JP2010189337A - Granule and tablet containing poorly soluble substance, and method for solubilizing poorly soluble substance - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new granule not only capable of solidifying a poorly soluble functional material by adsorbing a large amount of the material, but also having excellent properties for releasing the functional material in an aqueous environment. <P>SOLUTION: The granule containing a carrier containing porous calcium silicate, the functional material adsorbed on the carrier, a nonionic surfactant and a binder is regulated so that the functional material may be at least one kind selected from the group consisting of a poorly soluble liquid, a poorly soluble solid having the low melting point, and a crude drug extract containing a poorly soluble active ingredient. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to granules and tablets and methods for producing them, and more particularly to granules and tablets containing a hardly soluble substance as a functional substance and methods for producing them.

  Examples of dosage forms for ingesting functional substances that are active ingredients of pharmaceuticals and health foods include powders, granules, capsules and tablets. Of these, tablets are the most commonly used because they are easy to handle and take.

  Generally, tablets are granulated by adding water and / or an organic solvent to a mixed powder containing a functional substance, an excipient, and an optional component of a binder. Or synthetic or naturally-occurring polymer additives) and lubricants to make granules for tableting. This granule is quantified from a hopper (a container containing the granules for tableting) onto the rotary table of the tableting machine. It is produced by compressing the granulated granules in a hole (mortar) formed in a rotating disk with two sets of upper and lower steel bars (upper and lower irons).

  Since tablets are compressed and shaped in this way, if the functional substance is an oily liquid or a low-melting-point solid in a normal temperature environment, if the functional substance is an oily liquid, it can be molded into a tablet as it is. It is difficult to cause tableting troubles such as sticking and capping when it is a low melting point solid. Therefore, when the functional substance has such a property, a process for converting the form into a solid or powder is performed.

  In Patent Document 1, a liquid drug dissolved in a non-volatile solvent is simply mixed with a pre-calculated amount of a carrier substance such as crystalline cellulose and a coating substance such as light anhydrous silicic acid, A method for providing a compressible liquid / powder mixture (Liquisolid) is described. However, this liquid solid has a small amount of liquid that can be carried and the liquid drug content is insufficient. In addition, it is necessary to first determine the amount of the non-volatile solvent in which the liquid drug is dissolved, and calculate the amount of the carrier and the coating substance based on a mathematical model. There are many restrictions to satisfy compressibility.

  Patent Document 2 describes a liquid solid system using calcium silicate as a carrier for adsorbing and powdering a functional substance that is an oily liquid or a low melting point solid, and using starches or sugars as a binder. By doing so, the loose bulk density of the powder obtained was appropriately adjusted, and it became possible to make a thick tablet with a tableting machine. As a result, an appropriate diameter and thickness that can withstand actual use and an appropriate weight can be imparted to a tablet using calcium silicate as a carrier.

  Calcium silicate can carry a relatively large amount of liquid, and a tablet using calcium silicate as a carrier can contain a functional substance such as a liquid drug at a high concentration. However, particularly when the functional substance to be powdered or tableted is poorly soluble, it is required to improve the dissolution of the functional substance from the preparation into water and the transferability to the digestive fluid.

  Patent Document 3 describes a technique for increasing the absorbability of fat-soluble or water-soluble difficult / low-absorbable drugs in the body. This technique solidifies a surfactant exhibiting an absorption improving action in the body by using a porous adsorbent and combines it with a difficult / low absorbable drug to form a solid preparation. However, Patent Document 3 is a technique for increasing the absorbability of a drug in a living body by the effect of a surfactant, and does not describe the solubility of a poorly soluble drug in water. The effect of the surfactant to increase the passage of the drug through the biological membrane does not necessarily mean to increase the solubility in water. This is because surfactants often affect the interaction with biological membranes, and the mechanism of action is not necessarily the same. Therefore, it can be said that the technique described in Patent Document 3 is basically an invention in a region different from the technique described in the present invention.

Special table 2000-512295 International Publication No. 2007/97333 Pamphlet JP 2006-56781 A

  The present invention solves the above-mentioned conventional problems, and the object of the present invention is to absorb a large amount of a poorly soluble functional substance and solidify it, while the functional substance is soluble in water. It is to provide a novel granule excellent in the above.

The present invention is a granule comprising a carrier containing porous calcium silicate, a functional substance adsorbed on the carrier and a nonionic surfactant, and a binder,
The functional substance provides a granule that is at least one selected from the group consisting of a sparingly soluble liquid, a low melting point and sparingly soluble solid, and a herbal extract containing a sparingly soluble active ingredient. Is achieved.

  In one certain form, the said carrier contains a cellulose further.

  In one embodiment, the functional substance is at least one selected from the group consisting of vitamin E, coenzyme Q10, docosahexaenoic acid, eicosapentaenoic acid, lipoic acid, lutein, saw palmetto extract, ginkgo biloba extract, St. John's wort and royal jelly. It is.

  In one certain form, the said nonionic surfactant corresponds to a food additive or a pharmaceutical additive, and contains the compound which has a polyether chain as a hydrophilic part.

  In one certain form, the said nonionic surfactant contains at least 1 type selected from the group which consists of polysorbates and polyoxyethylene hydrogenated castor oil.

  In one certain form, the said nonionic surfactant further contains at least 1 type selected from the group which consists of sucrose fatty acid ester and polyglycerol fatty acid ester.

  In one embodiment, the surfactant is a mixture of polysorbates and polyoxyethylene hydrogenated castor oil in a ratio of 1: 1 to 1: 3, or polysorbates and sucrose fatty acid esters of 1: 1 to 1. : A mixture of 3 or a polysorbate and a polyglycerol fatty acid ester in a ratio of 1: 1 to 1: 3.

  In one certain form, the said surfactant is mix | blended in the quantity of 20-1000 weight part with respect to 100 weight part of functional substances.

  In one certain form, the said binder is at least 1 type selected from the group which consists of saccharides and sugar alcohols.

  In one embodiment, the carrier is blended in an amount of 50 to 400 parts by weight with respect to 100 parts by weight of the functional substance, the binder is blended in an amount of 50 to 1500 parts by weight with respect to 100 parts by weight of the carrier, and The loose bulk density is 0.20 to 0.80 g / ml.

Further, the present invention provides a functional substance and a nonionic surfactant that are at least one selected from the group consisting of a sparingly soluble liquid, a low melting point and sparingly soluble solid and a herbal extract containing a sparingly soluble active ingredient. Adsorbing to a carrier containing basic calcium silicate; and mixing the resulting support with water and a binder to granulate;
The manufacturing method of the granule containing this is provided.

  In one embodiment, the functional substance and the nonionic surfactant are adsorbed to the carrier by dissolving or dispersing the functional substance and the nonionic surfactant in ethanol to lower the viscosity, and mixing with the carrier. By evaporating the ethanol.

  Moreover, this invention provides the manufacturing method of the tablet including the process of compressing the granule in any one of the said description.

  Moreover, this invention provides the tablet obtained by said method.

Furthermore, the present invention provides a functional substance that is at least one selected from the group consisting of a sparingly soluble liquid, a low melting point and sparingly soluble solid and a sparingly active active ingredient, together with a nonionic surfactant, Adsorbing to a carrier containing porous calcium silicate; and eluting the functional substance in water;
A method for solubilizing a hardly soluble substance including

  The granule of the present invention is excellent in water elution even if the solidified functional substance is hardly soluble. Therefore, this problem can be solved by using the granule according to the present invention even if it is a functional substance that is hardly transferred to the digestive juice.

Granule The granule of the present invention comprises a carrier, a functional substance, a nonionic surfactant, and a binder. At least the functional substance and the nonionic surfactant are adsorbed on the carrier.

  The carrier means a solid substance that can be solidified by supporting a liquid. In general, fine powders and porous materials excellent in chemical stability are used as the carrier. As specific examples of the carrier, inorganic substances such as silicic acids and celluloses are widely known.

  Among them, porous calcium silicate has an average particle size of 18 to 32 μm, a loose bulk density of 0.07 to 0.15 g / ml, and an oil absorption of 300 to 550 ml / 100 g. Calcium silicate powder having such characteristics is represented by the formula

[Chemical 1]
2CaO · 3SiO ₂ · mSiO ₂ · nH ₂ O
[Wherein 1 <m <2 and 2 <n <3. ]

And a gyrolite-type calcium silicate powder having a petal-like crystal structure as observed with an electron microscope. Specifically, there is a product name “Flowlight” of Tokuyama Corporation.

  The carrier is blended at a ratio of preferably 20 to 200 parts by weight, more preferably 50 to 150 parts by weight with respect to 100 parts by weight of the functional substance. When the amount of the carrier is less than 20 parts by weight, the functional substance is likely to be leached from the carrier, and problems such as capping and sticking when tablets are compressed, insufficient hardness of the tablet, and poor appearance occur. When the amount of the carrier exceeds 200 parts by weight, it can be made into a tablet, but the content of the active ingredient is reduced, resulting in a large tablet that is difficult to drink.

  As the carrier, it is preferable to use a non-porous substance such as crystalline cellulose in addition to porous calcium silicate. This is because the poorly soluble substance held in the porous part has poor water penetration and is difficult to elute, which can avoid this problem. In that case, the amount of the non-porous substance used is up to 50% by weight, preferably up to 40% by weight of the whole carrier. If the amount of crystalline cellulose used exceeds 60% by weight, the amount of liquid that can be supported decreases, and subsequent granulation becomes difficult.

  Specific examples of the non-porous substance include crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose / light anhydrous silicic acid, and the like. Of these, the preferred non-porous material is crystalline cellulose.

  A functional substance refers to a substance that exhibits the desired action in the body after ingestion into the human body, and is a concept that includes an active ingredient in pharmaceuticals and health foods. The functional substance is not limited as long as it can be adsorbed to the carrier by any method, but preferred functional substances are herbal medicines containing a hardly soluble liquid, a low melting point and hardly soluble solid and a hardly soluble active ingredient. It is at least one selected from the group consisting of extracts. This is because a hardly soluble functional substance is inherently difficult to dissolve in digestive fluid and is poorly absorbed in the body. Here, the liquid refers to a substance that exhibits fluidity at room temperature (20 ° C.), and the solid refers to a substance that does not exhibit fluidity at room temperature. The low melting point means that the melting point is 100 to 120 ° C. or lower.

  Specific examples of the hardly soluble liquid include vitamin A, vitamin A derivative, vitamin E, docosahexaenoic acid, eicosapentaenoic acid and the like. A hardly soluble liquid derived from a natural product is a substance extracted from a natural product, and generically refers to an oily extract mainly composed of fat-soluble components. A specific example of a hardly soluble liquid derived from a natural product is a saw palmetto extract.

  Since a low melting solid often causes a sticking phenomenon when compressed, it is difficult to compress into a tablet in the same manner as a hardly soluble liquid. Therefore, a low melting point solid is also useful as the functional substance of the present invention. Specific examples of the low melting point solid include coenzyme Q10, α lipoic acid, ribose and the like.

  Particularly preferred poorly soluble functional substances for use in combination with porous calcium silicate and nonionic surfactant include, for example, vitamin E, coenzyme Q10, docosahexaenoic acid, eicosapentaenoic acid, lipoic acid, lutein, saw palmetto extract, It is at least one selected from the group consisting of ginkgo biloba extract, St. John's wort and royal jelly.

  The nonionic surfactant is preferably a compound having a polyether moiety such as a polyoxyethylene chain and a polyoxypropylene chain as the hydrophilic portion. This is because the nonionic surfactant having a polyether chain as the hydrophilic portion improves the dissolution property of the solidified hardly soluble substance in an aqueous environment. Moreover, what corresponds to a food additive or a pharmaceutical additive is preferable so that a nonionic surfactant may not have a bad influence on a human body.

  Preferred nonionic surfactants include, for example, polyoxyethylene hydrogenated castor oil, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene polyoxypropylene glycol and polysorbates. Among these, particularly preferred nonionic surfactants are polysorbate 80 and polyoxyethylene hydrogenated castor oil.

  In addition to those having a polyether chain as the hydrophilic portion, fatty acid esters may be used as nonionic surfactants. This is because a synergistic effect between those having a polyether chain and those having a fatty acid ester can be expected. In that case, the amount of the fatty acid ester used is 90% by weight, preferably 80% by weight of the entire nonionic surfactant. When the usage-amount of fatty acid ester exceeds 90 weight%, a synergistic effect with what has a polyether chain will become weak.

  Specific examples of the fatty acid ester include sucrose fatty acid ester and polyglycerin fatty acid ester.

  The nonionic surfactant is blended at a ratio of 20 to 1000 parts by weight, preferably 50 to 600 parts by weight, and more preferably 200 to 500 parts by weight with respect to 100 parts by weight of the functional substance. When the amount of the nonionic surfactant is less than 20 parts by weight, the functional substance is hardly eluted from the carrier in an aqueous environment. When the amount of the nonionic surfactant exceeds 1000 parts by weight, the amount of the functional substance to be blended becomes small, so that the intake quantity increases and becomes impractical.

  The binder refers to a component used to bind carrier particles into granules. From the standpoint of elution as in the present invention, the types of binders preferred for use are limited to some extent.

  A preferred binder is a saccharide. For example, when only calcium silicate is used as a carrier, calcium silicate is light and difficult to granulate, but by adding saccharides and granulating in this way, appropriate loose bulk density, particle size Granules with a distribution can be obtained.

  Known sugars can be used without limitation, and may be sugar alcohols obtained by hydrogenating these sugars, such as glucose and malt-strehalose. Preferably, sugar alcohol is used. As the sugar alcohol, any of sorbitol, erythritol, xylitol and maltitol can be used.

  The amount of binder used is not particularly limited. If the amount used is too small, the granule becomes light, and if it is too much, the content of the functional substance decreases, and not only a large amount of granules are required for tableting, but also granulation with water, especially granulation is rapid. It is difficult to produce a granule, and it is not practical. A binder is mix | blended in the ratio used as 20-500 weight part with respect to 100 weight part of support | carriers, Preferably it is 30-300 weight part, More preferably, it is 50-200 weight part. When the amount of the binder is less than 20 parts by weight, the loose bulk density of the granules becomes too small, and the tablet is difficult to be meat pressure. When the amount of the binder exceeds 500 parts by weight, the amount of the functional substance that can be blended becomes small, and the concentration of the functional substance contained in the tablet becomes too low.

  The granule of the present invention may contain additives such as a lubricant and a disintegrant, if necessary, in addition to the carrier, the functional substance, the nonionic surfactant and the binder. For example, hardened oil, hardened castor oil as a lubricant, stearic acid, magnesium stearate, calcium stearate, behenic acid glyceride, sodium stearyl fumarate, sucrose fatty acid ester, etc., low-substituted hydroxypropylcellulose, carmellose, Carboxymethyl starch sodium, crospovidone, croscarmellose sodium, starch, agar and the like may be added.

  In the granule of the present invention, when only calcium silicate is used as a carrier, the content of the functional substance is 10 to 50% by weight, preferably 25 to 35% by weight, and the content of the functional substance is greatly increased. be able to. The granules of the present invention have a loose bulk density of 0.20 to 0.80 g / ml, preferably 0.30 to 0.60 g / ml.

  By adjusting the loose bulk density of the granules to such a range, a tablet having an appropriate diameter and thickness and an appropriate weight can be obtained using a normal tableting machine. That is, if the granule of the present invention is used, a tablet having a shape and size that is practically sufficient in strength and convenient for handling can be provided.

  The granules of the present invention may be coated with a water-soluble polymer as necessary. By applying the coating, it is possible to reduce the odor and taste derived from the water-soluble antioxidant component. In addition, the dosage and moisture resistance of the granules are improved. In addition, about the coating to the granule by this invention, the method and the raw material to be used are not limited. Examples of water-soluble polymers generally include hydroxypropyl methylcellulose.

Production method of granule The functional substance-containing liquid is converted into a hardly soluble liquid or a low melting point solid by a conventional method or a method described in JP-A No. 2001-97858, JP-A No. 2007-15970 or JP-A No. 6-32774. Prepare by dissolving or dispersing.

  Adsorption and loading of a functional substance on a carrier is performed by dissolving or dispersing the functional substance in a solvent, if necessary, to lower the viscosity, mixing with the carrier, granulating with a binder, and then drying. To do. As a result, the functional material after granulation is held tightly in the pores of the carrier, and at the time of tableting, the functional material does not exude to the granule surface, the compression moldability is improved, the hardness is reduced, A capping or sticking phenomenon is suppressed.

  Ethanol is preferred as the organic solvent used to lower the viscosity of the functional substance. This is because safety is high. The organic solvent in which the functional substance is dissolved or dispersed and the carrier are usually mixed under stirring using a mixer or a stirring granulator used in the granulation step described later.

  The amount of the organic solvent in which the functional substance is dissolved or dispersed is sufficient if it dissolves or disperses the functional substance to be dissolved to lower the viscosity. If the amount of the organic solvent is too small, the functional substance will not be adsorbed uniformly, and if it is too large, the supported material will be wetted.

  Adsorption and loading of the nonionic surfactant on the carrier is performed by adding a nonionic surfactant and a functional substance dissolved in ethanol to the carrier and stirring and mixing. Moreover, you may heat as needed, when melt | dissolving.

  Next, the obtained carrier (a mixture of a carrier and a functional substance or a liquid containing the same) is granulated and granulated. The granulation of the support is performed by a usual method using a binder and water.

  The granulation is preferably performed by stirring granulation. This is because a strong stirring force is required for the interaction between the surfactant and the functional substance, and granules with a higher bulk density can be obtained. Agitation granulation has various forms, and there are one using a rotating arm at the top of the container, one using a rotary blade at the bottom of the container, and one obtained by adding stirring in a different direction.

  Examples of the apparatus used for granulation include a vertical granulator, a high shear mixer, a high speed mixer, a planetary mixer, a collet glal granulator, and a chopper type planetary mixer. For granulation, any device capable of appropriately mixing powders may be used, and the stronger the stirring force, the faster the granulation proceeds.

  The granules thus obtained are dried to remove the contained water and organic solvent. The drying temperature is 20 to 90 ° C, preferably 25 to 75 ° C, more preferably 30 to 60 ° C.

Tablet production method The dried granule is sized, added with a polymer additive, a disintegrant and a lubricant to give granules for tableting, and compressed into tablets. As the polymer additive, those generally used for making granules and tablets can be used. Specific examples include celluloses such as crystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; synthetic polymers such as polyvinylpyrrolidone; and natural polymers such as gum arabic, agar, and pullulan.

  The polymer additive is used alone or in combination of two or more, but it is desirable to use it separately as an excipient, a binder and a disintegrant depending on its use. The tablets produced as described above may be appropriately provided with a coating process for applying film coating or sugar coating.

  The tableting granules for production are made into tablets using a tableting machine. In addition, since the method of making the granule for tableting into a tablet is the same as that in the past, the description is omitted.

Method of solubilizing poorly soluble substances As described above, the functional substance adsorbed on the carrier containing porous calcium silicate together with the nonionic surfactant is eluted in water even though it is poorly soluble. Excellent in properties. This is probably due to the action of the porous calcium silicate, in which the nonionic surfactant and the functional substance are mixed homogeneously and good mutual contact is achieved.

  In order to elute the functional substance in water, the functional substance adsorbed on the carrier is brought into contact with water. The water is not limited to pure water and may be a liquid containing water. For example, a body fluid such as digestive fluid is included in the water here. Although the temperature of water can be suitably adjusted according to the kind of functional substance, generally it is about 15-25 degreeC.

  For example, if the granules and tablets prepared as described above are put into water and left as needed or stirred, the adsorbed functional substance comes into contact with water. In addition, for example, if a human or animal takes granules or tablets prepared as described above into the body, the adsorbed functional substance comes into contact with water.

  Regarding the dissolution of functional substances, in general, if the dissolution of tablets is good, the dissolution of granules is also good. However, it seems that it cannot always be said that the dissolution of tablets is good just because the dissolution of granules is good.

  The following examples further illustrate the present invention, but the present invention is not limited thereto.

Examples 1-21 and Comparative Examples 1-3
Step 1
A volatile solvent such as ethanol and a nonionic surfactant such as polysorbate were mixed using a stirrer. While stirring, functional substances such as vitamin E, coenzyme Q10 or herbal extract were gradually added, and stirred sufficiently to dissolve or disperse uniformly.

  At that time, since coenzyme Q10 does not dissolve at room temperature, it was dissolved by raising the temperature to around 45 ° C. In the case of a crude drug extract, since it contains substances insoluble in ethanol, it is difficult to dissolve 100%, but the temperature was raised to around 50 ° C., and it was dispersed and partially dissolved over time. When a non-volatile solvent such as glycerin was used in combination, it was added and mixed here.

Step 2
On the other hand, the amount of florite used was charged into a vertical granulator (granulator, manufactured by Paulex Co., Ltd.). When using crystalline cellulose together, it was put together and mixed well using the mixing function of the vertical granulator.

Step 3
The liquid produced in Step 1 was charged into florite (or mixed powder of fluorite and crystalline cellulose), stirred using the mixing function of a vertical granulator, and uniformly adsorbed.

Step 4
A predetermined amount of water was added to the adsorbed powder.

Step 5
There, sugar alcohol was added and granulation was started. Some crude herbal extracts contain ingredients that are necessary for granulation, so some sugar alcohols do not need to be added at this stage. However, granulation is essential.

Step 6
Drying was performed using a fluidized bed. Ethanol was completely removed at this stage.

Step 7
To the obtained granules, 5 parts by weight of agar and 1 part by weight of sucrose fatty acid ester are added to obtain granules for tableting, and tableting is performed using a tableting machine (manufactured by Hata Ironworks Co., Ltd., model number: HT-AP12SS-U). A tablet was obtained.

Step 8
About the obtained tablet, the dissolution property of the functional substance in water was tested. That is, first, a tablet corresponding to a single intake of a functional substance was used for the test. For the dissolution test, the test method listed in the Japanese Pharmacopoeia was used. The test was performed by the paddle method, and the paddle was rotated at a speed of 50 revolutions per minute, and the active ingredient eluted from the tablet into water was measured by the liquid chromatography method.

  Table 1 shows the sources of materials used in each example. In addition, Table 2 shows the types and amounts of materials used and the results of the dissolution test.

[Table 1]

Comparative Example 4
A commercially available St. John's wort tablet (“Sato St. John's wort” manufactured by Sato Pharmaceutical Co., Ltd.) was obtained, and a functional substance dissolution test in water was performed in the same manner as in the above Examples. The elution of hyperforin, an active ingredient of St. John's Wort Extract, was evaluated. The results are shown in Table 2.

Comparative Example 5
A commercially available soft capsule of saw palmetto extract (“Nature's Resource Saw Palmetto” manufactured by Otsuka Pharmaceutical Co., Ltd.) was obtained, and a functional substance dissolution test in water was performed in the same manner as in the above Examples. Since no specific active ingredient is determined for saw palmetto, the component dissolved in the eluate was subjected to pattern analysis, and the elution was evaluated based on the total area of the obtained peaks. The results are shown in Table 2.

  Except for some of the tablets of the examples, the functional substances were more soluble than the comparative examples. The formulation of Example 14 did not contain a solvent component, and the expected dissolution property was not obtained.

  Note that the necessity of a solvent such as ethanol or ester, and the preferred type and appropriate amount thereof vary depending on the type of functional substance used. Therefore, the above-mentioned result that the expected dissolution property in Example 14 was not obtained does not indicate that the formulation containing no solvent is generally inappropriate for functional substances other than Coenzyme Q10. .

  And the result of these Examples has shown that a poorly soluble substance is solubilized in water, when a poorly soluble substance is made to adsorb | suck to porous calcium silicate with a nonionic surfactant.

Claims (15)

A carrier comprising porous calcium silicate, a functional substance adsorbed on the carrier and a nonionic surfactant, and a granule comprising a binder,
The functional substance is a granule that is at least one selected from the group consisting of a sparingly soluble liquid, a low melting point and sparingly soluble solid and a sparingly soluble active ingredient.   The granule according to claim 1, wherein the carrier further contains cellulose.   The functional substance is at least one selected from the group consisting of vitamin E, coenzyme Q10, docosahexaenoic acid, eicosapentaenoic acid, lipoic acid, lutein, saw palmetto extract, ginkgo biloba extract, St. John's wort and royal jelly. 2. Granule according to 2.   The granule according to any one of claims 1 to 3, wherein the nonionic surfactant corresponds to a food additive or a pharmaceutical additive and contains a compound having a polyether chain as a hydrophilic part.   The granule according to any one of claims 1 to 4, wherein the nonionic surfactant contains at least one selected from the group consisting of polysorbates and polyoxyethylene hydrogenated castor oil.   The granule according to claim 5, wherein the nonionic surfactant further contains at least one selected from the group consisting of a sucrose fatty acid ester and a polyglycerol fatty acid ester.   The surfactant is a mixture of polysorbate and polyoxyethylene hydrogenated castor oil in a ratio of 1: 1 to 1: 3, or polysorbate and sucrose fatty acid ester in a ratio of 1: 1 to 1: 3. The granule according to any one of claims 1 to 6, which is a mixture of polysorbate and polyglycerin fatty acid ester in a ratio of 1: 1 to 1: 3.   The granule according to any one of claims 1 to 7, wherein the surfactant is blended in an amount of 20 to 1000 parts by weight with respect to 100 parts by weight of the functional substance.   The granule according to any one of claims 1 to 8, wherein the binder is a kind selected from the group consisting of sugars and sugar alcohols.   The carrier is blended in an amount of 50 to 400 parts by weight with respect to 100 parts by weight of the functional substance, the binder is blended in an amount of 50 to 1500 parts by weight with respect to 100 parts by weight of the carrier, and the loose bulk density is 0.1. The granule according to any one of claims 1 to 9, which is 20 to 0.80 g / ml. A functional substance that is at least one selected from the group consisting of a sparingly soluble liquid, a low melting point and sparingly soluble solid, and a herbal extract containing a sparingly soluble active ingredient and a nonionic surfactant, including porous calcium silicate Adsorbing on a carrier; and mixing the resulting support with water and a binder to granulate;
The manufacturing method of the granule containing this.   The adsorption of the functional substance and the nonionic surfactant to the carrier is performed by dissolving or dispersing the functional substance and the nonionic surfactant in ethanol to lower the viscosity, mixing with the carrier, and evaporating the ethanol. 12. The method of claim 11, wherein the method is performed.   The manufacturing method of the tablet including the process of tableting the granule in any one of Claims 1-10.   A tablet obtained by the method according to claim 13. A functional substance that is at least one selected from the group consisting of a sparingly soluble liquid, a low melting point and sparingly soluble solid, and a herbal extract containing a sparingly soluble active ingredient, together with a nonionic surfactant and porous calcium silicate A step of adsorbing the carrier on a carrier, and a step of eluting the functional substance in water;
A method for solubilizing a poorly soluble substance comprising