JPS5959611A - Stable solubilized composition of riboflavin butyrate and its preparation - Google Patents

Abstract

PURPOSE:To provide the titled stable composition containing sorbitan sesquiolate and/or sorbitan monoolate and ethanol, having improved solubility of riboflavin butyrate in oils or fats, and exhibiting the synergistic pharmacological activity of the drug components. CONSTITUTION:The titled stable composition is prepared by dissolving (A) riboflavin butyrate useful for the prevention and remedy of hyperlipemia and ariboflavinosis, in (B) sorbitan sesquiolate and/or sorbitan monoolate and (C) ethanol, and dissolving the solution in (D) an oil or fat containing an unsaturated fatty acid having antilipemic activity. The composition exhibits the synergistic pharmacological activity of the component (A) and the component (D). The solubility of the component (A) to the component (D), which is at most 0.2wt% by conventional process, can be increased to >=1wt%, and the solution can be maintained stably for a long period. Accordingly, the amount of the oil or fat can be remarkably decreased resulting in the easy administration.

Description

[Detailed description of the invention] related to products and their manufacturing methods.

Ruff acid boflavin is vitamin B, (riboflapine)
is insoluble in fats and oils, poorly soluble in water, and has a bitter taste, so it is made into an ester derivative with rough vinegar to improve its solubility in fats and oils, and is effective against hyperlipidemia, vitamin B, Widely used to prevent and treat deficiency diseases.

On the other hand, the present inventors have discovered that oils and fats containing large amounts of unsaturated fatty acids such as oleic acid, linoleic acid, lylunic acid, and eicosapentaenoic acid have been known to have antilipemic effects. By adding rough acid boflavin to fats and oils containing unsaturated fatty acids, these unsaturated fatty acids can be removed.
In anticipation of the additive effect of the antilipidemia effect of IQ fatty acids and the antihyperlipidemic preventive and therapeutic effects (antilipidemia effect) of rough acid boflavin, we have developed the combination of rough acid boflapine and oil. A study of solubilized compositions was conducted.

However, the solubility of rough acid boflavin in edible oils and fats is not necessarily high;
As shown on page 66. ll] 11 [There is a limit of 0.2 (w/w)%.

When administering rough-acided boflavin to the skin in hopes of improving performance and mulberry effects, it is usually preferable for adults to administer 1115 to 120 mg divided into 2 to 3 doses.

However, in order to dissolve this 11k of oil and fat, at least 2.5 to 60g of oil and fat are required. ) oils and fats are commonly used in the capsule name ').
tl'i for those taking 3. It forces you to ・f・ stool.

Therefore, in order to prepare the i+T fW introduction product of rough acid boflavin, it is necessary to dissolve rough acid boflavin in oil and fat containing unsaturated fatty acids at a temperature of 61 degrees Celsius.

In order to overcome the above-mentioned problems, the inventor of the present invention has completed the present invention as a result of extensive research into a method for dissolving Rl'+riboflavin in fats and oils.

That is, the present invention provides LacM riboflavin, sorbitan sesquiolate or sorbitan monooleate, or sorbitan sesquiolate and sorbitan monoole 1.
#Which mixture consists of ethanol and fat?
! Stable rough acid boflavin iir f as jj71
The W composition and rough shaved bofrapine are dissolved in sorbitan sesquiolate, sorbitan monooleate 1, or a mixture of sorbitan sesquiolate and sorbitan monooleate, and ethanol, and then the dissolved product is dissolved in fats and oils. The present invention relates to a method for producing a stable rough-shaving Bofrapin 1-1f atomized phase composition.

First, to determine the composition of the stable rough acid boflavin town solubilized composition of the present invention? ■The trial that became; I will explain the risk next.

As a method for dissolving 1 (w/w) % or more of boflavin into fats and oils, a solubilizing agent (for example, ethanol, propylene glycol, chrycerin, polyenalene glycol, medium chain fatty acid chrycerite, etc.) may be used. ), a method using a nonionic surfactant (for example, sorbitan fatty acid ester, chrycerin fatty acid ester, propylene glycol fatty acid ester, sucrose fatty acid ester, etc.), and a method using +tif solubilizing agent and...I non-ionic surfactant. A method using both ionic interfacial agents was conducted, and the state of dissolution and stability were observed.

That is, 200 mg of rough acid boflavin, 3 mQ of solubilizing agents (ethanol, propylene glycol, chrycerin, polyethylene glycol 400, caprylic triglyceride) and/or surfactants (sorbitan triolate HLB 1.8, sorbitan sesquiole 1-
HLB3.7, sorbitan monooleate HL B 4-
3. Sorbitan monostearate HLB4.7. Sorhitan monobalmite-1-HLB6-7, Sorbitan monooleate-1-HLB8.6, Chrycerin monooleate HLB2.8. Propylene glycol monostearate 1-HL B3.5, sucrose fatty acid ester H
LB2-0.5・7) 4g with force 11 and 70°C water 7
The mixture was stirred with a force of 117 x 111 at a temperature of 1] 1 and then cooled with water. The dissolved product was added to 20 g of safflower oil, beaten for 41 hours, and kept at room temperature, o'clock and 40°C for 4 weeks, and then its stability was observed. The results are shown in Table 1. Shown below.

Table 1 A A transparent solution (stable) was obtained under all conditions.

B: Separation was observed under any of the conditions.

C: Turbidity or precipitation was observed under any of the conditions.

D: It was not added to fats and oils because it was insoluble.

As is clear from these results, only when ethanol and sorbitan sesquiolate or ethanol and sorbitan monooleate were used in combination could they be dissolved in fats and oils and maintained stably even during long-term storage. .

In the case of that pond, either the rough acidic boflavin cannot be dissolved transparently, or even if it can be dissolved transparently, if the rough acidic boflavin is dissolved and then added to the fat.
Immediately or over time, boflavin separates from fats and oils or crystallizes out, making it rough and ugly, making it difficult to solubilize and stabilize it in fats and oils.

Therefore, the composition of the stable rough acid boflavin r+f solubilized composition of the present invention includes, in addition to rough acid boflavin, surfactants such as sorbitan sesquiolate and sorbitan monoole 1., ethanol, and fats and oils.

The surfactant used in the present invention is sorbitan sesquiolate [for example, Arasel 83 (manufactured by Kao Atlas Co., Ltd.]) or sorbitan triolate [for example,
Span 80 (manufactured by Kao A.R.S. Co., Ltd.)] or a mixture of both, or one or more other surfactants may be appropriately mixed therewith as required.

Other surfactants include sorbitan fat esters [
For example, sorbitan triolate, sorbitan monolaurate, etc.], chrycerin fatty acid esters (e.g., glycerin monoole 1, etc.), propylene glycol fatty acid esters (e.g., provilleclicol monostearate, etc.), lecithin, etc. .

Fats include safflower oil, sesame oil, soybean oil, mensilla oil,
111 tons of edible oils such as rapeseed oil, corn oil, bran oil, peanut oil, olive oil, camellia oil, castor oil, coconut oil, palm oil, corn oil, wheat liver oil, sardine oil, taracan oil, etc. can be used, Preferably, it contains a large amount of unsaturated fatty acids.

When producing the stable rough acid boflavin-soluble composition of the present invention, sorbitan sesquiolate, sorbitan monoole 1, or a mixture of sorbitan sesquiolate and sorbitan monooleate, and ethanol are added to the rough acid boflavin. Addition, addition? 1. t ffi After stirring and dissolving, cool and stir and dissolve the melted material in fats and oils.

The amount of ethanol and the amount of surfactant (sorbitan sesquiolate or sorbitan monooleate or a mixture of both) used in the present invention are as shown in the figure. The figure shows 1 part by weight of rough acid boflavin and 1 part by weight of safflower oil.
00 is a diagram showing the relationship between the amount of ethanol and the amount of surfactant used for +7f W conversion and stabilization in the Qi-exposing part, and each of , a composition consisting of oils and fats, etc.).

+2f Chuunin can solubilize rough acid boflavin, and
Storage at room temperature, 0°C, and 40°C for 6 months (rF), the range is stable under any of the conditions, and the others are the ranges where separation or precipitation occurs under any of the conditions. The amount of surfactant used is
'w/w)% or more 1: is sufficient. However, safety +11
If you use J+, you should use as little as possible; use Cf or 1-! Delicious.

The tiJI of the ethanol used is 11 (
The amount can be increased or decreased as appropriate, but the amount of
% is preferable. Too much ethanol will cause dilution, and too little will cause smearing or precipitation.

Depending on the needs, fat-soluble + 11 mulberry substances, fat-soluble = l'l vitamins, etc. can be added to the rough 1-sun ribofura soluble phase acid produced by the present invention, and soft capsules can be added. te1
Fumizuki J is like “4.)”.

As described below, according to the present invention, compared to conventional oils and fats,
．． 2 (w/w)% or less of rough acid bofurahin, which was the limit, was reduced to 1 (w/w)% or more. Nima C pull)
In fact, it can be maintained stably for a long period of time. In this way, it is possible to dissolve boflavin by rough acid in fats and oils containing unsaturated fatty acids to +:'6h''':j degrees and to keep it stable for a long period of time. When the leaf effect Tv1 of rough acid boflavin is dissolved in J&oil and administered as 1-1 lj, the amount of oil and fat can be significantly reduced, making it easy to take.

Furthermore, if 1 finger of oil containing 1 interfacial viscosity agent is poured into 11 pieces of oil, Ann, Intcrn, Mcd, 29.1 (
1948), it is well known that it improves digestion and absorption. In addition, by dissolving rough acid boflavin in fats and oils to a high degree of talk, it has been found that the intestines' ≧
7/i membrane C) It is easily absorbed, and the absorption rate is 1 lJ compared to when administered orally in the form of tablets, capsules, etc.
) rate increases.

Therefore, it is possible to exert the anti-lipidemia effect of 4Jts by administering rough acid poflahin together with 1 finger of oil containing saturated fatty acids.

In addition, according to the production method of the present invention, it is possible to produce large amounts of 1119% by using easily available special raw materials.

That’s it! The invention will be illustrated by way of example.

Example 77 200 ml of riboflavin and 3 ethanol
mQ [9.2 (w/w)% based on 11 solubilizing oxides]
and 4 g of surfactants ((a) to (f)) (15 (w/v)% based on the solubilized composition) were added and dissolved by heating and stirring in a 70°C water bath for 5 minutes. The solution was cooled with water.The resulting solution was added to safflower oil 208, stirred, and stored at room temperature, 0°C and 40°C, and its stability was observed for 6 months.

The surfactants ((a) to (f)) are as follows.

(a) Sorbitan jasquiolate Sorbitan triolate (11) (b) Sorbitan monooleate.

Chrycerin monooleate [12] (c) Sorbitan sesquiolate Sorbitan monoole 1-(1:1) (d) Sorbitan sesquiolate: Sorbitan monolaurate (11) (c) Solpitan monooleate: Propylene glycol monosteare root (l: 1) (f) Sorbitan monooleate.

Sorbitan sesquiolate glycerol monooleate (1.1:1) As a result, any surfactant could be dissolved and maintained stably under any conditions.

As is clear from the above results, sorbitan triolate, glycerol monooleate, propylene glycol monostearate, etc. cannot be converted into TiT'm and stabilized alone, but when mixed with sorbitan sesquiolate, sorbitan monooleate, or a mixture of the two, Can be used.

Example: 200 mg of rough shaved hofrapine and 3 mQ of ethanol [
g, 2 (w/w)%] for solubilized composition and sorbitan monoole) 4 g (15% for solubilized composition)
w/v)%] was added, heated and stirred in a 70°C water bath for 5 minutes to dissolve, and then cooled with water. The dissolved matter is mixed with oil ((a)
~(p)) 20g and stirred at room temperature, 0°C and 40°C.
It was stored at °C and its stability was observed for 6 months.

The fats and oils ((a) to (p)) are as shown.

ra) Sesame oil, ('b) Tize oil, ('c) Menzi oil, (d) Rapeseed oil, (c) Kyonin oil, (f) Bran oil, ('g) Peanut oil, (h) Olive I' I11,
(i) Camellia oil, N) Castor oil, (k) Coconut oil, (1)
Par 1\ oil, (m) corn oil, (1) sardine oil,
(o) Tarakan oil, (p) wheat germ oil.

As a result, it was able to be solubilized in any fat or oil and was stably maintained under any conditions.

Example 3 (1) Ethanol 5Q and sorbitan monooleate 3 kg were added to 200 g of boflavin and 200 g of y-oryzanol, and heated at about 70°C.
After dissolving L, it was cooled.

(2) 2 kg of d-α-tocopherol acetate was added to 30 kg of sardine oil and stirred.

(3) (1) and (2) were mixed, stirred I'P, and treated in a conventional manner to form soft capsules.

Example 4 (1) 200 g of rough acid boflavin, 300 g of ursodeoxycholic acid, 200 g of y-oryzanol, 5Q ethanol, 1.5 kg of sorbitan monooleate and 1.3 kg of chrycerin monooleate were mixed and heated at about 70°.
The mixture was heated and stirred at C to dissolve it, and then cooled.

(2) 200 g of d-α-tocopherol acetate, 10 kg of soybean lecithin, 1□ 2 kg of sorbitan triole
and 20.2 kg of safflower oil were mixed.

(3) (After mixing and stirring Rito (2), soft capsules were prepared in a conventional manner.

The inventive solubilized compositions of Examples 3 and 4 remained stable at room temperature, O''C and 40°C after 6 months.

[Brief explanation of drawings]

The figure shows 1 part by weight of rough acid boflavin and 100 parts by weight of safflower oil.
It is a diagram showing the relationship between the amount of ethanol used for solubilization and stabilization in parts by weight and the amount of surfactant +1 agent, where the horizontal axis is the surface viscosity agent, and the vertical axis is the amount of ethanol rj. In the figure, A indicates the range in which boflavin, which is rough and ugly, can be solubilized and stabilized.

Claims (1)

[Claims] ■) It is characterized by consisting of rough acid boflavin, sorbitan sesquiolet 1 or sorbitan monooleate, or a mixture of sorbitan sesquioleate and sorbitan monoole 1 to 1, ethanol, and oil or fat. Stable rough acid boflavin town solubility phase composition. 2] After dissolving rough acid bofurahin in sorbitan sesquiolate or sorbitan monoole=1, or a mixture of sorbitan sesquiolete 1 and sorbitan monoole 1, and ethanol, the dissolved product is dissolved in fats and oils. A method for producing a particularly stable rough acid boflavin II solution M1 product.