KR102377975B1 - Biodegradable polymer microparticles containing steroid drugs and a method for manufacturing the same - Google Patents

Abstract

The present invention relates to biodegradable polymer microparticles containing a steroid-based drug and a method for preparing the same, wherein an anti-inflammatory steroid-based drug and a biodegradable polyester-based polymer are dissolved in an appropriate organic solvent and sprayed in a low-temperature hydrocarbon solution. After making microparticles, biodegradable polymer microparticles containing steroid-based drugs were prepared through a manufacturing method of dissolving the organic solvent contained in microparticles by putting them in a low-temperature aqueous salt solution, and containing the prepared steroid-based drugs. By using the biodegradable polymer microparticles containing the steroid drug of the present invention, it is confirmed that the biodegradable polymer microparticles have excellent biocompatibility, biodegradability, porosity and mechanical strength, and the steroid drug is slowly released for a long time It is expected to be able to develop a composition for delivery of steroids that can minimize side effects while exhibiting the maximum anti-inflammatory activity caused by steroids.

Description

Biodegradable polymer microparticles containing steroid drugs and a method for manufacturing the same

The present invention relates to biodegradable polymer microparticles containing a steroid drug and a method for preparing the same.

Until recently, drug research has focused on developing new drugs to increase the therapeutic effect of new diseases or diseases that are difficult to cure with existing drugs. However, due to the difficulties of new drug development, the risk of high investment cost, and the difference between actual laboratory research results and clinical application, only some large biotechnology companies have conducted related research and development abroad. Development has been limited. In addition, the fact that the drug has a great influence on the disease treatment effect according to the way the drug is delivered to the actual disease site has been proven through various research results, highlighting the need for research and development on drug delivery methods as well as the development of new drugs. .

Drug delivery system technology is a generic term for a series of technologies that control the delivery and release of pharmacologically active substances to cells, tissues, organs and organs so that they can exert optimal effects using various physicochemical techniques. do. The most basic form of drug delivery system technology started by controlling the delivery rate of drugs by controlling the rate of dissolution in body fluids like oral capsules and tablets. This is the most commercialized technology at present, and a method of mixing a drug with a polymer material or coating the surface is often used, and the method uses a method in which the drug flows out and is absorbed into the body while the polymer material is melted in water. In addition, a matrix-type delivery device made by mixing a drug with a biocompatible polymer, a biodegradable delivery device that controls the rate of drug delivery according to the rate of biodegradation using a biodegradable polymer, or implanted A method using a hydrogel material for controlling drug delivery by using a method in which the degree of swelling varies according to the temperature, pH, electrical strength, etc. of the surrounding environment has been developed.

Drug delivery particles are usually produced in a size of several hundred micrometers (㎛) to several tens of nanometers (nm) in size. Research is being conducted in the direction of improving the uniformity of particle size or producing particles with various shapes beyond simple spherical particles (Ryu Won-hyeong, 2012).

Steroids are drugs with strong anti-inflammatory and immunomodulatory effects, and are used in various diseases including rheumatoid arthritis. Long-term and high-dose use of steroids showed side effects and resistance to drugs, and while the effect disappeared as the steroid dose was reduced, it was thought that steroids should be used temporarily for symptom relief. Most side effects tend to be proportional to the dose and duration of steroid use. Therefore, it is necessary to develop a technology that can control inflammation by steroids but minimize side effects.

Therefore, in the process of developing a new method for producing microparticles containing therapeutic drugs, the present inventors dissolved an anti-inflammatory steroid-based drug and a biodegradable polyester-based polymer in an organic solvent and sprayed it into a low-temperature hydrocarbon solution to freeze organic After the solvent microparticles were prepared, biodegradable polymer microparticles having excellent biocompatibility, biodegradability, porosity and mechanical strength were prepared by dissolving the organic solvent in a low-temperature salt aqueous solution. In addition, the present invention could be completed by confirming that the steroid-based drug contained therein was slowly released for a long period of time from the prepared biodegradable polymer microparticles.

In Korea Patent No. 1105292 registered by the present inventors, a biodegradable polyester-based polymer is dissolved in DMSO and sprayed in a low-temperature hydrocarbon solution to make frozen DMSO microparticles, and then put into a low-temperature salt solution to dissolve DMSO. Biodegradable polymer microparticles for tissue regeneration are described, which is similar to the configuration of the present invention, but biodegradable polymer microparticles containing the steroid-based drug of the present invention are used as a cell carrier by culturing cells on biodegradable polymer microparticles. The effects of the particles and their sustained release formulation are not described. In addition, US Patent No. 4530840 describes microparticles containing an anti-inflammatory agent and a method for producing the same, which is similar to that of the present invention, but is different from the method for producing biodegradable polymer microparticles of the present invention.

Korean Patent No. 1105292, biodegradable polymer microparticles and manufacturing method thereof, registered on 01.05.2012. Registered U.S. Patent No. 4530840, Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents, July 23, 1985.

Wonhyung Ryu, Nanostructure-based drug delivery technology, Journal of Machinery, 52(6), 43-47, 2012. Velasco, M.A., et al., Design, Materials, and Mechanobiology of Biodegradable Scaffolds for Bone Tissue Engineering, BioMed. Research International, 2015, 729076, 2015.

It is an object of the present invention to provide biodegradable polymer microparticles containing a steroid-based drug and a method for preparing the same.

The present invention comprises the steps of: (a) dissolving a steroid-based drug and a biodegradable polyester-based polymer mixture in an organic solvent to prepare a solution containing a steroid-based drug and a biodegradable polyester-based polymer; (b) preparing microparticles by spraying a solution containing the steroid-based drug and a biodegradable polyester-based polymer into a C5-10 hydrocarbon solution having a temperature below the melting point of an organic solvent; (c) removing the organic solvent by dissolving the organic solvent by adding the fine particles to the aqueous salt solution; and (d) removing the salt from the microparticles from which the organic solvent has been removed; relates to a method for producing biodegradable polymer microparticles comprising a steroid-based drug.

The dissolution in step (a) may be to dissolve the steroid-based drug and the biodegradable polyester-based polymer mixture in an organic solvent so as to be 1 to 25% (w/v) based on the solution.

The steroid-based drug and biodegradable polyester-based polymer mixture of step (a) may be a mixture of steroid-based drug and biodegradable polyester-based polymer in a weight ratio of 1:99 to 3:7.

The steroid-based drugs include deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, diflupred. Nate (difluprednate), loteprednol etabonate (loteprednol etabonate), rimexolone (rimexolone), mazipredone (mazipredone), medrysone (medrysone), methylprednisolone (methylprednisolone), meprednisone (meprednisone) Son furoate, beclomethasone, betamethasone, budenonide, algestone, alclometasone, amcinonide, enox Solon, corticosterone, cortisone, cortivazol, chloroprednisone, clobetasol, clobetasone, clocortolone, Cloprednol, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone methasone, triamcinolone hexacetonide pregnenolone acetate, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone Prednisolone sodium phosphate, prednisone, prednival, prednylidene, fluazacort, flucloronide, flumethasone, fluni Flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluferolone acetate ( fluperolone acetate), fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide (halcinonide), halobetasone propionate, halometasone, halopredone acetate, hydrocortamate, and hydrocortisone selected from the group consisting of There may be more than one type.

The biodegradable polyester-based polymer is polylactic acid (PLA), polyglycolic acid (PGA), poly(D,L-lactic-co-glycolic acid) (poly(D,L-lactic) -co-glycolic acid), PLGA), poly-carprolactone (PCL), poly(valerolacton) (poly(valerolacton)), poly(hydroxy butylate)) and poly( It may be at least one selected from the group consisting of hydroxy valerate) (poly(hydroxy valerate)).

The biodegradable polyester-based polymer may have a weight average molecular weight of 10,000 to 250,000.

The organic solvent is DMSO (dimethyl sulfoxide), PCL (poly caprolactone), chloroform (chloroform), acetone (acetone), dichloromethane (dichloromethane), benzene (benzene), toluene (toluene), isopropyl ether (isopropyl ether) and It may be at least one selected from the group consisting of chlorobenzene.

C5-10 hydrocarbons of step (b) are pentane, hexane, heptane, octane, nonane, decane, and petroleum ether ) may be at least one selected from the group consisting of.

The aqueous salt solution of step (c) may be 5-30% (w/v) of NaCl or CaCl ₂ aqueous solution.

The biodegradable polymer microparticles containing the steroid-based drug may have a diameter of 10 to 1000 μm.

The present invention also relates to biodegradable polymer microparticles containing a steroid-based drug prepared by the above preparation method.

The present invention also relates to an anti-inflammatory composition containing the biodegradable polymer microparticles containing the steroid-based drug.

Hereinafter, the present invention will be described in detail.

The present invention comprises the steps of: (a) dissolving a steroid-based drug and a biodegradable polyester-based polymer mixture in an organic solvent to prepare a solution containing a steroid-based drug and a biodegradable polyester-based polymer; (b) preparing microparticles by spraying a solution containing the steroid-based drug and a biodegradable polyester-based polymer into a C5-10 hydrocarbon solution having a temperature below the melting point of an organic solvent; (c) removing the organic solvent by dissolving the organic solvent by adding the fine particles to the aqueous salt solution; and (d) removing the salt from the microparticles from which the organic solvent has been removed; relates to a method for producing biodegradable polymer microparticles comprising a steroid-based drug.

In general, since organic solvents are well mixed with each other, fine particles cannot be prepared by spraying the organic solvent into different organic solvents (that is, expressed as organic solvent A and organic solvent B). This is because the organic solvent A in which the polymer is dissolved is sprayed and the two organic solvents are mixed at the moment they come into contact with the organic solvent B, so the organic solvent A cannot be frozen, so fine particles cannot be produced.

However, although the organic solvent and hydrocarbon of the present invention correspond to commonly used organic solvents, they do not mix with each other due to a large difference in polarity. In addition, it can be used because the organic solvent dissolves steroid-based drugs and biodegradable polyester-based polymer mixtures well, and since the organic solvent is very soluble in water, if the frozen particles are put into water after freezing, the organic solvent is easily dissolved, whereas , Since the biodegradable polyester-based polymer dissolved in the organic solvent is not soluble in water, microparticles can be prepared in the form frozen in the organic solvent.

The organic solvent is DMSO (dimethyl sulfoxide), PCL (poly caprolactone), chloroform (chloroform), acetone (acetone), dichloromethane (dichloromethane), benzene (benzene), toluene (toluene), isopropyl ether (isopropyl ether) and It may be at least one selected from the group consisting of chlorobenzene. Preferably, it is at least one selected from the group consisting of DMSO, PCL, and chloroform, and more preferably, it is at least one selected from the group consisting of DMSO and chloroform. Most preferably DMSO. However, the present invention is not limited thereto.

In general, emulsification-solvent evaporation is mainly used as a method for manufacturing fine particles, but the manufacturing process is complicated, such as using a surfactant, and there is a limitation in controlling the size of fine particles. It is not easy to control the porosity of the particles. However, when using the production method of the present invention, the porosity is determined according to the concentration of dissolving the steroid-based drug and biodegradable polyester-based polymer mixture in the organic solvent, so it is easy to control the porosity, and the steroid-based drug and biodegradable polyester-based polymer mixture The fine particle size can be easily controlled by controlling the amount of solution and the amount of air flowing when spraying this dissolved organic solvent solution through a valve from the outside. In addition, since it is manufactured by simply spraying the solution, the process is simple and the productivity is good.

The dissolution in step (a) may be to dissolve the steroid-based drug and biodegradable polyester-based polymer mixture in an organic solvent so as to be 1 to 25% (w/v) based on the solution prepared in step (a). When the steroid-based drug and biodegradable polyester-based polymer mixture is less than 1% (w/v), the mechanical strength of the microparticles is weak, which makes it impractical, and when it exceeds 25% (w/v), the viscosity is too high, so It is undesirable because of poor efficiency such as formation of fibers.

In the steroid-based drug and biodegradable polyester-based polymer mixture of step (a), the steroid-based drug and biodegradable polyester-based polymer may be mixed in a weight ratio of 1:99 to 3:7. In the mixture, when the steroid-based drug exceeds 30% by weight (steroid-based drug and biodegradable polyester-based polymer are mixed in a 3:7 weight ratio), the mechanical strength of the biodegradable polyester-based polymer is weak and the shape of microparticles is distorted. It is undesirable as it may become brittle or clumped.

The hydrocarbon solution of step (b) should be phase-separated from an organic solvent without freezing at 0° C. or less, and a hydrocarbon having 5 to 10 carbon atoms (C5 to 10) is preferable.

The C5-10 hydrocarbon may be pentane, hexane, hepatane, octane, nonane, decane, petroleum ether, or a mixture thereof. . Preferably it is hexane. The hexane can be easily removed in the final freeze-drying process or natural drying process due to its high volatility.

In the case of a hydrocarbon having less than 5 carbon atoms in the hydrocarbon, there is a difficulty in manufacturing because the volatility is too large, and a hydrocarbon having more than 10 carbon atoms is not preferable due to poor practicality.

The temperature of the hydrocarbon solution may be less than the melting point of the organic solvent for freezing the organic solvent. For example, when the organic solvent is DMSO, the temperature of the hydrocarbon solution is preferably less than about 18° C. at 1 atm. More preferably, it is -20 to 0°C, and most preferably -10 to -5°C.

The melting point of the organic solvent may be controlled by the content and type of substances mixed in the organic solvent. For example, in the case of chloroform as an organic solvent, the melting point is -63.5°C, but when the steroid-based drug of the present invention and the biodegradable polymer are mixed, it can be frozen at -5°C.

The injection of step (b) is to spray the solution containing the steroid-based drug and biodegradable polyester-based polymer of step (a) into a C5-10 hydrocarbon solution by applying pressure, and microparticles containing a steroid-based drug is for manufacturing

The spraying method used in the present invention includes using a commercialized nozzle, and by controlling the amount of sprayed air and controlling the amount of a solution containing a steroid-based drug and a biodegradable polyester-based polymer to be sprayed, it is sprayed into a hydrocarbon solution. Any method that can be used can be used without limitation. Preferably it is a method of spraying into a cryogenic fluid.

The injection amount of the solution containing the steroid-based drug and the biodegradable polyester-based polymer can be variously adjusted in the range of 0.2 to 20.0 g/min, and the amount of the injection air is varied in the range of 1.0 to 30.0 ℓ/min. By doing so, the size of the produced fine particles can be easily controlled.

The microparticles prepared in step (b) may maintain their shape by phase separation and freezing and sink into a frozen state. Most of the frozen microparticles are organic solvents used to dissolve steroid-based drugs and biodegradable polyester-based polymer mixtures. do.

The aqueous salt solution of step (c) is preferably maintained in a non-freezing state at 0° C. or less. Although water may be used to remove the organic solvent, it is preferable to remove the organic solvent with a solution at 0° C. or less for stability of the fine particles.

The aqueous salt solution may be an aqueous solution of NaCl or CaCl ₂ . Preferably it is 5-30% (w/v) NaCl or CaCl ₂ aqueous solution, More preferably, it is 20-25% (w/v) NaCl aqueous solution.

The temperature of the aqueous salt solution may be -20 ~ 0 ℃. If the temperature is less than -20 ℃, it is impossible to use the aqueous salt solution because it is frozen, and if it is more than 0 ℃, the stability of the fine particles during manufacturing is deteriorated, and even the manufactured fine particles may agglomerate, resulting in decreased productivity.

The salt removal in step (d) is to remove the salt present in the microparticles due to the aqueous salt solution used in step (c) to remove the organic solvent of the microparticles.

The salt can be removed by dilution with the addition of an excess of water, preferably deionized distilled water.

The method for producing biodegradable polymer microparticles containing a steroid-based drug of the present invention uses the phase separation properties of an organic solvent for dissolving a steroid-based drug and a biodegradable polyester-based polymer and a hydrocarbon, which is a cooling organic solvent. It is simpler and more efficient than the conventional method, and the mass production process is simple. In addition, since the size of the microparticles can be easily adjusted, it can be injected into the living body.

The steroid drug is deplazacort, desonide, desoximethasone, dexamethasone, diflorasone, diflucortolone, difluprednate, loteprednol etabonate, rimexolone, mazipredone, medry Soone, methylprednisolone, meprednisone, mometasone furoate, beclomethasone, betamethasone, budesonide, alzestone, alclomethasone, amcinonide, enoxolone, corticosterone, cortisone, cortibazole, chloro prednisone, clobetasol, clobetasone, clocortolone, cloprednol, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, paramethasone, pregnenolone acetate, prednicarbate, Prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednibal, prednylidene, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluosinonide, Fluorocortin Butyl, Flucortolone, Fluorometolone, Fluferolone Acetate, Fluprednidene Acetate, Fluprednisolone, Flurandrenolide, Fluticasone Propionate, Formocortal, Halsinonide, Halobeta It may be sol propionate, halomethasone, halopredone acetate, hydrocortamate, hydrocortisone, etc., but is not limited thereto.

The steroidal drug is preferably deplazacort, desonide, desoximethasone, dexamethasone, diflorasone, diflucortolone, difluprednate, loteprednol etabonate, rimexolone, mazipredone , medrisone, methylprednisolone, meprednisone, mometasone furoate, beclomethasone, betamethasone, budesonide, alzestone, alclomethasone, amcinonide, enoxolone, corticosterone, cortisone, corticosterone Bazole, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, paramethasone, pregnenolone acetate, predni Carbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednibal, prednylidene, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluoro Cinonide, Fluorocortin Butyl, Fluocortolone, Fluorometolone, Fluferolone Acetate, Flupredniden Acetate, Fluprednisolone, Flurandrenolide, Fluticasone Propionate, Formocortal, Halsinonide , may be at least one selected from the group consisting of halobetasol propionate, halomethasone, halopredone acetate, hydrocortamate and hydrocortisone.

The biodegradable polyester-based polymer of the present invention is an aliphatic polyester-based polymer, polylactic acid (PLA), polyglycolic acid (PGA), poly(D,L-lactic-co-glycolic acid) ) (poly (D,L-lactic-co-glycolic acid), PLGA), poly-carprolactone (PCL), poly (valerolactone) (poly (valerolacton)), poly (hydroxybutyrate) ( It may be at least one selected from the group consisting of poly(hydroxy butylate)), poly(hydroxy valerate), and derivatives thereof. Preferably, it is at least one selected from the group consisting of polylactic acid, polyglycolic acid, poly(D,L-lactic-co-glycolic acid) and derivatives thereof, more preferably polylactic acid or poly(D, L-lactic-co-glycolic acid).

The biodegradable polyester-based polymer may have a weight average molecular weight of 10,000 to 250,000. However, the method for producing fine particles of the present invention has the characteristics of easily producing spherical fine particles and of easily controlling the size of the fine particles, so that the fine particles can be produced by the weight average molecular weight of the biodegradable polyester-based polymer. Control of size is not limited.

The diameter of the biodegradable polymer microparticles containing the steroid-based drug of the present invention may be appropriately adjusted depending on the concentration of the steroid-based drug and the biodegradable polyester-based polymer in the organic solvent solution, the solution injection amount and the injection air amount when spraying into the hydrocarbon solution. can Specifically, the higher the concentration of the biodegradable polyester-based polymer in the solution containing the steroid-based drug and the biodegradable polyester-based polymer, the greater the amount of solution sprayed when spraying into the hydrocarbon solution, the greater the amount of sprayed air when spraying into the hydrocarbon solution. The smaller it is, the larger the diameter.

The biodegradable polymer microparticles containing the steroid-based drug may have a diameter of 10 to 1000 μm.

The biodegradable polymer microparticles containing the steroid-based drug may allow the steroid-based drug to be slowly released in the body for a long period of time. For example, when a steroid drug is injected, the level of the steroid drug in the blood increases and then rapidly decreases after the injection, so that the action time of the drug is short. Therefore, by repeatedly using a high dose for the therapeutic effect of a steroid-based drug, resistance to the drug and side effects may appear. However, when the biodegradable polymer microparticles containing the steroid-based drug of the present invention are injected, the biodegradable polymer microparticles are slowly decomposed in the blood, and the steroid-based drug is slowly released for a long period of time during this decomposition process, resulting in a single administration. It can show a long-acting effect. Therefore, by using the biodegradable polymer microparticles containing the steroid-based drug of the present invention to obtain a long-term therapeutic effect of the steroid-based drug, side effects and drug resistance due to the high dose and repeated use of the existing steroid-based drug are reduced. can do it

The release of the steroid-based drug from the biodegradable polymer microparticles containing the steroid-based drug may be different depending on the biodegradable polymer. For example, in the case of poly(D,L-lactic-co-glycolic acid), which is one of the biodegradable polymers of the present invention, the biodegradation period is different depending on the ratio of lactic acid and glycolic acid, and specifically, When the ratio is 85:15, it takes 5-6 months, when the ratio is 75:25, it takes 4-5 months, when it is 65:35, it takes 3-4 months, and when it is 50:50, it takes about 1-2 months (Velasco). , MA, et al., 2015).

The biodegradable polymer microparticles containing the steroid-based drug of the present invention can release the steroid-based drug for at least one month.

The biodegradable polymer microparticles containing the steroid-based drug of the present invention can be cultured to contain cells and used as an injectable cell carrier.

The present invention also provides a biodegradable polymer microparticle comprising a steroid-based drug prepared by the above preparation method.

In addition, the present invention provides an anti-inflammatory composition containing the biodegradable polymer microparticles containing the steroid-based drug.

The anti-inflammatory composition may be a pharmaceutical composition for preventing or treating inflammatory diseases including biodegradable polymer microparticles containing a steroid-based drug and a pharmaceutical excipient.

The pharmaceutical composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories and sterile injection solutions according to conventional methods, respectively. Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient, It is prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.

The dosage of the pharmaceutical composition of the present invention will vary depending on the age, sex, weight, pathology of the disease, the severity of the pathology, the route of administration, and the judgment of the prescriber of the subject to be treated.

The pharmaceutical composition of the present invention may be administered to mammals such as mice, livestock and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, dermal, intrauterine or intracerebrovascular injection, topical application.

The inflammatory disease is allergic disease, inflammatory bowel disease, atherosclerosis, inflammatory collagen vascular disease, glomerulonephritis, inflammatory skin disease, sarcoidosis, retinitis, gastritis, hepatitis, enteritis, arthritis, tonsillitis, pharyngitis, bronchitis, pneumonia, pancreatitis, Sepsis, pressure sores, degenerative chronic inflammatory disease, nephritis, calcific tendinitis, rotator cuff tear, frozen shoulder, degenerative arthritis, etc., but is not limited thereto.

The pharmaceutical composition may exhibit an immune-modulating or anti-inflammatory effect.

The present invention relates to biodegradable polymer microparticles containing a steroid-based drug and a method for preparing the same, wherein an anti-inflammatory steroid-based drug and a biodegradable polyester-based polymer are dissolved in an appropriate organic solvent and sprayed in a low-temperature hydrocarbon solution. After making microparticles, biodegradable polymer microparticles containing steroid-based drugs were prepared through a manufacturing method of dissolving the organic solvent contained in microparticles by putting them in a low-temperature aqueous salt solution, and containing the prepared steroid-based drugs. It was confirmed that the biodegradable polymer microparticles having excellent biocompatibility, biodegradability, porosity and mechanical strength, etc., and the steroid drug were slowly released for a long period of time.

Through this, it is expected to be able to develop a composition for delivering a steroid drug that can minimize side effects while exhibiting the maximum anti-inflammatory activity caused by the steroid drug using the biodegradable polymer microparticles containing the steroid drug of the present invention. do.

1 shows the results of observation with an electron microscope of the size of biodegradable polymer microparticles containing a steroid-based drug prepared according to the manufacturing method of the present invention (×200; polymer solution 4.2% (w/v); Polymer solution injection rate: 1.0 g/min; injection air quantity: 5 ℓ/min).
Figure 2 shows the results of observing the appearance of biodegradable polymer microparticles containing a steroid-based drug prepared according to the method of the present invention with an electron microscope (×5,000; polymer solution 4.2% (w/v); Polymer solution injection rate: 1.0 g/min; injection air quantity: 5 ℓ/min).
Figure 3 shows the results of observing the surface of the biodegradable polymer microparticles containing the steroid-based drug prepared according to the preparation method of the present invention with an electron microscope (×10,000; polymer solution 4.2% (w/v); Polymer solution injection rate: 1.0 g/min; injection air quantity: 5 ℓ/min).
Figure 4 shows the results of observation with an electron microscope of the internal structure of the biodegradable polymer microparticles containing the steroid-based drug prepared according to the production method of the present invention (x 500; polymer solution 4.2% (w / v)) ; Polymer solution injection rate: 1.0 g/min; Injection air quantity: 5 ℓ/min).

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, it is provided so that this disclosure will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

<Example 1. Preparation of biodegradable polymer microparticles containing steroid drugs>

Anti-inflammatory triamcinolone as a steroid drug, poly(lactic-co-glycolic acid, PLGA) as a biodegradable polyester polymer, DMSO (as an organic solvent) dimethyl sulfoxide) was used.

1 g of triamcinolone and 20 g of PLGA having a weight average molecular weight of 110,000 and a ratio of lactic acid to glycolic acid of 75:25 were dissolved in 500 ml DMSO to prepare a 4.2% (w/v) drug and biodegradable polymer mixed solution. The drug and biodegradable polymer mixture solution was injected into n-hexane cooled to -5 ° C under conditions of a solution injection amount of 1.0 g / min and an amount of sprayed air 5.0 ℓ / min, and the injected drug and biodegradation The polymer mixture solution was frozen in a spherical shape in n-hexane at low temperature to form fine particles.

Frozen microparticles were obtained and left in 1,000 ml of 25% (w/v) NaCl aqueous solution cooled to -20°C for 72 hours to dissolve the DMSO component, followed by filtration to obtain DMSO-removed drug and biodegradable polymer. Mixed fine particles were obtained. The obtained microparticles were washed again with 5,000 ml of distilled water, filtered to remove residual DMSO and NaCl, and then freeze-dried to prepare biodegradable polymer microparticles containing the steroid-based drug of the present invention.

<Example 2. Confirmation of physical properties of biodegradable polymer microparticles containing steroid drugs>

In order to confirm the physical characteristics of the biodegradable polymer microparticles containing the steroid-based drug prepared in Example 1, the size, particle shape, particle surface, and inside of the particles were photographed using an electron microscope, and the results were 1 is shown.

In addition, the production yield of the biodegradable polymer microparticles containing the steroid drug was calculated by measuring the amount of microparticles finally obtained compared to the amount of the injected polymer, and the results are shown in Table 1 below.

spray conditions fine particle size
(μm) transference number
(%) Polymer solution mixed with drug
(%, w/v) solution injection amount
(g/min) amount of blown air
(ℓ/min) 4.2 1.0 5 ≤100 62

As shown in FIG. 1 and Table 1, it was confirmed that the size of the biodegradable polymer microparticles containing the steroid-based drug prepared in Example 1 was 100 μm or less.

In addition, as shown in FIG. 2, which is the result of observing the appearance of the biodegradable polymer microparticles containing the steroid-based drug prepared in Example 1, the appearance of the prepared microparticles is spherical, and the surface of the microparticles in FIG. As a result of observation, it was confirmed that the prepared microparticles were porous. Furthermore, as shown in FIG. 4 which is the result of observing the inside of the prepared microparticles, it was confirmed that the inside was empty.

Through this, it was found that the size of the microparticles prepared according to the method for producing the biodegradable polymer microparticles containing the steroid-based drug of the present invention is a size suitable for intra-body administration with a syringe, and economical even in terms of yield. .

Claims (12)

(a) A steroid-based drug and a biodegradable polyester-based polymer mixture are mixed in a weight ratio of 1:99 to 3:7 and dissolved in DMSO (dimethyl sulfoxide) to 1 to 25% (w/v) to obtain a steroid drug and Preparing a solution containing a biodegradable polyester-based polymer;
(b) preparing microparticles having a diameter of 10-100 μm by spraying a solution containing the steroid-based drug and a biodegradable polyester-based polymer into a C5-10 hydrocarbon solution at a temperature of -10 to -5°C;
(c) adding the microparticles to an aqueous salt solution to dissolve DMSO to remove DMSO; and
(d) removing the salt from the DMSO-removed microparticles;
In the method for producing microparticles, the biodegradable polyester-based polymer containing a steroid-based drug consisting of
The biodegradable polyester-based polymer is poly(D,L-lactic-co-glycolic acid),
The C5-10 hydrocarbons in step (b) are pentane, hexane, heptane, octane, nonane, decane, and petroleum ether. ) is at least one selected from the group consisting of,
The aqueous salt solution of step (c) is 5-30% (w/v) NaCl or CaCl2 aqueous solution, characterized in that the biodegradable polyester-based polymer containing a steroid-based drug has a spherical porosity and a diameter of 10-100 A method for producing microparticles having the characteristic of continuously releasing a steroid-based drug having a thickness of ㎛ for one month. delete delete The method of claim 1,
The steroid-based drugs include deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, diflupred. Nate (difluprednate), loteprednol etabonate (loteprednol etabonate), rimexolone (rimexolone), mazipredone (mazipredone), medrysone (medrysone), methylprednisolone (methylprednisolone), meprednisone (meprednisone) Son furoate, beclomethasone, betamethasone, budenonide, algestone, alclometasone, amcinonide, enox Solon, corticosterone, cortisone, cortivazol, chloroprednisone, clobetasol, clobetasone, clocortolone, Cloprednol, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone methasone, triamcinolone hexacetonide pregnenolone acetate, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone Prednisolone sodium phosphate, prednisone, prednival, prednylidene, fluazacort, flucloronide, flumethasone, fluni Flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluferolone acetate ( fluperolone acetate), fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide (halcinonide), halobetasone propionate, halometasone, halopredone acetate, hydrocortamate, and hydrocortisone selected from the group consisting of A method for producing microparticles, characterized in that at least one biodegradable polyester-based polymer containing a steroid-based drug has a spherical porosity and a continuous release of a steroid-based drug having a diameter of 10 to 100 μm for one month. delete According to claim 1,
The poly(D,L-lactic-co-glycolic acid) is a biodegradable polyester-based polymer containing a steroid-based drug, characterized in that it has a weight average molecular weight of 10,000 to 250,000, has a spherical porosity, and has a diameter of 10 to 100 μm. A method for producing microparticles having the property of continuously releasing a steroid-based drug for one month. delete delete delete delete delete delete

Images