Solid preparation

Abstract

To provide a solid preparation containing a culture extract of Bacillus subtilis var. natto, with suppressed absorption of moisture.SOLUTION: By blending (B) ang-khak and / or a processed product thereof into a solid preparation containing (A) a culture extract of Bacillus subtilis var. natto, it is possible to suppress moisture absorption of the solid preparation.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a solid preparation containing a Bacillus natto culture extract, while suppressing moisture absorption.

Background Art

[0002] Nattokinase is an enzyme produced during the fermentation of soybeans by Bacillus natto and is known to have a thrombolytic effect. For the purpose of enjoying the excellent health effects of nattokinase, health foods containing a Bacillus natto culture extract, which is a material rich in nattokinase, are on the market.

[0003] The Bacillus natto culture extract is, in essence, a Bacillus natto culture, and can be obtained by subjecting the culture solution obtained by culturing Bacillus natto to appropriate concentration and / or appropriate treatment as required. Since Bacillus natto co-produces vitamin K2, which is a blood coagulation factor, along with nattokinase, which is a thrombolytic factor, methods for producing a Bacillus natto culture extract with reduced vitamin K2 (Patent Documents 1 and 2) are also known.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] The nattokinase culture extract powder is hygroscopic. For example, the nattokinase culture extract powder or a powder containing the same will come into contact with water vapor in the air and form lumps due to moisture absorption even in a normal storage environment, provided that the storage environment is not an open system. Among the granulated products, tablets, and capsules containing the nattokinase culture extract powder, although there are some dosage forms in which lumps cannot be visually recognized, since the opportunity to come into contact with water vapor in the air cannot be completely eliminated, they will naturally absorb moisture in the same way as when confirmed as lumps in powder form. In order to preserve the enzyme activity of nattokinase and maximize its usefulness, it is desirable to suppress the moisture absorption of solid preparations containing the nattokinase culture extract powder.

[0006] Therefore, an object of the present invention is to provide a solid preparation containing a nattokinase culture extract, which is suppressed in moisture absorption.

Means for Solving the Problems

[0007] Since other active ingredients are often blended together in health foods, in order to enable more efficient intake of the blended active ingredients, it is desirable to take moisture absorption countermeasures without relying on additives other than the active ingredients. As a result of intensive studies, the present inventor has found that by blending red yeast rice and / or its processed product in a solid preparation containing a nattokinase culture extract, the moisture absorption of the solid preparation can be suppressed. Further, as a result of further intensive studies, it has also been found that by blending red yeast rice and / or its processed product in a solid preparation containing a nattokinase culture extract, discoloration due to the nattokinase culture extract can be suppressed. The present invention has been completed by further studies based on these findings.

[0008] That is, the present invention provides an invention in the following aspects. Item 1. A solid preparation containing (A) a nattokinase culture extract and (B) red yeast rice and / or its processed product, wherein 0.8 to 10 parts by weight of the (B) component is contained per 1 part by weight of the (A) component. Item 2. The solid preparation according to Item 1, containing 3 to 40% by weight of the (A) component. Item 3. A method for suppressing moisture absorption of a solid preparation containing a Bacillus natto culture extract, wherein in the solid preparation, (B) red yeast rice and / or its processed product is blended together with the component (A). A method for suppressing moisture absorption. Item 4. A method for suppressing discoloration of a solid preparation containing a Bacillus natto culture extract, wherein in the solid preparation, (B) red yeast rice and / or its processed product is blended together with the component (A). A method for suppressing discoloration.

Advantages of the Invention

[0009] According to the present invention, there is provided a solid preparation containing red yeast rice and / or its processed product, and the discoloration of the solid preparation is suppressed.

Embodiments for Carrying Out the Invention

[0010] 1. Solid preparation The solid preparation of the present disclosure is characterized by containing (A) a Bacillus natto culture extract (hereinafter also referred to as “component (A)”) and (B) red yeast rice and / or its processed product (hereinafter also referred to as “component (B)”). The solid preparation of the present disclosure has suppressed moisture absorption. Further, the solid preparation of the present disclosure has also suppressed discoloration. Hereinafter, the solid preparation of the present disclosure will be described in detail.

[0011] 1-1. (A) Natto bacteria culture extract The solid preparation of the present disclosure contains a Bacillus natto culture extract as the component (A). Although the Bacillus natto culture extract causes problems of moisture absorption and discoloration, the solid preparation of the present disclosure suppresses these moisture absorption and discoloration.

[0012] The Bacillus natto culture extract is a material that can be blended into a food composition, contains nattokinase, and is known as a blood flow improver, a thrombolytic agent, etc.

[0013] As the Bacillus natto used for producing the Bacillus natto culture extract, known microorganisms can be used without particular limitation, and typically Bacillus subtilis natto can be mentioned.

[0014] The medium used for culturing Bacillus natto is not particularly limited, but is not particularly limited as long as it is edible and enables the production of nattokinase by Bacillus natto. Carbon sources such as starch (e.g., corn starch), glucose, sucrose, etc.; nitrogen sources such as defatted soybeans, meat extract, etc.; inorganic salts such as calcium carbonate, magnesium chloride, etc.; and a medium containing fatty acids, etc. as required can be used.

[0015] The nattokinase culture extract can be obtained by subjecting the culture solution obtained by culturing Bacillus natto to a treatment for reducing or removing vitamin K2 as required (contact with an inorganic flocculant, a cationic polymer flocculant, and / or chitosan), and then subjecting it to a purification treatment (filtration, chromatography, etc.) to increase the content concentration of nattokinase and removing water to obtain a dry powder.

[0016] The content of nattokinase contained in the nattokinase culture extract is, for example, 20,000 FU or more, preferably 25,000 FU or more, more preferably 30,000 FU or more, and still more preferably 35,000 FU or more per 1 g (dry weight) of the nattokinase culture extract. The content of nattokinase contained in the nattokinase culture extract is not particularly limited even at its upper limit, but examples include 70,000 FU or less, 60,000 FU or less, 50,000 FU or less, or 45,000 FU or less.

[0017] In addition, in this specification, the activity (FU) of nattokinase is measured by a method of allowing nattokinase to act on fibrin and measuring the amount of acid-soluble low-molecular-weight degradation products that increase with the degradation of fibrin by measuring the absorbance at ultraviolet light (275 nm).

[0018] The specific method for measuring the activity of nattokinase is as follows. In a test tube, measure 1.4 ml of 50 mM borate buffer and 0.4 ml of an aqueous fibrinogen solution [prepared by dissolving an amount equivalent to 72 mg of fibrinogen in 10 ml of 50 mM borate buffer (pH 8.5, containing 150 mM NaCl), 0.72% aqueous fibrinogen solution]. After heating in a constant temperature water bath at 37°C ± 0.3°C for 5 minutes, add 0.1 ml of a thrombin solution [thrombin dissolved in 50 mM borate buffer, prepared at a concentration of 1000 U / ml, and diluted 50-fold (i.e., 20 U / ml) with the same borate buffer at the time of use], and stir. After leaving the mixture in this constant temperature water bath for 10 minutes, add 0.1 ml of the sample solution to the mixture, stir for 5 seconds, and leave it in the constant temperature water bath. 20 minutes and 40 minutes after adding the sample solution, stir for 5 seconds each, and after 60 minutes, add 2 ml of 0.2 M trichloroacetic acid solution, stir, and leave it for another 20 minutes. Centrifuge this reaction solution at 15,000×g for 5 minutes, and measure the absorbance (Ar) at 275 nm of the supernatant. On the other hand, measure 1.4 ml of 50 mM borate buffer and 0.4 ml of the above-mentioned aqueous fibrinogen solution, heat in a constant temperature water bath at 37°C ± 0.3°C for 5 minutes, then add 0.1 ml of the above-mentioned thrombin solution, and stir. After leaving the mixture in this constant temperature water bath for 10 minutes, add 2 ml of 0.2 M trichloroacetic acid solution to the mixture and stir. Next, add 0.1 ml of the sample solution, stir, and leave it for 20 minutes. Centrifuge this reaction solution at 15,000×g for 5 minutes, measure the absorbance (Ac) at 275 nm of the supernatant, and use it as a control. Based on the following formula (D is the dilution factor), derive the nattokinase activity A. A (FU / ml) = {(Ar - Ac) / (0.01×60×0.1)}×D

[0019] The content of vitamin K2 in the natto bacteria culture extract is not particularly limited, but in terms of the amount per 1 g (dry weight) of the natto bacteria culture extract, for example, 100 μg or less, preferably 50 μg or less, more preferably 10 μg or less, still more preferably 1 μg or less, even more preferably 0.5 μg or less, and particularly preferably 0.1 μg or less can be mentioned.

[0020] For the natto bacillus culture extract, commercially available products can also be used. For example, the natto bacillus culture extract is sold as "Natto Bacillus Culture Extract NSK-SD" (manufactured by Nippon Bioscience Laboratory Co., Ltd.), and these commercial products can also be used in the solid preparations of the present disclosure.

[0021] As the content of the component (A) contained in the solid preparation of the present disclosure, for example, 3 to 40% by weight, preferably 5 to 40% by weight or 6 to 40% by weight, more preferably 7 to 40% by weight, still more preferably 9 to 40% by weight, 9 to 35% by weight, 9 to 20% by weight, 9 to 15% by weight, or 9 to 12% by weight can be mentioned.

[0022] 1-2. (B) Red yeast rice and / or its processed products The solid preparation of the present disclosure contains red yeast rice and / or its processed product as the component (B). In the solid preparation of the present disclosure, the component (B) suppresses the moisture absorption and discoloration of the component (A).

[0023] Red yeast rice is koji obtained by attaching Monascus purpureus to grains and fermenting them.

[0024] The Monascus purpureus used for the production of red yeast rice may be any filamentous fungus belonging to the family Monascaceae. Examples of the filamentous fungi belonging to the family Monascaceae include filamentous fungi belonging to the genus Monascus and the genus BasIpetospora, and preferably the genus Monascus.

[0025] Examples of filamentous fungi belonging to the genus Monascus include, for example, Monascus pilosus, Monascus purpureus, Monascus pubigerus, Monascus anka, Monascus serorubescens, Monascus rubellus, Monascus kaoliang, Monascus rubiginosus, Monascus major, Monascus ruber, Monascus paxii, Monascus fuliginosus, Monascus vitreus, Monascus barkeri, Monascus sp., their varieties or mutants. The red yeast rice used in the present disclosure may be produced using one type of Monascus or a combination of two or more types of Monascus. Among these Monascus, Monascus pilosus is preferably mentioned.

[0026] The types of grains used as raw materials for red yeast rice are not particularly limited as long as they are edible and can be fermented by Monascus. Examples include rice such as white rice and brown rice; wheat, barley, rye, oats and other cereals, soybeans (white soybeans, black soybeans, green soybeans, etc.), defatted soybeans thereof, and beans such as their hypocotyls. The red yeast rice used in the present disclosure may be produced using one type of grain or a combination of two or more types of grains. Among these grains, rice is preferably used, and white rice is more preferably used.

[0027] Red yeast rice can be produced by a conventional method using Monascus and grains. Specifically, red yeast rice can be produced by inoculating Monascus into cooked (boiled or steamed) grains and statically culturing them under aerobic conditions at about 20 to 40°C. Further, the grains used as raw materials may be subjected to fine cutting or pulverization treatment before or after cooking, if necessary.

[0028] (B) As the component, the red yeast rice after fermentation may be used as it is, or a processed product of red yeast rice that has been subjected to one or more treatments such as heating, drying, crushing, grinding, milling, extraction, etc. after fermentation may also be used.

[0029] Specific examples of the processed product of red yeast rice include dried products such as dried red yeast rice, powdered dried red yeast rice, fine-grained dried red yeast rice, and powdered red yeast rice extract; red yeast rice paste; red yeast rice extract (including concentrated extract), etc. Among these processed products of red yeast rice, dried products are preferably used, powdered dried red yeast rice is more preferably used, fine-grained dried red yeast rice is even more preferably used, and powdered dried red yeast rice is even more preferably used. Also, the Monascus bacteria and enzymes contained in the processed product of red yeast rice may be viable bacteria or in a state where their activity is maintained, or may have been inactivated by heat treatment or the like.

[0030] For the processed product of red yeast rice, commercially available products can also be used. For example, the powdered product of dried rice red yeast rice is sold under the trade names "V. Red Yeast Rice 3P-D" and "V. Red Yeast Rice 3P-D20" (both manufactured by Kobayashi Value Support Co., Ltd.), and these commercial products can also be used in the solid preparations of the present disclosure.

[0031] In the solid preparation of the present disclosure, the content of the (B) component is 0.8 to 10 parts by weight as the content of the (B) component per 1 part by weight of the (A) component. From the viewpoint of enhancing the moisture absorption suppression effect and / or the discoloration suppression effect, the preferable content of the (B) component per 1 part by weight of the (A) component is 1 to 10 parts by weight, more preferably 1.1 to 10 parts by weight, even more preferably 1.2 to 10 parts by weight, still more preferably 1.4 to 6 parts by weight or 1.4 to 4 parts by weight, and even more preferably 1.8 to 3 parts by weight.

[0032] In the solid preparation of the present disclosure, specific contents of the component (B) include, for example, 10 to 91% by weight, preferably 12 to 70% by weight or 14 to 70% by weight, more preferably 16 to 70% by weight, still more preferably 18 to 70% by weight, 18 to 60% by weight, 18 to 50% by weight, 18 to 40% by weight, 18 to 35% by weight, 18 to 30% by weight, or 18 to 25% by weight.

[0033] 1-3. Other components In addition to the components (A) and (B), the solid preparation of the present disclosure may or may not contain other nutritional components and / or pharmacological components as necessary. Nutritional components and pharmacological components regardless of such inclusion are not particularly limited as long as they can be used in foods and / or pharmaceuticals. Examples include vitamins, minerals, carbohydrates, fatty acids, flavors, seasonings, plant extracts, antioxidants, and the like. These components may be used alone or in combination of two or more. Also, the contents of these components are appropriately set according to the types of nutritional components and / or pharmacological components used and the uses of the solid preparation.

[0034] Furthermore, the solid preparation of the present disclosure may or may not contain a base and / or an additive as necessary to prepare it into a desired dosage form. Bases and additives regardless of such inclusion are not particularly limited as long as they can be used in foods and / or pharmaceuticals. Examples include excipients, disintegrants, binders, lubricants, and the like. These components may be used alone or in combination of two or more. Also, the contents of these components are appropriately set according to the types of bases and / or additives used and the uses of the solid preparation.

[0035] Among the above-mentioned bases and additives, the solid preparation of the present disclosure preferably contains crystalline cellulose used as an excipient, a binder, a disintegrant, etc. When the solid preparation of the present disclosure contains crystalline cellulose, the content of crystalline cellulose is not particularly limited, and examples thereof include 2 to 70% by weight, preferably 4 to 65% by weight, 10 to 65% by weight, 30 to 65% by weight, or 40 to 65% by weight.

[0036] The content of other components (that is, components other than component (A) and component (B)) contained in the solid preparation of the present disclosure is, for example, 4 to 80% by weight, preferably 10 to 70% by weight, 30 to 70% by weight, 40 to 70% by weight, 50 to 70% by weight, or 60 to 70% by weight in total.

[0037] 1-4. Dosage form and packaging Regarding the dosage form of the solid preparation of the present disclosure, typically, any solid preparation that can be orally administered (taken internally) may be used. Specific dosage forms of the solid preparation of the present disclosure include tablets (preferably plain tablets), troches (preferably troches without coating), capsules (preferably ordinary hard capsules in which the capsule body and the cap are not integrated by adhesion or bonding, etc., more preferably hard capsules filled with a further light-transmitting (particularly preferably transparent) hard capsule), powders, fine granules, granules (including dry syrups).

[0038] To prepare the solid preparation of the present disclosure into the above dosage form, the above component (A) and component (B), and other components compounded as necessary may be used and formulated according to ordinary formulation methods.

[0039] When the dosage form of the solid preparation of the present disclosure is a tablet or a capsule, the total content of component (A) and component (B) contained in the solid preparation of the present disclosure constituting one tablet, or the total content of component (A) and component (B) contained in the solid preparation of the present disclosure filled in one capsule, is, for example, 40 to 90 mg, preferably 60 to 80 mg, more preferably 70 to 80 mg, and still more preferably 73 to 77 mg. Since the solid preparation of the present disclosure has moisture absorption countermeasures without depending on additives other than the active ingredient, such a large amount of component (A) and component (B) can be included in one tablet or capsule, and it has excellent administration efficiency.

[0040] When the dosage form of the solid preparation of the present disclosure is a capsule, the size of the hard capsule filled with the solid preparation of the present disclosure, when the single-dose is two capsules, is preferably No. 2 to No. 5, more preferably No. 2 to No. 3, and still more preferably No. 2 in the Japanese Pharmacopoeia capsule size standard. Since the solid preparation of the present disclosure has moisture absorption countermeasures without depending on additives other than the active ingredient, the necessary dosages of component (A) and component (B) can be filled in a small-sized capsule, and it has excellent administrability (easiness to drink).

[0041] The packaging of the solid preparation of the present disclosure is not particularly limited, and examples include individual packaging (PTP packaging, strip packaging, blister packaging, etc.) and loose packaging. Although individual packaging also has a risk of accidental opening such as tearing, piercing, and pinholes, the solid preparation of the present disclosure exhibits excellent moisture absorption inhibitory properties even if the individual packaging is accidentally opened. Although loose packaging is frequently exposed to the moisture in the outside air, the solid preparation of the present disclosure exhibits excellent moisture absorption inhibitory properties even when it is in loose packaging.

[0042] In addition, among the packaging materials in which the pharmaceutical composition of the present disclosure is packaged, the interior may be filled with air or may be filled with an inert gas such as nitrogen. Since the pharmaceutical composition of the present disclosure is excellent in moisture absorption suppression, or moisture absorption suppression and discoloration suppression, in a preferred form, the interior of the packaging material may be filled with air. Further, a desiccant may or may not be included in the packaging material in which the pharmaceutical composition of the present disclosure is packaged. Since the pharmaceutical composition of the present disclosure is excellent in moisture absorption suppression, in a preferred form, a desiccant may not be included in the packaging material. 2. Moisture absorption suppression method As described above, the component (B) can suppress the moisture absorption of the solid preparation containing the component (A). Therefore, the present disclosure further provides a method for suppressing the moisture absorption of a solid preparation containing (A) natto bacteria culture extract, wherein in the solid preparation, (B) red kojic rice and / or its processed product is blended together with the component (A).

[0043] In the method for suppressing moisture absorption of the present disclosure, the details such as the types and amounts of components used are as shown in the column of "1. Solid Preparation" above.

[0044] 3. Discoloration suppression method As described above, the component (B) can suppress the discoloration of the solid preparation containing the component (A). Therefore, the present disclosure further provides a method for suppressing the discoloration of a solid preparation containing (A) natto bacteria culture extract, wherein in the solid preparation, (B) red kojic rice and / or its processed product is blended together with the component (A).

[0045] In the method for suppressing discoloration of the present disclosure, the details such as the types and amounts of components used are as shown in the column of "1. Solid Preparation" above.

Examples

[0046] Hereinafter, the present disclosure will be described in more detail with reference to examples, but the present disclosure is not limited to these examples.

[0047] Test example Solid preparations (powders) with the compositions shown in Tables 1 to 3 were prepared. The details of the components (A) and (B) shown in each table are as follows.

[0048] Component (A) Natto bacteria culture extract powder (nattokinase activity 40,000 FU / g, vitamin K2 content 0.1 μg / g or less) Component (B) Red yeast rice: Powder of dried rice red yeast rice (trade name "3P-D20", manufactured by Kobayashi Value Support Co., Ltd. This powder of dried rice red yeast rice is a dried powder of red yeast rice obtained by fermenting white rice with Monascus pilosus, and the red yeast rice bacteria and enzymes are in an inactivated state by heat treatment.) Other components Crystalline cellulose FD-301 (Asahi Kasei Corporation)

[0049] Each component was put into a colorless and transparent bag and mixed well, and then sieved through a 100-mesh sieve. Again, 2.5 g was put into a colorless and transparent bag (made of polyethylene with a chuck, 85 mm × 60 mm) and mixed to obtain a solid preparation (powder). The bagged solid preparation (with the chuck closed) was stored in a thermostatic chamber at 50 °C and a relative humidity of 60% RH.

[0050] <Evaluation of moisture absorption inhibition> Regarding the solid preparation after 1 month of storage, the degree of moisture absorption was evaluated by the amount of the solid preparation that formed lumps. Specifically, it was evaluated that when no lumps were formed, it was 0, and when the amount of the solid preparation that formed lumps in Comparative Example 1 was 10. The smaller the score, the higher the moisture absorption inhibition effect. The results are shown in Tables 1 and 2.

[0051] <Evaluation of discoloration inhibition> The change amount (ΔE) between the color of the solid preparation before storage and the color of the solid preparation after 1 month of storage was measured using a colorimeter. The smaller the ΔE value, the higher the discoloration inhibition effect. The results are shown in Table 3.

[0052]

Table 1

[0053]

Table 2

[0054]

Table 3

[0055] As shown in Tables 1 and 2, the solid preparation containing the component (A) (Comparative Example 1) formed lumps due to moisture absorption even when stored in a polyethylene container with a chuck (with the chuck closed). This moisture absorption was not effectively eliminated even when a small amount of the component (B) was additionally blended (Comparative Examples 2 to 4). However, when the component (B) was additionally blended in an amount of 0.8 parts by weight or more per 1 part by weight of the component (A), the moisture absorption was significantly suppressed (Examples 1 to 7). Among them, when the component (B) was additionally blended in an amount of 1.1 parts by weight or more per 1 part by weight of the component (A), the moisture absorption was significantly suppressed at each stage (Examples 1, 2, 5 to 7). When the component (B) was additionally blended in an amount of 1.2 parts by weight or more per 1 part by weight of the component (A), the moisture absorption was particularly significantly suppressed (Examples 1, 2, 6, 7).

[0056] As shown in Table 3, severe discoloration was observed in the solid preparation containing the component (A) (Comparative Example 5). This discoloration could be suppressed even when a small amount of the component (B) was blended (Comparative Examples 4 and 6). However, when the component (B) was additionally blended in an amount of 1.1 parts by weight or more per 1 part by weight of the component (A), the discoloration was significantly suppressed (Examples 5 to 7). Among them, when the component (B) was additionally blended in an amount of 1.2 parts by weight or more per 1 part by weight of the component (A), a more excellent discoloration suppressing effect was observed (Examples 6 and 7).

[0057] Formulation example Solid preparations (powders) having the formulations shown in Tables 4 to 6 below were prepared. The details of each component shown in Tables 4 to 6 below are the same as those used in the test examples. In any of the solid preparations (powders) according to the formulation examples, even when contained in a polyethylene with a chuck (with the chuck closed), compared with the case where the component (B) is not contained and the case where the component (B) is contained in an amount less than 0.8 parts by weight per 1 part by weight of the component (A), the moisture absorption was significantly suppressed and discoloration was also suppressed. Among these effects, in particular, Formulation Examples 3 to 6, 9 to 12, and 15 to 18 were particularly excellent. Also, any of the solid preparations of the formulation examples could be manufactured as a capsule preparation designed such that the daily intake amount was 50 mg in terms of the intake amount of the component (A) and 2 capsules in terms of the number of capsules by filling them into No. 2 capsules.

[0058]

Table 4

[0059]

Table 5

[0060]

Table 6

Claims

1. A solid preparation comprising (A) a culture extract of Bacillus natto and (B) red yeast rice and / or a processed product thereof, wherein 0.8 to 10 parts by weight of the component (B) is contained per 1 part by weight of the component (A).

2. The solid preparation according to claim 1, comprising 3 to 40% by weight of the component (A).

3. A method for suppressing moisture absorption of a solid preparation containing (A) a culture extract of Bacillus natto, wherein in the solid preparation, (B) red yeast rice and / or a processed product thereof is blended together with the component (A).

4. A method for suppressing discoloration of a solid preparation containing (A) a culture extract of Bacillus natto, wherein in the solid preparation, (B) red yeast rice and / or a processed product thereof is blended together with the component (A).

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