KR100827784B1 - Poly(caprolactone-co-methylmethacrylate), method for preparing the same using super critical fluid, and method for preparing therapeutic agent for skin diseases such as acne, atopy and athlete's foot comprising the same - Google Patents

Abstract

A novel poly(caprolactone-methyl methacrylate) copolymer, a method for preparing the copolymer, and a method for preparing an agent for treating the skin disease such as acne, atopy, athlete's foot, etc. by using the copolymer are provided to control the drug delivery velocity and to improve skin disease treatment efficiency by increasing effective crosssectional area. A poly(caprolactone-methyl methacrylate) copolymer comprises the repeating unit represented by the formula and has a number average molecular weight of 5,000-50,000, wherein m and n are 10-1,000, respectively. The copolymer is prepared by injecting caprolactone and methyl methacrylate into a reactor in a ratio of 1:1 TO 1:1.5 by weight; injecting a 2,2-azobisisobutyronitrile initiator in a ratio of 0.1-1.0 by weight to the total amount of the monomers; and polymerizing them at a temperature of 283.15-353.15 K and at a pressure of 50-300 atm for 1-168 hours.

Description

Poly-caprolactone-methyl methacrylate copolymer, preparation method thereof using supercritical fluid and preparation method for treating acne, atopy, and athlete's foot skin disease containing same {POLY (CAPROLACTONE-CO-METHYLMETHACRYLATE), METHOD FOR PREPARING THE SAME USING SUPER CRITICAL FLUID, AND METHOD FOR PREPARING THERAPEUTIC AGENT FOR SKIN DISEASES SUCH AS ACNE, ATOPY AND ATHLETE'S FOOT COMPRISING THE SAME}

1 is a scanning electron micrograph (Scanning Electron Microscopy) of the poly-caprolactone-methyl methacrylate copolymer according to the present invention.

The present invention relates to a poly-caprolactone-methyl methacrylate copolymer, a method for preparing the same using a supercritical fluid, and a method for preparing a skin disease treatment agent containing the same, in detail, a novel poly-caprolactone-methylmethacryl The present invention relates to a method for preparing a skin disease treatment agent such as acne, atopy, athlete's foot, etc., using the above-mentioned copolymer, a supercritical fluid, and a poly-caprolactone-methyl methacrylate copolymer and salicylic acid as an active ingredient.

Salicylic acid is widely known to be effective for skin diseases such as athlete's foot, atopic dermatitis, acne, and attempts to use it as a skin disease treatment, but has not been used as a skin disease treatment yet due to side effects due to the remaining organic solvent. In the present invention, in order to solve the problem of the residual organic solvent, it is intended to use a supercritical fluid as an alternative solvent.

Such supercritical fluids have been actively studied for obtaining recrystallized particles or microparticles by using them as solvents or anti-solvents. Supercritical fluids are incompressible fluids at temperatures and pressures above the critical point and exhibit unique characteristics not found in conventional organic solvents. In particular, supercritical fluids have molecular associaton due to density fluctuations near the critical point, so they have a high density close to liquid, low viscosity close to gas and high diffusion coefficient, and very low surface tension. Has excellent physical properties at the same time. Supercritical fluids can continuously change their density from lean to near ideal gas to high density near liquid density, so that the fluid's equilibrium properties (solubility, entrainer effect) and transfer properties (viscosity, diffusion coefficient, and thermal conductivity). Fig. 2), molecular clustering (clustering) state can be adjusted.

Recently, the technique using the supercritical fluid has been widely used in the polymer industry in various fields, including the use as a polymerization solvent. In particular, carbon dioxide has a relatively low critical point, nontoxicity, nonflammability, and is obtained as a by-product in various chemical reactions, and thus is inexpensive. In addition, the reduced pressure can be changed from a supercritical state to a gaseous state, which has the advantage of easily separating the polymer and carbon dioxide. As a result, energy can be saved in terms of separation process, and in terms of chemistry, carbon dioxide can no longer be oxidized and is a very stable material, and does not include hydrogen in the structure and does not participate in a chain transfer reaction. Therefore, it has the advantage that the polymerization reaction according to various synthesis methods and synthesis routes. Taking advantage of these advantages, the invention of synthesizing biodegradable polymers using a supercritical fluid has been in progress.

In addition, in order to improve the skin penetration of the skin disease treatment agent particles of the therapeutic agent should have a particle size of 50-100 nanometers. This is because the penetration of the skin may be less than 100 nm in particle size, and the drug having a particle size of 50 nm or less may penetrate into the dermal layer of the skin, thereby increasing toxicity. However, since the size of the drug produced by the conventional supercritical method has a size of 1-10 microns, there is a problem that the skin penetration is poor.

Biodegradable polymers are used in the treatment of skin diseases to control the rate of drug delivery. Such biodegradable polymers must be formed into spherical particles to maximize the surface area so that the amount of skin adsorption can be turned on. Currently, polycaprolactone is widely used as a biodegradable polymer. However, polycaprolactone is formed by free radical polymerization of 2-methylene-1,3-dioxaphene (MDOP), which is a low glass transition temperature, 213.15 K (Glass Transition Temperature). Because of the difficulty in forming the spherical particles at room temperature, the surface area is small, there was a problem that the amount of skin adsorption is not much.

The present invention provides a spherical novel poly-caprolactone-methyl methacrylate copolymer as a biodegradable polymer used in the treatment of skin diseases to solve the above problems and a method for producing the same. It is an object of the present invention to provide a method for preparing a spherical skin disease therapeutic agent having a size of 50 to 100 nm using a supercritical fluid with a caprolactone-methyl methacrylate copolymer together with salicylic acid.

The poly-caprolactone-methyl methacrylate copolymer according to the present invention has a structure in which a caprolactone and a methyl methacrylate monomer are in the form of a copolymer.

이고, 메틸메타아클레이트 단량 체는

이며, 본 발명에 따른 폴리-카프로락톤-메틸메타아크릴레이트 공중합체는

이다.Caprolactone monomers

And methyl methacrylate monomer is

The poly-caprolactone-methyl methacrylate copolymer according to the present invention is

to be.

M represents the number of units of caprolactone, and n is the number of methylmethacrylate units. Typically m and n range from 10 to 1000, respectively.

The spherical poly-caprolactone-methyl methacrylate copolymer according to the present invention is injected into the reactor by weight ratio of monomers caprolactone and methyl methacrylate 1: 1 to 1: 1.5 and 0.1 to 1.0 with respect to the entire monomer 2,2-azobisisobutyronitrile, also known as ivyene (AIBN), which is an initiator by weight, was injected into the reactor, and then 50 to 300 atm and a temperature of 283.15 K to 353.15 K. It is prepared by polymerizing for 168 hours.

Hereinafter, the method for preparing the poly-caprolactone-methyl methacrylate copolymer will be described in detail.

First, the monomer caprolactone and methyl methacrylate are injected into the reactor at a weight ratio of 1: 1 to 1: 1.5, and the initiator 2,2-azobisisobutyronitrile is added at 0.1 to 1.0 weight ratio based on the whole monomer. Inject into.

When the weight ratio of the monomers caprolactone and methyl methacrylate is less than 1: 1, the proportion of caprolactone is relatively high, and thus, spherical biodegradable polymers are not produced due to the low glass transition temperature. Due to the high proportion of methacrylates, the affinity with the supercritical fluid is reduced, resulting in agglomeration, and polymerization is not properly performed. In addition, when the content of the initiator 2,2-azobisisobutyronitrile is less than 0.1 weight ratio based on the entire monomer, polymerization does not start, and when the initiator content exceeds 1.0 weight ratio, the reaction rate is too fast and the molecular weight is large. Copolymer cannot be obtained.

Next, in order to make the reaction conditions in which the polymerization reaction can occur in the reactor, the oxygen remaining in the reactor is removed by using about 2 atm of nitrogen, and then the nitrogen is removed by using about 2 atm of carbon dioxide. Observe the liquid level using the see-through window and inject carbon dioxide into the gas booster pump until it reaches 50 atm. At room temperature, increase the temperature of the reactor using a constant temperature water bath to raise the temperature to 283.15 K. To 353.15 K and additionally add carbon dioxide into the reactor to operate the reactor at a condition of 50 to 300 atmospheres, thereby causing a polymerization reaction of the monomer caprolactone and methyl methacrylate to poly-caprolactone-methylmethacryl Prepare a latex copolymer. The polymerization time was carried out from 1 hour up to 168 hours based on the time at which each of the predetermined temperatures were reached.

If the pressure is less than 50 atm, the mixture does not exist as a single phase, phase separation occurs, and the reaction cannot proceed uniformly. If the temperature is less than 283.15 K, the state of the mixture does not become a single phase below the critical point, so that the uniform reaction cannot proceed, and if the temperature is higher than 353.15 K, the biodegradable polymer may be decomposed. The polymerization time is not properly polymerized at less than 1 hour to obtain a high molecular weight copolymer. If the polymerization time is 168 hours or more, the viscosity is increased due to the high molecular weight, so that the mixing is not performed properly and a uniform polymerization reaction cannot occur. .

After all polymerization was completed for a predetermined time, the reactor was cooled rapidly using ice water. When the temperature of the reactor falls below 283.15 K, gas / liquid phase separation occurs and the solubility of the polymer is very low in the gas phase, so that carbon dioxide can be slowly separated from the gas phase. Once all of the carbon dioxide has been sold, a solid polymer product in the foamed form is obtained, which is washed in methanol and dried in vacuo to obtain a spherical biodegradable polymer poly-caprolactone-methylmethacrylate copolymer which is a very fine white powder. It can be obtained (see Fig. 1).

Poly-caprolactone-methyl methacrylate copolymer according to the present invention is a biodegradable polymer, and the glass transition temperature is measured by differential scanning calorimeter (Source: B. Wunderich, Thermal Analysis of Polymeric Materials, Springer, 2004). The measured result is 303.15 K to 313.15 K, which is higher than the transition temperature of polycaprolactone. And the number average molecular weight was 5,000 to 50,000 as measured by gel chromatography (Gel Permeation Chromatography, Source: J.F. Johnson; R. S. Porter, Analytical gel permeation chromatography, Interscience Publishers, 1968).

Poly-caprolactone-methyl methacrylate copolymer according to the present invention can be used as a raw material for treating athlete's foot, atopy, acne skin disease with salicylic acid, especially in order to maximize the therapeutic effect, the particle size is 50 to 100nm The shape must be spherical. The method for producing such a skin disease treatment

A mixed solution preparation step of preparing a mixed solution by mixing poly-caprolactone-methylmethacrylate in an amount of 0.0013 to 0.0015 weight ratio with respect to the total mixed solution and salicylic acid in an amount of 0.0015 to 0.0018 weight ratio with respect to the total mixed solution in ethanol which is an organic solvent;

While spraying the mixed solution in the mixed solution preparation step at a temperature of 313.0 to 313.4K, pressure 149.5 to 151.3 bar at a rate of 0.47 to 0.50 ml / min, at the same time 2.5 to 2.7 kg / hr carbon dioxide in the reactor Spherical structure generation step of producing a spherical structure particles by injection into a supercritical state;

An organic solvent removing step of removing ethanol which is an organic solvent by introducing new carbon dioxide into the reactor while maintaining the pressure of the reactor outlet at 150 bar;

And a recovery step of recovering spherical structure particles from which the organic solvent has been removed in the organic solvent removal step.

This will be described in detail below.

1) Mixed Solution Manufacturing Step

First, a mixed solution is prepared by dissolving salicylic acid and a poly-caprolactone-methyl methacrylate copolymer which is a biodegradable polymer in an organic solvent.

Salicylic acid is used in an amount of 0.0015 to 0.0018 parts by weight based on the total mixed solution. If the salicylic acid content is less than 0.0015% by weight, the nucleation rate is too fast, the particle size is larger than the micron level, and if the salicylic acid content is more than 0.0018% by weight, the nuclear growth rate is too fast to obtain a non-spherical plate-shaped particles.

Biodegradable polymer was used to control the delivery rate of the drug, it is preferable to use the spherical biodegradable polymer poly-caprolactone-methyl methacrylate copolymer prepared in the present invention. In the case of the poly-caprolactone-methyl methacrylate copolymer, it contains a hydrophilic part caprolactone and a hydrophilic part methyl methacrylate at the same time. The nucleation and growth of drugs can be prevented from agglomeration of particles, resulting in smaller nanoparticle size drug structures.

The content is used in 0.0013 to 0.0015 weight ratio based on the total mixed solution. In the case of biodegradable polymers, the rate of nucleation is too fast when the fraction is less than 0.0013 parts by weight, and the particle size becomes larger than the micron level. When the fraction is more than 0.0015 parts by weight, the nuclear growth rate is too fast to obtain non-spherical plate-shaped particles. Because. Another reason for using poly-caprolactone-methylmethacrylate copolymers as biodegradable polymers is that spherical particles do not form with other biodegradable polymers such as poly-caprolactone.

Although methanol, ethanol, etc. are used as an organic solvent, in this invention, ethanol which is less toxic to a human body is used.

2) Spherical Structure Formation Step

Supercritical fluids include supercritical carbon dioxide, supercritical dinitrogen monoxide, supercritical methane trifluoride, supercritical propane, supercritical ethylene or supercritical xenon, and the like.

The carbon dioxide is injected into the reaction port so that the reaction port made of stainless steel is at a temperature of 313.0K to 313.4K and a pressure of 149.5 to 151.3 bar, and pressurized and warmed. In this case, the critical temperature of the carbon dioxide is 304.2K and the critical pressure of 73.8 bar or more, and the carbon dioxide in the reaction port is maintained in the supercritical state. Wait until the reaction equilibrium is achieved in a supercritical state, and when equilibrium is reached, carbon dioxide is injected at a rate of 2.5 to 2.7 kg / hr, and 0.47 to 0.50 ml / min of the mixed solution in the mixed solution preparation step. Spray at a rate of. In a condition lower than the temperature and pressure of the above operating conditions, it is less than a critical temperature and a uniform phase is not obtained, and there is a possibility that the active ingredient may be denatured in a condition higher than the temperature and the pressure of the above operating conditions. In addition, when the carbon dioxide flow rate and the solution flow rate are larger than the above-mentioned areas, unwanted particle sizes of 100 nm or more are obtained. If the carbon dioxide flow rate and the solution flow rate are smaller than the above-mentioned areas, plate-shaped particles are obtained, and thus the desired spherical particles are not obtained. Do not.

In order to know the flow rate and exact amount of carbon dioxide injected into the reaction port, a syringe pump is used. It is preferable to use a circulating thermostat or a thermostat to maintain a constant pressure by a back pressure regulator, and to change the pressure due to the injected carbon dioxide.

Meanwhile, the mixed solution prepared in the mixed solution preparation step 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 supercritical fluid may be further injected to prevent the mixture from being saturated at the same time as the injection of the mixed solution.

3) Organic Solvent Removal Step

After the spraying of the mixed solution, a particle washing process for introducing carbon dioxide, a supercritical fluid, is required to remove the organic solvent in the produced particles. In the process, the supercritical fluid is injected into the reactor at a constant rate, but the reaction port is discharged through the outlet at the same rate as the injection rate to induce the pressure to 150 bar, the particle size can be 100nm or less. At this time, the back pressure regulator is connected to the outlet to maintain a 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. If 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 of the 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 stage

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.

Example

(1) Synthesis of Poly-caprolactone-methylmethacrylate Copolymer

4 g of a mixture of 2 g of monomers caprolactone and methyl methacrylate and 2 g of initiator 2,2-azobisisobutyronitrile (AIBN) are injected into a 30 mL high pressure reactor. Remove oxygen remaining inside by using 2 atm of nitrogen and then remove nitrogen using 2 atm of carbon dioxide. Observe the liquid level using the see-through window and inject carbon dioxide into the gas booster pump until it reaches 50 atm. When the temperature rises to a predetermined polymerization temperature using a constant temperature bath, the pressure also increases. Here, the temperature was adjusted by adding carbon dioxide at 333.15 K so that the pressure was 255 atm. At this time, the mass of carbon dioxide injected is 27.5 g. The polymerization time was carried out up to 70 hours on the basis of the time when the respective temperature reached. After all polymerization was completed for a predetermined time, the reactor was cooled rapidly using ice water. Carbon dioxide was slowly separated from the gas phase on the assumption that gas / liquid phase separation would occur when the temperature of the reactor was lowered below 283.15 K and that the polymer had very low solubility in the gas phase. At this time, it was observed whether the precipitate was formed in the methanol contained in the trep to confirm whether the polymer was discharged together. Once all of the carbon dioxide has been sold, a solid polymer product in a foamed form is obtained, which is washed in methanol and dried in vacuo to give a spherical biodegradable polymer poly-caprolactone-methylmethacrylate copolymer in the form of a very fine white powder. .

(2) Preparation of skin disease treatment

First, the pre-treated salicylic acid shows a particle size of 50-100 microns, and the embodiment measures the particle size of the salicylic acid structure particles produced under the following conditions, and the poly-caprolactone-methyl methacrylate copolymer as a biodegradable polymer. The spherical microparticle size of 50 to 300 nm was obtained depending on the presence of and reaction conditions in the reaction zone.

As shown in Table 1, the present embodiment relates to the operating conditions of the reactor in the step of forming a spherical structure, the temperature and pressure of the reaction sphere should be more than the critical temperature of 304.2 K, critical pressure of 72.8 atm. Operational variables in the reactor are the reactor temperature and pressure, the flow rate of carbon dioxide which is a supercritical fluid, the mixed solution flow rate prepared in the step of preparing a mixed solution, and Example 1 shows a 0.0016 weight ratio of salicylic acid, which is a drug without a biodegradable polymer. Example 2-8 is a case in which the salicylic acid as a drug is contained in a 0.0016 weight ratio, and the biodegradable polymer poly-caprolactone-methyl methacrylate copolymer contains a 0.0014 weight ratio. It can be seen that the particle size decreases to about 100 nm when the poly-caprolactone-methylmethacrylate copolymer is included as a biodegradable polymer. In Examples 1 and 3, the reactor temperature was adjusted to determine the change of 313 and 323 K. When the temperature was increased, the particle size tended to increase. In Examples 1, 4 and 5, the optimum particle size was obtained at 150 bar when the reactor pressure was adjusted to 130-170 bar. In Examples 1, 6 and 7, when the carbon dioxide flow rate was changed from 2.5 to 3.0 kg / hr, the optimum particle size was obtained at 2.5 to 2.7 kg / hr. In Examples 1 and 8, the mixed solution flow rate was 0.5 to 1.0. The ml / min was changed, and it was found that the particle size was increased by increasing the flow rate of the mixed solution.

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

 Example Reactor temperature (K) Reactor pressure (bar) CO2 flow rate (kg / hr) Mixed solution flow rate (ml / min) Particle Size (nm)  Example 1  313   150   2.5   0.5   589  Example 2  313   150   2.5   0.5    86  Example 3  323   150   2.5   0.5   135  Example 4  313   130   2.5   0.5   120  Example 5  313   170   2.5   0.5   103  Example 6  313   150   2.7   0.5    73  Example 7  313   150   3.0   0.5   149  Example 8  313   150   2.5   1.0   200

Working conditions for obtaining the size of the nanoparticle region of 50 to 100 nm, which is the desired particle size in the present invention, are the case of Example 2 and Example 6. In other words, the biodegradable polymer, poly-caprolactone-methyl methacrylate copolymer, was able to reduce the particle size significantly, the temperature was 313 K, the pressure was 150 bar, and the carbon dioxide flow rate was 2.5-2.7 kg / hr. The optimum solution flow rate is 0.5 ml / min.

As a result of experiments at more detailed intervals, the drug content and biodegradable content to obtain supercritical nanostructures of 50 to 100 nm was 0.0016 weight ratio of the salicylic acid drug, and 0.0014 to the poly-caprolactone-methylmethacrylate copolymer of biodegradable polymer. It contains the weight ratio, and the working condition is the desired area only under the conditions of temperature of 313.0-313.4 K, pressure of 149.5-151.3 bar, carbon dioxide flow rate of 2.5-2.7 kg / hr, solution flow rate of 0.47-0.50 ml / min. Particle size was obtained. Any deviation from the temperature and pressure, carbon dioxide flow rate and solution flow rate of the above operating conditions will result in unwanted particle sizes above 100 nm.

Poly-caprolactone-methyl methacrylate copolymer of spherical biodegradable polymer was prepared according to the present invention, and salicylic acid used for acne treatment effect was contained together with poly-caprolactone-methyl methacrylate copolymer of biodegradable polymer. The drug delivery rate can be controlled, and by controlling the process conditions, the supercritical nanostructures (Examples 2 and 6) can obtain a nanoparticle region of 50 to 100 nm, thereby improving skin efficacy due to an increase in effective cross-sectional area. .

Claims (3)

A poly-caprolactone-methyl methacrylate copolymer having a number average molecular weight of 5000 to 50000 having a main chain of the following repeating units.

Where m and n are each 10-1000. Inject the monomer caprolactone and methyl methacrylate into the reactor in a weight ratio of 1: 1 to 1: 1.5 and inject the reactor 2,2-azobisisobutyronitrile into the reactor in a weight ratio of 0.1 to 1.0 based on the entire monomer. And a poly-caprolactone-methyl methacrylate copolymer having a number average molecular weight of 5,000 to 50,000 under a 50 to 300 atmosphere and 283.15 K to 353.15 K conditions. A mixed solution was prepared by mixing the poly-caprolactone-methylmethacrylate copolymer of claim 1 in an amount of 0.0013 to 0.0015 weight ratio with respect to the total mixed solution and salicylic acid in an amount of 0.0015 to 0.0018 weight ratio with respect to the total mixed solution in ethanol which is an organic solvent. Mixed solution preparation step; While spraying the mixed solution in the mixed solution preparation step at a temperature of 313.0 to 313.4K and a pressure of 149.5 to 151.3 bar at a rate of 0.47 to 0.50 ml / min, while simultaneously injecting carbon dioxide into the reactor at 2.5 to 2.7 kg / hr Spherical structure generation step of making a spherical structure particles by making a supercritical state; An organic solvent removing step of removing ethanol which is an organic solvent by introducing new carbon dioxide into the reactor while maintaining the pressure of the reactor outlet at 150 bar; A method for preparing acne, atopy, and athlete's foot disease treatment containing poly-caprolactone-methyl methacrylate copolymer comprising a recovery step of recovering spherical structure particles from which the organic solvent has been removed in the organic solvent removal step. .

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