CN102895197B - Method for preparing microspheres through oil in nano-particle suspension-oil in oil and sustained-release microspheres - Google Patents
Method for preparing microspheres through oil in nano-particle suspension-oil in oil and sustained-release microspheres Download PDFInfo
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Abstract
The invention provides a method for preparing microspheres through oil in nano-particle suspension-oil in oil. The method includes that step one, embedded medical ingredients are prepared to a medicine oil solution; step two, the medicine oil solution is added into a polymer organic solution, namely the medicine oil solution is added into an oil phase, and a suspension is formed through uniformly mixing; step three, the suspension prepared in the step two is dropwise added into mineral oil, and a multiple emulsion is formed through stirring, whirling or ultrasound; step four, the multiple emulsion prepared in the step three is dropwise added into a suspension containing the nano-particles, and the microspheres are formed through stirring, whirling or ultrasound; step five, the microspheres prepared in the step four are dispersed into cottonseed oil for curing; and step six, the microspheres are collected in a centrifuged mode, and drying is performed to obtain the microspheres with surfaces self assembled with the nano-particles. Compared with methods for preparing microspheres in prior art, the method for preparing the microspheres through oil in nano-particle suspension-oil in oil has the advantages that a layer of nano-particles is assembled on the surfaces of the microspheres, and the microspheres with surfaces assembled with the nano-particles have effects of enhancing cell adhesion and reducing inflammation and microencapsulation caused by local peracid and a hydrophobic material.
Description
Technical field
The present invention relates to a kind of preparation method of microsphere, particularly a kind of nano-particle suspension bag oil-oil bag oil (O/O/S) is prepared method and the sustained-release micro-spheres of 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 the topicals such as targeting.Reach these objects, crude drug must be prepared into corresponding dosage form.For example, need long term administration but short medicine of half-life in vivo, should be prepared into PLA(polylactic acid) dosage form; For the treatment of some tumors, need some drug targetings in focus, such as targeting is in tumor vascular embolism microball preparation etc.Find by prior art documents, wherein, " Double walled PLA/PLGA microspheres:encapsulation of water-soluble and water-insoluble proteins and their release properties " " Journal of Controlled Release " 89 (2003) 167 – 177], [Meng Shi etc., double-deck POE/PLGA microsphere: seal water solublity and water-insoluble protein and their release feature, control and discharge magazine, 89 (2003) 167 – 177], the people such as Meng Shi have reported and have utilized W/O/W method that bovine serum albumin (BSA) and Ciclosporin A (CyA) are encapsulated in PLGA/PLA shell-core microsphere in the document.The multi-emulsion method that the document utilizes W/O/W to see is most prepared double-deck microsphere, and the oil-water interfaces of multi-emulsion method are generally acknowledged albumen killers, causes the gathering of water miscible albumen at this interface, causes envelop rate not high, and has incomplete release and prominent releasing.Morita T. etc. were " Journal of Controlled Release " (controlled discharge magazine) (2000, the 69th phase, the 435th page to the 444th page) on deliver " Protein encapsulation into biodegradable microspheres by a novel S/O/W emulsion method using poly (ethylene glycol) as a protein micronization adjuvant " [with Polyethylene Glycol as the micronized excipient of albumen (surfactant), then by the method for oil-in-water-oil bag solid, albumen microcapsule is wrapped in biodegradable microsphere], the document has been reported and has been utilized new S/O/W emulsion process preparation to carry protein microsphere.Wherein, just changed surfactant, reporting in the past more is with PVA, uses PEG instead at this section of document.But, still can not overcome the shortcoming of envelop rate low and the caused local microencapsulation in hydrophobic surface and inflammation.
Summary of the invention
The method that the object of the invention is to provide a kind of nano-particle suspension bag oil-oil bag oil to prepare microsphere, can not overcome the technical matters of envelop rate low and the caused local microencapsulation in hydrophobic surface and inflammation to solve microsphere of the prior art.
Another object of the present invention is to provide a kind of sustained-release micro-spheres, can not overcome the technical matters of envelop rate low and the caused local microencapsulation in hydrophobic surface and inflammation to solve microsphere of the prior art.
The object of the invention is achieved through the following technical solutions:
Nano-particle suspension bag oil-oil bag oil is prepared a method for microsphere, comprises the following steps:
(1) will be prepared into medicine oil solution by the ingredient of embedding;
(2) medicine oil solution is joined in the organic solution of polymer,, in oil phase, be mixed evenly formation suspension;
(3) suspension of step (2) is added drop-wise in mineral oil to stirring, vortex or ultrasonic formation emulsion emulsion;
(4) the emulsion emulsion droplets of step (3) is added in the suspension that contains nano-particle to stirring, vortex or ultrasonic formation microsphere;
(5) microsphere of step (4) is distributed in Oleum Gossypii semen and solidifies;
(6) centrifugal collection microsphere, obtains the microsphere of surface self-organization nano-particle after dry.
Preferably, the described ingredient by embedding comprises the mixture of medicine or medicine and excipient substance.
Preferably, described medicine comprises small-molecule drug and macromolecular drug; Described small-molecule drug comprises chemicals; Described macromolecular drug comprises biopharmaceutical macromolecular drug, and described biopharmaceutical macromolecular drug comprises protein macromolecule medicine, vaccine, antibody, nucleic acid or liposome medicament.
Preferably, described pharmaceutic adjuvant is selected from one or more of little saccharide, polyhydroxy compounds, polysaccharide compound, amino-acid compound or inorganic salts material.Wherein, described little saccharide comprises one or more in sucrose, trehalose, glucose, maltose or lactose; Described polyhydroxy compounds comprises one or more in mannitol, sorbitol, glycerol, 1,2-PD, erythritol, Polyethylene Glycol, polyvinyl alcohol, poly(ethylene oxide) or polypyrrole alkane ketone; Described polysaccharide compound comprises one or more in glucosan, sodium alginate, chitosan, starch, cellulose or cyclodextrin material; Described amino-acid compound comprises one or more in glycine, lysine, arginine, glutamic acid or histidine; Described inorganic salts material comprises one or more in zinc salt, calcium salt, mantoquita, magnesium salt or molybdenum salt.
Preferably, step (1) further comprises: the described ingredient by embedding is dissolved in organic solvent and forms medicine oil solution, and described organic solvent is selected from the wherein a kind of of dimethyl sulfoxide, dichloromethane, ethanol, acetonitrile, ethyl acetate, methanol or glycerol.
Preferably, the organic solution that the oil phase of described step (2) is polymer, described polymer is selected from one or more in polycaprolactone, polylactic acid, poly lactic-co-glycolic acid, polylactic acid-polyglycol, PLGA-Polyethylene Glycol or polycaprolactone-polyethylene glycol.
Preferably, the organic solution of described polymer for adding 0.1-20%(w/w in polymer) Polyethylene Glycol or poloxamer; Or for polymer is dissolved in to the solution forming in dichloromethane, ethyl acetate, acetonitrile, heptane, chloroform or acetone.
Preferably, the weight percent concentration that contains nano-particle in the suspension of nano-particle described in is 1%-80%.
Preferably, the suspension that contains nano-particle described in is selected from the wherein a kind of of the aqueous suspension of organic nanometer granule aqueous suspension, inorganic nanoparticles, the aqueous suspension that mixes organic nanometer granule and inorganic nanoparticles or nano-particle and surfactant aqueous suspension.Wherein, the aqueous suspension of described inorganic nanoparticles be selected from aqueous suspension, calcium carbonate nano granule, calcium phosphate nanoparticles, magnesium carbonate nano-particle or the magnesium hydroxide nanoparticles of aqueous suspension, the aluminium sesquioxide nano-particle of aqueous suspension, the gold nano grain of aqueous suspension, the ferric oxide particle of aqueous suspension, the ferroferric oxide nano granules of aqueous suspension, the hydroxyapatite nanoparticle of aqueous suspension, the titanium dioxide of nano SiO 2 particle aqueous suspension wherein one or more.Described nano-particle and surfactant aqueous suspension are selected from the aqueous suspension of aqueous suspension, nano-particle and ethyl cellulose or the aqueous suspension of nano-particle and tween of aqueous suspension, nano-particle and the poly-sorbic alcohol ester of aqueous suspension, nano-particle and the poloxamer of aqueous suspension, nano-particle and the polyvinylpyrrolidone of aqueous suspension, nano-particle and the Polyethylene Glycol of nano-particle and polyvinyl alcohol.
Preferably, the particle diameter of described microsphere is 1-500 μ m.
A kind of sustained-release micro-spheres, is characterized in that, comprises microsphere and the nano-particle that covers microsphere surface, and microsphere comprises medicine, polymer and pharmaceutic adjuvant, wherein,
The percentage by weight of medicine is 0.01-20%;
The percentage by weight of nano-particle is 0.01-20%;
The percentage by weight of polymer is 20-99.98%;
Pharmaceutic adjuvant is 0-30%.
Compared with prior art, microsphere surface assembling one deck nano-particle that preparation method of the present invention is made, the microsphere that this surface has nano-particle has the effect that strengthens cell adhesion, also can reduce inflammation and microencapsulation that local overacidification and hydrophobic material cause.
Brief description of the drawings
Fig. 1 is the scanning electron microscope (SEM) photograph (scanning electron microscope (SEM) photograph that A is microsphere of microsphere; B is the surperficial enlarged drawing of microsphere);
Fig. 2 is the release in vitro curve chart of microsphere;
Fig. 3 is the antibacterial action comparison diagram of microsphere;
Fig. 4 is the antitumaous effect comparison diagram of microsphere;
Fig. 5 is the microsphere Experiment of Histocompatibility result schematic diagram in vivo of preparing with conventional method;
Fig. 6 is the release in vitro curve comparison figure of microsphere;
Fig. 7 is the drug effect contrast schematic diagram of microsphere;
Fig. 8 is the release in vitro curve comparison figure of microsphere;
Fig. 9 is the drug effect contrast schematic diagram of microsphere;
Figure 10 is the release in vitro curve chart of microsphere;
Figure 11 is the drug effect contrast schematic diagram of microsphere;
Figure 12 is the release in vitro curve chart of microsphere;
Figure 13 is the drug effect contrast schematic diagram of microsphere;
Figure 14 is the release in vitro curve chart of microsphere;
Figure 15 is the drug effect contrast schematic diagram of microsphere;
Figure 16 is the particle diameter detection figure of microsphere.
Detailed description of the invention
Below embodiments of the invention are elaborated, embodiments of the invention are implemented under taking technical solution of the present invention as prerequisite, provided detailed embodiment and concrete operating process, but protection scope of the present invention are not limited to following embodiment.
Nano-particle suspension bag oil of the present invention-oil bag oil (O/O/S) is prepared the method for microsphere, and concrete operations are as follows.
(1) mixture of small-molecule drug or small-molecule drug and pharmaceutic adjuvant is prepared into medicine oil solution.
Wherein, the small-molecule drug of employing can be that chemotherapy of tumors class medicine (can be selected from one or more in AC, dactinomycin, bleomycin, daunorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), semustine, cisplatin, etoposide, camptothecin analogues, phenesterin, paclitaxel and derivant, Docetaxel and derivant thereof, vinblastine, vincristine, zitazonium, etoposide, piposulfan, cyclophosphamide or flutamide and derivant thereof.) or antibiotics (can be selected from ciclosporin, levofloxacin, ofloxacin or epinastine hydrochloride; Or polypeptide drug, one or more that receive in peptide or octreotide etc. as Ethiopia).
Wherein, the pharmaceutic adjuvant of employing can be 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 histidine.
(2) medicine oil solution is joined in the organic solution of polymer,, in oil phase, be mixed evenly formation suspension, be i.e. oil bag oil (O/O) emulsion.
(3) suspension of step (2) is added drop-wise in mineral oil, within stirring, vortex or ultrasonic 0.1-5 minute, forms emulsion emulsion.
(4) emulsion emulsion droplets step (3) being obtained is added to stirring in the aqueous suspension of certain density nano-particle aqueous suspension or nano-particle and surfactant, vortex or ultrasonic 0.1-5 minute formation microsphere.
(5) microsphere of step (4) is added drop-wise to curing 2-3 hour in 200-500ml Oleum Gossypii semen.
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying obtains microsphere.
Microsphere prepared by this method can, for needing the disease of long-term treatment, especially need the disease of topical therapeutic as the blood vessel embolism microsphere of tumor.High minimum can the reaching more than 80% of microsphere envelop rate prepared by this method, prominently releases very littlely, and almost there is no incomplete release, can reach zero level and discharge.And the microsphere that this surface has nano-particle has the effect that strengthens cell adhesion, also can reduce inflammation and microencapsulation that local overacidification and hydrophobic material cause.
Embodiment 1 has the preparation of amycin poly lactic-co-glycolic acid (PLGA) microsphere of antibacterial action and anticancer effect
(1) 20mg amycin is dissolved in the solution in 0.5ml dimethyl sulfoxide (DMSO);
(2) the ratio ultrasonic 1-5 minute of the dichloromethane solution of the PLGA that is 0.1% said medicine solution and percent concentration taking weight ratio as 1:9 forms even oil phase;
(3) oil phase of step (2) is added drop-wise in mineral oil (4-10ml), within stirring, vortex or ultrasonic 0.1-5 minute, forms emulsion (O/O) emulsion;
(4) in the suspension of the emulsion emulsion droplets of step (3) nano-particle that to be added to weight percent concentration be in 1% titania nanoparticles suspension or weight percent concentration is 20% and PVA surfactant and stirring, vortex or within ultrasonic 0.1-5 minute, form emulsion (O/O/S) emulsion;
(5) the emulsion emulsion droplets of step (4) is added to curing 2-3 hour in 200-500ml Oleum Gossypii semen;
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying obtains microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, it is good that microsphere form is prepared in result demonstration, surface self-organization one deck nano-particle; The particle diameter of microsphere detects as shown in figure 16, and the particle diameter of microsphere is 1-500 μ m, mainly concentrates on 65 ± 18.54 μ m; As shown in Figure 2, its release in vitro curve also meets the requirements the release in vitro curve of microsphere; Its antibacterial effect as shown in Figure 3; Anticancer effect as shown in Figure 4; Microsphere prepared by itself and conventional method in vivo Experiment of Histocompatibility result as shown in Figure 5, result shows: within microsphere prepared by the non-nano suspension 3-6 after treatment month, there is fibrosis tissue; And the microsphere of preparing of nanosuspension is being treated the appearance (microencapsulation that is injection site does not occur, overcomes the generation of microencapsulation) that also there is no fibrous tissue after a year.
Embodiment receives 2 Ethiopias peptide poly lactic-co-glycolic acid (PLGA) microsphere preparation
(1) 20mg Ethiopia is received peptide and 10mg Polyethylene Glycol (PEG molecular weight 6000) and is dissolved in the solution in 0.5ml dimethyl sulfoxide (DMSO);
(2) the ratio ultrasonic 1-5 minute of the dichloromethane solution of the PLGA that is 10% said medicine solution and percent concentration taking weight ratio as 1:9 forms uniform oil phase;
(3) oil phase of step (2) is added drop-wise in mineral oil (4-10ml), within stirring, vortex or ultrasonic 0.1-5 minute, forms emulsion (O/O) emulsion;
(4) in the suspension of the emulsion droplets of step (3) nano-particle that to be added to weight percent concentration be in 60% hydroxyapatite nanoparticle suspension or weight percent concentration is 30% and PVA surfactant and stirring, vortex or within ultrasonic 0.1-5 minute, form emulsion (O/O/S) emulsion;
(5) the emulsion emulsion droplets of step (4) is added to curing 2-3 hour in 200-500ml Oleum Gossypii semen;
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying obtains microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, it is good that microsphere form is prepared in result demonstration, surface self-organization one deck silver nano-grain; The particle diameter of microsphere detects as shown in figure 16, and the particle diameter of microsphere is 1-500 μ m, mainly concentrates on 65 ± 18.54 μ m; As shown in Figure 6, its release in vitro curve also meets the requirements the release in vitro curve of microsphere; Its drug effect as shown in Figure 7; Microsphere prepared by itself and conventional method in vivo Experiment of Histocompatibility result as shown in Figure 5, result shows: within microsphere prepared by the non-nano suspension 3-6 after treatment month, there is fibrosis tissue; And the microsphere of preparing of nanosuspension is being treated the appearance (microencapsulation that is injection site does not occur, overcomes the generation of microencapsulation) that also there is no fibrous tissue after a year.
Embodiment 3 octreotide poly lactic-co-glycolic acid (PLGA) microsphere preparations
(1) 20mg octreotide is dissolved in the solution in 0.5ml dimethyl sulfoxide (DMSO);
(2) the ratio ultrasonic 1-5 minute of the dichloromethane solution of the PLGA that is 20% said medicine solution and percent concentration taking weight ratio as 1:9 forms uniform oil phase;
(3) oil phase of step (2) is added drop-wise to also stirring in (4-10ml) in mineral oil, vortex or within ultrasonic 0.1-5 minute, forms emulsion (O/O) emulsion;
(4) in the suspension of the emulsion emulsion droplets of step (3) nano-particle that to be added to weight percent concentration be in 80% hydroxyapatite nanoparticle suspension or weight percent concentration is 50% and PVA surfactant and stirring, vortex or within ultrasonic 0.1-5 minute, form emulsion (O/O/S) emulsion;
(5) emulsion of step (4) is added drop-wise to curing 2-3 hour in 200-500ml Oleum Gossypii semen;
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying obtains microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, it is good that microsphere form is prepared in result demonstration, surface self-organization one deck silver nano-grain; The particle diameter of microsphere detects as shown in figure 16, and the particle diameter of microsphere is 1-500 μ m, mainly concentrates on 65 ± 18.54 μ m; As shown in Figure 8, its release in vitro curve also meets the requirements the release in vitro curve of microsphere; Its drug effect as shown in Figure 9; Microsphere prepared by itself and conventional method in vivo Experiment of Histocompatibility result as shown in Figure 5, result shows: within microsphere prepared by the non-nano suspension 3-6 after treatment month, there is fibrosis tissue; And the microsphere of preparing of nanosuspension is being treated the appearance (microencapsulation that is injection site does not occur, overcomes the generation of microencapsulation) that also there is no fibrous tissue after a year.
The preparation of embodiment 4 carmustines (BCNU) polylactic acid (PLA) microsphere
(1) 20mg carmustine is dissolved in the solution in 0.5ml dichloromethane (DCM);
(2) the ratio ultrasonic 1-5 minute of the dichloromethane solution of the PLGA that is 10% said medicine solution and percent concentration taking weight ratio as 1:9 forms uniform oil phase;
(3) oil phase of step (2) is added drop-wise to also stirring in (4-10ml) in mineral oil, vortex or within ultrasonic 0.1-5 minute, forms emulsion (O/O) emulsion;
(4) the emulsion emulsion droplets of step (3), to be added to weight percent concentration be in 60% hydroxyapatite nanoparticle suspension or weight percent concentration is in the suspension of 50% nano-particle and PVA surfactant and stirring, vortex or within ultrasonic 0.1-5 minute, form emulsion (O/O/S) emulsion;
(5) emulsion of step (4) is added drop-wise to curing 2-3 hour in 200-500ml Oleum Gossypii semen;
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying obtains microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, it is good that microsphere form is prepared in result demonstration, surface self-organization one deck silver nano-grain; The particle diameter of microsphere detects as shown in figure 16, and the particle diameter of microsphere is 1-500 μ m, mainly concentrates on 65 ± 18.54 μ m; As shown in figure 10, its release in vitro curve also meets the requirements the release in vitro curve of microsphere; Its drug effect as shown in figure 11; Microsphere prepared by itself and conventional method in vivo Experiment of Histocompatibility result as shown in Figure 5, result shows: within microsphere prepared by the non-nano suspension 3-6 after treatment month, there is fibrosis tissue; And the microsphere of preparing of nanosuspension is being treated the appearance (microencapsulation that is injection site does not occur, overcomes the generation of microencapsulation) that also there is no fibrous tissue after a year.
The preparation of embodiment 5 carmustines (BCNU) polylactic acid (PLA) microsphere
(1) 20mg carmustine is dissolved in the solution in 0.5ml dichloromethane (DCM);
(2) the ratio ultrasonic 1-5 minute of the dichloromethane solution of the PLA that is 10% said medicine solution and percent concentration taking weight ratio as 1:9 forms uniform oil phase;
(3) oil phase of step (2) is added drop-wise to also stirring in (4-10ml) in mineral oil, vortex or within ultrasonic 0.1-5 minute, forms emulsion (O/O) emulsion;
(4) in the suspension of the emulsion emulsion droplets of step (3) nano-particle that to be added to weight percent concentration be in 60% hydroxyapatite nanoparticle suspension or weight percent concentration is 50% and PVA surfactant and stirring, vortex or within ultrasonic 0.1-5 minute, form emulsion (O/O/S) emulsion;
(5) emulsion of step (4) is added drop-wise to curing 2-3 hour in 200-500ml Oleum Gossypii semen;
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying obtains microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, it is good that microsphere form is prepared in result demonstration, surface self-organization one deck silver nano-grain; The particle diameter of microsphere detects as shown in figure 16, and the particle diameter of microsphere is 1-500 μ m, mainly concentrates on 65 ± 18.54 μ m; As shown in figure 12, its release in vitro curve also meets the requirements the release in vitro curve of microsphere; Its drug effect as shown in figure 13; Microsphere prepared by itself and conventional method in vivo Experiment of Histocompatibility result as shown in Figure 5, result shows: within microsphere prepared by the non-nano suspension 3-6 after treatment month, there is fibrosis tissue; And the microsphere of preparing of nanosuspension is being treated the appearance (microencapsulation that is injection site does not occur, overcomes the generation of microencapsulation) that also there is no fibrous tissue after a year.
The preparation of embodiment 6 carmustines (BCNU) PLA-PEG microsphere
(1) 20mg carmustine is dissolved in the solution in 0.5ml dichloromethane (DCM);
(2) the ratio ultrasonic 1-5 minute of the dichloromethane solution of the PLA-PEG that is 10% said medicine solution and percent concentration taking weight ratio as 1:9 forms uniform oil phase;
(3) oil phase of step (2) is added drop-wise to also stirring in (4-10ml) in mineral oil, vortex or within ultrasonic 0.1-5 minute, forms emulsion (O/O) emulsion;
(4) in the suspension of the emulsion emulsion droplets of step (3) nano-particle that to be added to weight percent concentration be in 60% hydroxyapatite nanoparticle suspension or weight percent concentration is 50% and PVA surfactant and stirring, vortex or within ultrasonic 0.1-5 minute, form emulsion (O/O/S) emulsion;
(5) emulsion of step (4) is added drop-wise to curing 2-3 hour in 200-500ml Oleum Gossypii semen;
(6) centrifugal collection microsphere, and obtain microsphere after washing 3-5 time with ether, then vacuum drying obtains microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, it is good that microsphere form is prepared in result demonstration, surface self-organization one deck silver nano-grain; The particle diameter of microsphere detects as shown in figure 16, and the particle diameter of microsphere is 1-500 μ m, mainly concentrates on 65 ± 18.54 μ m; As shown in figure 14, its release in vitro curve also meets the requirements the release in vitro curve of microsphere; Its drug effect as shown in figure 15; Microsphere prepared by itself and conventional method in vivo Experiment of Histocompatibility result as shown in Figure 5, result shows: within microsphere prepared by the non-nano suspension 3-6 after treatment month, there is fibrosis tissue; And the microsphere of preparing of nanosuspension is being treated the appearance (microencapsulation that is injection site does not occur, overcomes the generation of microencapsulation) that also there is no fibrous tissue after a year.
Disclosed is above only several specific embodiments of the application, but the application is not limited thereto, and the changes that any person skilled in the art can think of, all should drop in the application's protection domain.
Claims (7)
1. nano-particle suspension bag oil-oil bag oil is prepared a method for microsphere, it is characterized in that, comprises the following steps:
(1) will be prepared into medicine oil solution by the ingredient of embedding; Wherein, the described ingredient by embedding is dissolved in organic solvent and forms described medicine oil solution, the described ingredient by embedding comprises the mixture of medicine or medicine and excipient substance;
(2) medicine oil solution is joined in the organic solution of polymer,, in oil phase, mix homogeneously forms suspension;
(3) suspension of step (2) is added drop-wise in mineral oil to stirring, vortex or ultrasonic formation emulsion emulsion;
(4) the emulsion emulsion droplets of step (3) is added in the suspension that contains nano-particle to stirring, vortex or ultrasonic formation microsphere, the described suspension that contains nano-particle is selected from the aqueous suspension of nano SiO 2 particle, the aqueous suspension of titanium dioxide, the aqueous suspension of hydroxyapatite nanoparticle, the aqueous suspension of ferroferric oxide nano granules, the aqueous suspension of ferric oxide particle, the aqueous suspension of gold nano grain, the aqueous suspension of aluminium sesquioxide nano-particle, calcium carbonate nano granule, calcium phosphate nanoparticles, the aqueous suspension of magnesium carbonate nano-particle or magnesium hydroxide nanoparticles wherein one or more,
(5) microsphere of step (4) is distributed in Oleum Gossypii semen and solidifies;
(6) centrifugal collection microsphere, obtains the microsphere of surface self-organization nano-particle after dry, and the particle diameter of described microsphere is 1-500 μ m, and wherein, the percentage by weight of medicine is 0.01-20%; The percentage by weight of nano-particle is 0.01-20%; The percentage by weight of polymer is 20-99.98%; Pharmaceutic adjuvant is 0-30%.
2. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil is prepared the method for microsphere, it is characterized in that, described medicine comprises small-molecule drug and macromolecular drug; Described small-molecule drug comprises chemicals; Described macromolecular drug comprises biopharmaceutical macromolecular drug, and described biopharmaceutical macromolecular drug is selected from protein macromolecule medicine, vaccine or nucleic acid.
3. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil is prepared the method for microsphere, it is characterized in that, described pharmaceutic adjuvant is selected from one or more in little saccharide, polyhydroxy compounds, polysaccharide compound, amino-acid compound or inorganic salts material; Described little saccharide is selected from one or more in sucrose, trehalose, glucose, maltose or lactose; Described polyhydroxy compounds is selected from one or more in mannitol, sorbitol, glycerol, 1,2-PD, erythritol, Polyethylene Glycol, polyvinyl alcohol, poly(ethylene oxide) or polypyrrole alkane ketone; Described polysaccharide compound is selected from one or more in glucosan, sodium alginate, chitosan, starch, cellulose or cyclodextrin material.
4. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil is prepared the method for microsphere; it is characterized in that, the described organic solvent in step (1) is selected from the wherein a kind of of dimethyl sulfoxide, dichloromethane, ethanol, acetonitrile, ethyl acetate, methanol or glycerol.
5. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil is prepared the method for microsphere; it is characterized in that; the organic solution that the oil phase of described step (2) is polymer, described polymer is selected from one or more in polycaprolactone, polylactic acid, poly lactic-co-glycolic acid, polylactic acid-polyglycol, PLGA-Polyethylene Glycol or polycaprolactone-polyethylene glycol.
6. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil is prepared the method for microsphere, it is characterized in that, described in contain nano-particle suspension in the weight percent concentration of nano-particle be 1%-80%.
7. a sustained-release micro-spheres, is characterized in that, comprises the microsphere that contains medicine, polymer and pharmaceutic adjuvant and covers the nano-particle on microsphere surface, wherein,
The percentage by weight of medicine is 0.01-20%;
The percentage by weight of nano-particle is 0.01-20%;
The percentage by weight of polymer is 20-99.98%;
Pharmaceutic adjuvant is 0-30%;
The preparation method of described sustained-release micro-spheres comprises the following steps:
(1) will be prepared into medicine oil solution by the ingredient of embedding; Wherein, the described ingredient by embedding is dissolved in organic solvent and forms described medicine oil solution, the described ingredient by embedding comprises the mixture of medicine or medicine and excipient substance;
(2) medicine oil solution is joined in the organic solution of polymer,, in oil phase, mix homogeneously forms suspension;
(3) suspension of step (2) is added drop-wise in mineral oil to stirring, vortex or ultrasonic formation emulsion emulsion;
(4) the emulsion emulsion droplets of step (3) is added in the suspension that contains nano-particle to stirring, vortex or ultrasonic formation microsphere, the described suspension that contains nano-particle is selected from the aqueous suspension of nano SiO 2 particle, the aqueous suspension of titanium dioxide, the aqueous suspension of hydroxyapatite nanoparticle, the aqueous suspension of ferroferric oxide nano granules, the aqueous suspension of ferric oxide particle, the aqueous suspension of gold nano grain, the aqueous suspension of aluminium sesquioxide nano-particle, calcium carbonate nano granule, calcium phosphate nanoparticles, the aqueous suspension of magnesium carbonate nano-particle or magnesium hydroxide nanoparticles wherein one or more,
(5) microsphere of step (4) is distributed in Oleum Gossypii semen and solidifies;
(6) centrifugal collection microsphere, obtains the microsphere of surface self-organization nano-particle after dry, and the particle diameter of described microsphere is 1-500 μ m, and wherein, the percentage by weight of medicine is 0.01-20%; The percentage by weight of nano-particle is 0.01-20%; The percentage by weight of polymer is 20-99.98%; Pharmaceutic adjuvant is 0-30%.
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| EP3589218A4 (en) * | 2017-03-03 | 2020-12-09 | Regents of the University of Minnesota | Materials and treatments using piezoelectric embolic materials |
| CN107412164B (en) * | 2017-04-26 | 2020-10-20 | 温州医科大学附属口腔医院 | Preparation method of double-targeting drug-loaded nanoparticle lipid-polymer for osteoporosis |
| CN107281159B (en) * | 2017-06-29 | 2019-12-20 | 安徽大学 | Preparation method of sustained-release drug-loaded microcapsule with multilayer core-shell structure |
| CN107320770A (en) * | 2017-07-12 | 2017-11-07 | 江苏西宏生物医药有限公司 | One kind injection implant |
| CN108918448B (en) * | 2018-06-28 | 2020-10-02 | 河南省肿瘤医院 | Preparation method of nano-gold-based enhanced enzyme biosensing material |
| CN110339183B (en) * | 2019-06-21 | 2020-08-11 | 厦门大学 | Preparation method of cellulose-based poorly water-soluble or slightly water-soluble drug sustained-release microspheres |
| CN111388739B (en) * | 2020-01-06 | 2021-11-16 | 太原理工大学 | Nano silicon dioxide/decomposition enzyme/polycaprolactone composite microsphere and preparation method and application thereof |
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| CN102358783A (en) * | 2011-07-27 | 2012-02-22 | 武汉大学 | Preparation method of polystyrene/gold composite microspheres |
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