CN102188391B - Method for preparing granulocyte-macrophage colony stimulating factor microsphere - Google Patents
Method for preparing granulocyte-macrophage colony stimulating factor microsphere Download PDFInfo
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- CN102188391B CN102188391B CN 201110107988 CN201110107988A CN102188391B CN 102188391 B CN102188391 B CN 102188391B CN 201110107988 CN201110107988 CN 201110107988 CN 201110107988 A CN201110107988 A CN 201110107988A CN 102188391 B CN102188391 B CN 102188391B
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Abstract
A method for preparing a granulocyte-macrophage colony stimulating factor microspheres, belonging to the technical field of nano medicaments, comprises the steps of dispersing granulocyte-macrophage colony stimulating factor glucan particles in organic solution of materials with a sustained release or controlled release function to form suspension, then adding the suspension in an oil phase (O), stirring or swirling to form microspheres, transferring the microspheres into an aqueous phase modified by glycerol to form multiple emulsion, and finally carrying out curing on the multiple emulsion to obtain granulocyte-macrophage colony stimulating factor microspheres. The microspheres prepared by the invention have no adhesion, high encapsulation efficiency, small burst release and high drug loading rate.
Description
Technical field
What the present invention relates to is a kind of method of Nano medication technical field, specifically is a kind of method that is equipped with granulocyte-macrophage colony stimutaing factor (GM-CSF) microsphere with the glycerol legal system.
Background technology
Pharmaceutical industry is from drug discovery, and to Clinical Application, last link is pharmaceutical preparation.Wherein some medicine needs long term administration to cure; Some needs topicals such as targeting.Reach these purposes, crude drug must be prepared into corresponding dosage form.For example need long term administration but short medicine of in vivo half-life should be prepared into slow release formulation; For some tumor treatment, need some drug targetings in the disease photograph, for example targeting is in tumor vascular embolism microball preparation etc.; Gene recombination technology be used for the treatment of the expression of albumen and production 20 for many years, up to the present, existing more than 30 protein drug product drops into clinical use, nearly 200 examine with R﹠D process in, emerge and a collection ofly enter (Amgen), gene technology a collection of new large-scale medical companies such as (Genentech) such as peace.With respect to the fast development of protein macromolecule medicine itself, its dosage form technical progress is slow.On the one hand, the protein macromolecule drug oral does not absorb, the interior half-life of body is short, needs drug administration by injection; On the other hand, the protein drug treatment cycle of many He Ermeng, cytokine class is long, and injection for a long time and continually becomes necessary, also influences the main cause of patient's compliance.The research and development of the dosage form of slow release protein drug are owing to cause the not high S/O/W method of active loss such as W/O/W method, envelop rate and the easy prominent S/O/O method of releasing etc. in preparation microgranule process.The protein microsphere that development preparation has an active protection can improve envelop rate again and the prominent method of releasing is imperative.Yet there are no the report that utilizes the glycerol legal system to be equipped with the granulocyte-macrophage colony stimutaing factor microsphere up till now.
Find by prior art documents, [Lee E.S., Kwon M.J., Lee H., and Kim J.J., Stabilization of protein encapsulated in poly (lactide-co-glycolide) microspheres by novel viscous S/W/O/W method, International Journal of Pharmaceutics 331 (2007) 27-37l, (Lee E.S., Kwon M.J., LeeH., and KimJ.J. has reported and has utilized new viscosity S/W/O/W method that protein stabilized is encapsulated in the PLGA microsphere Inpharm magazine, 2007,331:27-37).People such as Lee E.S. have reported in the document and have utilized the S/W/O/W method to prepare microsphere.The document utilizes the lyophilizing of albumen cyclodextrin to grind then, and the albumen cyclodextrin that grinds is added to the dichloromethane solution emulsifying of full-bodied polysaccharide solution and PLGA, arrives aqueous phase sclerosis microsphere at last and just at protein medicaments, other drug does not appear in the newspapers.But the granule of protein loop dextrin contacts unavoidable protein undissolved with polysaccharide solution, after the dissolving protein solution be easy to contact with the dichloromethane of PLGA, have oil-water interfaces and cause assembling.Cause envelop rate also not high equally, exist not exclusively to discharge.[Morita T.; Sakamura Y.; Horikiri Y.; Suzuki T.; Yoshino H.; Protein encapsulation into biodegradable microspheres by a novel S/O/W emulsion method using poly (ethylene glycol) as a protein micronization adjuvant; Journal of Controlled Release 69 (2000) 435-444] (Morita T.Sakamura Y.; Horikiri Y.; Suzuki T.; Yoshino H.; carry a protein microsphere as the adjuvant of protein particleization by the preparation of S/O/W emulsion process by PEG; " control discharge magazine ", 2000,69:435-444) people such as Morita T has reported in the document and has utilized new S/O/W emulsion process preparation to carry a protein microsphere.Just changed surfactant in the past report more be use PVA, use PEG instead at this piece document.But it is low still can not to overcome envelop rate, has the prominent shortcoming of releasing and not exclusively discharging, and yet there are no the report that utilizes the glycerol legal system to be equipped with the granulocyte-macrophage colony stimutaing factor microsphere up till now.
Summary of the invention
The present invention is directed to the prior art above shortcomings, a kind of method for preparing the granulocyte-macrophage colony stimutaing factor microsphere is provided, the microsphere regular without adhesion for preparing; The envelop rate height, prominent release little, the drug loading height.
The present invention is achieved by the following technical solutions, the present invention is by forming suspension in the organic solution that the granulocyte-macrophage colony stimutaing factor glucan particles is dispersed in the functional material with slow release or controlled release, then suspension is added in the oil phase (O) through stirring or whirlpool formation microsphere, and microsphere transferred in the water (W) that glycerol modifies form emulsion, will obtain the granulocyte-macrophage colony stimutaing factor microsphere after the emulsion cured at last.
Described granulocyte-macrophage colony stimutaing factor glucan particles is that 1-50wt% forms by granulocyte-macrophage colony stimutaing factor 1-50wt% and glucosan, and its size is 0.1-10 μ m; This granulocyte-macrophage colony stimutaing factor glucan particles prepares by the method for the complex that aqueous phase-aqueous phase emulsion method, low temperature spray drying method, phase separation method, supercritical methanol technology or metal ion and granulocyte-macrophage colony stimutaing factor form.
Described oil phase (O) refers to: contain the organic solution of slow release or controlled-release material, this oil phase (O) prepares by controlled release or slow-release function material are dissolved in organic solvent, and its weight percent concentration is 1-30% (w/w).
Described functional material with slow release or controlled release adopts polylactic acid (PLA), polylactic acid-polyglycolic acid (PLGA), the combination of PLA and PLGA, polyethylene glycol-lactic acid (PLA-PEG), polyethylene glycol-hydroxyacetic acid (PLGA-PEG), polyglycolic acid-polyethylene glycol-hydroxyacetic acid (PLGA-PEG-PLGA), polylactic acid-polyglycol-polylactic acid (PLA-PEG-PLA), the combination of polylactic acid and polylactic acid-polyglycolic acid, polyethylene glycol-caprolactone (PEG-PCL), polycaprolactone gathers-ethylene glycol-polycaprolactone (PCL-PEG-PCL) or polycaprolactone (PCL);
Described organic solution adopts dichloromethane, ethyl acetate, acetonitrile or acetone organic solution.
Described organic solution weight percent concentration with functional material of slow release or controlled release is: 1-30% (w/w).
The water (W) that described glycerol is modified refers to: contain the combination of surfactant, glycerol, water and NaCl, by being that NaCl and 0-98% (wt) the water mixing of surfactant, 1.5-100% (w/w) glycerol and the 0-10% (w/w) of 0.5-10% (w/w) obtains with weight percent concentration.
Described surfactant adopts polyvinyl alcohol (PVA), Polyethylene Glycol (PEG), polyvinylpyrrolidone (PVP), poloxamer (poloxmer), tween, poly-sorbic alcohol or ethyl cellulose;
Described stirring refers to: mechanical agitation 0.1-5min, the microsphere of formation 10-500 μ m;
Described cured refers to: emulsion is added drop-wise to the sodium chloride solution that 1000mL contains 1-10% (w/w), and stirs 1-4 hour, and centrifugal collection microsphere also washs 3-5 time, and lyophilizing gets microsphere then.
The present invention relates to the microsphere that method for preparing obtains, its component and mass percent are: glucan particles 1-20%, functional material 80-99%, the particle diameter of this microsphere are 1-500 μ m.
The invention has the advantages that: not high, the prominent important disadvantages of releasing of the granulocyte-macrophage colony stimutaing factor envelop rate that has overcome good water solubility; For the granulocyte-macrophage colony stimutaing factor medicine, overcome oil-water interfaces, high shear force, interface and cross-linking agent etc., at the following bioactive substance of the condition of gentleness, can keep active for a long time.The expense of reduce preserving greatly and improve curative effect, and than the envelop rate of matched group be higher than 40%, activity is higher than 50%, external release profiles is better than matched group.
The present invention has selected suitable oils (O) and the water (W) of glycerol modification and the material of suitable controlled release or slow release, make water miscible drug particles or oil-soluble medicine be prepared into the insoluble granule of oil by the method for preparation, avoid not high with the envelop rate of conventional W/O, W/O/W, S/O/W, release seriously with the prominent of S/O/O, and the shortcoming of the environmental pollution that causes; Adopt this method to prepare microsphere, the size of its particle diameter can be controlled according to different needs, and is free from environmental pollution; Can avoid the function influence to the treatment of medicine, especially those physicochemical properties are unsettled, to the medicine of oil-water interfaces sensitivity, as the granulocyte-macrophage colony stimutaing factor medicine.The smooth surface rounding of microgranule, the granule regular without adhesion, particle diameter can be regulated and control from 1 μ m as required to 500 μ m, and its freeze dried powder is that white is fine and smooth, and is loose, can not subside, adhesion, redispersibility is good.Can apply to the preparation of various medicament slow-release microspheres and the adjuvant of vaccine.The biological cell activity of the granulocyte-macrophage colony stimutaing factor sustained-release micro-spheres of preparation is higher than 20% of matched group microsphere; Release in vitro also is better than matched group.
Description of drawings
Fig. 1 is the microsphere microscope figure of glycerol method preparation;
Among the figure: (A) m5-S/O/W:100% (w/w) glycerol (B) m4-S/O/W:80% (w/w) glycerol, (C) m3-S/O/W:60% (w/w) glycerol, (D) m2-S/O/W:40% (w/w) glycerol, (E) m1-S/O/W:20% (w/w) glycerol, (F) W/O/W matched group.
Fig. 2 is the microsphere sem photograph of glycerol method preparation;
Among the figure: (A) m5-S/O/W:100% (w/w) glycerol (B) m4-S/O/W:80% (w/w) glycerol, (C) m3-S/O/W:60% (w/w) glycerol, (D) m2-S/O/W:40% (w/w) glycerol, (E) m1-S/O/W:20% (w/w) glycerol, (F) W/O/W matched group.
Fig. 3 is the release in vitro curve synoptic diagram;
Among the figure: ◇: m4-S/O/W:80% (w/w) glycerol, ▲: m3-S/O/W:60% (w/w) glycerol; ●: m2-S/O/W:40% (w/w) glycerol; △: m1-S/O/W:20% (w/w) glycerol; The W/O/W matched group.
The specific embodiment
Below embodiments of the invention are elaborated, present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment one: a kind of method that is equipped with granulocyte-macrophage colony stimutaing factor (GM-CSF) microsphere with the glycerol legal system
(1) get the granulocyte-macrophage colony stimutaing factor glucan particles 10mg of 5 μ m and weight percent concentration be 20% molecular weight be 4.7 ten thousand polylactic acid-glycolic guanidine-acetic acid (50: 50, formed i.e. oil bag solid (S/O) emulsion of even suspension in dichloromethane solution 1mL stirring, whirlpool or ultrasonic 1-5 PLGA) minute;
(2) step (1) emulsion droplets be added to contain weight percent concentration be the water (W) modified of 20% glycerol (W) and formed emulsion in stirring, whirlpool or ultrasonic 0.1-5 minute;
(3) be added drop-wise to the emulsion of step (2) in the 1000mL sodium chloride solution that weight percent concentration is 5% (w/w) and stirred 2-4 hour;
(4) the centrifugal collection microsphere that step (3) is obtained, and wash with water 3-5 time, microsphere obtained after the lyophilizing.
(5) being placed on room temperature and humidity then is to preserve 2 years under 30% the environment, takes out with its biological activity of raji cell assay Raji;
Above-mentioned microsphere is shown the about 40 μ m-80 μ m of particle diameter by microscope (as Figure 1A), scanning electron microscope (as Fig. 2 A); Envelop rate be 90% and matched group only be 50% and cytoactive only lack 11% (crude drug of newly buying) than active high 49% of matched group with the activity of the crude drug that is used for preparing.The release in vitro curve has reduced prominent releasing than matched group as shown in Figure 3.
Embodiment two: a kind of method that is equipped with granulocyte-macrophage colony stimutaing factor (GM-CSF) microsphere with the glycerol legal system
(1) get the granulocyte-macrophage colony stimutaing factor glucan particles 50mg of 10 μ m and concentration be 20% molecular weight be 4.7 ten thousand polylactic acid-glycolic guanidine-acetic acid (50: 50, formed i.e. oil bag solid (S/O) emulsion of even suspension in dichloromethane solution 1mL stirring, whirlpool or ultrasonic 1-5 PLGA) minute;
(2) step (1) emulsion droplets be added to contain weight percent concentration be the water (W) modified of 40% glycerol (W) and formed emulsion in stirring, whirlpool or ultrasonic 0.1-5 minute;
(3) be added drop-wise to the emulsion of step (2) in the 1000mL sodium chloride solution that weight percent concentration is 10% (w/w) and stirred 2-4 hour;
(4) the centrifugal collection microsphere that step (3) is obtained, and wash with water 3-5 time, microsphere obtained after the lyophilizing.
(5) being placed on room temperature and humidity then is to preserve 2 years under 30% the environment, takes out with its biological activity of raji cell assay Raji;
Above-mentioned microsphere is shown the about 40 μ m-80 μ m of particle diameter by microscope (as Figure 1B), scanning electron microscope (as Figure 1B); Envelop rate be 90% and matched group only be 50% and cytoactive only lack 11% (crude drug of newly buying) than active high 48.7% of matched group with the activity of the crude drug that is used for preparing.The release in vitro curve has reduced prominent releasing than matched group as shown in Figure 3.
Embodiment three: a kind of method that is equipped with granulocyte-macrophage colony stimutaing factor (GM-CSF) microsphere with the glycerol legal system
(1) getting the granulocyte-macrophage colony stimutaing factor glucan particles 5mg of 5 μ m and concentration is that 20% molecular weight is that dichloromethane solution 1mL stirring, whirlpool or ultrasonic 1-5 minute of 8.3 ten thousand polylactic acid (PLA) forms i.e. oil bag solid (S/O) emulsion of even suspension;
(2) step (1) emulsion droplets be added to contain weight percent concentration be the water (W) modified of 60% glycerol (W) and formed emulsion in stirring, whirlpool or ultrasonic 0.1-5 minute;
(3) be added drop-wise to the emulsion of step (2) in the 1000mL sodium chloride solution that weight percent concentration is 1% (w/w) and stirred 2-4 hour;
(4) the centrifugal collection microsphere that step (3) is obtained, and wash with water 3-5 time, microsphere obtained after the lyophilizing.
(5) being placed on room temperature and humidity then is to preserve 2 years under 30% the environment, takes out with its biological activity of raji cell assay Raji;
Above-mentioned microsphere is shown the about 40 μ m-80 μ m of particle diameter by microscope (as Fig. 1 C), scanning electron microscope (as Fig. 1 C); Envelop rate be 91% and matched group only be 50% and cytoactive only lack 11% (crude drug of newly buying) than active high 49% of matched group with the activity of the crude drug that is used for preparing.The release in vitro curve has reduced prominent releasing than matched group as shown in Figure 3.
Embodiment four: a kind of method that is equipped with granulocyte-macrophage colony stimutaing factor (GM-CSF) microsphere with the glycerol legal system
(1) getting the granulocyte-macrophage colony stimutaing factor glucan particles 5mg of 1 μ m and concentration is that 20% molecular weight is that dichloromethane solution 1mL stirring, whirlpool or ultrasonic 1-5 minute of 8.3 ten thousand polylactic acid (PLA) forms i.e. oil bag solid (S/O) emulsion of even suspension;
(2) step (1) emulsion droplets be added to contain weight percent concentration be the water (W) modified of 80% glycerol (W) and formed emulsion in stirring, whirlpool or ultrasonic 0.1-5 minute;
(3) be added drop-wise to the emulsion of step (2) in the 1000mL sodium chloride solution that percent concentration is 5% (w/w) and stirred 2-4 hour;
(4) the centrifugal collection microsphere that step (3) is obtained, and wash with water 3-5 time, microsphere obtained after the lyophilizing.
(5) being placed on room temperature and humidity then is to preserve 2 years under 30% the environment, takes out with its biological activity of raji cell assay Raji;
Above-mentioned microsphere is shown the about 40 μ m-80 μ m of particle diameter by microscope (as Fig. 1 D), scanning electron microscope (as Fig. 1 D); Envelop rate be 91% and matched group only be 50% and cytoactive only lack 11% (crude drug of newly buying) than active high 49% of matched group with the activity of the crude drug that is used for preparing.The release in vitro curve has reduced prominent releasing than matched group as shown in Figure 3.
Embodiment five: a kind of method that is equipped with granulocyte-macrophage colony stimutaing factor (GM-CSF) microsphere with the glycerol legal system
(1) getting the granulocyte-macrophage colony stimutaing factor glucan particles 5mg of 1 μ m and concentration is that 20% molecular weight is that dichloromethane solution 1mL stirring, whirlpool or ultrasonic 1-5 minute of 8.3 ten thousand polylactic acid (PLA) forms i.e. oil bag solid (S/O) emulsion of even suspension;
(2) step (1) emulsion droplets be added to contain weight percent concentration be the water (W) modified of 100% glycerol (W) and formed emulsion in stirring, whirlpool or ultrasonic 0.1-5 minute;
(3) be added drop-wise to the emulsion of step (2) in the 1000mL sodium chloride solution that weight percent concentration is 8% (w/w) and stirred 2-4 hour;
(4) the centrifugal collection microsphere that step (3) is obtained, and wash with water 3-5 time, microsphere obtained after the lyophilizing.
(5) being placed on room temperature and humidity then is to preserve 2 years under 30% the environment, takes out with its biological activity of raji cell assay Raji;
Above-mentioned microsphere is shown the about 20 μ m-80 μ m of particle diameter by microscope (as Fig. 1 E), scanning electron microscope (as Fig. 1 E); Envelop rate be 92% and matched group only be 50% and cytoactive only lack 10% (crude drug of newly buying) than active high 50% of matched group with the activity of the crude drug that is used for preparing.The release in vitro curve has reduced prominent releasing than matched group as shown in Figure 3.
Claims (4)
1. granulocyte-macrophage colony stimutaing factor microsphere, it is characterized in that, its component and mass percent are: the functional material 80-99% of granulocyte-macrophage colony stimutaing factor glucan particles 1-20%, slow release or controlled release, the particle diameter of this microsphere are 1-500 μ m;
By forming the i.e. oil bag solid emulsion of suspension in the organic solution that the granulocyte-macrophage colony stimutaing factor glucan particles is dispersed in the functional material with slow release or controlled release, and described emulsion transferred in the water (W) that glycerol modifies form emulsion, will obtain described granulocyte-macrophage colony stimutaing factor microsphere after the emulsion cured at last;
Described granulocyte-macrophage colony stimutaing factor glucan particles is that 1-50wt% forms by granulocyte-macrophage colony stimutaing factor 1-50wt% and glucosan, its size is 0.1-10 μ m, and this granulocyte-macrophage colony stimutaing factor glucan particles prepares by the method for the complex that aqueous phase-aqueous phase emulsion method, low temperature spray drying method, phase separation method, supercritical methanol technology or metal ion and granulocyte-macrophage colony stimutaing factor form;
The functional material of described slow release or controlled release adopts combination, polyethylene glycol-caprolactone, polycaprolactone-polyethylene glycol-polycaprolactone or the polycaprolactone of combination, polyethylene glycol-lactic acid, polyethylene glycol-hydroxyacetic acid, polyglycolic acid-polyethylene glycol-hydroxyacetic acid, polylactic acid-polyglycol-polylactic acid, polylactic acid and the polylactic acid-polyglycolic acid of polylactic acid, polylactic acid-polyglycolic acid, PLA and PLGA;
The water (W) that described glycerol is modified refers to: contain the combination of surfactant, glycerol, water and NaCl, by being that NaCl and 0-98% (wt) the water mixing of surfactant, 1.5-100% (w/w) glycerol and the 0-10% (w/w) of 0.5-10% (w/w) obtains with weight percent concentration.
2. granulocyte-macrophage colony stimutaing factor microsphere according to claim 1, it is characterized in that, described organic solution with slow release or control-release function material is to prepare by the functional material of slow release or controlled release is dissolved in organic solvent, and its weight percent concentration is 1-30% (w/w).
3. granulocyte-macrophage colony stimutaing factor microsphere according to claim 1 is characterized in that, described surfactant adopts polyvinyl alcohol, Polyethylene Glycol, polyethylene arsenic pyrrolidone, poloxamer, tween, poly-sorbic alcohol or ethyl cellulose.
4. granulocyte-macrophage colony stimutaing factor microsphere according to claim 1, it is characterized in that, described cured refers to: emulsion is added drop-wise to the sodium chloride solution that 1000mL contains 1-10% (w/w), and stirred 1-4 hour, centrifugal collection microsphere also washs 3-5 time, and lyophilizing gets microsphere then.
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| CN113230036B (en) * | 2021-04-15 | 2022-10-14 | 杭州千岛湖天鑫有限公司 | Sea-buckthorn oil slow-release diaper |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1122690A (en) * | 1995-06-09 | 1996-05-22 | 浙江大学 | Polypeptide protein micro-beads medicine prepn. method |
| CN101485627A (en) * | 2009-01-08 | 2009-07-22 | 上海交通大学 | Microsphere prepared from glycerol modified solid-in-oil-in-water and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1122690A (en) * | 1995-06-09 | 1996-05-22 | 浙江大学 | Polypeptide protein micro-beads medicine prepn. method |
| CN101485627A (en) * | 2009-01-08 | 2009-07-22 | 上海交通大学 | Microsphere prepared from glycerol modified solid-in-oil-in-water and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 徐迪等.重组人粒细胞集落刺激因子缓释微球的研究.《现代生物医学进展》.2007,第7卷(第7期), * |
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