tablet

Abstract

To provide a tablet containing chitosan and other useful substance, which facilitates the elution of chitosan and co-blended other useful substance from the tablet.SOLUTION: The foregoing problem is solved by a tablet containing (A) useful substance and (B) chitosan, the tablet formed from a plurality of layers, the component (A) and the component (B) being contained in different layers. The present invention can provide a tablet containing chitosan and other useful substance, which facilitates the elution of chitosan and co-blended other useful substance from the tablet.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a tablet containing chitosan and a useful substance, more particularly to a tablet containing chitosan and a useful substance and formed of multiple layers. [Background technology]

[0002] Chitosan is an animal-derived dietary fiber obtained by alkali treatment of chitin, which forms the shells of crustaceans such as crabs and shrimp, and squid shells. Chitosan has been reported to have a wide variety of physiological functions, including the suppression of fat absorption, cholesterol elevation, and blood pressure elevation, and has been widely used in recent years in the fields of pharmaceuticals and health foods.

[0003] For example, Patent Document 1 describes an agent for suppressing obesity and lifestyle-related diseases, which contains chitosan and an active ingredient extracted from Cassia capillaris, a leguminous plant, with water or an organic solvent such as alcohol.

[0004] Furthermore, Patent Document 2 describes a health food composition containing a component that inhibits digestive enzyme activity, a mushroom chitosan complex polysaccharide component, and a component that adjusts mineral balance and has the effect of activating insulin production and insulin receptors. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Laid-Open No. 2005-343808 [Patent Document 2] Japanese Patent Application Laid-Open No. 2006-20606 Summary of the Invention [Problem to be solved by the invention]

[0006] As seen in the patent documents cited above, when chitosan is incorporated into a preparation, it is common for other useful substances to be incorporated as well. However, as a result of experiments conducted by the present inventors, when a preparation containing chitosan and other useful substances is administered to a living body, the problem of in vivo absorption of the other useful substances incorporated together is confirmed, and it has been further confirmed that this problem is caused by the inhibition of the release of the other useful substances by chitosan. It has also been confirmed that the release of chitosan itself is inhibited by the addition of other useful substances.

[0007] When chitosan is rapidly dissolved in the stomach, it becomes viscous and forms a loose gel in the neutral region of the intestine, thereby exerting its effects. However, it is known that if chitosan is not dissolved sufficiently in the stomach, it will not be able to exert its intended effects. Based on the above-mentioned conventional findings, the present inventors confirmed the lipid absorption inhibitory effect of chitosan by conducting a blood triglyceride absorption test in rats with the addition of fats and oils. The test results showed that enteric-coated hard capsules, which do not dissolve in the stomach, have a lower lipid absorption inhibitory effect than regular hard capsules containing chitosan, thereby confirming the influence of chitosan dissolution on the lipid absorption inhibitory effect.

[0008] The present invention has been made based on the above findings, and an object of the present invention is to provide a tablet containing chitosan and other useful substances, which has improved dissolution of chitosan and the other useful substances blended therewith from the tablet. [Means for solving the problem]

[0009] As a result of intensive research into the above-mentioned problems, the present inventors have discovered that, in a tablet containing a useful substance and chitosan, the dissolution of the useful substance from the tablet can be improved by forming the tablet from multiple layers and containing the useful substance and chitosan in separate layers, and have completed the present invention. Furthermore, it was found that the dissolution of chitosan itself is also improved, and therefore the bioavailability of useful substances and chitosan can also be improved.

[0010] That is, the present invention provides the following [1] to [4]. [1] A tablet comprising (A) a useful substance and (B) chitosan and formed of multiple layers, A tablet characterized in that the component (A) and the component (B) are contained in separate layers. According to the present invention, tablets can be obtained that have improved dissolution of useful substances from the tablets. [2] The tablet according to [1], characterized in that the (A) useful substance is one or more selected from the group consisting of wisteria tea extract, ampelopsin, polymethoxyflavone, pyridoxine hydrochloride, riboflavin, and quercetin glycoside. According to this feature, it is possible to obtain tablets with improved dissolution of wisteria tea extract, ampelopsin, polymethoxyflavone, pyridoxine hydrochloride, riboflavin, and quercetin glycoside from the tablets. [3] The tablet according to [1] or [2], characterized in that the ratio (B / A) of the mass of the layer containing component (B) to the mass of the layer containing component (A) in the tablet is 0.1 or more and 1.0 or less. According to this feature, it is possible to obtain tablets in which the dissolution of useful substances from the tablets is improved. [4] The tablet according to any one of [1] to [3], wherein the tablet is a layered tablet. According to this feature, it is possible to obtain tablets in which the dissolution of useful substances from the tablets is further improved. [Effects of the Invention]

[0011] According to the present invention, it is possible to provide a tablet containing chitosan and other useful substances, in which the release of chitosan and other useful substances blended together from the tablet is improved. [Brief explanation of the drawings]

[0012] [Figure 1]The results of evaluating the dissolution of useful substances relative to the chitosan content in ordinary tablets containing useful substances and chitosan are shown below. [Figure 2] 1 shows the results of evaluating the dissolution of a useful substance from a regular tablet containing the useful substance and chitosan or a gelling agent. [Figure 3] The results of evaluating the dissolution of a useful substance from a layered tablet, a regular tablet, and a hard capsule containing a useful substance and chitosan are shown below. [Figure 4] The results of evaluating the dissolution of chitosan from layered tablets, regular tablets, and hard capsules containing a useful substance and chitosan are shown below. [Figure 5] 1 shows the results of a pharmacokinetic test of a useful substance when a preparation containing the useful substance and chitosan was administered to a living body. [Figure 6] 1 shows the results of evaluating the blood concentration of a useful substance when a preparation containing a useful substance and chitosan was administered to a living body. [Figure 7] The results of evaluating the dissolution of useful substances from layered tablets, ordinary tablets, and hard capsules containing useful substances and chitosan using five types of useful substances are shown below. [Figure 8] The results of an evaluation of the effect of the layer ratio on the dissolution of useful substances and chitosan in layered tablets containing useful substances and chitosan are shown below. DETAILED DESCRIPTION OF THE INVENTION

[0013] [tablet] The tablet of the present invention contains (A) a useful substance and (B) chitosan and is formed from multiple layers, characterized in that the (A) component and the (B) component are contained in separate layers.

[0014] The tablet of the present invention contains a useful substance and chitosan. However, when a formulation containing chitosan and other useful substances is administered to a living body, there is a problem of suppressed absorption of the other useful substances in the body. Furthermore, the inventors have confirmed that this problem is due to the chitosan suppressing the dissolution of the other useful substances. In the present invention, by forming a tablet from multiple layers and containing the useful substance and chitosan in separate layers, the layers formed from each powder composition disintegrate without mixing, thereby suppressing the interaction between the useful substance and chitosan. This improves the dissolution of the other useful substances formulated with chitosan and improves their absorbability in the body. Furthermore, the dissolution of chitosan itself is also improved, thereby improving the bioavailability of the useful substance and chitosan.

[0015] <Tablet shape> The tablet of the present invention is a tablet formed from multiple layers, in which (A) a useful substance and (B) chitosan are contained in separate layers. Examples of such tablets include, but are not limited to, tablets having two layers, a first layer containing a useful substance and a second layer containing chitosan, or tablets having an additional layer other than these two layers. These separate layers may be in contact with each other, or an intermediate layer may be provided between them. The first layer containing the useful substance is substantially free of (B) chitosan. Furthermore, the second layer containing chitosan is substantially free of (A) a useful substance. "Substantially free" means that the content in each layer is 0.5% by mass or less.

[0016] The types of tablets formed from multiple layers are not particularly limited, and include layered tablets, dry-coated tablets, etc. In these tablets formed from multiple layers, when administered to a living body, the layers formed from each powder composition disintegrate without being mixed, thereby suppressing the interaction between the useful substance and chitosan. Such an effect can be obtained with tablets formed from multiple layers, but in layered tablets, the tablet is formed by simply stacking two or more layers formed from each powder composition, and the layers are not mixed together, for example, one enveloping the other, so the interaction between the useful substance and chitosan can be more effectively suppressed, resulting in a significant effect.

[0017] Layered tablets can be manufactured using methods conventionally used in the fields of pharmaceuticals, quasi-drugs, veterinary products, foods, supplements, etc. In the case of two-layered layered tablets, for example, the lower layer material loaded into the die of a tablet press is compressed with a pestle to form the lower layer, and then the upper layer material loaded on top of the lower layer in the die is compressed with a pestle to form the upper layer, thereby forming the upper layer on top of the lower layer. The above manufacturing method can also be performed by omitting the compression step after filling the lower layer, and instead filling the lower layer material, followed by filling with the upper layer material and tableting. The upper and lower layers can be either the first layer containing a useful substance or the second layer containing chitosan.

[0018] In the tablet of the present invention, the ratio (B / A) of the mass of the layer containing component (B) to the mass of the layer containing component (A) in the tablet is not particularly limited, but is, for example, 0.05 or more and 2.0 or less. The lower limit is preferably 0.1 or more, more preferably 0.2 or more. The upper limit is preferably 1.0 or less, more preferably 0.6 or less, and even more preferably 0.4 or less.

[0019] The shape of the tablet is not particularly limited, and examples thereof include round tablets, oval tablets, flower-shaped tablets, etc. Furthermore, the tablet may be provided with one or two scoring lines for dividing into two or four pieces as needed.

[0020] The size of the tablet is not particularly limited, but preferably has a diameter of 3 mm or more and 25 mm or less. The lower limit is more preferably 4 mm or more, even more preferably 5 mm or more, and particularly preferably 6 mm or more. On the other hand, the upper limit is more preferably 20 mm or less, even more preferably 15 mm or less, and particularly preferably 10 mm or less.

[0021] The thickness of the tablet is not particularly limited, but is preferably 1.0 mm or more and 10 mm or less. The lower limit is more preferably 1.5 mm or more, even more preferably 2.0 mm or more, and particularly preferably 2.5 mm or more. On the other hand, the upper limit is more preferably 8 mm or less, and even more preferably 6 mm or less. By setting the size and thickness of the tablet within the above ranges, it is possible to make the tablet a preparation that is easy to take.

[0022] <(A) Useful substances> The useful substance is not particularly limited, and examples thereof include medicinal ingredients and functional ingredients used in pharmaceuticals, quasi-drugs, over-the-counter drugs, herbal medicines, natural medicines, cosmetics, health foods, supplements, and veterinary medicines. Specific examples of medicinal ingredients and functional ingredients include lipid regulators, antidiabetic agents, appetite suppressants, antihypertensive agents, vasodilators, β-adrenergic receptor blockers, cardiac ion channel agents, antiarrhythmic agents, anticoagulants, hemostatic agents, anti-inflammatory agents, analgesics, antiallergic agents, immunosuppressants, corticosteroids, steroids, antitumor agents, sympathomimetics, parasympathomimetics, antimuscarinic agonists, dopaminergic agents, antidiarrheals, antiemetics, sedatives, astringents, tranquilizers, antidepressants, antiepileptics, antianxiety agents, hypnotics, stimulants, bronchodilators, antitussives, diuretics, muscle relaxants, bisphosphonates, antibiotics, antiviral agents, diagnostic agents, imaging diagnostic agents, radiopharmaceuticals, rapidine, nobiletin, sulforaphane, ampelopsin, polymethoxyflavone, pyridoxine hydrochloride, riboflavin, Examples of such ingredients include quercetin glycosides, curcumins, resveratrols, geraniol, osajin, isoliquiritigenin, hydroxytyrosol, 25-hydroxycholecalciferol, coenzyme Q-10, S-adenosylmethionine, anthocyanins, ascorbic acid 2-glucoside, proteoglycans, N-acetylglucosamine, collagen, wisteria tea extract, bilberry extract, carrot powder, gokahi, licorice, peony, cinnamon bark, fennel, scutellaria, bifidobacteria, lactic acid bacteria, vitamins such as vitamin A, vitamin B, and vitamin C, minerals such as calcium, magnesium, and iron, dietary fiber such as polydextrose, polyphenols, proteins, amino acids, oligosaccharides, lecithin, carotenoids, and chlorophyll. Among these, wisteria tea extract, ampelopsin, polymethoxyflavone, pyridoxine hydrochloride, riboflavin, and quercetin glycosides are preferred. These medicinal ingredients and functional ingredients may be formulated singly or in combination of two or more.

[0023] <Chitosan> The tablet of the present invention contains chitosan. Chitosan has various physiological activities and is formulated to obtain these physiological activities, such as the suppression of fat absorption, the suppression of cholesterol elevation, and the suppression of blood pressure elevation.

[0024] Chitosan as used herein refers to a polysaccharide having a β-1,4-polyglucosamine structure as a basic unit. Chitosan can generally be obtained by deacetylating chitin, a polysaccharide having a 1,4-poly-N-acetylglucosamine structure as a basic unit.

[0025] Chitosan can generally be obtained by decalcifying and deproteinizing the carapace of crustaceans such as crabs, shrimp, and krill, the carapace of insects, or the bones of squid, and then deacetylating the resulting chitin. Chitosan can also be obtained from mushrooms and microorganisms. The chitosan used in the present invention may be chitosan obtained from any raw material, but chitosan obtained from the shells of crustaceans such as crabs and shrimp is preferred because its safety when ingested as food is clear and it is considered to be economically superior. Furthermore, the chitosan used in the composition of the present invention is preferably one whose safety when orally ingested by humans has been clear and which has a proven track record as a food additive, etc.

[0026] The average molecular weight of the chitosan used in the present invention is preferably 100,000 or more, more preferably 1,000,000 or more, from the viewpoint of the physiological activity of chitosan. The degree of deacetylation is preferably 50% or more, more preferably 65% ​​or more, and even more preferably 85% or more, from the viewpoint of the physiological activity of chitosan.

[0027] The molecular weight of chitosan can be measured by the GPC method using an aqueous GPC column. In addition, unless otherwise specified, the degree of deacetylation refers to the degree of deacetylation using a potassium polyvinyl sulfate solution. It can be measured by colloid titration method. The chitosan used in the present invention can be any commercially available food additive. Such a product is the food grade chitosan manufactured by Nippon Kayaku Food Techno Co., Ltd. An example is San (product name: Chitosamine, registered trademark).

[0028] The chitosan content in the tablet is not particularly limited as long as it is a content that allows the physiological activity of chitosan to be obtained, but is, for example, 1% by mass or more and 40% by mass or less. The lower limit is preferably 2% by mass or more, more preferably 5% by mass or more. The upper limit is preferably 30% by mass or less, more preferably 20% by mass or less. By keeping the chitosan content within the above range, the physiological activity of chitosan can be obtained more effectively.

[0029] <Other ingredients> The solid preparation may contain additives such as excipients, binders, disintegrants, lubricants, stabilizers, preservatives, fluidizing agents, and coloring agents, as needed.

[0030] The excipient is not particularly limited, and examples thereof include microcrystalline cellulose, lactose, sucrose, mannitol, glucose, starch, calcium phosphate, calcium sulfate, etc. These excipients may be used alone or in combination of two or more. The addition of an excipient can adjust the volume of the useful substance.

[0031] The binder is not particularly limited, and examples thereof include carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, macrogol, paraffin, gum arabic, gelatin, agar, starch, pullulan, etc. These binders may be blended alone or in combination of two or more. The addition of a binder imparts binding strength to the powder components, allowing the production of a stable solid preparation.

[0032] The disintegrant is not particularly limited, and examples thereof include corn starch, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, microcrystalline cellulose, croscarmellose sodium, carboxymethyl starch sodium, crosspolyvinylpyrrolidone, alginate, etc. These disintegrants may be used alone or in combination of two or more. The addition of a disintegrant can promote disintegration of the solid preparation and improve its absorbability.

[0033] The lubricant is not particularly limited, and examples thereof include talc, colloidal silica, magnesium stearate, calcium stearate, magnesium carbonate, sodium benzoate, palmitic acid, sodium stearyl fumarate, waxes, hydrogenated vegetable oils, fats, polyethylene glycol, etc. These lubricants may be blended alone or in combination of two or more. Addition of a lubricant can prevent tableting problems such as sticking during tablet production. [Example]

[0034] Hereinafter, examples of the present invention will be described, but the present invention is not limited to these examples, and various modifications are possible within the technical concept of the present invention.

[0035] (1) Test 1: Effect of chitosan on the release of useful substances from tablets The effect of chitosan concentration on the dissolution of useful substances in tablets containing useful substances and chitosan was evaluated by manufacturing plain tablets of Test Examples 1 to 6 shown in Table 2 and conducting dissolution tests. In this test, wisteria tea extract containing ampelopsin was used as the useful substance. The raw materials used in the examples are shown in Table 1 below.

[0036] [Table 1]

[0037] (Regular tablet manufacturing) The regular tablets of Test Examples 1 to 6 were produced according to the following procedure. The powder compositions shown in Table 2 were mixed for 10 minutes to prepare powder for tableting. The powder for tableting was compressed into regular tablets with a diameter of approximately 8 mm and a weight of 300 mg using a single punch tableting machine (Okada Seiko Co., Ltd.) with a punch size of φ8 mm, R10, and a tableting pressure of 1000 kgf.

[0038] [Table 2]

[0039] (Dissolution test) The produced preparation was subjected to a dissolution test using NTR-6400A (manufactured by Toyama Sangyo Co., Ltd.) according to the paddle method of the dissolution test method of the general test method of the Japanese Pharmacopoeia. The volume of the test solution (Japanese Pharmacopoeia Dissolution Test Solution 1 (pH 1.2)) was 900 mL, and 200 μL of the dissolution test solution was sampled at 0, 10, 20, 30, 40, 60, 90, and 120 minutes after the start of the test, with the paddle rotating at 50 rpm. The eluted concentration of ampellopsin (AMP) contained in the wisteria tea extract eluted from the tablets contained in the measurement sample was calculated from the absorbance at 290 nm using a UV measuring device UV-1800 (manufactured by Shimadzu Corporation).

[0040] As a result of the test, as shown in Figure 1, it was confirmed that chitosan, especially chitosan at a content of 2.8 mass % or more, significantly reduces the dissolution of useful substances blended together in the tablet.

[0041] (2) Test 2: Effect of gelling agents other than chitosan on the dissolution of useful substances from tablets Regarding the effect of chitosan and gelling agents other than chitosan on the dissolution of useful substances, the ordinary tablets of Test Examples 7 and 8 shown in Table 3 were produced by the same method as in Test 1 in Test Examples 1 and 5, and evaluated by a dissolution test similar to Test 1.

[0042] [Table 3]

[0043] As a result of the test, as shown in Figure 2, it was confirmed that chitosan significantly reduced the dissolution of useful substances when combined with other gelling substances.

[0044] (3) Test 3: Effect of dosage form on dissolution Three types of formulations (layered tablets, regular tablets, and hard capsules) were used to manufacture the formulations and evaluate the effect on the dissolution of useful substances through dissolution tests.Layered tablets and hard capsules were manufactured according to the following manufacturing methods.

[0045] (Hard capsule manufacturing) Hard capsules were prepared according to the following procedure. The raw materials in Table 4 (Test Example 9) were weighed and mixed for 10 minutes in a V-type mixer (Tsutsui Scientific Instruments: micro-type see-through mixer), and then calcium stearate was added and mixed for 5 minutes to obtain a powder composition for capsule filling. Next, a capsule filling machine (ProFiller 1100 (Capsugel)) was used to fill No. 2 HPMC capsules with 255 mg of the powder composition per capsule to obtain hard capsules.

[0046] [Table 4]

[0047] (Layered tablet manufacturing) Layered tablets were prepared according to the following procedure. The powder compositions for the first and second layers, each having the composition shown in Table 5, were mixed for 10 minutes to prepare powders for tableting for the first and second layers. Tableting was performed using a single-punch tableting machine (manufactured by Okada Seiko Co., Ltd.) with a punch size of φ8 mm and R10. Specifically, the powder for tableting for the first layer was compressed at a tableting pressure of 50 kgf, and then the powder for tableting for the second layer was added and compressed at a tableting pressure of 1000 kgf to obtain layered tablets with a diameter of approximately 8 mm and a weight of 300 mg.

[0048] [Table 5]

[0049] (Dissolution test) The produced preparation was subjected to a dissolution test using NTR-6400A (manufactured by Toyama Sangyo Co., Ltd.) according to the paddle method of the dissolution test method of the general test method of the Japanese Pharmacopoeia. The volume of the test solution (Japanese Pharmacopoeia Dissolution Test Solution 1 (pH 1.2)) was 900 mL, and 200 μL of the dissolution test solution was sampled at 0, 10, 20, 30, 40, 60, 90, and 120 minutes after the start of the test, with the paddle rotating at 50 rpm. The concentration of eluted ampelopsin eluted from the tablets contained in the measurement sample was calculated from the absorbance at 290 nm using a UV measuring device UV-1800 (Shimadzu Corporation). The amount of chitosan dissolved from the tablets contained in the measurement sample was measured using a chitosan assay kit (manufactured by CELL BIOLABS, INC.) according to the manufacturer's manual.

[0050] As a result of the test, as shown in Figure 3, higher dissolution of useful substances was confirmed in Test Example 10, which was a layered tablet, compared to Test Example 5, which was a regular tablet, and Test Example 9, which was a hard capsule. Furthermore, as shown in Figure 4, it was confirmed that higher dissolution of chitosan was obtained in Test Example 10, which was a layered tablet, compared to Test Example 5, which was a regular tablet, and Test Example 9, which was a hard capsule. This indicates that the layered tablet can be used to produce a formulation with high bioavailability of useful substances and chitosan.

[0051] (4) Test 4: Effect of dosage form on administration to living organisms The formulations of Test Examples 5, 9, and 10 produced in Test 3 were administered to humans according to the following procedure, and a clinical trial was conducted to evaluate the changes in blood concentration and pharmacokinetics of the useful substance after administration. The pharmacokinetic parameters (drug blood concentration (AUC), time to reach maximum blood concentration (Tmax), maximum blood concentration (Cmax)) obtained from the test are shown in Table 6. Analysis of variance (ANOVA) was performed for each of the layered tablet results, followed by a Tukey-Kramer test.

[0052] (Clinical trial) The test was conducted as an open-label, randomized, three-drug, phase III Latin square crossover trial on 9 subjects (3 subjects × 3 groups). For subjects in a fasting state for 10 hours or more, fasting blood samples were collected before drug administration (0 minutes), and then 4 capsules or 4 tablets of each drug (154.6 mg as ampelopsin and 133.6 mg as chitosan) were administered to the subjects together with 200 mL of water. After drug administration, blood samples were collected at 30 minutes, 60 minutes, 120 minutes, 180 minutes, and 240 minutes to obtain serum samples from the subjects.

[0053] (Analysis of serum samples) The serum samples collected in the clinical trial were analyzed for the amount of ampelopsin, a useful component of Ampelopsis grossedentata, according to the following procedure. First, as a pretreatment of the serum, 100 μL of serum was dissolved, 100 μL of enzyme solution (Sulfatase Type H-1 4 mg / mL, 0.1 M sodium acetate buffer) was added, and incubated at 37 °C for 1 hour for glucuronide conjugation treatment. Next, solid-phase extraction plates (96-well plate STRATA-X 10 mg, manufactured by Shimadzu GL Sciences Inc.) were used to perform protein precipitation treatment according to the manufacturer's manual to obtain measurement samples. LC / MSMS analysis was performed on the measurement samples under the following conditions. <LC / MSMS analysis conditions> LC conditions (Method: DMY) Column: ACQUITY UPLC HSST3 1.8 μm 2.1×100 mm Column temperature: 40 °C Mobile phase: Solution A (0.1% aqueous formic acid): Solution B (acetonitrile containing 0.1% formic acid) = 88:12 Flow rate: 0.4 mL / min<t Injection volume: 2 μL

[0054] [Table 6]

[0055] As shown in Figures 5 and 6 and Table 6, the results of the study confirmed that the layered tablet significantly improved the blood drug concentration (AUC) of the useful substance when administered to humans compared with regular tablets and hard capsules (vs. hard capsules: P = 0.0054, vs. regular tablets: P = 0.036). At each blood sampling time point, the layered tablet showed significantly higher blood concentrations of the useful substance at 30, 60, and 120 minutes after ingestion than the hard capsule, and at 120 minutes after ingestion for the regular tablet (P < 0.05). A significant increase in maximum blood concentration (Cmax) was also confirmed (vs. hard capsules, vs. regular tablets: P < 0.05).

[0056] (5) Test 5: The effect of chitosan when other types of useful substances are used and the effect of layered tablets Preparations with the compositions shown in Tables 7 and 8 containing five useful substances other than the wisteria tea extract containing ampelopsin used in Experiments 1 to 3, namely polymethoxyflavone, pyridoxine hydrochloride, riboflavin, quercetin glycoside, and curcumin, were manufactured in the same manner as Experiment 3. The inhibition of dissolution of the useful substances by chitosan and the effect of layered tablets were evaluated using the dissolution test described below. The useful substances in Tables 7 and 8 represent either polymethoxyflavone, pyridoxine hydrochloride, riboflavin, or quercetin glycoside or curcumin.

[0057] [Table 7]

[0058] [Table 8]

[0059] (Dissolution test) The produced preparation was subjected to a dissolution test using NTR-6400A (manufactured by Toyama Sangyo Co., Ltd.) according to the paddle method of the dissolution test method of the general test method of the Japanese Pharmacopoeia. The volume of the test solution (Japanese Pharmacopoeia Dissolution Test Solution 1 (pH 1.2)) was 900 mL, and 200 μL of the dissolution test solution was sampled at 0, 10, 20, 30, 40, 60, 90, and 120 minutes after the start of the test, with the paddle rotating at 50 rpm. The concentrations of useful substances dissolved from the tablets contained in the measurement samples were calculated from the absorbance at the wavelengths set for each useful substance (polymethoxyflavone: 260 nm, riboflavin: 267 nm, pyridoxine hydrochloride: 290 nm, quercetin glycoside: 370 nm) using a UV measuring device UV-1800 (Shimadzu Corporation).

[0060] As a result of the test, as shown in Figure 7, of the five useful substances tested, polymethoxyflavone, pyridoxine hydrochloride, riboflavin, and quercetin glycoside were also observed to have their dissolution inhibited by chitosan and improved by forming them into layered tablets, just like ampelopsin.

[0061] (6) Test 6: Examination of layer ratio in layered tablets In order to investigate the appropriate ratio of each layer in a layered tablet containing a useful substance and chitosan, layered tablets were manufactured with varying ratios of the first layer containing the useful substance and the second layer containing chitosan, and the effect on the dissolution of the useful substance was evaluated.

[0062] (Layered tablet manufacturing) Layered tablets of Test Examples 11 to 13 were produced in the following manner, with the ratio of the first layer containing a useful substance to the second layer containing chitosan being 1:1, 2:1, or 4:1. The powder compositions for the first and second layers, each having the composition shown in Table 9, were mixed for 10 minutes to prepare powders for tableting for the first and second layers. Tableting was performed using a single-punch tableting machine (manufactured by Okada Seiko Co., Ltd.) with a punch size of φ8 mm and R10. Specifically, the powder for tableting for the first layer was compressed at a tableting pressure of 50 kgf, and then the powder for tableting for the second layer was added and compressed at a tableting pressure of 1000 kgf to obtain layered tablets with a diameter of approximately 8 mm and a weight of 300 mg.

[0063] [Table 9]

[0064] (Dissolution test) Each of the produced preparations was subjected to a dissolution test using NTR-6400A (manufactured by Toyama Sangyo Co., Ltd.) according to the paddle method of the dissolution test method in the general test method of the Japanese Pharmacopoeia. The volume of the test solution (Japanese Pharmacopoeia Dissolution Test Solution 1 (pH 1.2)) was 900 mL, and 200 μL was sampled from the dissolution test solution 60 minutes after the start of the test at a paddle rotation speed of 50 rpm. The concentration of eluted ampelopsin eluted from the tablets contained in the measurement sample was calculated from the absorbance at 290 nm using a UV measuring device UV-1800 (Shimadzu Corporation). The amount of chitosan dissolved from the tablets contained in the measurement sample was measured using a chitosan assay kit (manufactured by CELL BIOLABS, INC.) according to the manufacturer's manual. The amount of dissolved chitosan was shown assuming that the amount dissolved from the layered tablets (1:1) was 100%.

[0065] As a result of the test, as shown in Figure 8, the layered tablets of Test Example 12, in which the ratio of the second layer containing chitosan to the first layer containing a useful substance was 2:1, and Test Example 13, in which the ratio was 4:1, showed improved dissolution of the useful substance compared to Test Example 11, in which the ratio was 1:1. In particular, a significant improvement in dissolution of the useful substance was confirmed in Test Example 13, in which the ratio was 4:1. [Industrial Applicability]

[0066] The present invention provides a tablet containing chitosan and other useful substances, which has improved bioavailability of the other useful substances blended with chitosan. The present invention can be utilized in various fields, such as pharmaceuticals, quasi-drugs, veterinary products, foods, and supplements.

Claims

1. A tablet comprising multiple layers containing (A) a useful substance and (B) chitosan, the plurality of layers are layers formed from respective powder compositions, (B) containing chitosan as an active ingredient, The content of the (B) chitosan is 1% by mass or more and 40% by mass or less, the component (A) and the component (B) are contained in separate layers, The tablet is a layered tablet or a press-coated tablet, A tablet, characterized in that the separate layers are different stacked layers in the layered tablet, or different layers constituting the inner core and outer shell in the dry-coated tablet.

2. The tablet according to claim 1, characterized in that the (A) useful substance is one or more selected from the group consisting of wisteria tea extract, ampelopsin, polymethoxyflavone, pyridoxine hydrochloride, riboflavin, and quercetin glycoside.

3. 3. The tablet according to claim 1, wherein the ratio (B / A) of the mass of the layer containing component (B) to the mass of the layer containing component (A) in the tablet is 0.1 or more and 1.0 or less.

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