KR20070058279A - A nano-particle process of zinc pyrithione and it's application to antidandruff otc products - Google Patents

Abstract

A method for preparing nano-sized zinc pyrithione is provided to micronize zinc pyrithione particles by changing self-crystallization degree of the zinc pyrithione through temperature and pressure change or flow change of a solution of zinc pyrithione and an organic solvent and supercritical CO2, thereby increasing skin efficacy of the zinc pyrithione due to increased cross-sectional area thereof. The method comprises the steps of: (a) spray-contacting a mixture solvent prepared by dissolving zinc pyrithione in an organic solvent such as methanol and ethanol with supercritical fluid to generate zinc pyrithione particles; and (b) introducing supercritical fluid such as supercritical CO2, supercritical N2O, supercritical CHF3, supercritical propane, supercritical ethylene and supercritical xenon into a reactor of the step(a) to remove the organic solvent used for the mixture solvent, wherein the content of the organic solvent used regarding the zinc pyrithione is 0.0001-0.50 wt.%, and preferably 0.001-0.20 wt.%.

Description

Nanoparticle Particle Process of Zinc Pyrithione and It's Application to Antidandruff OTC Products

The present invention relates to a method for nanoparticle zinc pyrithione formulations using a supercritical fluid process and application to dandruff quasi-drugs, by contacting a supercritical fluid by spraying a mixed solution of zinc pyrithione dissolved in an organic solvent Ultrafine zinc pyrithione particles using a supercritical fluid process comprising producing zinc pyrithione particles and introducing a supercritical fluid into the particles to remove organic solvents used in the mixed solution. It relates to a method of manufacturing.

There are many causes of dandruff, but it is accepted as a major factor by dandruff, a kind of fungus that is parasitic in the body. Although there are many such dandruff treatments, there are still insufficient 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 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 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 zinc pyrithione having an increased skin absorption rate by increasing the effective area by miniaturizing the particle size of zinc pyrithione in a supercritical fluid process using supercritical carbon dioxide. The pyrithione formulation changes the crystallization of the drug itself through the change of temperature and pressure, which are the operating variables of the supercritical fluid process, or the flow rate of the solution and the flow rate of supercritical carbon dioxide. It is intended to complete the present invention to obtain a refined zinc pyrithione 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 miniaturizing the zinc pyrithione having a large particle size using a supercritical fluid process.

Hereinafter, the present invention will be described in detail.

The present invention is to produce a zinc pyrithione particles by spraying a mixed solution of zinc pyrithione dissolved in an organic solvent by spraying the supercritical fluid and to introduce the supercritical fluid to the particles, the organic solution used in the mixed solution Provided is a method for preparing micronized zinc pyrithione using a supercritical fluid process comprising removing a solvent.

The basic principle of the manufacturing method is to dissolve zinc pyrithione in an appropriate amount of an organic solvent, and then spray it through a nozzle into a reaction port equilibrated with supercritical carbon dioxide to obtain particles, and then flow the supercritical carbon dioxide several times. By extracting the carbon dioxide is removed to prepare a fine zinc pyrithione.

More specifically, in the present invention, the method for producing micronized zinc pyrithione using a supercritical fluid process comprises the steps of: 1) dissolving zinc pyrithione in an organic solvent and preparing a mixture thereof; 2) spraying the mixed solution with a supercritical fluid to make zinc pyrithione 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 zinc pyrithione 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.

The organic solvent used preferably has a zinc pyrithione value 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, zinc pyrithione is 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 the carbon oxide, 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 mixed solution of zinc pyrithione 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 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, when the temperature and pressure are lowered to collect the particles, the solvent is re-precipitated to re-dissolve the produced particles to form agglomerations. Therefore, the washing process should be sufficiently performed until all solvent is 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 shows the zinc pyrithione before the treatment of the particle size of 50-100 microns, the Example was measured for the particle size of the zinc pyrithione particles produced under the following conditions by the particle size analyzer, at 50 A fine particle size of 150 nm was obtained. The content of the mixed solution used to prepare the zinc pyrithione having a small surface area using the supercritical fluid process is 0.12 g of zinc pyrithione, 23.67 g of ethanol, and the height of the precipitation 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 Example 5-6, the refined zinc pyrithione was obtained while changing the carbon dioxide flow rate at 2.5-3.5 kg / hr, and Example 7-8 at 0.5-1.5 mL / 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 0.5 110 Example 2 333 150 2.5 0.5 136 Example 3 313 130 2.5 0.5 134 Example 4 313 170 2.5 0.5 67 Example 5 313 150 2.5 0.5 150 Example 6 313 150 3.5 0.5 50 Example 7 313 150 2.5 0.5 137 Example 8 313 150 2.5 1.5 50

As described above, the zinc pyrithione (Example 1-8) obtained using the supercritical fluid process of the present invention was able to obtain ultrafine particles compared to the conventional zinc pyrithione (comparative example), and the effective cross-sectional area The preparation of the ultrafine zinc pyrithione formulation, which is expected to increase skin efficacy due to the increase, has been completed. The nanoparticle zinc pyrithione may be applied to quasi-drugs and the like to be used as a dandruff treatment.

Claims (1)

Spraying a mixed solvent in which zinc pyrithione is dissolved in an organic solvent by spraying the supercritical fluid to generate zinc pyrithione particles and introducing a supercritical fluid to remove the organic solvent used in the mixed solution. In the process for producing nanoparticle zinc pyrithione using a supercritical fluid process comprising, it is preferable that the use of the organic solvent is zinc pyrithione is 0.0001 to 0.50 parts by weight, more preferably 0.001 To 0.20% by weight of the method and the application to the dandruff therapy quasi-drugs.