JP7779673B2 - tablet - Google Patents

Description

The present invention relates to a tablet containing chitosan and a useful substance. More specifically, it relates to a tablet containing chitosan and a useful substance and formed from multiple layers.

Chitosan is an animal-derived dietary fiber obtained by alkaline 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 range of physiological functions, including inhibiting fat absorption, lowering cholesterol levels, and lowering blood pressure, and has been widely used in recent years in the pharmaceutical and health food fields.

For example, Patent Document 1 describes an agent for suppressing obesity and lifestyle-related diseases that contains chitosan and an active ingredient extracted from the legume Cassia capillaris with water or an organic solvent such as alcohol.

Patent Document 2 also describes a health food composition containing a component that inhibits digestive enzyme activity, a mushroom chitosan complex polysaccharide component, and a component that regulates mineral balance, promotes insulin production, and activates insulin receptors.

Japanese Patent Application Laid-Open No. 2005-343808 Japanese Patent Application Laid-Open No. 2006-20606

As can be seen in the patent documents cited above, when chitosan is incorporated into a formulation, it is common for other useful substances to be incorporated as well. However, as a result of experiments conducted by the present inventors, it was confirmed that when a formulation containing chitosan and other useful substances is administered to a living body, the absorption of the other useful substances incorporated together is inhibited in the body, and it was further confirmed that this problem is caused by chitosan inhibiting the elution of the other useful substances. It was also confirmed that the elution of chitosan itself is inhibited when other useful substances are incorporated together.

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 original 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.

The present invention was made based on the above findings, and the objective of the present invention is to provide a tablet containing chitosan and other useful substances that improves the dissolution of chitosan and the other useful substances blended therewith.

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.

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 described in [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 the component (B) to the mass of the layer containing the 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], characterized in that 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.

The present invention provides tablets containing chitosan and other useful substances that exhibit improved dissolution of the chitosan and other useful substances.

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. 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. 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. 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. 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. 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. 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. 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.

[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.

The tablets of the present invention contain 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 in that the absorption of the other useful substances in the body is suppressed. Furthermore, the inventors have confirmed that this problem is caused by 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 absorption in the body. Furthermore, the dissolution of chitosan itself is also improved, thereby improving the bioavailability of the useful substance and chitosan.

<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 additional layers 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" refers to a content of 0.5% by mass or less in each layer.

Tablets formed from multiple layers include, but are not limited to, layered tablets and dry-coated tablets. When administered to a living body, these multi-layered tablets disintegrate without the layers formed from each powder composition mixing, thereby suppressing the interaction between the useful substance and chitosan. While this effect can be achieved with any tablet formed from multiple layers, layered tablets are formed by simply stacking two or more layers formed from each powder composition. Because the layers are not mixed together, such as by wrapping one over the other, the interaction between the useful substance and chitosan can be further suppressed, resulting in a significant effect.

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 a continuous tableting operation using a single tablet press. The above manufacturing method can also be performed by omitting the tableting step after filling the lower layer, and instead filling the lower layer material, and then filling the upper layer material, followed by tableting. The upper and lower layers can be either the first layer containing a useful substance or the second layer containing chitosan.

In the tablet of the present invention, the ratio of the mass of the layer containing component (B) to the mass of the layer containing component (A) in the tablet (B/A) 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, and 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.

The shape of the tablets is not particularly limited, and examples include round tablets, oval tablets, and flower-shaped tablets. Furthermore, the tablets can be provided with one or two scoring lines to divide them into two or four pieces, if necessary.

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.

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, 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.

<(A) Useful substance>
The useful substance is not particularly limited, and examples thereof include medicinal ingredients and functional ingredients used in pharmaceuticals, quasi-drugs, over-the-counter (OTC) pharmaceuticals, 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 ginseng, quercetin glycosides, curcumins, resveratrols, geraniol, osajin, isoliquiritigenin, hydroxytyrosol, 25-hydroxycholecalciferol, coenzyme Q-10, S-adenosylmethionine, anthocyanin, ascorbic acid 2-glucoside, proteoglycan, 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.

<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.

In the present invention, chitosan refers to a polysaccharide whose basic unit is a β-1,4-polyglucosamine structure. Chitosan can generally be obtained by deacetylating chitin, a polysaccharide whose basic unit is a 1,4-poly-N-acetylglucosamine structure.

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.

From the viewpoint of the physiological activity of chitosan, the average molecular weight of the chitosan used in the present invention is preferably 100,000 or more, and 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.

The molecular weight of chitosan can be measured by GPC using an aqueous GPC column. Unless otherwise specified, the degree of deacetylation can be measured by colloid titration using a polyvinyl potassium sulfate solution.
The chitosan used in the present invention can be any commercially available food additive-grade chitosan, such as food-grade chitosan (product name: Chitosamine, registered trademark) manufactured by Nippon Kayaku Food Techno Co., Ltd.

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, and more preferably 5% by mass or more. The upper limit is preferably 30% by mass or less, and 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.

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

The excipient is not particularly limited, and examples 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 bulk of the useful substance.

Binders are not particularly limited, and examples 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, and pullulan. These binders may be used alone or in combination of two or more. Adding a binder provides binding strength to the powder ingredients, allowing for the production of a stable solid formulation.

Disintegrants are not particularly limited, and examples 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. Addition of a disintegrant can promote disintegration of the solid preparation and improve its absorbability.

Lubricants are not particularly limited, and examples include talc, colloidal silica, magnesium stearate, calcium stearate, magnesium carbonate, sodium benzoate, palmitic acid, sodium stearyl fumarate, waxes, hydrogenated vegetable oils, fats, and polyethylene glycol. These lubricants may be used alone or in combination of two or more. Adding a lubricant can prevent tableting problems such as sticking during tablet production.

The following describes examples of the present invention, but the present invention is not limited to these examples, and various modifications are possible within the technical concept of the present invention.

(1) Test 1: Effect of chitosan on the dissolution 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 regular tablets of Test Examples 1 to 6 shown in Table 2 and conducting a dissolution test. 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.

(Manufacturing of ordinary tablets)
The ordinary 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.

(Dissolution test)
The prepared preparation was subjected to a dissolution test using NTR-6400A (manufactured by Toyama Sangyo Co., Ltd.) according to the paddle method of the general dissolution 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 each was sampled from the dissolution test solution at a paddle rotation speed of 50 rpm at 0, 10, 20, 30, 40, 60, 90, and 120 minutes after the start of the test.
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).

As shown in Figure 1, the test results confirmed that chitosan, especially chitosan at a content of 2.8% by mass or more, significantly reduces the dissolution of useful substances incorporated into the tablet.

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

As shown in Figure 2, the test results confirmed that, compared to other gelling substances, chitosan significantly reduced the dissolution of useful substances when combined with it.

(3) Test 3: Effect of dosage form on dissolution Three types of dosage forms (layered tablets, regular tablets, and hard capsules) were used to prepare formulations, and the effect of the formulations on the dissolution of useful substances was evaluated by dissolution tests. Layered tablets and hard capsules were prepared according to the following manufacturing method.

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

(Manufacture of layered tablets)
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.

(Dissolution test)
The prepared preparation was subjected to a dissolution test using NTR-6400A (manufactured by Toyama Sangyo Co., Ltd.) according to the paddle method of the general dissolution 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 each was sampled from the dissolution test solution at a paddle rotation speed of 50 rpm at 0, 10, 20, 30, 40, 60, 90, and 120 minutes after the start of the test.
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 instrument UV-1800 (manufactured by 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.

As a result of the test, as shown in Figure 3, it was confirmed that Test Example 10, which was a layered tablet, had a higher dissolution rate of the useful substance than 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 with Test Example 5, which was a regular tablet, and Test Example 9, which was a hard capsule. This indicates that by forming a layered tablet, a preparation with high bioavailability of useful substances and chitosan can be obtained.

(4) Test 4: Effect of Dosage Forms 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 change in blood concentration of the useful substance after administration and the pharmacokinetics according to the following procedure. The pharmacokinetic parameters (drug blood concentration (AUC), time to reach maximum blood concentration (Tmax), maximum blood concentration (Cmax)) obtained as a result of the test are shown in Table 6. Analysis of variance (ANOVA) was performed on each result of the layered tablets, followed by a Tukey-Kramer test.

(Clinical trials)
The study was an open-label, randomized, three-drug, three-period Latin square crossover study involving nine subjects (three subjects x three groups). Subjects were fasted for at least 10 hours, and a fasting blood sample (0 minutes) was taken before administration. Four capsules or four tablets of each formulation (154.6 mg of ampelopsin and 133.6 mg of chitosan) were then administered with 200 mL of water. Blood samples were then taken 30, 60, 120, 180, and 240 minutes after administration to obtain serum samples.

(Serum sample analysis)
Serum samples collected during clinical trials were analyzed for the amount of ampelopsin, a useful component of wisteria tea, using the following procedure.
First, as a serum pretreatment, 100 uL of serum was dissolved, 100 uL of enzyme solution (4 mg/mL Sulfatase Type H-1, 0.1 M sodium acetate buffer) was added, and the mixture was incubated at 37°C for 1 hour to perform deglucuronidation. Next, a deproteinization treatment was performed using a solid phase extraction plate (96-well plate STRATA-X 10 mg, manufactured by Shimadzu GLC) according to the manufacturer's manual to obtain a measurement sample. The measurement sample was subjected to LC/MSMS analysis 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% formic acid aqueous solution): Solution B (0.1% formic acid-containing acetonitrile) = 88:12
Flow rate: 0.4 mL/min Injection volume: 2 μL

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

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

(Dissolution test)
The prepared preparation was subjected to a dissolution test using NTR-6400A (manufactured by Toyama Sangyo Co., Ltd.) according to the paddle method of the general dissolution 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 each was sampled from the dissolution test solution at a paddle rotation speed of 50 rpm at 0, 10, 20, 30, 40, 60, 90, and 120 minutes after the start of the test.
The concentrations of useful substances dissolved from the tablets contained in the measurement samples were calculated from the absorbance at wavelengths set for each useful substance (polymethoxyflavone: 260 nm, riboflavin: 267 nm, pyridoxine hydrochloride: 290 nm, quercetin glycoside: 370 nm) using a UV measuring instrument UV-1800 (Shimadzu Corporation).

As shown in Figure 7, the test results showed that, of the five useful substances tested, polymethoxyflavone, pyridoxine hydrochloride, riboflavin, and quercetin glycoside also showed inhibition of dissolution by chitosan and improvement of dissolution by forming layered tablets, just as with ampelopsin.

(6) Test 6: Investigation 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.

(Manufacture of layered tablets)
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.

(Dissolution test)
Each of the prepared preparations was subjected to a dissolution test using NTR-6400A (manufactured by Toyama Sangyo Co., Ltd.) according to the paddle method of the general dissolution 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 instrument UV-1800 (manufactured by 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 of dissolved chitosan from the layered tablets (1:1) was 100%.

As shown in Figure 8, the test results confirmed that the layered tablets of Test Example 12, in which the ratio of the first layer containing the useful substance to the second layer containing chitosan 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, Test Example 13, in which the ratio was 4:1, showed a significant improvement in dissolution of the useful substance.

The present invention provides tablets containing chitosan and other useful substances, in which the other useful substances blended with chitosan are more easily absorbed by the body. The present invention can be used in a variety of fields, including pharmaceuticals, quasi-drugs, veterinary products, foods, and supplements.

Claims (3)

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