CN102895197A - 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) prepares 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 purposes, crude drug must be prepared into corresponding dosage form.For example, need long term administration but in vivo short medicine of half-life, should be prepared into the PLA(polylactic acid) dosage form; For the treatment of some tumors, need some drug targetings in focus, such as targeting 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 discharges magazine, 89 (2003) 167 – 177], the people such as Meng Shi have reported in the document and have utilized the W/O/W method that bovine serum albumin (BSA) and Ciclosporin A (CyA) are encapsulated in PLGA/PLA shell-nuclear microsphere.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 water miscible albumen in the gathering at this interface, causes envelop rate not high, and has incomplete release and prominent releasing.Morita T. etc. were " Journal of Controlled Release " (control 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 the method with oil-in-water-oil bag solid wraps in the albumen microcapsule in the 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 to use PVA, uses PEG instead at this piece document.But, still can not overcome the low shortcoming that reaches the caused local microencapsulation in hydrophobic surface and inflammation of envelop rate.
Summary of the invention
The object of the invention is to provide a kind of nano-particle suspension bag oil-oil bag oil prepare the method for microsphere, can not overcome the low technical matters that reach the caused local microencapsulation in hydrophobic surface and inflammation of envelop rate 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 low technical matters that reach the caused local microencapsulation in hydrophobic surface and inflammation of envelop rate to solve microsphere of the prior art.
The object of the invention is achieved through the following technical solutions:
A kind of nano-particle suspension bag oil-oil bag oil prepares the method for microsphere, may further comprise the steps:
(1) will be prepared into the medicine oil solution by the ingredient of embedding;
(2) the medicine oil solution is joined in the organic solution of polymer, namely in the oil phase, mix and evenly form suspension;
(3) suspension of step (2) is added drop-wise in the mineral oil stirring, vortex or ultrasonic formation emulsion emulsion;
(4) the emulsion emulsion droplets of step (3) is added in the suspension that contains nano-particle stirring, vortex or ultrasonic formation microsphere;
(5) microsphere of step (4) is distributed in the Oleum Gossypii semen solidifies;
(6) centrifugal collection microsphere obtains the microsphere of surface self-organization nano-particle after the drying.
Preferably, 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 the lactose; Described polyhydroxy compounds comprises in mannitol, sorbitol, glycerol, 1,2-PD, erythritol, Polyethylene Glycol, polyvinyl alcohol, poly(ethylene oxide) or the polypyrrole alkane ketone one or more; Described polysaccharide compound comprises one or more in glucosan, sodium alginate, chitosan, starch, cellulose or the cyclodextrin material; Described amino-acid compound comprises one or more in glycine, lysine, arginine, glutamic acid or the histidine; Described inorganic salts material comprises one or more in zinc salt, calcium salt, mantoquita, magnesium salt or the molybdenum salt.
Preferably, step (1) further comprises: described ingredient by embedding is dissolved into forms the medicine oil solution in the organic solvent, described organic solvent is selected from the wherein a kind of of dimethyl sulfoxide, dichloromethane, ethanol, acetonitrile, ethyl acetate, methanol or glycerol.
Preferably, the oil phase of described step (2) is the organic solution of polymer, and described polymer is selected from one or more in polycaprolactone, polylactic acid, poly lactic-co-glycolic acid, polylactic acid-polyglycol, PLGA-Polyethylene Glycol or the polycaprolactone-polyethylene glycol.
Preferably, the organic solution of described polymer is for adding 0.1-20%(w/w in polymer) Polyethylene Glycol or poloxamer; Or for polymer is dissolved in the solution that forms in dichloromethane, ethyl acetate, acetonitrile, heptane, chloroform or the acetone.
Preferably, the weight percent concentration of nano-particle is 1%-80% in the described suspension that contains nano-particle.
Preferably, the described suspension that contains nano-particle 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, 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, aluminium sesquioxide nano-particle aqueous suspension, calcium carbonate nano granule, calcium phosphate nanoparticles, magnesium carbonate nano-particle or magnesium hydroxide nanoparticles 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 of aqueous suspension, nano-particle and poly-sorbic alcohol ester of aqueous suspension, nano-particle and poloxamer of aqueous suspension, nano-particle and polyvinylpyrrolidone of aqueous suspension, nano-particle and Polyethylene Glycol of nano-particle and polyvinyl alcohol or the aqueous suspension of nano-particle and tween.
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 the 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.
Description of drawings
Fig. 1 is that (A is the scanning electron microscope (SEM) photograph of microsphere for the scanning electron microscope (SEM) photograph 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 and the microsphere of conventional method preparation Experiment of Histocompatibility result schematic diagram in vivo;
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.
The specific embodiment
The below elaborates to embodiments of the invention, and embodiments of the invention are implemented under take technical solution of the present invention as prerequisite, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Nano-particle suspension bag oil of the present invention-oil bag oil (O/O/S) prepares the method for microsphere, and concrete operations are as follows.
(1) mixture with small-molecule drug or small-molecule drug and pharmaceutic adjuvant is prepared into the 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 the derivant thereof.) or antibiotics (can be selected from ciclosporin, levofloxacin, ofloxacin or epinastine hydrochloride; Or polypeptide drug, as receiving in peptide or the octreotide etc. one or more in the 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 the histidine.
(2) the medicine oil solution is joined in the organic solution of polymer, namely in the oil phase, mix and evenly form suspension, be i.e. oily (O/O) emulsion of oil bag.
(3) suspension of step (2) is added drop-wise in the mineral oil stirring, vortex or ultrasonic 0.1-5 minute formation emulsion emulsion.
(4) the emulsion emulsion droplets that step (3) is 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 in the 200-500ml Oleum Gossypii semen solidified 2-3 hour.
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying gets microsphere.
The microsphere of this method preparation can needing be used for the disease of long-term treatment, especially needs the blood vessel embolism microsphere of 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 prominently released very littlely, and almost do not have 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.
(1) the 20mg amycin is dissolved in the solution in the 0.5ml dimethyl sulfoxide (DMSO);
(2) be said medicine solution and percent concentration that the ratio of dichloromethane solution take weight ratio as 1:9 of 0.1% PLGA formed even oil phase in ultrasonic 1-5 minute;
(3) oil phase of step (2) is added drop-wise in the mineral oil (4-10ml) stirring, vortex or ultrasonic 0.1-5 minute formation emulsion (O/O) emulsion;
(4) to be added to weight percent concentration be in 1% the titania nanoparticles suspension or weight percent concentration is in the suspension of 20% nano-particle and PVA surfactant and stirring, vortex or formed emulsion (O/O/S) emulsion in ultrasonic 0.1-5 minute the emulsion emulsion droplets of step (3);
(5) the emulsion emulsion droplets of step (4) is added in the 200-500ml Oleum Gossypii semen solidified 2-3 hour;
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying gets microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, the result shows that preparation microsphere form is good, 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; The release in vitro curve of microsphere as shown in Figure 2, its release in vitro curve also meets the requirements; Its antibacterial effect as shown in Figure 3; Anticancer effect as shown in Figure 4; The microsphere of itself and conventional method preparation in vivo the Experiment of Histocompatibility result as shown in Figure 5, the result shows: the fibrosis tissue appears in the 3-6 of microsphere after treatment month of non-nano suspension preparation; And the preparation microsphere of nanosuspension does not have the appearance (microencapsulation that is the injection site does not occur, and overcomes the generation of microencapsulation) of fibrous tissue yet after 1 year in treatment.
Embodiment receives 2 Ethiopias peptide poly lactic-co-glycolic acid (PLGA) microsphere preparation
(1) the 20mg Ethiopia is received peptide and 10mg Polyethylene Glycol (PEG molecular weight 6000) and is dissolved in the solution in the 0.5ml dimethyl sulfoxide (DMSO);
(2) be said medicine solution and percent concentration that the ratio of dichloromethane solution take weight ratio as 1:9 of 10% PLGA formed uniform oil phase in ultrasonic 1-5 minute;
(3) oil phase of step (2) is added drop-wise in the mineral oil (4-10ml) stirring, vortex or ultrasonic 0.1-5 minute formation emulsion (O/O) emulsion;
(4) to be added to weight percent concentration be in 60% the hydroxyapatite nanoparticle suspension or weight percent concentration is in the suspension of 30% nano-particle and PVA surfactant and stirring, vortex or formed emulsion (O/O/S) emulsion in ultrasonic 0.1-5 minute the emulsion droplets of step (3);
(5) the emulsion emulsion droplets of step (4) is added in the 200-500ml Oleum Gossypii semen solidified 2-3 hour;
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying gets microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, the result shows that preparation microsphere form is good, 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; The release in vitro curve of microsphere as shown in Figure 6, its release in vitro curve also meets the requirements; Its drug effect as shown in Figure 7; The microsphere of itself and conventional method preparation in vivo the Experiment of Histocompatibility result as shown in Figure 5, the result shows: the fibrosis tissue appears in the 3-6 of microsphere after treatment month of non-nano suspension preparation; And the preparation microsphere of nanosuspension does not have the appearance (microencapsulation that is the injection site does not occur, and overcomes the generation of microencapsulation) of fibrous tissue yet after 1 year in treatment.
The preparation of embodiment 3 octreotide poly lactic-co-glycolic acid (PLGA) microspheres
(1) the 20mg octreotide is dissolved in the solution in the 0.5ml dimethyl sulfoxide (DMSO);
(2) be said medicine solution and percent concentration that the ratio of dichloromethane solution take weight ratio as 1:9 of 20% PLGA formed uniform oil phase in ultrasonic 1-5 minute;
(3) oil phase of step (2) is added drop-wise to also stirring in (4-10ml) in the mineral oil, vortex or formed emulsion (O/O) emulsion in ultrasonic 0.1-5 minute;
(4) to be added to weight percent concentration be in 80% the hydroxyapatite nanoparticle suspension or weight percent concentration is in the suspension of 50% nano-particle and PVA surfactant and stirring, vortex or formed emulsion (O/O/S) emulsion in ultrasonic 0.1-5 minute the emulsion emulsion droplets of step (3);
(5) emulsion of step (4) is added drop-wise in the 200-500ml Oleum Gossypii semen solidified 2-3 hour;
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying gets microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, the result shows that preparation microsphere form is good, 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; The release in vitro curve of microsphere as shown in Figure 8, its release in vitro curve also meets the requirements; Its drug effect as shown in Figure 9; The microsphere of itself and conventional method preparation in vivo the Experiment of Histocompatibility result as shown in Figure 5, the result shows: the fibrosis tissue appears in the 3-6 of microsphere after treatment month of non-nano suspension preparation; And the preparation microsphere of nanosuspension does not have the appearance (microencapsulation that is the injection site does not occur, and overcomes the generation of microencapsulation) of fibrous tissue yet after 1 year in treatment.
The preparation of embodiment 4 carmustines (BCNU) polylactic acid (PLA) microsphere
(1) the 20mg carmustine is dissolved in the solution in the 0.5ml dichloromethane (DCM);
(2) be said medicine solution and percent concentration that the ratio of dichloromethane solution take weight ratio as 1:9 of 10% PLGA formed uniform oil phase in ultrasonic 1-5 minute;
(3) oil phase of step (2) is added drop-wise to also stirring in (4-10ml) in the mineral oil, vortex or formed emulsion (O/O) emulsion in ultrasonic 0.1-5 minute;
(4) to be added to weight percent concentration be in 60% the hydroxyapatite nanoparticle suspension or weight percent concentration is in the suspension of 50% nano-particle and PVA surfactant and stirring, vortex or formed emulsion (O/O/S) emulsion in ultrasonic 0.1-5 minute the emulsion emulsion droplets of step (3);
(5) emulsion of step (4) is added drop-wise in the 200-500ml Oleum Gossypii semen solidified 2-3 hour;
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying gets microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, the result shows that preparation microsphere form is good, 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; The release in vitro curve of microsphere as shown in figure 10, its release in vitro curve also meets the requirements; Its drug effect as shown in figure 11; The microsphere of itself and conventional method preparation in vivo the Experiment of Histocompatibility result as shown in Figure 5, the result shows: the fibrosis tissue appears in the 3-6 of microsphere after treatment month of non-nano suspension preparation; And the preparation microsphere of nanosuspension does not have the appearance (microencapsulation that is the injection site does not occur, and overcomes the generation of microencapsulation) of fibrous tissue yet after 1 year in treatment.
The preparation of embodiment 5 carmustines (BCNU) polylactic acid (PLA) microsphere
(1) the 20mg carmustine is dissolved in the solution in the 0.5ml dichloromethane (DCM);
(2) be said medicine solution and percent concentration that the ratio of dichloromethane solution take weight ratio as 1:9 of 10% PLA formed uniform oil phase in ultrasonic 1-5 minute;
(3) oil phase of step (2) is added drop-wise to also stirring in (4-10ml) in the mineral oil, vortex or formed emulsion (O/O) emulsion in ultrasonic 0.1-5 minute;
(4) to be added to weight percent concentration be in 60% the hydroxyapatite nanoparticle suspension or weight percent concentration is in the suspension of 50% nano-particle and PVA surfactant and stirring, vortex or formed emulsion (O/O/S) emulsion in ultrasonic 0.1-5 minute the emulsion emulsion droplets of step (3);
(5) emulsion of step (4) is added drop-wise in the 200-500ml Oleum Gossypii semen solidified 2-3 hour;
(6) centrifugal collection microsphere, and with ether washing 3-5 time, then vacuum drying gets microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, the result shows that preparation microsphere form is good, 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; The release in vitro curve of microsphere as shown in figure 12, its release in vitro curve also meets the requirements; Its drug effect as shown in figure 13; The microsphere of itself and conventional method preparation in vivo the Experiment of Histocompatibility result as shown in Figure 5, the result shows: the fibrosis tissue appears in the 3-6 of microsphere after treatment month of non-nano suspension preparation; And the preparation microsphere of nanosuspension does not have the appearance (microencapsulation that is the injection site does not occur, and overcomes the generation of microencapsulation) of fibrous tissue yet after 1 year in treatment.
The preparation of embodiment 6 carmustines (BCNU) PLA-PEG microsphere
(1) the 20mg carmustine is dissolved in the solution in the 0.5ml dichloromethane (DCM);
(2) be said medicine solution and percent concentration that the ratio of dichloromethane solution take weight ratio as 1:9 of 10% PLA-PEG formed uniform oil phase in ultrasonic 1-5 minute;
(3) oil phase of step (2) is added drop-wise to also stirring in (4-10ml) in the mineral oil, vortex or formed emulsion (O/O) emulsion in ultrasonic 0.1-5 minute;
(4) to be added to weight percent concentration be in 60% the hydroxyapatite nanoparticle suspension or weight percent concentration is in the suspension of 50% nano-particle and PVA surfactant and stirring, vortex or formed emulsion (O/O/S) emulsion in ultrasonic 0.1-5 minute the emulsion emulsion droplets of step (3);
(5) emulsion of step (4) is added drop-wise in the 200-500ml Oleum Gossypii semen solidified 2-3 hour;
(6) centrifugal collection microsphere, and with must microsphere after ether washing 3-5 time, then vacuum drying gets microsphere.
Prepare the scanning electron microscope (SEM) photograph of microsphere as shown in Figure 1, the result shows that preparation microsphere form is good, 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; The release in vitro curve of microsphere as shown in figure 14, its release in vitro curve also meets the requirements; Its drug effect as shown in figure 15; The microsphere of itself and conventional method preparation in vivo the Experiment of Histocompatibility result as shown in Figure 5, the result shows: the fibrosis tissue appears in the 3-6 of microsphere after treatment month of non-nano suspension preparation; And the preparation microsphere of nanosuspension does not have the appearance (microencapsulation that is the injection site does not occur, and overcomes the generation of microencapsulation) of fibrous tissue yet after 1 year in treatment.
Above disclosed only be several specific embodiments of the application, but the application is not limited thereto, the changes that any person skilled in the art can think of all should drop in the application's the protection domain.
Claims (11)
1. nano-particle suspension bag oil-oil bag oil prepares the method for microsphere, it is characterized in that, may further comprise the steps:
(1) will be prepared into the medicine oil solution by the ingredient of embedding;
(2) the medicine oil solution is joined in the organic solution of polymer, namely in the oil phase, mix and evenly form suspension;
(3) suspension of step (2) is added drop-wise in the mineral oil stirring, vortex or ultrasonic formation emulsion emulsion;
(4) the emulsion emulsion droplets of step (3) is added in the suspension that contains nano-particle stirring, vortex or ultrasonic formation microsphere;
(5) microsphere of step (4) is distributed in the Oleum Gossypii semen solidifies;
(6) centrifugal collection microsphere obtains the microsphere of surface self-organization nano-particle after the drying.
2. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil prepares the method for microsphere, it is characterized in that, described ingredient by embedding comprises the mixture of medicine or medicine and excipient substance.
3. a kind of nano-particle suspension bag oil as claimed in claim 2-oil bag oil prepares 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 comprises protein macromolecule medicine, vaccine, antibody, nucleic acid or liposome medicament.
4. a kind of nano-particle suspension bag oil as claimed in claim 2-oil bag oil prepares 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 the inorganic salts material.
5. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil prepares the method for microsphere; it is characterized in that; step (1) further comprises: described ingredient by embedding is dissolved into forms the medicine oil solution in the organic solvent, described organic solvent is selected from the wherein a kind of of dimethyl sulfoxide, dichloromethane, ethanol, acetonitrile, ethyl acetate, methanol or glycerol.
6. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil prepares the method for microsphere; it is characterized in that; the oil phase of described step (2) is the organic solution of polymer, and described polymer is selected from one or more in polycaprolactone, polylactic acid, poly lactic-co-glycolic acid, polylactic acid-polyglycol, PLGA-Polyethylene Glycol or the polycaprolactone-polyethylene glycol.
7. a kind of nano-particle suspension bag oil as claimed in claim 6-oil bag oil prepare the method for microsphere, it is characterized in that, the organic solution of described polymer is to add 0.1-20%(w/w in polymer) Polyethylene Glycol or poloxamer; Or for polymer is dissolved in the solution that forms in dichloromethane, ethyl acetate, acetonitrile, heptane, chloroform or the acetone.
8. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil prepares the method for microsphere, it is characterized in that, the weight percent concentration of nano-particle is 1%-80% in the described suspension that contains nano-particle.
9. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil prepares the method for microsphere; it is characterized in that, the described suspension that contains nano-particle 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.
10. a kind of nano-particle suspension bag oil as claimed in claim 1-oil bag oil prepares the method for microsphere, it is characterized in that, the particle diameter of described microsphere is 1-500 μ m.
11. a sustained-release micro-spheres is characterized in that, comprises microsphere and the nano-particle that covers the microsphere surface, 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%.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103751856A (en) * | 2014-01-22 | 2014-04-30 | 同济大学 | Polylactic acid embolism microsphere with good dispersity |
| CN105764338A (en) * | 2013-08-30 | 2016-07-13 | 大阪燃气化学有限公司 | Extended release particles, method for producing same, molding material and molded article |
| CN107281159A (en) * | 2017-06-29 | 2017-10-24 | 安徽大学 | A kind of preparation method of the sustained release drug-loading microcapsule with multi-layer 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 |
| CN107412164A (en) * | 2017-04-26 | 2017-12-01 | 温州医科大学附属口腔医院 | A kind of double targeted medicament carrying nano particle lipopolymer preparation methods for osteoporosis |
| CN105764338B (en) * | 2013-08-30 | 2018-02-09 | 大阪燃气化学有限公司 | Slow release particle, its manufacture method, moulding material and products formed |
| CN108918448A (en) * | 2018-06-28 | 2018-11-30 | 河南省肿瘤医院 | A kind of preparation method based on the enhanced enzyme biological sensing material of nanogold |
| CN110339183A (en) * | 2019-06-21 | 2019-10-18 | 厦门大学 | A kind of cellulose base shipwreck is molten or the preparation method of microsolubility medicament slow-release microsphere |
| CN110753520A (en) * | 2017-03-03 | 2020-02-04 | 明尼苏达大学校董事会 | Materials and treatments using piezoelectric embolic materials |
| CN111388739A (en) * | 2020-01-06 | 2020-07-10 | 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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| CN101618208A (en) * | 2008-06-30 | 2010-01-06 | 江苏先声药物研究有限公司 | Method for preparing sustained-release microspheres containing micronized recombinant human vascular endothelial inhibin |
| CN102358783A (en) * | 2011-07-27 | 2012-02-22 | 武汉大学 | Preparation method of polystyrene/gold composite microspheres |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105764338A (en) * | 2013-08-30 | 2016-07-13 | 大阪燃气化学有限公司 | Extended release particles, method for producing same, molding material and molded article |
| CN105764338B (en) * | 2013-08-30 | 2018-02-09 | 大阪燃气化学有限公司 | Slow release particle, its manufacture method, moulding material and products formed |
| CN103751856B (en) * | 2014-01-22 | 2015-07-29 | 同济大学 | A kind of polylactic acid embolism microsphere with good dispersion |
| CN103751856A (en) * | 2014-01-22 | 2014-04-30 | 同济大学 | Polylactic acid embolism microsphere with good dispersity |
| CN110753520A (en) * | 2017-03-03 | 2020-02-04 | 明尼苏达大学校董事会 | Materials and treatments using piezoelectric embolic materials |
| US11890045B2 (en) | 2017-03-03 | 2024-02-06 | Regents Of The University Of Minnesota | Materials and treatments using piezoelectric embolic materials |
| CN107412164A (en) * | 2017-04-26 | 2017-12-01 | 温州医科大学附属口腔医院 | A kind of double targeted medicament carrying nano particle lipopolymer preparation methods for osteoporosis |
| 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 |
| CN107281159A (en) * | 2017-06-29 | 2017-10-24 | 安徽大学 | A kind of preparation method of the sustained release drug-loading microcapsule with multi-layer core-shell structure |
| 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 |
| CN108918448A (en) * | 2018-06-28 | 2018-11-30 | 河南省肿瘤医院 | A kind of preparation method based on the enhanced enzyme biological sensing material of nanogold |
| CN110339183A (en) * | 2019-06-21 | 2019-10-18 | 厦门大学 | A kind of cellulose base shipwreck is molten or the preparation method of microsolubility medicament slow-release microsphere |
| CN111388739A (en) * | 2020-01-06 | 2020-07-10 | 太原理工大学 | Nano silicon dioxide/decomposition enzyme/polycaprolactone composite microsphere and preparation method and application thereof |
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