CN101461786A - PLA/PLGA shell-core microballoons prepared by oil in water-solid in oil method, and preparation method thereof - Google Patents
PLA/PLGA shell-core microballoons prepared by oil in water-solid in oil method, and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a PLA/PLGA shell-core microsphere prepared by solid-in-oil-in-water in the technical field of pharmacy and a preparation method thereof. The microsphere comprises 0.01 to 50 percent of medicine, 20 to 99.99 percent of polylactic acid and/or polylactic acid-glycolic acid, or/and 0 to 30 percent of pharmaceutical excipient (weight percentage). The method comprises the steps of: adding medicine particles into a PLA and/or PLGA organic solution to be emulsified, then selecting a hydrophilic organic solvent to re-emulsify to form unhardened balls, finally hardening in another large oil phase, removing the organic solvent and collecting micropheres. The method overcomes the disadvantages of low envelope rate of the prior W/O and W/O/W, serious burst release of S/O/O, and environmental pollution, controls the grain diameter of the microsphere according to the need, does not pollute the environment, and can be applied to the preparation of slow release or controlled release microspheres of various medicines and adjuvants of vaccines.
Description
Technical field
What the present invention relates to is the preparation shell-nuclear microsphere in a kind of pharmaceutical technology field and preparation method thereof, and especially a kind of oil-in-water-oil bag solid (S-O-W) of using prepares the method for PLA (polylactic acid)/PLGA (polylactic acid-hydroxyacetic acid) shell-nuclear microsphere.
Background technology
Pharmaceutical industry is from drug discovery, and to Clinical Application, last link is pharmaceutical preparation.Wherein some medicine needs long term administration to cure; Some needs topicals such as targeting.Reach these purposes, crude drug must be prepared into corresponding dosage forms.For example need long term administration but short medicine of in vivo half-life should be prepared into the PLA dosage form; For some tumor treatment, need some drug targetings in the disease photograph, for example targeting is in tumor vascular embolism microball preparation etc.; Gene recombination technology be used for the treatment of proteic expression and production 20 for many years, up to the present, existing more than 30 protein drug product drops into clinical use, nearly 200 examine with R﹠D process in, emerge and a collection ofly enter (Amgen), gene technology a collection of new large-scale medical companies such as (Genentech) such as peace.With respect to the fast development of protein macromolecule medicine itself, its dosage form technical progress is slow.On the one hand, the protein macromolecule drug oral does not absorb, the interior half-life of body is short, needs drug administration by injection; On the other hand, the protein drug treatment cycle of many He Ermeng, cytokine class is long, and injection for a long time and continually becomes necessary, also influences the main cause of patient's compliance.The research and development of the dosage form of slow release protein drug are owing to cause the easily prominent shortcoming such as release of the microsphere of active loss such as W/O/W method preparation in preparation microgranule process.It is imperative that the protein microsphere that development preparation has an active protection can improve envelop rate again and reduce the prominent method of releasing.People have studied the double-deck microsphere of preparation in order to reduce prominent releasing, but still can not solve this difficult problem up till now.
Find by prior art documents, " Double walled PLA/PLGAmicrospheres:encapsulation of water-soluble and water-insoluble proteinsand their release properties " " Journal of Controlled Release " 89 (2003) 167-177 that Meng Shi etc. delivers], [Meng Shi etc., double-deck POE/PLGA microsphere: seal water solublity and water-insoluble protein and their release feature, the sustained release magazine, 89 (2003) 167-177], people such as Meng Shi have reported in the document and have utilized W/O/W method being encapsulated in PLGA/PLA shell-nuclear microsphere bovine serum albumin (BSA) and Ciclosporin A (CyA).The multi-emulsion method that the document utilizes W/O/W to see most prepares double-deck microsphere, and the oil-water interfaces of multi-emulsion method are the albumen killers who generally acknowledges, causes the gathering of water miscible albumen at this interface, causes envelop rate also not high equally, exists not exclusively to discharge and prominent releasing.Morita T. etc. were " Journal of Controlled Release " (sustained release magazine) (2000, the 69th phase, the 435th page to the 444th page) on deliver " Proteinencapsulation into biodegradable microspheres by a novel S/O/W emulsionmethod using poly (ethylene glycol) as a protein micronization adjuvant " (with Polyethylene Glycol as the micronized excipient of albumen (surfactant), use oil-in-water-solid method of oil bag that the albumen microcapsule is wrapped in the biodegradable microsphere then), the document has been reported and has been utilized new S/O/W emulsion process preparation to carry protein microsphere.Just changed surfactant in the past report more be use PVA, use PEG instead at this piece document.But still it is low to overcome envelop rate, has the prominent shortcoming of releasing and not exclusively discharging.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, a kind of PLA/PLGA shell-nuclear microsphere that wraps the solid preparation with oil-in-water-oil and preparation method thereof is provided, make the smooth rounding of microparticle surfaces of its preparation, good evenness, granule regular without adhesion; The envelop rate height, prominent release little, the drug loading height.
The present invention is achieved by the following technical solutions:
PLA/PLGA shell-nuclear microsphere with oil-in-water-oil bag solid preparation involved in the present invention, comprise medicine, polylactic acid and/or polylactic acid-hydroxyacetic acid or/and pharmaceutic adjuvant, their weight percent content is: medicine 0.01-50%, polylactic acid and/or polylactic acid-hydroxyacetic acid 20-99.99%, pharmaceutic adjuvant are 0-30%.This microsphere drug loading is controlled, envelop rate is high, prominent release and not exclusively release.
Described medicine comprises small-molecule drug and macromolecular drug.What described small-molecule drug referred to mainly is chemicals, and macromolecular drug mainly is meant biopharmaceutical macromolecular drug, especially finger protein macromolecular drug, vaccine, antibody, nucleic acid or liposome medicament.
Described protein macromolecule medicine is: erythropoietin (EPO), recombinant human granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimutaing factor (GM-CSF), vaccine, interferon (IFN), growth hormone (GH), insulin (Insulin), epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF-β), insulin like growth factor (IGF), vascular endothelial cell growth factor (VEGF), PDGF (PDGF), endothelial cell growth factor (ECGF) (EGF), 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), or plasma thromboplastin component genetic factor.
Described nucleic acid is: antisense nucleotide (anti-RNA), microRNA (RNAi) or gene (DNA).
Described adjuvant refers to mainly is can the injection rank, especially little saccharide (sucrose, trehalose, glucose, maltose, or lactose), polyhydroxy compounds (mannitol, sorbitol, glycerol, 1,2-propylene glycol, erythritol, Polyethylene Glycol, polyvinyl alcohol, poly(ethylene oxide), or polypyrrole alkane ketone), polysaccharide compound (glucosan, sodium alginate, chitosan, starch, cellulose, or cyclodextrin material), amino-acid compound (glycine, lysine, arginine, glutamic acid or histidine), or inorganic salts material (zinc salt, calcium salt, mantoquita, magnesium salt, or molybdenum salt) a kind of or combination in any.
Preparation method with oil-in-water-PLA/PLGA shell-nuclear microsphere that oil bag solid prepares involved in the present invention is that drug particles is dispersed in the organic solution of PLA and/or PLGA, and the formation suspensions that make it to be uniformly dispersed such as stirring or whirlpool; Then suspension is added to outer oil phase, restir or whirlpool form microsphere, at last it are transferred to big aqueous phase and solidify; Centrifugal then collection microsphere, lyophilizing is preserved.
Said method of the present invention specifically may further comprise the steps:
1. medicine or medicine and pharmaceutic adjuvant are prepared into drug particles;
2. drug particles is joined the organic solution of PLA and PLGA or the organic solution of hydrophilic drug particles and PLGA mixed after, mixed with the organic solution of PLA again; Or it is mixed earlier hydrophobic drug particles and PLA, mixed with the organic solution of PLGA again; Form suspension, i.e. oil phase-1 (O
1) in stir or whirlpool etc. makes it homodisperse and forms uniform suspension;
3. 2. completing steps is formed the aqueous solution emulsifying that microsphere suspension is added drop-wise to sodium chloride solution and surfactant, form emulsion;
4. then step emulsion 3. being transferred to sodium chloride solution solidifies;
5. completing steps sample lyophilizing is 4. obtained PLA/PLGA shell-nuclear microsphere.
Described drug particles refers to hydrophilic drug particles, or medicine is loaded into the granule for preparing in the adjuvant, or the method for hydrophobic medicine by preparation is prepared into the granule that is insoluble to organic solvent;
Described drug particles, the size of its drug particles be at 0.2-10 μ mm, preferred 0.5-5 μ mm.
Described drug particles, it accounts for the 0.2-50% of drug particles gross weight; Preferred 1-20% (w/w).
Described oil phase-(O) be: the organic solution of PLA and/or PLGA;
The organic solution of described PLA and/or PLGA is: the organic solution of PLA and PLGA is added 0.1-20% (w/w) Polyethylene Glycol (PEG) or poloxamer (poloxmer); The dichloromethane of PLA and PLGA, ethyl acetate, acetonitrile, heptane, chloroform or acetone organic solution are good with a kind of in dichloromethane, ethyl acetate or the acetonitrile or their organic solution of combination in any;
The organic solution concentration of described PLA and/or PLGA is: the percent concentration that the weight of PLA accounts for total oil phase is 0.5-80% (w/w), is good with 5-30% (w/w) wherein; Hundred percent concentrations of the total oil phase of weight of PLGA are 20-99.5% (w/w), are good with 70-95% wherein;
Described surfactant is: polyvinyl alcohol (PVA), Polyethylene Glycol (PEG), polyvinylpyrrolidone (PVP), poloxamer (poloxmer), poly-sorbic alcohol, ethyl cellulose (EC) or tween;
The concentration of described surface active agent 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 the saline solution that contains 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, poly-sorbic alcohol concentration 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 1-500 μ m, is good with 10-100 μ m.
The present invention has selected the PLGA of proper ratio and concentration and the composite material of PLA, make water miscible drug particles or oil-soluble medicine be prepared into oily insoluble granule by the method for preparation, avoid not high with the envelop rate of conventional W/O and W/O/W, and the prominent of S/O/O released seriously the shortcoming of the environmental pollution that causes; Adopt this method to prepare microsphere, the size of its particle diameter can be controlled according to different needs, and is free from environmental pollution; Can avoid the function influence to the treatment of medicine, especially those physicochemical properties are unsettled, to the medicine of oil-water interfaces sensitivity, as biopharmaceutical macromolecular drug such as protein macromolecule medicine, DNA, RNA or siRNA medicine.The smooth surface rounding of microgranule, the granule regular without adhesion, particle diameter can be regulated and control from 1 μ m as required to 500 μ m, and its freeze dried powder is that white is fine and smooth, loose, can not subside, adhesion, and redispersibility is good.Can apply to the preparation of various medicament slow releases or control-release microsphere 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.
Adopt the inventive method to prepare the microsphere of medicine carrying, when wherein preparing drug particles, to small-molecule drug can be conventional grinding method, the sedimentation method, comminuting method or comminution granulation; For biopharmaceutical macromolecular drug can be the method for the complex of water-aqueous phase emulsion method, low temperature spray drying method, phase separation method, supercritical methanol technology or metal ion and biomacromolecule formation.
Embodiment one: be loaded with the preparation of small-molecule drug granule PLA/PLGA shell-nuclear microsphere
(1) small-molecule drug or small-molecule drug and pharmaceutic adjuvant are prepared into drug particles;
In the present embodiment, the small-molecule drug 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 pharmaceutic adjuvant 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 as follows:
| Medicine | Adjuvant | Medicine accounts for the percentage by weight of drug particles | Medicine | Adjuvant | Medicine accounts for the percentage by weight of drug particles |
| Amycin | Cyclodextrin | 100%, 80%, 50 %, 25% or 0% | Carboplatin | Cyclodextrin | 100%, 80%, 50 %, 25% or 0% |
| Amycin | Polyethylene Glycol | 100%, 80%, 50 %, 25% or 0% | Carmustine | Polyethylene Glycol | 100%, 80%, 50 %, 25% or 0% |
| Amycin | Polyvinyl alcohol | 100%, 80%, 50 %, 25% or 0% | Semustine | Polyvinyl alcohol | 100%, 80%, 50 %, 25% or 0% |
| Amycin | Poly(ethylene oxide) | 100%, 80%, 50 %, 25% or 0% | Cisplatin | Poly(ethylene oxide) | 100%, 80%, 50 %, 25% or 0% |
| Amycin | Polypyrrole alkane ketone | 100%, 80%, 50 %, 25% or 0% | Etoposide | Polypyrrole alkane ketone | 100%, 80%, 50 %, 25% or 0% |
| Cyclophosphamide | Polyethylene Glycol | 100%, 80%, 50 %, 25% or 0% | Camptothecine | Polyethylene Glycol | 100%, 80%, 50 %, 25% or 0% |
| Dactinomycin | Poly(ethylene oxide) | 100%, 80%, 50 %, 25% or 0% | Phenesterin | Poly(ethylene oxide) | 100%, 80%, 50 %, 25% or 0% |
| Daunorubicin | Polyethylene Glycol | 100%, 80%, 50 %, 25% or 0% | Paclitaxel | Polyethylene Glycol | 100%, 80%, 50 %, 25% or 10% |
| Amycin | Poly(ethylene oxide) | 100%, 80%, 50 %, 25% or 0% | Docetaxel | Poly(ethylene oxide) | 100%, 80%, 50 %, 25% or 0% |
| Epirubicin | Polypyrrole alkane ketone | L00%, 80%, 50 %, 25% or 0% | Vinblastine | Polypyrrole alkane ketone | L00%, 80%, 50 %, 25% or 0% |
| Methotrexate | Polyethylene Glycol | 100%, 80%, 50 %, 25% or 0% | Vincristine | Polyethylene Glycol | 100%, 80%, 50 %, 25% or 0% |
| Fluorouracil | Poly(ethylene oxide) | 100%, 80%, 50 %, 25% or 0% | Zitazonium | Poly(ethylene oxide) | 100%, 80%, 50 %, 25% or 0% |
| Etoposide | Cyclodextrin | 100%, 80%, 50 %, 25% or 0% | Piposulfan | Polyethylene Glycol | 100%, 80%, 50 %, 25% or 0% |
| Flutamide | Polyethylene Glycol | 100%, 80%, 50 %, 25% or 0% | Daunorubicin and carboplatin | Poly(ethylene oxide) | 100%, 80%, 50 %, 25% or 0% |
| Amycin and paclitaxel | Polyvinyl alcohol | 100%, 80%, 50 %, 25% or 0% | Ciclosporin | Polypyrrole alkane ketone | 100%, 80%, 50 %, 25% or 0% |
| Ciclosporin | Poly(ethylene oxide) | 100%, 80%, 50 %, 25% or 0% | Levofloxacin | Poly(ethylene oxide) | 100%, 90%, 80 %, 40% or 20% |
| Levofloxacin | Polypyrrole alkane ketone | 100%, 80%, 40 %, 20% or 0% | Ofloxacin | Polyethylene Glycol | 100%, 80%, 40 %, 20% or 0% |
| Ofloxacin | Glucosan | 100%, 80%, 40 %, 10% or 0% | Epinastine hydrochloride | Poly(ethylene oxide) | 100％、80％、40 ％、20％、0.1％ |
| Epinastine hydrochloride | Sodium alginate | 100%, 80%, 40 %, 20% or 0% | Levofloxacin | Mannitol | 100%, 80%, 40 %, 20% or 0% |
| Levofloxacin | Chitosan | 100%, 80%, 40 %, 20% or 0% | Ofloxacin | Sorbitol | 100%, 80%, 40 %, 20% or 0% |
| Ofloxacin | Starch | 100％、80％、40 ％、20％、0.1％ | Epinastine hydrochloride | Lactose | 100%, 80%, 40 %, 20% or 0% |
| Epinastine hydrochloride | Cellulose | 100%, 80%, 40 %, 20% or 0% | Levofloxacin | Glycine | 100%, 80%, 40 %, 20% or 0% |
| Ofloxacin | Sucrose | 100%, 80%, 40 %, 20% or 0% | Ofloxacin | Lysine | 100%, 80%, 40 %, 20% or 0% |
| Epinastine hydrochloride | Trehalose | 100%, 80%, 40 %, 20% or 0% | Epinastine hydrochloride | Histidine | 100%, 80%, 40 %, 20% or 0% |
(2) dichloromethane, acetonitrile or the ethyl acetate solution weight ratio according to small-molecule drug granule 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 the even suspension that gets in ultrasonic 1-5 minutes, again the organic solution of PLA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. oil bag solid (S/O) emulsion; Or be the dichloromethane of drug molecule granule and PLA, acetonitrile or ethyl acetate solution weight ratio 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 suspension in ultrasonic 1-5 minutes, again the organic solution of PLGA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. oil bag solid (S/O) emulsion;
(3) step (2) being got emulsion droplets is added to aqueous surfactant solution and stirring, the whirlpool of 1-10% (w/w) sodium chloride and 1-10% (w/w) or formed emulsion in ultrasonic 0.1-5 minutes;
(4) emulsion of step (3) being added drop-wise to concentration is that the 1000ml sodium chloride solution of 1-10% (w/w) solidified 1-4 hours;
(5) the centrifugal collection microsphere that step (4) is obtained, and wash with water 3-5 times, microsphere obtained after the lyophilizing.
The microsphere that present embodiment obtains, concrete set of dispense ratio sees the following form:
| Drug particles | The weight ratio of PLGA/PLA | Drug particles accounts for the percentage by weight of microsphere | Drug particles | The weight ratio of PLGA/PLA | Drug particles account for microsphere percentage by weight |
| The amycin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The carboplatin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The amycin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The carmustine granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The amycin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The semustine granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 40%, 80%, 70% or 99.99% |
| The amycin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 40%, 80%, 70% or 99.99% | The cisplatin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 50% or 99.99% |
| The amycin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 50% or 99.99% | The etoposide granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 50%, 80%, 70% or 99.99% |
| The cyclophosphamide granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 50%, 80%, 70% or 99.99% | The camptothecine granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The dactinomycin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The phenesterin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 40%, 70% or 99.99% |
| The daunorubicin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 40%, 70% or 99.99% | The paclitaxel granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The amycin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The Docetaxel granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The epirubicin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The vinblastine granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The methotrexate granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The vincristine granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The fluorouracil granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The zitazonium granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The etoposide granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The piposulfan granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The flutamide granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | Daunorubicin and carboplatin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| Amycin and paclitaxel granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The ciclosporin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 40%, 80%, 70% or 99.99% |
| The ciclosporin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The levofloxacin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 50% or 99.99% |
| The levofloxacin granule | 1、1/2、1/3、 1/4、1/5、2、 | 20%, 60%, 80%, 70% or 99.99% | The ofloxacin granule | 1、1/2、1/3、 1/4、1/5、2、 | 20％、50％、 80％、70％、 |
| 3,4 or 5 | 3,4 or 5 | Or 99.99% | |||
| The ofloxacin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The epinastine hydrochloride granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The epinastine hydrochloride granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The levofloxacin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 40%, 70% or 99.99% |
| The levofloxacin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The ofloxacin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The ofloxacin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The epinastine hydrochloride granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The epinastine hydrochloride granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 78%, 70% or 99.99% | The levofloxacin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The ofloxacin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The ofloxacin granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
| The epinastine hydrochloride granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% | The epinastine hydrochloride granule | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 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 80% of the microsphere envelop rate of this method preparation, dashing forward to release very little and almost do not have not exclusively discharges, and can reach zero level release.
Embodiment two: be loaded with the preparation of biopharmaceutical macromolecular drug granule PLA/PLGA shell-nuclear microsphere
(1) biopharmaceutical macromolecular drug or biopharmaceutical macromolecular drug and pharmaceutic adjuvant are prepared into drug particles;
In the present embodiment, the biopharmaceutical macromolecular drug of employing is erythropoietin (EPO), recombinant human granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimutaing factor (GM-CSF), vaccine, interferon (INF), growth hormone (GH), insulin (Insulin), epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF-β), insulin like growth factor (IGF), vascular endothelial cell growth factor (VEGF), PDGF (PDGF), 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 pharmaceutic adjuvant 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;
Composition proportioning concrete in the present embodiment is as follows:
| Medicine | Pharmaceutic adjuvant | Medicine accounts for the percentage by weight of granule gross weight | Medicine | Pharmaceutic adjuvant | Medicine accounts for the percentage by weight of granule gross weight |
| EPO | Glucosan | 80%, 50%, 25 %, 10%, 5% or 0% | NGF | Cyclodextrin and sucrose (5:1) | 100%, 80%, 50 %, 25%, 10%, 5% or 0% |
| G-CSF | Glucosan and trehalose (9: 1) | 80%, 50%, 25 %, 10%, 5% or 0% | BDGF | Polyethylene Glycol and sorbitol (8:1) | 100%, 80%, 50 %, 25%, 10%, 5% or 0% |
| GM-CSF | Glucosan and trehalose (9: 1) | 80%, 50%, 25 %, 10%, 5% or 0% | BMP | Glucosan | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0% |
| Vaccine | Glucosan | 100%, 80%, 50 %, 25%, 10%, 5% or 0% | TPA | Poly(ethylene oxide) and sucrose (9:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0% |
| GH | 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% |
| EGF | 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% |
| FGF | 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％、 | SiRNA | Glucosan | 50％、40％、30 ％、25％、15％、 |
| 5% or 0% | 10%, 5% or 0% | ||||
| VEGF | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0% | DNA | Glucosan | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0% |
| PDGF | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0% | BDGF and BMP (1:1) | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0% |
| ECGF | Cyclodextrin and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0% | PDGF and BMP (1:1) | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10% or 5% |
| VEGF and DNA (1:1) | Glucosan and trehalose (8:1) | 80%, 70%, 50 %, 25%, 10%, 5% or 0% | TGF-β, PDGF and BMP (1:1:1) | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%, 10% or 5% |
| NGF and BM P (1:1) | Glucosan and lactose (8:1) | 80%, 60%, 50 %, 25%, 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% | EPO | 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-CSF | Glucosan and sodium alginate (9:1) | 50%, 40%, 30 %, 25%, 15%, 10% or 5% |
| EGF and FG F (1:1) | Chitosan | 60%, 50%, 40 %, 20%, 10%, 5% or 0% | GM-CSF | 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% |
| BDGF | Cellulose and lactose (9:1) | 100%, 80%, 40 %, 20%, 10%, 5% or 0% | EPO | Glucosan and glycine | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0% |
| BMP | Glucosan and sucrose (9:1) | 100%, 80%, 40 %, 20%, 10%, 5% or 0% | G-CSF | Glucosan and lysine | 50%, 40%, 30 %, 25%, 15%, 10%, 5% or 0% |
| TPA | Trehalose | 100％、80％、40 | GM-CSF | Glucosan and group | 50％、40％、30 |
| %, 20%, 10%, 5% or 0% | Propylhomoserin | %, 25%, 15%, 10%, 5% or 0% |
(2) dichloromethane, acetonitrile, ethyl acetate or their the mixed solution weight ratio according to biopharmaceutical macromolecular drug granule 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 the even suspension that gets in ultrasonic 1-5 minutes, again the organic solution of PLA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. promptly oily solid (S/O) emulsion of wrapping of oil bag solid;
The enforcement of step (3), (4), (5) is identical with embodiment one.
The microsphere that present embodiment obtains, concrete set of dispense are such as following table:
| Drug particles | The weight ratio of PLGA/PLA | Drug particles accounts for the percentage by weight of microsphere | Drug particles | The weight ratio of PLGA/PLA | Medicine accounts for the percentage by weight of microsphere |
| EPO | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | NGF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| G-CSF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | BDGF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| GM-CSF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | BMP | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 40%, 80 %, 70% or 99.99% |
| Vaccine | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 40%, 80 %, 70% or 99.99% | TPA | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 50% or 99.99% |
| GH | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 50% or 99.99% | antibody | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 50%, 80 %, 70% or 99.99% |
| Insulin | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 50%, 80 %, 70% or 99.99% | Blood coagulation factor VIII | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| EGF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | The IX genetic factor | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 40 %, 70% or 99.99% |
| FGF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 40 %, 70% or 99.99% | anti-RNA | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| TGF-β | 1、1/2、1/3、 | 20％、60％、80 | RNAi | 1、1/2、1/3、 | 20％、60％、80 |
| 1/4,1/5,2,3,4 or 5 | %, 70% or 99.99% | 1/4,1/5,2,3,4 or 5 | %, 70% or 99.99% | ||
| IGF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | SiRNA | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| VEGF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | DNA | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| PDGF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | BDGF and BMP (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| ECGF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | PDGF and BMP (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| VEGF and DNA (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | TGF-β, PDGF and BMP (1:1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| NGF and BM P (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | SiRNA and DNA (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 40%, 80 %, 70% or 99.99% |
| EGF and FG F (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | BDGF and VEGF (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 50% or 99.99% |
| GM-CSF and G-CSF (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | IGF and GH (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 50%, 80 %, 70% or 99.99% |
| VEGF and DNA (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | EPO | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| NGF and BM P (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | G-CSF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 40 %, 70% or 99.99% |
| EGF and FG F (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | GM-CSF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| GM-CSF and G-CSF (1:1) | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | Vaccine | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| BDGF | 1、1/2、1/3、 1/4、1/5、2、3、 | 20%, 60%, 78 %, 70% or | EPO | 1、1/2、1/3、 1/4、1/5、2、3、 | 20%, 60%, 80 %, 70% or |
| 4 or 5 | 99.99％ | 4 or 5 | 99.99％ | ||
| BMP | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | G-CSF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% |
| TPA | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80 %, 70% or 99.99% | GM-CSF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 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 80% of the microsphere envelop rate of this method preparation, dashing forward to release very little and almost do not have not exclusively discharges, and can reach zero level release.Can make simultaneously biopharmaceutical macromolecular drug is non-inactivation in whole process of preparation and therapeutic process maintenance high activity.
Embodiment three: be loaded with the preparation of interferon (IFN) drug microparticles PLA/PLGA shell-nuclear microsphere
(1) interferon and pharmaceutic adjuvant are prepared into drug particles; Concrete proportioning is as follows:
| Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight | Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight |
| IFN | Glucosan | 80%, 50%, 25 %, 10% or 5% | IFN | Cyclodextrin and sucrose (9:1), (7:1), (6:1), (5:1) or (3:1) | 100%, 80%, 50 %, 25% or 10% |
| IFN | Glucosan, zinc salt and trehalose (9:1:1) | 80%, 50%, 25 %, 10% or 5% | IFN | Polyethylene Glycol, chitosan and sorbitol (8:1:1) or (5:1:1) | 100%, 80%, 50 %, 25% or 10% |
| IFN | Glucosan and trehalose (9:1) | 80%, 50%, 25 %, 10% or 5% | IFN | Glucosan, glycine and mannitol (8:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan, magnesium salt and trehalose (9:1:1) | 100%, 80%, 50 %, 25% or 10% | IFN | Poly(ethylene oxide) and sucrose (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan, zinc salt and mannitol (9:0.5:1) | 80%, 50%, 25 % or 10% | IFN | Polypyrrole alkane ketone and glycine (5:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Polyethylene Glycol and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10% | IFN | Glucosan and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Poly(ethylene oxide) and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10% | IFN | Glucosan and histidine (8:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Polyethylene Glycol and molybdenum salt (9:1) | 100%, 80%, 50 %, 25% or 10% | IFN | Polyethylene Glycol and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Poly(ethylene oxide) and calcium salt (9:1) | 100%, 80%, 50 %, 25% or 10% | IFN | Poly(ethylene oxide) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan, zinc salt and lactose (9:0.5:1) | 100%, 80%, 50 %, 25% or 10% | IFN | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% | IFN | Glucosan, poly(ethylene oxide) and zinc salt (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan and trehalose (6:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% | IFN | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Cyclodextrin and trehalose (8:1) or 6:1 | 50%, 40%, 30 %, 25%, 15%10 % or 5% | IFN | Glucosan, magnesium salt and trehalose (8:1) (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan, zinc salt and lactose (8:1:1) | 80%, 70%, 50 %, 25% or 10% | IFN | Glucosan, polypyrrole alkane ketone and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan and lactose (8:1) or 6:1 | 80%, 60%, 50 %, 25% or 10% | IFN | Polypyrrole alkane ketone | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan and trehalose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | IFN | Glucosan, starch and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan and lactose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | IFN | Glucosan, chitosan and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | IFN | Glucosan, trehalose and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5% | IFN | Glucosan, glycine and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Chitosan and sucrose (9:1) or 6: | 60%, 50%, 40 %, 20%, 10% or | IFN | Glucosan and sorbitol (9:1), (7:1), (6:1), | 50％、40％、30 ％、25％、15％10 |
| 1 | 5％ | (5:1) or (3:1) | % or 5% | ||
| IFN | Starch and lactose (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5%% | 1FN | Glucosan and lactose (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Cellulose and lactose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | IFN | Glucosan and glycine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Glucosan and sucrose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | IFN | Glucosan and lysine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| IFN | Starch and trehalose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | IFN | Glucosan and histidine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
(2) dichloromethane, acetonitrile, ethyl acetate or their the mixed solution weight ratio that is loaded with interferon (IFN) drug particles 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 suspension in ultrasonic 1-5 minutes, again the organic solution of PLA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. promptly oily solid (S/O) emulsion of wrapping of oil bag solid;
The enforcement of step (3), (4), (5) is identical with embodiment one.
The microsphere that present embodiment obtains, concrete set of dispense are such as following table:
| Drug particles | The weight ratio of PLGA/PLA | Drug particles accounts for the percentage by weight of microsphere |
| INF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
The IFN microsphere of this method preparation can be used for the frequent drug administration by injection of needs, long-term treatment antiviral such as hepatitis; Can reduce the frequency of injection and alleviate patient's misery.High minimum can the reaching more than 80% of the microsphere envelop rate of this method preparation, dashing forward to release very little and almost do not have not exclusively discharges, and can reach zero level release.Can make simultaneously the IFN medicine is non-inactivation in whole process of preparation and therapeutic process maintenance high activity.
Embodiment four: the preparation of erythropoietin (EPO) drug particles PLA/PLGA shell-nuclear microsphere
(1) EPO and pharmaceutic adjuvant are prepared into drug particles; Concrete proportioning is as follows:
| Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight | Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight |
| EPO | Glucosan | 80%, 50%, 25 %, 10% or 5% | EPO | Cyclodextrin and sucrose (9:1), (7:1), (6:1), (5:1) | 100%, 80%, 50 %, 25% or 10% |
| Or (3:1) | |||||
| EPO | Glucosan, zinc salt and trehalose (9:1:1) | 80%, 50%, 25 %, 10% or 5% | EPO | Polyethylene Glycol, chitosan and sorbitol (8:1:1) or (5:1:1) | 100%, 80%, 50 %, 25% or 10% |
| EPO | Glucosan and trehalose (9:1) | 80%, 50%, 25 %, 10% or 5% | EPO | Glucosan, glycine and mannitol (8:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan, magnesium salt and trehalose (9:1:1) | 100%, 80%, 50 %, 25% or 10% | EPO | Poly(ethylene oxide) and sucrose (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan, zinc salt and mannitol (9:0.5:1) | 80%, 50%, 25 % or 10% | EPO | Polypyrrole alkane ketone and glycine (5:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Polyethylene Glycol and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10% | EPO | Glucosan and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Poly(ethylene oxide) and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10% | EPO | Glucosan and histidine (8:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Polyethylene Glycol and molybdenum salt (9:1) | 100%, 80%, 50 %, 25% or 10% | EPO | Polyethylene Glycol and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Poly(ethylene oxide) and calcium salt (9:1) | 100%, 80%, 50 %, 25% or 10% | EPO | Poly(ethylene oxide) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan, zinc salt and lactose (9:0.5:1) | 100%, 80%, 50 %, 25% or 10% | EPO | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% | EPO | Glucosan, poly(ethylene oxide) and zinc salt (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan and trehalose (6:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% | EPO | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Cyclodextrin and trehalose (8:1) or 6:1 | 50%, 40%, 30 %, 25%, 15%10 % or 5% | EPO | Glucosan, magnesium salt and trehalose (8:1) (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan, zinc salt and lactose (8:1:1) | 80%, 70%, 50 %, 25% or 10% | EPO | Glucosan, polypyrrole alkane ketone and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan and lactose | 80％、60％、50 | EPO | Polypyrrole alkane ketone | 50％、40％、30 |
| (8:1) or 6:1 | %, 25% or 10% | %, 25%, 15%10 % or 5% | |||
| EPO | Glucosan and trehalose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | EPO | Glucosan, starch and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan and lactose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | EPO | Glucosan, chitosan and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | EPO | Glucosan, trehalose and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5% | EPO | Glucosan, glycine and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Chitosan and sucrose (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5% | EPO | Glucosan and sorbitol (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Starch and lactose (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5%% | EPO | Glucosan and lactose (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Cellulose and lactose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | EPO | Glucosan and glycine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Glucosan and sucrose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | EPO | Glucosan and lysine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| EPO | Starch and trehalose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | EPO | Glucosan and histidine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
(2) dichloromethane of erythropoietin (EP0) drug particles and PLGA, acetonitrile, ethyl acetate or their mixed solution weight ratio are 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 that gets in ultrasonic 1-5 minutes, again the organic solution of PLA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. promptly oily solid (S/0) emulsion of wrapping of oil bag solid;
The enforcement of step (3), (4), (5) is identical with embodiment one.
The microsphere that present embodiment obtains, concrete set of dispense are such as following table:
| Drug particles | The weight ratio of PLGA/PLA | Drug particles accounts for the percentage by weight of microsphere |
| EPO | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
The EPO microsphere of this method preparation can be used for the renal failure basin blood that basin blood that the frequent drug administration by injection of needs, long-term treatment a variety of causes cause such as oncotherapy cause; Can reduce the frequency of injection and alleviate patient's misery.High minimum can the reaching more than 80% of the microsphere envelop rate of this method preparation, dashing forward to release very little and almost do not have not exclusively discharges, and can reach zero level release.Can make simultaneously the EPO medicine is non-inactivation in whole process of preparation and therapeutic process maintenance high activity.
Embodiment five: the preparation of granulocyte colony-stimulating factor G-CSF drug particles PLA/PLGA shell-nuclear microsphere
(1) granulocyte colony-stimulating factor G-CSF and pharmaceutic adjuvant are prepared into drug particles; Concrete proportioning is as follows:
| Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight | Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight |
| G-CSF | Glucosan | 80%, 50%, 25 %, 10% or 5% | G-CSF | Cyclodextrin and sucrose (9:1), (7:1), (6:1), (5:1) or (3:1) | 100%, 80%, 50 %, 25% or 10 % |
| G-CSF | Glucosan, zinc salt and trehalose (9:1:1) | 80%, 50%, 25 %, 10% or 5% | G-CSF | Polyethylene Glycol, chitosan and sorbitol (8:1:1) or (5:1:1) | 100%, 80%, 50 %, 25% or 10 % |
| G-CSF | Glucosan and trehalose (9:1) | 80%, 50%, 25 %, 10% or 5% | G-CSF | Glucosan, glycine and mannitol (8:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan, magnesium salt and trehalose (9:1:1) | 100%, 80%, 50 %, 25% or 10% | G-CSF | Poly(ethylene oxide) and sucrose (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan, zinc salt and mannitol (9:0.5:1) | 80%, 50%, 25 % or 10% | G-CSF | Polypyrrole alkane ketone and glycine (5:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Polyethylene Glycol and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10% | G-CSF | Glucosan and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Poly(ethylene oxide) and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10% | G-CSF | Glucosan and histidine (8:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Polyethylene Glycol and molybdenum salt (9:1) | 100%, 80%, 50 %, 25% or 10% | G-CSF | Polyethylene Glycol and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Poly(ethylene oxide) and calcium salt (9:1) | 100%, 80%, 50 %, 25% or 10% | G-CSF | Poly(ethylene oxide) | 50％、40％、30 ％、25％、15 |
| %10% or 5% | |||||
| G-CSF | Glucosan, zinc salt and lactose (9:0.5:1) | 100%, 80%, 50 %, 25% or 10% | G-CSF | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% | G-CSF | Glucosan, poly(ethylene oxide) and zinc salt (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan and trehalose (6:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% | G-CSF | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Cyclodextrin and trehalose (8:1) or 6:1 | 50%, 40%, 30 %, 25%, 15%10 % or 5% | G-CSF | Glucosan, magnesium salt and trehalose (8:1) (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan, zinc salt and lactose (8:1:1) | 80%, 70%, 50 %, 25% or 10% | G-CSF | Glucosan, polypyrrole alkane ketone and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan and lactose (8:1) or 6:1 | 80%, 60%, 50 %, 25% or 10% | G-CSF | Polypyrrole alkane ketone | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan and trehalose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | G-CSF | Glucosan, starch and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan and lactose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | G-CSF | Glucosan, chitosan and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | G-CSF | Glucosan, trehalose and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5% | G-CSF | Glucosan, glycine and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Chitosan and sucrose (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5% | G-CSF | Glucosan and sorbitol (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Starch and lactose (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5%% | G-CSF | Glucosan and lactose (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Cellulose and lactose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | G-CSF | Glucosan and glycine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| G-CSF | Glucosan and sugarcane | 100％、80％、40 | G-CSF | Glucosan and lysine (9: | 50％、40％、30 |
| Sugar (9:1) or 6:1 | ％、20％、10％ | 1), (7:1), (6:1), (5:1) or (3:1) | %, 25%, 15 %10% or 5% | ||
| G-CSF | Starch and trehalose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | G-CSF | Glucosan and histidine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
(2) dichloromethane of granulocyte colony-stimulating factor (G-CSF) drug particles and PLGA, acetonitrile, ethyl acetate or their mixed solution weight ratio are 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 that gets in ultrasonic 1-5 minutes, again the organic solution of PLA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. promptly oily solid (S/O) emulsion of wrapping of oil bag solid;
The enforcement of step (3), (4), (5) is identical with embodiment one.
The microsphere that present embodiment obtains, concrete set of dispense is such as following:
| Drug particles | The weight ratio of PLGA/PLA | Drug particles accounts for the percentage by weight of microsphere |
| G-CSF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
The G-CSF microsphere of this method preparation can be used for the leukopenia that the frequent drug administration by injection of needs, long-term treatment a variety of causes cause and demonstrate,prove; Can reduce the frequency of injection and alleviate patient's misery.High minimum can the reaching more than 80% of the microsphere envelop rate of this method preparation, dashing forward to release very little and almost do not have not exclusively discharges, and can reach zero level release.Can make simultaneously the G-CSF medicine is non-inactivation in whole process of preparation and therapeutic process maintenance high activity.
Embodiment six: the preparation of granulocyte-macrophage colony stimutaing factor (GM-CSF) drug particles PLA/PLGA shell-nuclear microsphere
(1) granulocyte-macrophage colony stimutaing factor (GM-CSF) and pharmaceutic adjuvant are prepared into drug particles; Concrete proportioning is:
| Medicine | Pharmaceutic adjuvant | Medicine accounts for the percentage by weight of granule gross weight | Medicine | Pharmaceutic adjuvant | Medicine accounts for the percentage by weight of granule gross weight |
| GM-CSF | Glucosan | 80%, 50%, 25%, 10% or 5% | GM-CSF | Cyclodextrin and sucrose (9:1), (7:1), (6:1), (5:1) or (3:1) | 100%, 80%, 50 %, 25% or 10% |
| GM-CSF | Glucosan, zinc salt and trehalose (9:1:1) | 80%, 50%, 25%, 10% or 5% | GM-CSF | Polyethylene Glycol, chitosan and sorbitol (8:1:1) or (5:1:1) | 100%, 80%, 50 %, 25% or 10% |
| GM-CSF | Glucosan and trehalose (9:1) | 80%, 50%, 25%, 10% or 5% | GM-CSF | Glucosan, glycine and mannitol (8:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan, magnesium salt and trehalose (9:1:1) | 100%, 80%, 50%, 25% or 10% | GM-CSF | Poly(ethylene oxide) and sucrose (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan, zinc salt and mannitol (9:0.5:1) | 80%, 50%, 25% or 10% | GM-CSF | Polypyrrole alkane ketone and glycine (5:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Polyethylene Glycol and zinc salt (9:1) | 100%, 80%, 50%, 25% or 10% | GM-CSF | Glucosan and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Poly(ethylene oxide) and zinc salt (9:1) | 100%, 80%, 50%, 25% or 10% | GM-CSF | Glucosan and histidine (8:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Polyethylene Glycol and molybdenum salt (9:1) | 100%, 80%, 50%, 25% or 10% | GM-CSF | Polyethylene Glycol and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Poly(ethylene oxide) and calcium salt (9:1) | 100%, 80%, 50%, 25% or 10% | GM-CSF | Poly(ethylene oxide) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan, zinc salt and lactose (9:0.5:1) | 100%, 80%, 50%, 25% or 10% | GM-CSF | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan and trehalose (8:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % | GM-CSF | Glucosan, poly(ethylene oxide) and zinc salt (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan and trehalose (6:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % | GM-CSF | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Cyclodextrin and trehalose (8:1) or 6:1 | 50%, 40%, 30%, 25%, 15%10% or 5 % | GM-CSF | Glucosan, magnesium salt and trehalose (8:1) (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan, zinc salt and lactose (8:1:1) | 80%, 70%, 50%, 25% or 10% | GM-CSF | Glucosan, polypyrrole alkane ketone and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan and lactose (8:1) or 6:1 | 80%, 60%, 50%, 25% or 10% | GM-CSF | Polypyrrole alkane ketone | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan and trehalose (8:1) or 6:1 | 60%, 50%, 25%, 10% or 5% | GM-CSF | Glucosan, starch and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan and lactose (8:1) or 6:1 | 60%, 50%, 25%, 10% or 5% | GM-CSF | Glucosan, chitosan and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 25%, 10% or 5% | GM-CSF | Glucosan, trehalose and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 40%, 20%, 10% or 5% | GM-CSF | Glucosan, glycine and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Chitosan and sucrose (9:1) or 6:1 | 60%, 50%, 40%, 20%, 10% or 5% | GM-CSF | Glucosan and sorbitol (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Starch and lactose (9:1) or 6:1 | 60%, 50%, 40%, 20%, 10% or 5%% | GM-CSF | Glucosan and lactose (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Cellulose and lactose (9:1) or 6:1 | 100％、80％、 40％、20％、 10％ | GM-CSF | Glucosan and glycine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Glucosan and sucrose (9:1) or 6:1 | 100％、80％、 40％、20％、 10％ | GM-CSF | Glucosan and lysine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
| GM-CSF | Starch and trehalose (9:1) or 6:1 | 100％、80％、 40％、20％、 10％ | GM-CSF | Glucosan and histidine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% |
(2) dichloromethane of granulocyte-macrophage colony stimutaing factor (GM-CSF) drug particles and PLGA, acetonitrile, ethyl acetate or their mixed solution weight ratio are 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 that gets in ultrasonic 1-5 minutes, again the organic solution of PLA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. promptly oily solid (S/O) emulsion of wrapping of oil bag solid;
The enforcement of step (3), (4), (5) is identical with embodiment one.
The microsphere that present embodiment obtains, concrete set of dispense are such as following table:
| Drug particles | The weight ratio of PLGA/PLA | Drug particles accounts for the percentage by weight of microsphere |
| GM-CSF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
The GM-CSF microsphere of this method preparation goes for cancer chemotherapy and caused leukopenia with the bone marrow depression therapy time, also be applicable to treatment marrow failure patient's low leukocyte counts, the potential infection complication of possibility in the time of also can preventing leukopenia can also make the recovery of infecting the neutrophilic granulocyte minimizing that causes accelerate.Can reduce the frequency of injection and alleviate patient's misery.High minimum can the reaching more than 80% of the microsphere envelop rate of this method preparation, dashing forward to release very little and almost do not have not exclusively discharges, and can reach zero level release.Can make simultaneously the GM-CSF medicine is non-inactivation in whole process of preparation and therapeutic process maintenance high activity.
Embodiment seven: the preparation of recombinant human somatropin (GH) drug particles PLA/PLGA shell-nuclear microsphere
(1) recombinant human somatropin (GH) and pharmaceutic adjuvant are prepared into drug particles; Concrete proportioning is as follows:
| Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight | Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight |
| GH | Glucosan | 80%, 50%, 25 %, 10% or 5% | GH | Cyclodextrin and sucrose (9:1), (7:1), (6:1), (5:1) or (3:1) | 100%, 80%, 50%, 25 % or 10% |
| GH | Glucosan, zinc salt and trehalose (9:1:1) | 80%, 50%, 25 %, 10% or 5% | GH | Polyethylene Glycol, chitosan and sorbitol (8:1:1) or (5:1:1) | 100%, 80%, 50%, 25 % or 10% |
| GH | Glucosan and trehalose (9:1) | 80%, 50%, 25 %, 10% or 5% | GH | Glucosan, glycine and mannitol (8:1:1) or (6:1:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan, magnesium salt and trehalose (9:1:1) | 100%, 80%, 50 %, 25% or 10 % | GH | Poly(ethylene oxide) and sucrose (9:1), (8:1) or (3:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan, zinc salt and mannitol (9:0.5:1) | 80%, 50%, 25 % or 10% | GH | Polypyrrole alkane ketone and glycine (5:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Polyethylene Glycol and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10 | GH | Glucosan and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| ％ | |||||
| GH | Poly(ethylene oxide) and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10 % | GH | Glucosan and histidine (8:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Polyethylene Glycol and molybdenum salt (9:1) | 100%, 80%, 50 %, 25% or 10 % | GH | Polyethylene Glycol and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Poly(ethylene oxide) and calcium salt (9:1) | 100%, 80%, 50 %, 25% or 10 % | GH | Poly(ethylene oxide) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan, zinc salt and lactose (9:0.5:1) | 100%, 80%, 50 %, 25% or 10 % | GH | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% | GH | Glucosan, poly(ethylene oxide) and zinc salt (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan and trehalose (6:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% | GH | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Cyclodextrin and trehalose (8:1) or 6:1 | 50%, 40%, 30 %, 25%, 15 %10% or 5% | GH | Glucosan, magnesium salt and trehalose (8:1) (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan, zinc salt and lactose (8:1:1) | 80%, 70%, 50 %, 25% or 10 % | GH | Glucosan, polypyrrole alkane ketone and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan and lactose (8:1) or 6:1 | 80%, 60%, 50 %, 25% or 10 % | GH | Polypyrrole alkane ketone | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan and trehalose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | GH | Glucosan, starch and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan and lactose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | GH | Glucosan, chitosan and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | GH | Glucosan, trehalose and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10 % or 5% | GH | Glucosan, glycine and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Chitosan and sugarcane | 60％、50％、40 | GH | Glucosan and sorbitol (9: | 50％、40％、30％、25 |
| Sugar (9:1) or 6:1 | %, 20%, 10 % or 5% | 1), (7:1), (6:1), (5:1) or (3:1) | %, 15%10% or 5% | ||
| GH | Starch and lactose (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10 % or 5%% | GH | Glucosan and lactose (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Cellulose and lactose (9:1) or 6:1 | 100％、80％、40 ％、20％、10 ％ | GH | Glucosan and glycine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Glucosan and sucrose (9:1) or 6:1 | 100％、80％、40 ％、20％、10 ％ | GH | Glucosan and lysine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
| GH | Starch and trehalose (9:1) or 6:1 | 100％、80％、40 ％、20％、10 ％ | GH | Glucosan and histidine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25 %, 15%10% or 5% |
(2) dichloromethane of recombinant human somatropin (GH) polysaccharide microgranule and PLGA, acetonitrile, ethyl acetate or their mixed solution weight ratio are 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 that gets in ultrasonic 1-5 minutes, again the organic solution of PLA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. promptly oily solid (S/O) emulsion of wrapping of oil bag solid;
The enforcement of step (3), (4), (5) is identical with embodiment one.
The microsphere that present embodiment obtains, concrete set of dispense are such as following table:
| Drug particles | The weight ratio of PLGA/PLA | Drug particles accounts for the percentage by weight of microsphere |
| GH | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
The GH microsphere of this method preparation goes for being used for child, adult's growth hormone deficiency, Turner's syndrome, the retardation of growth that child's chronic renal insufficiency causes, hypermetabolism state (negative nitrogen balance) after operation, the wound, burn, pyaemia septica.Can reduce the frequency of injection and alleviate patient's misery.High minimum can the reaching more than 80% of the microsphere envelop rate of this method preparation, dashing forward to release very little and almost do not have not exclusively discharges, and can reach zero level release.Can make simultaneously the GH medicine is non-inactivation in whole process of preparation and therapeutic process maintenance high activity.
Embodiment eight: the preparation of vascular endothelial cell growth factor (VEGF) drug particles PLA/PLGA shell-nuclear microsphere
(1) vascular endothelial cell growth factor (VEGF) and polysaccharide are prepared into drug particles; Concrete proportioning is as follows:
| Medicine | Pharmaceutic adjuvant | Medicine accounts for the percentage by weight of granule gross weight | Medicine | Pharmaceutic adjuvant | Medicine accounts for the percentage by weight of granule gross weight |
| VEGF | Glucosan | 80%, 50%, 25%, 10% or 5% | VEGF | Cyclodextrin and sucrose (9:1), (7:1), (6:1), (5:1) or (3:1) | 100%, 80%, 50%, 25% or 10% |
| VEGF | Glucosan, zinc salt and trehalose (9:1:1) | 80%, 50%, 25%, 10% or 5% | VEGF | Polyethylene Glycol, chitosan and sorbitol (8:1:1) or (5:1:1) | 100%, 80%, 50%, 25% or 10% |
| VEGF | Glucosan and trehalose (9:1) | 80%, 50%, 25%, 10% or 5% | VEGF | Glucosan, glycine and mannitol (8:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan, magnesium salt and trehalose (9:1:1) | 100%, 80%, 50%, 25% or 10% | VEGF | Poly(ethylene oxide) and sucrose (9:1), (8:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan, zinc salt and mannitol (9:0.5:1) | 80%, 50%, 25% or 10% | VEGF | Polypyrrole alkane ketone and glycine (5:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Polyethylene Glycol and zinc salt (9:1) | 100%, 80%, 50%, 25% or 10% | VEGF | Glucosan and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Poly(ethylene oxide) and zinc salt (9:1) | 100%, 80%, 50%, 25% or 10% | VEGF | Glucosan and histidine (8:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Polyethylene Glycol and molybdenum salt (9:1) | 100%, 80%, 50%, 25% or 10% | VEGF | Polyethylene Glycol and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Poly(ethylene oxide) and calcium salt (9:1) | 100%, 80%, 50%, 25% or 10% | VEGF | Poly(ethylene oxide) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan, zinc salt and lactose (9:0.5:1) | 100%, 80%, 50%, 25% or 10% | VEGF | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan and trehalose (8:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % | VEGF | Glucosan, poly(ethylene oxide) and zinc salt (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan and trehalose (6:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % | VEGF | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Cyclodextrin and trehalose (8:1) or 6:1 | 50%, 40%, 30%, 25%, 15%10% or 5 % | VEGF | Glucosan, magnesium salt and trehalose (8:1) (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan, zinc salt and lactose (8:1:1) | 80%, 70%, 50%, 25% or 10% | VEGF | Glucosan, polypyrrole alkane ketone and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan and lactose (8:1) or 6:1 | 80%, 60%, 50%, 25% or 10% | VEGF | Polypyrrole alkane ketone | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan and trehalose (8:1) or 6:1 | 60%, 50%, 25%, 10% or 5% | VEGF | Glucosan, starch and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan and lactose (8:1) or 6:1 | 60%, 50%, 25%, 10% or 5% | VEGF | Glucosan, chitosan and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 25%, 10% or 5% | VEGF | Glucosan, trehalose and sodium alginate (9:1; 1), (8:1:1) or 4:1:1 | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 40%, 20%, 10% or 5% | VEGF | Glucosan, glycine and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Chitosan and sucrose (9:1) or 6: 1 | 60%, 50%, 40%, 20%, 10% or 5% | VEGF | Glucosan and sorbitol (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Starch and lactose (9:1) or 6:1 | 60%, 50%, 40%, 20%, 10% or 5%% | VEGF | Glucosan and lactose (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Cellulose and lactose (9:1) or 6:1 | 100％、80％、 40％、20％、 10％ | VEGF | Glucosan and glycine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Glucosan and sucrose (9:1) or 6:1 | 100％、80％、 40％、20％、 10％ | VEGF | Glucosan and lysine (9:1), (7L1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| VEGF | Starch and trehalose (9:1) or 6:1 | 100％、80％、 40％、20％、 10％ | VEGF | Glucosan and histidine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
(2) dichloromethane of vascular endothelial cell growth factor (VEGF) drug particles and PLGA, acetonitrile, ethyl acetate or their mixed solution weight ratio are 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 that gets in ultrasonic 1-5 minutes, again the organic solution of PLA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. promptly oily solid (S/O) emulsion of wrapping of oil bag solid;
The enforcement of step (3), (4), (5) is identical with embodiment one.
The microsphere that present embodiment obtains, concrete set of dispense are such as following table:
| Drug particles | The weight ratio of PLGA/PLA | Drug particles accounts for the percentage by weight of microsphere |
| VEGF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
The VEGF microsphere of this method preparation goes for the short vascular endothelial cell growth of formation treatment with new vessels.Can reduce the frequency of injection and alleviate patient's misery.High minimum can the reaching more than 80% of the microsphere envelop rate of this method preparation, dashing forward to release very little and almost do not have not exclusively discharges, and can reach zero level release.Can make simultaneously the GM-CSF medicine is non-inactivation in whole process of preparation and therapeutic process maintenance high activity.
Embodiment nine: the preparation of bone morphogenetic protein(BMP) (BMP) drug particles PLA/PLGA shell-nuclear microsphere
(1) bone morphogenetic protein(BMP) (BMP) and polysaccharide are prepared into drug particles; Concrete proportioning is:
| Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight | Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight |
| BMP | Glucosan | 80%, 50%, 25 %, 10% or 5% | BMP | Cyclodextrin and sucrose (9:1), (7:1), (6:1), (5:1) or (3:1) | 100%, 80%, 50%, 25% or 10% |
| BMP | Glucosan, zinc salt and trehalose (9:1:1) | 80%, 50%, 25 %, 10% or 5% | BMP | Polyethylene Glycol, chitosan and sorbitol (8:1:1) or (5:1:1) | 100%, 80%, 50%, 25% or 10% |
| BMP | Glucosan and trehalose (9:1) | 80%, 50%, 25 %, 10% or 5% | BMP | Glucosan, glycine and mannitol (8:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan, magnesium salt and trehalose (9:1:1) | 100%, 80%, 50 %, 25% or 10 % | BMP | Poly(ethylene oxide) and sucrose (9:1), (8:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan, zinc salt and mannitol (9:0.5:1) | 80%, 50%, 25 % or 10% | BMP | Polypyrrole alkane ketone and glycine (5:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Polyethylene Glycol and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10 | BMP | Glucosan and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 |
| ％ | ％ | ||||
| BMP | Poly(ethylene oxide) and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10 % | BMP | Glucosan and histidine (8:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Polyethylene Glycol and molybdenum salt (9:1) | 100%, 80%, 50 %, 25% or 10 % | BMP | Polyethylene Glycol and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Poly(ethylene oxide) and calcium salt (9:1) | 100%, 80%, 50 %, 25% or 10 % | BMP | Poly(ethylene oxide) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan, zinc salt and lactose (9:0.5:1) | 100%, 80%, 50 %, 25% or 10 % | BMP | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% | BMP | Glucosan, poly(ethylene oxide) and zinc salt (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan and trehalose (6:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% | BMP | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Cyclodextrin and trehalose (8:1) or 6:1 | 50%, 40%, 30 %, 25%, 15 %10% or 5% | BMP | Glucosan, magnesium salt and trehalose (8:1) (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan, zinc salt and lactose (8:1:1) | 80%, 70%, 50 %, 25% or 10 % | BMP | Glucosan, polypyrrole alkane ketone and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan and lactose (8:1) or 6:1 | 80%, 60%, 50 %, 25% or 10 % | BMP | Polypyrrole alkane ketone | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan and trehalose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | BMP | Glucosan, starch and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan and lactose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | BMP | Glucosan, chitosan and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | BMP | Glucosan, trehalose and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10 % or 5% | BMP | Glucosan, glycine and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Chitosan and sugarcane | 60％、50％、40 | BMP | Glucosan and sorbitol (9: | 50％、40％、30％、 |
| Sugar (9:1) or 6:1 | %, 20%, 10 % or 5% | 1), (7:1), (6:1), (5:1) or (3:1) | 25%, 15%10% or 5 % | ||
| BMP | Starch and lactose (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10 % or 5%% | BMP | Glucosan and lactose (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Cellulose and lactose (9:1) or 6:1 | 100％、80％、40 ％、20％、10 ％ | BMP | Glucosan and glycine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Glucosan and sucrose (9:1) or 6:1 | 100％、80％、40 ％、20％、10 ％ | BMP | Glucosan and lysine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
| BMP | Starch and trehalose (9:1) or 6:1 | 100％、80％、40 ％、20％、10 ％ | BMP | Glucosan and histidine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30%, 25%, 15%10% or 5 % |
(2) dichloromethane of bone morphogenetic protein(BMP) (BMP) drug particles and PLGA, acetonitrile, ethyl acetate or their mixed solution weight ratio are 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 that gets in ultrasonic 1-5 minutes, again the organic solution of PLA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. promptly oily solid (S/0) emulsion of wrapping of oil bag solid;
The enforcement of step (3), (4), (5) is identical with embodiment one.
The microsphere that present embodiment obtains, concrete set of dispense is such as following:
| Drug particles | The weight ratio of PLGA/PLA | Drug particles accounts for the percentage by weight of microsphere |
| BMP | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
The BMP microsphere of this method preparation goes for the treatment behind the miscellaneous fracture.Can reduce the frequency of injection and alleviate patient's misery.High minimum can the reaching more than 80% of the microsphere envelop rate of this method preparation, dashing forward to release very little and almost do not have not exclusively discharges, and can reach zero level release.Can make simultaneously the BMP medicine is non-inactivation in whole process of preparation and therapeutic process maintenance high activity.
Embodiment ten: the preparation of bone-derived growth factor (BDGF) polysaccharide microgranule PLA/PLGA shell-nuclear microsphere
(1) bone-derived growth factor (BDGF) and polysaccharide are prepared into drug particles; Concrete proportioning is as follows:
| Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight | Medicine | Pharmaceutic adjuvant | Medicine accounts for particulate percentage by weight |
| BDGF | Glucosan | 80％、50％、25 | BDGF | Cyclodextrin and sucrose (9:1), | 100％、80％、50 |
| %, 10% or 5% | (7:1), (6:1), (5:1) or (3:1) | %, 25% or 10 % | |||
| BDGF | Glucosan, zinc salt and trehalose (9:1:1) | 80%, 50%, 25 %, 10% or 5% | BDGF | Polyethylene Glycol, chitosan and sorbitol (8:1:1) or (5:1:1) | 100%, 80%, 50 %, 25% or 10 % |
| BDGF | Glucosan and trehalose (9:1) | 80%, 50%, 25 %, 10% or 5% | BDGF | Glucosan, glycine and mannitol (8:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan, magnesium salt and trehalose (9:1:1) | 100%, 80%, 50 %, 25% or 10% | BDGF | Poly(ethylene oxide) and sucrose (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan, zinc salt and mannitol (9:0.5:1) | 80%, 50%, 25 % or 10% | BDGF | Polypyrrole alkane ketone and glycine (5:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Polyethylene Glycol and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10% | BDGF | Glucosan and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Poly(ethylene oxide) and zinc salt (9:1) | 100%, 80%, 50 %, 25% or 10% | BDGF | Glucosan and histidine (8:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Polyethylene Glycol and molybdenum salt (9:1) | 100%, 80%, 50 %, 25% or 10% | BDGF | Polyethylene Glycol and lysine (9:1), (8:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Poly(ethylene oxide) and calcium salt (9:1) | 100%, 80%, 50 %, 25% or 10% | BDGF | Poly(ethylene oxide) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan, zinc salt and lactose (9:0.5:1) | 100%, 80%, 50 %, 25% or 10% | BDGF | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan and trehalose (8:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% | BDGF | Glucosan, poly(ethylene oxide) and zinc salt (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan and trehalose (6:1) | 50%, 40%, 30 %, 25%, 15%10 % or 5% | BDGF | Glucosan, Polyethylene Glycol and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Cyclodextrin and trehalose (8:1) or 6:1 | 50%, 40%, 30 %, 25%, 15%10 % or 5% | BDGF | Glucosan, magnesium salt and trehalose (8:1) (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan, zinc salt and lactose (8:1:1) | 80%, 70%, 50 %, 25% or 10% | BDGF | Glucosan, polypyrrole alkane ketone and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan and lactose (8:1) or 6:1 | 80%, 60%, 50 %, 25% or 10% | BDGF | Polypyrrole alkane ketone | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan and trehalose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | BDGF | Glucosan, starch and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan and lactose (8:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | BDGF | Glucosan, chitosan and trehalose (8:1:1), (7:1:1) or (6:1:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 25 %, 10% or 5% | BDGF | Glucosan, trehalose and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan and sodium alginate (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5% | BDGF | Glucosan, glycine and sodium alginate (9:1:1), (8:1:1) or 4:1:1 | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Chitosan and sucrose (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5% | BDGF | Glucosan and sorbitol (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Starch and lactose (9:1) or 6:1 | 60%, 50%, 40 %, 20%, 10% or 5%% | BDGF | Glucosan and lactose (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Cellulose and lactose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | BDGF | Glucosan and glycine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Glucosan and sucrose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | BDGF | Glucosan and lysine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
| BDGF | Starch and trehalose (9:1) or 6:1 | 100％、80％、40 ％、20％、10％ | BDGF | Glucosan and histidine (9:1), (7:1), (6:1), (5:1) or (3:1) | 50%, 40%, 30 %, 25%, 15 %10% or 5% |
(2) dichloromethane of bone-derived growth factor (BDGF) drug particles and PLGA, acetonitrile, ethyl acetate or their mixed solution weight ratio are 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 that gets in ultrasonic 1-5 minutes, again the organic solution of PLA is added in the above-mentioned suspension, the even suspension that gets of restir, whirlpool or formation in ultrasonic 1-5 minutes, i.e. promptly oily solid (S/O) emulsion of wrapping of oil bag solid;
The enforcement of step (3), (4), (5) is identical with embodiment one.
The microsphere that present embodiment obtains, concrete set of dispense is such as following:
| Drug particles | The weight ratio of PLGA/PLA | Drug particles accounts for the percentage by weight of microsphere |
| BDGF | 1,1/2,1/3,1/4,1/5,2,3,4 or 5 | 20%, 60%, 80%, 70% or 99.99% |
The BMP microsphere of this method preparation goes for the treatment behind the miscellaneous fracture.Can reduce the frequency of injection and alleviate patient's misery.High minimum can the reaching more than 80% of the microsphere envelop rate of this method preparation, dashing forward to release very little and almost do not have not exclusively discharges, and can reach zero level release.Can make simultaneously the BDGF medicine is non-inactivation in whole process of preparation and therapeutic process maintenance high activity.
Claims (10)
1, a kind of PLA/PLGA shell-nuclear microsphere with oil-in-water-oil bag solid preparation, it is characterized in that, comprise medicine, polylactic acid and/or polylactic acid-hydroxyacetic acid or/and pharmaceutic adjuvant, their weight percent content is: medicine 0.01-50%, polylactic acid and/or polylactic acid-hydroxyacetic acid 20-99.99%, pharmaceutic adjuvant are 0-30%.
2, the PLA/PLGA shell-nuclear microsphere with oil-in-water-oil bag solid preparation according to claim 1, it is characterized in that, described medicine comprises small-molecule drug and macromolecular drug, and described small-molecule drug refers to chemicals, and macromolecular drug is meant biopharmaceutical macromolecular drug.
3, the PLA/PLGA shell-nuclear microsphere with oil-in-water-oil bag solid preparation according to claim 2 is characterized in that described macromolecular drug is finger protein macromolecular drug, vaccine, antibody, nucleic acid or liposome medicament especially, wherein:
Described protein macromolecule medicine is: erythropoietin, recombinant human granulocyte colony stimulating factor, granulocyte-macrophage colony stimutaing factor, vaccine, interferon, growth hormone, insulin, epidermal growth factor, fibroblast growth factor, transforming growth factor, insulin like growth factor, vascular endothelial cell growth factor, PDGF, endothelial cell growth factor (ECGF), nerve growth factor, bone-derived growth factor, bone morphogenetic protein(BMP), tissue polypeptide antigen, antibody, blood coagulation factor VIII, or it is a kind of in the plasma thromboplastin component genetic factor;
Described nucleic acid is: antisense nucleotide, microRNA or gene.
4, the PLA/PLGA shell-nuclear microsphere with oil-in-water-oil bag solid preparation according to claim 1, it is characterized in that, it is a kind of or combination in any of little saccharide, polyhydroxy compounds, polysaccharide compound, amino-acid compound or inorganic salts material that described pharmaceutic adjuvant refers to, wherein:
Described little saccharide is a kind of in sucrose, trehalose, glucose, maltose or the lactose;
Described polyhydroxy compounds is a kind of in mannitol, sorbitol, glycerol, 1,2-propylene glycol, erythritol, Polyethylene Glycol, polyvinyl alcohol, poly(ethylene oxide) or the polypyrrole alkane ketone;
Described polysaccharide compound is a kind of in glucosan, sodium alginate, chitosan, starch, cellulose or the cyclodextrin material;
Described amino-acid compound is a kind of in glycine, lysine, arginine, glutamic acid or the histidine;
Described inorganic salts material is a kind of in zinc salt, calcium salt, mantoquita, magnesium salt or the molybdenum salt.
5, a kind of preparation method with oil-in-water-PLA/PLGA shell-nuclear microsphere that oil bag solid prepares as claimed in claim 1 is characterized in that may further comprise the steps:
1. medicine or medicine and pharmaceutic adjuvant are prepared into drug particles;
2. drug particles is joined the organic solution of PLA and PLGA or the organic solution of hydrophilic drug particles and PLGA mixed after, mixed with the organic solution of PLA again; Or it is mixed earlier hydrophobic drug particles and PLA, mixed with the organic solution of PLGA again; Form suspension, i.e. oil phase O
1Middle stirring or whirlpool make it homodisperse and form uniform suspension;
3. 2. completing steps is formed the aqueous solution emulsifying that microsphere suspension is added drop-wise to sodium chloride solution and surfactant, form emulsion;
4. then step emulsion 3. being transferred to sodium chloride solution solidifies;
5. completing steps sample lyophilizing is 4. obtained PLA/PLGA shell-nuclear microsphere.
6, the preparation method with oil-in-water-PLA/PLGA shell-nuclear microsphere that oil bag solid prepares according to claim 5, it is characterized in that, described drug particles, the size of its drug particles is at 0.2-10 μ mm, and its weight accounts for the 0.2-50% of drug particles gross weight.
7, the preparation method with oil-in-water-PLA/PLGA shell-nuclear microsphere that oil bag solid prepares according to claim 5, it is characterized in that the organic solution of described PLA and/or PLGA is: the organic solution of PLA and PLGA is added 0.1-20%w/w Polyethylene Glycol or poloxamer; The dichloromethane of PLA and PLGA, ethyl acetate, acetonitrile, heptane, chloroform or acetone organic solution.
8, the preparation method with oil-in-water-PLA/PLGA shell-nuclear microsphere that oil bag solid prepares according to claim 5, it is characterized in that the organic solution concentration of described PLA and/or PLGA is: the weight percent concentration that accounts for total oil phase of PLA is 0.5-80%; The weight percent concentration that PLGA accounts for total oil phase is 20-99.5%.
9, the preparation method with oil-in-water-PLA/PLGA shell-nuclear microsphere that oil bag solid prepares according to claim 5, it is characterized in that, described surfactant is polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone, poloxamer, poly-sorbic alcohol, ethyl cellulose or tween, and wherein: the concentration of surface active agent polyvinyl alcohol is 0.5-10% or contains 0.5-10% sodium chloride salt solution; The concentration of Polyethylene Glycol is 0.5-20% or contains the saline solution of 0.5-10% sodium chloride; Polyvinylpyrrolidone concentration is 0.5-20% or contains 0.5-10% sodium chloride salt solution; Poloxamer concentration is 0.5-20% or contains 0.5-10% sodium chloride salt solution; Poly-sorbic alcohol concentration is 0.5-20% or contains 0.5-10% sodium chloride salt solution; Ethyl cellulose concentration is 0.5-20% or contains 0.5-10% sodium chloride salt solution that above concentration is weight percent concentration.
10, the preparation method with oil-in-water-PLA/PLGA shell-nuclear microsphere that oil bag solid prepares according to claim 5 is characterized in that the particle diameter of described microsphere is 1-500 μ m.
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