KR20130047232A - Manufacturing method of sustained-release particle containing drugs using supercritical fluid and manufacturing method of medical stent - Google Patents

Abstract

PURPOSE: A method for preparing a sustained release drug-containing fine particle using supercritical fluid and a method for manufacturing a medical stent using the same are provided to obtain fine particles without a residual organic solvent. CONSTITUTION: A method for preparing a sustained release drug-containing fine particle using supercritical fluid comprises: a step of dissolving a paclitaxel drug and a biodegradable polymer in a solvent and preparing a polymer solution; a step of inputting the polymer solution into a reactor and dissolving the polymer solution in the supercritical fluid; a step of removing the solvent and forming a fine particle containing the drug; and a step of washing the fine particle with distilled water and drying.

Description

Manufacturing method of sustained-release particle containing drugs using supercritical fluid and manufacturing method of medical stent using supercritical fluid

The present invention relates to a method for producing sustained-release drug-containing microparticles using a supercritical fluid, and to a method for producing a medical stent using the same, and more specifically, to preparing particles containing drug-containing microparticles from which an organic solvent is removed using a supercritical fluid. At the same time, the present invention relates to a method for producing microparticles having excellent drug content, drug release rate, particle size, and thermal properties of particles, and a method for manufacturing a medical stent using the same.

A medical stent is a spring-type device made of a biocompatible material, preferably a metal or plastic material, and implanted into a phloem. Stents are used, for example, in the treatment of stenosis, stenosis or aneurysms in blood vessels.

The stent is implanted into a permanent stent in the phloem that strengthens the portion of the phloem that has collapsed, partially occluded, weakened or abnormally expanded, or a temporary stent that provides treatment to the damaged phloem. Stents can also be applied to the urethra and bile ducts, but are typically used after balloon angioplasty to prevent restenosis of damaged vessels.

However, neointimal hyperplasia occurs due to vascular endothelial damage when a conventional metal stent is implanted. Because of this, blood vessels develop restenosis within a few months, and in this case, surgery has been performed, and drug-release stents have been developed in which a drug that prevents endothelial hyperplasia is coated on the surface of the stent.

Representative examples include Taxus ^™ containing paclitaxel (PTX) and Cypher ^™ containing sirolimus. Several studies have shown that the rate of restenosis when implanting drug-releasing stents coated with polymer and paclitaxel or sirolimus into wounded blood vessels is significantly lower than that of metal stents (BL Hoatt, F. Ikeno, and AC Yeung, Catheter . Cardiovasc . Interv ., 55, 409 (2002); GW Stone, SG Ellis, and DA Cox, Circulation ., 109, 1942 (2004)).

Representative methods for improving the efficacy and bioavailability of the drug coated on the stent include a method of encapsulating the drug in a biodegradable polymer to produce fine or nanoparticles having a desired shape and size to release the drug at a desired rate for a specific time. (Langer, R., Biomaterials for drug delivery and tissue engineering, MRS Bull ., 31, 6 (2006); Feng, SS and S. Chin, Chemotherapeutic engineering, Chem . Eng . Sci ., 58 (2003) ; Kim, KK and DW Pack, AP Lee and LJ Lee, Eds ., P19 , Springer , New York (2006)).

In the stent field, the polymer material is necessary to support the drug for a certain period of time and release the drug at a desired rate. The polymer coating to minimize vascular endothelial and tissue reactions can minimize inflammation and blood clots.

The biodegradable polymer of polyester system, which is widely used in the development of microparticle drug delivery system, can easily control the decomposition rate by changing the composition and molecular weight of the polymer. It can maintain the effective concentration of the drug in the body for much longer than the general form of the formulation, and rarely cause the foreign body reaction in the body, and after performing a certain function, it is decomposed into carbon dioxide and water through metabolism and released into the body. Emissions have several advantages.

Conventional methods for preparing drug carriers in the form of drug-containing microparticles include melting, emulsion, phase separation, solvent evaporation and extraction, spray drying, and the like. However, the conventional method has many problems such as excessive energy consumption, environmental pollution due to the large amount of organic solvents and wastewater discharge, high cost, low yield, deterioration of the efficacy of the heat-sensitive drug, drug denaturation, remaining of the organic solvent in the drug.

In particular, the conventional method of forming particles while simultaneously removing the solvent by using the evaporation method of the drug-containing emulsion has the advantage that the particle size can be controlled, but the particles in the evaporation drying process to remove the solvent There is a possibility that cracks are generated, solvent may remain in the particles, and the recovery and containing efficiency of the particles are low. For example, the rotary evaporator process, which is a typical solvent removal process, removes the solvent by using the boiling point of the solvent, thereby degrading the stability of the particles.

The present invention has been made to improve the above problems, by using a supercritical fluid to produce fine particles containing a drug in a biodegradable polymer material to easily remove the organic solvent at a low temperature, at the same time drug content, drug release rate It is an object of the present invention to provide a method for producing fine particles having excellent particle size, particle thermal properties, and a method for producing a medical stent using the same.

Method for producing a sustained release drug-containing microparticles using the supercritical fluid of the present invention for achieving the above object is a) dissolving a paclitaxel drug and a biodegradable polymer in a solvent to obtain a polymer solution; ; b) dissolving the polymer solution in the supercritical fluid by introducing the polymer solution into the reaction tank and then introducing a supercritical fluid into the reactor; c) releasing the mixture inside the reactor to the outside to remove the solvent and simultaneously form the microparticles contained in the polymer material; and d) washing the fine particles with distilled water and drying the same.

In the step a), the solvent is ethyl acetate, and the high molecular material is polylactic-co-glycolide (Poly (lactide-co-glycolide)).

Step b) is characterized in that for maintaining the inside of the reactor for 80 to 200 bar, 38 ℃ conditions for 30 to 90 minutes.

Step c) is characterized in that the mixture is released by expanding the mixture to atmospheric conditions.

In addition, the method for producing a sustained release drug-containing microparticles using the supercritical fluid of the present invention for achieving the above object comprises the steps of a) dissolving aspirin drug and a biodegradable polymer in a solvent to obtain a polymer solution; ; b) dissolving the polymer solution in the supercritical fluid by introducing the polymer solution into the reaction tank and then introducing a supercritical fluid into the reactor; c) releasing the mixture inside the reactor to the outside to remove the solvent and simultaneously form the microparticles contained in the polymer material; and d) washing the fine particles with distilled water and drying the same.

And the method for producing a medical stent of the present invention for achieving the above object is characterized in that the drug-containing microparticles prepared by the above-described manufacturing method is prepared by coating the surface.

As described above, according to the present invention, nanoscale fine particles free of residual organic solvents can be prepared by applying a rapid expansion of supercritical solution (RESS) process to the preparation of drug-containing microparticles for use in medical stents. Can be.

In addition, the size and shape of the particles can be easily controlled by adjusting the temperature, pressure, nozzle size, etc. in the RESS process.

In addition, the drug-containing efficiency of the microparticles can be increased and the release rate of the drug can be slowed, so that the drug can be released into the blood cells and the surroundings gradually for a long time. Therefore, it is possible to prevent vascular restenosis by inhibiting endovascular neovascular hyperplasia and to smoothly improve blood flow.

1 is a configuration diagram schematically showing an example of a RESS apparatus applied to the present invention,
2 is a scanning electron micrograph of the prepared microparticles,
3 and 4 are graphs showing the results of FT-IR measurement of the prepared microparticles,
5 and 6 are graphs showing the glass transition temperature of the prepared fine particles,
7 and 8 are graphs showing the drug release results of the prepared microparticles.

Hereinafter, a method of preparing sustained-release drug-containing microparticles using a supercritical fluid according to a preferred embodiment of the present invention and a method of manufacturing a medical stent using the same will be described in detail.

The method for preparing sustained-release drug-containing microparticles using the supercritical fluid of the present invention comprises the steps of obtaining a polymer solution by dissolving a drug and a biodegradable polymer in a solvent, adding a polymer solution to a reactor and then adding a supercritical fluid to the reactor. Dissolving the polymer solution in a supercritical fluid by introducing the same, releasing the mixture inside the reactor to the outside to remove the solvent, and forming the microparticles in which the drug is encapsulated in the polymer material, and washing the microparticles with distilled water. And then drying.

Specifically, step by step, first, the drug and the biodegradable polymer is dissolved in a solvent to obtain a polymer solution.

In the present invention, paclitaxel (PTX) and aspirin are applied as drugs. Paclitaxel and aspirin can be used individually or in mixed form. Paclitaxel inhibits neointimal hyperplasia to prevent vascular restenosis, while aspirin dissolves the thrombus to facilitate blood flow. The drug to biodegradable polymeric material is preferably adjusted to 1: 5-15 by weight ratio.

As the polymer material, a biodegradable polymer of polyester system may be used. Polyester-based biodegradable polymer has the advantage that it is possible to easily control the decomposition rate by changing the composition and molecular weight of the polymer, to maintain the effective concentration of the drug for a long time, and rarely cause a foreign body reaction in vivo.

Polyester-based biodegradable polymer material, for example, copolymerization of polylactide (Poly L- (lactide)), polydielactide (Poly DL- (lactide)) and polyglycolide (Poly (glycolide)) Chain polylactic-co-glycolide (Poly (lactide-co-glycolide)), polyhydroxybutylate (Poly (hydroxybutylate)), poly (valerolactone), polycaprolactone (Poly ( ε-caprolactone)) or a mixture of two or more thereof.

In particular, preferred biodegradable polymeric materials are polylactic-co-glycolide. Polylactic-co-glycolide is a polymer that is harmless to the human body and has the advantage of obtaining polymer microparticles having different dissolution rates depending on the molecular weight and the mixing ratio of lactide and glycolide. The average molecular weight of the polylactic-co-glycolide is 5,000 to 200,000 Da, preferably 40,000 to 75,000 Da, and the weight ratio of lactide to glycolide can be mixed at 65:35.

In addition, a hydrophilic polymer such as polyvinyl alcohol may be used together with the biodegradable polymer.

As the solvent for dissolving the drug, distilled water, alcohols, or the like may be used depending on the type of the drug. For example, alcohols such as methanol, ethanol, t-butanol, n-butanol, n-propanol and 2-methyl-1-propanol may be used as a solvent of paclitaxel, and distilled water may be applied as a solvent of aspirin.

There is no limitation as long as it can dissolve the polymer material as a solvent for dissolving the biodegradable polymer material, but dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran Can be used. Preferred organic solvents are ethylacetate.

The two solutions in which the drug and the biodegradable polymer are dissolved in each solvent are mixed to form an emulsion polymer solution. Next, the polymer solution is prepared into fine particles using a rapid expansion of supercritical solution (RESS) process.

The supercritical liquid rapid expansion (hereinafter referred to as RESS) process dissolves the solute that is desired to be made into nanoparticles in the supercritical fluid and rapidly expands it through a fine nozzle. It is to take advantage of the phenomenon that the solute that is lost and supersaturated and dissolved within a short time is precipitated. This supersaturation state is achieved in a very short time of 10 ⁻⁵ to 10 ⁻⁶ seconds. The RESS process was proposed by Krukonis for engineering applications at the American Institute of Chemical Engineering in 1984 (Krukonis, V., "Supercritical Fluid Nucleation of Difficult to Comminute Solids", the AIChE Annual Meeting, San Francisco (1984)). The RESS process has the characteristic of leaving no harmful organic solvents in the particles produced (G. DELLA PORTA, N. FALCO, E. REVERCHON, 2009. NSAID Drugs Release from Injectable Microspheres Produced by Supercritical Fluid Emulsion Extraction. Wiley InterScience. 10.1002 / jps.21920.)

Supercritical fluids used in the RESS process are fluids that exist at temperatures and pressures above the critical point, and have thermodynamic properties (high solubility, selectivity, compressibility, Spontaneous separability due to reduced pressure) and transfer characteristics (low surface tension and viscosity, high diffusion coefficient).

Carbon dioxide may be used as the supercritical fluid in the present invention. Carbon dioxide has a relatively low critical pressure (73.8 bar) and a critical temperature (31 ° C) near room temperature. By changing the pressure or temperature within a narrow range, properties such as solubility and diffusion can be easily controlled. In addition to being inexpensive and inexpensive, it is not explosive and flammable, and can be easily recovered by decompression.

A RESS apparatus using carbon dioxide as a supercritical fluid is schematically illustrated in FIG. 1.

Referring to FIG. 1, the RESS apparatus includes a pressurizing unit, a reaction unit, an expansion tank, and a recovery tank. The pressurization section includes a carbon dioxide source 1, a low temperature water tank 3, a high pressure pump 5, and an auxiliary device (back pressure regulator, check valve, pressure gauge). The reaction section includes a storage tank 7 for preventing pulsation of pressure and a reaction tank 9 for contacting the supercritical fluid with the solute. The storage tank 7 and the reaction tank 9 are installed in a constant temperature water tank. The reactor 9 is provided with a thermometer and a manometer for measuring temperature and pressure. And the expansion tank 11 is discharged the mixture of the reaction tank (9) through a nozzle installed therein. The mixture expands under rapid depressurization upon release to form fine particles. The formed particles are collected in the recovery tank 13.

Looking at the method of producing the fine particles using the RESS apparatus described above, the prepared polymer solution is introduced into the reaction tank (9) and then supercritical carbon dioxide is introduced into the reaction tank (9). The carbon dioxide is compressed to 80 to 200 bar by the high pressure pump (5) and supplied into the reactor (9). In the reactor 9, carbon dioxide is maintained for 30 to 90 minutes in a supercritical state, that is, 80 to 200 bar and 38 ° C.

Then, the valve is opened to release the mixture in the reaction tank 9 to the expansion tank 11 through the nozzle. For example, the mixture is rapidly expanded to atmospheric conditions and released. When the mixture is rapidly expanded to atmospheric pressure through the nozzle, the supercritical fluid is supersaturated in the process of becoming gaseous and the dissolved solute is precipitated in the form of fine particles. This crystallization process occurs almost simultaneously with very high supersaturation, and the size of the formed particles is very small and has a narrow particle size distribution. In addition, during the crystallization of the particles, together with the supercritical fluid, the organic solvent is separated from the particles.

The recovered fine particles may be washed with distilled water and then dried to prepare fine particles containing a drug in a biodegradable polymer material.

The fine particles may be coated on the surface of the medical stent to prepare a medical stent. Coating can be carried out in a variety of ways. For example, it may be applied to the stent through a conventional coating process, that is, injection coating, spray coating, dip coating and the like. Drugs coated on the medical stent are slowly released into the blood vessels and tissues around the blood vessels over time.

Hereinafter, the present invention will be described through examples. However, the following examples are intended to illustrate the present invention in detail, and the scope of the present invention is not limited to the following examples.

<Production of Drug-Containing Fine Particles>

1. Substance

Biodegradable polymers Poly (DL-lactide-co-glycolide) (Mw 40,000-75,000, lactide: glycolide (65:35), USA) (hereinafter referred to as PLGA), drugs paclitaxel (USA) and aspirin ( USA) was purchased from Sigma-Aldrich. Poly (vinyl alcohol) (99 +% hydrolyzed (M.w89,000 to 98,000, USA) was purchased from Sigma-Aldrich, and ethyl acetate (OCI company. Ethanol was used as a solvent for Litaxel, and distilled water was prepared as a solvent for Aspirin.

2. First embodiment

A PLGA 1% solution in which 0.05 g of PLGA was dissolved in 4.95 g of ethyl acetate and a solution of 0.005 g of paclitaxel in 1 g of ethanol were mixed at a weight ratio of 100: 1 using a Homogenizer (Polytron system PT2100, KINEMATICA, Switzerland). And homogenized at 30,000 rpm for 5 min. In addition, 20% of a 1% polyvinyl alcohol solution in which polyvinyl alcohol was dissolved in distilled water was homogenized at 30,000 rpm for 5 min to prepare an emulsion polymer solution.

The prepared polymer solution was crystallized into fine particles using the RESS apparatus shown in FIG. In other words, after supercritical carbon dioxide is injected into the reaction tank into which the polymer solution is added, the supercritical state is maintained at a temperature of 38 ° C. for 60 minutes at a pressure of 80 bar, and then the mixture is rapidly expanded to atmospheric pressure through a nozzle having a diameter of 500 μm in an expansion tank. Microparticles were formed. The prepared microparticles were centrifuged at 20000 rpm for 10 min to remove impurities to remove impurities, and then the supernatant was lyophilized for 3 days using a freeze drying (FDT-8650). The fine particles contained therein were prepared.

3. Second Embodiment

Fine particles were prepared in the same manner as in the first embodiment, but maintained in a supercritical state at a pressure of 200 bar.

4. Third embodiment

Homogenizer (Polytron system PT2100, KINEMATICA, Switzerland) by mixing a solution of PLGA 1% (w / w) in which 0.05 g of PLGA was dissolved in 4.95 g of ethyl acetate and a solution of 0.005 g of aspirin in 1 g of ethanol at a weight ratio of 100: 1. ) Was homogenized at 30,000 rpm for 5 min. In addition, 20% of a polyvinyl alcohol 1% (w / w) solution in which polyvinyl alcohol was dissolved in distilled water was homogenized at 30,000 rpm for 5 min to prepare an emulsion polymer solution.

The prepared polymer solution prepared microparticles containing aspirin under the same conditions using the same RESS apparatus as in the first embodiment.

5. Fourth embodiment

Fine particles were prepared in the same manner as in the third embodiment, but the supercritical state was maintained at a pressure of 200 bar.

6. Comparative Example 1

The polymer solution prepared in Example 1 was prepared through the conventional evaporation drying method (evaporation drying for 20 minutes at 78 ° C. or higher) to prepare microparticles containing paclitaxel.

7. Comparative Example 2

Aspirin-containing microparticles were prepared by using the polymer solution prepared in Example 3 through a conventional evaporation drying method (evaporation drying for 20 minutes at 78 ° C. or higher).

Experimental Analysis

Experiments were conducted to examine the properties of the microparticles prepared in the examples and comparative examples.

1.Form and size of fine particles

A small amount of the prepared fine particles were collected, dissolved in distilled water, and dropped on a carbon tape to dry. The dried sample was then observed using a scanning electron microscope (SEM), MIRA 3 LMU, Tescan, Czech Republic to observe the shape of the particles. And the average size of the particles prepared by particle size analyzer (Particle size analyzer, ELS-8000, Otsuka Electronics, Japan) was analyzed.

(A) shows fine particles of the first comparative example, (b) shows fine particles of the first example, (c) shows fine particles of the second comparative example, and (d) shows fine particles of the third example.

2, the size of the microparticles prepared according to the embodiment of the present invention was confirmed that the average size is smaller than the size of the microparticles prepared through conventional evaporation drying. That is, while the fine particles of the first comparative example were about 3271.2 nm, the fine particles of the first example were about 229 nm, and the fine particles of the second comparative example were about 976.9 nm, while the fine particles of the third example were about 237.9 nm.

The experimental results show that PLGA, a biodegradable polymer material, has a swelling phenomenon due to high pressure and temperature, and after a certain period of time, it suddenly drops the pressure and is injected through a nozzle to improve the density of the polymer structure. It seems to be the cause.

2. Whether the microparticles contain drugs

In order to check the drug content, an infrared spectrometer (Nicolet 6700, Thermo scientific, USA) was used to check the chemical structure of the fine particles.

3 shows FT-IR measurement results of PLGA, paclitaxel, microparticles of the first comparative example, and microparticles of the first example. Referring to Figure 3, in the PLGA particles containing paclitaxel 3339cm ^-1 in the presence of paclitaxel via the CH in-plane deformation in the CC bond bond and 848cm ^-1 in NH / OH streching bond, 1652cm ^-1 Could know. Therefore, the first embodiment could confirm that the PLGA particles containing paclitaxel were well prepared.

4 shows the results of PLGA, aspirin, fine particles of the second comparative example, and fine particle FT-IR of the third example. Referring to Figure 4, in the PLGA particles containing aspirin is confirmed the 3300 ~ OH (carboxylic acids) combined at 2500cm ^-1 and the presence of aspirin through CO (ester / carboxylic acid) bonded at 1300 ~ 1000cm ^-1. Therefore, the third embodiment was confirmed that the PLGA particles containing aspirin was well prepared.

3. Thermal Characteristics of Particulates

Differential scanning calorimetry (DSC; DSC star system, Mettler Toledo, Switzerland) was used to investigate the thermal properties of the drug-containing microparticles, and the results are shown in FIGS. 5 and 6. In addition, Table 1 shows the starting point and the middle point of the glass transition temperature.

In FIG. 5, (a) shows the fine particles of the first comparative example, (b) shows the fine particles of the first embodiment, and (c) shows the fine particles of the second embodiment. 6, (a) shows the fine particles of the second comparative example, (b) shows the fine particles of the third embodiment, and (c) shows the fine particles of the fourth embodiment.

5 and 6, the glass transition temperature ( T g) of the microparticles of the examples was higher than in the first and second comparative examples, due to the interaction due to hydrogen bonding between the drug and the polymer chain. It can be explained. The lower the glass transition temperature, the more the free volume in the polymer increases, and thus the drug is easily released due to the easy movement of the drug, while the higher the glass transition temperature, the slower the drug is released.

Park Litaxel aspirin Comparative Example 1 First Embodiment Second Embodiment Comparative Example 2 Third Embodiment Fourth Embodiment Tg
onset 25.89 47.95 45.01 26.00 50.03 55.43 midpoint 27.16 60.24 56.11 27.43 58.03 58.25

4. Drug Release Test of Particulates

In order to evaluate the release rate of the drug from the prepared microparticles, a certain amount of sample was put in a vial and dispersed in PBS, and then the solution was placed in a shaking incubator maintained at a constant temperature of 37.0 ± 0.5 ° C and stirred at a constant speed (50 rpm). The elution of the drug over time for 4 weeks was investigated. 2 ml of samples were taken at regular time intervals after the start of elution, and the concentration thereof was measured using a spectrophotometer (UV-visible; Biomate 3S, Thermo scientific, USA). The results are shown in FIGS. 7 and 8.

In FIG. 7, (a) shows the fine particles of the first comparative example, (b) shows the fine particles of the first embodiment, and (c) shows the fine particles of the second embodiment. In FIG. 8, (a) shows the fine particles of the second comparative example, (b) shows the fine particles of the third embodiment, and (c) shows the fine particles of the fourth embodiment.

Referring to FIG. 7, two days after the start of the release experiment, the release amount of paclitaxel was rapidly increased and a steady rise curve thereafter was shown. In addition, the microparticles of Examples 1 and 2 showed a more slow release of the drug than the microparticles of the first comparative example. This result is considered to be a result of the more compact structure of the polymer PLGA in the case of the first and second embodiments to increase the sustained release of the drug.

On the other hand, the aspirin shown in Figure 8 was confirmed that the release of the rapid increase in the day after the release experiment, after 9 days of the release experiment there was almost no change in release. This result is different from the release behavior of paclitaxel in FIG. 7, which is thought to be due to the faster release rate of the drug at the early stage because of a better interaction due to hydrogen bonds between the polymer chains than paclitaxel. .

In addition, both the paclitaxel and the aspirin were shown to have a slower release rate in the fine particles produced by the higher pressure, which resulted in a greater swelling phenomenon and a denser structure of the polymer.

5. Drug content of microparticles

To determine the encapsulation efficiency of the microparticles, the drug content efficiency was calculated from the theoretical drug loading and the actual drug loading values.

The theoretical drug content and the actual drug content were calculated as follows.

Theoretical drug content = drug (tot.) / [Drug (tot.) + Polymer]

Actual drug content = drug (enc.) / [Drug (tot.) + Polymer]

And drug content is calculated as follows and the results are shown in Table 2 below.

Drug content efficiency (%) = (actual drug content / theoretical drug content) × 100

Park Litaxel aspirin Comparative Example 1 First Embodiment Second Embodiment Comparative Example 2 Third Embodiment Fourth Embodiment Theoretical drug loading (%) 9.34 8.55 9.26 7.85 8.4 8.47 Actual drug loading (%) 6.8 7.9 8.1 5.6 7.4 8.2 Encapsulation Efficiency (%) 72.8 92.4 87.5 71.3 88.1 96.8

Referring to the results of Table 2, in the case of the content efficiency of paclitaxel, the fine particles of the first and second examples were increased by about 12 to 20% compared to the fine particles of the first comparative example, and the third and fourth implementations of the aspirin The fine particles of Example were shown to be increased by about 17 to 25% compared to the fine particles of the first comparative example. As a result, the release rate of the drug of the microparticles prepared according to the present invention was slowed, and the drug content and the drug content efficiency were increased.

Through the above experimental results, it was confirmed that the present invention can produce nano-level fine particles free of residual organic solvent by applying the RESS process to the preparation of drug-containing fine particles for use in medical stents. At the same time, the drug-containing efficiency of the microparticles can be increased and the release rate of the drug can be slowed, so that the drug can be released into the blood cells and the surroundings gradually over a long period of time. Therefore, it is possible to prevent vascular restenosis by inhibiting endovascular neovascular hyperplasia and to smoothly improve blood flow.

In the above, the present invention has been described with reference to one embodiment, which is merely exemplary, and it will be understood by those skilled in the art that various modifications and equivalent embodiments are possible.

Accordingly, the true scope of protection of the present invention should be determined only by the appended claims.

1: CO2 source 3: Constant temperature water tank
5: high pressure pump 7: storage tank
9: reactor 11: expansion tank
13: Recovery tank

Claims (6)

a) dissolving a paclitaxel drug and a biodegradable polymer in a solvent to obtain a polymer solution;
b) injecting the polymer solution into the reaction tank and adding a supercritical fluid to dissolve the polymer solution in the supercritical fluid;
c) releasing the mixture inside the reactor to the outside to remove the solvent and simultaneously form the microparticles contained in the polymer material;
and d) washing the microparticles with distilled water and drying the same. The method for preparing sustained-release drug-containing microparticles using a supercritical fluid, comprising: d) washing the microparticles with distilled water. The method of claim 1, wherein in the step a), the solvent is ethyl acetate, and the polymer material is polylactic-co-glycolide (Poly (lactide-co-glycolide)). Method for producing sustained release drug-containing microparticles using a supercritical fluid. According to claim 1, wherein the step b) is a method for producing a sustained-release drug-containing microparticles using supercritical fluid, characterized in that for 30 to 90 minutes at 80 to 200 bar, 38 ℃ conditions inside the reactor. According to claim 1, wherein the step c) is a method for producing a sustained-release drug-containing microparticles using a supercritical fluid, characterized in that the mixture is released by expanding the mixture to atmospheric pressure conditions. a) dissolving an aspirin drug and a biodegradable polymer in a solvent to obtain a polymer solution;
b) dissolving the polymer solution in the supercritical fluid by introducing the polymer solution into the reaction tank and then introducing a supercritical fluid into the reactor;
c) releasing the reaction mixture to the outside to remove the solvent and simultaneously forming the microparticles contained in the polymer material;
d) washing the microparticles with distilled water and drying the same; a sustained-release drug-containing microparticles using supercritical fluid, comprising: A method for producing a medical stent, characterized in that the drug-containing microparticles produced by the method of any one of claims 1 to 5 coated on the surface of the drug.

Images