JP2014118391A - Pharmaceutical preparation comprising component having hardly water-soluble property - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hard capsule pharmaceutical preparation comprising an aqueous solution in which curcuminoid or other substance having a hardly water-soluble property is dispersed.SOLUTION: A capsule pharmaceutical preparation is prepared by including an aqueous solution containing curcuminoid or other substance having a hardly water-soluble property, thickening polysaccharides, glycerin, salt and water in a capsule composed of hydroxypropyl methylcellulose.

Description

  The present invention relates to a hard capsule formulation containing an aqueous solution in which a hardly soluble substance is dispersed in an aqueous solvent such as microparticulated curcuminoid.

In order to ingest a substance that is difficult to dissolve in water orally, a method is known in which it is administered after being dissolved in an oily solvent such as edible oil. In this case, the administration substance is emulsified and dispersed in the digestive tract together with the oily solvent and absorbed. However, depending on the substance, there is a problem that precipitation occurs during emulsification, resulting in a decrease in absorbability. Moreover, since the solubility in oil is low, there is a problem that the total dose per administration increases. Examples of poorly water-soluble substances include various plant extracts such as curcumin and silymarin.
Curcuminoids obtained from the rhizomes of Curcuma longa L., a ginger family plant that has long been known as a water-insoluble natural colorant, have recently attracted attention as a health promotion material. Curcuminoid is a general term for compounds containing curcumin and its analogs, demethoxycurcumin and bisdemethoxycurcumin, and is also a kind of polyphenol.
In the present invention, curcuminoid refers to linear diallyl heptanoids such as curcumin, demethoxycurcumin, bisdemethoxycurcumin, yaktinone A, yaktinone B, tetrahydrocurcumin, and dihydroxytetrahydrocurcumin. It is a generic term for a salt of an oid, an ester, and other analogs of a linear diallyl heptanoid, for example, Kashmunin A, Kashmunin B, and Kashmunin C, which are called polymers of curcumin.

  Curcuminoid is a substance having excellent heat resistance, oxidation resistance and reduction resistance. Tablets obtained by compressing curcuminoid powder and capsule supplement preparations are stable. For this reason, these preparations are widely used. However, curcuminoids are soluble in hot water, ethanol, propylene glycol, and glacial acetic acid, but are hardly soluble in water (cold water or room temperature water). Therefore, even when curcuminoid powder or turmeric powder is taken orally, it has become clear that curcuminoids are hardly absorbed in the digestive tract because they are poorly soluble in water (non-patent literature). 1: Biological & Pharmaceutical Bulletin 34 (5), 660-665, 2011). For this reason, when taking curcuminoid as a supplement, it was necessary to take a large amount in consideration of low absorption efficiency. In order to solve this, it has been proposed to use a water-soluble curcuminoid glycoside that improves the in vivo absorbability of curcuminoid and exhibits excellent drug efficacy in vivo (Patent Document 1: JP-A-2005-41817). Issue gazette). This technology uses a glycosylated aromatic aldehyde compound as a starting material to condense with an acetylacetone-boron oxide complex to form a curcuminoid glycoside, and remove the boron by heating the reaction product with a lower alcohol. A water-soluble curcumin glycoside is obtained. However, since the absorption rate and safety of the obtained curcumin glycoside in the digestive tract have not been clarified, it is practically difficult to use it for foods and health foods.

On the other hand, curcuminoids are widely used as food pigments. Research in this field has proposed a technique for solubilizing (dispersing) curcuminoids in water.
For example, an aqueous turmeric pigment preparation has been developed in order to color an aqueous substance with a turmeric pigment, and a method of coloring using the turmeric pigment formulation has been proposed (Patent Document 2: JP-A-2005-185237). In the technique of Patent Document 2, curcumin is dissolved in water-soluble polysorbate, and then this polysorbate is dispersed in water. However, curcumin precipitates (insolubilizes) during storage.

As another example, by dispersing an alcohol solution in which a poorly water-soluble component such as curcumin or tetrahydrocurcumin is dissolved in water, the poorly soluble component is first made into fine particles, and then the fine particles are emulsified (glycerin fatty acid esters, sucrose fatty acid). Esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, calcium stearate lactate, lecithins, cyclodextrins, etc.) There is a method of obtaining (Patent Document 3: Japanese Patent Application Laid-Open No. 2005-328839).
In Patent Document 4 (Japanese Patent Laid-Open No. 2009-263638), an aqueous solution containing gati gum and curcuminoid is subjected to high pressure treatment with an ultra-high pressure homogenizer or the like to regenerate insoluble curcuminoid particles to nano size (particle size of 1 μm or less). A technique for obtaining an ultrafine particle dispersion without aggregation has been proposed.
The composition of Patent Document 4 has been confirmed to increase the absorption rate (AUC) by 30 times when administered orally to humans (Non-Patent Document 1). The composition of the invention of Patent Document 4 is marketed as curcumin (trade name: ceracurcumin) having good absorbability.
This product is a water-soluble composition containing 30% or more of water, and is suitable for blending into beverages and foods. However, in the case of such beverages and foods, in order to ingest the amount of curcumin that should be absorbed into the body on a daily basis, in the case of beverages, it is necessary to ingest 100 ml or more. In many cases, it is difficult to take a large amount.
On the other hand, supplement tablets and capsules are difficult. In particular, in the case of capsules, the capsules are dissolved by the contained water, making it difficult to manufacture.
The above-mentioned problem that occurs in curcuminoids is a problem that always occurs when a hard capsule is filled with a composition in which a poorly water-soluble substance is dispersed in a water-soluble solvent such as water.

JP 2005-41817 A Japanese Patent Application Laid-Open No. 2005-185237 JP 2005-328839 A JP 2009-263638 A

Biological & Pharmaceutical Bulletin 34 (5), 660-665, 2011.

  An object of the present invention is to provide a hard capsule preparation filled with an aqueous solution in which curcuminoids and other poorly water-soluble substances are dispersed.

  As a result of researches on capsule formulations encapsulating curcuminoids, the present inventors have found that the formulation is stabilized by the combination of capsules made of a specific material and the curcuminoid composition to be encapsulated, and the present invention has been completed.

The present invention has the following configuration.
(1) A capsule preparation containing a water-soluble solution in which a poorly water-soluble substance is dispersed, wherein glycerin, water, and sodium chloride are contained in the water-soluble solution, and hydroxypropylmethylcellulose is used as a capsule constituent.
(2) The capsule formulation as the capsule constituent according to (1), wherein the poorly water-soluble substance has an average particle size of 1 μm or less.
(3) The capsule preparation according to (1) or (2), wherein the water-soluble solution in which the poorly water-soluble substance is dispersed has a water content of 40% or less, glycerin 40% or more, and sodium chloride 1% or more.
(4) The capsule preparation according to (1) or (2), wherein glycerin is 40 to 70% by mass and sodium chloride is 1 to 8% by mass.
(5) The capsule preparation according to any one of (1) to (4), wherein the poorly water-soluble substance is a curcuminoid.
(6) The capsule preparation according to (5), which contains a thickening polysaccharide.
(7) The capsule formulation according to (6), wherein the thickening polysaccharide is gati gum.
(8) The capsule preparation according to (7), wherein curcuminoid is contained in an encapsulated solution by 7% by mass or more.
(9) The capsule preparation according to any one of (6) to (8), wherein water in the encapsulated liquid is 25 to 36% by mass, glycerin is 44 to 63% by mass, and sodium chloride is 1.25 to 6% by mass.

  By carrying out the present invention, a hard capsule formulation containing a water-soluble solution in which a poorly water-soluble substance is dispersed is provided. Further, by implementing the present invention, a capsule preparation having high storage stability and a curcuminoid absorption rate increased by 30 times compared to a capsule preparation filled with a conventional curcumin powder is provided. In addition, since a small amount of intake is sufficient compared to beverages and foods, there is no burden in drinking, so daily management becomes easy.

It is an image of the result of having tested the water resistance by the material of the hard capsule marketed. It is the image which image | photographed the state after the preservation | save of the hard capsule which includes the solution containing sodium chloride of various density | concentration, glycerin, and curcuminoid.

The present invention will be described by exemplifying curcuminoids as poorly water-soluble substances. For poorly water-soluble substances other than curcuminoids, it can be carried out according to curcuminoids.
(1) Curcuminoid solution and production method thereof The curcuminoid solution (hereinafter, also referred to as “curcuminoid liquid composition”) included in the capsule of the present invention contains gati gum, curcuminoid having an average particle size of 1 μm or less, glycerin, and water. It is characterized by doing. This curcuminoid solution can be prepared according to the description in Patent Document 4 (Japanese Patent Laid-Open No. 2009-263638). This solution may contain other solvents in addition to water and glycerin when the capsule is filled. For example, lower alcohols such as ethanol compatible with water: polyhydric alcohols such as propylene glycol: sugar solutions such as fructose glucose solution, sucrose solution, and isomerized sugar solution. Water is 40 mass% or less, Preferably it is 25-36 mass%.
The amount of glycerin can be reduced by adding salt. It becomes possible to make glycerin 80 mass% or less by adding salt 1 mass% or more. Preferably, glycerin is 40 to 70% by mass and sodium chloride is 1 to 8% by mass.
By using an aqueous solution in which such a poorly water-soluble substance is dispersed, an encapsulated solution in which 7% by mass or more of curcuminoid is dispersed can be prepared.

  The thickening polysaccharide is dissolved in a mixed solvent of water, glycerin and other solvents. At this time, the composition must be such that curcuminoids do not dissolve. Water is preferably blended in the curcuminoid liquid composition in an amount equal to or greater than the thickening polysaccharide.

  The “curcuminoid” as used in the present invention is mainly composed of curcumin obtained from the rhizome of Curcuma longa LINNE. In addition to linear diallyl heptanoids such as dihydroxytetrahydrocurcumin, salts and esters of these linear diallyl heptanoids, and other analogs of linear diallyl heptanoids, such as polymers of curcumin It contains Kashmunin A, Kashmunin B, Kashmunin C, etc., and all of these components may not be contained. Also, a turmeric pigment used as a food additive, which is a turmeric powder obtained by pulverizing a dried rhizome of Curcuma longa LINNE, and using the turmeric powder as a suitable solvent (for example, ethanol, fats and oils, propylene glycol) , Hexane, acetone, etc.) to obtain crude curcumin or oleoresin (turmeric oleoresin), and purified curcumin.

“Curcuminoid” is preferably curcumin prepared by extraction from dried turmeric rhizomes (turmeric powder) with ethanol, propylene glycol, hexane or acetone. More preferably, curcumin purified to such an extent that the bitterness and hotness derived from the turmeric powder and the turmeric odor are reduced or removed is preferably used. More preferred is curcumin in a crystalline state. Such curcumin can be prepared by extracting turmeric powder with hexane and acetone, filtering the extracted solution, and drying to volatilize the solvent.
For convenience, a commercially available curcuminoid (curcumin powder) can be used.

  Examples of the thickening polysaccharide used in the present invention include gati gum, xanthan gum, guar gum, locust bin gum, tamarind gum, carrageenan, caraya gum, pectin, gellan gum and the like. Gati gum is particularly preferred as the thickening polysaccharide. Gati gum is mainly composed of polysaccharides obtained by drying the stem secretion of Anogeissus Latifolia WALL. And is known as a thickening stabilizer (food additive). . The gati gum used in the present invention is commercially available. An example of such is Gati Gum SD manufactured by San-Ei Gen FFI Co., Ltd.

It is preferable to dissolve the thickening polysaccharide in a solvent in advance to obtain a thickening polysaccharide solution, and then add and mix the curcuminoid. The solvent for dissolving the thickening polysaccharide is not particularly limited as long as it is a solvent used in foods and does not dissolve curcuminoids, but preferably in addition to water and glycerin, a solvent compatible with water and water. Can be mentioned. Examples of such solvents include lower alcohols such as ethanol: propylene glycol polyhydric alcohols: sugar solutions such as fructose glucose solution, sucrose solution, and isomerized sugar solution.
The thickening polysaccharide is dissolved in a water-containing solvent (preferably water) so as to be 1 to 10% by mass.
Next, the curcuminoid is added to and mixed with this thick polysaccharide-containing aqueous solution.
The mixture of the thickening polysaccharide-containing aqueous solution and the curcuminoid is then subjected to micronization. A physical crushing method is preferable as the method for the fine particle treatment. Examples of the physical crushing method include a treatment using a wet pulverizer capable of micronizing curcuminoids until the average particle size (median size: d50) is 1 μm or less. Specific examples of the wet pulverizer include ultra visco mill and dyno mill. A wet pulverizer such as a sand mill or a coball mill can also be used.
By making the particles fine until the average particle diameter of the curcuminoid becomes 1 μm or less, the curcuminoid is stably dispersed in water, and absorption in the intestinal tract is promoted. Furthermore, even when stored for a long period of time, a curcuminoid in which curcuminoid is stably dispersed in a water-containing solvent can be obtained in a state where aggregation and precipitation are significantly suppressed.

  The fine particle treatment is performed so that the average particle size (median diameter: d50) is 1 μm or less, preferably 0.9 μm or less, more preferably 0.5 μm or less. Curcuminoids are prepared in aqueous solutions containing thickening polysaccharides to have an average particle size of less than this, thereby improving absorbability in the digestive tract, dispersibility and dispersion stability in aqueous solutions, The effect of suppressing precipitation and the effect of improving absorbability in the body are more likely to be exhibited.

The average particle diameter (median diameter) of curcuminoid in the liquid curcuminoid composition of the present invention, in other words, the average particle diameter (median diameter) of curcuminoid in the thickening polysaccharide solution is a (wet) laser diffraction particle size distribution measuring device. It can be measured using Microtrac MT-3000II (manufactured by Microtorac INC.) (Conditions: refractive index: 1.81, measurement range: 0.021 to 2000 μm, particle size distribution: volume basis).
Further, the homogenization treatment can be performed again to make fine particles. The homogenization method is not particularly limited as long as it is a method in which components such as finely divided curcuminoids are uniformly dispersed, and an emulsification / dispersion device such as a nanomizer, a microfluidizer, a homogenizer, or an ultrasonic disperser is used. Can be done. By performing the homogenization treatment, the aggregation of the finely divided curcuminoid is loosened, and the dispersibility in water and the dispersion stability are further improved.

  This curcuminoid liquid composition is stable in charge. However, the pH can be adjusted as necessary. Preferably, the pH is adjusted to 8 or less. Examples of the pH adjusting agent to be used include inorganic acids such as phosphoric acid, sulfuric acid and hydrochloric acid, and organic acids such as citric acid, lactic acid and malic acid. Citric acid is particularly preferred.

  The curcuminoid liquid composition thus prepared is commercially available, and may be filled into a hard capsule after purchase and further adjustment of the desired concentration. Examples of the commercially available curcuminoid liquid composition include “Ceracrumin (CR-011L, CR-031P)” manufactured by TheraValues Co., Ltd. In addition, since the curcuminoid liquid composition marketed is usually adjusted to have a water content of 30% and a glycerin content of about 40%, glycerin must be further added to adjust the glycerin content to 70% or more. . When adjusting by adding glycerin, it is preferable to perform the homogenization operation again using a high-pressure homogenizer or the like.

  Hydroxypropyl methylcellulose (hereinafter “HPMC”) capsules filled with a liquid composition containing this curcuminoid are prepared based on hydroxypropylmethylcellulose. As an example, Japanese Patent Application Laid-Open No. 03-279325 describes a production method, which is commercially available from Qualicaps Co., Ltd. and Capsugel Japan.

Hereinafter, the contents of the present invention will be further described in the following examples and test examples.

<Reference Example 1>
Method for preparing curcuminoid liquid composition based on JP2009-263638

Preparation of curcuminoid liquid composition having the composition shown in Table 1

Gati gum (Gati gum SD: Saneigen FFI Co., Ltd.) was added to water, and glycerin was further added to prepare an aqueous solution.
Next, curcuminoid powder (powder curcumin No. 3705: Saneigen FFI Co., Ltd., average particle size (d50): 13.81 μm, crystalline) was added to the aqueous solution and dispersed and mixed with water. The mass was adjusted.
The mixed liquid in which the curcuminoid powder is dispersed is applied to a wet mill DYNOMILL (WAB DYNOMILL KDL) and wet pulverized, and then dispersed and homogenized with a homogenizer (APV GAULIN high pressure homogenizer 15MR-8TA). Thus, a liquid curcuminoid (curcuminoid liquid composition) was obtained.

  The average particle diameter of the obtained curcuminoid liquid composition was evaluated by measuring the median diameter (d50). Median diameter (d50) is laser diffraction particle size distribution analyzer Microtrac MT-3000II (manufactured by Microtorac INC.) (Wet) (measurement conditions; refractive index: 1.81, measurement range: 0.021-2000 μm, particle size distribution: volume basis) It measured using. The particle diameter was 0.19 μm.

<Test Example 1>
Selection of hard capsules that are resistant to aqueous solutions.

As a reference example, a curcuminoid liquid composition shown in Table 1 was used, and glycerin was added thereto to prepare a composition having the composition shown in Table 2 below, which was filled in various hard capsules.

Samples 1 to 4 were filled in 400 mg each in pullulan capsules, gelatin capsules, and hydroxypropylmethylcellulose capsules (both No. 2 capsules manufactured by Capsugel Japan) to produce a capsule preparation containing curcuminoids.
Each capsule was allowed to stand in a room at room temperature and a relative humidity of 40 to 50%, and the state was observed.

<Result>
The observation results are shown in FIG.
From the observation results of each sample, only the preparations filled in the hydroxypropylmethylcellulose capsules of Sample 3 and Sample 4 were stable. Based on this result, the following tests were conducted using hydroxypropylmethylcellulose hard capsules.

<Test Example 2>
In order to confirm that the addition of glycerin and sodium chloride contributed to the stability of hydroxypropylmethylcellulose capsules, the following test was conducted.
First, salt is dissolved in warm water and diluted with glycerin to have a water content of 20 to 32% by mass, salt of 0 to 8% by mass, and glycerin of 60 to 80% by mass as shown in Table 3. An aqueous solution having a concentration adjusted so as to be was prepared. The adjustment was carried out by mixing and stirring (non-heated) the weighed aqueous solutions of various salt concentrations and glycerin with a disperser until uniform, and visually confirming that they were uniformly mixed to prepare a test solution. Subsequently, 400 mg each was filled into No. 2 hard capsules (manufactured by Capsugel Co., Ltd.) made of hydroxypropylmethylcellulose. Each capsule was allowed to stand in a room at room temperature and a relative humidity of 40 to 50%, and the state was observed. The stability at room temperature was confirmed.

  The test solution has the composition shown in Table 3.

<Result>
The image which observed the state of each capsule is shown in FIG.
From Table 3 and FIG. 2, the following became clear.
(1) When no salt was added, the hydroxypropylmethylcellulose hard capsule was stable when a solution adjusted to a water content of 20% and glycerin 80% was filled. When the water content was 30% and the glycerin was 70%, the hydroxypropylmethylcellulose hard capsule was deformed.
(2) By adding 3 to 8% of sodium chloride, it is possible to maintain the stability of the hydroxypropylmethylcellulose hard capsule even if the glycerin content is 60 to 70% and the water content is increased to 27 to 32%. there were.
(3) It has been found that by adding salt, the amount of glycerin can be decreased and the water content can be increased.

<Test Example 3>
Stability test of hydroxypropylmethylcellulose hard capsules filled with curcuminoid dispersion

Using the curcuminoid liquid composition shown in Table 1 in the same procedure as in the test of Test Example 2, glycerin and sodium chloride were added thereto to prepare a composition having the composition shown in Table 4 below. In the same manner as in No. 2, the capsules were filled into hydroxypropylmethylcellulose hard capsules. In addition, the inclusion solution was prescribed with the goal of making capsules containing 30 mg or more of curcumin per capsule.
Each capsule was allowed to stand in a room at room temperature and a relative humidity of 40 to 50%, and the state was observed. The stability at room temperature was confirmed.

<Result>
As described above, Samples 10 to 12 contained 30 mg or more of curcuminoid per capsule and were stable capsules.
The following conditions were necessary to fill a hard capsule made of hydroxypropylmethylcellulose with 400 mg of the encapsulated solution to form a stable capsule formulation.
(1) When the glycerin concentration is 44 to 63% and the salt is 1.25 to 6% by mass, the water content is 25 to 35% by mass.
(2) By increasing the salt concentration, the amount of glycerin can be decreased, the relative water content can be increased, and the curcumin content can be increased.

<Human absorption test>
Absorption of healthy individuals was confirmed according to the method of human test described in Biological & Pharmaceutical Bulletin 34 (5), 660-665, 2011. Ten capsules of hydroxypropylmethylcellulose encapsulating the capsule of Sample 10 of Test Example 3 and 32 mg of powdered curcuminoid were orally administered (per person), and curcumin appearing in the blood after 4 hours was measured. When the capsule preparation of the present invention was administered, curcumin in the blood was detected, but when powdered curcuminoid was administered, curcumin was not detected in the blood.

Claims (9)

  A capsule preparation containing a water-soluble solution in which a poorly water-soluble substance is dispersed, wherein glycerin, water and sodium chloride are contained in the water-soluble solution, and hydroxypropylmethylcellulose is used as a capsule constituent.   2. The capsule preparation as a capsule component according to claim 1, wherein the poorly water-soluble substance has an average particle size of 1 μm or less.   The capsule preparation according to claim 1 or 2, wherein the water-soluble solution in which the poorly water-soluble substance is dispersed has a water content of 40% or less, glycerin 40% or more, and sodium chloride 1% or more.   The capsule preparation according to claim 1 or 2, wherein glycerin is 40 to 70 mass% and sodium chloride is 1 to 8 mass%.   The capsule preparation according to any one of claims 1 to 4, wherein the poorly water-soluble substance is a curcuminoid.   The capsule preparation according to claim 5, comprising a thickening polysaccharide.   The capsule preparation according to claim 6, wherein the thickening polysaccharide is gati gum.   The capsule preparation according to claim 7, wherein the curcuminoid is contained in an encapsulated solution by 7% by mass or more.   The capsule preparation according to any one of claims 6 to 8, wherein water in the encapsulated liquid is 25 to 36% by mass, glycerin is 44 to 63% by mass, and sodium chloride is 1.25 to 6% by mass.