Method for producing composite particles

Abstract

To provide a technique for producing composite particles having improved temporal stability under high-temperature storage in which an active ingredient is encapsulated in a coating agent.SOLUTION: There is provided a method for producing composite particles, which comprises the steps of: dissolving a coating agent in a molten state and an active ingredient dissolved in a co-solvent to obtain a dispersion in the presence of carbon dioxide at a temperature of 60°C or more and in a supercritical or subcritical state; and ejecting the dispersion under atmospheric pressure and in an environment below the melting point of the coating agent, wherein the coating agent contains a solid fat and / or semi-solid fat which do not contain a component having a melting point of 40°C or less and the co-solvent dissolves the active ingredient without dissolving the coating agent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing composite particles containing an active ingredient and a coating agent that encapsulates the active ingredient. [Background technology]

[0002] Many active ingredients incorporated into compositions such as cosmetics and pharmaceuticals decompose or denature over time when they come into contact with water, resulting in a significant decrease or loss of their desired effects. Therefore, when such active ingredients are incorporated into a composition, they are usually contained in a medium that is substantially free of water.

[0003] However, because aqueous media compositions are easy to use and have an excellent feel, there is a demand for incorporating the above-mentioned active ingredients into aqueous media compositions. For this reason, it has been conventional to coat such active ingredients with a water-insoluble substance to form capsules, thereby shielding the active ingredients from water and stabilizing them. For example, Patent Document 1 discloses that a water-insoluble substance is precipitated on particles of an active ingredient in an organic solvent to coat the particles, thereby enhancing stability against water. Patent Document 2 also discloses that a wax is used to coat the active ingredient, and a film-forming agent containing wax is sprayed onto the powdered active ingredient. A method using a supercritical fluid has also been proposed as a method for coating an active ingredient with a coating agent. For example, Patent Document 3 discloses that a coating agent dissolved in a supercritical fluid is sprayed onto particles of an active ingredient and solidified at the same time as the supercritical state is released, thereby coating the particles. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 08-325117 [Patent Document 2] Japanese Patent Application Publication No. 06-292825 [Patent Document 3] Patent No. 5358948 Summary of the Invention [Problem to be solved by the invention]

[0005] With conventional composite technology, the stability of composite particles when placed at high temperatures (e.g., 40°C or higher) was not necessarily high, resulting in leakage of the encapsulated substances and poor water-blocking properties, making it difficult to ensure sufficient stability of the encapsulated active ingredients over time. In this situation, an object of the present invention is to provide a technique for producing composite particles in which an active ingredient is encapsulated in a coating agent and which have improved stability over time when stored at high temperatures. [Means for solving the problem]

[0006] As a result of intensive research, the present inventors have come up with the idea that the above-mentioned problems can be solved by using a solid fat and / or semi-solid fat that does not contain a low-melting point component as a coating agent, mixing the coating agent with an active ingredient in the presence of carbon dioxide in a supercritical or subcritical state, and spraying the mixture at the same time as releasing the supercritical or subcritical state, thereby completing the present invention.

[0007] That is, the present invention is as follows. [1] A step of dispersing a molten coating agent and an active ingredient dissolved in a cosolvent at a temperature of 60°C or higher in the presence of carbon dioxide in a supercritical or subcritical state to obtain a dispersion; ejecting the dispersion into an environment at atmospheric pressure and below the melting point of the coating material; The coating agent contains solid fat and / or semi-solid fat that does not contain a component having a melting point of 40°C or less, The method for producing composite particles, wherein the cosolvent does not dissolve the coating agent but dissolves the active ingredient. [2] The manufacturing method described in [1], wherein the coating agent contains 50% by weight or more of solid fats and / or semi-solid fats that do not contain components with a melting point of 40°C or lower. [3] The manufacturing method according to [1] or [2], wherein the solid fat and / or semi-solid fat not containing components having a melting point of 40°C or less contains one or more selected from the group consisting of tristearin, candelilla wax, rice bran wax, and hydrogenated rapeseed seed oil. [4] The method according to any one of [1] to [3], wherein the co-solvent contains ethanol. [5] The method according to any one of [1] to [4], wherein the amount of the co-solvent present in the dispersion step is at least 1 time the amount capable of dissolving the entire amount of the active ingredient. [Effects of the Invention]

[0008] According to the present invention, composite particles having improved stability over time when stored at high temperatures can be produced. Furthermore, the composite particles produced by the present invention contain the active ingredient at a high encapsulation rate and are excellent in shielding the active ingredient from water. Furthermore, the composite particles produced by the present invention have shells that easily collapse under stress, so the encapsulated active ingredient can be easily extracted by shearing during use. Furthermore, the present invention makes it possible to produce fine composite particles, so composite particles with a smooth and pleasant feel can be obtained, and the feeling of familiarity when the shell collapses during use is also excellent. DETAILED DESCRIPTION OF THE INVENTION

[0009] The manufacturing method of the present invention includes a step of dispersing a molten coating agent and an active ingredient dissolved in a cosolvent in the presence of carbon dioxide in a supercritical or subcritical state to obtain a dispersion (dispersion step); The method includes a step of spraying the dispersion under atmospheric pressure in an environment below the melting point of the coating agent (spouting step).

[0010] The coating agent of the present invention contains solid fat and / or semi-solid fat that does not contain any component with a melting point of 40° C. or lower. It is preferable that 50% by weight or more, preferably 75% by weight or more, and more preferably 90% by weight or more of the entire coating agent is solid fat and / or semi-solid fat that does not contain any component with a melting point of 40° C. or lower. There is no particular upper limit, and it may be 100% by weight or less of the entire coating agent.

[0011] In addition to the aforementioned melting point property, the coating agent preferably does not dissolve in carbon dioxide in a supercritical or subcritical state. That is, the coating agent preferably has a relative dielectric constant of 2.6 or more. Note that the relative dielectric constant of carbon dioxide in a supercritical or subcritical state is approximately 1.1 to 1.6.

[0012] By using solid or semi-solid fat as a coating agent, the outer shell is easily disintegrated by stress, and the encapsulated active ingredient can be easily extracted by shearing during use, resulting in composite particles with excellent usability. Solid means that there is no fluidity at 25°C, and semi-solid means that there is almost no deformation in a stress-free environment at 20°C under 1 atmosphere, but there is a slight stress (10 to 100 g / cm 2 In addition, those with a melting point of over 40°C are more preferable from the viewpoint of the stability of the composite particles.

[0013] Examples of solid fats and / or semi-solid fats that do not contain components with a melting point of 40°C or lower include tristearin, candelilla wax, rice bran wax, and hydrogenated rapeseed oil. Of these, tristearin is particularly preferred because it is less likely to cause aggregation of composite particles. These solid fats and / or semi-solid fats can be used alone or in combination of two or more.

[0014] The coating agent may contain components other than solid fats and / or semi-solid fats that do not contain components with a melting point of 40°C or lower, as long as the effects of the present invention are not impaired, such as fatty acid glyceryl such as tri(caprylic / capric / myristic / stearic)glyceryl, various polymers, etc. Examples of polymers include natural polymers such as plant-derived polymers (e.g., carrageenan, starch (rice, corn, potato, wheat), glycyrrhizic acid), microbial polymers (e.g., dextran, pullulan, etc.), and animal-derived polymers (e.g., collagen, casein, albumin, gelatin, etc.). Other examples include synthetic polymers such as starch-based polymers (e.g., carboxymethyl starch, methylhydroxypropyl starch, etc.); cellulose-based polymers (hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose stearoxy ether, sodium cellulose sulfate, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, cellulose powder, etc.); vinyl-based polymers (e.g., polyvinyl alcohol, polyvinyl methyl ether, polyvinylpyrrolidone, carboxyvinyl polymer, etc.); polyoxyethylene-based polymers (e.g., polyethylene glycol 20,000, 40,000, 60,000, etc.); acrylic-based polymers (e.g., sodium polyacrylate, polyethyl acrylate, polyacrylamide, etc.); polyethyleneimine; and cationic polymers.

[0015] The active ingredient in the present invention is not particularly limited, but is usually a solid or liquid at room temperature and normal pressure, and is preferably a solid from the viewpoint of increasing the encapsulation rate. For example, anti-inflammatory agents (glycyrrhizinic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc.); whitening agents (placenta extract, saxifrage extract, arbutin, etc.); various extracts (phellodendron bark, coptis rhizome, Lithospermum root, peony, Swertia japonica, birch, sage, loquat, carrot, aloe, mallow, iris, grape, coix seed, loofah, lily, saffron, Cnidium rhizome, angelica, St. John's wort, ononis, garlic, chili pepper, tangerine peel, angelica acutiloba, seaweed, etc.), activators (royal jelly, photosensitizers, cholesterol derivatives, etc.); blood circulation promoters (no Nitric acid valenilamide, nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, zingerone, cantharides tincture, ichthammol, tannic acid, α-borneol, tocopherol nicotinate, inositol hexanicotinate, cyclandelate, cinnarizine, tolazoline, acetylcholine, verapamil, cepharanthine, γ-oryzanol, etc.; antiseborrheic agents (sulfur, thianthol, etc.); anti-inflammatory agents (tranexamic acid, thiotaurine, hypotaurine, etc.); vitamins (vitamins A, B1, B2, B6, C, E and their derivatives, pantothenic acid and its derivatives) derivatives, biotin, etc.)

[0016] The cosolvent used in the present invention is not particularly limited as long as it does not dissolve the coating agent but dissolves the active ingredient. Here, "not dissolving the coating agent" means that the amount of the coating agent that dissolves in the cosolvent is 0.01 wt % or less at a temperature above the melting point of the coating agent and a pressure of 15 MPa. Furthermore, "dissolving the active ingredient" means that the amount of the active ingredient that dissolves in the cosolvent is 1 wt % or more at room temperature and atmospheric pressure. The co-solvent is preferably volatile at room temperature and normal pressure, since it is desirable that it volatilizes during the spraying step, is separated from the composite particles, and does not remain in the composite particles that are produced. Specific examples of the cosolvent include alcohols, ketones, toluene, etc., each having a dielectric constant of 10 to 35. Examples of such alcohols include methanol, ethanol, i-propanol, etc., and examples of ketones include acetone, methyl ethyl ketone, etc., and one or more of these can be used. Of these, ethanol is particularly preferred.

[0017] In the dispersion step, a molten coating agent and an active ingredient dissolved in a co-solvent are dispersed in the presence of carbon dioxide in a supercritical or subcritical state to obtain a dispersion. The supercritical or subcritical state refers to a state in which carbon dioxide is in a temperature and / or pressure condition higher than its critical value, or lower than but close to its critical value, and carbon dioxide in such a state is normally a fluid.

[0018] The dispersion step is usually carried out in a system such as a closed cell. The pressure inside the cell is preferably 7.5 to 15 MPa, more preferably 7.5 to 12 MPa, and even more preferably 7.5 to 9 MPa. The temperature inside the cell is 60°C or higher, and preferably 90°C or lower. Furthermore, stirring inside the cell is preferred since this makes it easier to obtain a dispersion. The stirring speed is preferably 100 to 1000 rpm, more preferably 500 to 1000 rpm, and even more preferably 800 to 1000 rpm. The time for which the dispersion step is carried out is not particularly limited as long as a sufficient dispersion is obtained, but is preferably 5 to 30 minutes, more preferably 15 to 30 minutes, and even more preferably 20 to 30 minutes.

[0019] In the dispersion step, the coating agent is in a molten state and is not dissolved in the carbon dioxide in a supercritical or subcritical state. In the dispersion step, the active ingredient is dissolved in the cosolvent. By dissolving the active ingredient in the cosolvent, the core of the active ingredient to be subsequently coated with the coating agent can be made fine, resulting in composite particles with a small particle size and a uniform particle size distribution. In the cell where carbon dioxide in a supercritical or subcritical state is present, the molten coating agent and the active ingredient dissolved in the co-solvent come into contact with each other and become a dispersion dispersed within the system.

[0020] The amount of the active ingredient introduced in the dispersion step is preferably 0.1 to 50 g / L, more preferably 0.5 to 20 g / L, and even more preferably 1 to 13 g / L relative to the volume of carbon dioxide in a supercritical or subcritical state. Within such a range, sufficient dispersion and coating with a coating agent can be easily achieved. The amount of the coating agent introduced in the dispersion step is preferably 10 to 500 g / L, more preferably 20 to 250 g / L, and even more preferably 30 to 100 g / L relative to the volume of carbon dioxide in a supercritical or subcritical state. Within such a range, sufficient dispersion and coating of the active ingredient can be easily achieved. The amount of co-solvent introduced in the dispersion step is preferably 0.1 to 200 g / L, more preferably 0.5 to 150 g / L, and even more preferably 1 to 100 g / L relative to the volume of carbon dioxide in a supercritical or subcritical state. Within this range, it becomes easier to dissolve the active ingredient and to volatilize it in the subsequent spraying step.

[0021] The weight ratio of the active ingredient to the coating agent introduced in the dispersion step is preferably 1:2 to 1:15, more preferably 1:5 to 1:15, and even more preferably 1:10 to 1:15. Within this range, the active ingredient can be more easily coated with the coating agent, and the resulting composite particles have a better balance between shielding properties and disintegrability by shear. The amount of cosolvent introduced in the dispersion step is preferably at least 1 time, more preferably at least 3 times, and even more preferably at least 5 times the amount capable of dissolving the entire amount of active ingredient. Within this range, the active ingredient can be easily finely dispersed in a dissolved state. Furthermore, the amount of cosolvent introduced in the dispersion step is preferably less than 3 times, more preferably less than 2.5 times, and even more preferably less than 2 times the amount of coating agent. If the amount of cosolvent is too much compared to the coating agent, it becomes difficult for the coating agent to coat the active ingredient, and composite particles with poor shielding properties tend to result.

[0022] In the jetting step, the dispersion is jetted into an environment at atmospheric pressure and below the melting point of the coating material. Typically, spraying is carried out by transferring the dispersion from a closed system such as a cell in the dispersion process to an environment below the melting point of the coating agent through a spray port equipped with a nozzle or the like. The temperature of the environment at the ejection destination is preferably 10 to 25° C., more preferably 15 to 25° C., and even more preferably 20 to 25° C. The pressure is preferably 0 to 0.2 MPa, more preferably 0 to 0.1 MPa, and even more preferably atmospheric pressure. In the spraying process, the temperature and pressure are suddenly lowered, so that the coating agents that were in contact with each other in the dispersion coat the active ingredient during spraying, and the coating agent immediately solidifies with the active ingredient encapsulated. The cosolvent evaporates, causing the active ingredient to precipitate. As a result, composite particles are obtained in which a solid active ingredient is encapsulated in a solid coating agent shell.

[0023] The nozzle of the injection port serves to adjust the particle size of the composite particles and to make their distribution uniform. The nozzle can have any diameter, for example, a diameter of 0.1 to 2.0 mm.

[0024] After the ejection step, the composite particles are captured and collected in any suitable manner.

[0025] The composite particles produced by the present invention contain an active ingredient and a coating agent. The coating agent is present in a manner that encapsulates the active ingredient, in other words, forms an outer shell, thereby shielding the active ingredient from contact with other components around the composite particle, such as water. Although the presence of an active ingredient attached to the outside of the shell (exposed and not encapsulated) is not excluded, preferably 60% by weight or more, more preferably 80% by weight or more, and even more preferably 95% by weight or more of the total active ingredient contained in the composite particles is encapsulated in the coating agent. In this specification, the ratio of the active ingredient encapsulated in the coating agent to the total active ingredient contained in the composite particles is referred to as the "encapsulation rate." The composite particles produced by the present invention have a high encapsulation rate of the active ingredient. Furthermore, the active ingredient may be present in one or more locations within the composite particle, so long as 60% by weight or more of the active ingredient is encapsulated in the outer shell.

[0026] The shape of the composite particles produced by the present invention is not particularly limited, but is preferably spherical or approximately spherical. The particle size is usually as small as about 10 to 50 μm, which provides a smooth and pleasant feel to the touch and also provides an excellent feel when the outer shell is broken down during use.

[0027] The weight ratio of the active ingredient to the coating agent in the composite particles produced by the present invention is preferably 1:2 to 1:15, more preferably 1:5 to 1:15, and even more preferably 1:10 to 1:15. Within this range, a better balance is achieved between the ability to shield the active ingredient and the disintegration by shear. The thickness of the shell of the composite particle is not particularly limited as long as it coats the active ingredient, and it does not have to be uniform within the composite particle.

[0028] The composite particles produced by the present invention have excellent and sustained shielding properties from water and other substances present outside the composite particles because the active ingredient is sufficiently coated with the coating agent. Furthermore, the outer shell is stably formed even at high temperatures (e.g., 40°C or higher). This maintains the stability of the composite particles over time and the chemical stability of the active ingredient. Furthermore, the composite particles produced by the present invention have shells that easily collapse under stress, allowing the encapsulated active ingredient to be easily extracted by shearing during use, resulting in excellent usability. Furthermore, the fine particle size provides a smooth and pleasant feel, and the shell collapses during use, providing a comfortable feel, leaving the user satisfied. Therefore, the composite particles produced by the present invention are preferably incorporated into compositions such as cosmetics, and more preferably into aqueous media. Those used by the above are preferred.

[0029] The shielding ability of the composite particles produced according to the present invention can be confirmed by the fact that the residual rate of the active ingredient is preferably 30% or more after the composite particles are left standing in water at 40°C for 24 hours. Here, the residual rate is expressed as the ratio of the total active ingredients contained in the composite particles after storage in water to the total active ingredients contained in the composite particles. The amount of the active ingredients at each time point may be quantified by HPLC or the like as in the Examples described later. [Example]

[0030] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples as long as it does not depart from the gist of the invention.

[0031] Composite particles were produced using the ingredients shown in Table 1. Specifically, ingredient B was melted at 85°C. Component A was dissolved in ingredient C, and the resulting mixture was added to and mixed with ingredient B. The mixture was then placed in the high-pressure cell of the supercritical carbon dioxide device. The temperature of the high-pressure cell was raised to 80°C, and carbon dioxide was then introduced to increase the pressure to 9 MPa. The contents of the cell were stirred at 940 rpm for 30 minutes, after which the contents of the cell were ejected at room temperature and atmospheric pressure, and the resulting powder was collected.

[0032] The resulting powder was evaluated as follows, and the results are shown in Table 1. (1) Composite particle formation The powder was visually observed to evaluate whether the active ingredient (3-O-ethyl ascorbic acid) and the coating agent were formed into composite particles. If they were formed into composite particles, they were marked with an O, and if they were not, they were marked with an X.

[0033] (2) Active ingredient content The degree of inclusion of the active ingredient in the coating agent was evaluated by the following procedure. 50 mg of powder was placed in 10 mL of THF, and the coating agent was completely dissolved at room temperature. Purified water was then added to make 100 mL. 6 mL of this solution was taken and purified water was added to make 10 mL. This was used as a sample solution and measured by high-performance liquid chromatography (HPLC). The "initial amount" of the active ingredient in the powder was calculated from the peak area. Note that the initial amount includes the active ingredient encapsulated in the coating agent in the powder and the active ingredient not encapsulated in the coating agent but exposed on the powder surface. Separately, 50 mg of powder was placed in 100 mL of purified water and allowed to stand at room temperature for 10 minutes. After 10 minutes, 6 mL of the aqueous solution was collected and purified water was added to make 10 mL. This was used as a sample solution and measured by HPLC. The "initial unencapsulated amount," which is the amount of active ingredient that was not encapsulated in the coating agent and was exposed on the powder surface, was calculated from the peak area. The initial encapsulation rate of the active ingredient was calculated using the following formula, and the encapsulation was evaluated as follows: an initial encapsulation rate of 60% or more was marked as ◯, and an initial encapsulation rate of less than 60% was marked as ×. [Initial Included Amount] = [Initial Amount] - [Initial Non-Included Amount] [Initial inclusion rate] (%) = [Initial inclusion amount] / [Initial amount] x 100

[0034] (3) Water-impermeable The water blocking ability of the active ingredient in the powder was evaluated by the following procedure. 50 mg of powder was placed in 100 mL of purified water and allowed to stand at 40°C. After 24 hours, one week, or two weeks, the aqueous solution was collected and used as a sample solution for measurement by HPLC, and the "elution amount" was calculated from the peak area. The remaining rate of the active ingredient was calculated using the following formula and used as an evaluation value for water impermeability. [Residual amount]=[Initial amount]-[Elution amount] [Residual rate](%)=[Residual amount] / [Initial amount]×100

[0035] (4) Collapsibility 10 mg of powder was placed on the back of the hand, and the ease of disintegration of the outer shell was evaluated when shear stress was applied by moving the fingers back and forth. The fingers were moved back and forth 10 times, and the magnitude of the shear stress was the same as when applying a normal cosmetic product, and an experienced evaluator performed the test so that a uniform shear stress was applied for each sample. After applying the shear stress, the back of the hand was visually observed, and if particles remained, it was marked with an X, and if not, it was marked with an O. (5) Texture 10 mg of powder was placed on the back of the hand, and the powder was applied by moving the fingers back and forth to apply shear stress. The feel of the powder when applied was evaluated using the following three-point scale. 1: Strong foreign body sensation 2: I feel a slight foreign body sensation 3: No foreign body sensation at all

[0036] The HPLC conditions used in the present examples were as follows: column: Inertsil ODS column 4.6 × 150 mm; column temperature: 40°C; mobile phase: anionic sulfonic acid surfactant, aqueous phosphoric acid solution / THF 17%, pH: 3; flow rate: 1.0 mL / min; detection: 240 nm.

[0037] [Table 1]

Claims

1. A step of dispersing a molten coating agent and an active ingredient dissolved in a cosolvent at a temperature of 60°C or higher in the presence of carbon dioxide in a supercritical or subcritical state to obtain a dispersion; ejecting the dispersion into an environment at atmospheric pressure and below the melting point of the coating material; The coating agent contains solid fat and / or semi-solid fat that does not contain a component having a melting point of 40°C or less, The method for producing composite particles, wherein the cosolvent does not dissolve the coating agent but dissolves the active ingredient.

2. The method according to claim 1, wherein the coating agent contains 50% by weight or more of solid fat and / or semi-solid fat that does not contain a component having a melting point of 40°C or lower.

3. 3. The method according to claim 1, wherein the solid fat and / or semi-solid fat not containing a component having a melting point of 40°C or lower contains one or more selected from the group consisting of tristearin, candelilla wax, rice bran wax, and hydrogenated rapeseed seed oil.

4. The process according to claim 1 or 2, wherein the co-solvent comprises ethanol.

5. 3. The method according to claim 1, wherein the amount of the cosolvent present in the dispersion step is at least one time the amount capable of dissolving the entire amount of the active ingredient.

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