CN101461785B - Oil in water-oil in oil-water in oil method for preparing microballoons - Google Patents

Oil in water-oil in oil-water in oil method for preparing microballoons Download PDF

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CN101461785B
CN101461785B CN200910045024A CN200910045024A CN101461785B CN 101461785 B CN101461785 B CN 101461785B CN 200910045024 A CN200910045024 A CN 200910045024A CN 200910045024 A CN200910045024 A CN 200910045024A CN 101461785 B CN101461785 B CN 101461785B
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peg
plga
pla
microsphere
oil
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CN101461785A (en
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金拓
袁伟恩
吴飞
郭梅燕
窦学文
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Shanghai Jiaotong University
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Shanghai Jiaotong University
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Abstract

The invention relates to a method for preparing microspheres by water-in-oil-in-oil-in-water in the technical field of pharmacy, which comprises the following steps: a medicine solution is prepared first, and is dispersed into an organic solution with a slow release or controlled release functional material, and the stirring or swirling and so on is preformed to make the medicine solution dispersed evenly to form a suspension; then the suspension is added into an external oil phase to be stirred or swirled to form microspheres, and finally the microspheres are transferred into a large water phase for solidification; and then the microspheres are centrifugally collected, freeze-dried and preserved, wherein in the obtained microspheres, the medicine accounts for 0.01 to 50 percent of the weight of the entire microshperes, the slow release or controlled release material accounts for 20 to 99.99 percent of the weight of the entire microshperes, and an auxiliary material accounts for 0 to 30 percent of the weight of the entire microshperes. The microspheres prepared by the method have smooth and round surfaces and good uniformity, are regular, have no adhesion, and have adjustable grain diameters; the used organic solvent is environment-friendly, is easy to remove by water, and does not affect the treatment effect of the medicine; and the microspheres have high envelope rate, and small burst release and incomplete release.

Description

Oil-in-water-oil bag oil-Water-In-Oil prepares the method for microsphere
Technical field
What the present invention relates to is the medicine microspheres method for preparing in a kind of pharmaceutical technology field, and especially a kind of oil-in-water-oil bag oil-Water-In-Oil (W/O/O/W) prepares the method for microsphere.
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 forms.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 to treat proteic expression 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 be prone to the prominent S/O/O method of releasing etc. in preparation microgranule process.It is imperative with the prominent method of releasing that the protein microsphere that development preparation has an active protection can improve envelop rate again.Also do not see up till now and utilize oil-in-water-oil bag oil-oil bag solid (W/O/O/W) method to prepare the report of microsphere.
Retrieval through to the prior art document is found; O ' Donnell; P.B. wait Biopharmaceutics at European Journal ofPharmaceutics and, 1998,45:83-94; Publishing an article, " Influece ofprocessing on the stability and release prosperities of biodegradablemicrospheres containing thioridazine hydrochloride " (the preparation process is to the stability of the mellaril of mellaril biodegradable microsphere and the influence of release; Europe biological agent and journal of Practical Pharmacy, 1998,45:83-94).O ' Donnell; P.B. wait the people to report that in the document W/O/W and W/O/O multi-emulsion method prepare microsphere; Simultaneously at document the such printed words of W/O/O/O appear also; But read over find that this is that editor misplays or clerical mistake causes W/O/O/O appears in this article because the document has only been reported this common W/O/W and W/O/O multi-emulsion method.The document has been reported the W/O/W method: medicine is dissolved in and forms water (W) in the 0.5ml distilled water.0.8g PLGA is dissolved in the dichloromethane of 8ml and forms oil phase (O).These two solution are mixed and use dispersing emulsification machine emulsifying, make it to form colostrum, add colostrum in the aqueous solution that 80ml contains 2% polyvinyl alcohol (W) to then, and stir 3 hours solidified microspheres.The W/O/O multi-emulsion method: the aqueous solution of medicine is dispersed in the colostrum that forms W/O in the acetonitrile solution of PLGA, then the colostrum that forms again at 0.5% sorbester p17 and stir solidified microsphere, in the document the 3rd oil phase do not appear at all.But all there be easy prominent the releasing of the medicine that is wrapped up in these two kinds of methods, and envelop rate is not high, and has not exclusively release, and also there are the shortcomings such as pollution to environment in the W/O/O method that the document is reported.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, provide a kind of oil-in-water-oil bag oil-Water-In-Oil to prepare the method for microsphere.Make the smooth rounding of microparticle surfaces of its preparation, good evenness, granule regular without adhesion; Envelop rate is high, prominently releases for a short time, and drug loading is high, and can overcome the method for above-mentioned shortcoming, and environmentally safe.
The present invention realizes that through following technical scheme the present invention prepares drug solution earlier, drug solution is dispersed in the organic solution with slow release or control-release function material, and the formation suspensions that make it to be uniformly dispersed such as stirring or whirlpool; Then suspension is added to outer oil phase, restir or whirlpool form microsphere, transfer to big aqueous phase to it at last and solidify; Centrifugal then collection microsphere, lyophilizing is preserved.
The present invention includes following steps:
1. prepare drug solution, directly be dissolved in the water medicine or medicine be dissolved in the water through adding adjuvant;
2. the organic solution that drug solution is joined slow release or controlled-release material is oil phase-1 (O 1) in stir or whirlpool etc. makes it homodisperse and forms uniform suspension;
3. suspension being added in another organic solution is oil phase-2 (O 2), this oil phase is not allowed slow release or sky to release material but can be extracted organic solvent 2., and stirring, whirlpool or ultrasonic formation contain the emulsion of 20-500 μ m microsphere;
4. the completing steps emulsion that contains microsphere 3. being transferred to salt water (W) solidifies;
5. completing steps sample lyophilizing is 4. got microsphere, in this microsphere: medicine is that percentage by weight (w/w) 0.01-50%, slow release or the controlled-release material of whole microsphere is that 20-99.99% (w/w), adjuvant are 0-30% (w/w).
Described drug solution refers to medicine dissolution and in water, forms solution, or medicine forms aqueous solution through adding adjuvant;
Described medicine comprises small-molecule drug and macromolecular drug;
Described small-molecule drug is meant chemicals, and macromolecular drug is meant biopharmaceutical macromolecular drug.Further finger protein macromolecular drug, vaccine, antibody, nucleic acid or liposome medicament;
Described protein macromolecule medicine is: erythropoietin (EPO); Recombinant human granulocyte colony stimulating factor (G-CSF); Granulocyte-macrophage colony stimutaing factor (GM-CSF); Vaccine; Interferon (IFN); Growth hormone (GH); Insulin (Insulin); Epidermal growth factor (EGF); Fibroblast growth factor (FGF); Transforming growth factor (TGF-β); Insulin like growth factor (IGF); Vascular endothelial cell growth factor (VEGF); PDGF (PDGF); ECGF (ECGF); Nerve growth factor (NGF); BDGF (BDGF); BMP (BMP); Tissue polypeptide antigen (TPA); Antibody (antibody); Blood coagulation factor VIII (VIII); Or plasma thromboplastin component genetic factor.
Described nucleic acid is: GEM 132 (anti-RNA), microRNA (RNAi) or gene (DNA).
Described adjuvant is meant the little saccharide of injection (sucrose, trehalose, glucose, maltose or lactose), polyhydroxy compounds (mannitol, sorbitol, glycerol, 1,2-propylene glycol, erythritol, Polyethylene Glycol, polyvinyl alcohol, PEO or polypyrrole alkane ketone; ), a kind of or combination in any of polysaccharide compound (glucosan, sodium alginate, chitosan, starch, cellulose or cyclodextrin material), amino-acid compound (propylhomoserin, lysine, arginine, glutamic acid or histidine) and inorganic salts material (zinc salt, calcium salt, mantoquita, magnesium salt or molybdenum salt).
In the described drug solution, the percentage by weight of medicine (w/w) content is between the 0.2-50%; With 1-20% (w/w) is good.
The material of described slow release or controlled release is: polylactic acid; Polylactic acid-polyglycolic acid; Silicon is as glue; Politef; Polrvinyl chloride; Polyethylene; Polypropylene; Polystyrene; PETG; Polybutylcyanoacrylate; Poly phosphazene; Poly phosphate; Fibrinogen; Fibrin; Polyethylene glycol-lactic acid; The polyethylene glycol-hydroxyacetic acid; Polyglycolic acid-polyethylene glycol-hydroxyacetic acid; Polylactic acid-polyglycol-polylactic acid; With polylactic acid; Merlon; Carmomer; Hyaluronic acid; Gelatin; A kind of in collagen protein and the caprolactone.
Described oil phase-1 (O 1) be: the organic solution of the material of slow release or controlled release;
The organic solution of the material of described slow release or controlled release, wherein organic solution is meant a kind of or combination in dichloromethane, ethyl acetate, acetonitrile, heptane, chloroform or the acetone, and is a kind of or be combined as good with dichloromethane, ethyl acetate and acetonitrile.
In the organic solution of the material of described slow release or controlled release, the percentage by weight of the material of slow release or controlled release (w/w) content is 0.5-80%, is good with 5-30% (w/w) wherein.
Described oil phase-2 (O 2) be: a kind of or their combination in any in surfactant, glycerol, ethanol, propylene glycol, ethylene glycol solution and the liquid macrogol;
Described their combination in any is: glycerol and ethanol add that aqueous solution that the aqueous solution of surfactant, aqueous solution, glycerol and propylene glycol that ethanol adds surfactant add surfactant, aqueous solution, glycerol and ethylene glycol that propylene glycol adds surfactant add the aqueous solution of surfactant, aqueous solution, glycerol and the liquid macrogol that ethylene glycol adds surfactant adds the aqueous solution of surfactant and the combination in any that liquid macrogol adds surfactant;
Described aqueous surfactant solution is: polyvinyl alcohol (PVA), Polyethylene Glycol (PEG), polyvinylpyrrolidone (PVP), poloxamer (poloxmer), gather in sorbic alcohol, ethyl cellulose (EC) or the tween a kind of; Wherein: the weight concentration percentage by weight (w/w) of polyvinyl alcohol (PVA) is for 0.5-10% or contain saline solution such as 0.5-10% (w/w) sodium chloride; The weight concentration of Polyethylene Glycol (PEG) is 0.5-20% (w/w) or the saline solution that contains 0.5-10% (w/w) sodium chloride; Polyvinylpyrrolidone (PVP) weight concentration is 0.5-20% (w/w) or contains saline solution such as 0.5-10% (w/w) sodium chloride; Poloxamer (poloxmer) weight concentration is 0.5-20% (w/w) or contains saline solution such as 0.5-10% (w/w) sodium chloride; To gather the sorbic alcohol weight concentration be 0.5-20% (w/w) or contain saline solution such as 0.5-10% (w/w) sodium chloride, and ethyl cellulose (EC) weight concentration is 0.5-20% or contains saline solution such as 0.5-10% sodium chloride.
Said oil phase-2 (O 2) ratio be: glycerol percentage by weight (w/w) 0-50%, aqueous surfactant solution 0-30% (w/w), ethanol, propylene glycol, ethylene glycol or liquid macrogol 50-100% (w/w).
The particle diameter of said microsphere is 1-300 μ m, is good with 20-100 μ m.
The present invention has selected suitable oils-1 (O 1) and oil phase-2 (O 2) and the material of suitable controlled release and slow release; Make water miscible drug solution or oil-soluble medicine be prepared into oily insoluble granule through the method for preparation; Avoid the not high and S/O/O of envelop rate with conventional W/O, W/O/W, S/O/W prominent release serious, 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, and the medicine responsive to oil-water interfaces is like biopharmaceutical macromolecular drug protein macromolecule medicine.The smooth surface rounding of microgranule, the granule regular without adhesion, particle diameter can be regulated and control from 1 μ m to 500 μ m as required, 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 specific embodiment
Elaborate in the face of embodiments of the invention down: present embodiment provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment being to implement under the prerequisite with technical scheme of the present invention.
Embodiment one: be loaded with the preparation of small-molecule drug PLGA microsphere
(1) preparation drug solution directly or through adding adjuvant is dissolved in the water small-molecule drug;
In the present embodiment, the small-molecule drug of employing is that (tumor chemotherapeutic drug is selected from chemotherapy of tumors class medicine: AC, dactinomycin, bleomycin, daunorubicin, amycin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), semustine, cisplatin, etoposide, camptothecine and derivant, phenesterin, paclitaxel and derivant thereof, Docetaxel and derivant thereof, vinblastine, vincristine, zitazonium, etoposide, piposulfan, cyclophosphamide or flutamide and derivant thereof; Sustained-release micro-spheres can be loaded with one or more in the said medicine; ) or antibiotics (antibiotics is selected from ciclosporin, levofloxacin, ofloxacin or epinastine hydrochloride; Sustained-release micro-spheres can be loaded with one or more in the said medicine).
In the present embodiment, the adjuvant of employing is one or more in glucosan, sodium alginate, chitosan, starch, cellulose, cyclodextrin, Polyethylene Glycol, polyvinyl alcohol, PEO, polypyrrole alkane ketone, sucrose, trehalose, mannitol, sorbitol, lactose, glycine, lysine, zinc salt, calcium salt, mantoquita, magnesium salt, molybdenum salt or the histidine said medicine;
In the present embodiment, the weight ratio of adjuvant and small-molecule drug is 0%-99.99% (w/w); Concrete proportioning situation such as following table:
Medicine Adjuvant Medicine accounts for the percentage by weight of solution gross weight Medicine Adjuvant Medicine accounts for the percentage by weight of solution gross weight
Amycin 1 Cyclodextrin 100%, 80%, 50 %, 25% or 0% Carboplatin 1 Cyclodextrin 100%, 80%, 50 %, 25% or 0%
Amycin 2 Polyethylene Glycol 100%, 80%, 50 %, 25% or 0% Carmustine Polyethylene Glycol 100%, 80%, 50 %, 25% or 0%
Amycin 3 Polyvinyl alcohol 100%, 80%, 50 %, 25% or 0% Semustine Polyvinyl alcohol 100%, 80%, 50 %, 25% or 0%
Amycin 4 PEO 100%, 80%, 50 %, 25% or 0% Cisplatin PEO 100%, 80%, 50 %, 25% or 0%
Amycin 5 Polypyrrole alkane ketone 100%, 80%, 50 %, 25% or 0% Etoposide Polypyrrole alkane ketone 100%, 80%, 50 %, 25% or 0%
Cyclophosphamide 1 Polyethylene Glycol 100%, 80%, 50 %, 25% or 0% Camptothecine Polyethylene Glycol 100%, 80%, 50 %, 25% or 0%
Dactinomycin 1 PEO 100%, 80%, 50 %, 25% or 0% Phenesterin PEO 100%, 80%, 50 %, 25% or 0%
Daunorubicin 1 Polyethylene Glycol 100%, 80%, 50 %, 25% or 0% Paclitaxel Polyethylene Glycol 100%, 80%, 50 %, 25% or 10%
Amycin 6 PEO 100%, 80%, 50 %, 25% or 0% Docetaxel PEO 100%, 80%, 50 %, 25% or 0%
Epirubicin 1 Polypyrrole alkane ketone 100%, 80%, 50 %, 25% or 0% Vinblastine Polypyrrole alkane ketone 100%, 80%, 50 %, 25% or 0%
Methotrexate 1 Polyethylene Glycol 100%, 80%, 50 %, 25% or 0% Vincristine Polyethylene Glycol 100%, 80%, 50 %, 25% or 0%
Fluorouracil 1 PEO 100%, 80%, 50 %, 25% or 0% Zitazonium PEO 100%, 80%, 50 %, 25% or 0%
Etoposide 1 Cyclodextrin 100%, 80%, 50 %, 25% or 0% Piposulfan Polyethylene Glycol 100%, 80%, 50 %, 25% or 0%
Flutamide 1 Polyethylene Glycol 100%, 80%, 50 %, 25% or 0% Daunorubicin and carboplatin PEO 100%, 80%, 50 %, 25% or 0%
Amycin and paclitaxel Polyvinyl alcohol 100%, 80%, 50 %, 25% or 0% Ciclosporin 2 Polypyrrole alkane ketone 100%, 80%, 50 %, 25% or 0%
Ciclosporin 1 PEO 100%, 80%, 50 %, 25% or 0% Levofloxacin 3 PEO 100%, 90%, 80 %, 40% or 20%
Levofloxacin 1 Polypyrrole alkane ketone 100%, 80%, 40 %, 20% or 0% Ofloxacin 3 Polyethylene Glycol 100%, 80%, 40 %, 20% or 0%
Ofloxacin 1 Glucosan 100%, 80%, 40 %, 10% or 0% Epinastine hydrochloride 3 PEO 100％、80％、40 ％、20％、0.1％
Hydrochloric acid according to Sodium alginate ?100％、80％、40 Levofloxacin Mannitol 100％、80％、40
This spit of fland 1 %, 20% or 0% Star 3 %, 20% or 0%
Levofloxacin 2 Chitosan 100%, 80%, 40 %, 20% or 0% Ofloxacin 4 Sorbitol 100%, 80%, 40 %, 20% or 0%
Ofloxacin 2 Starch 100％、80％、40 ％、20％、0.1％ Epinastine hydrochloride 3 Lactose 100%, 80%, 40 %, 20% or 0%
Epinastine hydrochloride 1 Cellulose 100%, 80%, 40 %, 20% or 0% Levofloxacin 4 Glycine 100%, 80%, 40 %, 20% or 0%
Ofloxacin 3 Sucrose 100%, 80%, 40 %, 20% or 0% Ofloxacin 5 Lysine 100%, 80%, 40 %, 20% or 0%
Epinastine hydrochloride 2 Trehalose 100%, 80%, 40 %, 20% or 0% Epinastine hydrochloride 4 Histidine 100%, 80%, 40 %, 20% or 0%
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and PLGA is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
(3) getting emulsion droplets to step (2) is added to oil phase-2 and stirring, whirlpool or formed emulsion in ultrasonic 0.5-5 minute;
(4) be added drop-wise to the emulsion of step (3) in the 1000ml sodium chloride solution that concentration is 1-10% (w/w) and stir and solidified 1-4 hour;
(5) the centrifugal collection microsphere that obtains step (4), and, obtain microsphere after the lyophilizing with water washing 3-5 time.
The microsphere that present embodiment obtains, its concrete set of dispense ratio sees the following form:
Drug solution PLGA Drug solution accounts for the percentage by weight of microsphere Drug solution PLGA Drug solution accounts for the percentage by weight of gross weight
Amycin 1 PLGA 20%, 60%, 80%, 70% or 99.99% Carboplatin 1 PLGA 20%, 60%, 80%, 70% or 99.99%
Amycin 2 PLGA 20%, 60%, 80%, 70% or 99.99% Carmustine PLGA 20%, 60%, 80%, 70% or 99.99%
Amycin 3 PLGA 20%, 60%, 80%, 70% or 99.99% Semustine PLGA 20%, 40%, 80%, 70% or 99.99%
Amycin 4 PLGA 20%, 40%, 80%, 70% or 99.99% Cisplatin PLGA 20%, 60%, 80%, 50% or 99.99%
Amycin 5 PLGA 20%, 60%, 80%, 50% or 99.99% Etoposide PLGA 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 PLGA 20%, 50%, 80%, 70% or 99.99% Camptothecine PLGA 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 PLGA 20％、60％、80％、 Phenesterin PLGA 20％、60％、40％、
70% or 99.99% 70% or 99.99%
Daunorubicin 1 PLGA 20%, 60%, 40%, 70% or 99.99% Paclitaxel PLGA 20%, 60%, 80%, 70% or 99.99%
Amycin 6 PLGA 20%, 60%, 80%, 70% or 99.99% Docetaxel PLGA 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 PLGA 20%, 60%, 80%, 70% or 99.99% Vinblastine PLGA 20%, 60%, 80%, 70% or 99.99%
Methotrexate 1 PLGA 20%, 60%, 80%, 70% or 99.99% Vincristine PLGA 20%, 60%, 80%, 70% or 99.99%
Fluorouracil 1 PLGA 20%, 60%, 80%, 70% or 99.99% Zitazonium PLGA 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 PLGA 20%, 60%, 80%, 70% or 99.99% Piposulfan PLGA 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 PLGA 20%, 60%, 80%, 70% or 99.99% Daunorubicin and carboplatin PLGA 20%, 60%, 80%, 70% or 99.99%
Amycin and paclitaxel PLGA 20%, 60%, 80%, 70% or 99.99% Ciclosporin 2 PLGA 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 PLGA 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLGA 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 PLGA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 PLGA 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 PLGA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLGA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLGA 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLGA 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 PLGA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 PLGA 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 PLGA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLGA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLGA 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 PLGA 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 PLGA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 PLGA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 PLGA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 PLGA 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment two: be loaded with the preparation of biopharmaceutical macromolecular drug PLGA microsphere
(1) preparation biopharmaceutical macromolecular drug solution is dissolved in the water biopharmaceutical macromolecular drug through adding adjuvant;
In the present embodiment, the biopharmaceutical macromolecular drug of employing is erythropoietin (EPO), recombinant human granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimutaing factor (GM-CSF), vaccine, interferon (INF), growth hormone (GH), insulin (Insulin), epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF-β), insulin like growth factor (IGF), vascular endothelial cell growth factor (VEGF), PDGF (PDGF), ECGF (ECGF), nerve growth factor (NGF), BDGF (BDGF), BMP (BMP), tissue polypeptide antigen (TPA), antibody (antibody), blood coagulation factor VIII (VIII), IX genetic factor, GEM 132 (anti-RNA), microRNA (RNAi), SiRNA, gene (DNA); Sustained-release micro-spheres can be loaded with one or more in the said medicine.
In the present embodiment, the adjuvant of employing is one or more in glucosan, sodium alginate, chitosan, starch, cellulose, cyclodextrin, Polyethylene Glycol, polyvinyl alcohol, PEO, polypyrrole alkane ketone, sucrose, trehalose, mannitol, sorbitol, lactose, glycine, lysine or the histidine said medicine;
In the present embodiment, the proportioning of concrete material sees the following form:
Medicine Adjuvant Medicine accounts for the percentage by weight of solution Medicine Adjuvant Medicine accounts for the percentage by weight of solution
EPO1 Glucosan 80%, 50%, 25 %, 10% or 5% ?NGF Cyclodextrin and sucrose (5: 1) 100%, 80%, 50 %, 25% or 10 %
G-CSF1 Glucosan and trehalose (9: 1) 80%, 50%, 25 %, 10% or 5% ?BDGF3 Polyethylene Glycol and sorbitol (8: 1) 100%, 80%, 50 %, 25% or 10 %
GM-CSF1 Glucosan and trehalose (9: 1) 80%, 50%, 25 %, 10% or 5% ?BMP2 Glucosan 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
Vaccine 1 Glucosan 100%, 80%, 50 %, 25% or 10% ?TPA2 PEO and sucrose (9: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
GH1 Glucosan zinc salt and mannitol (9: 80%, 50%, 25% or 10% ?antibody Polypyrrole alkane ketone and sweet ammonia ?50％、40％、30?％、25％、15
0.5∶1) Acid (5: 1) %, 10% or 5%
Insulin Polyethylene Glycol and zinc salt (9: 1) 100%, 80%, 50 %, 25% or 10% Blood coagulation factor VIII Glucosan and lysine (9: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
EGF1 PEO 100%, 80%, 50 %, 25% or 10% The IX genetic factor Glucosan and histidine (8: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
FGF1 Polyethylene Glycol 100%, 80%, 50 %, 25% or 10% anti-RNA Polyethylene Glycol 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
TGF-β PEO 100%, 80%, 50 %, 25% or 10% RNAi PEO 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
IGF Glucosan 100%, 80%, 50 %, 25% or 10 % SiRNA Glucosan 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
VEGF Glucosan and trehalose (8: 1) 50%, 40%, 30 %, 25%, 15%, 10% or 5% DNA Glucosan 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
PDGF1 Glucosan and trehalose (8: 1) 50%, 40%, 30 %, 25%, 15%, 10% or 5% BDGF and BMP (1: 1) Glucosan and trehalose (8: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
ECGF Cyclodextrin and trehalose (8: 1) 50%, 40%, 30 %, 25%, 15%, 10% or 5% PDGF and BMP (1: 1) Glucosan and trehalose (8: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
VEGF and DNA (1: 1) Glucosan and trehalose (8: 1) 80%, 70%, 50 %, 25% or 10 % TGF-β, PDGF and BMP (1: 1: 1) Glucosan and trehalose (8: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
NGF and BM P (1: 1) Glucosan and lactose (8: 1) 80%, 60%, 50 %, 25% or 10 % SiRNA and DNA (1: 1) Polypyrrole alkane ketone 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
EGF and FG F (1: 1) Glucosan and trehalose (8: 1) 60%, 50%, 25 %, 10% or 5% BDGF and VEGF (1: 1) Glucosan and trehalose (8: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
GM-CSF and G-CSF (1: 1) Glucosan and lactose (8: 1) 60%, 50%, 25 %, 10% or 5% IGF and GH (1: 1) Glucosan and trehalose (8: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
VEGF and DNA (1: 1) Glucosan and sodium alginate (9: 1) 60%, 50%, 25 %, 10% or 5% EPO2 Glucosan and sodium alginate (9: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
NGF and BM P (1: 1) Glucosan and sodium alginate (9: 1) 60%, 50%, 40 %, 20%, 10% or 5% G-CSF2 Glucosan and sodium alginate (9: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
EGF and FG F (1: 1) Chitosan 60%, 50%, 40 %, 20%, 10% or 5% GM-CSF2 Glucosan and sorbitol (9: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
GM-CSF and G-CSF (1: 1) Starch 60%, 50%, 40 %, 20%, 10% or 5%% Vaccine Glucosan and lactose (9: 1) 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
BDGF2 Cellulose and lactose (9: 1) ?100％、80％、40?％、20％、10％ EPO3 Glucosan and glycine 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
BMP1 Glucosan and sucrose (9: 1) ?100％、80％、40?％、20％、10％ G-CSF3 Glucosan and lysine 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
TPA1 Trehalose ?100％、80％、40?％、20％、10％ GM-CSF3 Glucosan and histidine 50%, 40%, 30 %, 25%, 15 %, 10% or 5%
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and PLGA of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, it specifically forms proportioning such as following table:
Drug solution PLGA Drug solution accounts for the percentage by weight of microsphere Drug solution PLGA Drug solution accounts for the percentage by weight of microsphere
EPO1 PLGA 20%, 60%, 80%, 70% or 99.99% NGF PLGA 20%, 60%, 80%, 70% or 99.99%
G-CSF1 PLGA 20%, 60%, 80%, 70% or 99.99% BDGF3 PLGA 20%, 60%, 80%, 70% or 99.99%
GM-CSF1 PLGA 20%, 60%, 80%, 70% or 99.99% BMP2 PLGA 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 PLGA 20%, 40%, 80%, 70% or 99.99% TPA2 PLGA 20%, 60%, 80%, 50% or 99.99%
GH1 PLGA 20％、60％、80％、 antibody PLGA 20％、50％、80％、
50% or 99.99% 70% or 99.99%
Insulin PLGA 20%, 50%, 80%, 70% or 99.99% Blood coagulation factor VIII PLGA 20%, 60%, 80%, 70% or 99.99%
EGF1 PLGA 20%, 60%, 80%, 70% or 99.99% The IX genetic factor PLGA 20%, 60%, 40%, 70% or 99.99%
FGF1 PLGA 20%, 60%, 40%, 70% or 99.99% anti-RNA PLGA 20%, 60%, 80%, 70% or 99.99%
TGF-β PLGA 20%, 60%, 80%, 70% or 99.99% RNAi PLGA 20%, 60%, 80%, 70% or 99.99%
IGF PLGA 20%, 60%, 80%, 70% or 99.99% SiRNA PLGA 20%, 60%, 80%, 70% or 99.99%
VEGF PLGA 20%, 60%, 80%, 70% or 99.99% DNA PLGA 20%, 60%, 80%, 70% or 99.99%
PDGF1 PLGA 20%, 60%, 80%, 70% or 99.99% BDGF and BMP (1: 1) PLGA 20%, 60%, 80%, 70% or 99.99%
ECGF PLGA 20%, 60%, 80%, 70% or 99.99% PDGF and BMP (1: 1) PLGA 20%, 60%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLGA 20%, 60%, 80%, 70% or 99.99% TGF-β, PDGF and BMP (1: 1: 1) PLGA 20%, 60%, 80%, 70% or 99.99%
NGF and BMP (1: 1) PLGA 20%, 60%, 80%, 70% or 99.99% SiRNA and DNA (1: 1) PLGA 20%, 40%, 80%, 70% or 99.99%
EGF and FGF (1: 1) PLGA 20%, 60%, 80%, 70% or 99.99% BDGF and VEGF (1: 1) PLGA 20%, 60%, 80%, 50% or 99.99%
GM-CSF and G-CSF (1: 1) PLGA 20%, 60%, 80%, 70% or 99.99% IGF and GH (1: 1) PLGA 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLGA 20%, 60%, 80%, 70% or 99.99% EPO2 PLGA 20%, 60%, 80%, 70% or 99.99%
NGF and BMP (1: 1) PLGA 20%, 60%, 80%, 70% or 99.99% G-CSF2 PLGA 20%, 60%, 40%, 70% or 99.99%
EGF and FGF (1: 1) PLGA 20%, 60%, 80%, 70% or 99.99% GM-CSF2 PLGA 20%, 60%, 80%, 70% or 99.99%
GM-CSF and G-CSF (1: 1) PLGA 20%, 60%, 80%, 70% or 99.99% Vaccine PLGA 20%, 60%, 80%, 70% or 99.99%
BDGF2 PLGA 20%, 60%, 78%, 70% or 99.99% EPO3 PLGA 20%, 60%, 80%, 70% or 99.99%
BMP1 PLGA 20%, 60%, 80%, 70% or 99.99% G-CSF3 PLGA 20%, 60%, 80%, 70% or 99.99%
TPA1 PLGA 20%, 60%, 80%, 70% or 99.99% GM-CSF3 PLGA 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment three: be loaded with the preparation of small-molecule drug PLA microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and PLA is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PLA Drug solution accounts for the percentage by weight of microsphere Drug solution PLA Drug solution accounts for the percentage by weight of microsphere
Amycin 1 PLA 20%, 60%, 80%, 70% or 99.99% Carboplatin 1 PLA 20%, 60%, 80%, 70% or 99.99%
Amycin 2 PLA 20%, 60%, 80%, 70% or 99.99% Carmustine PLA 20%, 60%, 80%, 70% or 99.99%
Amycin 3 PLA 20%, 60%, 80%, 70% or 99.99% Semustine PLA 20%, 40%, 80%, 70% or 99.99%
Amycin 4 PLA 20%, 40%, 80%, 70% or 99.99% Cisplatin PLA 20%, 60%, 80%, 50% or 99.99%
Amycin 5 PLA 20%, 60%, 80%, 50% or 99.99% Etoposide PLA 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 PLA 20%, 50%, 80%, 70% or 99.99% Camptothecine PLA 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 PLA 20%, 60%, 80%, 70% or 99.99% Phenesterin PLA 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 PLA 20%, 60%, 40%, 70% or 99.99% Paclitaxel PLA 20%, 60%, 80%, 70% or 99.99%
Amycin 6 PLA 20%, 60%, 80%, 70% or 99.99% Docetaxel PLA 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 PLA 20%, 60%, 80%, 70% or 99.99% Vinblastine PLA 20%, 60%, 80%, 70% or 99.99%
Methotrexate 1 PLA 20%, 60%, 80%, 70% or 99.99% Vincristine PLA 20%, 60%, 80%, 70% or 99.99%
Fluorouracil 1 PLA 20%, 60%, 80%, 70% or 99.99% Zitazonium PLA 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 PLA 20%, 60%, 80%, 70% or 99.99% Piposulfan PLA 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 PLA 20%, 60%, 80%, 70% or 99.99% Daunorubicin and carboplatin PLA 20%, 60%, 80%, 70% or 99.99%
Amycin and paclitaxel PLA 20%, 60%, 80%, 70% or 99.99% Ciclosporin 2 PLA 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 PLA 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLA 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 PLA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 PLA 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 PLA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLA 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLA 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 PLA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 PLA 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 PLA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLA 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 PLA 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 PLA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 PLA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 PLA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 PLA 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment four: be loaded with the preparation of biopharmaceutical macromolecular drug solution PLA microsphere
Step (1) is identical with embodiment two.
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and PLA of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PLA Drug solution accounts for the percentage by weight of microsphere Drug solution PLA Drug solution accounts for the percentage by weight of microsphere
EPO1 PLA 20%, 60%, 80%, 70% or 99.99% NGF PLA 20%, 60%, 80%, 70% or 99.99%
G-CSF1 PLA 20%, 60%, 80%, 70% or 99.99% BDGF3 PLA 20%, 60%, 80%, 70% or 99.99%
GM-CSF1 PLA 20%, 60%, 80%, 70% or 99.99% BMP2 PLA 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 PLA 20%, 40%, 80%, 70% or 99.99% TPA2 PLA 20%, 60%, 80%, 50% or 99.99%
GH1 PLA 20%, 60%, 80%, 50% or 99.99% antibody PLA 20%, 50%, 80%, 70% or 99.99%
Insulin PLA 20%, 50%, 80%, 70% or 99.99% Blood coagulation factor VIII PLA 20%, 60%, 80%, 70% or 99.99%
EGF1 PLA 20%, 60%, 80%, 70% or 99.99% The IX genetic factor PLA 20%, 60%, 40%, 70% or 99.99%
FGF1 PLA 20%, 60%, 40%, 70% or 99.99% anti-RNA PLA 20%, 60%, 80%, 70% or 99.99%
TGF-β PLA 20%, 60%, 80%, 70% or 99.99% RNAi PLA 20%, 60%, 80%, 70% or 99.99%
IGF PLA 20%, 60%, 80%, 70% or 99.99% SiRNA PLA 20%, 60%, 80%, 70% or 99.99%
VEGF PLA 20%, 60%, 80%, 70% or 99.99% DNA PLA 20%, 60%, 80%, 70% or 99.99%
PDGF1 PLA 20%, 60%, 80%, 70% or 99.99% BDGF and BMP (1: 1) PLA 20%, 60%, 80%, 70% or 99.99%
ECGF PLA 20%, 60%, 80%, 70% or 99.99% PDGF and BMP (1: 1) PLA 20%, 60%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLA 20%, 60%, 80%, 70% or 99.99% TGF-β, PDGF and BMP (1: 1: 1) PLA 20%, 60%, 80%, 70% or 99.99%
NGF and BMP PLA 20％、60％、80％、 SiRNA and DNA PLA 20％、40％、80％、
(1∶1) 70% or 99.99% ?(1∶1) 70% or 99.99%
EGF and FGF (1: 1) PLA 20%, 60%, 80%, 70% or 99.99% BDGF and VEGF (1: 1) PLA 20%, 60%, 80%, 50% or 99.99%
GM-CSF and G-CSF (1: 1) PLA 20%, 60%, 80%, 70% or 99.99% IGF and GH (1: 1) PLA 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLA 20%, 60%, 80%, 70% or 99.99% ?EPO2 PLA 20%, 60%, 80%, 70% or 99.99%
NGF and BMP (1: 1) PLA 20%, 60%, 80%, 70% or 99.99% ?G-CSF2 PLA 20%, 60%, 40%, 70% or 99.99%
EGF and FGF (1: 1) PLA 20%, 60%, 80%, 70% or 99.99% ?GM-CSF2 PLA 20%, 60%, 80%, 70% or 99.99%
GM-CSF and G-CSF (1: 1) PLA 20%, 60%, 80%, 70% or 99.99% Vaccine PLA 20%, 60%, 80%, 70% or 99.99%
BDGF2 PLA 20%, 60%, 78%, 70% or 99.99% ?EPO3 PLA 20%, 60%, 80%, 70% or 99.99%
BMP1 PLA 20%, 60%, 80%, 70% or 99.99% ?G-CSF3 PLA 20%, 60%, 80%, 70% or 99.99%
TPA1 PLA 20%, 60%, 80%, 70% or 99.99% ?GM-CSF3 PLA 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment five: be loaded with the preparation of small-molecule drug solution PGA microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and PGA is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PGA Drug solution accounts for the percentage by weight of microsphere Drug solution PGA Drug solution accounts for the percentage by weight of microsphere gross weight
Amycin 1 PGA 20％、60％、80％、 Carboplatin 1 PGA 20％、60％、80％、
70% or 99.99% 70% or 99.99%
Amycin 2 PGA 20%, 60%, 80%, 70% or 99.99% Carmustine PGA 20%, 60%, 80%, 70% or 99.99%
Amycin 3 PGA 20%, 60%, 80%, 70% or 99.99% Semustine PGA 20%, 40%, 80%, 70% or 99.99%
Amycin 4 PGA 20%, 40%, 80%, 70% or 99.99% Cisplatin PGA 20%, 60%, 80%, 50% or 99.99%
Amycin 5 PGA 20%, 60%, 80%, 50% or 99.99% Etoposide PGA 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 PGA 20%, 50%, 80%, 70% or 99.99% Camptothecine PGA 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 PGA 20%, 60%, 80%, 70% or 99.99% Phenesterin PGA 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 PGA 20%, 60%, 40%, 70% or 99.99% Paclitaxel PGA 20%, 60%, 80%, 70% or 99.99%
Amycin 6 PGA 20%, 60%, 80%, 70% or 99.99% Docetaxel PGA 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 PGA 20%, 60%, 80%, 70% or 99.99% Vinblastine PGA 20%, 60%, 80%, 70% or 99.99%
Methotrexate 1 PGA 20%, 60%, 80%, 70% or 99.99% Vincristine PGA 20%, 60%, 80%, 70% or 99.99%
Fluorouracil 1 PGA 20%, 60%, 80%, 70% or 99.99% Zitazonium PGA 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 PGA 20%, 60%, 80%, 70% or 99.99% Piposulfan PGA 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 PGA 20%, 60%, 80%, 70% or 99.99% Daunorubicin and carboplatin PGA 20%, 60%, 80%, 70% or 99.99%
Amycin and paclitaxel PGA 20%, 60%, 80%, 70% or 99.99% Ciclosporin 2 PGA 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 PGA 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PGA 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 PGA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 PGA 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 PGA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PGA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PGA 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PGA 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 PGA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 PGA 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 PGA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PGA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PGA 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 PGA 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 PGA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 PGA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 PGA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 PGA 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment six: be loaded with the preparation of biopharmaceutical macromolecular drug solution PGA microsphere
Step (1) is identical with embodiment two.
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and PGA of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PGA Drug solution accounts for the percentage by weight of microsphere Drug solution PGA Drug solution accounts for the percentage by weight of microsphere
EPO1 PGA 20%, 60%, 80%, 70% or 99.99% NGF PGA 20%, 60%, 80%, 70% or 99.99%
G-CSF1 PGA 20%, 60%, 80%, 70% or 99.99% BDGF3 PGA 20%, 60%, 80%, 70% or 99.99%
GM-CSF1 PGA 20%, 60%, 80%, 70% or 99.99% BMP2 PGA 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 PGA 20%, 40%, 80%, 70% or 99.99% TPA2 PGA 20%, 60%, 80%, 50% or 99.99%
GH1 PGA 20%, 60%, 80%, 50% or 99.99% antibody PGA 20%, 50%, 80%, 70% or 99.99%
Insulin PGA 20%, 50%, 80%, 70% or 99.99% Blood coagulation factor VIII PGA 20%, 60%, 80%, 70% or 99.99%
EGF1 PGA 20%, 60%, 80%, 70% or 99.99% The IX genetic factor PGA 20%, 60%, 40%, 70% or 99.99%
FGF1 PGA 20%, 60%, 40%, 70% or 99.99% anti-RNA PGA 20%, 60%, 80%, 70% or 99.99%
TGF-β PGA 20%, 60%, 80%, 70% or 99.99% RNAi PGA 20%, 60%, 80%, 70% or 99.99%
IGF PGA 20%, 60%, 80%, 70% or 99.99% SiRNA PGA 20%, 60%, 80%, 70% or 99.99%
VEGF PGA 20%, 60%, 80%, 70% or 99.99% DNA PGA 20%, 60%, 80%, 70% or 99.99%
PDGF1 PGA 20%, 60%, 80%, 70% or 99.99% BDGF and BMP (1: 1) PGA 20%, 60%, 80%, 70% or 99.99%
ECGF PGA 20%, 60%, 80%, 70% or 99.99% PDGF and BMP (1: 1) PGA 20%, 60%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PGA 20%, 60%, 80%, 70% or 99.99% TGF-β, PDGF and BMP (1: 1: 1) PGA 20%, 60%, 80%, 70% or 99.99%
NGF and BMP (1: 1) PGA 20%, 60%, 80%, 70% or 99.99% SiRNA and DNA (1: 1) PGA 20%, 40%, 80%, 70% or 99.99%
EGF and FGF (1: 1) PGA 20%, 60%, 80%, 70% or 99.99% BDGF and VEGF (1: 1) PGA 20%, 60%, 80%, 50% or 99.99%
GM-CSF and G-CSF (1: 1) PGA 20%, 60%, 80%, 70% or 99.99% IGF and GH (1: 1) PGA 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PGA 20%, 60%, 80%, 70% or 99.99% EPO2 PGA 20%, 60%, 80%, 70% or 99.99%
NGF and BMP (1: 1) PGA 20%, 60%, 80%, 70% or 99.99% G-CSF2 PGA 20%, 60%, 40%, 70% or 99.99%
EGF and FGF (1: 1) PGA 20%, 60%, 80%, 70% or 99.99% GM-CSF2 PGA 20%, 60%, 80%, 70% or 99.99%
GM-CSF and G-CSF (1: 1) PGA 20%, 60%, 80%, 70% or 99.99% Vaccine PGA 20%, 60%, 80%, 70% or 99.99%
BDGF2 PGA 20%, 60%, 78%, 70% or 99.99% EPO3 PGA 20%, 60%, 80%, 70% or 99.99%
BMP1 PGA 20%, 60%, 80%, 70% or 99.99% G-CSF3 PGA 20%, 60%, 80%, 70% or 99.99%
TPA1 PGA 20%, 60%, 80%, 70% or 99.99% GM-CSF3 PGA 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment seven: be loaded with the preparation of small-molecule drug polycaprolactone microballoon sphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and polycaprolactone is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution Polycaprolactone Drug solution accounts for the percentage by weight of microsphere Drug solution Polycaprolactone Drug solution accounts for the percentage by weight of microsphere gross weight
Amycin 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Carboplatin 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Amycin 2 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Carmustine Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Amycin 3 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Semustine Polycaprolactone 20%, 40%, 80%, 70% or 99.99%
Amycin 4 Polycaprolactone 20%, 40%, 80%, 70% or 99.99% Cisplatin Polycaprolactone 20%, 60%, 80%, 50% or 99.99%
Amycin 5 Polycaprolactone 20%, 60%, 80%, 50% or 99.99% Etoposide Polycaprolactone 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 Polycaprolactone 20%, 50%, 80%, 70% or 99.99% Camptothecine Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Phenesterin Polycaprolactone 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 Polycaprolactone 20%, 60%, 40%, 70% or 99.99% Paclitaxel Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Amycin 6 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Docetaxel Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Vinblastine Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Methotrexate 1 Polycaprolactone 20％、60％、80％、 Vincristine Polycaprolactone 20％、60％、80％、
70% or 99.99% 70% or 99.99%
Fluorouracil 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Zitazonium Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Piposulfan Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Daunorubicin and carboplatin Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Amycin and paclitaxel Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Ciclosporin 2 Polycaprolactone 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 Polycaprolactone 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 Polycaprolactone 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 Polycaprolactone 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 Polycaprolactone 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment eight: be loaded with the preparation of biopharmaceutical macromolecular drug solution polycaprolactone microballoon sphere
Step (1) is identical with embodiment two.
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and polycaprolactone of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution Polycaprolactone Drug solution accounts for the percentage by weight of microsphere Drug solution Polycaprolactone Drug solution accounts for the percentage by weight of microsphere
EPO1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% NGF Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
G-CSF1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% BDGF3 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
GM-CSF1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% BMP2 Polycaprolactone 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 Polycaprolactone 20%, 40%, 80%, 70% or 99.99% TPA2 Polycaprolactone 20%, 60%, 80%, 50% or 99.99%
GH1 Polycaprolactone 20%, 60%, 80%, 50% or 99.99% antibody Polycaprolactone 20%, 50%, 80%, 70% or 99.99%
Insulin Polycaprolactone 20%, 50%, 80%, 70% or 99.99% Blood coagulation factor VIII Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
EGF1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% The IX genetic factor Polycaprolactone 20%, 60%, 40%, 70% or 99.99%
FGF1 Polycaprolactone 20%, 60%, 40%, 70% or 99.99% anti-RNA Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
TGF-β Polycaprolactone 20%, 60%, 80%, 70% or 99.99% RNAi Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
IGF Polycaprolactone 20%, 60%, 80%, 70% or 99.99% SiRNA Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
VEGF Polycaprolactone 20%, 60%, 80%, 70% or 99.99% DNA Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
PDGF1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% BDGF and BMP (1: 1) Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
ECGF Polycaprolactone 20%, 60%, 80%, 70% or 99.99% PDGF and BMP (1: 1) Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) Polycaprolactone 20%, 60%, 80%, 70% or 99.99% TGF-β, PDGF and BMP (1: 1: 1) Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
NGF and BMP (1: Polycaprolactone 20%, 60%, 80%, 70% or 99.99% SiRNA and DNA (1: 1) Polycaprolactone 20%, 40%, 80%, 70% or 99.99%
1)
EGF and FGF (1: 1) Polycaprolactone 20%, 60%, 80%, 70% or 99.99% BDGF and VEGF (1: 1) Polycaprolactone 20%, 60%, 80%, 50% or 99.99%
GM-CSF and G-CSF (1: 1) Polycaprolactone 20%, 60%, 80%, 70% or 99.99% IGF and GH (1: 1) Polycaprolactone 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) Polycaprolactone 20%, 60%, 80%, 70% or 99.99% EPO2 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
NGF and BMP (1: 1) Polycaprolactone 20%, 60%, 80%, 70% or 99.99% G-CSF2 Polycaprolactone 20%, 60%, 40%, 70% or 99.99%
EGF and FGF (1: 1) Polycaprolactone 20%, 60%, 80%, 70% or 99.99% GM-CSF2 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
GM-CSF and G-CSF (1: 1) Polycaprolactone 20%, 60%, 80%, 70% or 99.99% Vaccine Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
BDGF2 Polycaprolactone 20%, 60%, 78%, 70% or 99.99% EPO3 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
BMP1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% G-CSF3 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
TPA1 Polycaprolactone 20%, 60%, 80%, 70% or 99.99% GM-CSF3 Polycaprolactone 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment nine: be loaded with the preparation of small-molecule drug solution PLA-PEG microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and PLA-PEG is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PLA-PEG Drug solution accounts for the percentage by weight of microsphere Drug solution PLA-PEG Drug solution accounts for the percentage by weight of microsphere
Amycin 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Carboplatin 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 2 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Carmustine PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 3 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Semustine PLA-PEG 20%, 40%, 80%, 70% or 99.99%
Amycin 4 PLA-PEG 20%, 40%, 80%, 70% or 99.99% Cisplatin PLA-PEG 20%, 60%, 80%, 50% or 99.99%
Amycin 5 PLA-PEG 20%, 60%, 80%, 50% or 99.99% Etoposide PLA-PEG 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 PLA-PEG 20%, 50%, 80%, 70% or 99.99% Camptothecine PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Phenesterin PLA-PEG 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 PLA-PEG 20%, 60%, 40%, 70% or 99.99% Paclitaxel PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 6 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Docetaxel PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Vinblastine PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Methotrexate 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Vincristine PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Fluorouracil 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Zitazonium PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Piposulfan PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Daunorubicin and carboplatin PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Amycin and paclitaxel PLA-PEG 20%, 60%, 80%, 70% or 99.99% Ciclosporin 2 PLA-PEG 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLA-PEG 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 PLA-PEG 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLA-PEG 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLA-PEG 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 PLA-PEG 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment ten: be loaded with the preparation of biopharmaceutical macromolecular drug solution PLA-PEG microsphere
Step (1) is identical with embodiment one.
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and PLA-PEG of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PLA-PEG Drug solution accounts for the percentage by weight of microsphere Drug solution PLA-PEG Drug solution accounts for the percentage by weight of microsphere
EPO1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% NGF PLA-PEG 20%, 60%, 80%, 70% or 99.99%
G-CSF1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% BDGF3 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
GM-CSF1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% BMP2 PLA-PEG 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 PLA-PEG 20%, 40%, 80%, 70% or 99.99% TPA2 PLA-PEG 20%, 60%, 80%, 50% or 99.99%
GH1 PLA-PEG 20%, 60%, 80%, 50% or 99.99% antibody PLA-PEG 20%, 50%, 80%, 70% or 99.99%
Insulin PLA-PEG 20%, 50%, 80%, 70% or 99.99% Blood coagulation factor VIII PLA-PEG 20%, 60%, 80%, 70% or 99.99%
EGF1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% The IX genetic factor PLA-PEG 20%, 60%, 40%, 70% or 99.99%
FGF1 PLA-PEG 20%, 60%, 40%, 70% or 99.99% anti-RNA PLA-PEG 20%, 60%, 80%, 70% or 99.99%
TGF-β PLA-PEG 20%, 60%, 80%, 70% or 99.99% RNAi PLA-PEG 20%, 60%, 80%, 70% or 99.99%
IGF PLA-PEG 20%, 60%, 80%, 70% or 99.99% SiRNA PLA-PEG 20%, 60%, 80%, 70% or 99.99%
VEGF PLA-PEG 20%, 60%, 80%, 70% or 99.99% DNA PLA-PEG 20%, 60%, 80%, 70% or 99.99%
PDGF1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% BDGF and BMP (1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99%
ECGF PLA-PEG 20%, 60%, 80%, 70% or 99.99% PDGF and BMP (1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99% TGF-β, PDGF and BMP (1: 1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99%
NGF and BM P (1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99% SiRNA and DNA (1: 1) PLA-PEG 20%, 40%, 80%, 70% or 99.99%
EGF and FG F (1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99% BDGF and VEGF (1: 1) PLA-PEG 20%, 60%, 80%, 50% or 99.99%
GM-CSF and G-CSF (1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99% IGF and GH (1: 1) PLA-PEG 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99% EPO2 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
NGF and BM P (1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99% G-CSF2 PLA-PEG 20%, 60%, 40%, 70% or 99.99%
EGF and FG F (1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99% GM-CSF2 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
GM-CSF and G-CSF (1: 1) PLA-PEG 20%, 60%, 80%, 70% or 99.99% Vaccine PLA-PEG 20%, 60%, 80%, 70% or 99.99%
BDGF2 PLA-PEG 20%, 60%, 78%, 70% or 99.99% EPO3 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
BMP1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% G-CSF3 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
TPA1 PLA-PEG 20%, 60%, 80%, 70% or 99.99% GM-CSF3 PLA-PEG 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment 11: be loaded with the preparation of small-molecule drug solution PLGA-PEG microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and PLA is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PLGA-PEG Drug solution accounts for the percentage by weight of microsphere Drug solution PLGA-PEG Drug solution accounts for the percentage by weight of microsphere
Amycin 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Carboplatin 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 2 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Carmustine PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 3 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Semustine PLGA-PEG 20%, 40%, 80%, 70% or 99.99%
Amycin 4 PLGA-PEG 20%, 40%, 80%, 70% or 99.99% Cisplatin PLGA-PEG 20%, 60%, 80%, 50% or 99.99%
Amycin 5 PLGA-PEG 20％、60％、80％、 Etoposide PLGA-PEG 20％、50％、80％、
50% or 99.99% 70% or 99.99%
Cyclophosphamide 1 PLGA-PEG 20%, 50%, 80%, 70% or 99.99% Camptothecine PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Phenesterin PLGA-PEG 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 PLGA-PEG 20%, 60%, 40%, 70% or 99.99% Paclitaxel PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 6 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Docetaxel PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Vinblastine PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Methotrexate 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Vincristine PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Fluorouracil 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Zitazonium PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Piposulfan PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Daunorubicin and carboplatin PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Amycin and paclitaxel PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Ciclosporin 2 PLGA-PEG 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLGA-PEG 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 PLGA-PEG 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLGA-PEG 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLGA-PEG 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 PLGA-PEG 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 PLGA-PEG 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment 12: be loaded with the preparation of biopharmaceutical macromolecular drug solution PLGA-PEG microsphere
Step (1) is identical with embodiment one.
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and PLGA-PEG of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PLGA- PEG Drug solution accounts for the percentage by weight of microsphere Drug solution PLGA- PEG Drug solution accounts for the percentage by weight of microsphere
EPO1 PLGA- PEG 20%, 60%, 80%, 70% or 99.99% NGF PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
G-CSF1 PLGA- PEG 20%, 60%, 80%, 70% or 99.99% BDGF3 PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
GM-CSF1 PLGA- PEG 20%, 60%, 80%, 70% or 99.99% BMP2 PLGA- PEG 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 PLGA- PEG 20%, 40%, 80%, 70% or 99.99% TPA2 PLGA- PEG 20%, 60%, 80%, 50% or 99.99%
GH1 PLGA- PEG 20%, 60%, 80%, 50% or 99.99% antibody PLGA- PEG 20%, 50%, 80%, 70% or 99.99%
Insulin PLGA- PEG 20%, 50%, 80%, 70% or 99.99% Blood coagulation factor VIII PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
EGF1 PLGA- PEG 20%, 60%, 80%, 70% or 99.99% The IX genetic factor PLGA- PEG 20%, 60%, 40%, 70% or 99.99%
FGF1 PLGA- PEG 20%, 60%, 40%, 70% or 99.99% anti-RNA PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
TGF-β PLGA- PEG 20%, 60%, 80%, 70% or 99.99% RNAi PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
IGF PLGA- PEG 20%, 60%, 80%, 70% or 99.99% SiRNA PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
VEGF PLGA- PEG 20%, 60%, 80%, 70% or 99.99% DNA PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
PDGF1 PLGA- PEG 20%, 60%, 80%, 70% or 99.99% BDGF and BMP (1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
ECGF PLGA- PEG 20%, 60%, 80%, 70% or 99.99% PDGF and BMP (1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99% TGF-β, PDGF and BMP (1: 1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
NGF and BM P (1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99% SiRNA and DNA (1: 1) PLGA- PEG 20%, 40%, 80%, 70% or 99.99%
EGF and FG F (1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99% BDGF and VEGF (1: 1) PLGA- PEG 20%, 60%, 80%, 50% or 99.99%
GM-CSF and G-CSF (1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99% IGF and GH (1: 1) PLGA- PEG 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99% EPO2 PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
NGF and BM P (1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99% G-CSF2 PLGA- PEG 20%, 60%, 40%, 70% or 99.99%
EGF and FG F (1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99% GM-CSF2 PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
GM-CSF and G-CSF (1: 1) PLGA- PEG 20%, 60%, 80%, 70% or 99.99% Vaccine PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
BDGF2 PLGA- PEG 20%, 60%, 78%, 70% or 99.99% EPO3 PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
BMP1 PLGA- PEG 20%, 60%, 80%, 70% or 99.99% G-CSF3 PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
TPA1 PLGA- PEG 20%, 60%, 80%, 70% or 99.99% GM-CSF3 PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment 13: be loaded with the preparation of small-molecule drug solution PLA-PEG-PLA microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and PLA-PEG-PLA is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PLA-PEG -PLA Drug solution accounts for the percentage by weight of microsphere Drug solution PLA-PEG -PLA Drug solution accounts for the percentage by weight of microsphere
Amycin 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Carboplatin 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Amycin 2 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Carmustine PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Amycin 3 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Semustine PLA-PEG -PLA 20%, 40%, 80%, 70% or 99.99%
Amycin 4 PLA-PEG -PLA 20%, 40%, 80%, 70% or 99.99% Cisplatin PLA-PEG -PLA 20%, 60%, 80%, 50% or 99.99%
Amycin 5 PLA-PEG -PLA 20%, 60%, 80%, 50% or 99.99% Etoposide PLA-PEG -PLA 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 PLA-PEG -PLA 20%, 50%, 80%, 70% or 99.99% Camptothecine PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Phenesterin PLA-PEG -PLA 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 PLA-PEG -PLA 20%, 60%, 40%, 70% or 99.99% Paclitaxel PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Amycin 6 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Docetaxel PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Vinblastine PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Methotrexate 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Vincristine PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Fluorouracil 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Zitazonium PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Piposulfan PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Daunorubicin and carboplatin PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Amycin PLA-PEG 20％、60％、80％、 Ciclosporin 2 PLA-PEG 20％、40％、80％、
And paclitaxel -PLA 70% or 99.99% -PLA 70% or 99.99%
Ciclosporin 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLA-PEG -PLA 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 PLA-PEG -PLA 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLA-PEG -PLA 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLA-PEG -PLA 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment 14: be loaded with the preparation of biopharmaceutical macromolecular drug solution PLA-PEG-PLA microsphere
Step (1) is identical with embodiment two.
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and PEG-PLA-PEG of complex is to form even suspension Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PLA-PEG -PLA Drug solution accounts for the percentage by weight of microsphere Drug solution PLA-PEG -PLA Drug solution accounts for the percentage by weight of microsphere
EPO1 PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% NGF PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
G-CSF1 PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% BDGF3 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
GM-CSF1 PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% BMP2 PLA-PEG -PLA 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 PLA-PEG -PLA 20%, 40%, 80 %, 70% or 99.99% TPA2 PLA-PEG -PLA 20%, 60%, 80%, 50% or 99.99%
GH1 PLA-PEG -PLA 20%, 60%, 80 %, 50% or 99.99% antibody PLA-PEG -PLA 20%, 50%, 80%, 70% or 99.99%
Insulin PLA-PEG -PLA 20%, 50%, 80 %, 70% or 99.99% Blood coagulation factor VIII PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
EGF1 PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% The IX genetic factor PLA-PEG -PLA 20%, 60%, 40%, 70% or 99.99%
FGF1 PLA-PEG -PLA 20%, 60%, 40 %, 70% or 99.99% anti-RNA PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
TGF-β PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% RNAi PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
IGF PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% SiRNA PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
VEGF PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% DNA PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
PDGF1 PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% BDGF and BMP (1: 1) PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
ECGF PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% PDGF and BMP (1: 1) PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
VEGF with PLA-PEG 20％、60％、80 TGF-β、 PLA-PEG 20％、60％、80％、
DNA(1∶1) -PLA %, 70% or 99.99% PDGF and BMP (1: 1: 1) -PLA 70% or 99.99%
NGF and BMP (1: 1) PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% SiRNA and DNA (1: 1) PLA-PEG -PLA 20%, 40%, 80%, 70% or 99.99%
EGF and FGF (1: 1) PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% BDGF and VEGF (1: 1) PLA-PEG -PLA 20%, 60%, 80%, 50% or 99.99%
GM-CSF and G-CSF (1: 1) PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% IGF and GH (1: 1) PLA-PEG -PLA 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% EPO2 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
NGF and BMP (1: 1) PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% G-CSF2 PLA-PEG -PLA 20%, 60%, 40%, 70% or 99.99%
EGF and FGF (1: 1) PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% GM-CSF2 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
GM-CSF and G-CSF (1: 1) PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% Vaccine PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
BDGF2 PLA-PEG -PLA 20%, 60%, 78 %, 70% or 99.99% EPO3 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
BMP1 PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% G-CSF3 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
TPA1 PLA-PEG -PLA 20%, 60%, 80 %, 70% or 99.99% GM-CSF3 PLA-PEG -PLA 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment 15: be loaded with the preparation of small-molecule drug solution PLGA-PEG-PLGA microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and PLGA-PEG-PLGA is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PLGA-PEG -PLGA Drug solution accounts for the percentage by weight of microsphere Drug solution PLGA-PEG -PLGA Drug solution accounts for the percentage by weight of microsphere
Amycin 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Carboplatin 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Amycin 2 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Carmustine PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Amycin 3 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Semustine PLGA-PEG -PLGA 20%, 40%, 80%, 70% or 99.99%
Amycin 4 PLGA-PEG -PLGA 20%, 40%, 80%, 70% or 99.99% Cisplatin PLGA-PEG -PLGA 20%, 60%, 80%, 50% or 99.99%
Amycin 5 PLGA-PEG -PLGA 20%, 60%, 80%, 50% or 99.99% Etoposide PLGA-PEG -PLGA 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 PLGA-PEG -PLGA 20%, 50%, 80%, 70% or 99.99% Camptothecine PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Phenesterin PLGA-PEG -PLGA 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 PLGA-PEG -PLGA 20%, 60%, 40%, 70% or 99.99% Paclitaxel PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Amycin 6 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Docetaxel PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Vinblastine PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Methotrexate 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Vincristine PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Fluorouracil 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Zitazonium PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Piposulfan PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 PLGA-PEG 20％、60％、80％、 Daunorubicin PLGA-PEG 20％、60％、80％、
-PLGA 70% or 99.99% And carboplatin -PLGA 70% or 99.99%
Amycin and paclitaxel PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Ciclosporin 2 PLGA-PEG -PLGA 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLGA-PEG -PLGA 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 PLGA-PEG -PLGA 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PLGA-PEG -PLGA 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PLGA-PEG -PLGA 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment 16: be loaded with the preparation of biopharmaceutical macromolecular drug solution PLGA-PEG-PLGA microsphere
Step (1) is identical with embodiment two.
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and PLGA-PEG-PLGA of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PLGA?- PEG - PLGA Drug solution accounts for the percentage by weight of microsphere Drug solution PLGA-PEG -PLGA Drug solution accounts for the percentage by weight of microsphere
EPO1 PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% NGF PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
G-CSF1 PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% BDGF3 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
GM-CSF1 PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% BMP2 PLGA-PEG -PLGA 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 PLGA?- PEG - PLGA 20%, 40%, 80%, 70% or 99.99% TPA2 PLGA-PEG -PLGA 20%, 60%, 80%, 50% or 99.99%
GH1 PLGA?- PEG - PLGA 20%, 60%, 80%, 50% or 99.99% antibody PLGA-PEG -PLGA 20%, 50%, 80%, 70% or 99.99%
Insulin PLGA?- PEG - PLGA 20%, 50%, 80%, 70% or 99.99% Blood coagulation factor VIII PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
EGF1 PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% The IX genetic factor PLGA-PEG -PLGA 20%, 60%, 40%, 70% or 99.99%
FGF1 PLGA?- PEG - PLGA 20%, 60%, 40%, 70% or 99.99% anti-RNA PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
TGF-β PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% RNAi PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
IGF PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% SiRNA PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
VEGF PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% DNA PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
PDGF1 PLGA?- PEG - 20%, 60%, 80%, 70% or 99.99% BDGF and BMP (1: 1) PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
PLGA
ECGF PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% PDGF and BMP (1: 1) PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% TGF-β, PDGF and BMP (1: 1: 1) PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
NGF and BM P (1: 1) PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% SiRNA and DNA (1: 1) PLGA-PEG -PLGA 20%, 40%, 80%, 70% or 99.99%
EGF and FG F (1: 1) PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% BDGF and VEGF (1: 1) PLGA-PEG -PLGA 20%, 60%, 80%, 50% or 99.99%
GM-CSF and G-CSF (1: 1) PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% IGF and GH (1: 1) PLGA-PEG -PLGA 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% EPO2 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
NGF and BM P (1: 1) PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% G-CSF2 PLGA-PEG -PLGA 20%, 60%, 40%, 70% or 99.99%
EGF and FG F (1: 1) PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% GM-CSF2 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
GM-CSF and G-CSF (1: 1) PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% Vaccine PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
BDGF2 PLGA?- PEG - PLGA 20%, 60%, 78%, 70% or 99.99% EPO3 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
BMP1 PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% G-CSF3 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
TPA1 PLGA?- PEG - PLGA 20%, 60%, 80%, 70% or 99.99% GM-CSF3 PLGA-PEG -PLGA 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment 17: be loaded with the preparation of small-molecule drug solution PEG-PLA-PEG microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and PEG-PLA-PEG is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PEG-PLA -PEG Drug solution accounts for the percentage by weight of microsphere Drug solution PEG-PLA -PEG Drug solution accounts for the percentage by weight of microsphere
Amycin 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Carboplatin 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 2 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Carmustine PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 3 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Semustine PEG-PLA -PEG 20%, 40%, 80%, 70% or 99.99%
Amycin 4 PEG-PLA -PEG 20%, 40%, 80%, 70% or 99.99% Cisplatin PEG-PLA -PEG 20%, 60%, 80%, 50% or 99.99%
Amycin 5 PEG-PLA -PEG 20%, 60%, 80%, 50% or 99.99% Etoposide PEG-PLA -PEG 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 PEG-PLA -PEG 20%, 50%, 80%, 70% or 99.99% Camptothecine PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Phenesterin PEG-PLA -PEG 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 PEG-PLA -PEG 20%, 60%, 40%, 70% or 99.99% Paclitaxel PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 6 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Docetaxel PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Vinblastine PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
First ammonia butterfly PEG-PLA 20％、60％、80％、 Vincristine PEG-PLA 20％、60％、80％、
Purine 1 -PEG 70% or 99.99% -PEG 70% or 99.99%
Fluorouracil 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Zitazonium PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Piposulfan PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Daunorubicin and carboplatin PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Amycin and paclitaxel PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Ciclosporin 2 PEG-PLA -PEG 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PEG-PLA -PEG 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 PEG-PLA -PEG 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 PEG-PLA -PEG 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PEG-PLA -PEG 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment 18: be loaded with the preparation of biopharmaceutical macromolecular drug solution PEG-PLA-PEG microsphere
Step (1) is identical with embodiment two.
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and PEG-PLA-PEG of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PEG-PLA -PEG Drug solution accounts for the percentage by weight of microsphere Drug solution PEG-PLA- PEG Drug solution accounts for the percentage by weight of microsphere
EPO1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% NGF PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
G-CS F1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% BDGF3 PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
GM-C SF1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% BMP2 PEG-PLA- PEG 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 PEG-PLA -PEG 20%, 40%, 80%, 70% or 99.99% TPA2 PEG-PLA- PEG 20%, 60%, 80%, 50% or 99.99%
GH1 PEG-PLA -PEG 20%, 60%, 80%, 50% or 99.99% antibod y PEG-PLA- PEG 20%, 50%, 80%, 70% or 99.99%
Insu lin PEG-PLA -PEG 20%, 50%, 80%, 70% or 99.99% Blood coagulation factor VIII PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
EGF1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% The IX genetic factor PEG-PLA- PEG 20%, 60%, 40%, 70% or 99.99%
FGF1 PEG-PLA -PEG 20%, 60%, 40%, 70% or 99.99% anti-RN A PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
TGF- β PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% RNAi PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
IGF PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% SiRNA PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
VEGF PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% DNA PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
PDGF 1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% BDGF and BMP (1: 1) PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
ECGF PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% PDGF and BMP (1: 1) PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
VEGF and DNA (1: PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% TGF-β, PDGF and BMP (1: 1: 1 PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
1) )
NGF and BM P (1: 1) PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% SiRNA and DNA (1: 1) PEG-PLA- PEG 20%, 40%, 80%, 70% or 99.99%
EGF and FG F (1: 1) PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% BDGF and VEGF (1: 1) PEG-PLA- PEG 20%, 60%, 80%, 50% or 99.99%
GM-C SF and G-CS F (1: 1) PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% IGF and GH (1: 1) PEG-PLA- PEG 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% EP02 PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
NGF and BM P (1: 1) PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% G-CSF2 PEG-PLA- PEG 20%, 60%, 40%, 70% or 99.99%
EGF and FG F (1: 1) PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% GM-CSF2 PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
GM-C SF and G-CS F (1: 1) PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% Vaccine PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
BDGF 2 PEG-PLA -PEG 20%, 60%, 78%, 70% or 99.99% EP03 PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
BMP1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% G-CSF3 PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
TPA1 PEG-PLA -PEG 20%, 60%, 80%, 70% or 99.99% GM-CSF3 PEG-PLA- PEG 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment 19: be loaded with the preparation of small-molecule drug solution PEG-PLGA-PEG microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and PEG-PLGA-PEG is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PEG-PLGA -PEG Drug solution accounts for the percentage by weight of microsphere Drug solution PEG-PLGA- PEG Drug solution accounts for the percentage by weight of microsphere
Amycin 1 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Carboplatin 1 PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 2 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Carmustine PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 3 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Semustine PEG-PLGA- PEG 20%, 40%, 80%, 70% or 99.99%
Amycin 4 PEG-PLGA -PEG 20%, 40%, 80%, 70 % or 99.99% Cisplatin PEG-PLGA- PEG 20%, 60%, 80%, 50% or 99.99%
Amycin 5 PEG-PLGA -PEG 20%, 60%, 80%, 50 % or 99.99% Etoposide PEG-PLGA- PEG 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 PEG-PLGA -PEG 20%, 50%, 80%, 70 % or 99.99% Camptothecine PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Phenesterin PEG-PLGA- PEG 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 PEG-PLGA -PEG 20%, 60%, 40%, 70 % or 99.99% Paclitaxel PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Amycin 6 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Docetaxel PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Vinblastine PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
First ammonia butterfly PEG-PLGA 20％、60％、80％、70 Vincristine PEG-PLGA- 20％、60％、80％、
Purine 1 -PEG % or 99.99% PEG 70% or 99.99%
Fluorouracil 1 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Zitazonium PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Piposulfan PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Daunorubicin and carboplatin PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Amycin and paclitaxel PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Ciclosporin 2 PEG-PLGA- PEG 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Levofloxacin 3 PEG-PLGA- PEG 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Ofloxacin 3 PEG-PLGA- PEG 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Epinastine hydrochloride 3 PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Levofloxacin 3 PEG-PLGA- PEG 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Ofloxacin 4 PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Epinastine hydrochloride 3 PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 PEG-PLGA -PEG 20%, 60%, 78%, 70 % or 99.99% Levofloxacin 4 PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Ofloxacin 5 PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 PEG-PLGA -PEG 20%, 60%, 80%, 70 % or 99.99% Epinastine hydrochloride 4 PEG-PLGA- PEG 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment 20: be loaded with the preparation of biopharmaceutical macromolecular drug solution PEG-PLGA-PEG microsphere
Step (1) is identical with embodiment two.
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and PEG-PLGA-PEG of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution PEG-PLGA -PEG Drug particles accounts for the percentage by weight of microsphere Drug solution PEG-PLGA -PEG Drug solution accounts for the percentage by weight of microsphere
EPO1 PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% NGF PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
G-CSF1 PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% BDGF3 PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
GM-CSF1 PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% BMP2 PEG-PLGA -PEG 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 PEG-PLGA -PEG 20%, 40%, 80 %, 70% or 99.99% TPA2 PEG-PLGA -PEG 20%, 60%, 80%, 50% or 99.99%
GH1 PEG-PLGA -PEG 20%, 60%, 80 %, 50% or 99.99% antibo dy PEG-PLGA -PEG 20%, 50%, 80%, 70% or 99.99%
Insulin PEG-PLGA -PEG 20%, 50%, 80 %, 70% or 99.99% Blood coagulation factor VIII PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
EGF1 PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% The IX genetic factor PEG-PLGA -PEG 20%, 60%, 40%, 70% or 99.99%
FGF1 PEG-PLGA -PEG 20%, 60%, 40 %, 70% or 99.99% anti-R NA PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
TGF-β PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% RNAi PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
IGF PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% SiRNA PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
VEGF PEG-PLGA 20％、60％、80 DNA PEG-PLGA 20％、60％、80％、
-PEG %, 70% or 99.99% -PEG 70% or 99.99%
PDGF1 PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% BDGF and BMP (1: 1) PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
ECGF PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% PDGF and BMP (1: 1) PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% TGF-β, PDGF and BMP (1: 1: 1) PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
NGF and BM P (1: 1) PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% SiRNA and DNA (1: 1) PEG-PLGA -PEG 20%, 40%, 80%, 70% or 99.99%
EGF and FG F (1: 1) PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% BDGF and VEGF (1: 1) PEG-PLGA -PEG 20%, 60%, 80%, 50% or 99.99%
GM-CSF and G-CSF (1: 1) PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% IGF and GH (1: 1) PEG-PLGA -PEG 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% EPO2 PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
NGF and BM P (1: 1) PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% G-CSF2 PEG-PLGA -PEG 20%, 60%, 40%, 70% or 99.99%
EGF and FG F (1: 1) PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% GM-CSF 2 PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
GM-CSF and G-CSF (1: 1) PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% Vaccine PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
BDGF2 PEG-PLGA -PEG 20%, 60%, 78 %, 70% or 99.99% EPO3 PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
BMP1 PEG-PLGA -PEG 20%, 60%, 80 %, 70% or G-CSF3 PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
99.99％
TPA1 PEG-PLGA -PEG 20%, 60%, 80 %, 70% or 99.99% GM-CSF 3 PEG-PLGA -PEG 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment 21: be loaded with the preparation of small-molecule drug solution hyaluronic acid microsphere
Step (1) is identical with embodiment one.
(2) be that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O according to drug solution and hyaluronic dichloromethane, acetonitrile or ethyl acetate solution 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
Drug solution Hyaluronic acid Drug solution accounts for the percentage by weight of microsphere Drug solution Hyaluronic acid Drug solution accounts for the percentage by weight of microsphere
Amycin 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Carboplatin 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Amycin 2 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Carmustine Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Amycin 3 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Semustine Hyaluronic acid 20%, 40%, 80%, 70% or 99.99%
Amycin 4 Hyaluronic acid 20%, 40%, 80%, 70% or 99.99% Cisplatin Hyaluronic acid 20%, 60%, 80%, 50% or 99.99%
Amycin 5 Hyaluronic acid 20%, 60%, 80%, 50% or 99.99% Etoposide Hyaluronic acid 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 Hyaluronic acid 20%, 50%, 80%, 70% or 99.99% Camptothecine Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Phenesterin Hyaluronic acid 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 Hyaluronic acid 20%, 60%, 40%, 70% or 99.99% Paclitaxel Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Amycin 6 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Docetaxel Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Vinblastine Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Methotrexate 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Vincristine Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Fluorouracil 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Zitazonium Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Piposulfan Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Daunorubicin and carboplatin Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Amycin and paclitaxel Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Ciclosporin 2 Hyaluronic acid 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 Hyaluronic acid 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 Hyaluronic acid 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 Hyaluronic acid 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 Hyaluronic acid 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 Hyaluronic acid 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment 22: be loaded with the preparation of biopharmaceutical macromolecular drug solution hyaluronic acid microsphere
Step (1) is identical with embodiment two.
(2) according to the biomacromolecule polysaccharide or form to such an extent that drug solution and hyaluronic dichloromethane, acetonitrile or the ethyl acetate solution of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The present embodiment thus obtained microsphere, it specifically forms proportioning such as following table:
Figure G2009100450248D00491
Figure G2009100450248D00501
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.
Embodiment 23: be loaded with the preparation of small-molecule drug solution gelatine microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to drug solution and gelatin is that formation in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute is even that suspension is Water-In-Oil (W/O 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The present embodiment thus obtained microsphere, it specifically forms proportioning such as following table:
Drug solution Gelatin Drug solution accounts for microsphere Drug particles Gelatin Drug solution accounts for the weight of microsphere
Percentage by weight Percentage ratio
Amycin 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Carboplatin 1 Gelatin 20%, 60%, 80%, 70% or 99.99%
Amycin 2 Gelatin 20%, 60%, 80%, 70% or 99.99% Carmustine Gelatin 20%, 60%, 80%, 70% or 99.99%
Amycin 3 Gelatin 20%, 60%, 80%, 70% or 99.99% Semustine Gelatin 20%, 40%, 80%, 70% or 99.99%
Amycin 4 Gelatin 20%, 40%, 80%, 70% or 99.99% Cisplatin Gelatin 20%, 60%, 80%, 50% or 99.99%
Amycin 5 Gelatin 20%, 60%, 80%, 50% or 99.99% Etoposide Gelatin 20%, 50%, 80%, 70% or 99.99%
Cyclophosphamide 1 Gelatin 20%, 50%, 80%, 70% or 99.99% Camptothecine Gelatin 20%, 60%, 80%, 70% or 99.99%
Dactinomycin 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Phenesterin Gelatin 20%, 60%, 40%, 70% or 99.99%
Daunorubicin 1 Gelatin 20%, 60%, 40%, 70% or 99.99% Paclitaxel Gelatin 20%, 60%, 80%, 70% or 99.99%
Amycin 6 Gelatin 20%, 60%, 80%, 70% or 99.99% Docetaxel Gelatin 20%, 60%, 80%, 70% or 99.99%
Epirubicin 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Vinblastine Gelatin 20%, 60%, 80%, 70% or 99.99%
Methotrexate 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Vincristine Gelatin 20%, 60%, 80%, 70% or 99.99%
Fluorouracil 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Zitazonium Gelatin 20%, 60%, 80%, 70% or 99.99%
Etoposide 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Piposulfan Gelatin 20%, 60%, 80%, 70% or 99.99%
Flutamide 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Daunorubicin and carboplatin Gelatin 20%, 60%, 80%, 70% or 99.99%
Amycin and paclitaxel Gelatin 20%, 60%, 80%, 70% or 99.99% Ciclosporin 2 Gelatin 20%, 40%, 80%, 70% or 99.99%
Ciclosporin 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 Gelatin 20%, 60%, 80%, 50% or 99.99%
Levofloxacin 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Ofloxacin 3 Gelatin 20%, 50%, 80%, 70% or 99.99%
Ofloxacin 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 Gelatin 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 Gelatin 20%, 60%, 80%, 70% or 99.99% Levofloxacin 3 Gelatin 20%, 60%, 40%, 70% or 99.99%
Levofloxacin 2 Gelatin 20%, 60%, 80%, 70% or 99.99% Ofloxacin 4 Gelatin 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 2 Gelatin 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 3 Gelatin 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 1 Gelatin 20%, 60%, 78%, 70% or 99.99% Levofloxacin 4 Gelatin 20%, 60%, 80%, 70% or 99.99%
Ofloxacin 3 Gelatin 20%, 60%, 80%, 70% or 99.99% Ofloxacin 5 Gelatin 20%, 60%, 80%, 70% or 99.99%
Epinastine hydrochloride 2 Gelatin 20%, 60%, 80%, 70% or 99.99% Epinastine hydrochloride 4 Gelatin 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation need can be used to the disease of long-term treatment, especially needs the blood vessel embolism microsphere of the disease such as the tumor of topical therapeutic.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release.
Embodiment 24: be loaded with the preparation of biopharmaceutical macromolecular drug solution gelatine microsphere
Step (1) is identical with embodiment two.
(2) according to the biomacromolecule polysaccharide or form to such an extent that dichloromethane, acetonitrile or the ethyl acetate solution of drug solution and gelatin of complex is to form even that suspension be Water-In-Oil (W/O in equal proportion stirring in 1: 1,1: 2,1: 3,1: 4,1: 5,1: 6,1: 7,1: 8,1: 9,1: 10, whirlpool or ultrasonic 1-5 minute with metal ion 1) emulsion;
Step (3), (4), (5) are identical with embodiment one.
The microsphere that present embodiment obtains, it specifically forms proportioning such as following table:
Drug solution Gelatin Drug solution accounts for the percentage by weight of microsphere Drug solution Gelatin Drug solution accounts for the percentage by weight of microsphere
EPO1 Gelatin 20%, 60%, 80%, 70% or 99.99% NGF Gelatin 20%, 60%, 80%, 70% or 99.99%
G-CSF1 Gelatin 20%, 60%, 80%, 70% or 99.99% BDGF3 Gelatin 20%, 60%, 80%, 70% or 99.99%
GM-CSF1 Gelatin 20%, 60%, 80%, 70% or 99.99% BMP2 Gelatin 20%, 40%, 80%, 70% or 99.99%
Vaccine 1 Gelatin 20%, 40%, 80%, 70% or 99.99% TPA2 Gelatin 20%, 60%, 80%, 50% or 99.99%
GH1 Gelatin 20%, 60%, 80%, 50% or 99.99% antibody Gelatin 20%, 50%, 80%, 70% or 99.99%
Insulin Gelatin 20%, 50%, 80%, 70% or 99.99% Blood coagulation factor VIII Gelatin 20%, 60%, 80%, 70% or 99.99%
EGF1 Gelatin 20%, 60%, 80%, 70% or 99.99% The IX genetic factor Gelatin 20%, 60%, 40%, 70% or 99.99%
FGF1 Gelatin 20%, 60%, 40%, 70% or 99.99% anti-RNA Gelatin 20%, 60%, 80%, 70% or 99.99%
TGF-β Gelatin 20%, 60%, 80%, 70% or 99.99% RNAi Gelatin 20%, 60%, 80%, 70% or 99.99%
IGF Gelatin 20%, 60%, 80%, 70% or 99.99% SiRNA Gelatin 20%, 60%, 80%, 70% or 99.99%
VEGF Gelatin 20%, 60%, 80%, 70% or 99.99% DNA Gelatin 20%, 60%, 80%, 70% or 99.99%
PDGF1 Gelatin 20%, 60%, 80%, 70% or 99.99% BDGF and BMP (1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99%
ECGF Gelatin 20%, 60%, 80%, 70% or 99.99% PDGF and BMP (1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99% TGF-β, PDGF and BMP (1: 1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99%
NGF and BMP (1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99% SiRNA and DNA (1: 1) Gelatin 20%, 40%, 80%, 70% or 99.99%
EGF and FGF (1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99% BDGF and VEGF (1: 1) Gelatin 20%, 60%, 80%, 50% or 99.99%
GM-CSF and G-CSF (1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99% IGF and GH (1: 1) Gelatin 20%, 50%, 80%, 70% or 99.99%
VEGF and DNA (1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99% EPO2 Gelatin 20%, 60%, 80%, 70% or 99.99%
NGF and BMP (1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99% G-CSF2 Gelatin 20%, 60%, 40%, 70% or 99.99%
EGF and FGF (1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99% GM-CSF2 Gelatin 20%, 60%, 80%, 70% or 99.99%
GM-CSF and G-CSF (1: 1) Gelatin 20%, 60%, 80%, 70% or 99.99% Vaccine Gelatin 20%, 60%, 80%, 70% or 99.99%
BDGF2 Gelatin 20%, 60%, 78%, 70% or 99.99% EPO3 Gelatin 20%, 60%, 80%, 70% or 99.99%
BMP1 Gelatin 20%, 60%, 80%, 70% or 99.99% G-CSF3 Gelatin 20%, 60%, 80%, 70% or 99.99%
TPA1 Gelatin 20%, 60%, 80%, 70% or 99.99% GM-CSF3 Gelatin 20%, 60%, 80%, 70% or 99.99%
The microsphere of this method preparation can be used for the disease of the frequent drug administration by injection of needs, long-term treatment, especially needs the treatment of major diseases such as anemia that disease such as the tumor of topical therapeutic, the various cause of disease cause, dwarf.High minimum can the reaching more than 70% of the microsphere envelop rate of this method preparation dashed forward and released little and almost not incomplete release, can reach zero level and discharge.

Claims (5)

1. oil-in-water-oil bag oil-Water-In-Oil prepares the method for microsphere, it is characterized in that, may further comprise the steps:
1. prepare drug solution, directly be dissolved in the water medicine or medicine be dissolved in the water through adding adjuvant;
2. the organic solution that drug solution is joined slow release or controlled-release material is to stir in the oil phase-1 or whirlpool makes it homodisperse and forms uniform suspension;
3. suspension being added in another organic solution is oil phase-2, insoluble slow release of this oil phase or controlled-release material but can extract organic solvent 2., and stirring, whirlpool or ultrasonic formation contain the emulsion of 20-500 μ m microsphere;
4. the completing steps emulsion that contains microsphere 3. being transferred to salt water W solidifies;
5. completing steps sample lyophilizing is 4. got microsphere, in this microsphere: medicine is that 0.01-50%, slow release or the controlled-release material of the weight of whole microsphere is that 20-99.99%, the adjuvant of the weight of whole microsphere is the 0-30% of the weight of whole microsphere;
Described medicine comprises small-molecule drug and macromolecular drug, and macromolecular drug is meant biopharmaceutical macromolecular drug;
Said small-molecule drug is chemotherapy of tumors class medicine or antibiotics;
Said chemotherapy of tumors class medicine is one or more mixing in AC, dactinomycin, bleomycin, daunorubicin, epirubicin, mitomycin, methylamine dish purine, fluorouracil, carboplatin, carmustine, semustine, cisplatin, etoposide, camptothecine, phenesterin, paclitaxel, Docetaxel, vinblastine, vincristine, zitazonium, etoposide, piposulfan, cyclophosphamide or the flutamide;
Said antibiotics is that ciclosporin, levofloxacin, ofloxacin or hydrochloric acid are according to one or more mixing in this spit of fland of an acid;
Described biopharmaceutical macromolecular drug is meant protein macromolecule medicine, vaccine, nucleic acid or liposome medicament, wherein:
Described protein macromolecule medicine is: erythropoietin; Recombinant human granulocyte colony stimulating factor; Granulocyte-macrophage colony stimutaing factor; Vaccine; Interferon; Growth hormone; Insulin; Epidermal growth factor; Fibroblast growth factor; Transforming growth factor; Insulin like growth factor; Vascular endothelial cell growth factor; PDGF; ECGF; Nerve growth factor; BDGF; BMP; Tissue polypeptide antigen; Antibody; Blood coagulation factor VIII or plasma thromboplastin component genetic factor; Antibody;
Described nucleic acid is: GEM 132, microRNA or gene;
The material of described slow release or controlled release is: polylactic acid; Polylactic acid-polyglycolic acid; Politef; Polrvinyl chloride; Polyethylene; Polypropylene; Polystyrene; PETG; Merlon; Hyaluronic acid; Gelatin; Collagen protein; Gather Acetic acid, hydroxy-, bimol. cyclic ester; Polybutylcyanoacrylate; Poly phosphazene; Poly phosphate; Fibrinogen; Fibrin; Polyethylene glycol-lactic acid; The polyethylene glycol-hydroxyacetic acid; Polyglycolic acid-polyethylene glycol-hydroxyacetic acid; Polylactic acid-polyglycol-polylactic acid; Or a kind of in the polycaprolactone;
The organic solution of the material of described slow release or controlled release; Wherein organic solution is meant a kind of or combination in dichloromethane, ethyl acetate, acetonitrile, heptane, chloroform and the acetone; In the organic solution of the material of this slow release or controlled release, the weight percent content of the material of slow release or controlled release is 0.5-80%;
Described oil phase-2 is: a kind of or their combination in any in surfactant, glycerol, ethanol, propylene glycol, the ethylene glycol solution, wherein:
Described their combination in any is: glycerol and ethanol add that the aqueous solution of surfactant, aqueous solution, glycerol and propylene glycol that ethanol adds surfactant add the aqueous solution of surfactant, aqueous solution, glycerol and the ethylene glycol that propylene glycol adds surfactant adds the aqueous solution of surfactant, the aqueous solution that ethylene glycol adds surfactant.
2. oil-in-water according to claim 1-oil bag oil-Water-In-Oil prepares the method for microsphere; It is characterized in that; Described adjuvant is meant a kind of or combination in any of little saccharide, polyhydroxy compounds, polysaccharide compound, amino-acid compound or inorganic salts material, wherein:
Said little saccharide is meant sucrose, trehalose, glucose, maltose or lactose;
Said polyhydroxy compounds is meant mannitol, sorbitol, glycerol, 1,2-propylene glycol, erythritol, Polyethylene Glycol, polyvinyl alcohol, PEO or polypyrrole alkane ketone;
Said polysaccharide compound is meant glucosan, sodium alginate, chitosan, starch, cellulose or cyclodextrin material;
Said amino-acid compound is meant lysine, arginine, glutamic acid or histidine;
Said inorganic salts material is meant zinc salt, calcium salt, mantoquita, magnesium salt or molybdenum salt.
3. oil-in-water according to claim 1-oil bag oil-Water-In-Oil prepares the method for microsphere, it is characterized in that in the described drug solution, the weight percent content of medicine is between the 0.2-50%.
4. oil-in-water according to claim 1-oil bag oil-Water-In-Oil prepares the method for microsphere; It is characterized in that; Described surfactant is: polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone, poloxamer, gather in sorbic alcohol, ethyl cellulose and the tween a kind of, wherein:
The weight concentration of polyvinyl alcohol is 0.5-10% or contains 0.5-10% sodium chloride salt solution; The weight concentration of Polyethylene Glycol is 0.5-20% or the saline solution that contains 0.5-10% sodium chloride; The polyvinylpyrrolidone weight concentration is 0.5-20% or contains 0.5-10% sodium chloride salt solution; The poloxamer weight concentration is 0.5-20% or contains 0.5-10% sodium chloride salt solution; To gather the sorbic alcohol weight concentration be 0.5-20% or contain 0.5-10% sodium chloride salt solution, and the ethyl cellulose weight concentration is 0.5-20% or contains 0.5-10% sodium chloride salt solution.
5. oil-in-water according to claim 1-oil bag oil-Water-In-Oil prepares the method for microsphere; It is characterized in that in the said oil phase-2, each substance weight percentage ratio is: glycerol 0-50%; Aqueous surfactant solution 0-30%, ethanol, propylene glycol, ethylene glycol 50-100%.
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