KR20180018892A - Polymer microsphere containing drug as stable crystalline form, and manufacturing method for the same - Google Patents

Abstract

The present invention relates to a polymer microsphere comprising a crystalline drug and a biocompatible and biodegradable polymer on which the crystalline drug is loaded. The polymer microsphere of the present invention is excellent in biocompatibility and biodegradability, has excellent physicochemical stability of the drug loaded in the microsphere, and at the same time, can effectively control the release of the drug, thereby reducing the number of administration and improving the compliance of patients with the medication. The polymer microsphere of the present invention can be utilized as a drug delivery system for delivering a drug in a differentiated crystalline form in the future as a crystalline drug-loaded sustained-release microsphere.

Description

TECHNICAL FIELD The present invention relates to a polymeric microparticle containing a stable crystalline drug and a method for preparing the same,

The present invention relates to a polymeric microparticle containing a crystalline drug and a method for producing the same. More particularly, the present invention relates to a polymeric microparticle which improves the physico-chemical stability of a drug during the manufacturing process and storage period by loading the biodegradable and biocompatible polymeric microparticles in a stable crystalline form, and a method for producing the same.

Conventional methods of producing sustained-release injection agents include the coacervation method, the melt injection method, the spray drying method, and the solvent evaporation method. Among these methods, the solvent evaporation method is classified into the dual emulsion evaporation method (W / O / W emulsion) and the single emulsion evaporation method (O / W emulsion). However, such microemulsions produced by the multi-emulsion method have a disadvantage of high initial over-release rate, and when the drug as an active ingredient is dissolved in an organic solvent or water, formation of microspheres as well as changes in properties of the drug, loss of stability, And so on.

Various attempts have been made to increase the rate of drug encapsulation of such sustained-release formulations or to produce microparticles which are easy to manufacture and have relatively low initial over-release, but are still unsatisfactory. Conventional methods for producing microspheres have problems such as difficulties in removing organic solvents used for dissolving biodegradable polymers, difficulty in processing due to changes in solvent removal rate in mass production, allergy caused by gelatin used for viscosity increase of primary emulsion, There are still disadvantages such as denaturation of the drug due to strong shear force applied to make small microspheres in the production of the primary emulsion, loss of activity and limitation of the drug encapsulation rate.

An attempt has been made to mount drugs on the microspheres using the spray drying method. The spray drying method generally involves spraying a solution of a substance to be dried or a biodegradable polymer and a drug uniformly in a suspension or an emulsion state, spraying the mixture with a hot air, and evaporating the solvent to obtain micronized particles Method.

Particularly, when the sustained-release microparticle is manufactured, the drug release rate of the microparticles prepared according to the conditions such as the composition and content of the biodegradable polymer, the drug content, the kind and content of the additive, and the composition of the solvent are greatly influenced. In addition to the above manufacturing variables, the properties, size, and properties of the microparticles are determined according to conditions such as the nozzle type for spraying the spray liquid, the feed rate of the spray liquid, the temperature of the dry air, the feed rate, and the like. In addition, the spray drying method is advantageous in that it can be easily produced through a continuous process, and thus can be easily transferred from a small amount to a mass production, unlike the other methods for producing sustained release microparticles.

Despite advantages such as ease of mass production, the spray drying method does not sufficiently remove the used solvent by merely spray drying, and the solvent that has not been removed does cause problems in the stability of the biodegradable polymer during long-term storage, And the biodegradable polymer, which is mainly used for drug encapsulation, is generally non-hydrophilic, which causes a phenomenon in which suspension is not performed well during dosing, making it difficult to accurately administer the biodegradable polymer.

On the other hand, corticosteroid drugs (eg, triamcinolone and its derivatives) are injected directly into joints for the purpose of relieving the pain and inflammation of patients suffering from osteoarthritis or rheumatoid arthritis.

However, it has been reported that when the drug solution is simply administered to joints as a method of treating osteoarthritis, the drug rapidly flows out from the joint synovial fluid to the blood, and the treatment effect is only a few hours.

Therefore, nanoparticles, hydrogels, suspended particles, and the like, which are based on various materials, in order to improve the efficacy and duration of the local tissues of the active substances administered in joints including corticosteroids and to reduce the side effects due to systemic exposure, Various localized release control formulations based on microparticles have been devised.

For example, drug suspension particles and microparticles have been devised to improve joint residence and duration of triamcinolone. Prodrug, which has a hydrophobic acetonide group attached to triamcinolone, has a low solubility in water and can be slowly dissolved by articular synovial fluid after being administered in the form of a suspension in the form of a suspension. The commercial product is nevertheless reported to have a duration of effect of only one week to a maximum of three weeks.

In addition, microparticles of triamcinolone and derivatives thereof based on biodegradable polymers are known in the patent document 10-2013-0093101. In this patent, both drug and polymer are dissolved in a solvent, and then the solvent is evaporated, extracted or dried to prepare particles. In such a preparation method, the active drug is dispersed amorphously in the polymer matrix, which sometimes causes physico-chemical instability of the drug during the manufacturing process and storage period. Particularly, triamcinolone acetonide has an easily hydrolyzed cyclic ketal group, so that when loaded in an amorphous thermodynamically unstable state, there is a problem that the drug is chemically decomposed during the storage period.

That is, the conventional drug-loaded microparticles have insufficient effect persistency upon administration or the instability of drug loaded in the microparticles. Accordingly, the present inventors have completed the present invention by devising a polymer microparticle capable of solving the instability of a drug loaded in microparticles and providing an extended drug efficacy after administration through an excellent release control effect.

SUMMARY OF THE INVENTION Accordingly, the present invention has been made to solve the above problems of the prior art, and it is an object of the present invention to provide a pharmaceutical composition which is excellent in biocompatibility and biodegradability and which is excellent in physicochemical stability of a drug loaded in the microsphere, And to provide a polymer microparticle based on a biodegradable polymer and a method for producing the same.

In addition, in the production of a sustained-release polymer microparticle containing a biocompatible and biodegradable polymer as a carrier and a physiologically active drug, it is not only easy to mass-produce, but also solves the residual toxic solvent problem of the conventional sustained-release microparticle preparation method A high drug encapsulation rate and uniform size suitable for injection, and a method for producing the same.

In order to solve the above problems, a first aspect of the present invention provides a polymeric microparticle comprising a biocompatible and biodegradable polymer on which a crystalline drug and the crystalline drug are mounted.

In addition, the second aspect of the present invention provides a method for producing a biocompatible biodegradable polymer, comprising: a first step of preparing a solution containing a crystalline drug and a biocompatible and biodegradable polymer; And a second step of supplying the solution to the nozzle and spray drying the polymer microparticle of the first aspect of the present invention.

Hereinafter, the present invention will be described in detail.

The polymeric microparticle of the present invention includes a crystalline drug which is excellent in stability and can have a thermodynamically safe energy level.

The polymer microspheres of the present invention can be physically and chemically stable during the manufacturing process and the storage period by including a drug dispersed in a crystalline state in a polymer matrix to provide an extended drug efficacy after the administration through the release control effect.

The drug may be triamcinolone and derivatives thereof such as triamcinolone, triamcinolone acetonide, triamcinolone acetonide 21-palmitate, triamcinolone venetonide, triamcinolone diacetate, triamcinolone hexasacetonide and the like.

The drug may be another corticosteroid drug. Examples thereof include betamethasone, betamethasone acetate, betamethasone dipropionate, betamethasone 17-valerate, cortibasol, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, hydrocortisone, hydrocortisone biphosphate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone, Methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone acetate, methylprednisolone acetate, methylprednisolone acetonate, methylprednisolone sodium succinate, Metasulfobenzoate, prednisolone sodium phosphate, prednisolone stearate, prednisolone tibutate, Chlomethasone dipropionate, amcinonide, ammelomethasone, beclomethasone, beclomethasone dipropionate, beclomethasone dipropionate monohydrate, budesonide, boutic microsomes, But are not limited to, but are not limited to, butyric acid, propionic acid, butyric acid, propionic acid, butyric acid, propionic acid, Cortisone, cortisone acetate, des plaza cort, domoprednate, deprodone, deprodion propionate, desonide, dexime sulphate, desoxyketone, desoxyketone acetate, Dextrin, dextrin, dextrin, dextrin, dextrin, dextrin, dextrin, dextrin, dextrin, dextrin, But are not limited to, rudoxocortide, rudoxocortide, flumethasone, flumethonone pivalate, fluneysolid, fluorocinolone, fluorocinone acetonide, fluorocortin, fluorocortolone, fluorometholone, fluticasone, , Fluticasone propionate, fluorometholone, acetate, fluoroxymasterone, fluperolone, flufrednidene, flufrednidene acetate, fluffrednisolone, formocortal, halinonide, halobetasol propionate , Haloperidone acetate, hydrocortamate, isoflurredone, isoflurredone acetate, ittrosinonide, rotefrednol etabonate, majepredone, mechloron, Meclofenadate, medryson, mederdonson, mometasone, mometasone furoate, mometasone furoate monohydrate, nibacortol, para Thymocortolpyruvate, thalidomide, thymocortolone, thymocortol, thymocortolate, thalidomide, paramethasone acetate, prednisolone, prednisolone, prednisolone, prednilidene, procinnonide, roflononide, Ronid and the like.

The polymer microparticle of the present invention contains the drug in an amount of 5 to 50% by weight based on the total weight of the polymer microparticles. When the content of the drug is less than 5% by weight, there is a problem that the amount of the polymer and the surface stabilizer for administering a proper amount of drug is excessively increased. When the content of the drug exceeds 50% by weight, do.

The average particle size of the active drug in the polymer microparticle preparation process and final formulation of the present invention is preferably 300 nm to 50 탆. When the particle size is less than 300 nm, the crystalline form of the drug can be converted to amorphous form, and if the particle size is larger than 50 μm, the uniformity of the prepared particles may be lowered.

The polymeric microparticles of the present invention form a matrix of microparticles and include biocompatible and biodegradable polymers that mount and release the drug.

The biocompatible and biodegradable polymers may be natural or synthetic biocompatible and biodegradable polymers.

Examples of the natural biocompatible and biodegradable polymers include proteins such as albumin, collagen, gelatin synthetic poly (amino acid), and prolamin; Glucose aminoglycans such as hyaluronic acid and heparin; Polysaccharides such as alginate, chitosan, starch and dextran; And other naturally occurring or chemically modified biodegradable polymers.

Examples of the synthetic biocompatible and biodegradable polymers include poly (lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PG), polyhydroxybutyric acid, poly (trimethylene carbonate ), Poly (caprolactone), polyvalerolactone, poly (alpha-hydroxy acid), poly (lactone), poly , Poly (lactide-co-urethane), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane , Polythioester methacrylate, poly (N-isopropylacrylamide), and copolymers thereof. However, the present invention is not limited thereto.

For example, the copolymer may be a PVA-g-PLGA copolymer, a PEGT-PBT copolymer (polyactive), a PEO-PPO-PEO (pluronic) copolymer, a PEO-PPO-PAA copolymer, a PLGA- , PLGA-PEG-PLGA, and the like.

The polymer may be a linear polyester. Linear polyesters can be prepared from alpha -hydroxycarboxylic acids such as lactic acid and glycolic acid by condensation of lactone dimers (see U.S. Patent No. 3,773,919). A preferred polyester chain in the linear polymer is a copolymer of lactic acid and glycolic acid or a lactone dimer, which is an alpha -carboxylic acid residue.

The linear polyester is preferably a linear polylactide-co-glycolide (PLG / PLGA). The lactide: glycolide molar ratio of the polylactide-co-glycolide may be 100: 0 to 40:60, preferably 90:10 to 40:60, more preferably 85:15 to 65:35 .

The linear polylactide-co-glycolide (PLG / PLGA) may have a weight average molecular weight (Mw) of 10,000 to 500,000 Da and a polydispersity Mw / Mn of 1.2 to 2.

Suitable examples thereof include those commercially available through Resomers® (Boehringer Ingelheim) and Lakeshore Biomaterials (Birmingham, Ala.).

The polymer microparticles of the present invention include biocompatible and biodegradable polymers in an amount of 30 to 95% by weight based on the total weight of the polymer microparticles. When the content of the polymer is less than 30% by weight, the effect of controlling the release of the drug is significantly reduced. When the content of the polymer is more than 95% by weight, the amount of the polymer for administering a proper amount of the drug is excessively increased.

The polymer microparticles of the present invention may further include a surface stabilizer capable of improving the water dispersibility of the particles.

The polymer microparticles of the present invention can be prepared by incorporating a surface stabilizer to prevent drug aggregation and to improve water dispersibility, or to further coat a surface stabilizer with the produced particles. The addition timing of the surface stabilizer is not particularly limited and may be mixed before, during, and / or after the particle production process. The surface stabilizer is a substance that physically adheres to the surface of the manufactured particles, excludes substances chemically bonded to the surface of the particles, and includes excipients used for general pharmaceutical formulation including surfactants, emulsifiers, It is a comprehensive concept.

Examples of the emulsifier include phosphatidylcholine, phosphatidyl ethanolamine, phosphatidyl-serine, phosphatidylinositol and derivatives thereof; Ester derivatives of fatty acids such as glyceryl stearate, sorbitan palmitate and sorbitan stearate; Polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan monolaurate , Polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monolaurate (Span 20), sorbitan monostearate (Span 60), sorbitan monooleate ( Sorbitan monooleate (Span 80), polyoxyethylene-polyoxypropylene copolymer (e.g., Poloxamer 407, Poloxamer 118), and the like.

The surfactant may be selected from the group consisting of casein, gelatin, phospholipids, tragacanth, lecithin, acacia gum, cholesterol, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate natural surfactants such as monostearate, natural phospholipids, waxes, enteric resins, paraffin, acacia and the like; But are not limited to, polyoxyethylene fatty alcohol ethers, sorbitan esters, glycerol monostearate, polyethylene glycols, cetyl alcohol, cetostearyl alcohol, alcohol, stearyl alcohol, poloxamers (e.g., poloxamer 188), polaxamines, methylcellulose, hydroxycellulose, hydroxypropylcellulose, hydroxypropylcellulose, Nonionic surfactants such as hydroxypropylmethylcellulose, noncrystalline cellulose and synthetic phospholipids; nonionic surfactants such as hydroxypropylmethylcellulose, noncrystalline cellulose and synthetic phospholipids; But are not limited to, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, But are not limited to, dioctyl sodium sulfosuccinate, negatively charged phosphatidylserine, phsophatidyl glycerol, phosphatidyl inosite, phosphatidylserine, phosphatidic acid Anionic surfactants such as sodium carboxymethylcellulose, calcium carboxymethylcellulose, and the like; anionic surfactants such as sodium carboxymethylcellulose, negatively charged glyceryl ester, sodium carboxymethylcellulose, and calcium carboxymethylcellulose; Cationic surfactants such as quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide and lauryldimethylbenzyl-ammonium chloride, and the like, ); Phosphatidylserine, phosphatidylinositol, phosphatidylserine, phosphatidylserine, phosphatidylethanolamine, phosphatidylserine, phosphatidylserine, phosphatidylserine, phosphatidylglycerol, But are not limited to, phosphatidylglycerol, phosphatidic acid, lysophospholipid, egg or soybean phospholipid, and the like.

Examples include lactose, sucrose fatty acid esters (e.g., rotoester L1695), polyethylene glycolated natural or hydrogenated castor oil (e.g., Cremophor RH 40), synthetic vitamin E derivatives such as vitamin E TPGS, polyoxyethylene alkyl esters (E.g., Brij 52), fatty acid macrogol glycerides (e.g., Geluciller 44/14), polyglyceryl fatty acid esters (e.g., fluorololakers), glyceryl fatty acid esters, polyethylene glycol stearate, phosphorylated lipids, calcium silicate , Chitosan, sucrose palmitate or a mixture thereof may be used as a surfactant. Preferably, anionic and nonionic surfactants and polyvinyl alcohol (PVA) are suitable.

The polymer microspheres of the present invention contain the surface stabilizer in an amount of 0.001 to 20% by weight based on the total weight of the polymer microspheres. If the content of the surface stabilizer is more than 20% by weight, the uniformity of the produced microparticles is decreased, and the drug can not be maintained in the crystalline form during the manufacturing process, and is dissolved by the surface stabilizer and converted into an amorphous form.

The polymer microparticles of the present invention preferably have an average particle size of 1 to 100 mu m, preferably 5 to 50 mu m. When the particle size is less than 1 탆, the drug release control function is markedly decreased. If the particle size is more than 100 탆, there is a problem that the drug may cause foreign objects and inconvenience when administered.

The dosage formulations containing the polymeric microparticles of the present invention may be suspended and used in injection water prior to administration.

The injection water may be an aqueous or non-aqueous solution, a suspension, an emulsion or an oil, and may contain or contain a pharmaceutically acceptable carrier. The aqueous solution may be distilled water, physiological saline, mannitol, aqueous dextrose solution. Non-aqueous solutions may be propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.

Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, such as saline and buffered media. The oils may be oils, animal, vegetable or synthetic origin oils, such as peanut oil, soybean oil, mineral oil, olive oil, sunflower oil and fish oil.

The polymer microparticles of the present invention may contain, if necessary, a carrier diluent (suspending agent), an antioxidant, a stabilizer, a viscosity increasing agent, a buffer, a preservative, an isotonic agent, an antiseptic agent,

Such carrier diluents include, but are not limited to, rubbers, starches (such as corn starch, pregelatinized starch), sugars (such as lactose, mannitol, sucrose, dextrose), cellulosic materials (E.g., microcrystalline cellulose), acrylates (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.

The antioxidant may be, but is not limited to, ascorbic acid, sodium metabisulfite, butylated hydroxyanisole, and the like.

The stabilizing agent may be, but is not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like.

The viscosity enhancer may be, but is not limited to, carbomer, colloidal silicon dioxide, ethylcellulose, guar gum, and the like.

The buffer is used to alleviate hemolysis and pain. For this purpose, butyric acid, tartaric acid, sodium hydroxide and the like can be used to adjust the pH to about 4 to 8.

To prevent deterioration, ascorbic acid, sodium hydrogen sulfite, sodium bisulfite, BHA, tocopherol or EDTA may be added as an antioxidant.

In order to prevent the growth of microorganisms, preservation systems such as mercury nitrate, mercuric chloride, thimerosal, benzalkonium chloride, phenol, cresol, methyl p-oxybenzoate, p-hydroxybenzoate, benzyl alcohol and paraben can be added.

The present invention also provides a method for producing polymer microspheres.

Conventional methods for producing sustained-release microparticles include phase separation, meltextrusion followed by cryopulverization, double emulsion evaporation (w / o / w, water / oil / water) Evaporation method (o / w, oil / water) and spray drying method are known. In the present invention, particles can be produced by spray-drying, but the present invention is not limited thereto.

Specifically, a second aspect of the present invention provides a method for producing a biodegradable polymer, comprising: a first step of preparing a solution containing a crystalline drug and a biocompatible and biodegradable polymer; And a second step of supplying the solution to the nozzle and spray drying the polymer microparticle of the first aspect of the present invention.

A 2-fluid nozzle system in which a single solvent is sprayed and dried by spray drying, and a 3-fluid nozzle system in which two solvents are simultaneously sprayed and dried can be used.

The first step may be a step of adding a crystalline drug, a biocompatible and biodegradable polymer to an optional solvent for dissolving the polymer but dispersing the drug for the two-liquid nozzle method.

In one embodiment of the present invention, the method for producing PLGA or PLA microparticles loaded with triamcinolone acetonide is a method of dissolving PLGA and PLA, but has very low solubility for triamcinolone acetonide, Reil, acetic acid, formic acid, or a mixture thereof may be used as a solvent.

The first step is to prepare a liquid in which a crystalline drug is dispersed in a solvent that does not dissolve the drug for injecting an inner-fluid nozzle for the three-liquid nozzle method, and a liquid for injecting an outer-fluid nozzle It may be a step of preparing a solution in which the polymer and the surface stabilizer are dissolved.

In one embodiment of the invention, distilled water or a small amount of distilled water and buffer containing not more than 1% of a surfactant can be used to prepare the drug dispersion. In addition, a fat-soluble solvent can be used as a solvent for dissolving the polymer and the surface stabilizer. Generally, any oil-soluble solvent used in the production of polymer microparticles as a sustained release agent can be used without limitation. Halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, trichloroethane and carbon tetrachloride; Ethers such as ethyl ether and isopropyl ether; Fatty esters such as ethyl acetate and butyl acetate; Aromatic hydrocarbons such as benzene, toluene and xylene.

The polymer microparticles of the present invention are excellent in biocompatibility and biodegradability and have excellent physico-chemical stability of the drug loaded in the microspheres and at the same time can effectively control the release of the drug, thereby decreasing the number of administration and improving the patient's compliance have.

The polymer microparticles of the present invention can be utilized as a drug delivery system for delivering drugs in a differentiated crystalline state in the future as crystalline drug-loaded sustained-release microparticles.

(B) polymer microparticles loaded with no drug, (C) microparticles prepared in accordance with Example 12 (a), (B) The results are shown in FIG.
FIG. 2 shows the results of the drug dissolution experiment conducted in Experimental Example 3 (Example 12, Comparative Example 1).
3 shows the results of a long-term storage stability test (25 ± 2/60% ± 5% RH (Relative humidity, relative humidity)) of the microparticles of Comparative Example 2 in which the microparticles of Example 12 and the amorphous drug were loaded ((A) after 6 months, (B) immediately after manufacture).

Hereinafter, the present invention will be described in more detail with reference to examples of the present invention. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Examples 1 to 14: Preparation of PLGA / PLA microparticles loaded with drug crystals by spray drying

Microparticles were prepared according to the composition and manufacturing conditions shown in Table 1 below. PLGA and PLA alone or in appropriate proportions and various types of surface stabilizers were dissolved and dissolved in organic solvent acetonitrile solvent for 10 minutes at various ratios. Then, the active drug triamcinolone acetonide was added to the solution in various weight ranges, and the mixture was stirred for 5 minutes using a magnetic stirrer. Ultrasonic waves were applied for 3 minutes using a bath-type sonicator (Branson 2210, output power 90 W) Solution. The prepared final solution was spray-dried under the spray drying conditions shown in Table 1 below with stirring.

≪ Comparative Example 1 &

A triamcinolone acetonide raw material powder having a particle size of 2 to 7 mu m was used as a reference.

Unit (탆) D ₁₀ D ₅₀ D ₉₀ Comparative Example 1 2.18 3.78 6.22

≪ Comparative Example 2 > Production of amorphous drug-loaded microparticles

Using a spray dryer, triamcinolone acetonide, PLGA, PLA and surface stabilizer Lecithin were dissolved in dichloromethane under the conditions shown in Table 4 below and spray dried to prepare microparticles loaded with an amorphous drug.

Comparative Example 2 <Composition> F15 TA (mg) 600 PLGA (mg) 750 PLA (mg) 2250 Lecithin (mg) 150 Dichloromethane (ml) 60 <Spray Drying Condition> Feed rate (ml / min) 6 Spray gas flow
(liters / hr) 357 T _in (캜) 35 T _out (° C) 24 Aspirator gas flow (m ³ / h) 35

<Experimental Example 1> Evaluation of physical and chemical properties: Particle size, LA, EE

The particle size of the particles of Examples 1 to 13 and Comparative Examples 1 and 2, the amount of drug loaded in the particle, and the loading efficiency were evaluated. The particle size distribution of the microparticles was determined by diluting the prepared particles with 10 mM phosphate buffered sine (PBS) containing 0.5% Tween 20 for dispersal and then using Mastersizer (MS 2000 - Hydro 2000s, Malvern Instrument, Worcestershire, UK) And measured by laser diffraction. The loading amount of the drug was determined by taking 10 mg of the microparticle powder in a 1.5 mL microtube, dissolving in 0.5 mL of dimethylsulfoxide (DMSO) and mixing vigorously, adding 0.5 mL of the analytical mobile phase to 1 mL, After centrifugation at 13,000 xg for 10 min, the supernatant was removed and diluted to the appropriate concentration with mobile phase and analyzed by HPLC system. The loading efficiency was expressed as a percentage of the amount of the drug in the particles obtained relative to the amount of the drug added at the time of manufacture, and the results are shown in Table 5 below.

As a result of the experiment, it was confirmed that the loading efficiencies of the microparticles of Examples 1 to 13 in which the crystalline drug was mounted were higher than those of the microparticles of Comparative Example 2 in which the amorphous drug was loaded, and the particle size and the drug loading amount in the particles were equal to or more than the same level .

&Lt; Experimental Example 2 >

(A) the microparticles of Comparative Example 1, (B) the polymer microparticles not loaded with the drug, (B) the microparticles of Comparative Example 1, (C) , (C) The diffraction pattern for the microspheres of Example 12 is shown in Fig.

Example 12 was stored in a desiccator immediately after preparation and then measured. As a result of the experiment, it can be confirmed that Example 12 is not transformed into an amorphous form in the production process but is distributed in the form of a crystal form.

&Lt; Experimental Example 3 >

The microparticles of Example 12 containing 15 mg of the triamcinolone acetonide drug powder of Comparative Example 1 and 15 mg of the drug were weighed and subjected to the elution test.

100 ml of a 10 mM phosphate buffered saline solution containing 0.5% SLS (sodium lauryl sulfate) at pH 7.4 was added to each sample to maintain the sink condition in a shaking incubator maintained at a temperature of 37.5 and stirred at a speed of 90 rpm. As an elution solvent. The results are shown in Figure 2. (●: Example 12, ○: Comparative Example 1)

As a result, the triamcinolone acetonide drug powder of Comparative Example 1 was completely dissolved within 2 hours, whereas the microparticles of Example 12 released about 75% of drug over 12 hours, and the drug was continuously released thereafter have. Such a sustained release pattern is expected to provide effective drug concentration in the joint for a longer period of time after single administration, thereby reducing the number of drug administration.

<Experimental Example 4> Evaluation of stability

The long-term storage stability test (25 ± 2/60% ± 5% RH (25 ± 2%) of the microparticles of Comparative Example 2 in which the amorphous drug of Example 12 was loaded with the crystalline form of triamcinolone acetonide prepared according to the present invention Relative humidity, relative humidity). The content of the drug in the microspheres was analyzed by HPLC, and the presence of the crystalline drug of Example 12 was evaluated by an X-ray diffractometer (Ultima IV, Rigaku Corporation, USA) at room temperature. As a result of the evaluation of the X-ray diffractometer in Example 12, it was confirmed that the crystal form of the drug was maintained without change for 6 months. The results are shown in Fig. 3 ((A) after 6 months, (B) immediately after production).

The drug content immediately after preparation of the microspheres of Example 12 and Comparative Example 2 and the drug content after storage for 6 months were respectively evaluated, and the results are shown in Table 6 below.

Example 12 Comparative Example 2 Immediately after manufacture 6 months later Immediately after manufacture 6 months later content(%) 99.99 + - 0.34 99.78 ± 0.15 94.56 ± 0.16 79.32 + - 0.62

As shown in Table 6, in the case of the microparticles of Example 12 in which the crystalline drug was loaded, there was no change in the content even after 6 months, whereas the microparticles of Comparative Example 2 loaded with the amorphous drug showed a drug content reduction of about 15%. Thus, it can be seen that the microparticle of Example 12 in which the crystalline drug is mounted according to the present invention is more stable than the microparticle of Comparative Example 2 in which the amorphous drug is loaded.

Claims (17)

A polymeric microparticle comprising a crystalline drug and a biocompatible and biodegradable polymer on which the crystalline drug is loaded. The polymer microparticle according to claim 1, wherein the drug is triamcinolone and its derivatives as triamcinolone, triamcinolone acetonide, triamcinolone acetonide 21-palmitate, triamcinolone venetonide, triamcinolone diacetate or triamcinolone hexasatonide. The polymer microparticle according to claim 1, wherein the drug is contained in an amount of 5 to 50% by weight based on the total weight of the polymer microspheres. The biocompatible and biodegradable polymer of claim 1, wherein the biocompatible and biodegradable polymer is a natural biocompatible and biodegradable polymer selected from the group consisting of albumin, collagen, gelatin synthetic poly (amino acid), prolamin, hyaluronic acid, heparin, alginate, chitosan, starch or dextran Polymeric microparticles. The biocompatible and biodegradable polymer of claim 1, wherein the biocompatible and biodegradable polymer is a synthetic biocompatible and biodegradable polymer selected from the group consisting of poly (lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide Poly (lactic acid), poly (amino acid), poly (anhydride), poly (lactic acid), poly Poly (lactide-co-urethane), polyethylene glycol (poly (ester-co-amide), poly PEG), polyvinyl alcohol (PVA), polyurethane, polythioester methacrylate, poly (N-isopropylacrylamide), and copolymers thereof. The polymeric microparticle of claim 1, wherein the biodegradable and biocompatible polymer is a linear polylactide-co-glycolide (PLG / PLGA). The polymer microparticle according to claim 1, wherein the polymer is contained in an amount of 30 to 95% by weight based on the total weight of the polymer microparticles. The polymer microparticle according to claim 1, wherein the polymer microparticle further comprises a surface stabilizer. The polymer microparticle according to claim 8, wherein the surface stabilizer is contained in an amount of 0.001 to 20% by weight based on the total weight of the polymer microparticles. The polymer microparticle according to claim 8, wherein the surface stabilizer is a surfactant, an emulsifier or an excipient. The polymer microparticle according to claim 1, wherein the polymeric microparticles have an average particle size of 1 to 100 μm. A first step of preparing a solution containing a crystalline drug and a biocompatible and biodegradable polymer; And a second step of supplying the solution to the nozzle and spray-drying the polymer microparticles. 13. The method according to claim 12, wherein the drug is triamcinolone and its derivatives as triamcinolone, triamcinolone acetonide, triamcinolone acetonide 21-palmitate, triamcinolone venethonide, triamcinolone diacetate or triamcinolone hexasatonide. 13. The method of claim 12, wherein the first step is a step of adding a crystalline drug and a biocompatible and biodegradable polymer to an optional solvent for dissolving the polymer but dispersing the drug for the two-liquid nozzle method . 15. The method of producing a polymeric microparticle according to claim 14, wherein the solvent is acetonitrile, acetic acid, formic acid, or a mixture thereof. 13. The method according to claim 12, wherein the first step is a step of preparing a solution in which a crystalline drug is dispersed in a solvent that does not dissolve the drug for injecting an inner-fluid nozzle for a three-liquid nozzle method, wherein the step of preparing the polymer microparticles is a step of preparing a solution in which the polymer and the surface stabilizer are dissolved for injecting a fluid nozzle. 17. The method of claim 16 wherein the solvent is selected from the group consisting of dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, ethyl ether, isopropyl ether, ethyl acetate, butyl acetate, benzene, toluene, and xylene as the fat- Wherein the polymer microparticles are at least one kind of polymer.

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