KR100908517B1 - Sustained Release Porous Microparticles for Respiratory System Drug Delivery and Its Manufacturing Method - Google Patents

Abstract

The present invention relates to a sustained-release porous microparticles and a method for producing the same for delivery of respiratory medicament, the sustained-release porous microparticles according to the present invention to reduce the destruction by macrophages with a sufficient particle size of about 20 ㎛, cyclodextrin Containing appropriate amount of derivatives ensures porosity, and contains protein drug stably and uniformly to move the drug to the core of the lungs, and it contains only sucrose acetate isobutylate (SAIB) to improve the drug encapsulation efficiency. In addition, it can be usefully used as a respiratory drug delivery formulation because it can suppress the initial release of the drug and thus sustained release for a long period of time, for a long time.

Description

Sustained release porous microparticles for the delivery of respiratory system drugs and a method of manufacturing the same {SUSTAINED-RELEASE POROUS MICROPARTICLE FOR PULMONARY DRUG DELIVERY AND PROCESS FOR PREPARARING THE SAME}

1 is a scanning electron for the porous microparticles obtained in Comparative Examples 1 (a), 2 (b), 4 (c), 5 (d), 6 (e and f) (where f is an enlarged view of e) Micrograph (SEM),

2 is a SEM photograph of the porous microparticles obtained in Comparative Example 7 (a) and Example (b),

3 is a graph showing the degree of drug release over time of the porous microparticles obtained in Comparative Examples 4 to 6,

4 is a graph showing the degree of drug release over time of the porous microparticles obtained in Comparative Example 8 and Example.

The present invention relates to sustained-release porous microparticles and methods for producing the same for delivery of respiratory system drugs.

Pulmonary drug delivery is characterized by fast delivery of drugs due to the large surface area of the lung, which is a delivery organ, and a thin absorption barrier, and significantly high permeability of the pulmonary mucosa to the polymeric material. Because of the systemic circulation, it is suitable for the administration route of immediate release medicine. In addition, the respiratory system drug delivery has the advantage of less patient pain when administered, and recently, research on the drug delivery system and delivery medium through the respiratory tract has been actively conducted.

For example, US Pat. No. 6,254,854 B1 discloses a method for preparing porous polymeric microspheres having an average particle diameter of 5 μm or more and a density of 0.4 g / cm 3 or less by introducing amino acid groups into a biodegradable polymer without the use of a separate pore-forming agent. Korean Patent Laid-Open Publication No. 2003-58431 proposes a method for preparing insulin microcrystals having an average particle diameter of 1-6 μm using additives, and US Patent Publication No. 2003/0068277 A1 treats multiple cationic agents. Inhaled sustained release composite particles obtained by complexing with. International Publication No. W001 / 13891 also discloses a method for controlling the release of a medicament for respiratory system administration by altering the substrate transition temperature through the selective addition of carboxylates, phospholipids and polyvalent salts, or ionic components. , Document [DA Edwords etc., Science, 276, 1868-1871, 1997 ] can not reach the deep lung to epithelial cells and is not removed by the ciliary movement and phagocytosis of waste 0.4 g / ㎤ density and less than 5 ㎛ A porous pharmaceutical particle having the above average particle diameter was presented, and International Publication No. 2004/060351 suggested a lung inhalation preparation consisting of porous particles having an average particle diameter of 3 μm. See also AI Bot et al., Pharm. Res., 17, 275-283, 2000 disclose porous microspheres prepared by spray drying chromolyn sodium, albuterol sulfate, and formoterol fumarate. HK Kim et al., J. Control. Release, 112, 167-174, 2006, describes a method for preparing porous microspheres using biodegradable polylactic acid-polyglycolic acid copolymers.

However, most of the existing porous particles are immediate release or cause denaturation of the drug, which does not sustain drug release for more than one day, or are easily destroyed by macrophages during delivery, resulting in low bioavailability or sustained release only in specific conditions. There was a limit to the development of long-term sustained release formulations of more than one day.

Accordingly, the present inventors have made a thorough study to solve the problems presented in the existing microparticles for respiratory drug delivery, cyclodextrin, viscous hydrophilic polymer, biodegradable polymer, sucrose acetate with protein drug as an active ingredient Sustained release porous microparticles, including isobutylate (SAIB) and water-based coating material, have a particle size of more than 5 μm, and move rapidly to the deep epithelial cells due to their low density while preventing lung ciliary movement and phagocytosis. The present invention was completed by finding that the drug maintains stability and sustained release.

An object of the present invention is to deliver the respiratory tract drug, which has a particle size large enough to prevent lung ciliary movement and phagocytosis, and rapidly moves to the deep epithelial cells to maintain stability and sustained release of the drug. To provide a sustained-release porous microparticles for.

Another object of the present invention is to provide a method for effectively preparing the porous microparticles.

In accordance with the above object, in the present invention has an average particle diameter of 5 to 100 ㎛, cyclodextrin derivatives, viscous hydrophilic polymer, biodegradable polymer, sucrose acetate isobutylate (SAIB) and aqueous with protein drug as active ingredient It provides a sustained release porous microparticles comprising a coating material.

According to the above another object, in the present invention

1) dissolving cyclodextrin derivatives, viscous hydrophilic polymers and protein drugs in water to produce an internal aqueous phase;

2) preparing an organic phase by adding a biodegradable polymer and SAIB to an organic solvent;

3) preparing a primary emulsion by mixing the internal aqueous composition obtained in step 1) and the organic phase composition obtained in step 2); And

4) It provides a method for producing the sustained-release porous microparticles comprising the step of spraying the primary emulsion obtained in step 3) to an external aqueous continuous phase containing an aqueous coating material.

Hereinafter, the present invention will be described in detail.

The sustained-release porous microparticles according to the present invention have an average particle diameter of 5 to 100 μm and include a cyclodextrin derivative, a viscous hydrophilic polymer, a biodegradable polymer, SAIB and an aqueous coating material together with an active protein drug. It is characterized by.

Sustained release porous microparticles of the present invention,

1) dissolving cyclodextrin derivatives, viscous hydrophilic polymers and protein drugs in water to produce an internal aqueous phase;

2) preparing an organic phase by adding a biodegradable polymer and sucrose acetate isobutylate (SAIB) to an organic solvent;

3) preparing a primary emulsion by mixing the internal aqueous phase obtained in step 1) and the organic phase obtained in step 2); And

And 4) spraying the primary emulsion obtained in step 3) onto an external aqueous continuous phase obtained by dissolving the aqueous coating material in water.

Hereinafter, the preparation method of the sustained-release porous microparticles of the present invention will be described in detail for each step.

Step 1) Internal Water Phase Manufacturing

In step 1), an internal aqueous phase is prepared by dissolving an active protein drug, a cyclodextrin derivative, and a viscous hydrophilic polymer in water.

1-1) Active Ingredients

As an active ingredient protein drug that may be included in the sustained-release porous microparticles of the present invention, any bioactive protein having a molecular weight in the range of 200 to 100,000 and consisting of two or more amino acids may be used. For example, human growth hormone, Insulin, bovine growth hormone, porcine growth hormone, growth hormone releasing peptide, B cell factor, T cell factor, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor , GM-CSF), macrophage-colony stimulating factor (M-CSF), erythropoietin, bone morphogenic protein, interferon, atriopeptin Tumor necrosis factor (TNF), macrophage activating factor, interleukin, tumor degenerating fact or), insulin-like growth factor, epidermal growth factor, tissue plasminogen activator, urokinase, protein A, allergic inhibitor, cell Necrotic glycoprotein, immunotoxin, lymphotoxin, tumor suppressor, metastatic growth factor, alpha-1 antitrypsin, albumin and fragments thereof, apolipoprotein-E, coagulation factor VII, coagulation factor VIII, coagulation factor IX, Pancreatic polypeptide, protein C, C-reactive protein, renin inhibitor, collagenase inhibitor, superoxide dismutase, platelet derived growth factor, osteogenic growth factor, bone formation promoting protein, calcitonin, cartilage Inducers, connective tissue activators, follicle stimulating hormones, luteinizing hormones, luteinizing hormone releasing hormones and their analogs, nerve growth factors, parathyroid hormones, secretin, jomatome , Adrenocorticotropic hormone, glucagon, cholecystokinin, gastrin releasing peptide, corticotropin releasing factor, thyroid stimulating hormone, monoclonal and polyclonal antibodies against various viruses, bacteria and toxins, various virus-derived vaccine antigens, humira (humira), remicade, octreotide acetate, salts thereof, mixtures thereof, and the like.

The active protein drug may be included in an amount of 1 to 40% by weight, preferably 5 to 25% by weight, based on the dry weight of the microparticles of the present invention.

1-2) cyclodextrin derivatives

Cyclodextrin derivatives used to prevent denaturation of the drug that may occur during the formulation process by forming a complex by inclusion of a protein drug in a cavity present in the chemical structure, which plays a critical role in pore formation of the microparticles of the present invention, for example 3-mono-ortho-methyl-cyclodextrin (3-mono- O -methyl-cyclodextrin ), 2,6- di-ortho-methyl-cyclodextrin (2,6-di- O- methyl-cyclodextrin ), 2,3,6-tri-ortho-methyl-cyclodextrin (2,3,6-tri- O- methyl-cyclodextrin), 2-hydroxyethyl-cyclodextrin, 2-hydroxypropyl-cyclodextrin, 3-hydroxypropyl-cyclodextrin, 6-ortho-glucosyl-cyclodextrin (6- O- Glucosyl-cyclodextrin ), 6-ortho-maltosyl-cyclodextrin (6- O- maltosyl-cyclodextrin ), 6-ortho-dimaltosyl-cyclodextrin (6- O- dimaltosyl-cyclodextrin), 2,6-di-ortho-ethyl-cyclodextrin (2,6-di- O- ethyl-cyclodextrin), 2 , 3,6-tri-ortho-ethyl-cyclodextrin (2,3,6-tri- O- ethyl-cyclodextrin), 2,3-di-ortho-hexanoyl-cyclodextrin (2,3-di O- hexanoyl-cyclodextrin), 2,3,6-tri-ortho-acetyl-cyclodextrin (2,3,6-tri- O- acetyl-cyclodextrin), 2,3,6-tri-ortho- Propanoyl-cyclodextrin (2,3,6-tri- O- propanoyl-cyclodextrin), 2,3,6-tri-ortho-butanoyl-cyclodextrin (2,3,6-tri- O- butanoyl -cyclodextrin), 2,3,6-tri-ortho-hexanoyl-cyclodextrin (2,3,6-tri- O -hexanoyl-cyclodextrin), 6-ortho-carboxymethyl-cyclodextrin (6- O -carboxymethyl-cyclodextrin, sulfated cyclodextrin, sulfobutyl-cyclodextrin, their induction Or a mixture thereof, preferably beta-cyclodextrin sulfobutyl ether sodium, a derivative of 2-hydroxypropyl-cyclodextrin and sulfobutyl-cyclodextrin, trade name: Captisol ( CAPTISOL)).

The cyclodextrin derivative may be included in an amount of 2 to 5 parts by weight based on 1 part by weight of the active ingredient, wherein less than 2 parts by weight hardly forms pores in the particles, and when it is more than 5 parts by weight, it is difficult to form microparticles. Can be.

1-3) viscous hydrophilic polymer

The viscous hydrophilic polymers included in the present invention for imparting viscosity to the internal aqueous phase while inhibiting denaturation of the protein drug upon mixing with the organic phase to inhibit the initial release of the protein drug and induce sustained release, range from about 340 to 300,000 Highly biocompatible polymers with low weight and molecular weight of, for example, starch, pectin, xanthan gum, curdlan, gelatin, dex It may be dextran, hyaluronic acid, salts thereof, or mixtures thereof, preferably starch, hyaluronic acid or gelatin, more preferably starch.

Viscous hydrophilic polymer may be included in an amount of 0.01 to 0.5 parts by weight, preferably 0.05 to 0.2 parts by weight based on 1 part by weight of the active ingredient.

Step 2) Organic Phase Preparation

In step 2), a biodegradable polymer and sucrose acetate isobutylate (SAIB) are added to an organic solvent to prepare an organic phase.

2-1) Biodegradable Polymers

Biodegradable polymers, which act as a matrix to encapsulate drugs in the formation of microparticles, have a weight average molecular weight of 2,000 to 100,000, and are usually administered to the body to provide water and carbon dioxide through the citric acid cycle, which is a normal biomechanical process. By biodegradation, it is possible to use an excellent biocompatibility and biodegradability (SJ Holland et al., J. Controlled Release , 4, 155-180, 1986). Representative examples of such biodegradable polymers include poly (acryloyl hydroxyethyl starch), copolymers of polybutylene terephthalate-polyethylene glycol, chitosan and derivatives thereof, and polyorthoester- Copolymers of polyethylene glycol, copolymers of polyethylene glycol terephthalate-polybutylene terephthalate, poly sebacic anhydride, pullulan and derivatives thereof, starch and derivatives thereof, cellulose acetate ) And derivatives thereof, polyanhydride, polycaprolactone, polycarbonate, polybutadiene, polyesters, polyhydroxybutyric acid, polymethyl meta Polymethyl methacrylate, polymethacrylic acid e ster, polyorthoester, polyvinyl acetate, polyvinyl alcohol, polyvinyl butyral, polyvinyl formal, protein (e.g. albumin) , Casein, collagen, fibrin, fibrinogen, gelatin, homoglobin, transferrin, zein), and mixtures thereof, preferably polylactic acid, polyglycolic acid, copolymers of polylactic acid-polyglycolic acid and polycaprolactone Etc. may be included. In particular, the copolymers of polylactic acid-polyglycolic acid have shorter in vivo metabolic half-lives at lung inhalation of 4 and 14 days at molecular weights of 10,000 and 20,000 (JM Anderson et al., Adv. Drug Delivery Rev., 28, 5-24, 1997) Long-term administration of drugs can eliminate side effects that may be caused by incomplete degradation of the polymer.

The biodegradable polymer may be used in an organic solvent in a concentration range of 5 to 60% (w / v), preferably 10 to 30% (w / v).

2-2) Sucrose Acetate Isobutylate (SAIB)

SAIB is a biodegradable polymer having affinity and viscosity for protein drugs and is included in the present invention to serve to delay the release of protein drugs.

SAIB may be used in an organic solvent in a concentration range of 5 to 60% (w / v), preferably 10 to 30% (w / v), wherein the mixed weight ratio of SAIB to biodegradable polymer is 1: 0.1 to 1: 1 preferably 1: 0.5, and when the mixing ratio of SAIB is greater than 1: 1, microparticle formation is impossible.

2-3) Organic Solvent

Organic solvents are miscible to prevent phase separation between biodegradable polymers and SAIB. Can be used.

Step 3) Prepare the Primary Emulsion

In step 3), the organic phase obtained in step 2) is added to the internal aqueous phase obtained in step 1), followed by vigorous stirring to prepare a primary emulsion (W / O, water-in-oil), wherein the internal aqueous phase and the organic phase The mixing volume ratio of can range from 1: 3 to 1:30, preferably from 1: 5 to 1:15.

Step 4) Preparation of Secondary Emulsion

In step 4), the secondary emulsion (W / O / W, water-in-oil-in-water) is added by adding the primary emulsion obtained in step 3) to an external aqueous continuous phase comprising an aqueous coating material. ), The solid produced in the secondary emulsion thus obtained is separated by filtration or centrifugation, and dried to prepare a sustained-release porous microparticles according to the present invention.

4-1) Waterborne Coating Material

An aqueous coating material is used to prevent phase separation when the primary emulsion obtained in step 3) is added to an external aqueous continuous phase. Examples of such aqueous coating materials include polyvinyl alcohol and methyl cellulose. , Cetyltrimethyl ammonium bromide, sodium dodecyl sulphate and polyoxyethylene sorbitan monooleate, and the like, and preferably polyvinyl alcohol. . In particular, polyvinyl alcohols preferably have a weight average molecular weight of 10,000 to 100,000, preferably 13,000 to 50,000, and a degree of hydrolysis in the range of 75 to 95%, preferably 83 to 89%.

The aqueous coating material is prepared and used in an aqueous solution (external aqueous continuous phase) in the concentration range of 0.1 to 5% (w / v), preferably 0.3 to 2% (w / v).

4-2) Sodium Chloride

In order to control the osmotic pressure in the microparticles of the present invention, the external aqueous phase continuous phase may further include 0.1 to 10% (w / v), preferably 0.1 to 1.0% (w / v) of sodium chloride.

Sustained-release porous microparticles according to the present invention have a sufficient particle size of about 20 μm to reduce destruction by macrophages, to contain porosity by containing an appropriate amount of cyclodextrin derivatives as well as to stably and uniformly contain protein drugs in the lungs. The drug can be transported to the core, and the SAIB can be used as a respiratory drug delivery formulation because it not only has excellent encapsulation efficiency of the drug but also suppresses the initial release of the drug so that the drug can be continuously released for a long period of time for a long time. Can be.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Example

An aqueous phase composition was prepared by dissolving 200 mg of captisol (CAPTISOL, CyDex) and 50 mg of bovine serum albumin (BSA) in 1.0 ml of 2.5% starch aqueous solution, and a copolymer of polylactic acid-polyglycolic acid ( Molar ratio of lactic acid: glycolic acid = 50:50) 300 mg of RG504H (molecular weight: 45,000, Boehringer Ingelheim) and 150 mg of SAIB (Aldrich) were added to 3 ml of dichloromethane to prepare an organic phase composition. An internal aqueous composition was added to the organic phase composition, followed by vigorous stirring to prepare a primary emulsion. An external aqueous continuous phase made by dissolving 0.5% (w / v) polyvinyl alcohol and 0.9% (w / v) sodium chloride in water. The secondary emulsion was prepared by spraying the primary emulsion solution on the composition at a volume ratio of 200: 1 and stirring at 4,000 rpm for 5 minutes. The obtained secondary emulsion was centrifuged at 3,000 rpm for 2 minutes to separate solids, and then the separated solids were dried for 48 hours at an early lyophilized state to prepare sustained-release porous microparticles according to the present invention.

Comparative Example 1

A solution of 0.25% hyaluronic acid instead of a 2.5% aqueous solution of starch and a polylactic acid-poly copolymer of polylactic acid-polyglycolic acid (molar ratio of lactic acid: glycolic acid = 50:50) RG504H 300 mg and SAIB (Aldrich) 150 mg Copolymer of glycolic acid (molar ratio of lactic acid: glycolic acid = 50:50) 300 mg of RG 502H (molecular weight: 7,800, Boehringer Ingelheim) and 100 mg of RG504H, except that 100 mg of captisol, The same process as in Example was carried out to prepare porous microparticles.

Comparative Example 2

A porous microparticle was prepared in the same manner as in Comparative Example 1, except that 200 mg of captisol was used.

Comparative Example 3

The same process as in Comparative Example 1 was conducted except that 300 mg of captisol was used.

As a result, microcapsules could not be formed due to the inclusion of excess captisol.

Comparative Example 4

A porous microparticle was prepared in the same manner as in Comparative Example 2 except that 150 mg of the copolymers RG 502H and RG504H of the polylactic acid-polyglycolic acid were used.

Comparative Example 5

A porous microparticle was prepared in the same manner as in Comparative Example 3, except that an aqueous 0.25% hyaluronic acid solution was used in 1.5 ml.

Comparative Example 6

A porous microparticle was prepared by the same process as Comparative Example 4, except that 250 mg of captisol was used.

Comparative Example 7

Except not using the captisol, the same process as in Comparative Example 1 was prepared to produce microparticles.

Comparative Example 8

Except not using SAIB, the same process as in Example was carried out to prepare microparticles.

Test Example 1 Measurement of Loading Efficiency of Drugs

The encapsulation rate of the drug was measured as follows on the porous microparticles prepared in Examples and Comparative Examples 1, 2, and 4 to 8.

10 mg of the porous microparticles were taken and placed in a capped test tube containing 0.5 ml of dichloromethane, respectively, and then completely dissolved. 5 ml of 6 M hydrochloric acid was added thereto, followed by vigorous stirring for 1 hour. The obtained solution was centrifuged at 5000 rpm for 5 minutes, and then 1 ml of the supernatant was shaken at a speed of 60 times per minute for 24 hours in a 37 ° C shaking water bath. 6 ml of 1 M sodium hydroxide solution was added thereto, followed by shaking for 24 hours under the same conditions. Then, 50 µl of the obtained reaction product was added to 125 µl and 0.5 µl of 4% (w / v) sodium bicarbonate (pH 9.0). 50 μl of% (w / v) trinitrobenzenesulfonic acid solution was mixed and left at room temperature for 2 hours. The drug concentration was calculated by measuring the absorbance at λ = 450 nm with a microplate reader of the obtained test solutions, and the amount of drug encapsulated in the microparticles was calculated based on the calculated drug concentration. Subsequent to 1 and 2 was calculated the content of the drug in the particles and the encapsulation efficiency, the results are shown in Table 1 below.

Drug content (%) = (amount of drug enclosed in microparticles / total amount of microparticles) x 100

Encapsulation efficiency (%) of drug = (quantity of drug encapsulated in microparticles / amount of drug used for manufacture) × 100

As shown in Table 1, the porous microparticles of Comparative Examples 1, 2 and 4 to 6 using hyaluronic acid as a viscous hydrophilic polymer had about 60% drug encapsulation efficiency, while including a cyclodextrin derivative. In the case of the non-porous microparticles Comparative Example 7, Comparative Example 8 using starch as the viscous hydrophilic polymer, and the porous microparticles of the Example was confirmed that the encapsulation efficiency increased to 87 to 91%.

Test Example 2: Observation of the porosity of particles and measurement of the average particle diameter

The porosity of the particles was observed by scanning electron microscope (SEM) imaging of the porous microparticles prepared in Examples and Comparative Examples 1, 2, and 4 to 8, and the results are shown in FIGS. 1 and 2. The microparticle sample population was randomly selected and the average particle diameter was calculated by measuring the diameters, and is shown in Table 2 below.

As a result, as shown in Figures 1 and 2, when the cyclodextrin is not included, it is difficult to secure the porosity of the microparticles (Fig. 2, Comparative Example 7 (a)), the higher the content of the cyclodextrin, the higher the porosity It was confirmed (Fig. 1, Comparative Examples 1 (a) and 2 (b)), it can be seen that in the case of Comparative Example 3 because the content of the cyclodextrin is too high it is impossible to form particles. In addition, as shown in Figure 2, it was confirmed that such porosity is also affected by the content of viscous hydrophilic and biodegradable polymers in addition to the cyclodextrin derivative (Fig. 1, Comparative Example 4 (c), 5 (d)) , 6 (e and f)). On the other hand, as shown in Figure 2 (b), it was confirmed that the porous microparticles of the present invention prepared in the example exhibits a porosity suitable for use as a respiratory system drug delivery formulation.

In addition, as shown in Table 2, it was confirmed that the polymer microspheres of the embodiment according to the present invention has an average particle diameter of about 20 ㎛ suitable for use as a respiratory system drug delivery formulation.

Test Example 3 In Vitro of Drug ( in vitro Release experiment

The release rate of the protein drug was confirmed in the following in vitro conditions for the porous microparticles prepared in Examples and Comparative Examples 4, 5, 6 and 8.

40 mg of each microparticle was placed in a test tube containing 10 ml of 0.033 M aqueous solution of 0.033 M phosphate (pH 7.4, 0.01% sodium azide, 0.02% Tween 80), sealed and shaken for 60 days at a rate of 60 times per minute in a 37 ° C shaking constant temperature bath. Protein drug release was confirmed. At this time, 5 ml of the solution containing the released drug was taken every unit time during the shaking process, and a new phosphate solution was supplemented with the same amount. The concentration of the released drug was measured using the micro BCA reagent kit (PIERCE Co., Ltd.) on the obtained release liquid, and the cumulative release amount was calculated for each unit time to determine the drug release rate according to time. FIGS. 3 and 4 Shown in

As a result, as shown in Figures 3 and 4, the porous microparticles of Comparative Examples 4, 5, 6 and 8 that do not contain SAIB showed immediate release within 4 hours, while the porosity of the Example using SAIB In the case of microparticles, drug release was effectively delayed, indicating sustained sustained release over 7 days.

As described above, the sustained-release porous microparticles according to the present invention reduce the destruction by macrophages with a sufficient particle size of about 20 μm, contain an appropriate amount of cyclodextrin derivatives to secure porosity as well as to stabilize protein drugs. The drug can be transported to the center of the lungs evenly and contains the SAIB, which not only improves the encapsulation efficiency of the drug but also suppresses the initial release of the drug, allowing continuous release for a long period of time and a week. It can be usefully used.

Claims (18)

Sustained release porosity with an average particle diameter of 5 to 100 μm, including cyclodextrin derivatives, viscous hydrophilic polymers, biodegradable polymers, sucrose acetate isobutylate (SAIB), and aqueous coating materials together with protein drugs as active ingredients As microparticles, the protein drug is human growth hormone, insulin, bovine growth hormone, porcine growth hormone, growth hormone releasing peptide, B cell factor, T cell factor, granulocyte-colony stimulating factor (G-CSF), granulocyte Macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), erythropoietin, bone morphogenic protein , Interferon, atriopeptin, tumor necrosis factor (TNF), macrophage activating factor, interleu Interleukin, tumor degenerating factor, insulin-like growth factor, epidermal growth factor, tissue plasminogen activator, urokinase urokinase), allergic inhibitors, cell necrosis glycoproteins, immunotoxins, lymphotoxins, tumor suppressors, metastatic growth factors, alpha-1 antitrypsin, albumin and fragments thereof, apolipoprotein-E, coagulation factor VII, blood coagulation Factor VIII, coagulation factor IX, pancreatic polypeptide, renin inhibitors, collagenase inhibitors, superoxide dismutase, platelet-derived growth factor, osteogenic growth factor, bone stimulating protein, calcitonin, cartilage Inducers, connective tissue activators, follicle stimulating hormones, luteinizing hormones, luteinizing hormone releasing hormones and their analogs, nerve growth factors, parathyroid hormones, secretin, Matomedin, adrenocorticotropic hormone, glucagon, cholecystokinin, gastrin releasing peptide, corticotropin releasing factor, thyroid stimulating hormone, monoclonal and polyclonal antibodies against viruses, bacteria or toxins, virus derived vaccine antigens, humira (humira), remicade, octreotide acetate, salts thereof and mixtures thereof, wherein the cyclodextrin derivative is 2 to 5 parts by weight based on 1 part by weight of the active ingredient Included as, sustained release porous microparticles. 1) dissolving a cyclodextrin derivative, a viscous hydrophilic polymer and an active protein drug in water to prepare an internal aqueous phase; 2) preparing an organic phase by adding a biodegradable polymer and sucrose acetate isobutylate (SAIB) to an organic solvent; 3) preparing a primary emulsion by mixing the internal aqueous phase obtained in step 1) and the organic phase obtained in step 2); And 4) A method for preparing the sustained-release porous microparticles of claim 1, comprising spraying the primary emulsion obtained in step 3) with an external aqueous continuous phase containing an aqueous coating material. The protein drug may be human growth hormone, insulin, bovine growth hormone, porcine growth hormone, growth hormone releasing peptide, B cell factor, T cell factor, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulation Granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), erythropoietin, bone morphogenic protein, interferon ), Atriopeptin, tumor necrosis factor (TNF), macrophage activating factor, interleukin, tumor degenerating factor, insulin-like growth factor ), Epidermal growth factor, tissue plasminogen activator, urokinase, allergic inhibitor, cell necrosis glycoprotein, cotton Toxin, lymphotoxin, tumor suppressor, metastatic growth factor, alpha-1 antitrypsin, albumin and fragments thereof, apolipoprotein-E, coagulation factor VII, coagulation factor VIII, coagulation factor IX, pancreatic polypeptide, lenin Inhibitors, collagenase inhibitors, superoxide dismutases, platelet-derived growth factors, osteogenic growth factors, osteogenic proteins, calcitonin, cartilage inducers, connective tissue activators, follicle stimulating hormones, corpus luteum Forming hormones, luteinizing hormone releasing hormone and its analogs, nerve growth factor, parathyroid hormone, secretin, jomatomedin, adrenocorticotropic hormone, glucagon, cholecystokinin, gastrin releasing peptide, corticotropin releasing factor, thyroid Monoclonal and polyclonal antibodies against viruses, vaccines against stimulating hormones, viruses, bacteria or toxins Raw, humira, remicade, octreotide acetate, salts thereof, and mixtures thereof, wherein the cyclodextrin derivative is 2 to 5 based on 1 part by weight of the active ingredient The amount in parts by weight. delete The method of claim 2, Protein drug is 1 to 40% by weight based on the dry weight of the microparticles of the present invention. The method of claim 2, Cyclodextrin derivative is 3-mono-ortho-methyl-cyclodextrin (3-mono- O -methyl-cyclodextrin ), 2,6- di-ortho-methyl-cyclodextrin (2,6-di- O- methyl -cyclodextrin), 2,3,6-tri-ortho-methyl-cyclodextrin (2,3,6-tri- O- methyl-cyclodextrin), 2-hydroxyethyl-cyclodextrin , 2-hydroxypropyl-cyclodextrin, 3-hydroxypropyl-cyclodextrin, 6-ortho-glucosyl-cyclodextrin (6- O- Glucosyl- cyclodextrin), 6- ortho-end tosyl-cyclodextrin (6- O -maltosyl-cyclodextrin), 6- ortho-dimal tosyl-cyclodextrin (6- O -dimaltosyl-cyclodextrin), 2,6- di-rise So-ethyl-cyclodextrin (2,6-di- O- ethyl-cyclodextrin), 2,3,6-tri-ortho-ethyl-cyclodextrin (2,3,6-tri- O -ethyl-cyclodextrin) , 2,3-di-ortho-hexanoyl- Cyclodextrin (2,3-di- O- hexanoyl-cyclodextrin), 2,3,6-tri-ortho-acetyl-cyclodextrin (2,3,6-tri- O- acetyl-cyclodextrin), 2,3 , 6-tri-ortho-propanoyl-cyclodextrin (2,3,6-tri- O- propanoyl-cyclodextrin), 2,3,6-tri-ortho-butanoyl-cyclodextrin (2,3 , 6-tri- O- butanoyl-cyclodextrin), 2,3,6-tri-ortho-hexanoyl-cyclodextrin (2,3,6-tri- O -hexanoyl-cyclodextrin), 6-ortho-carboxy Methyl-cyclodextrin (6- O- carboxymethyl-cyclodextrin), sulfated cyclodextrin (sulphated cyclodextrin), sulfobutyl-cyclodextrin (sulfobutyl-cyclodextrin), derivatives thereof, and mixtures thereof How to. delete The method of claim 2, Viscous hydrophilic polymers contain starch, pectin, xanthan gum, curdlan, gelatin, dextran, dextran, with weight average molecular weights ranging from 340 to 300,000. Hyaluronic acid, salts thereof, and mixtures thereof. The method of claim 7, wherein Wherein the viscous hydrophilic polymer is starch. The method of claim 2, The viscous hydrophilic polymer is characterized in that it comprises 0.01 to 0.5 parts by weight based on 1 part by weight of the active ingredient. The method of claim 2, Biodegradable polymers have poly (acryloyl hydroxyethyl starch), copolymers of polybutylene terephthalate-polyethyleneglycol, chitosan and derivatives thereof having an average molecular weight of 2,000 to 100,000, poly Copolymers of orthoester-polyethylene glycol, copolymers of polyethylene glycol terephthalate-polybutylene terephthalate, poly sebacic anhydride, pullulan and derivatives thereof, starch and derivatives thereof, cellulose Cellulose acetate and its derivatives, polyanhydrides, polycaprolactones, polycarbonates, polybutadienes, polyesters, polyhydroxybutyric acid , Polymethyl methacrylate, polymethacrylic acid ester (poly methacrylic acid ester, polyorthoester, polyvinyl acetate, polyvinyl alcohol, polyvinyl butyral, polyvinyl formal, albumin, casein, Collagen, fibrin, fibrinogen, gelatin, homoglobin, transferrin, zein, and mixtures thereof. The method of claim 2, Wherein the biodegradable polymer is used in an organic solvent at a concentration of 5 to 60% (w / v). The method of claim 2, Sucrose acetate isobutylate (SAIB) is used in an organic solvent at a concentration of 5 to 60% (w / v). The method of claim 2, A method characterized in that the mixing weight ratio of SAIB to biodegradable polymer is 1: 0.1 to 1: 1. The method of claim 2, Wherein the organic solvent is selected from the group consisting of dichloromethane, ethyl acetate, dimethylsulfoxide, dimethylformamide, chloroform, alcohols, acetone and mixtures thereof. The method of claim 2, Characterized in that the mixing volume ratio of the organic phase obtained in step 2) and the internal aqueous phase obtained in step 1) ranges from 1: 3 to 1:30. The method of claim 2, Aqueous coating materials include polyvinyl alcohol, methyl cellulose, cetyltrimethyl ammonium bromide, sodium dodecyl sulphate and polyoxyethylene sorbitan monooleate ( polyoxyethylene sorbitan monooleate). The method of claim 2, The external aqueous continuous phase composition is an aqueous solution comprising an aqueous coating material at a concentration of 0.1 to 5% (w / v). The method of claim 17, The external aqueous continuous phase composition further comprises 0.1 to 10% (v / v) sodium chloride.

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