CN1676121A - Slow-release micro-ball formulation for tissue, organ local therapy, and its preparing method and use - Google Patents
Slow-release micro-ball formulation for tissue, organ local therapy, and its preparing method and use Download PDFInfo
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- CN1676121A CN1676121A CN 200410029829 CN200410029829A CN1676121A CN 1676121 A CN1676121 A CN 1676121A CN 200410029829 CN200410029829 CN 200410029829 CN 200410029829 A CN200410029829 A CN 200410029829A CN 1676121 A CN1676121 A CN 1676121A
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Abstract
The present invention provides a slowly-released microsphere preparation for locally curing focus of human anticular cavity, eye, skin, tumor tissue, lymph tissue and brain, heart, liver, spleen, lung and kidney, etc. The average grain size of said slowly-released microsphere is less than 20 micrometers. Said microsphere paparation container active medicine, medicinal high-molecular auxiliary material which can be bio-degraded and has biological compatibility and other pharmaceutically acceptable additive. Said invention also provides the concrete steps of its preparation process.
Description
Technical field
The present invention relates to the sustained release microsphere agents that a class is used for focus topical therapeutics such as human synovial chamber, eyes, skin, tumor tissues, lymphoid tissue and brain, the heart, liver, spleen, lung, kidney, and its production and application.The medicine that is applicable to this class preparation comprises all kinds of antitumor drug, steroidal class or non-steroidal anti-inflammatory drug, hormone and relevant agonist or antagonist thereof, the treatment dermatosis treating medicine, treatment nervous system disease medicine, enzyme, cytokine and antibiotic or antiviral class medicine are as paclitaxel and derivant thereof, platinum complexes, carmustine class medicine, amycin, dexamethasone and derivant thereof, beclometasone and derivant thereof, triptolide and derivant thereof, galantamine, Huperzine A-Zhulin Antun, tissue plasminogen activator, epidermal growth factor and nerve growth factor etc.
Background technology
Existing each series antineoplastic medicament, steroidal class or non-steroidal anti-inflammatory drug, hormone and relevant agonist or antagonist, treatment dermatosis treating medicine, treatment nervous system disease medicine, enzyme, cytokine and antibiotic or antiviral class medicine etc. thereof exist the needs that exploitation has the preparation of more advantages.For example, the preparation of dexamethasone and derivant thereof or salt has tablet, capsule, injection, paster agent, vein emulsion etc.; These dosage forms or since half-life of dexamethasone shorter, cause eliminating very fast, or owing to non local use makes medicine on the low side and the whole body toxic and side effects is big in partial bioavailability; And the mean diameter of existing microball preparation, may produce grittiness and even produce friction when when local (as articular cavity, eye) uses all greater than 20 μ m, thus the exacerbate inflammation symptom.Therefore, press for a kind of being more suitable for of exploitation, make and when increasing patient compliance, improve bioavailability, reduce systemic toxic side effect in the drug-supplying system of topical therapeutics such as articular cavity, eye.The preparation of paclitaxel and derivant thereof is mainly injection, but now is used for the oil preparation mostly clinical formulation for paclitaxel is to use Cremopher EL (polyoxy ethyl Oleum Ricini+ethanol, each is 50% years old) to make.This pharmaceutical carrier can cause some side effect, comprising severe anaphylactic reaction.Therefore, selecting a kind of drug-supplying system of non-toxic efficient is the key of development paclitaxel clinical practice.
Summary of the invention
The purpose of this invention is to provide the be used for tissue of a kind of mean diameter less than 20 μ m, the sustained release microsphere agents of the local injection of organ topical therapeutic, it can be in the local long-time release of stablizing of focus, thereby the action time of prolong drug, reduce administration number of times, improve bioavailability of medicament, and the toxic and side effects of reduction medicine, simultaneously because microspherulite diameter is little, can significantly reduce local grittiness and friction stimulation, be suitable for local injection, be applied to the human synovial chamber, eyes, skin, tumor tissues, lymphoid tissue and brain, the heart, liver, spleen, lung, the topical therapeutic of kidney etc.
More particularly, the invention provides a kind of slow-release microshpere formulation for injection that is used for the topical therapeutic of tissue and/or organ, wherein contain one or more the active medicine that accounts for microsphere weight 0.2-40%, the molecular weight ranges that accounts for microsphere weight 60-99.8% is 5,000-100, biodegradable between 000 dalton and have the medicinal high polymer adjuvant of biocompatibility, and other pharmaceutically acceptable additives that account for microsphere weight 0-10.0%, described active medicine wraps up or is embedded in the biodegradable medicinal high polymer adjuvant, described active medicine is selected from antitumor drug, steroidal class or non-steroidal anti-inflammatory drug, hormone and relevant agonist or antagonist thereof, the treatment dermatosis treating medicine, treatment nervous system disease medicine, enzyme, cytokine and antibiotic or antiviral class medicine, preferably, described active medicine is selected from paclitaxel and derivant thereof, dexamethasone and derivant thereof, beclometasone and derivant thereof, triptolide and derivant thereof, galantamine, Huperzine A-Zhulin Antun, tissue plasminogen activator, epidermal growth factor and nerve growth factor.Described microsphere average grain diameter mainly is distributed in 1-20 μ m, and preferred mean diameter is less than 10 μ m.The envelop rate height of described active medicine, and local injection first day prominent behind the human body released very little.
Sustained release microsphere agents of the present invention is prepared into powder ampoule agent for injection when producing, organize after by medical personnel it being suspended in solvent for injection (being generally 5% mannitol solution that contains 0.2%-1% sodium carboxymethyl cellulose and 0-0.2% tween 80) before use, the organ local injection.
Active medicine in the preferred sustained release microsphere agents of the present invention is selected from paclitaxel and derivant thereof, the paclitaxel that comprises Ramulus et folium taxi cuspidatae terpene or derivatization, described preparation can be used for topical therapeutic ovarian cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma, gastric cancer, intestinal cancer, cerebroma and other entity cancers, also can be used for the topical therapeutic proliferative vitreoretinopathy.
Active medicine in the also preferred sustained release microsphere agents of the present invention is selected from dexamethasone and derivant, beclometasone and derivant thereof, betamethasone and derivant thereof, and described preparation is used for the inflammation of topical therapeutic articular cavity, eyes and liver spleen pulmonary.Wherein said dexamethasone and derivant thereof comprise dexamethasone acetate, dexamethasone sodium phosphate or Limethason.Wherein said beclometasone and derivant thereof comprise beclometasone and beclometasone propionic ester etc.Described betamethasone and derivant thereof comprise betamethasone and beclometasone sodium phosphate etc.
Active medicine in the also preferred sustained release microsphere agents of the present invention is selected from galantamine, Huperzine A-Zhulin Antun, and described preparation is used for the topical therapeutic Alzheimer.
Active medicine in the also preferred sustained release microsphere agents of the present invention is selected from tissue plasminogen activator, epidermal growth factor and nerve growth factor, and described preparation is used for topical therapeutic brain, neural muscular tissue's damage, blood stasis etc.
Can also comprise in the sustained release microsphere agents of the present invention that other pharmaceutically acceptable additives comprise cosolvent, stabilizing agent, antiseptic.
Used pharmaceutical polymers is selected from lactic acid/co-glycolic acid (PLGA), polylactic acid, polyglycolic acid, poly--the 3-butyric ester, Polyethylene Glycol/polybutylene terephthalate (PBT) (PEG/PBT), polyethylene terephthalate (PET), polybutylene terephthalate (PBT) (PBT), poly-adjacent ester, polylactone, polyanhydride, poly butyric ester-hydroxyl pentanoate copolymer, polypropylene glucosan, polylactic acid-polyglycol, polyglycolic acid-Polyethylene Glycol in the sustained release microsphere agents of the present invention, or their mixture.Preferably, medicinal high polymer adjuvant wherein is lactic acid/co-glycolic acid (PLGA).Preferably, its molecular weight of described lactic acid/co-glycolic acid (PLGA) is preferably 5, and 000-70 is between 000 dalton.Preferably, wherein the lactide of lactic acid/co-glycolic acid (PLGA) and Acetic acid, hydroxy-, bimol. cyclic ester polymerization ratio 10: 90-90: between 10.
The invention still further relates to the method for the described sustained release microsphere agents of preparation, it can adopt mon-galacta method preparation in emulsifying-solvent evaporation method, it is characterized in that using and active medicine and biodegradable medicinal high polymer adjuvant are dissolved in organic solvent are mixed with organic facies, described organic solvent is selected from: dichloromethane, chloroform, ethyl acetate, ethanol, methanol or acetone, and wherein the percetage by weight of high polymer adjuvant in organic solvent is 1-30%; Prepare continuous water in addition, nonionic emulsifier is soluble in water, they are 0.1-10% in the percetage by weight of aqueous phase, and described nonionic emulsifier is selected from polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium polyacrylate or sodium polymethacrylate; The step that mon-galacta method prepares microsphere is: medicine, high polymer adjuvant and other additive etc. are joined in dichloromethane or the mixed solvent, join after treating to dissolve fully in the continuous phase solution of the suitable concentration that stirs with per minute 400-5000 commentaries on classics (RPM), after forming emulsion, suitably dilute continuous phase solution, continuation is with lower speed stir about 4 hours, the volatilization organic solvent.Then, with 4000-10,000RPM is centrifugal, microsphere is collected in washing, carries out vacuum drying or lyophilization and promptly gets microsphere dry powder.Preferably, wherein used active medicine is the dexamethasone or derivatives thereof.When active medicine and biodegradable medicinal high polymer adjuvant are dissolved in organic solvent, can also add cosolvent, wherein said cosolvent is an isopropyl myristate, especially aptly, wherein said active medicine is paclitaxel or derivatives thereof, dexamethasone or derivatives thereof, triptolide.
The invention still further relates to the method for the described sustained release microsphere agents of another kind of preparation, it is to adopt the multi-emulsion method in emulsifying-solvent evaporation method to prepare, it is characterized in that medicine dissolution or be suspended in the aqueous solution that contains nonionic emulsifier, water in forming, wherein said emulsifying agent is selected from gelatin, sodium carboxymethyl cellulose, polyvinyl alcohol etc., and they are 0.1-10% in the percetage by weight of aqueous phase; In the organic solution with biodegradable medicinal high polymer adjuvant, used organic solvent is selected from dichloromethane, chloroform, ethyl acetate, ethanol, methanol or acetone; With the outer water of nonionic emulsifier preparation, preparing the nonionic emulsifier that outer water adopts is polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium polyacrylate, sodium polymethacrylate, they outside the percetage by weight of aqueous phase be 0.1-10%; The step that multi-emulsion method prepares microsphere is: with medicine dissolution or be suspended in the aqueous solution that contains above-mentioned nonionic emulsifier and make interior water; Interior water is joined carry out at a high speed in the solution of the dichloromethane that contains polymeric material or mixed solvent that (8,000-30 000RPM) stirs, and makes colostrum; Under the stirring at low speed colostric fluid is injected into the outer aqueous phase of preformulation, makes emulsion, suitably the outer aqueous phase solution of dilution continued stir about 4 hours, the volatilization organic solvent.Then, with 4000-10,000RPM is centrifugal, microsphere is collected in washing, carries out vacuum drying or lyophilization and promptly gets microsphere.Optimum ground, wherein used active medicine are galantamine or Huperzine A-Zhulin Antun or tissue plasminogen activator or epidermal growth factor or nerve growth factor.
Description of drawings
The particle size distribution of the taxol slow release microballoons of accompanying drawing 1: embodiment 1
The release in vitro curve of the taxol slow release microballoons of accompanying drawing 2: embodiment 1
The microspherulite diameter scattergram of the triptolide of accompanying drawing 3: embodiment 3
The particle size distribution of the dexamethasone acetate sustained-release micro-spheres of accompanying drawing 4: embodiment 4
The particle size distribution of the dexamethasone acetate sustained-release micro-spheres of accompanying drawing 5: embodiment 5
3 batches of dexamethasone acetate sustained-release micro-spheres of accompanying drawing 6: embodiment 4 carry out release in vitro degree result of the test respectively
The dexamethasone acetate sustained-release micro-spheres of accompanying drawing 7: embodiment 4 is in the intravital release test result of rabbit.By regulating dosage, can make microsphere reach stabilizing effective blood drug level in vivo, and can continue to discharge more than one month.
The particle size distribution figure of accompanying drawing 8: embodiment 8 carmustine sustained-release microspheres
The particle size distribution figure of accompanying drawing 9: embodiment 9 galantamine sustained-release micro-spheres
Accompanying drawing 10: embodiment 10 organizes the particle size distribution figure of fibrinolysin activator (TPA) sustained-release micro-spheres
The particle size distribution figure of accompanying drawing 11: embodiment 11 nerve growth factor (NGF) sustained-release micro-spheres
The particle size distribution figure of accompanying drawing 12: embodiment 12 betamethasone sustained-release micro-spheres
The particle size distribution figure of accompanying drawing 13: embodiment 13 ribavirin sustained-release micro-spheres
The specific embodiment
Further specify preparation method, particle diameter control, the prominent situation and the slow release effect released of local injection sustained-release micro-spheres of the present invention below by embodiment.
Embodiment 1: mon-galacta method prepares taxol slow release microballoons
Take by weighing 200mg (accounting for microsphere gross weight 10%) paclitaxel, accounted for microsphere gross weight 75%PLGA (75: 25, MW30000-40000) and 300mg isopropyl myristate (IPM) be dissolved in the 10ml dichloromethane, this solution is injected with the churned mechanically 200ml4% polyvinyl alcohol of 2500rpm (PVA) aqueous solution, with 2 times of this PVA solution dilutions, continue to stir more than 4 hours after 10 minutes.Wash afterwards, centrifugal, obtain microsphere after the lyophilization.The envelop rate of taxol slow release microballoons be 93.10%; The particle size range of thus obtained microsphere: 5～10 μ m, the profile rounding is uniformly dispersed.The gained result as shown in Figure 1.
Embodiment 2: paclitaxel microsphere extracorporeal releasing experiment
Will as the embodiment of the invention 1 prepared microballoon lyophilized powder 10 μ g of paclitaxel be dissolved in 10ml dissolution medium phosphate buffered solution (PBS, pH=7.4) in, 37 ℃ of horizontal joltings of constant temperature, timing sampling, HPLC measure to discharge the result.Taxol slow release microballoons release in vitro curve as shown in Figure 2.
Experimental technique: precision takes by weighing the about 10mg of laboratory sample, and the pH that places 10ml is 7.4 phosphate buffer solution, places constant temperature oscillator to keep uniform temperature and rotating speed, on time sampling.
Sampling method: the every time point of every batch sample is got sample respectively three times, takes out solution wherein, under the 3000rpm condition centrifugal 10 minutes, gets supernatant and carries out HPLC and measure.Sampling time point is respectively: 0 day, 1 day, 3 days, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days.
The gained result as shown in Figure 2.
Embodiment 3: mon-galacta method prepares the triptolide sustained-release micro-spheres
Take by weighing triptolide 200mg, accounted for microsphere gross weight 70%PLGA (50: 50, MW20000-30000) be dissolved among the ethyl acetate 10ml, this solution is injected with churned mechanically 6% polyvinyl alcohol of 2000rpm (PVA) 200ml, with 2 times of this PVA solution dilutions, continue to stir more than 4 hours after 10 minutes.Wash afterwards, centrifugal, obtain microsphere after the lyophilization.Mean diameter is less than 20 μ m.The gained result as shown in Figure 3.
Embodiment 4: mon-galacta method prepares the dexamethasone acetate microsphere
With the dexamethasone acetate of 500mg, contain the PLGA (75: 25 of microsphere gross weight 90%, MW15000-20000) be dissolved in methanol and the dichloromethane, this solution is added with among churned mechanically 3% polyvinyl alcohol of 2500rpm (PVA) the aqueous solution 500ml, after 10 minutes with 1 times of PVA solution dilution, continue to stir more than 4 hours, washing then, centrifugal, be drying to obtain.Mean diameter is less than 10 μ m.The gained result as shown in Figure 4.
Embodiment 5: multi-emulsion method prepares the dexamethasone acetate microsphere
500mg dexamethasone acetate is suspended in the 2ml aqueous gelatin solution, after (20000rpm) stirs at a high speed, join among the dichloromethane solution 10ml that contains microsphere gross weight 90%PLGA, with the rotating speed stirring and emulsifying of 5000rpm, join among the aqueous solution 500ml of 4% polyvinyl alcohol (PVA) stirring and emulsifying then and make emulsion, magnetic agitation 15 minutes, then with 3 times of PVA aqueous solution dilution dilutions, stirring was carried out solvent evaporates 5 hours, and washing, centrifugal, lyophilization then collected promptly.Mean diameter is less than 10 μ m.The gained result as shown in Figure 5.
Embodiment 6: the external release test of dexamethasone acetate sustained-release micro-spheres
Three batches of dexamethasone acetate sustained-release micro-spheres to embodiment carry out the test of release in vitro degree respectively, and the result as shown in Figure 6.
Laboratory sample: according to the microsphere described in the embodiment of the invention 4;
Experiment reagent: pH is 7.4 phosphate buffer;
Experiment condition: temperature: 37 ℃, rotating speed: 100rpm;
Experimental technique: precision takes by weighing the about 2mg of laboratory sample, and the pH that places 50ml is 7.4 phosphate buffer solution, draws 5ml respectively and be sub-packed in the ampoule under magnetic agitation, places constant temperature oscillator then, keeps certain temperature and rotating speed to take a sample on time;
Sampling method: the every time point of every batch sample is got 2 ampoules respectively, takes out solution wherein, under the 3000rpm condition centrifugal 10 minutes, gets supernatant and carries out HPLC and measure;
Sampling time point is respectively: 0 day, 10h, 1 day, 2 days, 7 days, 14 days, 21 days, 28 days, 35 days.
Embodiment 7: dexamethasone acetate sustained-release micro-spheres animal (rabbit) vivo releasing test of embodiment 4
Dexamethasone acetate sustained-release micro-spheres animal (rabbit) vivo releasing test shows that the dexamethasone acetate sustained-release micro-spheres can continue to discharge one month in animal body.The result as shown in Figure 7.The mensuration of microsphere release conditions in the rabbit body:
Laboratory sample: according to the microsphere described in the embodiment of the invention 4;
Experimental technique: the microsphere 100mg of sterilization is dissolved among the solvent 2ml that contains CMCNa, Tween 80 and mannitol, carry out injection under the rabbit, carrying out auricular vein respectively at 1.5h, 3h, 6h, 10h, 1d, 2d, 7d, 14d, 21d, 28d, 35d, 41d and get blood, is that interior mark carries out HPLC mensuration with the beclometasone propionic ester.
Embodiment 8: mon-galacta method prepares the carmustine microsphere
200mg carmustine, the PEG/PBT (MW15000-20000) that contains microsphere gross weight 90% are dissolved in methanol and the dichloromethane, this solution adding is carried out among the churned mechanically 3%PVA aqueous solution 500ml with the speed of 2500rpm, 10 minutes with 1 times of PVA solution dilution, continue to stir more than 4 hours, washing then, centrifugal, be drying to obtain.Mean diameter is less than 20 μ m.The result as shown in Figure 8.
Embodiment 9: multi-emulsion method prepares the galantamine microsphere
About 500mg galantamine is dissolved in the 4ml sodium carboxymethyl cellulose solution, join the PLGA that contains microsphere gross weight 85% (50: 50, MW20000-30000) among the chloroform soln 20ml, through at a high speed (20,000rpm) after the stirring and emulsifying, under the 1500rpm rotating speed stirs, join among the PVA aqueous solution 500ml of 6% concentration stirring and emulsifying and make emulsion, magnetic agitation is after 15 minutes, with 3 times of PVA dilutions, stir 3 hours solvent flashings, washing, centrifugal, lyophilization then collected promptly.Mean diameter is less than 20 μ m.The result as shown in Figure 9.
Embodiment 10: fibrinolysin activator (TPA) microsphere is organized in the multi-emulsion method preparation
Organize fibrinolysin activator (TPA) to be dissolved in the 2ml aqueous gelatin solution about 200mg, join then among the dichloromethane solution 10ml that contains microsphere gross weight 85%PLGA, after high speed (15000rpm) stirring and emulsifying, under the 2000rpm rotating speed stirs, join among the PVA aqueous solution 200ml of 5% concentration magnetic agitation 12 minutes, then with 2 times of PVA dilutions, continue to stir 5 hours solvent flashings, washing, centrifugal, lyophilization then collected promptly.Mean diameter is less than 15 μ m.The result as shown in Figure 10.
Embodiment 11: multi-emulsion method prepares nerve growth factor (NGF) microsphere
About 200mg nerve growth factor (NGF) is dissolved in the aqueous gelatin solution of 1.2ml, join among the chloroform soln 12ml that contains microsphere gross weight 85%PEG/PBT, after high speed (15000rpm) stirring and emulsifying, join among the PVA aqueous solution 300ml of 4% concentration, with 1000rpm rotating speed stirring and emulsifying, with 2 times of PVA solution dilutions, continue to stir 4 hours solvent flashings after 8 minutes, washing, centrifugal, lyophilization then collected promptly.Mean diameter is less than 15 μ m.The result as shown in Figure 11.
Embodiment 12: mon-galacta method prepares the betamethasone microsphere
With the about 300mg of betamethasone, contain the PLGA (50: 50 of microsphere gross weight 90%, MW20000-30000) be dissolved in methanol--in the chloroform 15, under with the rotating speed of 2500rpm with it to the PVA aqueous solution 150 of 5% concentration, stir after 8 minutes, with 2 times of PVA dilutions, continue to stir 5 hours, and carried out solvent evaporates, washing then, centrifugal, be drying to obtain.The particle size range 5-15 μ m of thus obtained microsphere.The result as shown in Figure 12.
Embodiment 13: multi-emulsion method prepares the ribavirin microsphere
The 500mg ribavirin is dissolved in the 2ml aqueous gelatin solution, join among the dichloromethane solution 25ml that contains microsphere gross weight 85%PLA, after high speed (15000rpm) stirring and emulsifying, under the 5000rpm rotating speed stirs, join among the PVA aqueous solution 500ml of 4% concentration magnetic agitation 10 minutes, then with 2 times of PVA aqueous solution dilutions, continue to stir 4 hours solvent flashings, washing, centrifugal, lyophilization then collected promptly.The gained particle size range is at 5～15 μ m.The result as shown in Figure 13.
More than among each embodiment, various assay methods are as follows respectively:
The mensuration of microspherulite diameter:
Laboratory sample: according to the microsphere of preparation in the embodiment of the invention 1,3,4,5,8,9,10,11,12,13
Experimental apparatus: inverted microscope;
Experimental technique: after above each batch microsphere disperseed with the aqueous solution that contains 0.2% Tween 80, having the mean diameter of observing microsphere under graduated 400 power microscopes, and carrying out statistical disposition, drawing the particle size distribution figure of microsphere.The result: the mean diameter of above each batch microsphere is all less than 20 μ m.
The mensuration of microsphere drug loading and envelop rate:
1, the microsphere drug loading among the embodiment 1,3 and the mensuration of envelop rate
Experimental technique: precision takes by weighing the about 3mg of laboratory sample, places the 3ml dichloromethane, adds acetonitrile: the mixed solution of water (1: 1), and vortex, centrifugal back adopts high performance liquid chromatograph to measure content of medicines, and calculates the drug loading and the envelop rate of microsphere.
2, the microsphere drug loading among the embodiment 4,5,8,12 and the mensuration of envelop rate
Experimental technique: precision takes by weighing the about 2mg of laboratory sample, place the volumetric flask of 10ml, add dichloromethane and alcoholic acid mixed solution (1: 1), vortex, ultraviolet first-derivative spectroscopy or determined by ultraviolet spectrophotometry content of medicines are adopted in centrifugal back, and calculate the drug loading and the envelop rate of microsphere.
3, the microsphere drug loading among the embodiment 9,10,11,13 and the determination experiment method of envelop rate: precision takes by weighing the about 3mg of test specimen, join in the 2ml acetonitrile-water (9: 1), ultrasonic dissolution, then after the dilute with water certain multiple, adopt fluorescence method or ultraviolet method to measure content of medicines, and calculate the drug loading and the envelop rate of microsphere.
Claims (20)
1. the slow-release microshpere formulation for injection that is used for the topical therapeutic of tissue and/or organ, wherein contain one or more the active medicine that accounts for microsphere weight 0.2-40%, the molecular weight ranges that accounts for microsphere weight 60-99.8% is 5,000-100, biodegradable between 000 dalton and have the medicinal high polymer adjuvant of biocompatibility, and other pharmaceutically acceptable additives that account for microsphere weight 0-10.0%, described active medicine wraps up or is embedded in the biodegradable medicinal high polymer adjuvant, described active medicine is selected from antitumor drug, steroidal class or non-steroidal anti-inflammatory drug, hormone and relevant agonist or antagonist thereof, the treatment dermatosis treating medicine, treatment nervous system disease medicine, enzyme, cytokine and antibiotic or antiviral class medicine, described microsphere average grain diameter mainly is distributed in 1-20 μ m.
2. according to the described sustained release microsphere agents of claim 1, wherein said active medicine is selected from paclitaxel and derivant, platinum complexes, carmustine class medicine, amycin, dexamethasone and derivant, beclometasone and derivant thereof, triptolide and derivant thereof, galantamine, Huperzine A-Zhulin Antun etc.
3. according to the described sustained release microsphere agents of claim 1, its mean diameter is less than 10 μ m.
4. according to the described sustained release microsphere agents of claim 2, wherein said active medicine is selected from paclitaxel and derivant (paclitaxel that comprises Ramulus et folium taxi cuspidatae terpene or derivatization) thereof, platinum medicine, carmustine class medicine, amycin, described preparation can be used for topical therapeutic ovarian cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma, gastric cancer, intestinal cancer, cerebroma and other solid tumors, and wherein paclitaxel and derivant etc. thereof also can be used for the topical therapeutic proliferative vitreoretinopathy.
5. according to the described sustained release microsphere agents of claim 2, wherein said active medicine is selected from dexamethasone and derivant, beclometasone and derivant thereof, betamethasone and derivant thereof, and described preparation is used for the inflammation of topical therapeutic articular cavity, eyes and liver spleen pulmonary.
6. according to the described sustained release microsphere agents of claim 5, wherein said dexamethasone and derivant thereof comprise dexamethasone acetate, dexamethasone sodium phosphate or Limethason.
7. according to the described sustained release microsphere agents of claim 5, wherein said beclometasone and derivant thereof comprise beclometasone and beclometasone propionic ester etc.
8. according to the described sustained release microsphere agents of claim 5, wherein said betamethasone and derivant thereof comprise betamethasone and beclometasone sodium phosphate etc.
9. according to the described sustained release microsphere agents of claim 2, wherein said active medicine is selected from galantamine or Huperzine A-Zhulin Antun, and described preparation is used for the topical therapeutic Alzheimer.
10. according to the described sustained release microsphere agents of claim 2, wherein said other pharmaceutically acceptable additives comprise cosolvent, stabilizing agent, antiseptic.
11. according to each described sustained release microsphere agents of claim 1-9, wherein said pharmaceutical polymers is selected from lactic acid/co-glycolic acid, polylactic acid, polyglycolic acid, poly--the 3-butyric ester, Polyethylene Glycol/polybutylene terephthalate (PBT), polyethylene terephthalate, polybutylene terephthalate (PBT), poly-adjacent ester, polylactone, polyanhydride, poly butyric ester-hydroxyl pentanoate copolymer, polypropylene glucosan, polylactic acid-polyglycol, polyglycolic acid-Polyethylene Glycol, or their mixture.
12. according to the described sustained-release micro-spheres of claim 9, medicinal high polymer adjuvant wherein is a polylactide-co-glycolide.
13. according to the described sustained-release micro-spheres of claim 10, its molecular weight of wherein said polylactide-co-glycolide is 5,000-70 is between 000 dalton.
14. according to the described sustained-release micro-spheres of claim 10, wherein the lactide of polylactide-co-glycolide and Acetic acid, hydroxy-, bimol. cyclic ester polymerization ratio are 40: 60-80: between 20.
15. prepare the method for each described sustained-release micro-spheres of claim 1-12, it is to adopt the mon-galacta method in emulsifying-solvent evaporation method to prepare, it is characterized in that using and active medicine and biodegradable medicinal high polymer adjuvant are dissolved in organic solvent are mixed with organic facies, described organic solvent is selected from: dichloromethane, chloroform, ethyl acetate, ethanol, methanol or acetone, and wherein the percetage by weight of high polymer adjuvant in organic solvent is 1-30%; Prepare continuous water in addition, nonionic emulsifier is soluble in water, they are 0.1-10% in the percetage by weight of aqueous phase, and described nonionic emulsifier is selected from polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium polyacrylate or sodium polymethacrylate; The step that mon-galacta method prepares microsphere is: medicine, high polymer adjuvant and other additive etc. are joined in dichloromethane or the mixed solvent, joining after treating to dissolve fully with per minute 400-5000 changes in the continuous phase solution of the suitable concentration that stirs, after continuing to stir the formation emulsion, continuous phase solution is diluted 2-6 doubly, with lower speed stir about 4 hours, the volatilization organic solvent.Then, with 4000-10,000RPM is centrifugal, microsphere is collected in washing, carries out vacuum drying or lyophilization and promptly gets microsphere dry powder.
16. in accordance with the method for claim 13, wherein said active medicine is the dexamethasone or derivatives thereof.
17. in accordance with the method for claim 12, wherein when active medicine and biodegradable medicinal high polymer adjuvant are dissolved in organic solvent, add cosolvent.
18. in accordance with the method for claim 15, wherein said cosolvent is an isopropyl myristate.
19. in accordance with the method for claim 16, wherein said active medicine is the paclitaxel or derivatives thereof.
20. prepare the method for each described sustained-release micro-spheres of claim 1-12, it is to adopt the multi-emulsion method in emulsifying-solvent evaporation method to prepare, it is characterized in that medicine dissolution or be suspended in the aqueous solution that contains nonionic emulsifier, water in forming, wherein said emulsifying agent is selected from gelatin, sodium carboxymethyl cellulose, polyvinyl alcohol etc., and they are 0.1-10% in the percetage by weight of aqueous phase; In the organic solution with biodegradable medicinal high polymer adjuvant, used organic solvent is selected from dichloromethane, chloroform, ethyl acetate, ethanol, methanol or acetone; With the outer water of nonionic emulsifier preparation, preparing the nonionic emulsifier that outer water adopts is polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium polyacrylate, sodium polymethacrylate, they outside the percetage by weight of aqueous phase be 0.1-10%; The step that multi-emulsion method prepares microsphere is: with medicine dissolution or be suspended in the aqueous solution that contains above-mentioned nonionic emulsifier and form interior water; Interior water is joined carry out at a high speed in the solution of the dichloromethane that contains polymeric material or mixed solvent that (8,000-30 000RPM) stirs, and forms colostrum; Colostric fluid is joined above-mentioned outer aqueous phase, to stir the formation emulsion than low velocity, about 4 hours of continuous stirring, volatilization organic solvent.Then, with 4000-10,000RPM is centrifugal, microsphere is collected in washing, carries out vacuum drying or lyophilization and promptly gets microsphere.In accordance with the method for claim 18, wherein said active medicine is the dexamethasone or derivatives thereof.
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1965839B (en) * | 2005-11-15 | 2010-11-10 | 上海医药工业研究院 | Sustained release microsphere of finasteride and its analogue, preparation process and use thereof |
| CN101292960B (en) * | 2006-04-29 | 2011-02-09 | 中国人民解放军军事医学科学院毒物药物研究所 | Sustained-release microsphere containing risperidone and preparation method thereof |
| CN1927183B (en) * | 2006-09-18 | 2012-10-17 | 厦门大学 | Antineoplasma medicine pidorubicin slow release microsphere preparation and method for preparing same |
| CN104382858A (en) * | 2014-10-28 | 2015-03-04 | 中国人民解放军第三军医大学 | Preparation method of oxymatrine/polylactic acid microspheres |
| CN104548210A (en) * | 2014-12-13 | 2015-04-29 | 浙江大学 | Controlled-release PLGA microsphere containing dexamethasone transforming growth factor and preparation method of controlled-release PLGA microsphere |
| CN105616359A (en) * | 2016-03-16 | 2016-06-01 | 四川大学 | Multi-block polymer nanofiber drug carrying microsphere and preparation method thereof |
| CN107412859A (en) * | 2017-04-26 | 2017-12-01 | 温州医科大学附属口腔医院 | A kind of preparation method of the tissue engineering bracket material of dual-gene timing sustained release |
| CN110141559A (en) * | 2019-06-18 | 2019-08-20 | 浦易（上海）生物技术有限公司 | It is a kind of for the pastille slow-release particle of schneiderian membrane and its application |
| CN111012761A (en) * | 2019-12-24 | 2020-04-17 | 中南大学湘雅医院 | Drug-loaded microsphere, anti-tumor drug and preparation method |
| CN111643483A (en) * | 2020-07-06 | 2020-09-11 | 济南大学 | Novel method for preparing galanthamine sustained-release microspheres |
| CN111714471A (en) * | 2020-06-15 | 2020-09-29 | 广东省医疗器械研究所 | Polymer microsphere for pulmonary drug delivery and preparation method and application thereof |
| CN112823792A (en) * | 2019-11-20 | 2021-05-21 | 鲁南制药集团股份有限公司 | Galanthamine pamoate sustained-release microspheres for injection and preparation method thereof |
| CN113384536A (en) * | 2020-03-14 | 2021-09-14 | 鲁南制药集团股份有限公司 | Galanthamine pamoate sustained-release particles for injection and preparation method thereof |
| CN114342930A (en) * | 2022-03-01 | 2022-04-15 | 中国农业科学院植物保护研究所 | Pesticide nanocapsule and preparation method thereof |
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2004
- 2004-03-29 CN CN 200410029829 patent/CN1676121A/en active Pending
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1965839B (en) * | 2005-11-15 | 2010-11-10 | 上海医药工业研究院 | Sustained release microsphere of finasteride and its analogue, preparation process and use thereof |
| CN101292960B (en) * | 2006-04-29 | 2011-02-09 | 中国人民解放军军事医学科学院毒物药物研究所 | Sustained-release microsphere containing risperidone and preparation method thereof |
| CN1927183B (en) * | 2006-09-18 | 2012-10-17 | 厦门大学 | Antineoplasma medicine pidorubicin slow release microsphere preparation and method for preparing same |
| CN104382858A (en) * | 2014-10-28 | 2015-03-04 | 中国人民解放军第三军医大学 | Preparation method of oxymatrine/polylactic acid microspheres |
| CN104382858B (en) * | 2014-10-28 | 2017-04-26 | 中国人民解放军第三军医大学 | Preparation method of oxymatrine/polylactic acid microspheres |
| CN104548210A (en) * | 2014-12-13 | 2015-04-29 | 浙江大学 | Controlled-release PLGA microsphere containing dexamethasone transforming growth factor and preparation method of controlled-release PLGA microsphere |
| CN105616359A (en) * | 2016-03-16 | 2016-06-01 | 四川大学 | Multi-block polymer nanofiber drug carrying microsphere and preparation method thereof |
| CN107412859B (en) * | 2017-04-26 | 2020-07-14 | 温州医科大学附属口腔医院 | Preparation method of double-gene time-sequence slow-release tissue engineering scaffold material |
| CN107412859A (en) * | 2017-04-26 | 2017-12-01 | 温州医科大学附属口腔医院 | A kind of preparation method of the tissue engineering bracket material of dual-gene timing sustained release |
| CN110141559A (en) * | 2019-06-18 | 2019-08-20 | 浦易（上海）生物技术有限公司 | It is a kind of for the pastille slow-release particle of schneiderian membrane and its application |
| CN112823792A (en) * | 2019-11-20 | 2021-05-21 | 鲁南制药集团股份有限公司 | Galanthamine pamoate sustained-release microspheres for injection and preparation method thereof |
| CN112823792B (en) * | 2019-11-20 | 2023-07-14 | 鲁南制药集团股份有限公司 | Sustained release microsphere of galanthamine pamoate for injection and preparation method thereof |
| CN111012761A (en) * | 2019-12-24 | 2020-04-17 | 中南大学湘雅医院 | Drug-loaded microsphere, anti-tumor drug and preparation method |
| CN113384536A (en) * | 2020-03-14 | 2021-09-14 | 鲁南制药集团股份有限公司 | Galanthamine pamoate sustained-release particles for injection and preparation method thereof |
| WO2021184610A1 (en) * | 2020-03-14 | 2021-09-23 | 山东新时代药业有限公司 | Galantamine pamoate sustained-release microparticles for injection, and preparation method therefor |
| CN113384536B (en) * | 2020-03-14 | 2024-04-02 | 鲁南制药集团股份有限公司 | Sustained release galanthamine pamoate particles for injection and preparation method thereof |
| CN111714471A (en) * | 2020-06-15 | 2020-09-29 | 广东省医疗器械研究所 | Polymer microsphere for pulmonary drug delivery and preparation method and application thereof |
| CN111643483A (en) * | 2020-07-06 | 2020-09-11 | 济南大学 | Novel method for preparing galanthamine sustained-release microspheres |
| CN114342930A (en) * | 2022-03-01 | 2022-04-15 | 中国农业科学院植物保护研究所 | Pesticide nanocapsule and preparation method thereof |
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