JPS6365945A - Preparation of microcapsule - Google Patents

Abstract

PURPOSE:To prepare a microcapsule within a short time by simple operation, by coating a hardly water-soluble substance with sugar fatty acid ester or lecithin and subsequently adding an inducing agent for phase separation to the coated one. CONSTITUTION:After a hardly water-soluble substance is preliminarily coated with sugar fatty acid ester or lecithin, an inducing agent for phase separation is added to the coated one to prepare the microcapsule of the hardly water-soluble substance by the phase separation of a film forming polymer composition. As the film forming polymer composition, there are gelatin, dextrane and a nonionic cellulose derivative etc. As the inducing agent for phase separation, there are Meglumine(R), alginine, lysine, hystidine, leucine, a water-soluble dye, etc., and, as the water-soluble dye, erythrosine, Tartrazine, Sunset Yellow, Brilliant Blue, etc., are pref.

Description

DETAILED DESCRIPTION OF THE INVENTION (1) Field of Industrial Application The present invention relates to a method for producing microcapsules whose core material is a poorly water-soluble substance. Therefore, the present invention can be used in the fields of pharmaceuticals, foods, paper manufacturing, and photographic films, but is particularly applicable to the pulverization of oily substances, the stabilization of unstable substances over time, and the taste of substances.

It is particularly useful in the pharmaceutical field because it is effective in masking odors and uses only substances that are highly safe for living organisms.

(2) Prior Art and Problems Many methods have been proposed for the production of microcapsules. The most commonly used method is the so-called phase separation method.1 For example, a method in which a material that forms the film of a microcapsule is phase-separated around a core material by adding inorganic salts or ethanol or by adjusting the pH has often been adopted.

Alternatively, a water-insoluble polymer can be dissolved in a low-boiling point solvent and forced to precipitate on the surface of the core material by heating and evaporating, or the solubility can be decreased by adjusting the temperature and precipitated on the surface of the core material, forming a film. There is also a method of setting the clock to 2:00, which has been used. However, each of these conventional methods is known to have its own troublesome problems. The biggest problem is that the operation is complicated and requires skill. For example, in conventional phase separation methods, it is necessary to gradually complete phase separation over a long period of time, and its success or failure largely depends on the skill of the operator.
Inadequate setting of conditions led to a failure in which the capsules adhered to each other and agglomerated together. In addition, formaldehyde must be added to harden the film, but it is difficult to completely remove excess formaldehyde from the finished product, especially when phase-separated microcapsules are used in the pharmaceutical and food fields. This becomes a problem. This problem also occurs in methods using low boiling point solvents such as dichloroethane and cyclohexane. In other words, the operations of removing solvent by heating and reducing solubility by cooling are complex and time-consuming operations that require a high level of skill on the part of the operator. This is a major problem in the food and food industries.

(3) Means for Solving the Problems In view of the above-mentioned problems9, the present inventors have developed a technique that allows phase-separated microcapsules to be instantly prepared by simple and convenient operations without requiring any special skill. Various studies were conducted with this aim.

As a result, they unexpectedly discovered that the intended purpose could be achieved simply by coating the core substance, which is a poorly water-soluble substance, with sucrose fatty acid ester or lecithin in advance.2 This led to the completion of the present invention. The present invention will be described in detail.

The object to be solved by the present invention is phase-separated microcapsules for poorly water-soluble substances. A water-soluble substance refers to a substance that does not mix or dissolve in water in any proportion, and may be in solid, semi-solid, or liquid form, such as vitamins A, D, and E.

Fat-soluble vitamins such as K, poorly water-soluble vitamins.

Examples include animal oil, vegetable oil, mineral oil, 2 synthetic oils, etc.

Phase separation is a phenomenon in which a lyophilic colloid solution such as a polymer solution or a colloidal electrolyte solution separates into two liquid phases, a colloid-rich liquid phase and a colloid-poor liquid phase, due to changes in conditions, and is called coacervation. Also called microcapsules, it is used as a means for manufacturing microcapsules. Phase separation in the present invention refers to a phenomenon in which a colloidal solution of the film-forming polymer composition according to the present invention separates into a colloid-rich liquid phase and a colloid-poor liquid phase by the addition of an inducing agent. The rich liquid phase (coacervate) is deposited around the poorly water-soluble substance and gradually loses water to form a film, leading to the formation of microcapsules. In the present invention, the microcapsules have an average diameter of 50 to 10
It is obtained as spherical or cone-shaped particles of 0 micron, but the average diameter can be adjusted arbitrarily.

A film-forming polymer composition refers to a composition consisting of one or more polymers that form a film through phase separation, and examples of such polymers include gelatin, casein, polypeptides such as fibrinogen, dextran, and gum arabic. , chitic acid, chipolysaccharide 1, hydroxypropyl methylcellulose.

Nonionic cellulose derivatives such as hydroxypropylcellulose and methylcellulose can be mentioned. For example, gelatin, dextran.

The combination of hydroxypropyl methylcellulose is one of the preferred compositions, and in this case, the appropriate composition ratio is 1 to 4 parts by weight each of dextran and hydroxymethylcellulose to 1 part by weight of gelatin. The concentration of the composition in an aqueous solution is 2
~20% W/V is appropriate, and 4-1α'N/V is particularly preferred.

However, the present invention is not limited to these composition ratios and concentrations (2) They may be appropriately determined depending on the type of selected polymer.

The composition aqueous solution may be prepared by individually dissolving each polymer constituting the composition in water and then mixing them.

It is not limited to this.

A feature of the present invention is that a poorly water-soluble substance is coated with sucrose fatty acid ester or lecithin, and then an inducer for phase separation is added. Here, as the sucrose fatty acid ester, those commercially available under the name of sugar ester may be obtained and used. The type of sugar ester is not particularly limited, but for example, Sugar Ester S-970 (Ryoto Sangyo) is preferred. There are no particular limitations on lecithin (soybean lecithin, egg yolk lecithin, and their hydrogenated lecithins may be selected and used as appropriate. Sucrose fatty acid esters and lecithin may be used in combination. The amount used is determined by water standards. The appropriate amount is 0.1 to 1 part by weight per 1 part by weight of the soluble substance, but it depends on the particle size of the target microcapsules or whether the poorly water-soluble substance is in a solid, semi-solid, or liquid state. In short, it is only necessary to determine the amount necessary to completely coat the poorly water-soluble substance (9) The present invention is not limited by this amount.

For example, the following methods are recommended for coating. First, warm and dissolve sucrose fatty acid ester or lecithin in a small amount of water or ethanol, and disperse or dissolve the poorly water-soluble substance therein.Next, while vigorously stirring the water, add the previously prepared Gradually pour in the solution that has been prepared.This completes the coating of the sucrose fatty acid ester or lecithin around the dispersed particles of the poorly water-soluble substance.

Therefore, for example, while vigorously stirring an aqueous solution of a film-forming polymer composition, a previously prepared solution may be gradually poured into the solution. However, this is merely an example of a preferred embodiment of the invention. Next, as an inducer for phase separation, any substance generally known as a coagulant or precipitant for colloids may be obtained and used. In the present invention, for example, meglumine is used.

Mention may be made of arginine, lysine, histidine, leucine, isoleucine, and valine. It has also surprisingly been found that water-soluble dyes such as erythrosine, tartrazine, sunset yellow, and brilliant blue also function as inducers in the present invention. Furthermore, in this case, light-shielding colored microcapsules can be obtained using these dyes. The amount of the inducing agent to be added can be small. Specifically, prepare an aqueous solution of the inducing agent in advance, and add the solution already coated with sucrose fatty acid ester or lecithin (with stirring) into the solution. While gradually dropping the inducer and observing the progress of phase separation using a microscope, add the amount necessary to complete the desired phase separation.Therefore, the amount and method of addition of the inducer should be determined as appropriate depending on the situation. Phase separation can be completed in a short time of about 5 to 15 minutes in the case of multi-phase separation, and the operation is simple and easy and does not require any special skill. When the temperature is maintained at 20 to 30°C and 2, for example, hydroxypropyl methyl cellulose phthalate or aluminum lake pigment is introduced as a fine powder or as a water suspension, these substances immediately adhere to the coacervate surface and are further incorporated into the interior. Enteric-coated microcapsules made of hydroxypropyl methylcellulose phthalate and light-shielding colored microcapsules made of aluminum lake dye are obtained.These are techniques added to the present invention, and the present invention is not limited thereby.

Finally, the microencapsulated dispersion is cooled,
The microcapsules are separated, washed with H50 water, '0 ethanol water, and absolute ethanol in this order, and dried with cold air to isolate the microcapsules. Alternatively, after cooling, the microcapsules may be taken out by spray drying or fluidized bed granulation drying while still containing the microcapsules.

(4) Effect Compared to the prior art, the method of the present invention takes a shorter time.

Microcapsules can be produced by simple and easy operations without requiring special skill, and the resulting microcapsules have various functions that microcapsules generally have.
For example, turning oily substances into powder, stabilizing unstable substances over time,
It has the effect of masking the taste and odor of substances. Furthermore, the method of the present invention uses only substances that are highly safe for living organisms and does not use toxic crosslinking agents such as bomaldehyde, so it can be advantageously used in the pharmaceutical field. Furthermore, the microcapsules obtained by the method of the present invention can be easily shielded from light by using a water-soluble dye as an inducer for phase separation, or by adding an aluminum lake dye immediately after phase separation is completed. Can be colored microcapsules.

It can stabilize substances that are unstable to light.

(5) Examples The present invention will be specifically explained by the examples described below.

Example 1 Sugar ester S-970 (Ryoto Sangyo) 0.5 # and vitamin E acetate 2 in 5 rnl of ethanol
．． 51I was dissolved at 50°C. On the other hand, a solution of 5.1 hydroxypropyl methyl cellulose and 5.9 of dextran (molecules i 40000) dissolved in 9 Q mi of water was mixed with a solution of 2 g of gelatin dissolved in 20 ml of water.

The mixture was stirred vigorously while maintaining the temperature at 40°C. The vitamin E acetate solution was gradually dropped therein. It was observed that the surface of oil droplets with a size of 1 to 50 microns was coated with sugar ester.

Next, 2 ml of 5% meglumine solution was gradually added while stirring gently, and the progress of phase separation was observed using a microscope. about 10
The process was completed within minutes, and spherical or spindle-shaped microcapsules were formed. Next, it was cooled to 28°C, and 0.5% of hydroxypropyl methyl cellulose phthalate was added to 5 ml of water. ! A suspension of i' was added. Cool to 7°C, separate the microcapsules, and wash with cold water at 100°C.

50 ”6 engineering 9/-le water 50rnl, anhydrous eta/
The microcapsules were washed with 5 Q ml of water and dried with cold air to obtain a fine powder consisting of microcapsules with an average diameter of 50 microns.

Example 2 0.5g of Sugar Ester S-970 (Ryoto Sangyo) was dissolved in 100ml of water at 80°C, and vitamin E acetate)2. ! M/ was added and dispersed. The following operations were carried out in the same manner as described in Example 1 to obtain fine powder consisting of microcapsules with an average diameter of 50 microns.

Example 3 The same procedure as described in Example 1 was carried out using vitamin B2 instead of vitamin E acetate to obtain a powder consisting of microcapsules with an average diameter of 20 microns.

Example 4 The same procedure as described in Example 1 was carried out using vitamin E acetate instead of vitamin A to obtain fine powder consisting of microcapsules with an average diameter of 100 microns.

Example 5 The same procedure as described in Example 1 was carried out except that 2 ml of 596 arginine solution was used instead of 2 ml of 5% meglumine solution in Example 1, to obtain fine powder consisting of microcapsules with an average diameter of 50 microns. .

Example 6 The same procedure as described in Example 1 was carried out except that 5% tartrazine solution IQmJ was used instead of 2 m of 5% meglumine solution in Example 4, and a fine powder consisting of microcapsules with an average diameter of 70 microns was prepared. Obtained.

Example 7 Example 3 The same procedure as described in Example 1 was repeated except that soybean lecithin was used instead of sugar ester S-970 in Example 1 to obtain a fine powder consisting of microcapsules with an average diameter of 50 microns.

Example 8 The same procedure as described in Example 1 was carried out except that 1 g of methyl cellulose was used instead of 5 g of hydroxypropyl methyl cellulose.

A fine powder consisting of microcapsules with an average diameter of 50 microns was obtained.

(6) Effect of the Invention Experimental Example 1 The same procedure as described in Example 1 was conducted except that sugar ester S-970 was not used in Example 1.

As a result, coacervate was not deposited around the vitamin E acetate oil droplets, and no microcapsules were formed. In contrast to the formation of microcapsules in Example 1, sugar ester S
-970 was found to be essential.

Experimental Example 2 Samples and Methods Three types of microcapsules were produced according to the formulation (weight ratio) shown in Table 1 by the method of the present invention.

Samples 1 to 3 were prepared. Sample 1 is non-colored microcapsule, sample 2. Sample 3 is a colored microcapsule. Each sample was irradiated with 1000 lux light, and the vitamin content was measured over time to determine the residual rate. Note that the measurement of vitamin 2 was performed by high performance liquid chromatography using a Unisel QC18 column.

Sample 100 from the peak height at absorption wavelength 248 nm
= The content of 2 vitamins in it was determined.

Table 1 Sample 1 Sample 2 Sample 3 Vitamin 7, 1 1 1 Gelatin 2 2 2 Sugar ester 0.25 0.25 0.25
Meglumine o, os -o, os erythrosin -0,08- Results The results are shown in Figure 1. In the figure, the marked lines, Δ marked lines, and ○ marked lines are for sample 1. Sample 2. The results of sample 3 are shown. From Figure 1, the microcapsules obtained by the method of the present invention can be obtained by using a water-soluble dye as an inducer for phase separation.
Alternatively, it is possible to add an aluminum lake dye immediately after phase separation is completed, thereby easily forming light-shielding colored microcapsules and stabilizing substances that are unstable to light. Prove.

[Brief explanation of the drawing]

FIG. 1 shows the experimental results of light irradiation on microcapsules, and is a graph showing the relationship between irradiation time and survival rate.

Claims (7)

[Claims] (1) When producing microcapsules of a poorly water-soluble substance by phase separation of a film-forming polymer composition, the poorly water-soluble substance is coated in advance with sucrose fatty acid ester or lecithin, and then induced for phase separation. A method for producing microcapsules characterized by adding an agent (2) The method for producing microcapsules according to claim 1, wherein the film-forming polymer composition is a composition containing gelatin as a main component. (3) The method for producing microcapsules according to claim 1, wherein the film-forming polymer composition is a composition comprising gelatin, dextran, and a nonionic cellulose derivative. (4) The method for producing microcapsules according to claim 3, wherein the nonionic cellulose derivative is hydroxypropylmethylcellulose or methylcellulose. (5) The method for producing microcapsules according to claims 1 to 4, wherein the inducer is any one of meglumine, arginine, lysine, histidine, leucine, isoleucine, and valine. (6) The method for producing microcapsules according to claims 1 to 4, wherein the inducing agent is a water-soluble dye. (7) The method for producing microcapsules according to claim 6, wherein the water-soluble dye is any one of erythrosine, tartrazine, sunset yellow, and brilliant blue.