JP6851868B2 - Vitamin D3 stabilizing composition - Google Patents

Description

The present invention relates to a vitamin D3 stabilizing composition.

Vitamin D (vitamin D) is a type of vitamin and is classified as a fat-soluble vitamin. Vitamin D is further divided into Vitamin D2 (Ergocalciferol) and Vitamin D3 (Cholecalciferol). Vitamin D2 is abundant in plants and vitamin D3 is abundant in animals, and vitamin D3 plays an important role in humans.
Vitamin D3 (cholecalciferol) undergoes hydroxylation metabolism at the C25 position in the liver, changes to 25-hydroxycholecalciferol (also known as 25 (OH) D3, calciumdiol) and is stored in hepatocytes. When needed, it binds to α-globulin and is released into the lymph. It is used as vitamin D3 including this metabolite.
In recent years, the action of 25-hydroxycholecalciferol, which is a metabolite of vitamin D3, has attracted attention. For example, promotion of muscle development (Patent Document 1), improvement of hyperglycemia (Patent Document 2), improvement of fertility (Patent Document 3), improvement of allergic diseases caused by an increase in eotaxin (Patent Document 4), etc. It is typical.
In addition, development of other new applications has begun.

On the other hand, 25-hydroxycholecalciferol and choleliciferol are known to be chemically extremely unstable. Especially, the influence of oxidation is large. It is usually known that it is oxidized in air and its activity is rapidly lost. Patent Document 5 discloses a technique for a stable microemulsion containing vitamin D, an oil component, and a polyglycerin fatty acid ester polyhydric alcohol. Patent Document 6 describes a stabilizing composition in which active vitamin Ds are dispersed in a basic polymer substance. In Patent Document 7, vitamin D3s and dibutylhydroxytoluene or butylhydroxyanisole are dissolved in lower alcohol, and then only crystalline cellulose or crystalline cellulose / sodium carboxymethyl cellulose is added as an excipient to adsorb vitamin D3s, and then lower grade. Stable vitamin D3s obtained by distilling off alcohol are described. Patent Document 8 discloses a technique for producing a stable vitamin D3-containing preparation, which comprises adding only crystalline cellulose or crystalline cellulose / carboxymethyl cellulose sodium as an excipient.

Japanese Patent Application Laid-Open No. 2011-511828 Japanese Patent Application Laid-Open No. 2011-511827 Special Table 2009-504699 Japanese Patent Application Laid-Open No. 2013-545766 Japanese Unexamined Patent Publication No. 11-236330 Japanese Unexamined Patent Publication No. 05-279260 Japanese Patent No. 2963718 Japanese Patent No. 2914690

The present inventors are studying the stabilization of the active form of 25-hydroxycholecalciferol, but the stability of 25-hydroxycholecalciferol and vitamin D3 (cholecalciferol) is increased by a specific fatty acid ester. I found a phenomenon to do. Such a phenomenon has not been described in the prior art. The present inventors have studied this phenomenon repeatedly and completed the present invention.

That is, it is an object of the present invention to provide a composition in which vitamin D3 is stabilized.

The main configuration of the present invention is as follows.
1. 1. A composition comprising vitamin D3 and sorbitan monolaurate or a glycerin fatty acid ester having a degree of polymerization of glycerin of 1 to 5.
2. The composition according to 1, wherein the vitamin D3 is cholcalciferol and / or the active vitamin D3.
3. 3. 2. The composition according to 2, wherein the active vitamin D3 is 25-hydroxycholecalciferol.
4. A method for producing a stabilized composition of vitamin D3, which comprises mixing an ethanol solution of vitamin D3 with sorbitan monolaurate or a glycerin fatty acid ester having a degree of polymerization of glycerin 1 to 5, and then drying the mixed solution containing ethanol under reduced pressure. ..

The present invention can provide a composition in which vitamin D3 is stabilized. Vitamin D3 is stable for a long time in the composition obtained by the present invention. Further, since the composition of the present invention dissolves or disperses in water, it is extremely useful as a raw material for foods and pharmaceuticals.

It is a graph which shows the result of the 25 (OH) D3 stability test of the composition of this invention.

The present invention relates to a composition comprising active vitamin D3 and a water-soluble cellulose derivative.
Vitamin D3 used in the present invention is choleciferol and active vitamin D3s.
Active vitamin D3s include 1α, 25- (OH) 2-D3 (25-hydroxycholecalciferol), 1α-hydroxyvitamin D3 (1α-OH-D3), 1α, 25-dihydroxyvitamin D3 (1α,). 25- (OH) 2-D3), 1α, 24-dihydroxyvitamin D3 (1α, 24- (OH) 2-D3), 1α, 24,25-trihydroxyvitamin D3 (1α, 24,25- (OH)) 3-D3), 1α-Hydroxy-24-oxovitamin D3, 1α,25-dihydroxy-24oxovitamin D3, 1α,25-dihydroxyvitamin D3-26,23-lactone, 1α,25-dihydroxyvitamin D3-26 , 23-Peroxylactone, 26,26,26,27,27,27-hexafluoro-1α, 25-dihydroxyvitamin D3 and other active vitamins D3 having a hydroxyl group at the 1α position, or 25-hydroxyvitamin D3 ( 25-OH-D3), 24-hydroxyvitamin D3 (24-OH-D3), 24-oxovitamin D3, 24,25-dihydroxyvitamin D3 (24,25-(OH) 2-D3), 25-hydroxy- Examples thereof include active vitamin D3s having no hydroxyl group at the 1α position such as 24-oxovitamin D3, 25-hydroxyvitamin D3-26,23-lactone and 25-hydroxyvitamin D3-26,23-peroxylactone.

Among these active vitamins D3, 1α, 25- (OH) 2-D3 (25-hydroxycholecalciferol or "25 (OH) D3") is preferable.

The glycerin fatty acid ester used in the present invention is a typical food emulsifier in which a fatty acid is ester-bonded to one or two of the three hydroxy groups of glycerin. The glycerin fatty acid ester used in the present invention preferably has a glycerin polymerization degree of 1 to 5.

The sorbitan fatty acid ester is an ester of sorbitan and a fatty acid, and is used alone or in combination with other surfactants as a food emulsifier or a cosmetic / industrial surfactant.
Sorbitan has four hydroxyl groups, and various fatty acids are ester-bonded to each.
There are many types. For the object of the present invention, those exhibiting sorbitan monolaurate (sorbitol type) are suitable.

To obtain the composition of the present invention, vitamin D3 is dissolved in a solvent such as ethanol. Water or ethanol is preferable as the solvent. This solution is homogeneously mixed with the glycerin fatty acid ester and / or the sorbitan fatty acid ester, and after the mixing is completed, the solution of the glycerin fatty acid ester and / or the sorbitan fatty acid ester containing vitamin D3 is dried with a drying device to remove the solvent. be able to. In mixing, vitamin D3 is dispersed so as to be dispersed as small particles as much as possible. A high pressure homogenizer can also be used if desired. The drying is preferably performed at a low temperature as much as possible, and it is more preferable to adopt a method such as vacuum freeze-drying or vacuum drying.

Glycerin fatty acid ester and / or sorbitan fatty acid ester and vitamin D3 are glycerin fatty acid ester and / or sorbitan fatty acid ester in a ratio of 0.1 to 10 parts by mass of choleciferol and / or 25-hydroxycholecalciferol per 1000 parts by mass. It is preferable to be.
The composition thus obtained is a state in which the active vitamin is dispersed in the glycerin fatty acid ester and / or the sorbitan fatty acid ester, and the glycerin fatty acid ester and / or the sorbitan fatty acid ester is dissolved and dispersed in water, and is dissolved in water or in an oil or oil. Dissolves quickly.
This composition can also be made into a powder by adding starch or sugar.

The present invention will be described below with reference to test examples.
<Stability test of vitamin D3 with glycerin fatty acid ester and / or sorbitan fatty acid ester>
(1) Vitamin D3
The test was conducted using vitamin D3 shown in Table 1 below.

(2) Glycerin fatty acid ester and sorbitan fatty acid ester used The compounds shown in Table 2 below were used as glycerin fatty acid ester and sorbitan fatty acid ester in the test.

(3) Test method <Preparation of sample>
1) Preparation of choleciferol 175 μg of choleciferol crystal powder was dissolved in 1750 mg of absolute ethanol to prepare a solution.
1.75 g of this solution was added to 1 g of each glycerin fatty acid ester and / or sorbitan fatty acid ester previously weighed in a vial, and the mixture was stirred and mixed for 3 minutes using a vortex mixer. Then, ethanol was dried under reduced pressure and removed to obtain a sample.

2) Preparation of 25 (OH) D3 10.205 mg of (25 (OH) D3) was dissolved in 500 g of absolute ethanol to prepare a solution. 2.5 g of this solution was added to 1 g of glycerin fatty acid ester or sorbitan fatty acid ester previously weighed in a vial, and the mixture was stirred and mixed for 3 minutes using a vortex mixer. Then, ethanol was dried under reduced pressure to obtain a sample.

3) Stability test The above sample was stored in a constant temperature bath at 60 ° C. for 2 weeks, and the residual rate of vitamin D3 was measured.
<Cholecalciferol analysis method>
1. 1. Precisely weigh about 0.01 g of a sample containing choleciferol, put it in a container of about 20 mL, add ethanol with a 10 mL volumetric pipette, stir, sonicate for 5 minutes, stir, and collect about 1 mL in an Eppen tube. Centrifuge for 5 minutes. The supernatant is used as a sample solution.
2. Adjust the standard cholecalciferol with ethanol to 1 mg / mL. Then, it is appropriately diluted with an ethanol solution to 0.1, 0.5, 1.0, 5.0, 10.0 μg / mL to prepare a standard solution.
10 μL of each of the sample solution and the standard solution was injected into high performance liquid chromatography under the following conditions to determine the peak area of cholecalciferol, and the calibration curve (y = bx + a: a = section, from the peak area of cholecalciferol in the standard solution, b = Inclination) is determined, and the content of cholecalciferol in the sample is determined according to the calculation method shown below.
3. 3. Measurement condition detector: Ultraviolet absorptiometer (measurement wavelength 265 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm filled with octadecylated silica gel with a particle size of 5 μm (Capcellpak C-18 UG-120, manufactured by Shiseido Co., Ltd.)
Column temperature: 40 ° C
Mobile phase: 80% aqueous acetonitrile solution Flow rate: 1 mL / min 4. Calculation method Cholecalciferol content (μg / g) = (Cholecalciferol area of sample solution-intercept) / slope x constant volume / sampling amount x purity

<Analysis method of 25 (OH) D3>
Weigh accurately about 0.1 g of a sample containing 1.25 (OH) D3 in a container of about 20 mL, add ethanol with a 10 mL volumetric pipette, stir, sonicate for 10 minutes, stir, and transfer about 1 mL to an Eppen tube. 15000plm Centrifuge for 5 minutes. The supernatant is used as a sample solution.
2.25 (OH) D3 standard product is adjusted with ethanol to 1 mg / mL, and then with ethanol solution to 0.1, 0.2, 0.5, 1.0, 2.0 μg / mL. Dilute appropriately to make a standard solution. 10 μL of each of the sample solution and the standard solution was injected into high performance liquid chromatography under the following conditions to determine the peak area of 25 (OH) D3, and the calibration curve (y = bx + a:) was obtained from the peak area of 25 (OH) D3 of the standard solution. (a = section, b = slope) is determined, and the 25 (OH) D3 content of the sample is determined according to the calculation method shown below.
3. 3. Measurement condition detector: Ultraviolet absorptiometer (measurement wavelength 265 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm filled with octadecylated silica gel with a particle size of 5 μm (Capcellpak C-18 UG-120, manufactured by Shiseido Co., Ltd.)
Column temperature: 40 ° C
Mobile phase: 80% aqueous acetonitrile solution Flow rate: 1 mL / min 4. Calculation method 25 (OH) D3 content (μg / g) = (25 (OH) D3 area of sample solution-intercept) / slope x constant volume / sampling amount x purity

(3) Results The stability test results of each sample are shown in Table 3 and FIG. The results are expressed as the residual rate after the storage period has elapsed.

Cholecalciferol is stabilized by condensed pentaglycerin ricinoleate, mono-diglyceride oleate, and pentaglycerin trioleate (Sunsoft No. 818R, Sunsoft O-30V, Sunsoft A-173E). However, such effects could not be confirmed for decaglycerin decaoleate and decaglycerin pentaoleate. That is, it is considered that the degree of glycerin polymerization of the glycerin fatty acid ester is related to the stabilization of choleciferol. That is, it was expected that the degree of glycerin polymerization was preferably 5 or less.
On the other hand, 25 (OH) D3 is stabilized by sorbitan monolaurate (L-300), pentaglycerin condensed ricinoleate (Sunsoft No. 818R), pentaglycerin monooleate (Sunsoft A-171E), and monoglyceride (Emulgy MH). It was confirmed that it became.

Claims (2)

A composition containing 25-hydroxycholecalciferol and condensed pentaglycerin ricinoleate or pentaglycerin monooleate. The composition according to claim 1, wherein a solution of condensed pentaglycerin ricinoleate or pentaglycerin monooleate and an ethanol solution of 25-hydroxycholecalciferol is mixed, and then the mixed solution containing ethanol is dried under reduced pressure. how to.

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