JPH03251536A - Bile acid internal liquid agent and preparation thereof - Google Patents

Abstract

PURPOSE:To provide a bile acid preparation accelerating emulsification of oily substances, well absorbed and useful for drugs, healthy foods and feed additives by compounding a bile acid and a fatty acid ester. CONSTITUTION:A bile acid and a sorbitan fatty acid ester or caprylic acid glycerol ester as essential components are heated at 80-150 deg.C, respectively, and subsequently mixed with each other. If necessary, an oil-soluble substance and an oily substance are dissolved in the mixture and a preservative, thickening agent, perfume, sweetener, colorant, etc., are further compounded with the mixture. The prepared composition is formed into the objective preparation as such or after filled into a soft capsule. The bile acid is selected from cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, conjugated bile acid and bile powder, and the fatty acid is selected from sorbitan monocaprylate, glyceryl monocaprylate, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to an internal bile acid solution comprising a bile acid and a fatty acid ester, and a method for producing the same. The bile acid oral liquid preparation of the present invention is a clear liquid preparation in which bile acids are dissolved in fatty acid esters, and has excellent stability. It can be widely used as a pharmaceutical, food, and feed additive by adding oily substances such as fish oil.

BACKGROUND OF THE INVENTION Bile acids are drugs that are widely used as choleretic agents and liver function improving agents. In addition to the effect of increasing the appetite of animals, bile acids have recently been known to have the effect of promoting the absorption of oily substances such as fish oil, animal oil, vegetable oil, and oily vitamins. It has also come to be widely used as a marine medicine. Therefore, it would be more effective if bile acids, which have the effect of promoting emulsification of oily substances and improving absorption, are dissolved in the oily substances.

However, bile acids are in powder form and do not dissolve in oily substances, and are bulky and highly scattering, making them extremely difficult to handle. Preparation of the liquid formulation was extremely difficult.

Conventionally, as a bile acid liquid preparation for internal use, a composition consisting of bile acid and polyglycerin fatty acid ester (Japanese Patent Application Laid-open No. 1-186
No. 817) has been reported.

Problems to be Solved by the Invention However, since the above bile acid composition is a preparation in which bile acid is simply dispersed in polyglycerol fatty acid ester, it forms a homogeneous phase with an oily substance. In the long term, bile acids and oil-like substances become separated, which not only results in a lack of uniformity in the formulation, but also reduces the effect of promoting emulsification of the target oil-like substance and improving absorption. There is a big drawback. Therefore, a formulation that does not have the above-mentioned drawbacks is desired.

Means to Solve the Problem When dissolving powder in an oily substance, there are various additives that can have a dissolving effect, but due to safety reasons, there are only a limited number of additives that can be used in food, feed, medicine, etc. There is.

The present inventors selected glycerin monooleate, glycerin monostearate, glycerin dioleate, decaglycerin trioleate, decaglycerin triisostearate, Many glycerin fatty acid esters such as decaglycerin pentaoleate, decaglycerin pentaisostearate, diglycerin monostearate, diglycerin monooleate, diglycerin monoisostearate are used to dissolve bile acids and oily substances. However, none of the tests were able to form a homogeneous phase of bile acid and oily substance.

However, when we attempted to prepare a bile acid solution using sorbitan fatty acid ester or caprylic acid glycerin ester, which are used as food emulsifiers, we found that the bile acid and sorbitan fatty acid ester or caprylic acid glycerin ester were heated to 80°C or higher. When the bile acids are mixed, the bile acid is dissolved and the mixture becomes a clear solution, and the inventors have discovered that a solution obtained by adding an oily substance to this clear solution remains stable over a long period of time, and has completed the present invention.

The concentration of bile acids in the liquid preparation of the present invention can be arbitrarily set depending on the purpose of use, but the maximum dissolution amount of these bile acids is 31% (W/W) for cholic acid and 27% (W/W) for ursodeoxycholic acid. /W), 27% with chenodeoxycholic acid
(W/W) and 24% (W/W) in the bile end.

The temperature necessary for preparing the internal liquid preparation of the present invention is 80 to 150°C, preferably 95 to 120°C. The reason for this requirement is that bile acids hardly dissolve when prepared at temperatures below 80°C, and when heated above 150°C, denaturation of fatty acid esters occurs.
This is because the long-term stability of the solution cannot be expected.

Bile acids that can be used in the present invention include cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, conjugated bile acids and bile powder. Examples of fatty acid esters include sorbitan fatty acid esters such as sorbitan monocaprylate, sorbitan monolaurylate, sorbitan monooleate, sorbitan trioleate, sorbitan monoisostearate, sorbitan sesquiisostearate, and sorbitan thol oil fatty acid ester, or glyceryl monocaprylate. Caprylic acid glycerin esters such as , tetraglyceryl monocaprylate, and tetraglyceryl hexacaprylate, or a mixture of two or more of these in arbitrary proportions are used.

The oral bile acid solution of the present invention contains bile acid and the sorbitan fatty acid ester or caprylic acid glycerin ester as essential components, and if necessary, dissolves an oil-soluble substance and an oil-like substance and then fills it as it is or into a soft capsule. However, ingredients other than these, such as preservatives such as butyl benzoate, ethyl benzoate, and ethanol, and additives such as tetraglycerol pentastearate, hexaglycerol pentastearate, and decaglycerol mixed fatty acid ester are added. Adhesives, flavors, sweeteners or coloring agents, etc. can be added.

Action and Effects of the Invention The bile acid solubility and stability of the fatty acid ester in the bile acid internal liquid preparation of the present invention will be explained.

First, the relationship between the temperature during the preparation of a bile acid liquid for internal use and the bile acid content in the internal bile acid liquid was tested using sorbitan monooleate, cholic acid, and chenodeoxycholic acid.

For the sample, bile acids and sorbitan monooleate were weighed so that the concentration of each bile acid was 5% (W/W), and the temperature was varied from the lowest temperature (22°C) to 170°C, and then 1. Prepared by stirring for hours.

Regarding bile acid solubility, the bile acid content in the centrifuged solution of the bile acid oral solution immediately after preparation, the absorbance at a wavelength of 660 nm measured with a spectrophotometer of the solution that was left to cool to room temperature after preparation, and the sample visually observed. Judging from the appearance.

The results are shown in Table 1. In Table 1, the visual appearance is indicated by 10 if it is cloudy or precipitated, 2 if it is slightly cloudy, and - if it is clear. Also,
The bile acid content rate is 5% (W/W) of the bile acid preparation concentration.
It was expressed as 0%. Table 1 shows that when the preparation temperature is 80°C or higher, the solubility of bile acids increases rapidly;
It is clear that when the temperature exceeds this level, the solution turns yellow and its properties change.

Next, a comparative test was conducted regarding bile acid solubility and solution stability using the fatty acid ester of the present invention and the glycerin fatty acid ester described in JP-A-1-186817.

Samples were prepared by changing the type of fatty acid ester for each fixed amount of cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, and bile powder, and containing 2.5% vitamin E (d1-α-tocopherol acetate) as an oily substance. (W/W
) was added to the test.

Bile acid solubility was determined from the absorbance at a wavelength of 660 nm measured with a spectrophotometer at the time of preparing each sample (however, for bile powder, an aqueous sodium hydroxide solution of bile powder was used as a blank) and the visual appearance of each sample. It was judged. Solution stability was determined by filling 40 ml of each sample into a 50 ml glass bottle, storing it in a thermostat at 30°C, and measuring the bile acid content on the sample surface (5 mm) after 2 weeks and 3 months. Judgment was made by measuring the bile acid content (bile acid content in bile powder) and vitamin E content, as well as the separation layer length of bile acid from the sample surface.

The results are shown in Tables 2 to 5. In each table, the visual appearance and bile acid and vitamin E contents are shown in the same manner as in Table 1. As is clear from Tables 2 to 5, the bile acid internal liquid preparation of the present invention comprising bile acid and sorbitan fatty acid ester or caprylic acid glycerin ester is disclosed in Japanese Patent Application Laid-open No. 1-1868.
It is observed that the solubility is much higher than that of the technology described in the publication No. 17@, and that the solution stability is excellent over a long period of time, and that the bile acid and the oil-like substance are uniformly mixed.

Therefore, the bile acid internal solution of the present invention can be widely used as a bile acid preparation that promotes emulsification of oily substances and improves absorption in pharmaceuticals, health foods, and feed additives.

(Left below) Example 1 125.0 l of cholic acid and 2322.50 l of sorbitan monooleate were placed in 31 beakers, and 1
After gradually heating the mixture to 15 to 125° C. with stirring, both were combined and stirred in a lab stirrer for about 1 hour to prepare cholic acid internal liquid preparation 2447.5 Cl. Add this liquid to 4
After being stored at 0°C for 3 months, the absorbance at a wavelength of 660 nm measured with a spectrophotometer was 0.002, and the appearance was clear.

Cholic acid 125. A liquid preparation prepared by the same procedure as above using 2322.5 g of OCl and sorbitan monooleate was left to cool to 50°C, and then 2275 g of vitamin
and vitamin A palmitate 25. Add OCl,
The mixture was stirred using a lab stirrer for about 5 minutes to prepare 2500.0 g of a cholic acid solution containing oily vitamins.

The stability of this solution was good, and no separation was observed even after storage at 40°C for 16 months. This solution can be administered orally to cattle as a tonic.

Example 2 22.0 g of bile powder and 1 glyceryl monocaprylate
Take 21.0CI in each 200d beaker and add 1
After gradually heating the mixture to 00 to 110° C. with stirring, both were combined and stirred in a lab stirrer for about 1 hour to prepare 143.0 g of a bile powder liquid for internal use. After storing this solution at 40°C for 3 months, the wavelength was 660 as measured by a spectrophotometer.
The absorbance at nm was 0.003, and the appearance was clear.

Bile terminal 22. Oq and glyceryl monocaprylate 1
21. 3. After cooling the liquid preparation prepared by the same procedure as above to 70° C. using Og, 0.7 Cl of vitamin C stearate was added and stirred, and after cooling to 50° C., vitamin E 3. Add 8Cl and 2.5g of retinol palmitate and stir for about 10 minutes to prepare a bile powder solution containing oily vitamins. OCl was prepared.

The stability of this solution is good and it can be mixed with eicosapentaenoic acid and perilla oil and used as a nourishing tonic.

Example 3 120.00 g of ursodeoxycol and 175.0 g of sorbitan monocaprylate were each placed in a 300 d beaker and heated to 120-130'C with gradual stirring, and then both were combined in a lab stirrer for about 2 hours. Stir to prepare ursodeoxycholic acid internal solution 195. O.C.
l was prepared. After this solution was stored at 40° C. for 3 months, the absorbance at a wavelength of 660 nm measured using a spectrophotometer was 0.002, and the appearance was clear.

Ursodeoxycol 12o, og and sorbitan monocaprylate 175. After cooling a liquid preparation prepared using OCl in the same manner as above to 40°C, vitamin E 3. OCl, retinol palmitate2. Oq
and 8000 IU of ergocalciferol were added and stirred for about 5 minutes to prepare 200.0 g of an oily vitamin-containing ursodeoxycholic acid solution.

The stability of this solution is good, and Part 1 (77) can be filled into soft capsules and used as an oral vitamin preparation.

Example 4 Chenodeoxycol 110. Oct] and sorbitan monolaurylate iao, og were each placed in a 300 d beaker and heated to 95°C with gradual stirring.Then, both were combined and stirred in a lab stirrer for about 1 hour and 30 minutes to prepare a chenodeoxycholic acid internal solution. 190Q was prepared.

After this solution was stored at 40° C. for 3 months, the absorbance at a wavelength of 6601 m measured with a spectrophotometer was 0.002, and the appearance was clear.

A liquid preparation prepared using chenodeoxycholic acid io, og and sorbitan monolaurylate iao, og in the same manner as above was allowed to cool to 50°C, and then vitamin E
io and og were added and stirred for about 5 minutes to prepare 2oo and og of an oily vitamin-containing chenodeoxycholic acid solution.

This solution had good stability and was used by mixing it with cod oil and sprinkling it on pelleted aquatic feed.

Claims (4)

[Claims] (1) A bile acid liquid for internal use consisting of a bile acid and a fatty acid ester. (2) The bile acid liquid for internal use according to claim 1, wherein the bile acid is one or more selected from the group consisting of cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, conjugated bile acids, and bile powder. (3) Fatty acid ester is sorbitan monocaprylate,
Sorbitan fatty acid esters such as sorbitan monolaurylate, sorbitan monooleate, sorbitan trioleate, sorbitan monoisostearate, sorbitan sesquiisostearate, sorbitan thol oil fatty acid ester, and glyceryl monocaprylate, tetraglyceryl monocaprylate, tetraglyceryl The bile acid liquid preparation for internal use according to claim 1, which is one or more selected from the group consisting of caprylic acid glycerin esters such as hexacaprylate. (4) A method for producing a bile acid liquid for internal use, which comprises heating a fatty acid ester and a bile acid to 80° C. or higher and then mixing them.