The content of invention
The objective of the invention is to overcome deficiency of the prior art, provide a kind of oil bag oil-Water-In-Oil to prepare the method for microsphere.Make the microsphere features smooth surface rounding of its preparation, good evenness, solution regular without adhesion.Can improve greatly to the material of good water solubility at the medium envelop rate of microsphere.
The present invention is achieved by the following technical solutions, the present invention adds the aqueous solution that contains water-soluble substances in the material organic solvent for preparing microsphere to and forms Water-In-Oil, and then it is added to another organic facies form oil bag oil, at last they are added drop-wise to aqueous phase and solidify, microsphere is collected in lyophilizing then.
The present invention specifically may further comprise the steps:
1. water miscible material or the material that adds various these water-soluble substanceses of protection are formed water;
2. microencapsulated material is dissolved in and forms oil phase-1 in the organic solvent;
3. completing steps drips of solution 1. is added to oil phase-1 2., and stirring makes it to form uniform emulsion;
4. completing steps emulsion droplets 3. is added to another oil phase (oil phase-2), and stirring makes it to form microsphere;
5. completing steps drips of solution 4. is added in another oil phase-3 and stirring, make microsphere solidify also centrifugal collection washing lyophilizing and get microsphere, described microsphere contains medicine, microencapsulated material, pharmaceutic adjuvant, and their weight percent contents are: medicine is that 0.01-50%, microencapsulated material are that 20-80%, pharmaceutic adjuvant are 0-10%.
Described water miscible material is that water miscible medicine refers to: protein and peptide drugs, DNA, RNA, etc. genetic stew, antibody, vaccine, virus and liposome cell, and chemical reagent such as various water miscible dyestuff or fluorescent material.
Described water miscible material, its weight percent concentration are between the 0.02%-50% (w/w); With 1%-30% (w/w) is good.
Described pharmaceutic adjuvant is the material of this water-soluble substances of protection.
The material of described this water-soluble substances of protection is polysaccharose substance, polyhydroxy compounds, little glucide, amino acids material or inorganic salts material.
Described polysaccharose substance is glucosan, sodium alginate, chitosan, starch, cellulose or cyclodextrin material;
Described polyhydroxy compounds is Polyethylene Glycol, polyvinyl alcohol, poly(ethylene oxide) or polypyrrole alkane ketone;
Described little glucide is sucrose, trehalose, mannitol, sorbitol or lactose.
Described inorganic salts material is zinc salt, calcium salt, mantoquita, magnesium salt or molybdenum salt.
Described amino acids material is glycine, lysine or histidine.
The weight percent concentration of the material of described this water-soluble substances of protection is 0%-50% (w/w); With 1%-20% (w/w) is good.
Described oil phase-1 is the organic solution of dichloromethane, ethyl acetate, acetonitrile or their mixture microencapsulated materials.
Described microencapsulated material is: polylactic acid (PLA), polylactic acid-polyglycolic acid (PLGA), the combination in any of PLA and PLGA, silicon is as glue, politef, polrvinyl chloride, polyethylene, polypropylene, polystyrene, polyethylene terephthalate, Merlon, Carmomer, hyaluronic acid, gelatin, collagen protein, polybutylcyanoacrylate, poly phosphazene, poly phosphate, Fibrinogen, fibrin, polyethylene glycol-lactic acid (PLA-PEG), polyethylene glycol-hydroxyacetic acid (PLGA-PEG), polyglycolic acid-polyethylene glycol-hydroxyacetic acid (PLGA-PEG-PLGA), polylactic acid-polyglycol-polylactic acid (PLA-PEG-PLA), the combination in any of polylactic acid and polylactic acid-polyglycolic acid, Merlon, Carmomer, hyaluronic acid, gelatin, collagen protein, poly-Acetic acid, hydroxy-, bimol. cyclic ester, Polyethylene Glycol-polycaprolactone (PEG-PCL), polycaprolactone gathers-ethylene glycol-polycaprolactone (PCL-PEG-PCL), or polycaprolactone (PCL);
Described microencapsulated material account for whole microsphere percentage composition be 20-80% (w/w), be good wherein with 50-80% (w/w);
Described oil phase-2 is for ethanol, ethylene glycol, glycerol, propylene glycol and micromolecular Polyethylene Glycol or add various surfactant materials, and their mixture; Mixture with ethylene glycol and glycerol and propylene glycol is good;
Described oil phase-3 is the arbitrary proportion mixture of ethanol, ethanol and propylene glycol;
Described surfactant is: the concentration of polyvinyl alcohol (PVA) is 0.5-10% (w/w) or contains saline solution such as 0.5-10% (w/w) sodium chloride, the concentration of Polyethylene Glycol (PEG) is 0.5-20% (w/w) or contains saline solution such as 0.5-10% (w/w) sodium chloride, polyvinylpyrrolidone (PVP) concentration is 0.5-20% (w/w) or contains saline solution such as 0.5-10% (w/w) sodium chloride, poloxamer (poloxmer) concentration is 0.5-20% (w/w) or contains saline solution such as 0.5-10% (w/w) sodium chloride, the concentration of poly-sorbic alcohol is 0.5-20% (w/w) or contains saline solution such as 0.5-10% (w/w) sodium chloride, or ethyl cellulose (EC) concentration is 0.5-20% (w/w) or contains saline solution such as 0.5-10% (w/w) sodium chloride;
The particle diameter of described microsphere is 0.1-500 μ m, is good with 1-100 μ m;
The resulting microsphere of the present invention, can be used for its therapeutant that supports the sustained-release micro-spheres dosage form, implant dosage form or inhalant dosage form;
Described inhalant dosage form is the polysaccharide itself that is loaded with therapeutant, and its particle diameter is 1 μ m-5 μ m.
The present invention forms solution with the substance dissolves of water miscible material or water miscible material and protection water-soluble active respectively earlier in water, it is mixed mutually forming uniform emulsion again with oil phase-1.Then this emulsion droplets is added to another oil phase (oil phase-2) third and stirs the formation microsphere, again microsphere is added drop-wise to aqueous phase and solidifies, solidify the back and collect microballoon lyophilized.
The present invention can prepare the micro-sphere method of various particle diameters (1 μ m-500 μ m) according to actual needs.Adopt the smooth rounding of microparticle surfaces of the inventive method preparation, the solution regular without adhesion, particle diameter can be regulated and control from 1 μ m as required to 500 μ m.
The present invention has selected two suitable oil phases, can improve the envelop rate of water miscible material, and improves the activity of water miscible material.Can avoid these function influences to the treatment of medicine, especially those physicochemical properties are unsettled, as biopharmaceutical macromolecular drug protein drug, polypeptide etc.The smooth surface rounding of microgranule, the solution regular without adhesion, particle diameter can be regulated and control from 1 μ m as required to 500 μ m, the span narrow distribution, its freeze dried powder is that white is fine and smooth, and is loose, do 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
Below embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment one: be loaded with the preparation of water miscible substance solution PLGA microsphere
(1) prepares water miscible substance solution, water miscible material directly is dissolved in the water or medicine is dissolved in the water by adding adjuvant;
In the present embodiment, the water miscible material of employing is that (tumor chemotherapeutic drug is selected from chemotherapy of tumors class medicine: amycin, cyclophosphamide, dactinomycin, bleomycin, daunorubicin, amycin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), semustine, cisplatin, etoposide, camptothecine and derivant thereof, 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 material of this water-soluble substances of protection of employing is one or more in glucosan, sodium alginate, chitosan, starch, cellulose, cyclodextrin, Polyethylene Glycol, polyvinyl alcohol, poly(ethylene oxide), 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, concrete proportioning is:
| Water-soluble substances | Protect the material of this water-soluble substances | Water-soluble substances accounts for solution weight percentage ratio | Water-soluble substances | Protect the material of this water-soluble substances | Water-soluble substances accounts for solution weight percentage ratio |
| Amycin 1 | Cyclodextrin | 100%, 80%, 50%, 25%, 10% or 0 | Carboplatin 1 | Cyclodextrin | 100%, 80%, 50%, 25%, 10% or 0 |
| Amycin 2 | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 | Carmustine | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 |
| Amycin 3 | Polyvinyl alcohol | 100%, 80%, 50%, 25%, 10% or 0 | Semustine | Polyvinyl alcohol | 100%, 80%, 50%, 25%, 10% or 0 |
| Amycin 4 | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 | Cisplatin | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 |
| Amycin 5 | Polypyrrole alkane ketone | 100%, 80%, 50%, 25%, 10% or 0 | Etoposide | Polypyrrole alkane ketone | 100%, 80%, 50%, 25%, 10% or 0 |
| Cyclophosphamide 1 | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 | Camptothecine | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 |
| Dactinomycin 1 | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 | Phenesterin | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 |
| Daunorubicin 1 | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 | Paclitaxel | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 |
| Amycin 6 | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 | Docetaxel | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 |
| Epirubicin 1 | Polypyrrole alkane ketone | 100%, 80%, 50%, 25%, 10% or 0 | Vinblastine | Polypyrrole alkane ketone | 100%, 80%, 50%, 25%, 10% or 0 |
| Methotrexate 1 | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 | Vincristine | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 |
| Fluorouracil 1 | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 | Zitazonium | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 |
| Etoposide 1 | Cyclodextrin | 100%, 80%, 50%, 25%, 10% or 0 | Piposulfan | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 |
| Flutamide 1 | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 | Daunorubicin and carboplatin | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 |
| Amycin and paclitaxel | Polyvinyl alcohol | 100%, 80%, 50%, 25%, 10% or 0 | Ciclosporin 2 | Polypyrrole alkane ketone | 100%, 80%, 50%, 25%, 10% or 0 |
| Ciclosporin 1 | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 | Levofloxacin 3 | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 |
| Levofloxacin 1 | Polypyrrole alkane ketone | 100%, 80%, 50%, 25%, 10% or 0 | Ofloxacin 3 | Polyethylene Glycol | 100%, 80%, 50%, 25%, 10% or 0 |
| Ofloxacin 1 | Glucosan | 100%, 80%, 50%, 25%, 10% or 0 | Epinastine hydrochloride 3 | Poly(ethylene oxide) | 100%, 80%, 50%, 25%, 10% or 0 |
| Epinastine hydrochloride 1 | Sodium alginate | 100%, 80%, 50%, 25%, 10% or 0 | Levofloxacin 3 | Mannitol | 100%, 80%, 50%, 25%, 10% or 0 |
| Levofloxacin 2 | Chitosan | 100%, 80%, 50%, 25%, 10% or 0 | Ofloxacin 4 | Sorbitol | 100%, 80%, 50%, 25%, 10% or 0 |
| Ofloxacin 2 | Starch | 100%, 80%, 50%, 25%, 10% or 0 | Epinastine hydrochloride 3 | Lactose | 100%, 80%, 50%, 25%, 10% or 0 |
| Epinastine hydrochloride 1 | Cellulose | 100%, 80%, 50%, 25% or 10% | Levofloxacin 4 | Glycine | 100%, 80%, 50%, 25%, 10% or 0 |
| Ofloxacin 3 | Sucrose | 100%, 80%, 50%, 25%, 10% or 0 | Ofloxacin 5 | Lysine | 100%, 80%, 50%, 25%, 10% or 0 |
| Epinastine hydrochloride 2 | Trehalose | 100%, 80%, 50%, 25%, 10% or 0 | Epinastine hydrochloride 4 | Histidine | 100%, 80%, 50%, 25%, 10% or 0 |
(2) be 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is oil bag solid (W/O in ultrasonic 1-5 minutes according to the solution of water-soluble substances and dichloromethane, acetonitrile or the ethyl acetate solution weight ratio of PLGA1) emulsion;
(3) step (1) being got emulsion droplets is added to oil phase-2 and stirring, whirlpool or formed emulsion in ultrasonic 0.1-5 minutes;
(4) be added drop-wise to the emulsion of step (2) in the ethanol of 200ml and stirred 2-4 hours;
(5) the centrifugal collection microsphere that step (3) is obtained, and wash with water 3-5 times, microsphere obtained after the lyophilizing.
The microsphere that present embodiment obtains, its concrete set of dispense are such as following table:
| Water soluble substance solution | PLGA | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLGA | Water soluble substance solution accounts for the percentage by weight of microsphere |
| 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%, 70% or 99.99% | Phenesterin | PLGA | 20%, 60%, 40%, 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 | PLGA | 20％、60％、80％、 | Ofloxacin 3 | PLGA | 20％、50％、80％、 |
| Star 1 | | 70% or 99.99% | | | 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 water miscible substance solution PLGA microsphere
(1) prepare water miscible substance solution, water miscible substance solution directly is dissolved in the water or the substance dissolves by adding this water-soluble substances of protection in water;
In the present embodiment, the water miscible material 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), endothelial cell growth factor (ECGF) (ECGF), nerve growth factor (NGF), bone-derived growth factor (BDGF), bone morphogenetic protein(BMP) (BMP), tissue polypeptide antigen (TPA), antibody (antibody), blood coagulation factor VIII (VIII), the IX genetic factor, antisense nucleotide (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 material of this water-soluble substances of protection of employing is one or more in glucosan, sodium alginate, chitosan, starch, cellulose, cyclodextrin, Polyethylene Glycol, polyvinyl alcohol, poly(ethylene oxide), polypyrrole alkane ketone, sucrose, trehalose, mannitol, sorbitol, lactose, glycine, lysine or the histidine said medicine;
Concrete proportioning is:
| Water-soluble substances | Protect the material of this water-soluble substances | Water-soluble substances accounts for solution weight percentage ratio | Water-soluble substances | Protect the material of this water-soluble substances | Water-soluble substances accounts for solution weight percentage ratio |
| EPO1 | Glucosan | 80%, 50%, 25 %, 10%, 5% or 0 | NGF | Cyclodextrin and sucrose (5:1) | 100%, 80%, 50 %, 25%, 10%, 5% or 0 |
| G-CSF1 | Glucosan and trehalose (9:1) | 80%, 50%, 25 %, 10%, 5% or 0 | BDGF3 | Polyethylene Glycol and sorbitol (8:1) | 100%, 80%, 50 %, 25%, 10%, 5% or 0 |
| GM-CSF1 | Glucosan and trehalose (9:1) | 80%, 50%, 25 %, 10%, 5% or 0 | BMP2 | Glucosan | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| Vaccine 1 | Glucosan | 100%, 80%, 50 %, 25%, 10%, 5% or 0 | TPA2 | Poly(ethylene oxide) and sucrose (9:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| GH1 | Glucosan zinc salt and mannitol (9:0.5:1) | 80%, 50%, 25 %, 10%, 5% or 0 | antibody | Polypyrrole alkane ketone and glycine (5:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| Insulin | Polyethylene Glycol and zinc salt (9:1) | 100%, 80%, 50 %, 25%, 10%, 5% or 0 | Blood coagulation factor VIII | Glucosan and lysine (9:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| EGF1 | Poly(ethylene oxide) | 100%, 80%, 50 %, 25%, 10%, 5% or 0 | The IX genetic factor | Glucosan and histidine (8:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| FGF1 | Polyethylene Glycol | 100%, 80%, 50 %, 25%, 10%, 5% or 0 | anti-RNA | Polyethylene Glycol | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| TGF-β | Poly(ethylene oxide) | 100%, 80%, 50 %, 25%, 10%, 5% or 0 | RNAi | Poly(ethylene oxide) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| IGF | Glucosan | 100%, 80%, 50 %, 25%, 10%, 5% or 0 | SiRNA | Glucosan | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| VEGF | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 12%, 10%, 5 % or 0 | DNA | Glucosan | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| PDGF1 | Glucosan and trehalose (8:1) | 50％、40％、30 ％、25％、15％、 12％、10％、5 | BDGF and BMP (1:1) | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| | % or 0 | | | |
| ECGF | Cyclodextrin and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 12%, 10%, 5 % or 0 | PDGF and BMP (1:1) | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| VEGF and DNA (1:1) | Glucosan and trehalose (8:1) | 80%, 70%, 50 %, 25%, 10%, 5% or 0 | TGF-β, PDGF and BMP (1:1:1) | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| NGF and BM P (1:1) | Glucosan and lactose (8:1) | 80%, 60%, 50 %, 25%, 10%, 5% or 0 | SiRNA and DNA (1:1) | Polypyrrole alkane ketone | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| EGF and FG F (1:1) | Glucosan and trehalose (8:1) | 60%, 50%, 25 %, 10%, 5% or 0 | BDGF and VEGF (1:1) | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| GM-CSF and G-CSF (1:1) | Glucosan and lactose (8:1) | 60%, 50%, 25 %, 10%, 5% or 0 | IGF and GH (1:1) | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| VEGF and DNA (1:1) | Glucosan and sodium alginate (9:1) | 60%, 50%, 25 %, 10%, 5% or 0 | EPO2 | Glucosan and sodium alginate (9:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| NGF and BM P (1:1) | Glucosan and sodium alginate (9:1) | 60%, 50%, 40 %, 20%, 10%, 5% or 0 | G-CSF2 | Glucosan and sodium alginate (9:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| EGF and and FG F (1:1) | Chitosan | 60%, 50%, 40 %, 20%, 10%, 5% or 0 | GM-CSF2 | Glucosan and sorbitol (9:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| GM-CSF and G-CSF (1:1) | Starch | 60%, 50%, 40 %, 20%, 10%, 5% or 0 | Vaccine | Glucosan and lactose (9:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| BDGF2 | Cellulose and lactose (9:1) | 100%, 80%, 40 %, 20%, 10%, 5% or 0 | EP03 | Glucosan and glycine | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| BMP1 | Glucosan and sucrose (9:1) | 100%, 80%, 40 %, 20%, 10%, 5% or 0 | G-CSF3 | Glucosan and lysine | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
| TPA1 | Trehalose | 100%, 80%, 40 %, 20%, 10%, 5% or 0 | GM-CSF3 | Glucosan and histidine | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0 |
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible material and PLGA is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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 | 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%, 50% or 99.99% | antibody | PLGA | 20%, 50%, 80%, 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 BM P (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 FG F (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 BM P (1:1) | PLGA | 20%, 60%, 80%, 70% or 99.99% | G-CSF2 | PLGA | 20%, 60%, 40%, 70% or 99.99% |
| EGF and FG F | PLGA | 20％、60％、80％、 | GM-CSF2 | PLGA | 20％、60％、80％、 |
| (1：1) | | 70% or 99.99% | | | 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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution PLA microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PLA is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PLA | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLA | Water soluble substance 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％、 | Phenesterin | PLA | 20％、60％、40％、70％、 |
| | 70% or 99.99% | | | 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 water miscible substance solution PLA microsphere
Step (1) is identical with embodiment two.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PLA is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PLA | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLA | Water soluble substance 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 BM P (1:1) | PLA | 20%, 60%, 80%, 70% or 99.99% | SiRNA and DNA (1:1) | PLA | 20%, 40%, 80%, 70% or 99.99% |
| EGF and FG F (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 | PLA | 20％、60％、80％、 | IGF and GH (1:1) | PLA | 20％、50％、80％、 |
| G-CSF(1：1) | | 70% or 99.99% | | | 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 BM P (1:1) | PLA | 20%, 60%, 80%, 70% or 99.99% | G-CSF2 | PLA | 20%, 60%, 40%, 70% or 99.99% |
| EGF and FG F (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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution PGA microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PGA is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PGA | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PGA | Water soluble substance solution accounts for the percentage by weight of microsphere |
| Amycin 1 | PGA | 20%, 60%, 80%, 70% or 99.99% | Carboplatin 1 | PGA | 20%, 60%, 80%, 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％、 | Cisplatin | PGA | 20％、60％、80％、 |
| | 70% or 99.99% | | | 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 water miscible substance solution PGA microsphere
Step (1) is identical with embodiment two.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PGA is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PGA | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PGA | Water soluble substance 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 | PGA | 20％、60％、80％、 | TGF-β、PDGF | PGA | 20％、60％、80％、 |
| (1：1) | | 70% or 99.99% | And BMP (1:1:1) | | 70% or 99.99% |
| NGF and BM P (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 FG F (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 BM P (1:1) | PGA | 20%, 60%, 80%, 70% or 99.99% | G-CSF2 | PGA | 20%, 60%, 40%, 70% or 99.99% |
| EGF and FG F (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% |
| BD6F2 | 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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution polycaprolactone microballoon sphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution weight ratio according to water miscible substance solution and polycaprolactone is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is oil bag solid (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | Polycaprolactone | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | Polycaprolactone | Water soluble substance solution accounts for the percentage by weight of microsphere |
| Amycin 1 | Poly-own | 20％、60％、80％、 | Carboplatin 1 | Polycaprolactone | 20％、60％、80％、 |
| Lactone | 70% or 99.99% | | | 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%, 70% or 99.99% | Vincristine | Polycaprolactone | 20%, 60%, 80%, 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 water miscible substance solution polycaprolactone microballoon sphere
Step (1) is identical with embodiment two.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and polycaprolactone is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | Polycaprolactone | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | Polycaprolactone | Water soluble substance 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 BM P (1:1) | Polycaprolactone | 20%, 60%, 80%, 70% or 99.99% | SiRNA and DNA (1:1) | Polycaprolactone | 20%, 40%, 80%, 70% or 99.99% |
| EGF and FG F (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 BM P (1:1) | Polycaprolactone | 20%, 60%, 80%, 70% or 99.99% | G-CSF2 | Polycaprolactone | 20%, 60%, 40%, 70% or 99.99% |
| EGF and FG F (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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution PLA-PEG microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution weight ratio according to water miscible substance solution and PLA-PEG is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is oil bag solid (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PLA— PEG | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLA— PEG | Water soluble substance 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 | PLA— | 20％、60％、80％、 | Levofloxacin | PLA— | 20％、60％、40％、 |
| 1 | PEG | 70% or 99.99% | Star 3 | PEG | 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 water miscible substance solution PLA-PEG microsphere
Step (1) is identical with embodiment two.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PLA-PEG is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PLA— PEG | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLA— PEG | Water soluble substance 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— | 20％、60％、80％、 | The IX genetic factor | PLA— | 20％、60％、40％、 |
| PEG | 70% or 99.99% | | PEG | 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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution PLGA-PEG microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution weight ratio according to water miscible substance solution and PLGA-PEG is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is oil bag solid (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PLGA —PEG | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLGA —PEG | Water soluble substance 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%, 50% or 99.99% | Etoposide | PLGA— PEG | 20%, 50%, 80%, 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 water miscible substance solution PLGA-PEG microsphere
Step (1) is identical with embodiment two.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PLGA-PEG is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PLGA— PEG | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLGA— PEG | Water soluble substance 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 | P1GA— 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— | 20％、60％、80％、 | GM-CSF3 | PLGA— | 20％、60％、80％、 |
| PEG | 70% or 99.99% | | PEG | 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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution PLA-PEG-PLA microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution weight ratio according to water miscible substance solution and PLA-PFG-PLA is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9,1:: 10 equal proportion stirrings, whirlpool or formation in ultrasonic 1-5 minutes are even that suspension is oil bag solid (W/O1) 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:
| Water soluble substance solution | PLA—PEG —PLA | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLA—PEG —PLA | Water soluble substance 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 | 20％、60％、80％、 | Vincristine | PLA—PEG | 20％、60％、80％、 |
| —PLA | 70% or 99.99% | | —PLA | 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 and paclitaxel | PLA—PEG —PLA | 20%, 60%, 80%, 70% or 99.99% | Ciclosporin 2 | PLA—PEG —PLA | 20%, 40%, 80%, 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 water miscible substance solution PLA-PEG-PLA microsphere
Step (1) is identical with embodiment two.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PEG-PLA-PEG is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed the even suspension Water-In-Oil (W/O of getting in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PLA—PEG —PLA | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLA—PEG —PLA | Water soluble substance 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 BP (1:1) | PLA—PEG —PLA | 20%, 60%, 80%, 70% or 99.99% |
| VEGF and DNA (1:1) | PLA—PEG —PLA | 20%, 60%, 80%, 70% or 99.99% | TGF-β, PDGF and BMP (1:1:1) | PLA—PEG —PLA | 20%, 60%, 80%, 70% or 99.99% |
| NGF and BM P (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 FG F (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 BM P (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 FG F (1:1) | PLA—PEG —PLA | 20%, 60%, 80%, 70% or 99.99% | GMCSF2 | 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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution PLGA-PEG-PLGA microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PLGA-PEG-PLGA is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is oil bag solid (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PLGA—PEG —PLGA | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLGA—PEG —PLGA | Water soluble substance 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—PEC —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 | 20％、60％、80％、 | Benzene mustard gallbladder steroid | PLGA—PEG | 20％、60％、40％、 |
| —PLGA | 70% or 99.99% | Alcohol | —PLGA | 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 —PLGA | 20%, 60%, 80%, 70% or 99.99% | Daunorubicin and carboplatin | PLGA—PEG —PLGA | 20%, 60%, 80%, 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 water miscible substance solution PLGA-PFG-PLGA microsphere
Step (1) is identical with embodiment two.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PLGA-PEG-PLGA is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PLGA—PEG —PLGA | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PLGA—PEG —PLGA | Water soluble substance 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 —PLGA | 20%, 60%, 80%, 70% or 99.99% | BDGF and BMP (1:1) | PLGA—PEG —PLGA | 20%, 60%, 80%, 70% or 99.99% |
| 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: | 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% |
| 1) | | | | | |
| 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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution PEG-PLA-PEG microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution weight ratio according to water miscible substance solution and PFG-PLA-PEG is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is oil bag solid (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PEG—PLA —PEG | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PEG—PLA— PEG | Water soluble substance 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% |
| Methotrexate 1 | PEG—PLA —PEG | 20%, 60%, 80%, 70% or 99.99% | Vincristine | PEG—PLA— PEG | 20%, 60%, 80%, 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 water miscible substance solution PEG-PLA-PEG microsphere
Step (1) is identical with embodiment two.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PEG-PLA-PEG is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PEG—PLA —PEG | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PEG—PLA —PEG | Water soluble substance 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-CSF1 | PEG—PLA —PEG | 20%, 60%, 80%, 70% or 99.99% | BDGF3 | PEG—PLA —PEG | 20%, 60%, 80%, 70% or 99.99% |
| GM-CSF1 | 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% | antibody | PEG—PLA —PEG | 20%, 50%, 80%, 70% or 99.99% |
| Insulin | 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-RNA | 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% |
| PDGF1 | 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 (1:1) | 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% |
| 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-CSF and G-CSF (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% | EPO2 | 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-CSF and G-CSF (1:1) | PEG—PLA —PEG | 20%, 60%, 80%, 70% or 99.99% | Vaccine | PEG—PLA —PEG | 20%, 60%, 80%, 70% or 99.99% |
| BDGF2 | PEG—PLA —PEG | 20%, 60%, 78%, 70% or 99.99% | EPO3 | 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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution PEG-PLGA-PEG microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution weight ratio according to water miscible substance solution and PEG-PLGA-PFG is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is oil bag solid (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PEG— PLGA— PEG | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | PEG— PLGA— PEG | Water soluble substance 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% |
| Methotrexate 1 | PEG—PLGA —PEG | 20%, 60%, 80%, 70% or 99.99% | Vincristine | PEG—PLGA —PEG | 20%, 60%, 80%, 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 water miscible substance solution PEG-PLGA-PEG microsphere
Step (1) is identical with embodiment two.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and PEG-PLGA-PEG is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | PEG—PLGA —PEG | Water soluble substance solution accounts for the weight hundred of microsphere | Water soluble substance solution | PEG—PLGA —PEG | Water soluble substance solution accounts for the percentage by weight of microsphere |
| | Proportion by subtraction | | | |
| 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% | antibody | PEG—PLGA —PEG | 20%, 50%, 80%, 70% or 99.99% |
| Insu1in | 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-RNA | 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 —PEG | 20%, 60%, 80%, 70% or 99.99% | DNA | PEG—PLGA —PEG | 20%, 60%, 80%, 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-CSF2 | PEG—PLGA —PEG | 20%, 60%, 80%, 70% or 99.99% |
| GM-CSF | PEG—PLGA | 20％、60％、80％、 | Vaccine | PEG—PLGA | 20％、60％、80％、 |
| And GCSF (1:1) | —PEG | 70% or 99.99% | | —PEG | 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 99.99% | G-CSF3 | PEG—PLGA —PEG | 20%, 60%, 80%, 70% or 99.99% |
| TPA1 | PEG—PLGA —PEG | 20%, 60%, 80%, 70% or 99.99% | GM-CSF3 | 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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution hyaluronic acid microsphere
Step (1) is identical with embodiment one.
(2) be that 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formation in ultrasonic 1-5 minutes are even that suspension is oil bag solid (W/O according to water miscible substance solution and hyaluronic dichloromethane, acetonitrile or ethyl acetate solution weight ratio1) 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:
| Water soluble substance solution | Hyaluronic acid | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | Hyaluronic acid | Water soluble substance 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 water miscible substance solution hyaluronic acid microsphere
Step (1) is identical with embodiment two.
(2) be that 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formation in ultrasonic 1-5 minutes are even that suspension is Water-In-Oil (W/O according to water miscible substance solution and hyaluronic dichloromethane, acetonitrile or ethyl acetate solution1) 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:
| Water soluble substance solution | Hyaluronic acid | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | Hyaluronic acid | Water soluble substance solution accounts for the percentage by weight of microsphere |
| EPO1 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | NGF | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| G-CSF1 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | BDGF3 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| GM-CSF1 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | BMP2 | Hyaluronic acid | 20%, 40%, 80%, 70% or 99.99% |
| Vaccine 1 | Hyaluronic acid | 20%, 40%, 80%, 70% or 99.99% | TPA2 | Hyaluronic acid | 20%, 60%, 80%, 50% or 99.99% |
| GH1 | Hyaluronic acid | 20%, 60%, 80%, 50% or 99.99% | antibody | Hyaluronic acid | 20%, 50%, 80%, 70% or 99.99% |
| Insulin | Hyaluronic acid | 20%, 50%, 80%, 70% or 99.99% | Blood coagulation factor VIII | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| EGF1 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | The IX genetic factor | Hyaluronic acid | 20%, 60%, 40%, 70% or 99.99% |
| FGF1 | Hyaluronic acid | 20%, 60%, 40%, 70% or 99.99% | anti-RNA | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| TGF-β | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | RNAi | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| IGF | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | SiRNA | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| VEGF | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | DNA | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| PDGF1 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | BDGF and BMP (1:1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| ECGF | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | PDGF and BMP (1:1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| VEGF and DNA (1: 1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | TGF-β, PDGF and BMP (1:1:1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| NGF and BM P (1:1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | SiRNA and DNA (1:1) | Hyaluronic acid | 20%, 40%, 80%, 70% or 99.99% |
| EGF and FG F (1:1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | BDGF and VEGF (1:1) | Hyaluronic acid | 20%, 60%, 80%, 50% or 99.99% |
| GM-CSF and G-CSF (1:1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | IGF and GH (1:1) | Hyaluronic acid | 20%, 50%, 80%, 70% or 99.99% |
| VEGF and DNA (1:1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | EPO2 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| NGF and BM P (1:1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | G-CSF2 | Hyaluronic acid | 20%, 60%, 40%, 70% or 99.99% |
| EGF and FG F (1:1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | GM-CSF2 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| GM-CSF and G-CSF (1:1) | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | Vaccine | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| BDGF2 | Hyaluronic acid | 20%, 60%, 78%, 70% or 99.99% | EPO3 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| BMP1 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | G-CSF3 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% |
| TPA1 | Hyaluronic acid | 20%, 60%, 80%, 70% or 99.99% | GM-CSF3 | Hyaluronic acid | 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 the disease of topical therapeutic such as tumor, 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 water miscible substance solution hyaluronic acid microsphere
Step (1) is identical with embodiment one.
(2) dichloromethane, acetonitrile or the ethyl acetate solution weight ratio according to water miscible substance solution and gelatin is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is oil bag solid (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | Gelatin | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | Gelatin | Water soluble substance solution accounts for the percentage by weight of microsphere |
| 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 water miscible substance solution gelatine microsphere
Step (1) is identical with embodiment two.
(2) dichloromethane, acetonitrile or the ethyl acetate solution according to water miscible substance solution and gelatin is 1:1,1:2,1:3,1:4,1:5,1:6,1:7,1:8,1:9, the stirring of 1:10 equal proportion, whirlpool or formed even that suspension is Water-In-Oil (W/O in ultrasonic 1-5 minutes1) 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:
| Water soluble substance solution | Gelatin | Water soluble substance solution accounts for the percentage by weight of microsphere | Water soluble substance solution | Gelatin | Water soluble substance 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 BM P (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 FG F | Gelatin | 20％、60％、80％、 | BDGF and VEGF | Gelatin | 20％、60％、80％、 |
| (1：1) | | 70% or 99.99% | (1：1) | | 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 BM P (1:1) | Gelatin | 20%, 60%, 80%, 70% or 99.99% | G-CSF2 | Gelatin | 20%, 60%, 40%, 70% or 99.99% |
| EGF and FG F (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% |
| BD6F2 | 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 the disease of topical therapeutic such as tumor, 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.