solid preparation is preferably 0.05% by mass or more and 35% by mass or less, more preferably 0.2% by mass or more and 30% by mass or less, even more preferably 0.75% by mass or more and 19% by mass or less, and particularly preferably 0.9% by mass or more and 15% by mass or less. If the content of the (C) dextrin in the enteric coated solid preparation is 0.05% by mass or more, the retention rate of intestinal fluid dissolution is improved, and the moldability is also improved, which is preferable. When the content of the (C) dextrin in the enteric coated solid preparation is 35% by mass or less, resistance to gastric juice after aging is improved, adhesion of the tablets during tableting is suppressed, and tableting problems such as binding are suppressed, which is preferable.

[0039] <Mass ratio [(C) / (A)]> In the present invention, the mass ratio of the content of the (C) component to the content of the (A) component [(C) / (A)] is preferably 0.05 or more, more preferably 0.05 or more and 0.6 or less, and even more preferably 0.1 or more and 0.36 or less, from the viewpoints of intestinal fluid dissolution property and gastric juice resistance. The mass ratio [(C) / (A)] of 0.05 or more is preferable because it improves the retention rate of intestinal fluid elution and improves moldability. A mass ratio [(C) / (A)] of 0.6 or less is preferable because it improves gastric juice resistance over time, suppresses adhesion to disks during tableting, and suppresses tableting problems such as binding.

[0040] <Other ingredients> Examples of the other components include excipients other than component (C), disintegrants, fluidizing agents, lubricants, binders, coating agents, enteric coating agents, and the like. The other components may be used alone or in combination of two or more.

[0041] - (C) Excipients other than ingredients - The excipient other than the component (C) (hereinafter, sometimes referred to as "excipient") is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include cellulose or cellulose derivatives, sugar alcohols, sugars (monosaccharides, disaccharides, oligosaccharides, polysaccharides), calcium hydrogen phosphate, sodium hydrogen phosphate, calcium carbonate, etc.

[0042] --Cellulose or cellulose derivatives-- The cellulose or cellulose derivative used as the excipient is contained to exhibit functions such as improving the tablet physical properties (moldability, disintegrability) immediately after production, promoting the dissolution of functional ingredients, improving the dissolution retention rate of functional ingredients, improving storage stability, suppressing tableting problems, etc. It is particularly useful for exhibiting the functions of improving the tablet physical properties (moldability, disintegrability, dissolution) immediately after production, storage stability, and the dissolution retention rate of functional ingredients, and suppressing tableting problems.

[0043] The cellulose or cellulose derivative used as the excipient is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include crystalline cellulose, methyl cellulose, microfibrous cellulose, hydroxypropyl cellulose, ethyl cellulose, etc. Among these, crystalline cellulose is preferred in terms of excellent moldability and disintegrability.

[0044] When the cellulose or cellulose derivative used as the excipient is crystalline cellulose, the bulk density of the crystalline cellulose is 0.15 g / cm 3 More than 0.40g / cm 3 Preferably less than 0.20 g / cm 3 More than 0.35g / cm 3 The following is more preferred: The bulk density can be measured by the method described in "Microcrystalline Cellulose" in the Seventeenth Edition of the Japanese Pharmacopoeia using a Scott volume meter.

[0045] The average particle size of the cellulose or cellulose derivative used as the excipient is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 20 μm to 180 μm, more preferably 40 μm to 150 μm. The average particle size can be determined in the same manner as for (A) lactoferrin.

[0046] The content of the cellulose or cellulose derivative used as the excipient in the enteric coated solid preparation is preferably 15% by mass or more and 80% by mass or less, more preferably 20% by mass or more and 65% by mass or less, and even more preferably 25% by mass or more and 45% by mass or less. When the content of the cellulose or cellulose derivative used as the excipient in the enteric coated solid preparation is 15% by mass or more, moldability, tablet disintegration property, dissolution property of the functional ingredient, disintegration property retention rate, and dissolution property retention rate are improved, and tableting problems are less likely to occur, which is preferable. When the content of the cellulose or cellulose derivative used as the excipient in the enteric coated solid preparation is 80% by mass or less, sufficient hardness and good disintegrability can be obtained, and the thickness can be reduced, which is preferable because the intake property is improved and the mixed powder is less likely to adhere to the tablet press.

[0047] --Sugar alcohols-- The sugar alcohol is contained to exhibit functions such as improving tablet moldability, tablet physical properties (moldability, disintegrability) immediately after production, storage stability, and dissolution of the functional ingredient, as well as improving the dissolution maintenance rate of the functional ingredient, etc. In particular, it is useful for exhibiting functions such as improving tablet physical properties (disintegrability) immediately after production, storage stability, and dissolution of the functional ingredient, as well as improving the dissolution maintenance rate of the functional ingredient.

[0048] The sugar alcohol is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include maltitol, erythritol, xylitol, fructose, sucrose, glucose, sorbitol, and lactitol.

[0049] The average particle size of the sugar alcohol is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 50 μm to 400 μm, more preferably 200 μm to 300 μm. The average particle size can be determined in the same manner as for (A) lactoferrin.

[0050] The content of the sugar alcohol in the enteric solid preparation is preferably 5% by mass or more and 50% by mass or less, more preferably 10% by mass or more and 40% by mass or less, and even more preferably 12% by mass or more and 30% by mass or less. When the content of the sugar alcohol in the enteric coated solid preparation is 5% by mass or more, it is preferable because it improves moldability, tablet disintegration, dissolution of the functional ingredient, maintenance of disintegration, and maintenance of dissolution. When the content of the sugar alcohol in the enteric coated solid preparation is 50% by mass or less, sufficient hardness and good disintegrability can be obtained, and resistance to gastric juice can be ensured, which is preferable.

[0051] -Disintegrant- The disintegrant is included to promote disintegration of the tablet.

[0052] The disintegrant is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include carboxymethylcellulose (CMC) or an alkali metal salt thereof, partially pregelatinized starch, etc. Among these, from the viewpoints of tablet disintegration property and dissolution property of functional ingredients, carboxymethylcellulose (CMC) or an alkali metal salt thereof is preferred, and carboxymethylcellulose calcium is more preferred.

[0053] The content of the disintegrant is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 0.1% by mass or more and 5% by mass or less, and more preferably 1% by mass or more and 2% by mass or less, in the enteric coated solid preparation. If the content of the disintegrant in the enteric coated solid preparation is 0.1% by mass or more, the disintegration property of the tablet and the dissolution property of the functional ingredient are improved, which is preferable. It is preferable that the content of the disintegrant in the enteric coated solid preparation is 5% by mass or less, since this reduces the delay in disintegration of the tablets during storage.

[0054] - Superplasticizer - The fluidizing agent is contained to promote fluidity by preventing adhesion between powder particles, which is advantageous because the promotion of fluidity by the fluidizing agent reduces variation in tablet mass.

[0055] The fluidizing agent is not particularly limited and can be appropriately selected depending on the purpose. Examples thereof include fine silicon dioxide (silica), light anhydrous silicic acid, calcium silicate, hydrous fine silicic acid powder, and talc.

[0056] When the fluidizing agent is silicon dioxide, the average particle size of the silicon dioxide is preferably 0.5 μm or more and 10 μm or less. The average particle size can be determined in the same manner as for (A) lactoferrin. The silicon dioxide is preferably porous fine particle silicon dioxide.

[0057] The content of the fluidizer is not particularly limited and can be appropriately selected depending on the purpose, but from the viewpoint of suppressing variation in tablet mass, it is preferably 0.1% by mass or more and 2.0% by mass or less in the enteric coated solid preparation. When the content of the fluidizing agent in the enteric coated solid preparation is 0.1% by mass or more, the fluidity of the mixed powder is improved and the variation in tablet mass is suppressed, which is preferable. If the content of the fluidizing agent in the enteric coated solid preparation is 2.0% by mass or less, the hardness of the tablet does not become too high, which is preferable.

[0058] -lubricant- The lubricant is added to prevent metal adhesion by reducing friction between the metal equipment and the powder particles, which is advantageous because it suppresses tableting problems.

[0059] The lubricant is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include metal stearates, sucrose fatty acid esters, etc. Among these, calcium stearate and magnesium stearate are preferred from the viewpoint of suppressing tableting problems (binding, sticking, picking).

[0060] The content of the lubricant is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of preventing adhesion to a tablet press and suppressing tableting problems (binding, sticking, picking), the content of the lubricant in the enteric coated solid preparation is preferably 0.01% by mass or more and 10% by mass or less, more preferably 0.05% by mass or more and 5.0% by mass or less, and even more preferably 0.10% by mass or more and 3.0% by mass or less. If the content of the lubricant in the enteric coated solid preparation is 0.01% by mass or more, adhesion to the tablet press is prevented, and tableting problems (binding, sticking, picking) are less likely to occur, which is preferable. If the content of the lubricant in the enteric coated solid preparation is 10% by mass or less, the tablet moldability, disintegrability, and dissolution properties are improved, which is preferable.

[0061] - Binder - The binder is included to control the hardness of the tablet and the disintegration time of the tablet.

[0062] The binder is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoints of suppressing tableting problems (capping and lamination), tablet physical properties (hardness and disintegration time), and storage stability of tablet physical properties, examples of the binder include starch such as corn starch, gum arabic, gelatin, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, and hydroxypropyl methylcellulose (hereinafter sometimes referred to as "HPMC").

[0063] The content of the binder is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoints of improving tablet formability, suppressing tableting problems, and improving the storage stability of the tablet physical properties, the content of the binder in the enteric coated solid preparation is preferably 0.01% by mass or more and 30% by mass or less, and more preferably 0.1% by mass or more and 10% by mass or less. If the content of the binder in the enteric coated solid preparation is 0.01% by mass or more, the tablet moldability is improved and tableting problems are less likely to occur, which is preferable. If the content of the binder in the enteric coated solid preparation is 30% by mass or less, the mixed powder is less likely to adhere to the tablet press, and the disintegration properties of the tablet are improved, which is preferable.

[0064] - Coating agent - The enteric coated solid preparation of the present invention may be a coated tablet provided with a coating layer containing a coating agent in order to improve ease of administration and mask the plain tablet (mainly the bitterness, odor, etc. caused by the functional ingredients). The coating layer may contain a plasticizer in addition to the coating agent. When the enteric coated solid preparation of the present invention is a coated tablet, the above-mentioned coating layer is present on the surface of the uncoated tablet.

[0065] The coating agent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include cellulose, cellulose derivatives, methacrylic acid-based polymer compounds, shellac, zein, polyuronic acid and its salts, fucoidan and its salts, carrageenan and its salts, etc. Among these, HPMC, shellac, zein, polyuronic acid and its salts (particularly alginates), and pectin and its salts are preferred. These may be used alone or in combination of two or more.

[0066] The cellulose derivative used in the coating agent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include HPMC. The polyuronic acid used in the coating agent is not particularly limited, and can be appropriately selected depending on the purpose, as long as it is a polymer of uronic acid such as guluronic acid, mannuronic acid, galacturonic acid, or glucuronic acid. Examples include alginic acid (a polymer of guluronic acid and mannuronic acid) and pectin (a polymer of galacturonic acid).

[0067] The plasticizer used together with the coating agent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include glycerin, polyethylene glycol, sucrose fatty acid esters, etc. Among these, glycerin and sucrose fatty acid esters are preferred.

[0068] When the enteric coated solid preparation of the present invention is a coated tablet, the content of the coating agent is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of improving the ease of taking the tablet and masking the bitter taste and odor derived from the functional ingredient, the content of the coating agent is preferably 0.5% by mass or more and 15% by mass or less, and more preferably 1% by mass or more and 10% by mass or less, per coated tablet. If the content of the coating agent is 0.5% by mass or more per coated tablet, it is preferable because it improves ease of administration and masks the bitter taste and odor derived from the functional ingredients. When the content of the coating agent is 15% by mass or less per coated tablet, the disintegration and dissolution properties of the tablet are good.

[0069] When the enteric coated solid preparation of the present invention is a coated tablet, the content of the coating agent is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoints of improving the ease of taking the tablet and masking the bitter taste and odor derived from the functional ingredient, the content of the coating agent in the enteric coated solid preparation is preferably 0.5% by mass or more and 15% by mass or less, and more preferably 1% by mass or more and 10% by mass or less. If the content of the coating agent in the enteric coated solid preparation is 0.5% by mass or more, it is preferable because the ease of administration is improved and the bitter taste and odor derived from the functional ingredients are masked. When the content of the coating agent in the enteric coated solid preparation is 15% by mass or less, the disintegration property and dissolution property of the tablet are good.

[0070] The content of the plasticizer used in the coating agent is not particularly limited and can be selected appropriately depending on the purpose, but from the viewpoint of improving the disintegration and dissolution properties of the coated tablet, it is preferably 0.05% by mass or more per coated tablet. Furthermore, from the viewpoint of exerting the coating effect, the content of the plasticizer used in the coating agent is preferably 10% by mass or less per coated tablet, more preferably 0.1% by mass or more and 5% by mass or less.

[0071] The content of the plasticizer used in the coating agent is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 0.05% by mass or more in the enteric coated solid preparation from the viewpoint of improving the disintegration and dissolution properties of the coated tablet. Also, the content of the plasticizer used in the coating agent is preferably 10% by mass or less, more preferably 0.1% by mass or more and 5% by mass or less, in the enteric coated solid preparation from the viewpoint of exerting the coating effect.

[0072] -Enteric coating agent- The enteric coated solid preparation of the present invention may be an enteric coated tablet provided with a coating layer containing an enteric coating agent in order to inhibit the decomposition of ingredients that are susceptible to deterioration by gastric acid. The enteric coating layer may contain a plasticizer in addition to the enteric coating agent. When the enteric coated solid preparation of the present invention is an enteric coated tablet, the tablet has an enteric coating layer on the outside.

[0073] The enteric coating agent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include methacrylic acid polymer compounds, shellac, zein, polyuronic acid and its salts, fucoidan and its salts, and carrageenan and its salts. Among these, shellac, zein, polyuronic acid and its salts (particularly alginates), and pectin and its salts are preferred. These may be used alone or in combination of two or more. The polyuronic acid used in the enteric coating agent is not particularly limited as long as it is a polymer of uronic acid such as guluronic acid, mannuronic acid, galacturonic acid, or glucuronic acid, and examples thereof include alginic acid (a polymer of guluronic acid and mannuronic acid) and pectin (a polymer of galacturonic acid). The enteric coating agent may be used in combination with a cellulose derivative (HPMC, etc.) exemplified as the coating agent. The enteric coating agent may be used in combination with the coating agent.

[0074] When the enteric coated solid preparation of the present invention is an enteric coated tablet, the content of the enteric coating agent is not particularly limited and can be selected appropriately depending on the purpose. From the viewpoint of preventing the degradation of the functional ingredient in the stomach, the content is preferably 1% by mass or more and 30% by mass or less, and more preferably 1% by mass or more and 15% by mass or less, per enteric coated tablet. It is preferable that the content of the enteric coating agent is 1% by mass or more per enteric coated tablet, since this can prevent the functional ingredient from being decomposed in the stomach. When the content of the enteric coating agent is 30% by mass or less per enteric coated tablet, the dissolution property in the intestinal environment is good.

[0075] When the enteric coated solid preparation of the present invention is an enteric coated tablet, the content of the enteric coating agent is not particularly limited and can be appropriately selected depending on the purpose. From the viewpoint of preventing the degradation of the functional ingredient in the stomach, the content of the enteric coating agent in the enteric coated solid preparation is preferably 0.1% by mass or more and 30% by mass or less, and more preferably 0.1% by mass or more and 15% by mass or less. The content of the enteric coating agent in the enteric solid preparation is preferably 0.1% by mass or more, since this can prevent the functional ingredient from being decomposed in the stomach. When the content of the enteric coating agent in the enteric solid preparation is 30% by mass or less, the dissolution property in the intestinal environment is good. When the enteric coating agent is used in combination with a cellulose derivative (HPMC, etc.) exemplified as the coating agent, it is preferable to use 0.1 to 5 parts by mass of the coating agent per 1 part by mass of the enteric coating agent.

[0076] The plasticizer used in the enteric coating agent is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include glycerin, polyethylene glycol, sucrose fatty acid esters, etc. Among these, glycerin and sucrose fatty acid esters are preferred.

[0077] The content of the plasticizer used in the enteric coating agent is not particularly limited and can be selected appropriately depending on the purpose, but from the viewpoint of improving the disintegration and dissolution properties of the enteric coated tablet, it is preferably 0.05% by mass or more per one enteric coated tablet. Furthermore, from the viewpoint of exerting the coating effect, the content of the plasticizer used in the enteric coating agent is preferably 10% by mass or less per one enteric coated tablet, and more preferably 0.1% by mass or more and 5% by mass or less.

[0078] The content of the plasticizer used in the enteric coating agent is not particularly limited and can be appropriately selected depending on the purpose, but from the viewpoint of improving the disintegration and dissolution properties of the enteric coated tablet, it is preferably 0.05% by mass or more in the enteric coated solid preparation. Furthermore, from the viewpoint of exerting the coating effect, the content of the plasticizer used in the enteric coating agent is preferably 10% by mass or less in the enteric coated solid preparation, more preferably 0.1% by mass or more and 5% by mass or less.

[0079] When the enteric coated solid preparation of the present invention is an enteric coated tablet, it is preferable to provide a pre-coating layer between the plain tablet and the enteric coating layer from the viewpoint of preventing a decrease in gastric juice resistance. Furthermore, an outermost layer may be provided outside the enteric coating layer to improve appearance, mouthfeel, and ease of administration. Components contained in the pre-coating layer and the outermost layer include the coating agent, plasticizers used in the coating agent, etc. Among these, it is preferable to use the same components as the coating agent. When the enteric coated solid preparation of the present invention has the pre-coating layer, the content of the pre-coating agent is not particularly limited and can be appropriately selected depending on the purpose, but it is preferably 0.1% by mass or more and 5% by mass or less in the enteric coated solid preparation. When the enteric coated solid preparation of the present invention has the outermost layer, the content of the pre-coating agent is not particularly limited and can be appropriately selected depending on the purpose, but it is preferably 0.1% by mass or more and 5% by mass or less in the enteric coated solid preparation.

[0080] The dosage form of the enteric coated solid preparation of the present invention is not particularly limited and can be appropriately selected depending on the purpose, and examples thereof include tablets (sugar-coated tablets, coated tablets, enteric-coated tablets, etc.), pills (sugar-coated tablets, coated tablets, enteric-coated tablets), hard capsules (coated hard capsules, enteric-coated hard capsules), etc. Among these, coated tablets and enteric-coated tablets are preferred because they allow the effects of the present invention to be more easily enjoyed.

[0081] When the enteric coated solid preparation of the present invention is a tablet, the size of the tablet is not particularly limited and can be appropriately selected depending on the purpose. However, from the viewpoint of ease of handling and swallowing of the tablet, the diameter of the tablet is preferably 5 mmφ or more and 15 mmφ or less. The thickness of the tablet is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 3 mm or more and 10 mm or less.

[0082] When the enteric coated solid preparation of the present invention is a tablet, the mass of each tablet is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 150 mg or more and 500 mg or less, and more preferably 250 mg or more and 400 mg or less. A tablet mass of 150 mg or more is preferable because the required amount of functional ingredients can be blended in. A tablet mass of 500 mg or less is preferable because it improves ease of administration.

[0083] When the enteric coated solid preparation of the present invention is a tablet, the shape of the tablet is not particularly limited and can be appropriately selected depending on the purpose, but square flat tablets, round flat tablets, rounded R tablets, or two-stage R tablets are preferred.

[0084] When the enteric coated solid preparation of the present invention is a tablet, the structure of the tablet is not particularly limited and can be appropriately selected depending on the purpose, and may be a single-layer structure (single-layer tablet) or a multi-layer structure (multi-layer tablet). Among these, from the viewpoint of more easily enjoying the effects of the present invention, it is preferable to have a layer in which the component (A), the component (B), and the component (C) are used in combination (i.e., the component (A), the component (B), and the component (C) are present in the same layer). In this specification, the "layer in which the component (A), the component (B), and the component (C) are used in combination" may be referred to as the "active ingredient-containing layer." When the enteric coated solid preparation of the present invention is a single-layer tablet, the enteric coated solid preparation is composed of an active ingredient-containing layer. When the enteric coated solid preparation of the present invention is a layered tablet, the enteric coated solid preparation is composed of an active ingredient-containing layer and a layer other than the active ingredient-containing layer (an optional layer).

[0085] When the enteric coated solid preparation of the present invention is a hard capsule, the size of the hard capsule is not particularly limited and can be appropriately selected depending on the purpose. The material of the capsule for the hard capsule is not particularly limited and can be appropriately selected depending on the purpose, and examples of materials that can be used include gelatin, hydroxypropyl methylcellulose, and pullulan. Examples of the filler filled into the hard capsule include a mixed powder containing the component (A), the component (B), and the component (C), and granules obtained by granulation.

[0086] The dosage form of the enteric coated solid preparation of the present invention is not particularly limited and can be appropriately selected depending on the purpose. For example, it is preferably a conventional oral, ie, swallowed, tablet. In the present invention, whether or not a preparation is an enteric coated solid preparation is determined by the disintegration test method of the Japanese Pharmacopoeia, 17th Edition. [Example]

[0087] Examples of the present invention will be described below, but the present invention is not limited to these examples. The contents of each component described in the examples and comparative examples are shown in "parts by mass" and are all values ​​converted into pure contents. The lactoferrin composition of the uncoated tablets in the examples of the present invention is the content of lactoferrin powder (raw material) (also listed is the pure lactoferrin content), and the content percentage in the solid preparation mentioned above is the content percentage of pure lactoferrin. The pure lactoferrin content in lactoferrin powder is calculated according to the lactoferrin (in a dried substance) quantification method and loss on drying (105°C, 5 hours) in the Japanese Food Additives Official Standards, 9th Edition, "Lactoferrin Concentrate," based on the following formula (5): Pure lactoferrin content = lactoferrin content (in dry matter) (%) × (100 - loss on drying (%)) / 100 (5)

[0088] (Preparation of uncoated tablets) Each of the raw tablet materials in Tables 2 to 7 was weighed and mixed so that the total mass of the mixed powder was 5 kg, and tableted using a rotary tablet press (LIBLA 2, manufactured by Kikusui Seisakusho) under the following conditions. Mortar and pestle: φ9.0 mm, two-stage R shape (R1 = 3.4 mm, R2 = 10 mm, land part (distance from the side of the tablet to the rising part of the R) = 1.4 mm) Feedstock agitator rotation speed: 60 rpm ·Tableting pressure: 8kN or more and 11kN or less

[0089] (Preparation of first layer coating liquid) The following materials were mixed to obtain a first layer coating liquid. Hydroxypropyl methylcellulose (HPMC): 6% by mass Glycerin: 2% by mass Ion-exchanged water: 92% by mass

[0090] (Preparation of second layer coating liquid) The following materials were mixed to obtain a second layer coating liquid. Hydroxypropyl methylcellulose (HPMC): 2.1% by mass Glycerin: 1.1% by mass Sodium alginate: 3.2% by weight Talc: 0.5% by mass ·Fine silicon dioxide: 0.5% by mass Ion-exchanged water: 93.1% by mass

[0091] (Preparation of coated tablets) Using a pan rotary coating machine (HiCoater FZ-Lab, manufactured by Freund Corporation), 33 g of the first layer coating solution (20°C) was sprayed onto 670 plain tablets at an average rate of 2 g / min, and coating was performed at a product temperature of approximately 50°C. Subsequently, 165 g of the second layer coating solution (60°C) was sprayed at an average rate of 2 g / min, and after spraying, the tablets were dried at approximately 45°C for 2 minutes to obtain enteric-coated solid preparations (coated tablets) of Examples 1 to 21 and Comparative Examples 1 to 4. The mass of the solid content derived from each coating layer per tablet is shown below. <First coating layer (solid content)> Hydroxypropyl methylcellulose (HPMC): 2.9% by mass Glycerin: 1.0% by mass <Second coating layer (solid content)> Hydroxypropyl methylcellulose (HPMC): 4.6% by mass Glycerin: 2.3% by mass Sodium alginate: 7.1% by weight ·Fine silicon dioxide: 1.1% by mass Talc: 1.1% by mass

[0092] The enteric coated solid preparations of Examples 1 to 21 and Comparative Examples 1 to 4 were evaluated for "tabletting trouble," "initial dissolution rate," "dissolution maintenance rate," and "acid resistance over time" by the following methods. The results are shown in Tables 2 to 7 below.

[0093] [Tableting problems] When the enteric coated solid preparations of Examples 1 to 21 and Comparative Examples 1 to 4 were compressed under the above-mentioned conditions, 20 tablets were sampled from each sample. Of the tablets obtained, those with vertical lines (binding) on ​​the side were visually inspected and counted. Evaluation was carried out according to the following criteria. [Criteria for determining tableting problems] 3 points: Binding not permitted 2 points: Binding was observed with 1 to 2 tablets. 1 point: Binding was observed with 3 to 5 tablets 0 points: Binding was observed with 6 or more tablets

[0094] <Dissolution test> The lactoferrin dissolution rate (%) was measured according to the tablet dissolution test method described in the 17th edition of the Japanese Pharmacopoeia. Specifically, lactoferrin was dissolved into the test solution using the paddle method at 50 revolutions per minute. The test solution used was the second dissolution test solution with a pH of approximately 6.8, at a volume of 900 mL per tablet. Two hours after the start of the test, the test solution was sampled, and the amount of lactoferrin dissolved in the test solution was quantified to calculate the dissolution rate. Furthermore, a test was also conducted using the first dissolution test fluid at a pH of about 1.2 to confirm that the coating had formed normally. Therefore, if it is confirmed that the tablets of this example have dissolution properties in the second dissolution test fluid, it will be confirmed that the tablets of this example are bioavailable as enteric-coated solid preparations. The amount of lactoferrin eluted into the test solution was determined as follows: First, 75 mg of lactoferrin standard (lactoferrin derived from milk, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was placed in a 50 mL volumetric flask, and then the volume was increased to the specified volume with Dissolution Test Solution 2 to obtain a 1 / 1 standard solution. This standard solution was further diluted with Dissolution Test Solution 2 to prepare 1 / 5, 1 / 20, and 1 / 50 standard solutions. Lactoferrin in each standard solution was detected by HPLC. A calibration curve was created by determining the peak area of ​​lactoferrin in each standard solution. Next, lactoferrin in the test solutions collected as described above was detected by HPLC to determine the lactoferrin peak area. The lactoferrin concentration in each test solution was determined from the peak area based on the calibration curve, and the amount of lactoferrin dissolved in the test solution was quantified. The purity of the lactoferrin standard was quoted from the content (HPLC) value listed in the test report issued by Fujifilm Wako Pure Chemical Industries, Ltd. The HPLC conditions were as follows: -Detector: UV absorption photometer (measurement wavelength: 280 nm) Column packing material: 5 μm butylated polyvinyl alcohol polymer gel for liquid chromatography (Shodex Asahipak C4P-50 4D) - Column tube: Stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm -Guard column: Shodex Asahipak C4P-50G 4A -Column temperature: 35℃ Mobile phase A: 0.03 w / v weight % trifluoroacetic acid-containing acetonitrile / sodium chloride solution (3 → 100) mixture (10:90) Mobile phase B: 0.03 w / v weight % trifluoroacetic acid-containing acetonitrile / sodium chloride solution (3 → 100) mixture (50:50) - Concentration gradient: A linear concentration gradient from A:B (50:50) to A:B (0:100) is applied over 25 minutes. -Flow rate: 0.8mL / min

[0095] [Initial lactoferrin dissolution rate] The enteric-coated solid preparations of Examples 1 to 21 and Comparative Examples 1 to 4 were subjected to the dissolution test described above to determine the initial lactoferrin dissolution amount from the enteric-coated solid preparations. To obtain the initial lactoferrin dissolution rate, tablets within 7 days after tableting were used. The test was performed three times each, and the initial lactoferrin dissolution rate (%) was calculated by dividing the measured initial lactoferrin dissolution amount by the theoretical amount of lactoferrin (converted to pure content) calculated from the weighed amount of lactoferrin. The average initial lactoferrin dissolution rate was then calculated. Evaluation was performed according to the following criteria. None of the formulations in these Examples had an initial dissolution rate of less than 75%. [Criteria for determining initial lactoferrin dissolution rate] 3 points: Initial lactoferrin dissolution rate is 96% or more 2 points: Initial lactoferrin dissolution rate is 93% or more but less than 96% 1 point: Initial lactoferrin dissolution rate is 90% or more but less than 93% 0 points: Initial lactoferrin dissolution rate is less than 90%

[0096] [Lactoferrin elution retention rate] The enteric coated solid preparations of Examples 1 to 21 and Comparative Examples 1 to 4 were filled into plastic bottles and stored at 60°C for 12 days, after which the above-mentioned dissolution test was carried out to determine the amount of lactoferrin eluted from the enteric coated solid preparations. The test was carried out three times each, and the average value of the lactoferrin elution retention rate was calculated from the measured values ​​of the lactoferrin elution rate. Evaluation was carried out according to the following criteria. The lactoferrin elution retention rate (%) was calculated according to the following formula (6). Lactoferrin elution retention rate (%) = 100 × {(elution amount after storage (mg)) / (initial elution amount (mg))} (6) [Criteria for determining lactoferrin elution retention rate] 3 points: 85% or more 2 points: 78% or more but less than 85% 1 point: 71% or more but less than 78% 0 points: Less than 71%

[0097] [Gastric juice resistance over time] The enteric-coated solid preparations of Examples 1 to 21 and Comparative Examples 1 to 4 were filled into plastic bottles and stored at 60°C for 12 days. A dissolution test was then conducted using the first dissolution test fluid (pH 1.2) in the dissolution test for tablets described in the Japanese Pharmacopoeia, Seventeenth Edition, in accordance with the general test method described in the Japanese Pharmacopoeia, Seventeenth Edition, by the paddle method (rotation speed: 50 rpm). The amount of lactoferrin in the dissolution test fluid sampled after 2 hours and 30 minutes was quantified according to the same test method. Six tablets were tested for each test. Evaluation was based on the following criteria: [Criteria for determining gastric juice resistance over time] 3 points: All 6 tablets had lactoferrin below the detection limit 2 points: 1 to 2 tablets have a lactoferrin dissolution rate of 5% or more 1 point: 3 to 4 tablets have a lactoferrin dissolution rate of 5% or more 0 points: 5 or more tablets have a lactoferrin elution rate of 5% or more

[0098] [Overall evaluation as an enteric-coated solid dosage form] A product with a total score of 10 or more in the evaluation of the tableting trouble, the evaluation of the initial lactoferrin dissolution rate, the evaluation of the lactoferrin dissolution maintenance rate, and the evaluation of gastric juice resistance after time was deemed to have passed.

[0099] [Table 2]

[0100] [Table 3]

[0101] [Table 4]

[0102] [Table 5]

[0103] [Table 6]

[0104] [Table 7]

[0105] Details of each component used in Examples 1 to 21 and Comparative Examples 1 to 4 are shown in Table 8 below.

[0106] [Table 8] (※1): Lacticaseibacillus casei (Lactobacillus casei, manufactured by THT, Belgium, sold by Seti Co., Ltd.) was anaerobically cultured in MRS medium (Oxoid), harvested, sterilized by high-pressure steam at 121°C for 20 minutes, and then freeze-dried. 2 mg of this dried product was prepared to correspond to 40 billion lactic acid bacteria. (※2): Lacticaseibacillus paracasei (Lactobacillus paracasei, manufactured by THT, Belgium, sold by Seti Co., Ltd.) was anaerobically cultured in MRS medium (Oxoid), harvested, sterilized by high-pressure steam at 121°C for 20 minutes, and then freeze-dried. 2 mg of this dried product was prepared to contain 40 billion lactic acid bacteria. (※3): Bifidobacterium longum (Bifidobacterium longum, Morinaga Milk Industry's Bifidus Drinking Yogurt) was used as a sample. After anaerobically culturing it in MRS medium (Oxoid), the bacteria were collected and freeze-dried. 20 mg of this dried product was prepared to contain 40 billion bifidobacteria. (※4): Lacticaseibacillus casei (Lactobacillus casei, manufactured by THT, Belgium, sold by Seti Co., Ltd.) was anaerobically cultured in MRS medium (manufactured by Oxoid), harvested, and sterilized by high-pressure steam at 121°C for 20 minutes. An equal amount of DE11.6 dextrin (Sanwa Starch Industry, Sandec #100) was added as a dilution excipient to the lactic acid bacteria, and the mixture was freeze-dried. The dried product was prepared so that 40 billion lactic acid bacteria cells were present in 40 mg of the dried product (20 mg of the 40 mg was dextrin). (*5): Bifidobacterium longum (Bifidobacterium longum, Morinaga Milk Industry's Bifidus Drinking Yogurt) was used as a sample. After anaerobically culturing in MRS medium (Oxoid), the bacteria were harvested and an equal amount of DE11.6 dextrin (Sanwa Starch Industry's Sandec #100) was added as a dilution excipient to the lactic acid bacteria, and the resulting product was freeze-dried. 40 mg of this dried product was prepared to contain 40 billion Bifidobacteria (20 mg of the 40 mg was dextrin). (※6): The DE value of dextrin is the DE value listed on the performance report of the purchased raw material (the DE value was measured using the measurement method described in the Central Customs Analysis Laboratory, "Quantitative Analysis Method for Reducing Sugars in Dextrin," in the Central Customs Analysis Laboratory mentioned above). (※7): The dextrin with a DE value of 35 in Comparative Example 4 was a mixture of 10 mg of dextrin with a DE value of 28.9 (GLUCIDEXIT 19) and 10 mg of dextrin with a DE value of 44 (GLUCIDEXIT 47).

Claims

1. (A) a plain tablet containing lactoferrin, (B) lactic acid bacteria, and (C) dextrin having a dextrose equivalent (DE) of 10 or more and 30 or less; an enteric coating layer on the surface of the uncoated tablet; An enteric solid preparation having a pre-coating layer between the uncoated tablet and the enteric coating layer, the pre-coating layer and the enteric coating layer comprise an enteric coating agent and a plasticizer; the enteric coating agent contains at least one selected from cellulose, hydroxypropyl methylcellulose, a methacrylic acid-based polymer compound, shellac, zein, polyuronic acid and its salt, fucoidan and its salt, and carrageenan and its salt; the plasticizer includes at least one selected from glycerin, polyethylene glycol, and sucrose fatty acid ester; An enteric coated solid preparation, wherein the mass ratio of the content of the component (C) to the content of the component (A) [(C) / (A)] is 0.1 or more and 0.36 or less.

2. The pre-coating layer comprises hydroxypropyl methylcellulose and glycerin, 2. The enteric coated solid dosage form according to claim 1, wherein the enteric coating layer comprises hydroxypropyl methylcellulose, glycerin, sodium alginate, fine silicon dioxide, and talc.

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