KR20160019022A - A method for producing micro particle for biodegradable filler - Google Patents

Abstract

The present invention relates to a method for preparing drug-containing sustained release microparticles, comprising the steps of: (a) dissolving a biodegradable polymer and a drug in a halogenated alkane solvent to form a drug-containing biodegradable polymer solution; (b) homogeneously mixing the drug-containing biodegradable polymer solution in a continuous phase containing a surfactant to form a dispersed phase; (c) maintaining an emulsion including the continuous phase and the dispersed phase at a temperature lower than the boiling point of the halogenated alkane solvent to form microparticles in the continuous phase; (d) primarily drying the microparticles; (e) mixing the primarily dried microparticles with an aqueous alcohol solution, and then maintaining the aqueous alcohol solution at a temperature more than or equal to the boiling point of the halogenated alkane solvent to extract and evaporate the remaining halogenated alkane solvent from the microparticles; and (f) secondarily drying the obtained microparticles for biodegradable filler. The microparticles for biodegradable filler prepared in accordance with the preparation method of the present invention minimize the hydrolysis of the biodegradable polymer in the microparticles, while easily removing the halogenated alkane solvent from the microparticles to inhibit reduction in the molecular weight so as to lower the resorption rate into body when being administered in vivo, thus being utilized effectively in biodegradable skin-care or medical filler.

Description

[0001] The present invention relates to a biodegradable filler for biodegradable filler,

The present invention relates to a method for producing fine particles for a biodegradable filler.

So far, many products have been used in dental treatment for inserting gums as well as for removing wrinkles, fine wrinkles, skin cracks, wounds and other scars in restorative surgery or cosmetic surgery and skin care fields. Lt; RTI ID = 0.0 > subcutaneous < / RTI > Each of these products has advantages and disadvantages.

Silicone gel (or silicone oil) is easy to use. However, it was observed that after the injection, the silicone droplets simply penetrated into the tissue below the injection site by gravity. Silicone is often responsible for chronic inflammation, granuloma formation, and even spastic allergic reactions. Silicon is not biodegradable and can be found in the liver.

The Teflon paste was prepared by suspending polytetrafluoroethylene particles (particle diameter: 10 to 100 mu m) in glycerin. This product frequently causes severe and chronic plasma infections and should be removed from the skin or subcutaneous tissue after a few months in most patients. This product also proved to be found in the liver of polytetrafluoroethylene particles.

Collagen suspensions have been the most widely used in recent decades. However, the result was disappointing because the collagen is reabsorbed within one to three months. An allergic reaction was also observed in about 2% of patients. Finally, you should know that collagen is obtained from cattle.

Although the idea of using a biological sample from the patient itself is obviously interesting, clinical studies have shown that re-transplantation of adipocytes does not occur because adipocytes are absorbed and disappeared within a few weeks.

Another system is adding the patient's plasma to the collagen gelatin obtained from cows and pigs. The result is even more disappointing and the product is obtained from animals.

Hyaluronate gels are biologically compatible and non-toxic and can be excellent substitutes. This replacement is more widely used in ophthalmology. However, hyaluronate gels are unsuitable for use in plastic surgery because they are biologically resorbed very quickly (e.g., within 2 months).

Bioplastics are prepared by dispersing silicone polymer particles (particle diameter: 70 to 140 mu m) in polyvinylpyrrolidone. This product has not been used because of chronic inflammation and the resulting rejection.

Polymethyl methacrylate (PMMA) microsphere PMMA suspended in gelatin solution or collagen solution with a diameter of 20 to 40 μm is not biodegradable and knows what will change after 5 to 6 years It does not take a long time. In addition, the vector remains in the collagen solution obtained from cattle and causes allergies as known.

Thus spherical microspheres, which are capable of avoiding aggregation, needle clogging and nodule forming upon injection, without inducing any unwanted reactions in the human body, There is still a need for a slow reabsorbable, biodegradable medical filler or implant that has excellent properties such as flow characteristics due to the high viscosity

The most widely used methods for preparing fine particles for biodegradable fillers are phase separation, spray drying, and solvent evaporation.

The phase separation process, also known as coacervation, reduces the solubility of the polymer by adding a non-solvent. In a general method for producing fine particles, a biodegradable polymer is dissolved in an organic solvent such as dichloromethane. Two phases are formed by the slow addition of the non-solvent (usually silicone oil); That is, it is a silicone oil phase containing a polymer and an organic solvent phase not containing a polymer. As the organic solvent is extracted or evaporated, the biodegradable polymeric microparticles solidify on the silicone oil. Coreacebate (silicone oil) is adsorbed on polymer microparticles.

In the spray drying method, the biodegradable polymer is dissolved in a volatile organic solvent such as dichloromethane. The solution or dispersion is sprayed into the heated air. The solvent is evaporated to form solid microparticles.

The solvent evaporation method is most commonly used for the production of fine particles. In the solvent evaporation method, an organic polymer solution is emulsified in a dispersion medium, and the dispersion medium is usually water-soluble, but may be an oil. The method can be further subdivided into an O / W method, a W / O / W method, and an O / O method.

In the O / W process, the biodegradable polymer is dissolved in an organic solvent such as dichloromethane or a methanol / dichloromethane mixture. The polymer-organic solvent solution is dispersed in the aqueous phase. To help form organic solvent droplets in the water phase, an emulsifier (usually a surfactant) is added to the water phase. The organic solvent is evaporated by stirring, and the droplets solidify into polymeric microparticles with the encapsulating drug.

In the W / O / W method, a water-soluble solution is prepared in order to make a W / O emulsion containing an organic solvent, and then it is dispersed in a polymer solution in an organic solvent. In order to form a W / O / W emulsion, the W / O polymer emulsion is emulsified in water phase. The organic solvent is evaporated while stirring, and the polymer droplets in the emulsion are solidified into fine particles.

In the O / O process, the polymer is dissolved in a solvent (e.g., acetonitrile) that is mixed with water. To prepare an O / O emulsion, the solution is emulsified on oil in the presence of an emulsifier such as SPAN 80. The organic solvent can be extracted by an oil and be obtained by filtration to obtain fine particles.

PCT / NL2008 / 050506 describes a method for producing microcapsules containing polycaprolactone using the O / W method in a solvent evaporation method. Specifically, the patent document describes a method for producing biodegradable microparticles by using a halogenated alkane solvent, for example, dichloromethane. However, when a halogenated alkane is used as a solvent, microparticles of a biodegradable high molecular weight polymer , The halogenated alkane solvent may remain and it is not easy to remove it. Residual halogenated alkane solvent in such biodegradable microparticles may cause toxicity and carcinogenicity. Therefore, for in vivo administration, it is one of the important problems that must be solved in the process of manufacturing biodegradable microparticles.

In order to remove such residual halogenated alkane solvent, generally heat is applied in the process of producing biodegradable microparticles. When the heat is applied, polyester biodegradable polymers such as polycaprolactone accelerate hydrolysis, And the biodegradable microparticles are rapidly reabsorbed in the biodegradable microparticles. Therefore, development of a process for producing fine particles for biodegradable fillers which can minimize the hydrolysis of the biodegradable polymer while easily removing the halogenated alkane solvent is required.

Disclosed is a method for producing fine particles for a biodegradable filler using a solvent evaporation method, which is capable of easily removing a halogenated alkane solvent remaining in the fine particles and minimizing a decrease in the molecular weight of the biodegradable polymer in the fine particles, It is an object of the present invention to provide a method for producing fine particles for biodegradable fillers that can be reabsorbed in vivo.

The present invention provides, as means for solving the above problems,

(a) dissolving a biodegradable polymer in a halogenated alkane solvent to form a biodegradable polymer solution;

(b) homogeneously mixing the biodegradable polymer solution in a continuous phase containing a surfactant to form a dispersed phase;

(c) maintaining the emulsion including the continuous phase and the dispersed phase at a temperature lower than the boiling point of the halogenated alkane solvent to form fine particles in the continuous phase;

(d) primary drying the fine particles;

(e) mixing the primary dried fine particles with an alcohol aqueous solution, and maintaining the alcohol aqueous solution at a temperature equal to or higher than the boiling point of the halogenated alkane solvent to extract and evaporate the halogenated alkane solvent remaining from the fine particles; And

(f) secondary drying the obtained microparticles to produce microparticles for biodegradable fillers.

A method for producing fine particles for a biodegradable filler is provided.

The method for producing fine particles for biodegradable filler according to the present invention minimizes the decrease in molecular weight due to the hydrolysis of the biodegradable polymer in the fine particles for biodegradable filler while easily removing the halogenated alkane solvent remaining in the fine particles for biodegradable filler Therefore, it is possible to produce fine particles for biodegradable filler that can be slowly reabsorbed in vivo when administered in vivo.

(A) dissolving a biodegradable polymer in a halogenated alkane solvent to form a biodegradable polymer solution; (b) homogeneously mixing the biodegradable polymer solution in a continuous phase containing a surfactant to form a dispersed phase; (c) maintaining the emulsion including the continuous phase and the dispersed phase at a temperature lower than the boiling point of the halogenated alkane solvent to form fine particles in the continuous phase; (d) primary drying the fine particles; (e) mixing the primary dried fine particles with an alcohol aqueous solution, and maintaining the alcohol aqueous solution at a temperature equal to or higher than the boiling point of the halogenated alkane solvent to extract and evaporate the halogenated alkane solvent remaining from the fine particles; And (f) secondary drying the obtained fine particles to produce fine particles for biodegradable fillers.

Hereinafter, the method for producing the biodegradable filler fine particles of the present invention will be described in detail.

As used herein, the term " solvent evaporation method "refers to a method in which a biodegradable polymer solution prepared by dissolving a biodegradable polymer in an organic solvent is added to a continuous phase containing a surfactant, and the resulting microparticles are added to an aqueous alcohol solution To form fine particles for biodegradable filler, and to remove the remaining organic solvent from the fine particles for biodegradable filler.

The production method of the present invention comprises (a) dissolving a biodegradable polymer in a halogenated alkane solvent to form a biodegradable polymer solution.

In the step (a), a biodegradable polymer solution may be prepared by dissolving the biodegradable polymer in a halogenated alkane solvent.

The weight average molecular weight of the biodegradable polymer is not particularly limited and may be 10,000 or more, preferably 30,000 or more, more preferably 50,000 or more, still more preferably 75,000 or more, and the upper limit thereof is preferably 500,000 or less May be 400,000 or less, more preferably 300,000 or less, and even more preferably 200,000 or less.

The type of the biodegradable polymer is not particularly limited, but polyester can be preferably used. Particularly, polycaprolactone, lactic acid-caprolactone copolymer, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, And mixtures thereof. More preferably, a lactic acid-glycolic acid copolymer may be used.

When a lactic acid-glycolic acid copolymer is used as the biodegradable polymer, the molar ratio of lactic acid to glycolic acid in the copolymer may be 99: 1 to 50:50, and preferably 75:25. Examples of commercially available biodegradable polymers that can be used in the present invention include Resomer RG 755S, Resomer RG756S and Resomer RG 858S from Ebonics.

The halogenated alkane used as a solvent for dissolving the biodegradable polymer in the step (a) preferably has a boiling point of 120 ° C or less, and is not miscible with water. By utilizing the property of the halogenated alkane solvent not to be miscible with water, it is possible to form a dispersed phase or a discontinuous phase by mixing the biodegradable polymer solution homogeneously in the continuous phase containing the surfactant in the step (b) have.

The kind of the halogenated alkane solvent used in the step (a) is not particularly limited, but may be preferably an alkane chloride, more preferably dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, , And dichloromethane may be most preferably used.

The production method of the present invention comprises the step of (b) homogeneously mixing the biodegradable polymer solution in a continuous phase containing a surfactant to form a dispersed phase.

The method of homogeneously mixing the continuous phase containing the biodegradable polymer solution and the surfactant in the step (b) is not particularly limited, but may preferably be performed using a high-speed stirrer.

When the emulsion containing the continuous phase and the dispersed phase is formed as in the step (b), the biodegradable polymer solution is homogeneously dispersed in the continuous phase containing the surfactant to form a dispersed phase or a discontinuous phase in a droplet form .

The kind of the surfactant used in the step (b) is not particularly limited, and if the biodegradable polymer solution can form a dispersed phase of stable droplets in the continuous phase to help form an oil-in-water (O / W) emulsion Either can be used. The surfactant is preferably a nonionic surfactant such as methylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, lecithin, gelatin, polyvinyl alcohol, polyoxyethylene sorbitan fatty acid ester and polyoxyethylene castor oil derivative; Anionic surfactants such as sodium lauryl sulfate and sodium stearate; Cationic surfactants such as imidazole, ester amine, linear diamine, and parathyamine, and mixtures thereof, and most preferably polyvinyl alcohol.

In step (b), the content of surfactant in the continuous phase containing the surfactant is preferably 0.01 w / v% to 20 w / v%, preferably 0.1 w / v% based on the total volume of the continuous phase containing the surfactant, v% to 5 w / v%. When the content of the surfactant is less than 0.01 w / v%, a dispersed phase or discontinuous phase in the form of droplets may not be formed in the continuous phase, and the content of the surfactant Above 20 w / v%, it may be difficult to remove the surfactant after the fine particles are formed in the continuous phase due to excess surfactant.

The continuous phase used in step (b) may be water. When water is used as the continuous phase, the continuous phase remaining on the fine particle surface through filtration and washing and the polyvinyl (meth) acrylate remaining after the fine particles are formed in the continuous phase in step (c) A water-soluble surfactant such as an alcohol can be easily removed.

The continuous phase containing the surfactant, which is used in the step (b), may preferably be a polyvinyl alcohol aqueous solution. That is, polyvinyl alcohol may be used as the surfactant, and water may be used as the continuous phase.

The production method of the present invention is characterized in that (c) an emulsion containing a dispersed phase and a continuous phase formed in the step (b) At a temperature below the boiling point of the halogenated alkane solvent to form fine particles in the continuous phase.

In the step (c), an emulsion containing a dispersed phase or a discontinuous phase in a droplet form (biodegradable polymer solution) and a continuous phase containing a surfactant is stirred at a temperature lower than the boiling point of the halogenated alkane solvent for a predetermined time, for example, 2 Hours to 3 hours, the halogenated alkane solvent may be extracted from the biodegradable polymer solution in the form of a droplet, which is a dispersed phase or a discontinuous phase, to the continuous phase. As the halogenated alkane solvent is extracted from the biodegradable polymer solution in the form of droplets, the dispersed or discontinuous phase in the form of droplets can be solidified to form fine particles.

In the conventional method for producing biodegradable fine particles using the solvent evaporation method, heat is applied to remove the halogenated alkane solvent from the dispersed phase or the discontinuous phase in the droplet form, and hydrolysis of the biodegradable polymer is caused by the heat, There is a problem.

However, in the present invention, since the step (c) is carried out at a temperature lower than the boiling point of the halogenated alkane solvent, the droplet-shaped dispersed phase or the discontinuous phase is solidified while minimizing the hydrolysis of the biodegradable polymer by heat, Polymer-containing fine particles can be formed in the continuous phase.

The production method of the present invention may further include a step of removing the continuous phase by filtration and washing to obtain fine particles between the step (c) and the step (d) described later.

As a result of carrying out the step (c), the biodegradable polymer and the remaining fine particles made of the halogenated alkane solvent are dispersed in the continuous phase, and a suspension is produced. In the suspension, a liquid continuous phase, a surfactant, an extracted halogenated alkane solvent, and dispersed fine particles are present. Thus, before performing the drying step (d) described below, the suspension is filtered to obtain solidified particulates, and the solidified particulates are washed with water one or more times, preferably one to three times, to remove the surfactant , And then filtered again to obtain washed fine particles.

The washing step for removing the remaining surfactant can be carried out usually using water used as a continuous phase, and the washing step can be repeated several times.

(D) after the step (c) or after the filtration and washing step, the fine particles And a primary drying step.

In the step (d), the primary drying method is not particularly limited, but may preferably be performed through vacuum drying in order to minimize the damage of the heat-induced biodegradable polymer. When vacuum drying is performed on the fine particles obtained through filtration and washing, water present in the fine particles can be removed through evaporation or sublimation. The vacuum drying may preferably be performed at room temperature.

As a result of the above-mentioned step (d), the solidified fine particles obtained by the primary drying are formed into a solid film so that even if the temperature of the aqueous alcohol solution is maintained at the boiling point or higher of the halogenated alkane solvent in the step (e) It is possible to prevent hydrolysis of the biodegradable polymer.

(E) mixing the primary dried fine particles obtained in the step (d) with the aqueous alcohol solution, and then maintaining the aqueous alcohol solution at a temperature equal to or higher than the boiling point of the halogenated alkane solvent, The halogenated alkane solvent is extracted and And evaporating.

Since the halogenated alkane solvent remains in the primary dried fine particles obtained in the step (d) in addition to the biodegradable polymer, it is necessary to remove the halogenated alkane solvent remaining from the fine particles.

Thus, when the primary dried fine particles obtained in step (d) are mixed in an alcohol aqueous solution and then maintained or stirred for a predetermined time, for example, 2 hours to 3 hours at a temperature equal to or higher than the boiling point of the halogenated alkane solvent, The remaining halogenated alkane solvent may be dissolved in the aqueous alcohol solution to be extracted and evaporated.

The type of alcohol used in step (e) is not particularly limited, but may be selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof, more preferably ethanol.

The content of alcohol in the alcohol aqueous solution may be 5% by volume to 80% by volume, preferably 10% by volume to 50% by volume, based on the total volume of the aqueous alcohol solution. If the content of the alcohol is less than 5 vol%, extraction of the halogenated alkane solvent remaining in the fine particles is not easy and the process time may be long. When the content of the alcohol exceeds 80 vol% Coagulation can occur between them.

The production method of the present invention may further comprise, during the step (e) and the step (f) described below, removing the aqueous alcohol solution through filtration and washing to obtain fine particles.

As a result of the above-mentioned step (e), the alcohol aqueous solution is an alcohol; water; And biodegradable polymer-containing fine particles. Therefore, before performing the drying step (f) to be described later, the aqueous alcohol solution is filtered to obtain solidified fine particles, and the solidified fine particles are washed with water at least once, preferably once to three times, to remove the alcohol , And then filtered again to obtain washed fine particles.

The washing step for removing the alcohol may be carried out using water which is ordinarily used as a continuous phase, and the washing step may be repeated several times.

The manufacturing method of the present invention includes the step of (f) secondary drying the obtained fine particles after the step (e) or after the filtration and washing step to produce biodegradable fine particles.

In the step (f), the secondary drying method is not particularly limited, but may preferably be performed by vacuum drying in order to minimize the damage of the heat-induced biodegradable polymer. When vacuum drying is performed on the fine particles obtained through filtration and washing, the water, the alcohol remaining after washing, and the halogenated alkane solvent remaining in water can be removed from the fine particles through evaporation or sublimation. The vacuum drying may preferably be performed at room temperature.

As a result of carrying out the step (f), fine particles for a biodegradable filler comprising a biodegradable polymer can be obtained.

Since the halogenated alkane solvent does not remain in the fine particles for the biodegradable filler produced according to the production method of the present invention, the problem of toxicity and carcinogenicity of the halogenated alkane solvent, which is problematic in the case of remaining, can be solved, The hydrolysis of the biodegradable polymer is minimized during the removal of the alkane solvent and the resorption of the biodegradable filler microparticles in vivo can be slowed down when the biodegradable filler microparticles are administered in vivo.

When the biodegradable polymer in the fine particles is hydrolyzed by heating for removing the halogenated alkane solvent in the process of producing the biodegradable filler fine particles by the solvent evaporation method to decrease the molecular weight as in the prior art, In the in vivo administration of the microparticles, in vivo resorption of microparticles for biodegradable fillers proceeds rapidly due to a decrease in molecular weight, which may be unsuitable for use as a biodegradable skin cosmetic or medical filler.

However, when the biodegradable filler fine particles are prepared according to the production method of the present invention, the hydrolysis of the biodegradable polymer is minimized to prevent the molecular weight from being reduced. Therefore, when the biodegradable filler fine particles are administered in vivo, A slow resorption effect in vivo of the fine particles can be achieved. Thus, the effect of a continuous biodegradable medical filler can be achieved through one in vivo administration.

The fine particles for biodegradable filler produced according to the production method of the present invention are made of biodegradable polymer and the residual amount of the halogenated alkane solvent in the fine particles for biodegradable filler is less than 1 ppm, preferably less than 0.1 ppm, 0 ppm. The residual amount of the halogenated alkane solvent in the fine particles for biodegradable filler can be minimized to prevent toxicity and carcinogenicity due to the halogenated alkane solvent.

The fine particles for biodegradable filler produced according to the production method of the present invention have a spherical shape. The mean diameter of the biodegradable filler particles is not particularly limited, but is, for example, from 5 탆 to 150 탆, preferably from 20 탆 to 90 탆, More preferably 25 占 퐉 to 75 占 퐉, still more preferably 30 占 퐉 to 70 占 퐉. In the present invention, by limiting the average diameter of the fine particles for biodegradable fillers to the above range, it is possible to facilitate subcutaneous or intradermal injection in vivo.

The biodegradable filler fine particles produced according to the production method of the present invention are not particularly limited in their use, but can be used, for example, as a skin beauty or medical filler requiring resorption in vivo, It can be used as a subcutaneous or intradermal injectable filler.

The resorption time of the biodegradable filler fine particles produced in accordance with the production method of the present invention is not particularly limited. However, considering biodegradable skin beauty or use as a medical filler, Absorbable.

[ Example ]

Hereinafter, the present invention will be described in more detail by way of examples according to the present invention and comparative examples which are not according to the present invention, but the scope of the present invention is not limited by the following examples.

Example  One

A biodegradable polymer solution was prepared by dissolving 10 g of PLGA (lactic acid-glycolic acid copolymer, molar ratio of lactic acid to glycolic acid = 75:25) as a biodegradable polymer in a solvent of 40 ml of dichloromethane (boiling point: 39.6 ° C) . 5 L of a polyvinyl alcohol aqueous solution (concentration: 0.25 w / v%) was prepared using polyvinyl alcohol as a surfactant and water as a continuous phase. Then, the biodegradable polymer solution was mixed with the polyvinyl alcohol aqueous solution and stirred at a high speed to form a dispersed phase in the form of a droplet. The emulsion containing the continuous phase and the dispersed phase is maintained at 15 캜 for 2 hours to 3 hours to extract a dichloromethane solvent from the biodegradable polymer solution in the form of droplets toward the polyvinyl alcohol aqueous solution, To form fine particles. Thereafter, the solidified fine particles were filtered, and the fine particles were washed three times with water to remove polyvinyl alcohol. Then, after obtaining the washed fine particles again through filtration, The first vacuum drying was performed to remove moisture and dichloromethane remaining in the fine particles By evaporation, primary dried fine particles were obtained. The primary dried fine particles were mixed with 500 ml of an aqueous ethanol solution (concentration: 25 v / v%), and the fine particles were stirred at 45 ° C for 2 hours to 3 hours to extract dichloromethane remaining in the fine particles toward the aqueous ethanol solution Evaporated. Subsequently, the ethanol aqueous solution containing the fine particles was filtered, and the fine particles were washed three times with water to remove ethanol. Thereafter, the washed fine particles were obtained again through filtration, and then subjected to secondary vacuum drying to remove moisture, dichloromethane and ethanol remaining in the fine particles, thereby obtaining fine particles for biodegradable fillers.

Comparative Example  One

A biodegradable polymer solution and 5 L of a polyvinyl alcohol aqueous solution were prepared in the same manner as in Example 1. Then, the biodegradable polymer solution was mixed with the polyvinyl alcohol aqueous solution and stirred at a high speed to form a dispersed phase in the form of a droplet. Further, the emulsion containing the continuous phase and the dispersed phase is maintained at 15 캜 for 2 hours to 3 hours to extract a dichloromethane solvent from the biodegradable polymer solution in the form of droplets toward the polyvinyl alcohol aqueous solution, To form fine particles. Thereafter, the continuous phase containing the fine particles was stirred at 45 캜 for 2 hours to 3 hours to evaporate dichloromethane from the fine particles, and the solidified fine particles were filtered. Thereafter, the filtered fine particles And then washed three times with water to remove polyvinyl alcohol. Then, after filtration again to obtain the washed fine particles, Vacuum drying was performed to remove moisture and dichloromethane remaining in the fine particles By evaporation, fine particles for biodegradable filler were obtained.

Comparative Example  2

A biodegradable polymer solution and 5 L of a polyvinyl alcohol aqueous solution were prepared in the same manner as in Example 1. Then, the biodegradable polymer solution was mixed with the polyvinyl alcohol aqueous solution and stirred at a high speed to form a dispersed phase in the form of a droplet. The emulsion containing the continuous phase and the dispersed phase is maintained at 15 캜 for 2 hours to 3 hours to extract a dichloromethane solvent from the biodegradable polymer solution in the form of droplets toward the polyvinyl alcohol aqueous solution, To form fine particles. Thereafter, the continuous phase containing the fine particles was stirred at 45 캜 for 2 hours to 3 hours to evaporate dichloromethane from the fine particles to further solidify the fine particles. Thereafter, the solidified fine particles were filtered and washed with water three times to remove polyvinyl alcohol. Then, the washed fine particles were obtained again through filtration, and then subjected to primary vacuum drying to evaporate water and dichloromethane remaining in the fine particles, thereby obtaining primary dried fine particles. The primary dried fine particles were mixed with 500 ml of an ethanol aqueous solution (concentration: 25 v / v%), and the fine particles were stirred at 45 ° C for 2 hours to 3 hours to extract dichloromethane remaining from the fine particles toward the aqueous ethanol solution Evaporated. Subsequently, the ethanol aqueous solution containing the fine particles was filtered to obtain fine particles, and the fine particles were washed with water three times to remove ethanol. Thereafter, the washed fine particles were obtained again through filtration, and then subjected to secondary vacuum drying to remove moisture, dichloromethane and ethanol remaining in the fine particles, thereby obtaining fine particles for biodegradable fillers.

Test Example  1: Measurement of the weight average molecular weight of the biodegradable polymer in the fine particles

The weight average molecular weight of the biodegradable polymer (i.e., PLGA) in the fine particles for biodegradable filler obtained in Example 1 and Comparative Examples 1 and 2 was measured using high performance liquid chromatography (Waters, GPC-150C Plus) as follows Respectively. The separation columns were connected in series in the order Shodex GPC KF-G, 804, 803, 802 and 801, respectively. The column temperature was adjusted to 50 캜, the mobile phase was moved to 1.0 ml / min using tetrahydrofuran, and a differential refractometer was used as the detector. Thereafter, the weight average molecular weight of the test solution was calculated using the calibration curve of the weight average molecular weight of each polystyrene standard solution.

Test Example  2: Residual in particulate Amount of solvent  Measure

The amount of residual solvent in the fine particles for biodegradable filler obtained in Example 1 and Comparative Examples 1 and 2 was measured by accurately taking 5 ml of the test solution and the standard solution in the headspace vial. The amount of residual solvent in the fine particles obtained by measuring the peak areas of dichloromethane and ethanol of the test solution and the standard solution, AT and AS, was calculated by the following formula.

Amount of residual dichloromethane in the particulate (ppm) =

 AT: Peak area of dichloromethane and ethanol in test solution

AS: Peak area of dichloromethane and ethanol in the standard solution

WT: Weight (g) of the obtained fine particles

WS: Weight of standard (g)

Test examples of Example 1 and Comparative Examples 1 and 2 The measurement results are shown in Table 1 below.

Remaining amount (ppm) of dichloromethane in the fine particles Weight average molecular weight of the biodegradable polymer in the fine particles Example One 0 139,876 Comparative Example One 9222 127,588 2 0 88,963

As shown in Table 1, in Example 1, the emulsion containing the continuous phase and the dispersed phase was maintained at a temperature lower than the boiling point of the halogenated alkane solvent to form fine particles in the continuous phase, followed by primary vacuum drying The fine particles are mixed with an alcohol aqueous solution and the mixture is kept at a temperature equal to or higher than the boiling point of the alkane halide solvent to remove the halogenated alkane solvent remaining in the fine particles to extract and evaporate them and then vacuum dried to minimize the hydrolysis of the biodegradable polymer in the fine particles The remaining halogenated alkane solvent in the fine particles was completely removed.

However, in the case of Comparative Example 1, unlike in Example 1, the continuous phase containing fine particles was maintained at a temperature higher than the boiling point of the halogenated alkane solvent without removing the additional halogenated alkane solvent and the second vacuum drying with the aqueous alcohol solution, By further solidifying and obtaining fine particles through vacuum drying, it can be seen that the residual halogenated alkane solvent remaining in the fine particles is present in a large amount and the weight average molecular weight of the biodegradable polymer is somewhat reduced.

In addition, in the case of Comparative Example 2, unlike Example 1, by further performing the step of further solidifying the fine particles by maintaining a continuous phase containing fine particles at a temperature equal to or higher than the boiling point of the halogenated alkane solvent before the first vacuum drying, All of the residual halogenated alkane solvents in the fine particles were removed, but the hydrolysis of the biodegradable polymer in the fine particles proceeded, and the weight average molecular weight of the biodegradable polymer was remarkably reduced.

As described above, when the fine particles for biodegradable filler are prepared according to the production method of the present invention, the remaining halogenated alkane solvent in the fine particles can be removed. In this process, the biodegradable polymer in the fine particles is hydrolyzed, The result of this reduction can also be minimized. Therefore, the biodegradable filler fine particles prepared according to the production method of the present invention can maintain the weight average molecular weight of the biodegradable polymer while completely removing the halogenated alkane solvent having toxicity and carcinogenicity, It is suitable for use as a biodegradable skin cosmetic or medical filler.

Claims (13)

(a) dissolving a biodegradable polymer in a halogenated alkane solvent to form a biodegradable polymer solution;
(b) homogeneously mixing the biodegradable polymer solution in a continuous phase containing a surfactant to form a dispersed phase;
(c) maintaining the emulsion including the continuous phase and the dispersed phase at a temperature lower than the boiling point of the halogenated alkane solvent to form fine particles in the continuous phase;
(d) primary drying the fine particles;
(e) mixing the primary dried fine particles with an alcohol aqueous solution, and maintaining the alcohol aqueous solution at a temperature equal to or higher than the boiling point of the halogenated alkane solvent to extract and evaporate the halogenated alkane solvent remaining from the fine particles; And
(f) secondary drying the obtained microparticles to produce biodegradable microparticles.
(Method for producing fine particles for biodegradable filler). The method according to claim 1,
The biodegradable polymer is selected from the group consisting of polycaprolactone, lactic acid-caprolactone copolymer, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, and mixtures thereof. The method according to claim 1,
The halogenated alkane solvent is selected from the group consisting of dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, and mixtures thereof. The method according to claim 1,
Wherein the surfactant is selected from the group consisting of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and mixtures thereof. The method according to claim 1,
Wherein the continuous phase containing a surfactant is a polyvinyl alcohol aqueous solution. The method according to claim 1,
Wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof. The method according to claim 1,
Wherein the primary drying and the secondary drying are carried out by vacuum drying. The method according to claim 1,
Further comprising, between steps (c) and (d), removing the continuous phase by filtration and washing to obtain fine particles. The method according to claim 1,
Further comprising, during steps (e) and (f), removing the aqueous alcohol solution through filtration and washing to obtain fine particles. The method according to claim 1,
Wherein the biodegradable filler fine particles have an average diameter of 5 占 퐉 to 150 占 퐉. The method according to claim 1,
Wherein the biodegradable filler microparticles are bioabsorbable within one year to three years. The method according to claim 1,
Wherein the residual amount of the halogenated alkane solvent in the fine particles for biodegradable fillers is less than 1 ppm. The method according to claim 1,
Wherein the biodegradable filler fine particles are used as a subcutaneous or intracutaneous injection-type filler that can be administered in vivo.