KR20060119612A - A method for micronized arbutin using supercritical fluid process - Google Patents

Abstract

A method for preparing micronized arbutin is provided to obtain the arbutin showing the increased absorptivity to skin by micronizing the particle size of the arbutin through a supercritical fluid process using supercritical CO2. The method comprises the steps of: (a) spraying a mixture solvent where arbutin is dissolved in an organic solvent to a supercritical fluid so as to prepare arbutin particles; and (b) introducing the supercritical fluid into the step(a) to remove the organic solvent used for preparing the mixture solvent and is characterized in that 0.0001-0.50 wt.% of the organic solvent regarding the arbutin is used.

Description

A method for micronized arbutin using supercritical fluid process

(FIG. 1) Electron micrograph of a comparative example and Example 1-2

(Fig. 2) Electron micrograph in Example 3-5

(Figure 3) Electron micrograph in Example 6-8

The present invention relates to a miniaturized arbutin preparation using a supercritical fluid process, comprising: contacting by spraying a mixed solution of arbutin dissolved in an organic solvent into a supercritical fluid to generate arbutin particles and introducing a supercritical fluid into the particles. It relates to a method for producing ultra-fine arbutin particles using a supercritical fluid process, comprising the step of removing the organic solvent used in the mixed solution.

Skin diseases with melanin hyperpigmentation such as blemishes, freckles, and senile surpluses, despite many treatment requirements, still lack satisfactory safe treatment. In the meantime, in the treatment of these diseases, hydroquinone, kojic acid, retinoid acid and the like have been used as a single agent or a combination with others. Hydroquinone preparations have been reported to be effective in about 80% of patients, but they are widely used, but they are unstable, have skin irritation, and dermatitis, post-inflammatory hyperpigmentation, permanent discoloration due to cytotoxicity, and tissue blackening at high concentrations. There are side effects such as back and there are cases where the effect of treatment is not satisfactory. Arbutin is a derivative in which glucopyranoside is combined with hydroquinone, and has little side effects when using hydroquinone and has melanin pigment inhibitory effect, suggesting that it may be used as a therapeutic agent for skin diseases in which melanin pigmentation is increased. It has good solubility in water and is widely used in functional basic cosmetics such as skins, lotions and creams.

However, in formulations using arbutin particles such as foundation as it is, the effective area is reduced due to the large particle size, resulting in a decrease in skin absorption rate. Therefore, research to refine the particle size has become necessary.

Supercritical fluids, on the other hand, are incompressible fluids at temperatures and pressures above the critical point, and exhibit unique characteristics not found in conventional organic solvents. That is, supercritical fluids have excellent physical properties such as high density close to liquid, low viscosity close to gas, high diffusion coefficient, and very low surface tension. Supercritical fluids can continuously vary in density from a lean state close to ideal gas to a high density close to liquid density, so that the fluid's equilibrium properties (solubility, entrainer effect), transfer properties (viscosity, diffusion coefficient, heat conductivity) Fig. 2), molecular clustering (clustering) state can be adjusted. Therefore, by utilizing the ease of controlling the physical properties of the supercritical fluid, it is possible to obtain solvent characteristics comparable to various liquid solvents with one solvent. In particular, carbon dioxide has a low critical temperature of 31.1 degrees, making it suitable for thermally denatured substances such as drugs, non-toxic, non-flammable, inexpensive, and easy to recover and reuse. It is ideal for pharmaceutical applications because it has many advantages.

Using these unique properties of supercritical fluids, much research has recently been conducted in the fields of selective extraction of specific substances and analysis of substances through extraction. Also, supercritical fluids are used as solvents or anti-solvents. There is an active research on how to obtain recrystallized or fine particles by using).

Accordingly, the present inventors have developed a method for producing arbutin having an increased skin absorption rate by increasing the effective area by miniaturizing the particle size of arbutin by a supercritical fluid process using supercritical carbon dioxide, and the arbutin preparation prepared therefrom is a supercritical fluid process. The crystallization of the drug itself is changed through the change of temperature and pressure, which are the operating variables of, or the flow rate of the solution and the supercritical carbon dioxide, so that the effective area is increased to obtain micronized arbutin particles whose skin absorption is predicted. Was completed.

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The present invention is to solve the problems of the prior art as described above, to provide a formulation in which the skin absorption rate is increased by miniaturizing arbutin having a large particle size using a supercritical fluid process.

Hereinafter, the present invention will be described in detail.

The present invention provides a step of generating arbutin particles by spraying a mixed solution in which arbutin is dissolved in an organic solvent by spraying the supercritical fluid and removing the organic solvent used in the mixed solution by introducing a supercritical fluid to the particles. It provides a method for producing micronized arbutin using a supercritical fluid process, comprising.

The basic principle of the manufacturing method is to dissolve arbutin in an appropriate amount of an organic solvent, and then spray it through a nozzle to a reaction port equilibrated with supercritical carbon dioxide to obtain particles, and then flow the supercritical carbon dioxide several times to extract the organic solvent. After the carbon dioxide is removed to refine the arbutin.

More specifically, the method for producing micronized arbutin using a supercritical fluid process in the present invention comprises the steps of 1) dissolving arbutin in an organic solvent and preparing a mixture thereof; 2) spraying the mixed solution with a supercritical fluid to make contact with the arbutin particles; 3) removing the organic solvent by introducing a separate supercritical fluid to the particles; 4) recovering the generated particles. The manufacturing method will be described in detail for each step as follows.

1) Preparation of mixed solution of arbutin for spraying

The organic solvent used in step 1) is methanol or ethanol, but in the present invention, ethanol having less toxicity to human body is used.

As the organic solvent to be used, arbutin is preferably used in an amount of 0.0001 to 0.50 parts by weight, more preferably 0.001 to 0.20 parts by weight. Below 0.0001 parts by weight, the amount of particles obtainable is too small, and above 0.50 parts by weight, arbutin does not dissolve in the organic solvent.

2) Generation of particles through the portion of the mixed solution in the supercritical fluid

Supercritical fluids that can be used in step 2) include supercritical carbon dioxide, supercritical dinitrogen monoxide, supercritical methane trifluoride, supercritical propane, supercritical ethylene or supercritical xenon, and the like in the present invention. Supercritical carbon dioxide was used.

The carbon dioxide is injected into the reaction port so that the temperature and pressure of the reaction port made of stainless steel are above the critical point of carbon dioxide of 31.1 degrees and 73.8 bar, and are pressurized and warmed to maintain the supercritical state. Wait for equilibrium. It is preferable to use a syringe pump to maintain a constant pressure when pressurizing carbon dioxide and to know an accurate injection amount, and to use a circulating thermostat or a thermostat to maintain a constant temperature. When the reaction port is equilibrated in a supercritical state, a mixture of the arbutin and the additive prepared in step 1) is injected into the reaction port at a constant speed using a small liquid pump capable of precise speed control. At this time, in order to prevent clogging of the nozzle, it is preferable to inject a small amount of empty solvent, for example, 3-4 ml, into the mixed solution.The higher the amount of the cosolvent to be injected, the more supercritical thereafter. The cleaning time by the fluid will be longer. The injected mixed solution is sprayed through the nozzle, and the organic solvent in the injected mixed solution is rapidly mixed into the supercritical carbon dioxide to generate particles. A separate supercritical fluid may be injected to prevent the saturation in the reaction port at the same time as the injection of the mixed solution.

3) Removal of organic solvent using supercritical fluid

After spraying the mixed solution, a particle washing process is required to introduce a supercritical fluid to remove the organic solvent in the resulting particles. In the above process, the supercritical fluid is injected into the reactor at a constant speed while being discharged through the outlet at the same rate as the injection speed to induce the reaction port state at a constant pressure. At this time, the back pressure regulator is connected to the outlet to maintain the constant pressure in the reaction port by adjusting the discharge rate. A double membrane filter with an aperture size of 0.45 μm is used to prevent particles from escaping. When the solvent remains, the solvent is reprecipitated when the temperature and pressure are lowered to collect the particles, so that the particles are re-dissolved to form agglomerates. Therefore, the washing process should be sufficiently performed until all solvents are removed. The amount of supercritical fluid for washing depends on the amount of solvent used and the size of the reaction port, preferably about 2,000-3,000 ml.

4) recovery of particles

At the end of the cleaning process, the supercritical fluid supply to the reactor is stopped and the supercritical fluid is discharged. At this time, if the discharge is made too fast, the produced particles may be damaged, so it is preferable to discharge slowly. After removing all of the supercritical fluid in the reactor, the particles are collected from the base wall or bottom of the reactor.

Hereinafter, the present invention will be described in detail with reference to comparative examples and examples.

First, the comparative example was measured by magnification of 2000 times with arbutin electron micrographs, the Example was measured by magnification 5000 times with arbutin particles produced under the following conditions. The content of the mixed solution used to prepare arbutin having a small surface area using a supercritical fluid process is 0.12 g of arbutin, 23.67 g of ethanol, the height of the settling tank where precipitation occurs is 200 mm, and the volume is 100 ml.

As shown in Table 1, the operating variables in this embodiment are the temperature and pressure, the carbon dioxide flow rate, the solution flow rate, Example 1-2 is to change the temperature of 313, 333K by adjusting the temperature, the pressure in Example 3-4 In 130-170 bar (Example 5-6), the refined arbutin was obtained while changing the carbon dioxide flow rate 2.5-3.5kg / hr, Example 7-8, while changing the solution flow rate 0.5-1.5ml / min.

Table 1 Working Conditions by Four Operational Variables in Example 1-8

1-3 shows that arbutin having a very small particle size of Examples 1-8 of the present invention can be obtained as compared to Comparative Example 1 measured at an electron microscope 2000 magnification as shown in FIGS. 1-3.

As described above, the arbutin (Example 1-8) obtained by using the supercritical fluid process of the present invention was able to obtain ultrafine particles as compared to the conventional arbutin (comparative example), and the effective skin area due to the increase in effective area was obtained. The preparation of the ultrafine arbutin formulations for which enhancement is anticipated has been completed.

Claims (1)

Supercritical fluid comprising spraying a mixed solvent in which arbutin is dissolved in an organic solvent to contact the supercritical fluid to produce arbutin particles and introducing a supercritical fluid to remove the organic solvent used in the mixed solution. A process for producing micronized arbutin using the process, wherein the organic solvent used preferably uses 0.0001 to 0.50 parts by weight of arbutin, and more preferably 0.001 to 0.20 parts by weight.

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