JP4997449B2 - Method for producing oil-coated composite particles using supercritical fluid and composite particles - Google Patents

Description

  The present invention relates to composite particles obtained by using fats and oils and a method for producing the same. More specifically, composite particles that can be suitably used for masking raw materials such as pharmaceuticals, cosmetics, and health foods, mainly masking health food materials, using supercritical fluids such as carbon dioxide or subcritical fluids, and their production Regarding the method.

The coating method using a supercritical fluid is known as follows.
The present inventors have continued research and development on this technology, and have already provided inventions such as the following Patent Documents 1 to 3.
In Patent Document 1 (Japanese Patent Laid-Open No. 11-197494), a high-pressure fluid including a supercritical fluid, a subcritical fluid, and a liquid substance, and a fluid obtained by adding an additive to these materials are used for microscopic treatment of organic and inorganic substances. Techniques for coating or encapsulating have been disclosed.
This invention uses a specific coexistence effect of a poor solvent for microencapsulation using the rapid expansion method, and is intended only for a polymer having a molecular weight of several tens of thousands as a coating material, and has a relatively small molecular weight. It is not intended to obtain particles having an excellent masking effect by using a hardened oil or the like having a very small specific coexistence effect with a poor solvent.

Japanese Patent Application Laid-Open No. 8-113652 discloses a technique for coating an organic substance with a polymer.
This technique is effective for polymers such as acrylics that cannot be used in foods having polar groups because they are dissolved in a polymer by a specific coexistence effect of a poor solvent. However, for extremely polar materials such as hardened fats and oils that can be used in foods, the specific coexistence effect of poor solvents is extremely small, so that particles with excellent masking effect can be obtained by using hardened fats and oils. Not suitable for.

Patent Document 3 (Japanese Patent Application Laid-Open No. 11-47681) discloses a composite particle using a supercritical fluid and a method for producing the composite particle by simply jetting supercritical carbon dioxide into the atmosphere to form a composite of inorganic fine particles. Disclosed a technology mainly aimed at performing Further, Patent Document 4 (Japanese Patent No. 3469223) discloses a technique for combining inorganic fine particles by reducing the pressure of inorganic fine particles and a fluorine-based acrylic resin having high carbon dioxide solubility in a high-pressure vessel.
However, in these methods, the polymer as the coating material is a fluorine polymer, a silanol polymer, or a poor solvent that cannot be used as a food additive that dissolves in supercritical carbon dioxide by 10% or more. It was limited to polyethylene glycol that could be dissolved. In addition, these are composite technologies that use inorganic particles that do not dissolve in supercritical carbon dioxide as the core, and are not suitable for composites such as foods that contain a large amount of organic substances in which the core material of the composite dissolves in supercritical carbon dioxide. .
A technique using a silicone compound or a fluorine compound as a coating agent is also disclosed in Patent Document 5 (Japanese Patent Laid-Open No. 2004-130296) and Patent Document 6 (Japanese Patent Laid-Open No. 2004-10499).

JP-A-11-197494 JP-A-8-113652 JP 11-47681 A Japanese Patent No. 3469223 JP 2004-130296 A JP 2004-10499 A

  This invention makes it a subject to obtain the composite particle | grains excellent in the masking effect with respect to the active ingredient containing material which is unpleasant in taste and smell, without using the organic solvent harmful | toxic to a human body. Moreover, this invention makes it a subject to provide the manufacturing method of the composite particle excellent in the masking effect.

  The present invention is to obtain composite particles by contacting the active ingredient-containing material and oil in the presence of a supercritical fluid, and then removing the supercritical fluid. In particular, it is a plant extract powder or an antioxidant bulk powder that is coated entirely with fats and oils.

(1) In the presence of a supercritical or subcritical high-pressure fluid, the oil and fat and the active ingredient-containing material are dispersed in a solid state under temperature and pressure conditions that do not melt below their inherent melting points, and then the oil and fat A method of producing composite particles by contacting an active ingredient-containing material and fats and oils with high-speed stirring under a temperature and pressure condition that melts below the inherent melting point, and then releasing them out of the container with stirring .
(2) Effective after being dispersed in the solid state under the temperature and pressure conditions in which the oil and fat and the active ingredient-containing material do not melt below their inherent melting points in the presence of a supercritical or subcritical high-pressure fluid Manufacture composite particles by bringing the active ingredient-containing material and oil into contact with the active ingredient-containing material and oil under high-speed agitation under temperature and pressure conditions that melt below the melting point inherent to the ingredient-containing material and oil and fat, and then releasing it out of the container with stirring. how to.
(3) The method for producing composite particles according to (1) or (2) , wherein the temperature and pressure conditions for melting are higher than the temperature and pressure conditions for dispersion in the solid state.
(4) The method for producing composite particles according to any one of (1) to ( 3) , wherein the supercritical fluid is supercritical carbon dioxide.
(5) The method for producing composite particles according to any one of (1) to ( 4) , wherein the active ingredient-containing material is α-lipoic acid.
(6) The method for producing composite particles according to any one of (1) to ( 5) , wherein the fat is rapeseed oil or fat or glycerin fatty acid ester.
(7) The method for producing composite particles according to ( 6) , wherein the main component of the fat is triglyceride fatty acid ester having a C22 alkyl chain length in the fatty acid part of stearic acid triglyceride hardened fat or glycerin fatty acid ester.
(8) The method for producing composite particles according to any one of (1) to ( 7) , wherein the temperature and pressure in the container before decompression are 60 ° C. or less and 200 kg / cm ² or less.

By this invention, it becomes possible to mask the active ingredient containing material which is unpleasant in taste and smell, without using an organic solvent harmful to the human body. In addition, since it can be carried out at a relatively low temperature as a production condition of the composite particles, it is effective for a heat-unstable raw material.
The resulting composite particles are finely divided, have a thin oil coating, are clean, have excellent coverage and density, have a sharp particle size distribution, and are excellent in uniformity.
Moreover, since the fats and oils to be used are selected for foods or food additives, they are suitable not only for the field of pharmaceuticals and cosmetics but also for improvement of materials for health foods. Application forms of the composite particles include powders, granules, and tablets used for pharmaceuticals and health foods. Further, the dispersibility is good and the stability over time is excellent.
It can be used as a disintegration delaying agent that can be disintegrated and absorbed in the stomach or intestine.
In particular, as an active ingredient of antioxidant capacity, it is effective for coenzyme Q10, α-lipoic acid, vitamin E, silymarin, and silybin. With α-lipoic acid, an oil finger coating powder having a content of 39% or more can be provided.
In the present invention, when blended with other materials, it is excellent in stability over time and often contains multiple active ingredient materials when commercialized. Can be suppressed. According to the present invention, it was possible to obtain oil-fat coating composite particles using a supercritical fluid that is excellent in masking ability and covering ability such as bitterness and is resistant to deterioration over time. An excellent masking effect was confirmed for mineral-containing yeasts such as silymarin and zinc yeast. Furthermore, in the preparation of tablets, granules, powders and the like, the uniform dispersibility is improved because of the uniform fine particle size. The oil-and-fat coating composite particles obtained in the present invention have improved fluidity and improved handling of the preparation process.

The present invention will be described in detail.
The composite particles in the present invention are composite particles in which the active ingredient-containing material particles are coated or encapsulated with fats and oils, particles in which the fat and oil particles are present on the surface of the active ingredient-containing material particles, and the particles aggregate together. The composite particle | grains in which the oil-and-fat particle | grains exist in the inside or the surface of the produced particle | grains. The oil / fat coating in the present invention may be coated in a state where a plurality of α-lipoic acids are connected, not individually.

  Examples of the fats and oils used in the present invention include natural waxes and glycerin fatty acid esters that can be applied to foods or health foods, and those that melt at 60 ° C. or lower in the presence of a supercritical fluid are preferable. For example, rapeseed oil powder having a melting point of 65 ° C. or higher shows a melting phenomenon at 60 ° C. or lower in the presence of a supercritical fluid.

  The active ingredient-containing material in the present invention refers to an active ingredient itself, a material containing the active ingredient as a main component, or a raw material containing a component that is effective in a small amount. In particular, in the health food field, extracts from plants and the like (ginkgo biloba extract, soybean extract, perilla extract, natto extract, ashitaba extract, etc.), zinc yeast, raw materials exhibiting antioxidant ability (coenzyme Q10, α-lipoic acid, Examples thereof include functional materials such as vitamin E, silymarin, and silybin) or mixtures thereof. In particular, a remarkable masking effect has been confirmed in α-lipoic acid, silymarin, and various mineral-containing yeasts. Examples of the mineral-containing yeast include zinc yeast, copper yeast, cobalt yeast, manganese yeast, chromium yeast, and molybdenum yeast.

  There are various methods for producing composite particles using high pressure, but after the active ingredient-containing material and fats and oils are charged into the container in advance, the container is maintained at the temperature and pressure at which the supercritical fluid exists. It is preferable to use a method of obtaining composite particles by reducing the solubility of the supercritical fluid by rapidly expanding (depressurizing) using a nozzle or the like from the state where the solute is separated from the supercritical fluid. .

  Examples of the gas used for the supercritical fluid include methane, propane, nitrogen, carbon dioxide and the like, but it is preferable to use carbon dioxide which is inexpensive and has good handling conditions.

  The entrainer is preferably a polar solvent. Among polar solvents, ethanol and water that are considered to be almost harmless to the human body are preferable.

  The temperature for the rapid expansion of supercritical carbon dioxide is preferably 35 ° C. (308.15 K) to 80 ° C. (353.15 K), more preferably from the viewpoint of efficiently performing the rapid expansion of supercritical carbon dioxide. Is 40 ° C. (313.15 K) to 60 ° C. (335.15 K).

The pressure for rapid expansion of supercritical carbon dioxide is preferably 72 to 400 kg / cm ² or less, more preferably 150 to 300 kg / cm ² from the viewpoint of efficiently performing rapid expansion of supercritical carbon dioxide. ² or less.

  As used herein, “inherent melting point” refers to the temperature at which a solid melts at room temperature and pressure. In the present invention, supercritical carbon dioxide dissolves in the solute and becomes a mixture of supercritical carbon dioxide and solute. Since the melting point of carbon dioxide is low, the melting point of this mixture also decreases as the proportion of carbon dioxide increases. . A composite particle obtained by utilizing this phenomenon and a method for producing the same.

  As a composite particle manufacturing apparatus used in the present invention, a fluid containing a solute mixed / dispersed / dissolved / molten in a high-pressure state is discharged out of a container by using a nozzle or the like and rapidly expanded to produce composite particles. The apparatus to which the method to obtain is applied is used. As this device itself, known devices disclosed in Patent Document 1, Patent Document 3, and the like can be used.

  It can be visually confirmed that the fats and oils in the present invention melt below the inherent melting point in the presence of supercritical carbon dioxide using a high-pressure cell having a sapphire pressure-resistant observation window.

An object of the present invention is to obtain composite particles by contacting an active ingredient-containing material with fats and oils in the presence of a supercritical fluid, and then removing the supercritical fluid to obtain composite particles.
(1) The active ingredient-containing raw material and the hardened oil / fat are brought into contact with each other under a temperature / pressure condition in which the hardened oil / fat melts at or below the inherent melting point.
(2) It is more preferable to contact the molten active ingredient-containing material with fats and oils.
(3) Further, it is more preferable to disperse and mix the active ingredient-containing material and the fat and oil in advance in the container by high-speed stirring under the temperature and pressure conditions in which the active ingredient-containing material and the fat and oil do not melt below their inherent melting points.
By taking such measures, 1) In a supercritical state controlled to appropriate temperature and pressure conditions, the active ingredient material having a relatively high viscosity comes close to a material having a relatively high affinity such as hardened oil and fat. As a result, the viscosity of the active ingredient material is lowered as a whole, and high-speed stirring makes the dispersion and mixing properties very good, resulting in an increased proportion of high-pressure fluid around the material. This is considered to cause a further decrease in viscosity. And 2) By discharging from the nozzle while stirring and rapidly expanding (depressurization treatment), the solubility of the supercritical fluid decreases, the solute is separated from the supercritical fluid, and composite particles can be produced. .
Specifically, it is to obtain composite particles capable of masking an active ingredient-containing material having an unpleasant taste and odor by the method as described above.

(Example)
Hereinafter, the present invention will be described in more detail with reference to examples. The present invention is not limited to the following examples.

A particle composite experiment using a combination of α-lipoic acid and rapeseed hydrogenated oil powder (Lovely Wax 102H) was conducted. An air bath (acrylic chamber) was used for particle recovery. In addition, as the temperature and pressure operating conditions, the pressure is increased while stirring (200 rpm) at 35 ° C. to 40 ° C. and about 100 to 130 kg / cm ^2, and the temperature is gradually increased while further stirring (200 rpm). Specifically, the mixture was stabilized with stirring (1000 rpm) at around 60 ° C. and 200 kg / cm ² and then sprayed under atmospheric pressure.
The formulation in Example 1 is shown in Table 1.

  The particles obtained in Example 1 were collected and weighed (sprayed once) to find about 380 mg. In addition, although it implemented even if the stirring speed at the time of spraying under atmospheric pressure was 200 rpm, 400 rpm, and 600 rpm, it was hardly collect | recovered particle | grains. Most of the unrecovered α-lipoic acid used in about 5 g remained in the container without being sprayed. In other embodiments, unrecovered portions remain in the container as well. This is considered to be caused by the fact that a sufficient mixing state cannot be obtained unless the stirring is sufficiently performed until the time of jetting, the degree of layer separation is increased, and almost only carbon dioxide is jetted.

  A particle composite experiment was conducted under the same conditions as in Example 1 except that the stirring speed before spraying under atmospheric pressure was 600 rpm. The formulation in Example 2 is shown in Table 2.

  The particles obtained in Example 2 were collected and weighed (one spray), which was about 300 mg.

A particle composite experiment was conducted under the same conditions as in Example 1 at a stirring speed of 1600 rpm.
The formulation of Example 3 is shown in Table 3, and a scanning electron micrograph of the particle structure of the obtained composite particles is shown in FIG.

  The particles obtained in Example 3 were collected and weighed, and it was about 3 g. In addition, although it implemented even if the stirring speed at the time of spraying under atmospheric pressure was 600 rpm and 800 rpm, it was hardly collect | recovered particle | grains. From the photomicrograph of FIG. 1, the particle size of the composite particles obtained in Example 3 is approximately 10 μm or less.

Under the same conditions as in Example 3, a particle composite experiment using a combination of α-lipoic acid and triglycerin fatty acid ester (Poem TR-FB) was performed.
The formulation of Example 4 is shown in Table 4, and a scanning electron micrograph of the particle structure of the obtained composite particles is shown in FIG.

[Measurement of particle size]
The particle diameters of the commercially available products (Nippon Yushi Coated Particles MC-50F), α-lipoic acid oil compounded particles obtained in Example 3 and Example 4 were measured. Measurement device (MASTERSIZER), measurement condition (4.0 Bar), particle size distribution measurement result (value of d (0.5)).

As a result, α-lipoic acid oil composite particles obtained from Example 3 were 1/25 or less of the commercially available product, and α-lipoic acid oil composite particles obtained from Example 4 were 1/25 of the commercial product. It was confirmed that the particles were 19 and extremely small particles.
At the same time, as a result of confirming the particle size distribution based on the scattering intensity, it is considered that in Example 3, relatively uniform particles are formed that are sharper than commercially available products.
Moreover, about 5 types of Example 3, Example 4, commercial product (MC-50F), α-lipoic acid bulk powder, α-lipoic acid bulk powder obtained by further finely pulverizing α-lipoic acid bulk powder, Since the particle size distribution was measured, the particle size distribution graphs are shown in FIGS. In each example, the results of three measurements are overlapped, so there are graphs in which a plurality of lines are displayed. As a result, in Examples 3 and 4, the peak is 4 to 6 μm, the particle size distribution is small, and the larger one is 20 μm or less. In contrast, even α-lipoic acid bulk powder was further pulverized and pulverized, so there was a peak at 20-30 μm. It can be seen that the material is smaller than the raw material powder.

[Test Example 1]
As a comparison product of α-lipoic acid oil composite particles obtained in Example 3, α-lipoic acid bulk powder, a commercially available oil coating product containing the same amount of α-lipoic acid as the present product (manufactured by Nippon Oil & Fats) 5 subjects (A, B, C, D) for a physical mixture of coated particles MC-50F) (use hardened rapeseed powder as coating fat) and rapeseed hardened fat containing the same amount of α-lipoic acid , E), sensory test was conducted for two types of taste, smell and touch as follows.
Sensory evaluation criteria 1 are: Bitterness, 2. 2. Numbness (such as tingling) The smell is judged in five stages from “I don't feel anything” to “I feel very much”. Table 6 shows the evaluation criteria, and Table 7 shows the evaluation results. In addition, in the evaluation criteria 1,-is converted into 0 points, ± is 1 point, + is 2 points, ++ is 3 points, and ++ is 4 points, and the total score is shown in a bar graph in Table 8. This is shown in FIG.
Sensory evaluation standard 2 is
1. About roughness, when it is included in the mouth, "Is it rough", "Is it smooth?"
2. About the residual grain feeling, it determines in two steps of "whether there is a grain touch" about 10 to 20 seconds after including in a mouth, and Table 9 shows each evaluation result.

  When the sensory evaluation results are converted into points, for example, for bitterness, Example 3 has 1 point, and the commercially available oil coating product has 6 points, whereas α-lipoic acid bulk powder has 13 points, and the physical mixture has 12 points. Therefore, it can be said that Example 3 suppresses the bitterness of the α-lipoic acid bulk powder alone to 1/13. Similarly, for numbness, Example 3 has 2 points, and commercially available oil-coated products have 6 points, whereas α-lipoic acid bulk powder has 17 points, and the physical mixture has 14 points. -It can be said that the numbness of the lipoic acid bulk powder alone is suppressed to 2/17. As for odor, Example 3 says that 0 points, that is, all 5 people feel no odor, 8 points of α-lipoic acid bulk powder, 4 points of commercially available oil coating product, 3 points of physical mixture In comparison, an advantageous effect was seen in masking the odor. Also in the total score, when Example 3 is set to 1, the commercially available oil-and-fat coating product obtained 5.3 times, the physical mixture obtained 9.7 times, and the α-lipoic acid bulk powder obtained 12.7 times. The composite particles such as the product of the present invention obtained in Example 3 and the commercially available α-lipoic acid oil / fat coating product have negative elements such as bitterness markedly suppressed with respect to the α-lipoic acid bulk powder and physical mixture. It is thought that there is. Moreover, when Example 3 and a commercially available oil coating product are compared, although there is some variation, the product of the present invention is considered to have significantly suppressed negative elements.

This evaluation result may be due to the difference in particle diameter. In the present embodiment such as the third embodiment, it is assumed that the surface is cleanly coated and smooth by performing the supercritical processing. The α-lipoic acid bulk powder has a flat shape, whereas the α-lipoic acid oil-complexed particles obtained in Example 3 have a relatively nearly spherical shape.
In addition, regarding the feeling of residual, it is considered that the particle size and disintegration / solubility after a certain period of time in the oral cavity are important. α-Lipoic acid and fats and oils are raw materials with poor affinity for water. In this case, the natural infusion by saliva in a few seconds, as well as the roughness and the disintegration of the particle size and shape of the particle It is thought that the factor accounts for a large part.

From FIG. 1 and FIG. 2, it can be seen that the composite particles obtained in Example 3 and Example 4 have a smaller particle size than the commercially available coating products. This is considered to have a great influence on the roughness of sensory test items and the feeling of residual grains.
Although the particle size is small, the α-lipoic acid bulk powder itself is rough and has a feeling of residual grains. On the other hand, commercially available oil coating products have a further increased roughness and residual grain feeling. As for the product of the present invention obtained in Example 3, as a result of sensory evaluation, no one felt that there was a feeling of roughness and a feeling of residual grains. Therefore, it is considered that the product of the present invention was coated and smoothened.

  From the results based on Evaluation Criteria 1 and Evaluation Criteria 2, the product of the present invention in Example 3 is superior in masking ability such as bitterness, and has a rough texture and a feeling of residual grains. The application to solid preparations such as tablets and chewable preparations is expected to expand.

  In addition, it was confirmed that the α-lipoic acid content of the product of the present invention obtained in Example 3 and the commercially available oil-fat coating product was contained in substantially the same amount by the quantitative test method shown below.

[Quantitative test method]
Quantitative method (HPLC method)
(1) About 0.01 to 0.05 g of each sample is accurately weighed into a 50 mL volumetric flask, an appropriate amount of methanol is added, and then the mobile phase is added to make exactly 50 mL. This is filtered through a membrane filter having a pore size of 0.45 μm, and the filtrate is used as a sample solution.
(2) Precisely weigh about 0.05 g of α-lipo (standard product) into a 50 mL volumetric flask, add an appropriate amount of methanol, and then add the mobile phase to make exactly 50 mL. This is filtered with a membrane filter with a pore size of 0.45 μm. Filter, and use the filtrate as the standard solution.
(3) Test each 20 μL of the sample solution and standard solution by high performance liquid chromatography under the following conditions, and determine the peak area At of the α-lipoic acid of the sample solution and the peak area As of the α-lipoic acid of the standard solution. taking measurement.
<Operation conditions>
Detector: UV absorption photometer (measurement wavelength: 330nm)
Column: shiseido capcellpak C-18 UG-120 4.6 × 250 (mm) No.AOAD14935
Column temperature: constant temperature around 40 ° C Mobile phase: 0.05% TFA aqueous solution: 0.05% TFA methanol = 35:65
Flow rate: 1.0mL / min
Injection volume: 20 μL

Calculation formula Concentration of α-lipoic acid in this product (W / W%)
= (Standard product weighed amount (g) / Sample weighed value (g)) × (At / As) × Sample constant capacity / Standard product constant capacity × 100
However,
At: Peak area of α-lipoic acid in the sample solution
As: Peak area of α-lipoic acid in standard solution

  When the α-lipoic acid content was calculated by the above formula, it was 39.9 (W / W%) for the particles obtained in Example 1 and 42.5 (W / W%) for the particles obtained in Example 2 ( n = 3, average). Therefore, it is considered that the stirring speed before raising the temperature affects the α-lipoic acid content of the composite particles. In Example 3, composite particles having an α-lipoic acid content of 43 (W / W%) or more are obtained. The α-lipoic acid content of the commercial product (Nippon Yushi Coated Particles MC-50F) was 45 (W / W%). In general, it is considered that the ratio of the coating layer increases as the particle size decreases. However, in the examples of the present application, since the α-lipoic acid content is approximately 40% or more, the coating layer is considered to be extremely thin.

[Test Example 2]
Color difference measurement was performed as one means of grasping the degree of coating and coating. The measured values are digitized according to the L * a * b * color system (L * is lightness, a * b * is hue and saturation, n = 3). In addition, since α-lipoic acid is strong in yellow, + b *, which is an index in the yellow direction, tends to indicate a large value. Therefore, the inventive product obtained in Example 3 and Example 4, the α-lipoic acid bulk powder as a comparative product, and a commercially available oil coating product containing the same amount of α-lipoic acid as the present product (rapeseed as a coating fat) L * a * b * of Poem TR-FB is shown below. Hardened oil and fat powder is used), rapeseed hardened oil and fat powder (Fabry wax 102H and oil powder used in commercially available coating products).

Comparing FIGS. 1 to 4, the inventive products obtained in Example 3 and Example 4 have a smaller particle size than commercially available oil coating products, and generally the larger the particle size, the more saturated Therefore, it is difficult to simply compare the results in Table 10.
The average value of b * was found to be 46.27 for α-lipoic acid bulk powder, 9.46 for the product obtained from Example 3, 10.47 for the product obtained from Example 4, 21.45 for the commercially available oil and fat coating product, The fats and oils are 1.52, 1.37, and 2.35 in this order. From this result, it can be seen that the α-lipoic acid bulk powder has a strong yellowish taste, and the fats and oils that coat it have almost no yellowishness. In addition, in relation to light scattering, in the case of α-lipoic acid, it seems that the b * value tends to be small as the particle diameter decreases. In the particle size distribution, the unground pulverized α-lipoic acid bulk product has a d (0.5) of about 50 μm and a b * value of about 46, and the crushed product has a d (0.5) of about 25 μm and a b * value of 39. Presuming from these, even if the b * value has the same level of α-lipoic acid particle size as that of the supercritical α-lipoic acid oil composite particle obtained in the present invention, the b * value is as high as the supercritical composite particle. * Value is considered not to decrease.
In order to compare the yellowishness of the product of the present invention and the commercially available oil coating product, when b * of the α-lipoic acid bulk powder is converted to 100, the product of Example 3 obtained from Example 3 was obtained from Example 4 The obtained invention product is 23, and the commercially available oil coating product is 46. From this result, it can be said that the product of the present invention is about ½, the commercially available oil coating product is about ¼, and the yellowishness is reduced compared to the α-lipoic acid bulk powder.
Therefore, it can be seen that the α-lipoic acid bulk powder is generally coated with the oil and fat in the product of the present invention and the commercially available oil and fat coated product. Furthermore, it can be said that the product according to the present invention has a marked improvement in the degree that the α-lipoic acid bulk powder is coated with fats and oils compared to the conventional product.
On the other hand, the α-lipoic acid content is 40% or more and the b * value is as small as 1/2 of the commercial product and 1/4 of the α-lipoic acid bulk powder. It is considered that the condition is good, and a small b * value is shown reflecting the effect of oil and fat.

[Test Example 3]
During formulation, the main ingredient may deteriorate (decrease in content) or change in color due to interaction with other ingredients. In order to ensure a high formulation quality, it is necessary to select a raw material with low reactivity or to coat the main agent. Therefore, in order to evaluate the stability (coating property, denseness) of the supercritically prepared α-lipoic acid composite particles, the content of α-lipoic acid with time change was measured and evaluated.

The composite particles and compounding materials used are shown below.
Composite particles: The product of the present invention and the commercial product obtained in Example 1 (Nippon Yushi Coated Particle MC-50F)
Ingredients (1): Garcinia (Garsinia Powder J, Nippon Shinyaku)
Compounding material (2): Ca stearate (manufactured by Sakai Chemical)

The preparation method is shown below.
(1) Compound particles and blended raw materials are blended at a weight ratio of 1: 1 and mixed in a mortar.
(2) Put the mixture in a plastic petri dish.
(3) Place the petri dish in a storage stability tester.
Note 1) Samples over time are charged at each set period (1 condition, 1 petri dish).
Note 2) For each petri dish, charge 300 mg of composite particles and 300 mg of blended raw materials.

The storage conditions are shown below.
Temperature and humidity: 40 ℃, 75% RH
Storage period: 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks

  From each petri dish, a certain amount of the mixture was collected with the elapsed time of the accelerated test, and the content of α-lipoic acid was measured by HPLC. FIG. 6 shows the% content of α-lipoic acid in the composite particles before storage with respect to the elapsed time of the accelerated test.

  From FIG. 6, it can be seen that the product according to the present invention has a lower content reduction rate than the commercial product. In addition, this indicates that the product of the present invention is highly likely to suppress deterioration in quality due to a decrease in the content of active ingredients, etc., for health foods and the like that often contain a plurality of active ingredient materials at the time of commercialization. It is thought that it shows.

In Test Example 1, a sensory test was performed for taste, smell and touch. From Test Example 1, the composite particles of the product of the present invention obtained in Example 3 are superior in masking ability such as bitterness and roughness as compared with α-lipoic acid bulk powder, physical mixture, and commercially available oil coating products. It was also found that the feeling of residual grains was eliminated.
In Test Example 2, color difference measurement was performed in order to grasp the degree of coating and coating. From Test Example 2, it was found that the α-lipoic acid coating ability of the products of the present invention obtained in Example 3 and Example 4 was superior to that of a commercially available oil coating product.
In Test Example 3, in order to evaluate the stability (coating property, compactness) of the supercritically prepared α-lipoic acid composite particles, the α-lipoic acid content accompanying changes with time was measured and evaluated. From Test Example 3, it was found that the product of the present invention had a lower content reduction rate with time change than the commercial product.
Therefore, according to the present invention, it was possible to obtain oil-fat coating composite particles using a supercritical fluid that are excellent in masking ability and covering ability such as bitterness and are resistant to deterioration over time.
Furthermore, in the preparation of tablets, granules, powders and the like, the uniform dispersibility is improved because of the uniform fine particle size.

[Silymarin composite particles]
Silymarin is a refined extract of fruit of the fruit lizard and is a generic name for a mixture of flavanolignans. This silymarin is a poorly water-soluble powder and tastes bitter (similar to traditional Chinese medicine). Therefore, we investigated the possibility of suppressing bitterness by preparing composite particles using supercritical fluid technology.

1. Preparation of composite particles <Sample>
In preparing the composite particles, Silymarin ET (Silymarin, manufactured by Indena), which is an active ingredient material, and Lovely Wax 102H (rapeseed hardened oil and fat powder, mp67-71 ° C., manufactured by Kawasaki Fine Chemical Co., Ltd.) were used as coating candidate materials. .
<Preparation method>
Put about 10g of Silymarin ET about 5g and Lovely Wax 102H about 5g into a 500mL high-pressure cell, in the presence of supercritical high-pressure fluid, 40-42 ℃, pressure 110-130kg / cm ² Then, stir at about 1600 rpm, then gradually raise the temperature while stirring, finally stabilize at 58-60 ° C, pressure around 200 kg / cm ² , and then stir (about 1550-1570 rpm) Composite particles were prepared by spraying under atmospheric pressure. The supercritical fluid is carbon dioxide.

2. CCD photograph of composite particle powder Fig. 12 shows a photograph of Silymarin ET bulk powder, physical mixture (compounding ratio 1: 1), and composite particles. The amount of silymarin in the physical mixture is almost the same as that of the composite particles. From the photograph shown in FIG. 12, it can be seen that the respective color tones are clearly different when compared. Since the silymarin bulk powder has a strong ocher color and the lovely wax 102H is white, the white color that is the color of the lovely wax 102H becomes strong when well coated. In this photograph, it can be judged that the supercritical composite particles are lighter in color and have a higher coating ratio than the physical mixture. In the physical mixture, the color of the silymarin bulk powder is emphasized because it is partially attached.

3. Electron micrographs of the composite particles The SEM images of the composite particles prepared above are shown in FIGS. 13, 14, and 15 together with Silymarin ET bulk powder and Lovely Wax 102H (supercritical preparation).
From the SEM photograph, the surface state of the composite particles was similar to that of the lovely wax 102H, and was different from that of the silymarin bulk powder. Since silymarin is not easily affected by the surface state change by Lovely Wax 102H or RESS (Rapid Expansion Supercritical Solution), it is considered that the composite particles are covered with Lovely Wax 102H.

4. Study on bitterness evaluation of composite particles In order to evaluate the bitterness evaluation of silymarin composite particles, a sensory test was conducted. As a comparative product of composite particles, 6 subjects (A, B, C, D, E, F) tasted as follows for a physical mixture containing silymarin ET bulk powder and silymarin similar to composite particles. Evaluation was made for two types of sense of smell and touch.
The sensory evaluation criteria are: 1. Bitterness, 2. Numbness (such as a tingling sensation), 3. Smell, items that are judged in five stages from "I don't feel anything" to "I feel very much", and 4. When it is contained in the mouth, “Is it rough”, “Is it smooth”, 5. About the feeling of residual grains, it is judged in two stages, “Is there a feeling of grain” after about 10-20 seconds in the mouth There are items to do.
The sensory evaluation criteria and the evaluation results are shown in Tables 11 and 12 below.

From this result, it can be said that the composite particles have suppressed negative (“non”) elements compared to other powders. In particular, bitterness is remarkably suppressed as compared with the bulk powder and physical mixture, and it is considered that particles having excellent bitterness masking effect are formed. In terms of application to product development, since there is a tendency to improve the feeling of residual particles in the oral cavity, composite particles with high applicability to dosage forms such as orally disintegrating tablets or chewable tablets It is thought that it was obtained.

5. Study on color difference measurement of composite particles Color difference measurement was performed as a means of grasping the degree of coating and coating. The measured values are digitized according to the L * a * b * color system (L * is lightness, a * b * is hue and saturation, n = 3). Further, since silymarin has an ocher color tone, the addition of white rapeseed oil powder tends to shift L * in the + direction, a * in the-direction, and b * in the-direction.
Therefore, for the product of the present invention (supercritical composite particles), as a comparative product, a silymarin ET powder, a physical mixture containing the same amount of silymarin active ingredient as the product of the present invention, and a rapeseed hardened oil and fat powder (Lovely Wax 102H) L * a * b * is shown in Table 13 below.

6). Discussion From the results, it can be seen that the product of the present invention tends to be lighter in color than the bulk powder or physical mixture, and is closest to the lovely wax 102H. Therefore, it is considered that the particle surface of the product of the present invention has a wide distribution range of rapeseed oil and fat powder and is likely to be coated.
The silymarin composite particles obtained from this example are particles excellent in the bitterness masking effect.

[Zinc yeast complex particles]
Zinc is a nutrient that helps maintain the normal taste and helps maintain the health of the skin and mucous membranes. Zinc yeast is an organic zinc produced by yeast culture. This zinc yeast powder has a unique smell (yeast odor) and taste. In this example, preparation of composite particles was attempted for the purpose of removing or suppressing the smell and taste of yeast odor.

1. Preparation of composite particles <Sample>
In preparing composite particles, LALMIN Zn50 (zinc yeast, manufactured by Miwa Pharmaceutical Co., Ltd.), which is an active ingredient material, and Lovely Wax 102H (rapeseed hardened oil and fat powder, mp67-71 ° C, manufactured by Kawasaki Fine Chemical Co., Ltd.) ) Was used.
<Preparation method>
A total of about 10 g of about 5 g of zinc yeast and about 5 g of lovely wax 102H is put into a 500 mL high-pressure cell, and in the presence of a supercritical high-pressure fluid, conditions of 40 to 45 ° C. and a pressure of 120 to 130 kg / cm ² Stir at about 1600 rpm, then gradually increase the temperature while stirring, finally stabilize at 60 ° C and pressure around 200-215 kg / cm ² , then under atmospheric pressure while stirring (about 1600 rpm) The composite particles were prepared by spraying on. The supercritical fluid is carbon dioxide.

2. CCD photograph of composite particle powder Fig. 16 shows a photograph of zinc yeast powder, physical mixture (blending ratio 1: 1) and composite particles. The zinc content in the physical mixture is almost the same as that of the composite particles. From the photograph shown in FIG. 16, it can be seen that the respective color tones are clearly different. Zinc yeast has a strong brown color and the lovely wax 102H is white. Therefore, when it is well coated, the white color of the lovely wax 102H tends to be strong. In this photograph, it can be determined that the supercritical composite particles have a stronger white color and a higher coating ratio than the brown physical mixture. In the physical mixture, the color of zinc yeast is emphasized because it is partially attached.

3. Electron micrograph of the composite particles The SEM photographs of the composite particles prepared above are shown in FIGS. 17, 18 and 19 together with the zinc yeast powder and Lovely wax 102H (supercritical preparation).
From the SEM photographs shown in FIG. 17 to FIG. 19, when the shape of the composite particles prepared this time is compared with the shape of the zinc yeast supercritical preparation and the lovely wax 102H particles, the zinc yeast particles seem to be covered with the lovely wax 102H powder. Looks like.

4. Study on taste and odor of yeast of composite particles In order to evaluate the taste and smell of yeast of composite particles of zinc yeast, a sensory test was conducted. As a comparative product of composite particles, the following were obtained in six subjects (A, B, C, D, E, F) from a physical mixture containing zinc yeast powder and the same zinc (yeast) as composite particles. Evaluation was made for two types of taste, smell and touch.
The sensory evaluation criteria are: 1. Yeast taste, 2. Odor, items to be judged in 5 stages from "I don't feel anything" to "I feel very much", and 3. There are items to be judged in two stages, “Is it rough?”, “Is it smooth?”, 4. About the residual grain feeling, “Is there a grain feel” after about 10 to 20 seconds in the mouth.
A table of sensory evaluation criteria and evaluation results is shown below.

  From these results, it was confirmed that the composite particles were excellent in the masking effect with respect to the taste of yeast. In terms of odor, the results are more significant than the bulk powder or physical mixture.

5. Study on color difference measurement of composite particles Color difference measurement was performed as a means of grasping the degree of coating and coating. The measured values are digitized according to the L * a * b * color system (L * is lightness, a * b * is hue and saturation, n = 3). Moreover, since zinc yeast has a brownish brown color tone, L * tends to move in the + direction, a * moves in the-direction, and b * moves in the-direction when white rapeseed oil powder is added.
Therefore, for the product of the present invention (supercritical composite particles), as a comparative product, a raw material of zinc yeast, a physical mixture containing the same amount of zinc (yeast) as the product of the present invention, and rapeseed hardened oil and fat powder (Lovely Wax 102H) The L * a * b * values are shown in Table 16.

6. Discussion From the results, it can be seen that the product of the present invention tends to be lighter in color than the bulk powder or physical mixture. In particular, L * and b * have shifted to very low values, and it can be seen that the overall color tone is much closer to white. From this, it is considered that the particle surface of the product of the present invention has a wide distribution range of rapeseed oil and fat powder and is coated.
It was confirmed that the zinc yeast composite particles obtained from this experiment were excellent in the masking effect unique to yeast.

1. Test on Coenzyme Q10 Coenzyme Q10 (CoQ10) is a widely recognized anti-aging material, and (1) low absorption in the body when taken orally (2) unstable to light (3) powder It is a compound having characteristics such as poor handling properties. Therefore, composite particles using supercritical fluid were manufactured for the purpose of improving these characteristics by using supercritical fluid technology.

1-1. Preparation of composite particles <Sample>
CoQ10 (mp47 ° C, Kaneka Co., Ltd.), which is an active ingredient material, and film candidate raw materials (1) Lovely wax 102H (hardened rapeseed oil powder, mp67-71 ° C, Kawasaki Fine Chemical Co., Ltd.) (2) Poem TR-FB (triglycerin fatty acid ester, mp69 ° C, manufactured by Riken Vitamin Co., Ltd.), (3) Sunsoft Q-185SP (polyglycerin fatty acid ester: decaglycerin pentastearate, HLB 4.5, (4) Sunsoft No.621B (Organic acid monoglyceride: Glycerol monostearate, HLB7, mp55-59 ° C), (5) Sunsoft No.621SA (Organic acid monoglyceride: Citric acid mono (6) Sunsoft Q-18B (polyglyceryl fatty acid ester: monoglyceryl monostearate, HLB6.5, mp53-59 ° C) was used. All Sunsoft series are manufactured by Taiyo Chemical Co., Ltd.

<Preparation method>
About 10 g of CoQ10 and about 5 g of each of the above-mentioned candidate coating materials for a coating are put into a 500 mL high-pressure cell, and in the presence of a supercritical high-pressure fluid, 32 to 45 ° C, pressure 110 to 150 kg. stirring at about 1600 rpm under the conditions of / cm ² , and then gradually increasing the temperature while stirring, finally the temperature corresponding to the melting point lowering characteristics of the candidate film raw materials (within a range of 43 to 55 ° C.), After stabilizing the pressure around 200 kg / cm ^2, composite particles were prepared by spraying under atmospheric pressure with stirring (about 1600 rpm). The supercritical fluid is carbon dioxide.

1-2. Electron micrographs of the composite particles Scanning electron microscope (SEM) photos of the composite particles prepared above are shown in FIGS. From these photographs, it can be seen that each composite particle has formed a particle having a different shape from the CoQ10 bulk powder. The (CoQ10 + 621SA) composite particles (Fig. 21) are relatively similar in shape to 621SA, and Fig. 20 (2) shows an enlarged view of the CoQ10 bulk powder. On the other hand, each composite particle shows a state in which primary particles of about 3 μm aggregate to form secondary particles. For each composite particle, its shape is relatively similar to the additive used in each (except Q-18B). As representative of oils and fats, an enlarged view of 621SA is shown in FIG. It has an irregular shape with many small protrusions like small petals.
Since the melting point of CoQ10 is lower than these oils and fats, when they are suddenly released from the melted state in the supercritical state, CoQ10 becomes fine particles first, and the oils and fats are coated around them. Therefore, small particles like petals of oils and fats are observed in each composite particle.
Note that Q-18B is originally a flat solid in the form of scaly, so it seems that the influence of the change in the surface state due to micronization is large.

1-3. Handling of composite particles
The handling property of the powder is one of the very important characteristics when evaluating the physical properties of the powder. For example, when weighing powder, a wet raw material or a raw material that tends to stick to a scoop has disadvantages such as a longer time for weighing and a larger loss. In the case of solid preparations such as tablets, if such powders with poor fluidity and separation properties are used as one of the ingredients, the mixing with other ingredients will be poor, resulting in a decrease in content uniformity. cause. In the formulation process, it is important to improve the fluidity of the powder. Therefore, the fluidity of the composite particles prepared by this method was examined.
The evaluation method was determined by measuring the angle of repose. In this example, measurement was performed using a powder tester manufactured by Hosokawa Micron, which is a device used, so that even a small amount of sample can be measured. Each powdered sample was dropped and deposited on the repose angle measuring table of the tester. In the measurement, the angle of repose was measured using a protractor for the sediment.
The repose angle of each sample is about 46-47 ° for (CoQ10 + Poem TR-FB) supercritically prepared composite particles shown in FIG. 25, and about about 46 to 47 ° for (CoQ10 + Lovely wax 102H) supercritically prepared composite particles shown in FIG. 45-46 °, (CoQ10 + No.621SA) supercritically prepared composite particles shown in FIG. 27 are about 45-46 °, and comparative example shown in FIG. 28 (CoQ10 + Lovely wax 102H). Physical mixture is about 52-53 °, CoQ10 bulk powder as a comparative example shown in FIG. 29 is about 63-65 °.
Since the angle of repose is the angle of the hypotenuse with respect to the base, a smaller one indicates a gentler inclination, and a smaller angle if the fluidity of the granular material is higher. In the composite particles corresponding to the present example shown in FIGS. 25 to 27, there are about 46 °, whereas in FIG. 28 in which oil and fat and CoQ10 are physically mixed, 52 ° and in CoQ10 bulk powder (FIG. 29) 64 °. In this example, it is clear that the fluidity is improved.
In particular, in the bulk powder of CoQ10, it is difficult for the powder to fall from the funnel to the angle of repose measurement table, and the volume shape is largely solidified and dropped out, so that a stable and constant inclined surface is not formed. This indicates that there is agglomeration of the powder and the fluidity is poor.

  From the above results, it is considered that the supercritically prepared composite particles have a repose angle smaller than that of the bulk powder or physical mixture, and become a powder useful for improving the handling property.

[Particle size analysis test of composite particles]
A particle size analysis test was carried out on the oil-coated composite particles using the supercritical fluid obtained in the present invention. Lovely wax 102H was used as the oil.
The analysis object used silymarin composite particle | grains, zinc yeast composite particle | grains, and each bulk powder.

<Silymarin composite particle size>
FIG. 30 shows the silymarin composite particle size distribution, FIG. 31 (1) shows the particle size distribution of the silymarin bulk powder, and FIG. 31 (2) shows the particle size of the lovely wax 102H used as the coating fat.
The particle size distribution of the silymarin bulk powder shown in FIG. 31 (1) has a median value of 6.512 μm and draws a gentle curve. The particle size distribution of the lovely wax 102H shown in FIG. 31 (2) has a median value of 60.576 μm, and draws a bicove curve having a peak as small as 1000 μm or more. The particle size distribution of the silymarin composite particles shown in FIG. 30 has a median of 6.684 μm and draws a sharp peak. From these contrasts, it can be seen that the fats and oils are dissolved and coated on the silymarin bulk powder particles to slightly increase the particle diameter. Moreover, although it measured 3 times, it turns out that the peak of the compound particle | grains has come out more clearly and the particle size is also equal.
Since silymarin has a high melting point, it is thought that the particle size was larger than the bulk particle size.

<Zinc yeast composite particle size>
FIG. 32 shows the particle size distribution of the zinc yeast composite particles coated with Lovely Wax 102H oil, and FIG. 33 shows the particle size distribution of the zinc yeast powder. Each measurement was performed three times.
The median value of the particle size distribution of the zinc yeast bulk powder shown in FIG. 33 is 33.209 μm. The particle size distribution of the zinc yeast composite particles shown in FIG. 32 has a median of 5.162 μm and two peaks. From these contrasts, it is considered that large zinc yeast bulk powder was finely pulverized by a mixing rotation process with a high-pressure supercritical fluid to form composite particles having two peaks. Further, although the measurement is performed three times, the particle size distribution curve is uniform, and further analysis is expected to analyze the attributes of each peak particle and recover the specific substance.

<CoQ10>
34 (1) to (3) show the coenzyme Q10 (CoQ10) composite particle size distribution graph, and FIG. 35 shows the particle size distribution of the CoQ10 bulk powder. Fig. 36 shows (1) (CoQ10 + Poem TR-FB) physical mixed particles, (2) (CoQ10 + 621B) physical mixed particles, and Fig. 37 shows fat and oil particles. As examples of the particle size distribution graph, (1) Poem TR-FB particles and (2) 621B particles are shown.
Each measurement was performed three times.
The median value of the (CoQ10 + Poem TR-FB) composite particle distribution shown in FIG. 34 (1) is 4.987 μm, and the median value of the (CoQ10 + 621B) composite particle distribution shown in (2) is 5.201 μm. The median of the (CoQ10 + 18B) composite particle distribution shown in (3) is 6.125 μm. The particle size distribution of the CoQ10 bulk powder shown in FIG. 35 has a median value of 6.597 μm, and each composite particle is smaller than the bulk powder. This is presumably because the CoQ10 has a low melting point, and in the supercritical stirring step, the CoQ10 is once melted and finely crystallized when it is released into the atmospheric pressure, and its surface is coated with an oil agent. In this test, a diameter of 1.1 mm of the discharge nozzle that discharges into the atmospheric pressure was used. However, when the nozzle system is enlarged, the particle diameter obtained tends to increase. Although measured three times, since the degree of dispersion is small and the particle size distribution curve is uniform, coenzyme Q10 (CoQ10) composite particles with high particle size uniformity can be obtained.
Fig. 36 (1) (CoQ10 + Poem TR-FB) Physical mixed particle distribution shows a median of 4.250μm, (2) (CoQ10 + 621B) Physical mixed particle distribution shows a median of 7.670μm, and Fig. 37 (1) ) Poem TR-FB particle distribution shows a median of 2.742 μm, and (2) 621B particle distribution shows a median of 402.505 μm. Each particle size exists in the fat and oil particles or physically mixed particles of fat and CoQ10, but since the composite particles have a low melting point of CoQ10, in the supercritical stirring process, the fat and CoQ10 are once melted in atmospheric pressure. It is thought that particles smaller than the CoQ10 bulk powder were obtained as a result of fine crystallization when released and coating the surface with an oil agent.

3 is a scanning electron micrograph of 3000 times the particle structure of the composite particles obtained in Example 3. 3 is a scanning electron micrograph of 3000 times the particle structure of the composite particles obtained in Example 4. A scanning electron micrograph of 1000 times the particle structure of α-lipoic acid bulk powder. Scanning electron micrograph of 3000 times the particle structure of commercially available oil coating composite particles. The graph which shows the sensory evaluation result regarding the taste and olfaction of this invention product and a comparative product. The graph which shows the content% with respect to (alpha) -lipoic acid in the composite particle | grains before a preservation | save with respect to acceleration test elapsed time. 6 is a graph showing the particle size distribution of composite particles obtained in Example 3. 5 is a graph showing the particle size distribution of composite particles obtained in Example 4. The graph which shows the particle size distribution of a commercially available oil-fat coating composite particle. The graph which shows the particle size distribution of alpha-lipoic acid bulk powder. The graph which shows the particle size distribution of alpha-lipoic acid bulk powder. Photo of Silymarin ET bulk powder, physical mixture (compounding ratio 1: 1) and composite particles. Silymarin composite particles obtained in Example 5. Silymarin ET bulk powder Lovely wax 102H (supercritical preparation) CCD photograph of zinc yeast bulk powder, physical mixture (blending ratio 1: 1) and composite particles. Scanning electron micrograph of zinc yeast bulk powder 1000 times. The scanning electron micrograph of the zinc yeast composite particle obtained in Example 6 1000 times. Lovely wax 102H (supercritical preparation) 1000x scanning electron micrograph. (1) (CoQ10 + TR-FB) Scanning electron micrograph of 5000 times the particle structure of the composite particles. (2) Scanning electron micrograph of 5000 times the CoQ10 bulk particles. (1) (CoQ10 + 621SA) Scanning electron micrograph of 5000 times the particle structure of the composite particles. (2) Scanning electron micrograph of 5000 times that of oil 621SA. (CoQ10 + 621B) Scanning electron micrograph of 5000 times the particle structure of the composite particles. (CoQ10 + Q-18B) Scanning electron micrograph of 5000 times the particle structure of the composite particles. (CoQ10 + Lovely Wax 102H) Scanning electron micrograph of 5000 times the particle structure of the composite particles. (CoQ10 + Poem TR-FB) Volumetric picture of supercritical composite particles (CoQ10 + Lovely Wax 102H) Volumetric photo of supercritical composite particles (CoQ10 + No.621SA) Volumetric photograph of supercritical composite particles (CoQ10 + Lovely Wax 102H) Volumetric picture of physical mixture particles Volumetric picture of CoQ10 bulk powder Graph showing silymarin composite particle size (1) Graph showing the silymarin particle size, (2) Graph showing the particle size of Lovely Wax 102H. Graph showing the particle size of zinc yeast composite particles Graph showing the particle size of zinc yeast particles The graph which shows a coenzyme Q10 (CoQ10) composite particle size to (1)-(3). The graph which shows Coenzyme Q10 (CoQ10) bulk particle size. It is a physical mixed particle size distribution graph of CoQ10 and fats and oils, (1) (CoQ10 + Poem TR-FB) physical mixed particle size distribution graph, (2) (CoQ10 + 621B) physical mixed particle size distribution graph. It is fat and oil particle size distribution graph, Comprising: (1) Poem TR-FB particle size distribution graph, (2) 621B particle size distribution graph.

Claims (8)

In the presence of high-pressure fluid in the supercritical state or subcritical state, the fat and oil and the active ingredient-containing material are dispersed in a solid state under the temperature and pressure conditions that do not melt below the specific melting point, respectively, and then the inherent melting point of the fat and oil A method for producing composite particles by bringing an active ingredient-containing material and fats and oils into contact with each other by high-speed stirring under melting temperature and pressure conditions below, and then releasing them out of the container under stirring . In the presence of high-pressure fluid in the supercritical state or subcritical state, the fat and oil and the active ingredient-containing material are dispersed in a solid state under temperature and pressure conditions that do not melt below their specific melting points, and then the active ingredient-containing material And a method of producing composite particles by bringing the active ingredient-containing material and oil into contact with each other at high speed stirring under a temperature / pressure condition that melts below the melting point inherent to the oil and fat, and then releasing the mixture out of the container with stirring . The method for producing composite particles according to claim 1 or 2 , wherein the temperature and pressure conditions for melting are higher than the temperature and pressure conditions for dispersion in a solid state. The method for producing composite particles according to any one of claims 1 to 3 , wherein the supercritical fluid is supercritical carbon dioxide. The method for producing composite particles according to any one of claims 1 to 4 , wherein the active ingredient-containing material is α-lipoic acid. The method for producing composite particles according to any one of claims 1 to 5 , wherein the fat is rapeseed hydrogenated fat or glycerin fatty acid ester. The method for producing composite particles according to claim 6 , wherein the main component of the fat is triglyceride fatty acid ester having a C22 alkyl chain length in the fatty acid part of stearic acid triglyceride hardened fat or glycerin fatty acid ester. The method for producing composite particles according to any one of claims 1 to 7 , wherein the temperature and pressure in the container before decompression are 60 ° C or less and 200 kg / cm ² or less.