JPH01221312A - Oral liquid containing fat-soluble substance - Google Patents

Abstract

PURPOSE:To provide a fat-soluble substance-containing oral liquid stable without producing any turbidity when preserved for a long period, having no bad taste on the taste thereof and capable of being readily administered orally, by containing the fat-soluble substance and a hardened castor oil polyoxyethylene derivative. CONSTITUTION:A fat-soluble substance such as vitamin E, a derivative thereof or tocopherol acetate and 200-500wt.%, based on the fat-soluble substance, of a hardened castor oil polyoxyethylene derivative (e.g., HCO-60) are mixed with each other and molten. The pH of the molten mixture is adjusted to 4.5-6 with sulfuric acid, citric acid, etc., to provide the objective liquid. A water-soluble vitamin, saccharides, flavor, buffer, aromatic agent, etc., may be, if necessary, added to the objective liquid. The fat-soluble substance is compounded in an amount of 0.0001-0.1wt.%.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to an oral solution containing a fat-soluble substance, and more particularly to an oral solution containing a fat-soluble substance, which is an aqueous solution, and which is stable even when stored for a long period of time without causing turbidity. The present invention also relates to an oral liquid containing a fat-soluble substance that does not have an unpleasant taste.

[Conventional technology and its problems]

Conventionally, various methods have been proposed for solubilizing fat-soluble substances and preparing aqueous solutions. For example, Tokko Sho 2
In No. 6-7145, a large amount of thioxyethylene sorbitan fatty acid ester is used for solubilization. but,
this? Since lyoxyethylene sorbitan fatty acid ester has a unique unpleasant taste, aqueous liquid preparations prepared using it have the disadvantage that it is difficult to take as a drink. For this reason, various studies have been conducted on solubilizing solutions using hydrogenated castor oil-lioxyethylene derivatives, which are surfactants that can be taken orally. In order to make a stable solubilized solution, methods have been considered to improve stability by adding phospholipids, sorbitan fatty acid esters, neutral oils and salts, broken glycerin fatty acid esters, etc.

However, the methods of adding these additives are injections,
This is not a problem with eye drops or external liquid formulations, but when taken as an internal liquid formulation, there is a peculiar unpleasant taste due to the additives, and the resulting aqueous liquid formulation cannot be said to be suitable for internal use.

Therefore, in order to obtain a drink containing a fat-soluble substance, it has been desired to develop a liquid preparation for internal use that is stable even when stored for a long time, does not become cloudy, and does not have a peculiar unpleasant taste.

[Means to solve the problem]

Under such circumstances, the present inventors have decided to use fat-soluble substances and hydrogenated castor oil. As a result of intensive research to elucidate the cause of the turbidity of solubilized solutions using lyoxyethylene derivatives, we found that this was hydrogenated castor oil? It is said that 12-hydroxystearic acid, which is extremely poorly soluble in water, is produced due to the decomposition of the lyoxyethylene derivative, and that 12-hydroxystearic acid is produced in the solubilized solution in hydrogenated castor oil?
It has been found that there is no change in the appearance or properties when the proportion of the lyoxyethylene derivative is up to 10%, but when it exceeds 10%, oozing is observed, and when it is 20% or more, clear cloudiness is observed. And this hydrogenated castor oil? As a result of research to suppress the decomposition of lyoxyethylene derivatives, 1
It has been found that the production rate of 2-hydroxystearic acid is highly dependent on the pH value. That is, by adjusting the pH value of this aqueous solution to 4.5 to 6, the production of 12-hydroxystearic acid, which causes cloudiness, is extremely reduced, and as a result, it is stable for a long time and does not cause oozing. Therefore, the present invention was completed based on the discovery that an aqueous solution containing a fat-soluble substance that is easy to take can be obtained since there is no need to incorporate additives that cause an unpleasant taste.

゛Therefore, the present invention comprises the following two components (A) and (B) (A)
Fat-soluble substances, (B) 200-500 8% hydrogenated castor oil based on component (4)? Rioxyethylene! The present invention provides a fat-soluble substance-containing oral liquid containing a conductor and having a pH of 4.5 to 6.

Examples of the fat-soluble substances that are component (A) of the present invention include vitamin E and its derivatives, vitamin A1, vitamin D
, 2-tamin 1, vitamin 2, γ-oryzanol, and coenzyme Q1 dafalnate.

In addition, as the polyoxyethylene hydrogenated castor oil derivative which is the component (B), for example, HCO-60°HCO-30
and HCO-30 (Nikko Chemicals Co., Ltd.).

The lipophilic substance-containing oral solution of the present invention (hereinafter referred to as "oral solution") can be prepared in a conventional manner. A solubilized solution of a fat-soluble substance is prepared using a hydrogenated castor oil derivative, and this is dissolved in hydrochloric acid, sodium hydroxide, citric acid, malic acid, lactic acid, tartaric acid, or their sodium salts.
It is manufactured by adjusting the value to 4.5-6.

In preparing the oral solution, component (A) is o, oooi~
It is preferable that the amount of component (B) is about 0.1% by weight (hereinafter simply referred to as "chi"), and the amount of component (B) is 200 to 500% of component (2). If the amount of component (B) is less than 200% of component (A), the fat-soluble substance will not be sufficiently solubilized, which is not preferable.

Furthermore, the oral solution of the present invention may further contain water-soluble vitamins, saccharides, flavoring agents, buffers, fragrances, and the like, if necessary.

〔Effect of the invention〕

In the oral liquid of the present invention thus obtained, hydrogenated castor oil? Lioxyethylene derivatives are stable even when stored for a long period of time, and the amount of 12-hydro-distearic acid that causes ooze or turbidity produced is extremely small, so there is no change in properties such as ooze or cloudiness.

In addition, since no additives are added to improve stability,
In terms of taste, it does not have an unpleasant taste, so it is suitable as an internal liquid preparation. [Examples] Next, the present invention will be explained in more detail by giving Examples and Reference Examples.

Example 1 (Composition) Tocopherol acetate 50 ■ Hydrogenated castor oil-lioxyethylene 66 mole ether (trade name - pvHco -60) 200
1F Refined white sugar 52 Sodium benzoate 35 Ki, 9 Butyl oxybenzoate 4 ■ Citric acid
500■ Sodium citrate appropriate amount (
(pH 4, 5) No. 50t/(manufacturing method) Lipid-soluble substances (tocopherol acetate), niracol HCO
-60 was mixed and melted on a water bath at about 80°C to make it homogeneous, and purified water at about 80°C was added to this while stirring, and after stirring and solubilization, other water-soluble substances were separately dissolved in purified water. An aqueous solution was added to make the volume 50 ml to prepare an oral solution. Set this to 0
．． Filtered using a 45 μm membrane filter,
It was filled into a 0- brown bottle and the cap was sealed.

Example 2 (Composition) Vitamin A oil 1000 units Tocopherol acetate 509 Hydrogenated castor oil polyoxyethylene 60 moles ether (trade name Nilacol HCO-60) 250 ■ Refined white sugar 5F Sodium benzoate 35 TIq no 9 Butyl oxybenzoate 4 ■ Malic acid
500■ Sodium hydroxide appropriate amount (pH 5.0) Caramel 100■Fragrance
Using a small amount of purified water 50d (Production method) The same procedure as in Example 1 was carried out.

Reference Example 1 (Composition) Tocopherol acetate 50 ■ Hydrogenated castor oil oxyethylene 60 mole ether (trade name Nilacol HCO-60) 200 ■ Refined white sugar 52 Sodium benzoate 35 ■, Q Butyl oxybenzoate 4 ■ Citric acid
500■Fragrance 50-(pH 3,2
) (Manufacturing method) The same procedure as in Example 1 was carried out.

Reference Example 2 (Composition) Tocopherol acetate 50 ■ Hydrogenated castor oil, 351 J Oxyethylene 60 mole ether (trade name = Tool x-ul HCO-60) 200 r
r9 Sorbitan sesquioleate 20η Refined white sugar 52 Sodium benzoate 35 mg, Q Butyl oxybenzoate 4 ■ Citric acid 50 (
11n? Fragrance: 50-(pH 3,2) with slightly purified water (Production method) Same as Example 1.

Test Example 1 When the oral solutions obtained in Example 1.2 and Reference Example 1.2 were taken and observed for the presence or absence of an unpleasant taste in terms of taste, only the solution obtained in Reference Example 2 had a peculiar unpleasant taste. Ta. For the remaining three oral solutions, immediately after production, and at 4°C, 30°C, and 50°C.
After storage at ℃ for 2 months, the development of cage was observed. The results are shown in the first moat.

Table 1 * Occurrence of discharge -2 None ±: Slightly observed ++: Frequently observed As is clear from Table 1, the oral solution of the present invention does not cause the occurrence of discharge over time, and the taste It also has excellent effects without any peculiar unpleasant taste.

Test Example 2 Regarding the oral solutions obtained in Example 1.2 and Reference Example 1, the occurrence of phlegm and the production of 12-hydroxystearic acid immediately after production and after storage at 4°C, 40°C, and 50°C for 2 months observed the rate. The results are shown in Table 2.

Table 2 *Occurrence occurrence -2 None ±: Slightly observed ++: Most observed ÷ Is the amount of rhombic 12-hydroxystearic acid produced in hydrogenated castor oil? As is clear from Table 2, the ratio to the lyoxyethylene derivative, the oral solution of the present invention does not cause the appearance of blemishes over time, and the production of 12-hydroxystearic acid, which causes blemishes. Example 3 Hardened castor oil was prepared using the following method under various temperature and pH conditions. 60 moles of lyoxyethylene ether (HC
The production reaction of 12-hydroxystearic acid by decomposition of O-60) was investigated, and the reaction rate constant was determined.

The results are shown in Table 3.

(Experiment method) (1) Preparation of specimen HCO-60200* was added to Vitamin 7F, 40'''9, dissolved by heating, and then diluted with citrate buffer of pH 3 to 6 to make 100 ml. At this time, the ionic strength of each sample was adjusted to 0.5 using KCl.

(2) Storage conditions Fill a 10ml white ampoule with the above sample,
．． 60. It was stored in a constant temperature bath at 70°C.

(3) Method of quantitative determination The above-mentioned preserved sample was sampled after a certain period of time. The quantitative method was to acidify the sample with hydrochloric acid, extract three times with chloroform, evaporate to dryness, dimethylate with diazomethane, then evaporate to dryness and inject into gas chromatography.

Below is Table 3 in the margin [-rco-6ol. ;? Sooxyethylene (60)
Initial concentration of hydrogenated castor oil [12-H8:]: Concentration of 12- and droxystearic acid after time t; Time (day) As is clear from Table 3, the reaction shows the production of 12-hydroxystearic acid. The rate constant is greatly affected by the pn value, and when H is less than 45, the production rate is slow, but in the range of 4.5 to 6.0 there is no significant change and it is quite stable.

that's all

Claims (1)

[Claims] 1. Contains the following two components (A) and (B): (A) a fat-soluble substance; (B) a hydrogenated castor oil polyoxyethylene derivative in an amount of 200 to 500% by weight based on component (A); and a lipophilic substance-containing oral solution having a pH of 4.5 to 6.