KR20080060082A - A nanoparticle process of phytoestrogen - Google Patents

Abstract

A process for preparing phytoestrogen nanoparticles is provided to improve acne-treating effects of phytoestrogen by increasing skin absorption rate and sectional area of phytoestrogen particles through the supercritical fluid process. The phytoestrogen nanoparticles are prepared by dissolving phytoestrogen in organic solvent selected from methanol and ethanol to prepare a mixture solution, contacting the mixture solution with the supercritical fluid selected from supercritical carbon dioxide, supercritical nitrogen monoxide, supercritical methane trichloride, supercritical propane, supercritical ethylene and supercritical xenon through spraying to form phytoestrogen nanoparticles, washing the phytoestrogen nanoparticles by introducing the additional supercritical fluid into the phytoestrogen nanoparticles, and recovering the phytoestrogen nanoparticles having the particle size of 100-300 nm.

Description

A nanoparticle process of phytoestrogen

The present invention relates to a method for the preparation of nanonized phytoestrogens using a supercritical fluid process and to application to an acne quasi-medical product. And a step of introducing a supercritical fluid to the particles to remove the organic solvent used in the mixed solution, and to a method for producing supernanophylized phytoestrogen particles using a supercritical fluid process.

There are many causes of acne, but there are still few satisfactory safe treatments. Many therapeutic agents have been used for the treatment of these diseases, but there are difficulties in treatment due to solubility problems in water or organic solvents and the limited absorbency to the skin and the side effects of residual solvents due to the use of organic solvents.

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 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 lean to near ideal gas to high density near liquid density, so that the fluid's equilibrium (solubility, entrainer effect) and transfer properties (viscosity, diffusion coefficient, and thermal 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 phytoestrogens with increased skin absorption rate by increasing the effective area by nanoparticle size of phytoestrogens in a supercritical fluid process using supercritical carbon dioxide, and prepared phytoestrogens prepared therefrom. Nanonized phytoestrogens whose effective area is increased by changing the crystallization of the drug itself through the change of temperature and pressure, which are operating variables of the supercritical fluid process, or the flow rate of the solution used together with the flow rate of supercritical carbon dioxide. It is intended to complete the present invention by obtaining particles.

The present invention is to solve the problems of the prior art as described above, to provide a formulation that increases the skin absorption rate by nanonizing phytoestrogens having a large particle size using a supercritical fluid process.

Hereinafter, the present invention will be described in detail.

The present invention comprises the steps of generating phytoestrogens particles by spraying a mixed solution of phytoestrogens dissolved in an organic solvent in a supercritical fluid and removing the organic solvent used in the mixed solution by introducing a supercritical fluid into the particles. It provides a method for producing nanonized phytoestrogens using a supercritical fluid process, including.

The basic principle of the manufacturing method is to dissolve the phytoestrogens in an appropriate amount of an organic solvent and then spray it through a nozzle to the 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 that, carbon dioxide is removed to prepare nanonized phytoestrogens.

More specifically, the method for producing nanonized phytoestrogens using the supercritical fluid process in the present invention comprises the steps of 1) dissolving phytoestrogens in an organic solvent to prepare a mixture thereof; 2) spraying the mixed solution with a supercritical fluid to make contact with each other to generate phytoestrogen 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 phytoestrogens 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, it is preferable to use 0.0001 to 0.50 parts by weight of phytoestrogens, and more preferably 0.001 to 0.20 parts by weight. Below 0.0001 parts by weight, the amount of particles obtained is too small, and above 0.50 parts by weight, phytoestrogens are not dissolved 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. When pressurizing carbon dioxide, it is preferable to use a syringe pump to maintain a constant pressure 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 phytoestrogens and additives 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 mixture from being saturated 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 rate, and discharged through the outlet at the same rate as the injection rate 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 cleaning 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 shows the phytoestrogens before the treatment of the particle size of 50-100 microns, the Example was measured the particle size of the phytoestrogens particles produced under the following conditions, the particle size of 100 to 300 nm according to the working conditions Could get the size. The content of the mixed solution used to prepare phytoestrogens having a small surface area using a supercritical fluid process is 0.12 g of phytoestrogens, 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 3-4 130-170 bar (bar), Example 5-6 in the carbon dioxide flow rate was 2.5-3.5kg / hr, in Example 7-8, the nanonized phytoestrogens were obtained while varying the solution flow rate 0.5-1.5ml / min.

Table 1 Working conditions and particle size by four operating variables in Example 1-8

Example Temperature (K) Pressure (bar) Carbon Dioxide Flow Rate (kg / hr) Solution flow rate (ml / min) Particle size (nm) Example 1 313 150 2.5 0.5 145 Example 2 333 150 2.5 0.5 154 Example 3 313 130 2.5 0.5 135 Example 4 313 170 2.5 0.5 100 Example 5 313 150 2.5 0.5 164 Example 6 313 150 3.5 0.5 250 Example 7 313 150 2.5 0.5 136 Example 8 313 150 2.5 1.5 300

As described above, the phytoestrogens (Examples 1-8) obtained by using the supercritical fluid process of the present invention were able to obtain ultrafine particles as compared to the existing phytoestrogens (Comparative Examples), and the skin due to the increase in effective cross-sectional area. The preparation of the supernanophylized phytoestrogen preparation, which is expected to enhance the efficacy, has been completed. The nanonized phytoestrogens can be applied to anti-salt products.

Claims (1)

Supercritical fluid comprising spraying and contacting a mixed solvent in which phytoestrogens are dissolved in an organic solvent to form a phytoestrogen particle, and introducing a supercritical fluid to remove the organic solvent used in the mixed solution. A process for producing nanonized phytoestrogens using a fluid process, wherein the organic solvent used preferably uses 0.0001 to 0.50 parts by weight of phytoestrogens, and more preferably 0.001 to 0.20 parts by weight.