WO2006093390A1 - Microspheres non poreuses renfermant un medicament et procede de fabrication associe - Google Patents

Microspheres non poreuses renfermant un medicament et procede de fabrication associe

Info

Publication number
WO2006093390A1
WO2006093390A1 PCT/KR2006/000740 KR2006000740W WO2006093390A1 WO 2006093390 A1 WO2006093390 A1 WO 2006093390A1 KR 2006000740 W KR2006000740 W KR 2006000740W WO 2006093390 A1 WO2006093390 A1 WO 2006093390A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
microsphere
polymer
vaccine
poly
Prior art date
Application number
PCT/KR2006/000740
Other languages
English (en)
Inventor
Hong-Kee Kim
Tae-Gwan Park
Hyun-Jung Chung
Original Assignee
Korea Advanced Institute Of Science And Technology
Daewoong Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Korea Advanced Institute Of Science And Technology, Daewoong Pharmaceutical Co., Ltd. filed Critical Korea Advanced Institute Of Science And Technology
Publication of WO2006093390A1 publication Critical patent/WO2006093390A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to nonporous polymer microspheres including a drug and a manufacturing method thereof, and a method for using nonporous polymer microspheres including a drug as a drug releasing formulation for sustained release of a drug in a human body, and more particularly, to nonporous microspheres of which multipores are sealed after a drug being introduced into the microspheres through pores, and a manufacturing method thereof, and a use of the nonporous polymer microsphere including a drug as a drug releasing formulation for sustained release of a drug in a human body.
  • a technology for controlling a drug release using a biodegradable polymer microsphere is focused on applying it into a physiologically active material having low molecular weight.
  • peptide or protein with a high moleculer weights have been developed as a new therapeutic agents, and there have been various attempts to continuously release by introducing a drug into a polymer microsphere.
  • polyesters are 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, polycaprolactone, polyvalerolactone, polyhy- droxybutylate and polyhydroxyvalerate.
  • a major reason causing this unstability is the existence of an interface between an aqueous solution and an organic solvent in the W/O/W process, and it has been known that the existence of the interface is one of the major reasons to denaturize a drug like protein, condense it and get rid of a pharmacological activity.
  • a formulating method for preventing forming of an aqueous solution/organic solvent interface in a process for introducing a protein drug in a microsphere For example, a protein is made into a microparticles to be directly dispersed in an organic solvent where a polymer is melted and to introduce it into a polymer microsphere.
  • a microsphere which continuously releases a drug in the human body is manufactured by a method comprising manufacturing a porous microsphere having a plurality of pores using a biodegradable polymer, introducing a soluble drug into a microsphers through the pores and closing the pores of the microsphere using an organic solvent to develop a microsphere where an release rate of a drug is controlled. It is confirmed that the microsphere continuously releases a drug with a constant concentration and the present invention is completed.
  • An object of the present invention is to provide a nonporous polymer microsphere including a drug.
  • Another object of the present invention is to provide a method for manufacturing a nonporous polymer microsphere including a drug.
  • Another object of the present invention is to provide a method for using the nonporous polymer microsphere including a drug as a drug releasing formulations for continuously releasing a drug in a human body.
  • a nonporous polymer microsphere including a drug has a structure formed by a process comprising the steps of introducing a drug into a microsphere comprising a biodegradable polyester polymer through pores formed a microsphere, dissolving the polymer around the pores and closing the pores by fusing the polymers to continuously release the drug.
  • a biodegradable polyester polymer one of the major components of a nonporous polymer microsphere including a drug in the present invention can use anything unharmful to a human body and gradually dissolved to release a drug in the human body.
  • the biodegradable polyester polymer used in the present invention does not require for particular limits.
  • the biodegradable polyester series polymer is one or a mixture of more than two selected from the group consisting of 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, polycaprolactone, polyvalerolactone, poly- hydroxybutylate and polyhydroxyvalerate.
  • a drug introduced through the pores into a biodegradable polyester polymer does not require for particular limits, in other words, can be selected from the group consisting of a human growth hormone, a human epidermal growth factor, FITC-Dextran, G-CSF (Granulocyte Colony- stimulating Factor), GM-CSF (Granulocyte-Macrophage Colony-stimulating Factor), erythropoietin, BCG vaccine, hepatitis B vaccine, influenza vaccine, Japanese encephalitis vaccine, influenza virus vaccine, measles biovirus vaccine, pneumonia coccus vaccine, typhoid vaccine, chicken pox virus, parotitis biodegradable virus vaccine, anti-hCG antibody, anti ⁇ - hCG antibody, anti ⁇ -hCG antibody, IgG antibody, anti LH monoclone antibody, H.pylori antibody combined protein, purified OKT3 monoclone antibody, insulin, calcitonin, adre
  • the present invention includes a method for manufacturing a nonporous polymer microsphere comprising: (1) dissolving a biodegradable polyester polymer and a hydrophilic polymer for pore-forming into an organic solvent;
  • a process for closing the pores in the process (4) can be obtained by contacting an organic solvent at a steam state to a porous microshere.
  • FIG. 1 shows an embodiment of a manufacturing process of a nonporous polymer microsphere including a protein as a drug into a porous polymer microsphere.
  • a nonporous polymer microsphere including a drug not only can continuously release a drug but also prevent forming of an interface between an organic solvent and aqueous solution in a manufacturing process and also prevent occurring harsh conditions denaturizing a protein drug.
  • FIG. 1 is a mimetic diagram showing a method for manufacturing a microsphere for continuously releasing a drug of the present invention using a porous microsphere.
  • Fig. 2 is a mimetic diagram of a fluidized bed reactor (FBR) being used to close pores of a porous microsphere.
  • FBR fluidized bed reactor
  • Fig. 3 A is a photograph of a surface and a cross-sectional scanning microscope of a porous biodegradable microsphere including a drug manufactured in accordance with an embodiment of the present invention.
  • Fig. 3B is a photograph of a surface and a cross-sectional scanning microscope of a biodegradable microsphere including a drug having closed pores of the microsphere (Fig. 3A) in accordance with an embodiment of the present invention.
  • Figs. 4 to 7 are graphs showing a behavior of a continuous releasing of a microsphere including a drug manufactured in an embodiment of the present invention.
  • the biodegradable polyester series polymer forms a basis of a nonporous polymer microsphere including a drug, which is introduced via pores of the biodegradable polyester polymer.
  • the biodegradable polyester polymer may include any polymers unharmful to a human body and gradually dissolved to release a drug in the human body.
  • the biodegradable polyester series polymer is one or a mixture of more than two selected from the group consisting of 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, polycaprolactone, polyvalerolactone, polyhydroxybutylate and polyhydroxy valerate with an average molecular weight of 500-100,000.
  • a biodegradable polyester polymer according to the present invention if a copolymer consisting of a lactic acid and a glycolic acid is used, a copolymer with a molar ratio of lactic acid to glycolic acid in the range of 10:90 ⁇ 90: 10 can be used.
  • a biodegradable polyester polymer in the present invention may be poly-
  • the hydrophilic polymer for pore-forming is not limited to any specific polymers provided that it can be melted into an organic solvent along with a polyester polymer, being released into an aqueous solution when contacting an aqueous solution and providing a polymer microsphere with pores by separation.
  • a hydrophilic polymer for pore-forming can be selected from a polymer with a hy- drophilic/hydrophobic average value (HLB) of 10-40 and an average molecular weight of 500-100,000, more particularly, may be one or a mixture of more than two selected from the group consisting of a Pluronic being a block copolymer with polyethylene glycol and polypropylene glycol, polyethylene glycol, polyethylene glycol derivatives, dextran or Bovine Serum Albumin (BSA).
  • HLB hy- drophilic/hydrophobic average value
  • BSA Bovine Serum Albumin
  • Pluronic uses Pluronic L35, Pluronic F127, Pluronic F77, Pluronic F88 or Pluronic F38 with a HLB value in 19-31, and more preferably, Pluronic fl27, Pluronic F77 and Pluronic F88 with an average molecular weight of 8000-12,000 and a HLB value in 22-28.
  • Polyethylene glycol may be one with an average molecular weight of 500-100,000, and more particularly, one with an average molecular weight of 10,000-50,000.
  • Polyethylene glycol derivatives may be one with an average molecular weight of
  • methoxy polyethylene glycol mPEG
  • polyethylene glycol butylether methoxy polyethylene amine
  • methoxy polyoxyethylene carboxylic acid methoxy polyethylene glycol butylether
  • methoxy polyethylene amine methoxy polyoxyethylene carboxylic acid
  • polyoxyethylene bisamine methoxy polyoxyethylene carboxylic acid
  • polyoxyethylene bisamine methoxy polyoxyethylene carboxylic acid
  • polyoxyethylene bisamine polyoxyethylene bisacetic acid
  • polyoxyethylene bis (6-aminohexyl 6-aminohexyl
  • the hydrophilic polymers can be suitably selected in consideration of HLB values, a molecular weight and kinds or amounts of a biodegradable polyester polymer.
  • an organic solvents include, but are not limited to the solvents having a solubility with respect to a biodegradable polyester polymer and a hydrophilic polymer for pore-forming, for example, one selected from methylene chloride, chloroform, acetone, dimethylsulfoxide, dimethylformamide, N- methyl pyrrolidone, dioxane, tetrahydrofuran, ethylacetate, methylethylketone or ace- tonitrile.
  • methylene chloride or chloroform having an excellent solubility with respect to a biodegradable polyester polymer and a hydrophilic polymer for pore- forming, being easily removed by evaporation as a volatile organic solvent and forming a porous polymer microsphere is used as a solvent and more particularly, methylene chloride is used as a solvent.
  • a biodegradable polyester series polymer and a polymer for pore-forming are melted into an organic solvent and an aqueous solution is emulsified to form a microsphere. Therefore, it is possible to form a porous microsphere of an object by properly controlling a ratio of polyester polymer playing a role as a frame including pores and a hydrophilic polymer playing a role for directly forming pores.
  • a composition ratio of a polyester polymer to a hydrophilic polymer for pore-forming which are melted into an organic solvent is 10:90-90:10 in a weight ratio, and more preferably, 20:80-30:70.
  • a biodegradable polyester polymer and a hydrophilic polymer for pore-forming are melted into an organic solvent and an aqueous solution is emulsified to form a microsphere.
  • the aqueous solution may include a hydrophilic surfactant so that the hydophilic polymer for pore-forming is released to the aqueous solution.
  • the hydrophilic surfactant include, but are not limited to those having a high reactivity with the hydrophilic polymer for pore-forming, thus letting out a hydrophile polymer for pore forming from a polyester polymer to an aqueous solution, for example, one or a mixture of more than two selected from the group consisting of Tween, Triton, Breeze, polyvinylpyrrolidone and polyvinyl alcohol.
  • the polyvinyl alcohols include, but are not limited to those with a molecular weight of 13,000-23,000 in 0.1 ⁇ 5wt% and more particularly, one with a molecular weight of 13,000-23,000 in 0.5 wt%.
  • a polymer for pore-forming is let out onto an aqueous solution from the organic solvent to form pores on a microsphere.
  • the polyester polymer is hardened to form a frame of the microsphere.
  • a volume ratio of an organic solvent is 1-20% and a volume ratio of an aqueous solution is 80-99%, and more particularly, a volume ratio of an organic solvent is 3-10% and a volume ratio of an aqueous solution is 90-97%.
  • the porous mircosphere is freeze-dried by a centrifugal separation to obtain a porous biodegradable polymer microsphere.
  • the porous biodegradable polymer microsphere is obtained by performing a centrifugal separation at 500 ⁇ 10,000rpm for 3 ⁇ 30minutes, freezing at 0°C ⁇ 70°C, drying at 4 ⁇ 35°C.
  • a drug is introduced into a porous polymer microsphere through pores obtained in the process (3) and the pores are closed to obtain a nonporous microsphere including a drug.
  • a drug can include a vaccine, a hormone medicine and other hydrophilic therapeutic agents requiring for administrating for a long period, for example, those selected from the group consisting of a human growth hormone, a human epidermal growth factor, FITC-Dextran, G-CSF (Granulocyte Colony- stimulating Factor), GM-CSF (Granulocyte-Macrophage Colony- stimulating Factor), erythropoietin, vaccine, antibody, insulin, calcitonin, adrenocorticotropic hormone ACTH, glucagons, somatostatin, somatotropin, somatomedin, parathyroid hormone, hypothalamus secretion material, thyroid hormone, prolactin, endorphin, vascular endothelial growth factor (VEGF), enkephalin, vasopressin, nerve growth factor, non- naturally occurring opioid, superoxide dismutase, interferon, asparaginase, arginase
  • G-CSF
  • a method for introducing a drug to be continuously released through pores of a biodegradable porous microsphere may include any methods used in introducing a conventional drug at a microsphere.
  • a drug to be introduced into a microsphere is manufactured in a solution state and the microsphere is dispersed into the drug solution.
  • a drug can be introduced or in another method, a drug element having the size less than the diameter of a pore of a porous microsphere is directly mixed with a porous microsphere.
  • a drug is introduced into a porous microsphere and the pores of the microsphere are closed to obtain a nonporous microsphere including a drug. After a drug is introduced, a nonporous microsphere is obtained by the processes for partially dissolving the polymers distributed around the pores and fusing them.
  • the organic solvents which can be vapourized include, but are not limited to those selected from the group consisting of ethanol, methanol, methylene chloride, chloroform, acetone, dioxane, tetrahydrofuran, ethylacetate or acetonitrile. It is preferable to use ethanol which is the least harmful to a human body and has a slight solubility with respect to a polyester polymer to be easily transformed into a steam state.
  • the organic solvent at a steam state can be contacted with a biodegradable porous microsphere in a fluidized bed reactor (FBR) with reference to Fig. 2.
  • FBR fluidized bed reactor
  • a pore of a porous microsphere may be closed with the following method using a fluidized bed reactor and an organic solvent.
  • the fluidized bed reactor uniformly floats a biodegradable porous microsphere including a drug into an air.
  • An organic solvent capable of melting a polyester polymer is sprayed in a steam state. This state is maintained for a proper time so that a porous microsphere becomes a nonporous microsphere and the microsphere maintains the shape of each object to close pores, therefore a nonporous microsphere can be obtained.
  • FIG. 2 The configuration of the fluidized bed reactor (FBR) is briefly shown in Fig. 2.
  • a nitrogen gas is sprayed into an organic solvent so that a composed organic solvent steam needs to be sprayed to a floating porous microsphere under a proper pressure.
  • the organic solvent steam swells a polymer of a microsphere to become a rubbery and sticky state.
  • the organic solvent at a steam state partially melts a porous microsphere polymer and fuses the polymers around the pores of porous microsphere to gradually decrease pore size and finally close it.
  • the present invention includes a method for using a nonporous polymer microsphere including a drug as a drug releasing formulation for sustained release in the human body.
  • Pluronic F127 of 0.7g and poly-D, L-lactic acid-co-glycolic acid (PLGA) of 0.3g with a ratio of lactic acid to glycolic acid of 75:25 and a molecular weight of 10,000 are melted into methylene chloride of 3ml.
  • Fig. 3A shows a surface and a cross-section of the porous microsphere manufactured in the above method taken by a scanning microscope.
  • An average diameter of a porous microsphere is 52.1+9.9D, and an average diameter of a pore is 5.5+1.0D.
  • the PLGA microsphere of 400mg manufactured in the embodiment 1 is dispersed into a physiological saline solution where a human growth hormone is melted with the concentration of 20mg/ml and stirred at a low speed of lOrpm for two hours so that the human growth hormone solution is infiltrated into the pore structure of the microsphere.
  • the microsphere is centrifuged at 2000rpm for 10 minutes and freeze-dried at -20°C to manufacture a porous polymer microsphere including a human growth hormone.
  • a fluidized bed reactor (FBR) shown in Fig. 2 is used to close pores of a porous polymer microsphere including the manufactured human growth hormone.
  • the fluidized bed reactor uses a glass with an internal diameter of 24mm and a height of 660mm and has a glass filter at the bottom so that a nitrogen gas for floating a porous microsphere is uniformly sprayed from the bottom.
  • the nitrogen gas is sprayed into an ethanol to become a steam state and the nitrogen gas saturated with the ethanol at the steam state is atomized through a silicon nozzle positioned on a glass filter of a reactor.
  • the reactor is maintained to have 25°C by a wafer jacket surrounding the reactor.
  • the arrow in Fig. 2 means that a nitrogen gas is flowed in.
  • a porous polymer microsphere of 40mg including a drug is put in the reactor and a nitrogen gas for floating is sprayed under the pressure of 0.04kgf/cm . Ethanol steam is atomized to a microsphere floating in the air under the same pressure. The nonporous polymer microsphere of which pores are closed is collected by the treatment for 10 minutes and cleaned with a distilled water and dried.
  • Fig. 3B shows a picture of a surface and a cross-section of a biodegradable polymer microsphere of which pores are closed taken by a scanning microsphere.
  • An average diameter of the microsphere of which pores are closed is 15.6+5.4D and it is known that the pores are completely closed.
  • a nonporous polymer microsphere including a human growth hormone is manufactured with the same method as the embodiment 2 except that the PLGA microsphere of 400mg manufactured in the embodiment 1 is dispersed into a physiological saline solution where a human growth hormone is melted with the concentration of 50mg/ml.
  • a porous polymer microsphere including a drug of 20mg and a nonporous polymer microsphere including a drug of 20mg manufactured in the embodiment 2 are dispersed into a physiological saline solution of 1.5ml including sodium azide of 0.01%(w/v) and Tween 20 of 0.02% (w/v) and preserved in the culture medium of a temperature at 37°C.
  • a porous polymer microsphere and a nonporous polymer microsphere including a drug are centrifuged once per two days and an upper liquid is collected to measure the amount of the released protein by a Microbicinchoninic acid method.
  • a human growth hormone remaining in the microsphere is extracted since the drug release period.
  • a sodium hydroxide solution of 0.5ml with the con- centration of 0.5N is added and preserved in the culture medium for one day to melt PLGA by a hydrolysis.
  • the total amount of a protein extracted by the method and an released protein is obtained to measure the total amount of a human growth hormone included in a microsphere.
  • the amount of the included human growth hormone can be controlled by controlling the concentration of a human growth hormone solution where a porous microsphere is soaked.
  • a human growth hormone with a weight ratio of 3.5+0. l(w/w)% is included at a porous microsphere state, and with a weight ratio of 3.1 ⁇ 0.1(w/w)% is included after pores are closed.
  • a human growth hormone with a weight ratio of 11.4 ⁇ 0.5(w/w)% is included at a porous microsphere state, and with a weight ratio of 7.0 ⁇ 0.3(w/w)% is included after pores are closed.
  • the amount of effective drug included in a microsphere can be easily controlled by changing the concentration of a drug solution.
  • Fig. 4 shows that a human growth hormone is released from a biodegradable polymer microsphere including the manufactured drug in accordance with a change of the time.
  • Fig. 4A is a graph showing the amount of a human growth hormone released from each polymer microsphere including a human growth hormone of 5mg/ml into a porous polymer microsphere and a nonporous polymer microsphere in accordance with a change of the time.
  • FIG. 4B is a graph showing the amount of a human growth hormone released from each polymer microsphere including a human growth hormone of 20mg/ml into a porous polymer microsphere and a nonporous polymer microsphere in accordance with a change of the time.
  • FIG. 4 Oshows an release amount of a human growth hormone included in a porous polymer microsphere manufactured in the embodiment 1 in accordance with time, and # shows an release amount of a human growth hormone included in a nonporous polymer microsphere manufactured in the embodiment 2 in accordance with time.
  • a nonporous polymer microsphere including FITC-dextran is manufactured with the same method as the embodiment 2 except that the PLGA microsphere of 400mg manufactured in the embodiment 1 is dispersed into a physiological saline solution where the FITC-dextran is melted with the concentration of 20mg/ml.
  • a nonporous polymer microsphere including rhEGF is manufactured with the same method as the embodiment 2 except that the PLGA microsphere of 400mg manufactured in the embodiment 1 is dispersed into a physiological saline solution where a human epidermal growth factor rhEGF is melted with the concentration of 20mg/ml.
  • a nonporous polymer microsphere including DNA is manufactured with the same method as the embodiment 2 except that the PLGA microsphere of 400mg manufactured in the embodiment 1 is dispersed into a physiological saline solution where DNA is melted with the concentration of 100D/ml.

Abstract

La présente invention concerne une microsphère polymère non poreuse renfermant un médicament, un procédé de fabrication associé et un procédé d'utilisation de ladite microsphère polymère non poreuse renfermant un médicament comme formulation de libération de médicament pour une libération continue dudit médicament dans le corps humain.
PCT/KR2006/000740 2005-03-03 2006-03-03 Microspheres non poreuses renfermant un medicament et procede de fabrication associe WO2006093390A1 (fr)

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KR10-2005-0017704 2005-03-03
KR1020050017704A KR100622996B1 (ko) 2005-03-03 2005-03-03 약물이 봉입된 비다공성 고분자 미립 담체 및 이의 제조방법

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CN103860392A (zh) * 2014-01-27 2014-06-18 广东职业技术学院 一种含表皮生长因子的疏水固体微球及其制备方法和应用
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