JP2021176825A - Curcumin-containing solid formulation for oral ingestion - Google Patents

Abstract

To provide amorphous curcumin-containing solid formulations with high disintegration rate.SOLUTION: Provided is a solid formulation for oral ingestion containing: (A) one or more selected from solid curcumin containing an amorphous substance, and analogs thereof; (B) hydroxypropylmethylcellulose in which the viscosity of 2 mass% aqueous solution at 20°C is 10 mm2/s or less; and (C) a gel non-forming pharmaceutical additive.SELECTED DRAWING: None

Description

The present invention relates to a solid preparation for oral ingestion containing curcumin.

In recent years, curcumin and its relatives have been attracting attention for their physiological activities such as antioxidant action, anti-inflammatory action, antiallergic action, tumor formation inhibitory action, cholesterol lowering action, brain disease preventive action, and cardiovascular disease preventive and therapeutic action. It is being considered for use in feeds, foods and drinks (for example, functional foods, etc.), pharmaceuticals, cosmetics, and the like. However, since curcumin and its analogs have extremely low absorption into the body by oral ingestion, there is a problem that the physiological activity of curcumin and its analogs cannot be sufficiently obtained by oral ingestion.

Therefore, as a means for improving the absorbability of curcumin and its relatives after oral ingestion, curcuminoids, thermoplastic polymers and phosphatides are melt-processed into a solid dispersion (Patent Document 1), and curcumin and polysaccharoids are used. (Patent Document 2) and means for forming a complex of curcumin and water-soluble cellulose (Patent Documents 3, 4 and 5) have been reported. There is also a report that the dissolution rate is improved by amorphizing curcumin (Non-Patent Documents 1 to 4). Furthermore, the present inventors have found that a solid composition in which amorphous curcumin or an analog thereof is physically mixed with a water-soluble polymer such as hydroxypropylmethylcellulose has good absorbability of curcumin or an analog thereof. Was found and a patent application was filed (Patent Document 6).

Japanese Patent Application Laid-Open No. 2014-503470 Japanese Unexamined Patent Publication No. 3-97761 International Publication No. 2015/174475 Pamphlet International Publication No. 2016/01093 Pamphlet International Publication No. 2017/061627 Pamphlet International Publication No. 2019/160146 Pamphlet

J Pharm Sci. 1994 Dec; 83 (12): 1700-5. Adv Drag Deliv Rev. 2012 May 1; 64 (6): 480-95. The Deliv. 2015 Mar; 6 (3): 339-52. Mol Palm. 2011 Jun 6; 8 (3): 807-13.

As a result of further research on a physically mixed solid composition using hydroxypropylmethyl cellulose among the water-soluble polymers described in Patent Document 6, the present inventors have found that the capsules encapsulated in the composition capsules are used. Alternatively, when the solid composition is made into a solid preparation such as granules, pills, capsules, tablets, dry syrups, etc., which is produced by compression processing with an arbitrary excipient, the disintegration property is delayed depending on the preparation. It has been found. It was presumed that the disintegration delay may reduce the absorption of curcumins from the intestinal tract after oral administration and increase the variation.
Therefore, the subject of the present invention is oral containing amorphous curcumins and hydroxypropyl methylcellulose, which have good disintegration properties when processed into solid formulations such as capsules, granules, pills, tablets, and dry syrups. The purpose of the present invention is to provide solid preparations such as capsules for ingestion, granules, pills, tablets and dry syrups.

Therefore, the present inventor has made various studies to solve the above-mentioned problems, and as a result, surprisingly, one or more kinds selected from curcumin containing a solid amorphous body and its relatives and the viscosity of a 2% by mass aqueous solution. Solid-form preparations for oral ingestion, such as capsules, granules, pills, tablets, and dry syrups, containing hydroxypropylmethyl cellulose having a size of 10 mm ^{2 / s or less and a gel non-forming pharmaceutical additive have disintegrated.} The present invention has been completed by finding that the properties are remarkably improved, the oral absorbability is good, and the storage stability is also good.

That is, the present invention provides the following inventions [1] to [7].
[1] (A) One or more selected from solid curcumin containing an amorphous substance and its relatives, and (B) ^{hydroxypropyl having a viscosity of a 2% by mass aqueous solution at 20 ° C. of 10 mm 2} / s or less. A solid preparation for oral ingestion containing methyl cellulose and (C) a gel-non-forming pharmaceutical additive.
[2] The solid preparation for oral ingestion according to [1], wherein the content mass ratio (A / B) of the component (A) to the component (B) is 0.2 to 1.
[3] The component (C) is a gel non-forming excipient, a gel non-forming disintegrant, a gel non-forming dispersant, a gel non-forming lubricant, a gel non-forming coloring agent, and a gel non-forming property. The solid preparation for oral ingestion according to [1] or [2], which is one or more selected from the group consisting of a fragrance and a gel-non-forming flavoring agent.
[4] The solid for oral ingestion according to any one of [1] to [3], wherein the component (B) is hydroxypropyl methylcellulose having a viscosity of a 2% by mass aqueous solution at 20 ° C. of 1 to 8 mm ^{2 / s or less.} pharmaceutical formulation.
[5] Any of [1] to [4] in which the content mass ratio (C / (A + B)) of the component (C) and the sum of the component (A) and the component (B) is 0.4 to 7. The above-mentioned solid preparation for oral ingestion.
[6] The solid preparation for oral ingestion according to any one of [1] to [5], wherein the dosage form is selected from capsules, granules, pills, tablets and dry syrups.
[7] The solid preparation for oral ingestion according to any one of [1] to [6], wherein curcumin and its analogs are curcumin and turmeric pigments.

The solid preparation of the present invention has good disintegration property, and after oral ingestion, curcumin or an analog thereof is rapidly absorbed, and a high blood concentration with little variation can be obtained. Moreover, since the amorphous curcumin or its analog can be formulated as it is, the storage stability can be maintained.

The background to the present invention will be described in more detail. In Patent Document 6, the present inventors describe amorphous curcumins and hydroxypropylmethylcellulose for the composition of the present invention, and a) the viscosity of the 2 wt% aqueous solution is 2.4 to 3.6 mm ² Compositions containing / s (manufactured by Rettenmeier Japan, E3) or b) having the same viscosity of 40 to 60 mm ² / s (manufactured by Shin-Etsu Chemical Co., Ltd., Metrose SE-50) have oral absorbability and storage stability. Described as excellent. In fact, there is Example 6 as these compositions, in which a 2 wt% aqueous solution having a viscosity of 40 to 60 mm ² / s is used, and as a composition containing maltodextrin in addition to these compositions. Examples 1 to 5 and 8 to 12, in which a) a 2 wt% aqueous solution having a viscosity of 2.4 to 3.6 mm ² / s or b) having the same viscosity of 40 to 60 mm ² / s. Is used. Then, the oral absorbability of rats was actually tested in Examples 2 to 7 and 9 to 12 (in each of these, those having a viscosity of a 2 wt% aqueous solution of 40 to 60 mm ² / s are used). There is.
Next, the present inventors prepared a solid composition described in the patent using hydroxypropylmethyl cellulose having a viscosity not described in the patent document, and the same method as in the patent document (the composition was subjected to physiological saline). As a result of examining the oral absorbability of rats (described in Reference Experiment 1 below), as described in the patent (Patent Document Paragraph (0020)), it is good regardless of the viscosity of hydroxypropylmethylcellulose. It showed oral absorbability.
However, the present inventors further studied the effect of the above-mentioned hydroxypropyl methylcellulose viscosity, (1) melt-treated curcumin powder, (2) different viscosity, 40-60 mm ² / s (Shin-Etsu Chemical, SE50), 12- 18mm ² / s (manufactured by Rettenmeier Japan, E15), 4.8 to 7.2mm ² / s (Shin-Etsu Chemical, SE06), 3.6 to 5.1mm ² / S (Shin-Etsu Chemical, Pharmacoat 645W), 3 .2-4.8 mm ² / s (Shin-Etsu Chemical, Pharmacoat 645W), 2.4-3.6 mm ² / s (Rettenmeier Japan, E3) hydroxypropyl methylcellulose, (3) Maltodextrin (Sanei Saccharification, Sanei Saccharification, NSD # 300), (4) calcium stearate, and (5) silicon dioxide are prepared into a powdery composition, which is filled in No. 2 capsules and disintegrated test method by the Japanese Pharmacy (conditions: water, 37 ° C.). , Using a sinker) confirmed the disintegration property (described in Reference Experiment 2 below). As a result, in the capsule using hydroxypropyl methylcellulose having a viscosity of 40 to 60 mm ² / s and 12 to 18 mm ² / s, the capsule contents remain on the mesh of the disintegration tester after the test, and the inside of the contents remains. Was not infiltrated with water and remained in the original composition. However, it was discovered that the capsule completely disintegrates when the viscosity is 10 mm ² / s or less (the capsule contents hardly remain on the mesh of the disintegration tester). It is not known at all that there is a correlation between the viscosity of a 2 wt% aqueous solution of hydroxypropylmethylcellulose and the disintegration property of the capsule containing it, much ^{less hydroxypropylmethylcellulose with a viscosity of 10 mm 2} / s as a boundary. It was an unpredictable finding to improve the disintegration of capsules containing the composition with coexisting amorphous curcumin.

Furthermore, the present inventors are solids for oral ingestion containing the component (A) (solid curcumin containing amorphous material and / or its analog) and the component (B) solid water-soluble polymer of Patent Document 6. When the composition is processed into a solid preparation for oral intake that is easy to ingest, it can be easily processed by adding the third component (C) to the component (A) and the component (B), but the component (C) is water. It was found that the disintegration property of the solid preparation is lowered even if hydroxypropylmethyl cellulose having ^{a viscosity of 10 mm 2} / s or less of the 2% by mass aqueous solution is used in (B) when it has the property of forming a gel in contact with. (Reference experiment 3). Further, a non-gel-forming pharmaceutical additive is added as the third component (C) to the solid composition using hydroxypropyl methylcellulose having ^{a viscosity of 10 mm 2} / s or less of the above-mentioned 2% by mass aqueous solution having good disintegration property. It was also newly discovered that the solid preparation for oral ingestion produced in the above-mentioned manner becomes a solid preparation having good disintegration property (reference experiment 3), and the present invention was reached.

The solid-form preparation for oral ingestion of the present invention has (A) one or more selected from solid curcumin containing an amorphous substance and its relatives, and (B) a 2 mass% aqueous solution having a viscosity of 10 mm ² / s. It is characterized by containing the following hydroxypropyl methylcellulose and (C) a gel non-forming pharmaceutical additive.

Curcumin is the main component of curcuminoids contained in turmeric pigment, and is a compound represented by the following structural formula (1).

As the curcumin used in the present invention, chemically synthesized curcumin may be used, or those commercially available as a turmeric pigment may be used. Examples of the turmeric pigment include turmeric powder obtained by powdering dried rootstock of a plant belonging to the genus Hidden-lilies of the family Gourd family (for example, Curcuma linga Linne), and a suitable solvent (for example, ethanol, fats and oils, propylene glycol, hexane, acetone, etc.) for the turmeric powder. ) Can be mentioned as crude curcumin or oleoledin (turmeric oleoledin) obtained by extraction using) and purified curcumin.
In addition, curcumin includes both keto type and enol type which are tautomers.

Examples of curcumin analogs include demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin, hexahydrocurcumin and the like. The turmeric pigment contains curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin.

The component (A) of the present invention contains one or more amorphous substances selected from curcumin and its analogs. Amorphous curcumin can be confirmed by not having a clear diffraction peak in the powder X-ray diffraction spectrum. Amorphous curcumin is obtained by melting treatment at a temperature at which curcumin melts, for example, 160 ° C. or higher.

The solid preparation of the present invention contains solid amorphous curcumin or an analog thereof. Here, the solid state means that it is in the form of powder, granules, or lumps, and indicates that it does not form a complex with other substances or a solid dispersion. The fact that solid amorphous curcumin does not form a complex and solid dispersion is similar to the thermophysical properties of amorphous curcumin alone in differential scanning calorific analysis, and the thermophysical properties are different from those of complex and solid dispersion. You can confirm that. Of these solids, it is more preferable that the powder has an average particle size of 300 μm or less.

In addition to the amorphous curcumin or its analog (amorphous), the component (A) of the solid preparation of the present invention may contain crystalline curcumin or its analog (crystal). The component (A) may be entirely amorphous, but when both the amorphous body and the crystalline body are contained, the content mass of the (A-1) crystal body and the (A-2) amorphous body is contained. The ratio (A-1 / A-2) is preferably 0.67 or less.

The solid preparation of the present invention contains (B) hydroxypropyl methylcellulose having a viscosity of a 2% by mass aqueous solution at 20 ° C. of 10 mm ² / s or less.
In the present invention, the hydroxypropylmethylcellulose used as the component (B) has a lower viscosity of a 2% by mass aqueous solution at 20 ° C. than ordinary hydroxypropylmethylcellulose, and is 10 mm ² / s or less. Here, the viscosity is the viscosity measured by a B-type viscometer at 20 ° C.
From the viewpoint of improving disintegration property, the viscosity of the 2% by mass aqueous solution at 20 ° C. ^{is preferably 1 mm 2} / s or more and 10 mm ² / s or less, ^{more preferably 2 mm 2} / s or more and 8 mm ² / s or less, and 2 mm ² / s. More preferably 7 mm ² / s or less.
As the hydroxypropyl methylcellulose having these viscosities, for example, those commercially available from Shin-Etsu Chemical Co., Ltd., Rettenmeier Japan, Dyupon Japan, ASP Japan and the like can be used.

The degree of substitution of the methoxy group of the hydroxypropylmethylcellulose used is preferably 16.5 to 30.0%, and the degree of substitution of the hydroxypropoxy group is preferably 4.0 to 32.0%. Among these, those having a methoxy group of 28.0 to 30.0% and a hydroxypropoxy group of 7.0 to 12.0% (corresponding to the USP2910 standard), a methoxy group of 27.0 to 30.0% and a hydroxy group. Those with 4.0 to 7.5% propoxy groups (corresponding to USP2906 standard), those with 19.0 to 24.0% methoxy groups and 4.0 to 12.0% hydroxypropoxy groups (to USP2208 standard) (Equivalent), those having 16.5 to 20.0% of methoxy groups and 23.0 to 32.0% of hydroxypropoxy groups (corresponding to USP1828 standard) are particularly preferable.

In the solid preparation of the present invention, the viscosity of (A) one or more selected from solid curcumin containing an amorphous substance and its relatives and (B) a 2% by mass aqueous solution at 20 ° C. is 10 mm ² /. It is contained in a state of being mixed with hydroxypropyl methylcellulose which is s or less.
The content mass ratio (A / B) of the component (A) to the component (B) in the solid preparation of the present invention is preferably 0.2 to 1 from the viewpoint of disintegration and storage stability.

Dosage forms of the solid preparation of the present invention include capsules, granules, pills, tablets and dry syrups. In order to produce these dosage forms, in addition to the component (A) and the component (B), pharmaceutical additives such as excipients, disintegrants, dispersants, and lubricants are required. However, in order to improve the disintegration property of the solid preparation of the present invention, that is, capsules, granules, pills, tablets and dry syrups, the component (C) must be a gel non-forming pharmaceutical additive. When the component (C) gels due to the body fluid that has entered the formulation when the solid formulation such as capsules, granules, pills, tablets, and dry syrup disintegrates, it takes time for the body fluid to enter the inside of the formulation. This is probably because the collapse is delayed. Ingredients (C) include gel non-forming excipients, gel non-forming disintegrants, gel non-forming dispersants, gel non-forming lubricants, gel non-forming colorants, gel non-forming fragrances and Included is one or more selected from the group consisting of non-gel-forming flavoring agents.

Gel non-forming excipients include lactose, fructose, crystalline cellulose, corn starch, dextrin, malt dextrin, isomalt, inositol, casein, fructose, xylitol, calcium citrate, citrate hydrate, sodium citrate, purified. A group consisting of sucrose, sorbitol, calcium carbonate, trehalose, potato starch, hydroxypropyl starch, glucose, partially pregelatinized starch, purulan, pectin, povidone, maltose hydrate, mannitol, anhydrous citric acid, anhydrous sodium citrate, and anhydrous lactose. One or more selected from.

Examples of the gel non-forming disintegrant include one or more selected from the group consisting of dextrin, crospovidone, croscarmellose, croscarmellose sodium, crystalline cellulose, partially pregelatinized starch, and povidone.

Examples of the gel non-forming dispersant include one or more selected from the group consisting of gum arabic, carrageenan, refined soybean lecithin, tragant powder, and gati gum.

Examples of the gel non-forming lubricant include one or more selected from the group consisting of magnesium stearate, calcium stearate, light anhydrous silicic acid, silicon dioxide, and talc.

Examples of the gel non-forming colorant are commonly used colorants, and examples thereof include food dyes, caramel, and iron oxides.

Examples of the gel non-forming fragrance are commonly used fragrances, and examples thereof include various flavors and various extracts.

Examples of the gel non-forming flavoring agent include commonly used flavoring agents such as ascorbic acids, citric acids, and various sweeteners.

Examples of the gel-forming additive that cannot be used in producing the solid preparation of the present invention include hydroxypropyl cellulose, pregelatinized starch, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose and the like.

The amount of the component (C) used in the solid preparation of the present invention is an amount added for processing the solid composition of the present invention into a solid preparation which is an administration form, but the lower limit is preferably a solid preparation. It is defined by the minimum amount required to show the disintegration property and the minimum amount required to physically form the solid preparation, and the upper limit is that the solid preparation is the unit-administered preparation (capsule, tablet, packaged granule). ) Is the maximum amount that can be administered reasonably. In addition, the total individual weight of the unit-administered formulation depends on the curcumin content, that is, when the amount of (A) + (B) in the unit-administered formulation is large or small, the former is (C). The amount of (C) is large in the latter case. Considering the total weight of the usual above-mentioned unit preparation and the recommended curcumin content in the above-mentioned unit preparation of curcumin, the amount of (C) has a mass ratio (C / (A + B)) of 0.4 to 10. It is preferable, more preferably in the range of 0.5 to 7. Excipients, disintegrants, dispersants, lubricants, colorants, fragrances, and flavoring agents in the component (C) are contained as needed, but the content ratio is granules, pills, capsules. , Tablets [including uncoated tablets, sugar-coated tablets, orally rapidly disintegrating tablets, chewable tablets (chewable tablets), effervescent tablets, troches, film-coated tablets, etc.], dry syrups, capsules, etc. It may be used at a conventionally known ratio.

As shown in Examples below, the solid preparation of the present invention has good disintegration property, good oral absorbability, and good storage stability. Therefore, the solid preparation of the present invention is a feed for demonstrating the physiological activity of curcumin or its relatives by oral ingestion, its additives, dietary supplements, functional foods, foods for specified health uses, pharmaceuticals, etc. It is useful as a non-pharmaceutical product and cosmetics.

The feed is not particularly limited as long as it contains the solid preparation for oral intake of the present invention. For example, livestock feed for fattening of cattle, pigs, horses, chickens, etc. It can be used as an additive for the purpose of antibacterial activity, as a feed additive / nutritional supplement for pets such as dogs and cats.

The food and drink is not particularly limited as long as it contains the solid preparation for oral ingestion of the present invention, and examples thereof include food and drink containing curcumin. Specifically, it is used as a food for specified health use, a food with nutritional function, a food for the elderly, a food for special use, a food with functional claims, and a dietary supplement (supplement), for example, for adjusting the function of the liver. It is considered that it will be possible to provide it with a display to that effect.

The solid preparation for oral ingestion of the present invention can be widely used as a pharmaceutical product, a quasi-drug, and the like. For example, dementia, diabetes, cardiovascular disease, digestive system disease, respiratory system disease, otolaryngology-classified disease, autoimmune disease, skeletal muscle and joint-derived disease, oral / dental area It can be used for the treatment and prevention of diseases such as malignant tumors.

Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 (powdered composition)
An appropriate amount of commercially available turmeric extract powder (curcumin content 86.8% (w / w)) was put into a hot plate type heating device (manufactured by Nissin Machinery Co., Ltd.) and melted at a treatment temperature of 220 ° C. Further, this melt was solidified by holding it at room temperature to prepare about 50 g of melt-treated curcumin (amorphous curcumin). This was crushed in a mortar and sieved through a No. 30 sieve (melted curcumin (amorphous curcumin) crushed product) 10.0 g, viscosity of a 2% by mass aqueous solution 2.4 to 3.6 mm ² / s hydroxypropyl methylcellulose (Rettenmeier Japan, E3) 10.0 g was mixed to obtain a uniform powdery composition (Example 1).
("Melting-treated curcumin (amorphous curcumin)" such as the following examples is prepared by the method described in Example 1 above.)

Example 2 (powdered composition)
Melt-treated curcumin (amorphous curcumin) crushed product 10.0 g, 2% by mass water-based viscosity 4.8 to 7.2 mm ² / s hydroxypropyl methylcellulose (Shin-Etsu Chemical, SE6) 10.0 g is mixed and uniform A powdery composition was obtained (Example 2).

Comparative Example 1 (powdered composition)
Melt-treated curcumin (amorphous curcumin) crushed product 10.0 g, 2% by mass aqueous solution viscosity 12-18 mm ² / s hydroxypropyl methylcellulose (Lettenmeier Japan, E15) 10.0 g mixed to make a uniform powdery composition (Comparative Example 1: Composition described in Patent Document 6).

Comparative Example 2 (powdered composition)
Melt-treated curcumin (amorphous curcumin) crushed product 10.0 g, 2 mass% aqueous solution with viscosity 40-60 mm ² / s hydroxypropyl methylcellulose (Shin-Etsu Chemical, SE50) 10.0 g was obtained as a uniform powdery composition. (Comparative Example 2: Composition described in Patent Document 6).

Reference Experiment 1 (Rat Absorption of Examples 1 and 2, Comparative Examples 1 and 2)
The oral absorbability of the water suspension dispersions of the compositions of Examples 1 and 2 and Comparative Examples 1 and 2 was examined using rats.
(1) Administration method The compositions of Examples 1 and 2 and the compositions of Comparative Examples 1 and 2 were suspended and dispersed in physiological saline in male SD rats of an appropriate age of 8-9, and then the talcumin concentration was 10 mg. The drug was orally administered to a concentration of / kg, and blood was collected before administration, 30 minutes after administration, 1 hour after administration, and 2 hours after administration. Blood was collected by the method shown below, and the total curcumin concentration in blood was measured. As a control, a highly absorbent curcumin preparation (TheracurminTM: CR-033P) sold by CeraValues Co., Ltd. was used.

(2) Measurement of curcumin concentration in blood bran a. Pretreatment Add 100 μL of 0.1 M acetate buffer (pH 5.0) and 10 μL of β-glucuronidase solution (about 68,000 units / mL) to 20 μL of blood suspected, and 1 hour at 37 ° C. Retained. Then, add 10 μL of 50% (v / v) methanol containing 20 ng / mL of mepronil, which is an internal standard solution, and 0.5 mL of chloroform, stir for 1 minute using a vortex mixer, and then use an ultrasonic generator. After mixing for 15 minutes, the chloroform layer and the aqueous layer were separated by centrifugation (13,000 × g, 5 minutes, room temperature). After repeating this extraction operation twice, the chloroform layer was collected and dried by distilling off the solvent using a vacuum centrifugal concentrator. To this, 100 μL of 50% (v / v) methanol was added, and centrifugation (13,000 Xg, 5 minutes, room temperature) was performed, and the supernatant was recovered.

b. Measurement method The plasma curcumin concentration was measured by analyzing 2 μL of the upper groove solution prepared in the above a. Using LC-MS / MS (manufactured by Shimadzu Corporation). The LC-MS / MS analysis conditions are that the LC column is Atlantis T3 (2.1 X 150 mm, 3 μm, manufactured by Waters), the column temperature is 40 ° C, the flow velocity is 0.2 mL / min, and the mobile phase is A: 0.1% ( The mixture was v / v) formic acid aqueous solution and B: 0.1% (v / v) formic acid / acetonitrile, and gradient elution was performed. The MS analysis conditions are Electron Spray ionaization (ESI), Positive for ionization mode, Multiple Reaction Monitoring (MRM) for measurement mode, curcumin 369.1 → 177.2 (m / 2), mepronil 270 → 119 (m /). It was evaluated by z).
On the other hand, the calibration curve used to quantify the amount of curcumin contained in the sample is 50% (v / v) of 1.0, 2.0, 3.9, 7.8, 15.6, 31.3, 62.5, 125 or 250 ng.mL as curcumin. ) The same as above using various standard solutions (curcumin concentration 0.9 to 225 ng / mL) prepared by adding 10 μL of 50% (v / v) methanol solution of mepronil 2 Ong / mL to 90 μL of methanol solution (curcumin standard solution). It was performed by measuring under the conditions.

(3) Results Cmax total curcumin in blood (Cmax (ng / mL)) and total curcumin concentration in blood-area under the time curve (AUC (ng / mL (0-2h)). 0-2h) Is shown in Table 1.
Compared with the control, both Examples 1 and 2 and Comparative Examples 1 and 2 were significantly higher, and the water suspension dispersions of these compositions had excellent oral absorption in rats regardless of the viscosity of hydroxypropylmethylcellulose. Showed sex.

Example 3 (powdered composition)
Melt-treated curcumin (amorphous curcumin) crushed product 10.0 g, 2% by mass aqueous solution viscosity 3.2-4.8 mm ² / s hydroxypropyl methylcellulose (Shin-Etsu Chemical, 904) 10.0 g mixed and uniform powder A composition was obtained (Example 3).

Example 4 (powdered composition)
Melt-treated curcumin (amorphous curcumin) pulverized product 10.0 g, 3.6 to 5.1 mm ² / s hydroxypropyl methylcellulose (Shin-Etsu Chemical, 645W) 10.0 g was mixed to obtain a uniform powdery composition. (Example 4).

Examples 5-8 (capsules), Comparative Examples 3 and 4 (capsules)
(1) 30 g of maltodextrin (Sanei Saccharification Co., Ltd., NSD # 300) was added to 20.0 g of each of the powdered composition of the present invention of Examples 1 to 4 and the powdered compositions of Comparative Examples 1 and 2. Mix until uniform.
(2) To the obtained mixture, 420 mg of Japanese Pharmacopoeia calcium stearate (vegetable, manufactured by Taihei Kagaku Sangyo Co., Ltd.) and 80 mg of food-added silicon dioxide were added and lightly mixed to obtain a powder composition.
(3) 300 mg of each of the obtained powder compositions was collected, filled in a No. 2 hard capsule, and the capsule of the present invention of Example 5 (capsule containing the composition of the present invention of Example 1). The capsule of the present invention of Example 6 (capsule containing the composition of the present invention of Example 2), the capsule of the present invention of Example 7 (capsule containing the composition of the present invention of Example 3), The capsule of the present invention of Example 8 (capsule containing the composition of the present invention of Example 4), the capsule of Comparative Example 3 (capsule containing the composition of Comparative Example 1), the capsule of Comparative Example 4. (Capsule containing the composition of Comparative Example 2) was obtained.

Collapse test 1 (reference experiment 2)
Using the hard capsules obtained in Examples 5 to 8 and Comparative Examples 3 and 4, the disintegration test of the capsule was performed according to the disintegration test method of the Japanese Pharmacopoeia. Deionized water was used as the test solution. A sample was placed in each of the tubes (6 tubes) of the tester (6 capsules of each sample were used), an auxiliary plate was further inserted, and the auxiliary plate was moved up and down for 20 minutes to test the disintegration property of the capsule.
The results are shown in Table 2. (Listed in ascending order of HPMC viscosity)

From Table 2, it was shown that the capsule containing a composition obtained by mixing amorphous curcumin with hydroxypropyl methylcellulose having a viscosity of a 2% by mass aqueous solution of 10 mm ^{2 / s or less was excellent in disintegration property.}

Examples 9 and 10 (capsules), Comparative Examples 5 and 6 (capsules)
(1) To 20 g each of the powdered compositions of Example 1, Example 2, Comparative Example 1 and Comparative Example 2, 4.2 g of molten maltodextrin (Sanei Saccharification Co., Ltd., NSD # 300) was added and mixed uniformly.
(2) To 21 g of the obtained mixture, 3955 mg of Nikkei corn starch (manufactured by Nissho Chemical Co., Ltd.) was added and mixed, and then 210 mg of calcium stearate and 35 mg of silicon dioxide were further added and mixed to prepare four powder compositions. Got
(3) From the obtained powder composition, 320 mg of each was collected, filled in No. 2 capsule, and the capsule of the present invention of Example 9 (capsule containing the powder composition of the present invention of Example 1). The capsule of the present invention of Example 10 (capsule containing the powder composition of the present invention of Example 2), the capsule of Comparative Example 5 (capsule containing the powder composition of Comparative Example 1), Comparative Example 6 Capsule (capsule containing the powder composition of Comparative Example 2).

Disintegration test 2 (Disintegration test of Examples 9 and 10 capsules)
Using the hard capsules obtained in Examples 9 and 10 and Comparative Examples 5 and 6, the disintegration test of the capsule was performed according to the disintegration test method of the Japanese Pharmacopoeia. Deionized water was used as the test solution. A sample was placed in each of the tubes (6 tubes) of the tester (6 capsules of each sample were used), an auxiliary plate was further inserted, and the auxiliary plate was moved up and down for 20 minutes to test the disintegration property of the capsule.
The results are shown in Table 3. (Listed in ascending order of HPMC viscosity)

From Table 3, it was shown that the capsule containing a composition obtained by mixing amorphous curcumin with hydroxypropyl methylcellulose having an average viscosity of 2% by mass aqueous solution of 6 mm ^{2 / s or less is excellent in disintegration property.} ..

Reference Experiment 3 (Disintegration test of Examples 10 to 13 capsules and Comparative Examples 7 to 12 capsules)
The following disintegration test was carried out for the type and amount of the component (C) of the capsule of the present invention.
The composition of the capsules used in the experiment is shown in Table 4. The compositions shown in Table 4 were filled with 300 mg of each of the compositions in 1 capsule in the same manner as in Examples 5 to 8 to prepare capsules, and the disintegration test was carried out by the method described in the section of disintegration test 1.

The results of the disintegration test are shown in Table 5.

Comparative Example 9 in which the ratio of C / A + B is as small as 0.28, and Comparative Examples 7, 8 and 10 to 12 in which most of the component (C) is a gel-forming additive do not have good disintegration property. It has been shown.

Example 14 (Tablet production and disintegration test)
10 g of melt-treated curcumin (amorphous curcumin) powder, 10 g of hydroxypropyl methylcellulose (E3), 20 g of crystalline cellulose (Theoras PH-101), and 9.5 g of croscarmellose sodium (chicolate ND-2HS) described in Example 1. The mixed powder obtained by further mixing 0.42 g of calcium stearate and 0.08 g of silicon dioxide was produced by a tabletop single-shot tableting machine at 190 mg / tablet with a strength of 50 N and a diameter of 6 mm. When this tablet was tested for disintegration by the same test as described in the disintegration test 1 (reference test 1), it was confirmed that all the tablets were completely disintegrated.

Comparative Example 13 (Production and disintegration test of comparative tablets)
10 g of melt-treated curcumin (amorphous curcumin) powder, 10 g of hydroxypropyl methylcellulose (SE50), 20 g of crystalline cellulose (Theoras PH-101), and 9.5 g of croscarmellose sodium (chicolate ND-2HS) described in Example 1. The mixed powder obtained by further mixing 0.42 g of calcium stearate and 0.08 g of silicon dioxide was produced by a tabletop single-shot tableting machine at 190 mg / tablet with a strength of 50 N and a diameter of 6 mm. When the disintegration property of this tablet was tested by the same test as described in the disintegration test 1 (reference test 1), it was confirmed that a part of the tablet remained on the mesh.

Example 15 (Production of Granules)
The tablets produced in Example 14 were pulverized and passed through a No. 18 (850 μm) sieve to obtain granular granules remaining on the No. 75 (200 μm) sieve. The percentage of the granules remaining on the No. 30 (500 μm) sieve was 20%.

Claims (7)

(A) One or more selected from solid curcumin containing an amorphous substance and its relatives, and (B) ^{hydroxypropyl methylcellulose having a viscosity of a 2% by mass aqueous solution at 20 ° C. of 10 mm 2} / s or less. (C) A solid preparation for oral ingestion containing a gel non-forming pharmaceutical additive. The solid preparation for oral ingestion according to claim 1, wherein the content mass ratio (A / B) of the component (A) to the component (B) is 0.2 to 1. Ingredient (C) is a gel non-forming excipient, a gel non-forming disintegrant, a gel non-forming dispersant, a gel non-forming lubricant, a gel non-forming coloring agent, a gel non-forming fragrance and a gel. The solid preparation for oral ingestion according to claim 1 or 2, which is one or more selected from the group consisting of non-forming flavoring agents. The solid preparation for oral ingestion according to any one of claims 1 to 3, wherein the component (B) is hydroxypropylmethyl cellulose having a viscosity of a 2% by mass aqueous solution at 20 ° C. of 1 to 8 mm ^{2 / s or less.} The oral according to any one of claims 1 to 4, wherein the content mass ratio (C / (A + B)) of the component (C) and the sum of the component (A) and the component (B) is 0.4 to 7. Solid preparation for ingestion. The solid preparation for oral ingestion according to any one of claims 1 to 5, wherein the dosage form is selected from capsules, granules, pills, tablets and dry syrups. The solid preparation for oral ingestion according to any one of claims 1 to 6, wherein curcumin and its analogs are curcumin and turmeric pigment.