KR100871988B1 - Method for preparing biodegradable microsphere carrier in which water-soluble macromolecular drug is encapsulated without water-soluble solvent and biodegradable microsphere carrier - Google Patents

Abstract

A method for preparing a biodegradable polymer microgranular carrier, and a polymer microgranular carrier prepared by the method are provided to prevent the degeneration of water-soluble macromolecular drugs such as proteins by not generating the interface of an organic solvent and an aqueous solution. A method for preparing a biodegradable polymer microgranular carrier comprises the steps of freeze-drying polyethylene glycol (PEG) and human growth hormone and dissolving it or dispersing into nano-sized one in an organic solvent; and dissolving a polyester-based polymer in the organic solvent where polyethylene glycol and human growth hormone are dissolved or dispersed by nano-size, so as to formulate it.

Description

Method of preparing biodegradable microsphere carriers in which a water-soluble macromolecular drug is encapsulated without a water-soluble solvent and a biodegradable microsphere carrier within a biodegradable microparticles and biodegradable microparticles}

1 is a schematic diagram showing a process of encapsulating a water-soluble drug in a biodegradable polymer microsphere carrier used in the present invention,

FIG. 2A shows a result of dissolving polyethylene glycol and human growth hormone in a methylene chloride organic solvent according to the weight ratio, and then checking the permeability of the solution and the methylene chloride at a weight ratio of PEG: human growth hormone = 1: 5. The size of the PEG / human growth hormone complex in the solvent was measured using dynamic light scattering (DLS).

FIG. 2B shows the results of the release behavior under physiological saline buffer solution for 30 days after encapsulating human growth hormone in the microsphere carrier using PLGA polymer (molecular weight 30000-34000) and the shape of the biodegradable microsphere carrier prepared Was observed using a scanning electron microscope,

3A and 3B show the shape of the microsphere carrier by spray drying using PLGA / polyethylene glycol / human growth hormone dissolved in methylene chloride, and then observed the shape using a scanning electron microscope.

Figure 3 C and D is a result of observing the shape change of the microparticles after freeze-drying the microsphere carrier showing the release behavior in physiological saline conditions for 20 days,

Figure 4A is a polyacrylamide gel (polyacrylamide gel), each of the human growth hormone not used in the formulation and the human growth hormone released for one day after being encapsulated in a biodegradable microsphere carrier,

FIG. 4B shows the results confirming that the original structure is maintained even after encapsulation in the microsphere carrier using size exclusion chromatography.

The present invention relates to a method for producing a biodegradable microsphere carrier and to a biodegradable microsphere carrier, and more particularly, to dissolve a water-soluble macromolecular drug in an organic solvent using polyethylene glycol in an organic solvent without using an aqueous solution, or The present invention relates to a method for producing a biodegradable microsphere support using a polyester-based polymer on a single organic solvent, and to a biodegradable polymer microsphere support prepared thereby.

Injectable and oral preparations which are generally used today have difficulty in maintaining the concentration of a drug having a long-term therapeutic effect in the body by a single administration. Therefore, many studies have been conducted on the preparation of the drug in the biodegradable polymer carrier so that the drug is continuously released slowly as the polymer carrier is decomposed.

Conventionally, a method for preparing a sustained-release drug delivery system (DDS) preparations is known as coacervation method, emulsion phase separation method, encapsulation by spray drying, and solvent evaporation in organic or aqueous phase. Among these methods, the solvent evaporation method in the water phase is most used, and the methods are largely classified into a double emulsion evaporation method and a single emulsion evaporation method.

In general, the double-emulsification evaporation method used for encapsulating a water-soluble macromolecular drug such as a peptide or a protein is obtained by dispersing a drug-containing aqueous solution prepared by dissolving the drug in an aqueous solution and dispersing it in an organic solvent containing a biodegradable polymer to form a primary emulsion. Next, a method of dispersing this in the water phase.

The above method is a method in which the organic solvent is removed by extraction or evaporation in the process of dispersing the polymer in the organic solvent in the aqueous phase, thereby solidifying due to the decrease in the solubility of the polymer and consequently forming the microspheres. This method has the advantage of being able to encapsulate most water soluble drugs into particulate carriers.

However, this method is complicated when the production method is complex, the amount of protein lost during the manufacturing process, protein entanglement at the interface between the aqueous solution and the organic solvent formed during the manufacturing process damage the structural properties of the original protein Has its drawbacks. In the case of macromolecular drugs such as peptides and proteins, instability problems of drugs such as covalent / non-covalent aggregation, nonspecific adsorption, and denaturation occur during the encapsulation into microsphere carriers.

Spray-drying can reduce the loss of drugs during the manufacturing process, but it is still necessary to use two different solvents to encapsulate the water-soluble biomacromolecule drug. do.

Attempts have been made in various respects to address the stability of the drug in the encapsulation of such a drug into the particulate carrier, in particular the modification of the protein at the aqueous / organic solvent interface during the encapsulation of the protein drug into the polymeric microsphere carrier. The research to solve the problem was outstanding.

One approach has been to improve the protein stability at the interface by adding stabilizers [OL Johnson et al. Pharm Res . 14 (1997) 730-735; MA Tracy, Biotech . Prog . 14 (1998) 108-115. For example, Tween 20, Tween 40, Tween 80, Polyethylene glycol (PEG), Carboxymethyl cellulose, Mannitol, Trehalose, Dex Detran 70 and Gelatin have been shown to reduce the denaturation of human growth hormones at the aqueous / organic solvent interface, and are found in Mannitol, Gelatin, Trehalose, Mannitol / There is an example applied to the preparation of a polymeric microsphere carrier in which human growth hormone is encapsulated using Trehalose, Carboxymethyl cellulose [JL Cleland and AJS Jones, Pharm. Res. 13 (1996) 1464-1475.

Another approach has been to formulate a method of changing the preparation itself so that the aqueous solution / organic solvent interface does not occur in the process of encapsulating the protein drug in the particulate carrier. For example, a method in which the protein itself is made into fine particles, directly dispersed in a dissolved organic solvent, and then encapsulated in a polymer microsphere carrier [T. Morita, Y. Sakamura, Y. Horikiri, T. Suzuki, H. Yoshino, J. Control . Rel . 69 (2000) 435-444], a method for preparing a microsphere carrier by dispersing human growth hormone in a solvent together with a polymer, spraying at low temperature, and extracting a solvent [JL Cleland, OL Johnson, S. Putney, AJS Jones, Adv . Drug Deliv . Rev. 28 (1997) 71-84; OL Johnson et al. Pharm . Res . 14 (1997) 730-735.

Recently, in order to solve the problem of protein denaturation during the preparation of microparticles for the delivery of protein drugs, a case of producing microparticles by spray-drying an aqueous solution of hyaluronic acid and human growth hormone in an aqueous solution was reported. However, protein denaturation did not occur, but more than 80% of the encapsulated protein was released within 1 day, showing no sustained protein release behavior (Sei Kwang Hahn et al., Pharm . Res . , 21, 1374 (2004). )). These are approaches that try to solve the problem by eliminating the generation of aqueous solutions / organic solvents that are the source of the problem.

The present invention is to solve the problems of the prior art as described above,

One object of the present invention is to provide a method for preparing a biodegradable polymer microsphere carrier that can enclose a hydrophilic macromolecular drug without using an aqueous solution.

      Another object of the present invention is to provide a biodegradable polymeric microsphere carrier prepared by the above method.

      One aspect of the present invention for achieving the above object is (1) lyophilizing a polyethylene glycol (PEG) polymer and a water-soluble macromolecular drug to be dissolved in an organic solvent or dispersed in nano-sized; And (2) dissolving the water-soluble macromolecule drug and the polyester-based polymer together on an organic solvent in which polyethylene glycol is dissolved or dispersed in nano size; It provides a method for producing a biodegradable polymer microsphere carrier comprising a.

The polyethyleneglycol polymer used in the present invention is a polymer synthesized using ethylene glycol as a monomer and does not show toxicity when entering the body, does not cause an immune reaction, and can be removed through kidney or liver. Due to these characteristics, polyethylene glycol has been most widely used as a polymer approved for use in humans in the US Food and Drug Administration (FDA) for intravenous injection, oral administration, and skin administration (Y Kodera, et al., Prog . Polym . Sci . , 23, 1233 (1998).

      To date, polyethylene glycol has been used for the development of carriers for the delivery of genes or protein drugs by conjugation with cationic polymers, and its biocompatibility has already been demonstrated.

      The polyethylene glycol polymer may be a polyethylene glycol substituted with an amine group (amine modified PEG), a thiol group substituted polyethylene glycol (thiol modified PEG), a carboxyl substituted polyethylene glycol (carboxyl modified PEG), a hydroxyl group or other active group at the end At least one selected from the group consisting of polyethylene glycol, linear polyethylene glycol (linear PEG) and branched polyethylene glycol (branched PEG) may be used, but is not limited thereto.

The polyethylene glycol substituted with the amine group may be methoxy polyethylene glycol amine or polyethylene glycol diamine, but is not limited thereto.

The mass average molecular weight of the polyethylene glycol polymer used in the present invention may be 400 to 1,000,000, preferably 400 to 50,000, more preferably 3,000 to 4,000.

The water-soluble macromolecule drug used in the present invention is preferably a drug that requires a long-lasting effect. Specific examples of the water-soluble macromolecule drug include human growth hormone (Human Growth Hormone) and G-CSF (Granulocyte Colony-Stiumulating Factor). ), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), erythropoietin, vaccine, antibody, insulin, calcitonin, adrenocorticotropic hormone, glucagon, somatostation, somatotropin (somatotropin), somatomedin, parathyroid hormone, hypothalamus, thyroid hormone, prolactin, endorphin, VEGF (vascular endothelial growth factor), enkephalin, vasopressin, and vasopressin (nerve growth factor), non-naturally occurring opioid, superoxide dismutase, interferon, asparagine Asparaginase, arginase, trypsin, chymotrypsin, pepsin, DNA, siRNA, oligonucleotide, heparin or hyaluronic acid. Any drug that requires a sustained effect can be used without limitation.

      The organic solvent used in the present invention is characterized in that it does not contain a surfactant or an emulsifier. Specific examples of the organic solvent include methylene chloride, chloroform, acetone, dimethyl sulfoxide, dimethylformamide, and N-methylpi. Although there may be mentioned rolidone, dioxane, tetrahydrofuran, ethyl acetate, methyl ethyl ketone or acetonitrile, and the like, any organic solvent having a property that may not contain a surfactant or an emulsifier may be used without limitation.

Aliphatic polyesters are currently used in the development of various polymer carriers, have been recognized for their biocompatibility, have been approved by the US Food and Drug Administration (FDA), and are widely used for materials for drug delivery carriers and surgical sutures. Specific examples of aliphatic polyesters include poly-L-lactic acid, polyglycolic acid, poly-D-lactic acid-co-glycolic acid, poly-L-lactic acid-co-glycolic acid, poly-D, L-lactic acid-co- Glycolic acid (poly (D, L-lactic-co-glycolic acid), hereinafter referred to as 'PLGA'), poly-caprolactone, poly-valerolactone, poly-hydroxy butyrate and poly-hydroxy valerate [LB Peppas, Inter . J. of Pharm . 116 (1995) 1-9].

      The polyester-based polymer used in the present invention is characterized in that the biodegradable polyester-based polymer, specific examples of the polyester-based polymer is poly-L-lactic acid (poly-L-lactic acid), poly-glycolic acid , Poly-D-lactic acid-co-glycolic acid, poly-L-lactic acid-co-glycolic acid, poly-D, L-lactic acid-co-glycolic acid, poly-caprolactone, poly-valerolactone, poly-hydr Hydroxy butyrate or poly-hydroxy valerate, and the like, but may be used without limitation as long as it has biodegradable properties.

In the step (1) of the preparation method according to the present invention, the weight ratio of the polyethylene glycol polymer and the water-soluble macromolecule on the organic solvent is preferably 1: 1 to 50: 1, but the weight ratio exceeds 50: 1 polyethylene glycol (PEG) is present in excess, which may cause problems in the release behavior during microsphere preparation.

In the method for producing a biodegradable polymer microsphere carrier according to the present invention, it is preferable that the weight ratio of the polyester-based polymer to the whole polymer is 0.3: 1 to 0.95: 1, but when the weight ratio is not 0.3: 1 The initial release amount of the drug from the microspheres may be increased, which may make it difficult to sustain the continuous release behavior. On the contrary, when the weight ratio exceeds 0.95: 1, the amount of the drug that may be contained in the microspheres may be reduced. have.

In the method for preparing a biodegradable polymer microsphere carrier according to the present invention, the formulation may be carried out by a spray drying method, ultrasonic dispersion method, coacervation method, emulsion phase separation method or solvent evaporation method in an organic phase, but the microsphere carrier If the method can be prepared, it can be used without limitation.

Another aspect of the present invention for achieving the above object is to provide a biodegradable polymeric microsphere carrier prepared by the above method.

      Since the biodegradable polymer microsphere carrier according to the present invention does not use an aqueous solution, the aqueous solution / organic solvent interface does not occur, thereby preventing structural modification of the water-soluble macromolecule drug, so that it can be stably encapsulated in the microsphere carrier, and the formulation process is simple. This has the advantage that the drug encapsulated from the microsphere carrier can be continuously controlled released.

      In other words, the biodegradable polymer microsphere carrier according to the present invention is a water-soluble macromolecular drug for treatment on a single organic solvent using only polyethylene glycol and biodegradable polyester polymer, which are clinically applicable polymers, without using a surfactant or an emulsifier. It is meaningful to prepare the encapsulated microsphere carrier to maintain the stability and bioactivity of the water-soluble macromolecule drug, and to show the behavior of the encapsulated drug continuously released slowly.

      Hereinafter, a method for preparing a biodegradable polymer microsphere support according to the present invention will be described in detail with reference to FIG. 1.

First step: dispersing the hydrophilic macromolecular drug into nanoparticles on an organic solvent.

The solubilization method of the water-soluble macromolecular drug in the organic solvent is prepared through a series of processes including the step of removing the salt from the water-soluble drugs, mixing the freeze-dried polyethylene glycol and water-soluble polymer, and dissolving in the organic solvent. At this time, polyethylene glycol and the water-soluble macromolecular drug react with non-covalent bonds to solubilize or form nano-sized particles in an organic solvent.

The polyethylene glycol polymer is a terminal having an amine group, a carboxyl group, a hydroxyl group, a thiol group, or other active groups which are functional groups, preferably a linear polymer, a branched polymer, or the like. The polyethylene glycol having a molecular weight of about 400 to 50000 is used, most preferably a straight polyethylene glycol having a hydroxyl group at the end of the molecular weight of about 3350.

In the first step of the present invention, the drug used as an active ingredient of the microsphere carrier can be applied to vaccines, hormone preparations and other hydrophilic therapeutic drugs that require long-term administration. For example, Human Growth Hormone, Granulocyte Colony-Stiumulating Factor (G-CSF), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Erythropoietin, Vaccines, Antibodies, Insulin, Calcitonin ( calcitonin, adrenocorticotropic hormone (ACTH), glucagon, somatostation, somatotropin, somatomedin, parathyroid hormone, hypothalamus, thyroid hormones, prolactin, and endorphins , Vascular endothelial growth factor (VEGF), enkephalin, vasopressin, nerve growth factor, non-naturally occurring opioid, superoxide dismutase ), Interferon, asparaginase, arginase, trypsin, chymotrypsin, pepsin, DNA, siRNA, and oligonucleotides nucleotides), polysaccharide polymers (hyaluronic acid, heparin, etc.), and the like, but are not limited thereto. All drugs requiring long-term administration are subject to the preparation method according to the present invention.

Second step: nano-sized water-soluble macromolecular drug particles formed on the organic solvent Polyester  With polymer Formulated Microsphere Carrier  Manufacturing step.

Polyethylene glycol / drug nanoparticles dispersed in the organic solvent prepared by the method described above are dissolved in the same solvent as the polyester-based polymer to obtain a polymer microsphere carrier to enable sustained release of the drug.

As a formulation method for preparing the microsphere carrier in the present invention, a spray drying method, an ultrasonic dispersion method, a coacervation method, an emulsion phase separation method or a solvent evaporation method in an organic phase can be used, and the microsphere carrier can be prepared. Any method that exists can be used in the preparation method of the present invention.

The biodegradable polyester-based polymer in the second step maintains the form of the microsphere carrier to be produced, and serves to keep the drug continuously release behavior.

The polyester polymer may be poly-L-lactic acid, poly-glycolic acid, poly-D-lactic acid-co-glycolic acid, poly-L-lactic acid-co-glycolic acid, poly- D, L-lactic acid-co-glycolic acid, poly-caprolactone, poly-valerolactone, poly-hydroxy butyrate or poly-hydroxy valerate, preferably poly-D-lactic acid-co-glycol Acid, poly-L-lactic acid-co-glycolic acid, or poly-D, L-lactic acid-co-glycolic acid (PLGA) may be used, and more preferably poly-D, L- having a molecular weight of about 5000 to 50,000. Lactic acid-co-glycolic acid (PLGA) is used, and most preferably poly-D, L-lactic-co-glycolic acid (PLGA) with a molecular weight of 30,000 having a ratio of lactic acid and glycolic acid of 50:50 can be used. have.

The organic solvent in the second step is preferably used having a solubility in both the biodegradable polyester-based polymer and hydrophilic drug / polyethylene glycol complex, for example, methylene chloride, chloroform, acetone, dimethyl Sulfoxide, dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, ethyl acetate, methyl ethyl ketone or acetonitrile, and the like, and are preferably soluble in the biodegradable polymer and are hydrophilic drugs. Methylene chloride, chloroform and the like, which are easy to disperse to polyethylene size of polyethylene glycol and have a high volatility and are easy to remove through evaporation, are used. More preferably, methylene chloride is used.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

< Example  1> Protein drug and polyethylene glycol ( PEG Preparation of complexes

The low salt human growth hormone is dissolved in distilled water at a concentration of 1 mg / ml, and polyethylene glycol having a molecular weight of 3,350 is 0, 1, 2, 5, 15, 45 mg (weight ratio of polyethylene glycol to protein 0, 1, 2 , 5, 15, and 45) were dissolved in 1 ml of tertiary distilled water, and the two solutions were mixed by vortexing for 1 ml each and then quenched in liquid nitrogen and lyophilized.

After dissolving the dried polyethylene glycol / human growth hormone mixture in methylene chloride organic solvent at a concentration of 0.5 mg / ml, the permeability of the methylene chloride solution containing human growth hormone / polyethylene glycol was measured using a spectrophotometer. In this case, under the condition that the weight ratio of polyethylene glycol / human growth hormone is 5/1, the size of the particles in the solution was measured by dynamic light scattering (dynamic light scattering) is shown in A of FIG.

< Example  2> protein drugs Enclosed Microsphere Carrier  Produce

8.3 mg of lyophilized low salt human growth hormone and 41.6 mg of polyethylene glycol (molecular weight 3,350) complex (weight ratio of polyethylene glycol to protein = 5) were dissolved in 20 ml of methylene chloride.

433 mg (89.6%; weight ratio of total components) of PLGA polymer was dissolved in the prepared methylene chloride solution. Methylene chloride solvent containing protein drug / polyethylene glycol / PLGA was spray-dried (nozzle diameter 0.5 mm, air flow rate 800 L / h, pumping speed 5%, aspiration 100%, inlet temperature 45 ° C., Microsphere support was prepared using an outlet temperature of 39 ° C.).

The shape and size of the microsphere carrier prepared by the above method was measured by scanning electron microscopy, and the results are shown in FIGS. 2B and 3A and B. See FIG. 2B and FIGS. 3A and 3B. The surface was a smooth microsphere support with an average diameter of 1.7 ± 0.4 μm.

The microsphere carrier prepared above was dispersed in a physiological saline buffer solution at a concentration of 10 mg / ml for 20 days, and placed in a 37 ° C. incubator. After the salt was removed, the shape was measured through a scanning electron microscope after freeze-drying. One result is shown in C and D of FIG. 3. Referring to C and D of FIG. 3, it can be seen that microchannels exist therein.

< Example  3> biodegradable Microsphere From carrier  Release of protein drugs

In order to ensure that the second embodiment a biodegradable polymeric drug carrier from the microspheres prepared in (human growth hormone) is continuously controlled release, to the laboratory (in the In vitro ) the amount of protein released was measured.

10 mg of the biodegradable microsphere carrier containing the drug was dispersed in 1 ml of physiological saline buffer solution and placed in an incubator at 37 DEG C, centrifuged at intervals of time, and the supernatant was collected to recover the amount of released protein. It was measured by the micro-BCA (microbicinchoninic acid) method.

In order to determine the weight ratio of the protein encapsulated in the microsphere carrier, 1 N concentration of sodium hydroxide solution was added to the physiological saline buffer solution in which the microsphere carrier was dispersed at a concentration of 10 mg / ml, and placed in a incubator at 37 ° C. for one day. Hydrolyze to dissolve. The amount of protein in the extracted supernatant was quantified by the micro-BCA method to determine the total amount of human growth hormone encapsulated in the microsphere carrier. In the microsphere carrier, the human growth was 2.9 ± 0.3 (w / w)% by weight. It contained hormones.

The release behavior of human growth hormone according to the change of time from the prepared drug-containing biodegradable polymer microsphere carrier is shown in FIG. 2B. As shown in B of FIG. 2, the human growth hormone encapsulated in the microsphere carrier is about 30 days. Emissions are continuously controlled throughout.

Initially with a release amount of 29.4 ± 4.5% and continuously released for about 30 days, about 90% of the microsphere carrier prepared in Example 2 can be confirmed that the formulation is excellent for sustained release of the drug.

Referring to A and B of Figure 4, the human growth hormone released from the microsphere carrier for one day is a polyacrylamide gel (size exclusion chromatography) with a control human growth hormone that has not undergone formulation process It can be seen that there is no change in size compared to the original protein using this, it can be seen that no structural denaturation such as agglomeration of proteins during the formulation process.

As described above, the biodegradable polymeric microsphere carrier according to the present invention does not use an aqueous solution in the manufacturing process, so that the interface of the organic solvent / aqueous solution does not occur and thus does not denature the properties of water-soluble macromolecular drugs such as proteins. Have

In addition, the biodegradable polymeric microsphere carrier according to the present invention has the advantage that the manufacturing process is simple and the drug is continuously released for a certain period from the biodegradable polymeric microsphere carrier prepared by the method of the present invention.

Claims (14)

(One). Lyophilizing polyethylene glycol (PEG) polymer and human growth hormone (Human Growth Hormone) to dissolve or disperse nanoscale in an organic solvent; And (2). Dissolving the human growth hormone and the polyethylene glycol in an organic solvent in which the polyethylene glycol is dissolved or dispersed in a nano size to form a polyester polymer; Method of producing a biodegradable polymer microspheres carrier comprising a. The method of claim 1, wherein the polyethylene glycol polymer is amine-modified polyethylene glycol (amine modified PEG), thiol-substituted polyethylene glycol (thiol modified PEG), carboxyl-substituted polyethylene glycol (carboxyl modified PEG), the end of the hydride A method for producing a biodegradable polymeric microsphere carrier, characterized in that at least one member selected from the group consisting of polyethylene glycol having a hydroxyl group or another active group, linear polyethylene glycol and branched polyethylene glycol. The method of claim 2, wherein the polyethylene glycol substituted with the amine group is methoxy polyethylene glycol amine or polyethylene glycol diamine. The method for producing a biodegradable polymer microsphere support according to claim 1 or 2, wherein the polyethylene glycol polymer has a mass average molecular weight of 400 to 1,000,000. The method of claim 1, wherein the human growth hormone is a drug that requires a long-term sustained effect. delete The method of claim 1, wherein the organic solvent does not contain a surfactant or an emulsifier. The method of claim 1 or 7, wherein the organic solvent is methylene chloride, chloroform, acetone, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, ethyl acetate, methyl ethyl ketone And acetonitrile. The method of claim 1, wherein the polyester-based polymer is a biodegradable polyester-based polymer. The method of claim 1 or 9, wherein the polyester-based polymer is poly-L-lactic acid (poly-L-lactic acid), poly-glycolic acid, poly-D- lactic acid-co-glycolic acid, poly-L- Selected from the group consisting of lactic acid-co-glycolic acid, poly-D, L-lactic acid-co-glycolic acid, poly-caprolactone, poly-valerolactone, poly-hydroxy butyrate and poly-hydroxy valerate A method for producing a biodegradable polymeric microsphere carrier. The method of claim 1, wherein the weight ratio of the polyethylene glycol polymer and the human growth hormone on the organic solvent in the step (1) is 1: 1 to 50: 1. The method of claim 1, wherein the weight ratio of the polyester-based polymer to the total polymer is 0.3: 1 to 0.95: 1. The biodegradable polymer microspheres according to claim 1, wherein the formulation is performed by a spray drying method, ultrasonic dispersion method, coacervation method, emulsion phase separation method and solvent evaporation method in organic phase. Method for producing a carrier. A biodegradable polymeric microsphere carrier prepared by any one of claims 1 to 3, 5, 7, 9, and 11 to 13.

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