JPH0462773B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for uniformly dispersing and solubilizing water-insoluble substances in an aqueous system using a specific triglycerol fatty acid monoester. Moreover, in the present invention, "solubilization" means solubilization and microemulsion formation. In general, the solubilization of water-insoluble substances into aqueous systems is a phenomenon that first occurs due to the presence of a surfactant, and the type of surfactant, the compound to be solubilized, and the amount of solubilization are extremely selective. The presence of a significant amount of active agent is necessary for the phenomenon to occur. On the other hand, when we look at solubilization from an industrial perspective, it covers a wide range of applications such as foods, cosmetics, and pharmaceuticals, but the types of surfactants that can be used are limited in terms of solubilizing ability and safety. ing. For example, examples of the application of solubilization to pharmaceuticals include injections and infusions, and in the case of such drugs, the properties of surfactants prevent the drug from clogging in capillaries. Therefore, solubilization or microemulsification ability is required so that the dissolution equilibrium or particle size distribution is narrow and the average particle size is 0.3 μm or less, and furthermore, it is necessary to have no safety problems. It has become a mandatory requirement. Solubilizers or emulsifiers conventionally used for this purpose include lecithin, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monooleate, and hydrogenated castor oil ethylene oxide adduct. Among these, lecithin is a biologically derived substance and is highly safe and widely used as an emulsifier. However, as a surfactant, it has weak hydrophilicity and is insoluble in water, so it can solubilize non-water-soluble substances in aqueous systems. I can't. Furthermore, since it is a biologically derived ingredient,
It had drawbacks such as lack of safety such as preservatives and rancidity. On the other hand, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monooleate, and hydrogenated castor oil ethylene oxide adducts all have ethylene oxide chains as hydrophilic groups, so there is a risk of elution of formalin and a decrease in pH due to decomposition of the ethylene oxide chains. It comes with gender. A decrease in PH was a fatal defect, especially when PH stability was required for substances to be solubilized or emulsified. Therefore, the present inventors focused on polyglycerin-based emulsifiers, which have been used as emulsifiers for food and cosmetics in recent years and have excellent safety, and after various studies, the inventors discovered that The present invention was completed based on the discovery that certain specific fatty acid esters of glycerin have excellent solubilization ability and can solubilize not only animal and vegetable oils but also various water-insoluble substances. In the present invention, when solubilizing water-insoluble substances in an aqueous system, the content concentration of a monoester of triglycerin and an unsaturated fatty acid having 14 to 24 carbon atoms or an α-branched fatty acid is 90% by weight or more based on the total weight%. The present invention relates to a method for solubilizing a water-insoluble substance, which comprises adding a surfactant. The fatty acid component of the triglycerin fatty acid monoester contained in the surfactant used in the present invention includes unsaturated fatty acids having 14 to 24 carbon atoms, such as myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, Examples include arachidonic acid, jojoba fatty acid, and α-branched fatty acids such as isomyristic acid, isopalmitic acid, isostearic acid, isoarachidic acid, and isolignoceric acid. All of the monoesters obtained here have a low melting point, are liquid or paste-like at room temperature, have good water solubility or water dispersibility, and have solubilizing ability. Among these, those having a Krafft point of 0° C. or lower are particularly preferred from the viewpoint of practical use. Therefore, even if they are monoesters, saturated fatty acid esters or terminally branched fatty acid esters that give a high melting point or cause crystallization cannot be applied to the present invention. Next, the amount of the surfactant according to the present invention added to the aqueous system may vary depending on the type of water-insoluble substance to be solubilized and the purpose of the obtained solubilized material, but it is usually 0.5-20% by weight,
Preferably a range of 0.5 to 10% by weight is selected.
If the amount added is less than 0.5 to 10% by weight, the solubilizing power will not be sufficient and the object of the present invention will not be achieved. Also,
If the amount added exceeds 20% by weight, the entire surfactant phase becomes a continuous phase, in which water-insoluble substances are dissolved, and it cannot be called solubilization. Such a state is unfavorable from a cosmetic and pharmaceutical standpoint in terms of safety, and the industrial usefulness is reduced. In addition, in the surfactant, the triglycerin fatty acid monoester accounts for 90% of the total surfactant weight.
It is necessary that the content be at least % by weight. If the content is less than 90% by weight, the solubilizing ability decreases and the object of the present invention cannot be achieved. Here, it has not been possible to obtain a surfactant containing such a highly purified triglycerin fatty acid monoester. This is because conventional polyglycerin fatty acid ester surfactants are synthesized by esterifying polyglycerin and fatty acid, which are usually difficult to separate due to polymerization degree or isomer, under an alkali catalyst. ,
This is because the result is a complex ester mixture containing di- and tri-esters, making it difficult to obtain triglycerin fatty acid monoester in high purity using methods such as molecular distillation or column chromatography. . Therefore, the present inventors did not use the conventional esterification reaction between polyglycerin and fatty acids, but first synthesized highly purified triglycerin, esterified it with fatty acids, and then used the method described above. A surfactant having a triglycerin fatty acid monoester content of 90% by weight or more was obtained by separating the surfactant using the following methods. In addition, in order to obtain this highly purified triglycerin, epihalohydrin and allyl alcohol,
Diallylglyceryl ether was synthesized by a reaction in the presence of an alkali, then oxidized with organic or inorganic peroxides or metal oxides such as osmium tetroxide or permanganate, and then purified by molecular distillation. Synthesis examples will be shown below to further explain the triglycerin fatty acid monoester according to the present invention. Synthesis Example 1 Synthesis of triglycerin. After dissolving 56 g (1 mol) of potassium hydroxide in 580 g (10 mol) of allyl alcohol, 92.5 g (1 mol) of epichlorohydrin is gradually added. After the addition is complete, the reaction is continued at 60°C for 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and after filtering out insoluble matter, distillation was performed under reduced pressure to obtain 150 g of diallyl glyceryl ether. This diallyl glyceryl ether was mixed with 1050 g of 98% formic acid and 130 g of 30% hydrogen peroxide solution.
Add to the mixture and stir well. After a while it will generate heat, so after it subsides, heat it in a hot water bath at 100℃.
Heat for 2 hours. Then, most of the formic acid was distilled off, and the residue was dissolved in 500 ml of a 20% aqueous sodium hydroxide solution.
and heat to 100°C for 45 minutes. After cooling, the liquid is neutralized with hydrochloric acid and the solvent is distilled off under reduced pressure. Molecularly distill the residue to obtain 124g of triglycerin (51% yield)
Obtained. Synthesis Example 2 Synthesis of triglycerin monooleate. 24 g (0.1 mol) of triglycerin and 100 g of pyridine
ml and gradually add 30 g (0.1 mol) of oleic acid chloride. After standing overnight, ethyl acetate
Extract with 250 ml, wash with 1N hydrochloric acid, saturated sodium bicarbonate, and remove the solvent. Perform silica gel column chromatography and chloroform/methanol =
The distillate fraction at 95/5 (V/V) was collected to obtain 25 g of triglycerin monooleate. Synthesis Example 3 Synthesis of triglycerin-2-octyldodecanate. Instead of oleic acid chloride in Synthesis Example 2,
Using 32g of 2-octyldodecanoic acid chloride,
Synthesis was carried out in the same manner as in Synthesis Example 2 to obtain 22 g of the desired product. Next, there are many substances that can be solubilized by the solubilization method of the present invention, such as animal and vegetable oils, transesterified oils and fats, fatty acid esters, aliphatic alcohols, fatty acid hydrocarbons, aromatic hydrocarbons, alicyclic carbonated Examples include hydrogen, naphthenic hydrocarbons, various mineral oils, other fat-soluble vitamins, fragrances, and silicone oils, but all can be solubilized to varying degrees as long as they are substantially water-insoluble. Furthermore, a mixture of the above substances or a substance dissolved in a solvent can be similarly solubilized. Furthermore, when solubilizing a substance to be solubilized in an aqueous system containing the surfactant, the amount of solubilization varies depending on the type of substance to be solubilized;
Usually, the amount can be up to 3 to 6 times the weight of the surfactant. In addition, as a means of solubilization, a method for obtaining the solubilization in a short time is to stir and add an aqueous phase containing a water-soluble substance to an oil phase containing a surfactant. Even if the method of adding the aqueous phase and the oil phase is changed, there is no problem in obtaining a solubilized system. The surfactant of the present invention overturns the conventional wisdom that fatty acid esters of polyglycerin, mainly diglycerin and triglycerin, are W/O emulsifiers, and is water-soluble or easily dispersible. It is surprising that a large amount of water-insoluble substances can be solubilized therein. This is because, as mentioned above, conventional polyglycerol fatty acid ester surfactants have a distribution in the number of added moles of glycerin, and are insoluble in water because they are a mixture of mono-, di-, and triesters. Therefore,
Even in the case of conventional triglycerin fatty acid esters, systems using them as surfactants are currently only used as lipophilic emulsifiers and stabilizers for W/O emulsions. Ta. On the other hand, fatty acid esters of hexaglycerin, octaglycerin, and decaglycerin, which have a higher degree of polymerization of glycerin to increase hydrophilicity, have become commercially available, but they are all water-insoluble and have not yet been able to provide a solubilized system. It's not on. Furthermore, even if the substance is water-soluble, it is difficult to solubilize a water-insoluble substance using a solubilizer, since the concept of HLB is ignored. Both of these contain esterified products of unpolymerized glycerin and di- or triesters of polyglycerin.
This is because HLB becomes lipophilic. Furthermore, even if the monoester content of all polyglycerol fatty acid esters is increased, the object of the present invention cannot be achieved.
That is, the glycerin component in the nonionic surfactant has more hydroxyl groups than the ethylene oxide component, and has stronger hydrophilicity. Therefore, addition of 1 mole of glycerin component has a very large effect on HLB. Glycerol fatty acid monoesters and diglycerol fatty acid monoesters have strong lipophilic properties, and conversely, tetraglycerol fatty acid monoesters or higher have strong hydrophilic properties, and both of these are unsuitable for providing a solubilized system. Next, the solubilization method of the present invention can be applied to a wide range of fields, including pharmaceuticals such as the above-mentioned infusions and injections, foods and cosmetics that require safety. It is something. Here, in order to evaluate the solubilizing ability of the surfactant according to the present invention, a comparison was made with triglycerin monooleate obtained in Synthesis Example 2 and triglycerin-2-octyldodecanate obtained in Synthesis Example 3. Commercially available decaglycerin monooleate and decaglycerin monolaurate (mixtures of mono-, di-, and triesters with a distribution of added moles of glycerin) are water-soluble, so they can be used to improve the soybean oil content. A solubilizing power test was conducted. As a method,
1 g of soybean oil was added to 100 g of the aqueous phase containing 3% by weight of each of the above surfactants at 20°C.
The solubilization state was evaluated when 5 g, 10 g, and 15 g were added. The results are shown in Table-1.

[Table] ○: Transparent solubilization △: Microemulsion
×: Cloudy As is clear from the results in Table 1, the surfactant according to the present invention has much better solubilizing power than the comparative surfactant, and the solubilization method of the present invention is superior. gender has been proven. Furthermore, formalin elution tests (interfacial activator
Table 2 shows the results for 1wt% aqueous solution).

[Table] As shown in Table 2, the surfactant according to the present invention is highly safe because formalin is less eluted than conventional surfactants. Examples are shown below. Example 1 Vitamin K injection 7g of triglycerin monooleate and vitamin
1 g of K ₂ and 0.1 g of olive oil were added, and 91.9 g of an aqueous phase containing 3 g of glucose and 2 g of glycerin was added under stirring to obtain a transparent solubilized solution. Example 2 Intravenous nutritional supplement Triglycerin monooleate 9g, POE (20)
1 g of sorbitan monolaurate, 5 g of corn oil,
5 g of soybean oil was added, and 80 g of an aqueous phase containing 5 g of glycerin was added thereto under stirring to obtain a nutritional supplement in the form of a microemulsion. Example 3 Lotion Triglycerin-2-octyldodecanate 1
g, fragrance 0.2 g, preservative 0.1 g, polyethylene glycol (400) 3 g, and glycerin 2 g were mixed and dissolved, and 93.7 g of an aqueous phase containing 4 g of ethanol was added under stirring to obtain a solubilized lotion. .

Claims (1)

[Claims] 1. When solubilizing a water-insoluble substance in an aqueous system,
A water-insoluble substance characterized by adding a surfactant containing a monoester of triglycerin and an unsaturated fatty acid having 14 to 24 carbon atoms or an α-branched fatty acid in a concentration of 90% by weight or more based on the total weight%. Solubilization method. 2 The amount of surfactant added is based on the total weight of the aqueous system.
A method for solubilizing a water-insoluble substance according to claim 1, wherein the amount is 0.5 to 20% by weight.