CN1410056A - Preparation method of water soluble anticancer medical microsphere - Google Patents
Preparation method of water soluble anticancer medical microsphere Download PDFInfo
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- CN1410056A CN1410056A CN 02137781 CN02137781A CN1410056A CN 1410056 A CN1410056 A CN 1410056A CN 02137781 CN02137781 CN 02137781 CN 02137781 A CN02137781 A CN 02137781A CN 1410056 A CN1410056 A CN 1410056A
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Abstract
A water-soluble microspherical anticancer medicine is prepared by oil-in-oil technique, where the medicine and the organic solution of polylactic acid and its copolymer are used as internal oil phase, the atoleine or vegetable oil is used as external oil phase, and the Span or lecithine is used as emulsifier. It is prepared through stirring internal oil phase in external oil phase for emulsifying it, evaporating the solvent of internal oil phase at 30-100 deg.C awaiting microsphere hardening, then centrifugal separation, washing with petroleum ether, and vacuum drying. Its advantages are high coated rate (70-90%), long release time (20-60 days) and controllable diameter (0.5-200 microns).
Description
Technical field
The present invention relates to the method for preparing microsphere of cancer therapy drug, especially the water solublity antitumor drug comprises that mustine hydrochlcride, cyclophosphamide, plug replace the preparation method of the microsphere of medicines such as group, cisplatin, 5-fluorouracil, cytarabine hydrochloride, actinomycin D, bleomycin, doxorubicin hydrochloride, daunorubicin, epirubicin, zorubicin, aclarubicin.
Background technology
In recent decades, the medicine controlled releasing microsphere has obtained extensive use at field of medicaments.The first, as the controlled release and the multipath drug-delivery preparation of various medicines, as can be used as multipaths such as injection, oral, nasal cavity suction, dosing eyes and use; The second, as various chemoembolization preparation performance thromboembolisms and controlled release dual-use function; The 3rd, realize that as the carrier of cancer therapy drug single administration reaches long-time antitumor action.At present, the carrier material that is used for control-release microsphere has multiple.By sources can be divided into (1) natural macromolecular material, as cellulose, chitosan, protein; (2) synthesized polymer material can be divided into again by biodegradation character: non-biodegradation type macromolecular material, as polyacrylate and derivant thereof; The Biodegradable macromolecular material, as polyester, poly-anhydride, poe, Merlon etc., polylactic acid wherein, poly-(lactide-co-glycolide) since its excellent biological compatibility and biological degradability by drugs approved by FDA as the clinical use of medical material.Poly-(trimethylene carbonate) and poly-(trimethylene carbonate-be total to-lactide) is the novel biomaterial of a class, experiment has proved that it has excellent biological compatibility and vivo degradation performance in the animal body, thereby is subjected to extensive concern in recent years as potential bio-medical material.Active medicine can be hydrophobic in the control-release microsphere, also can be hydrophilic, and wherein cancer therapy drug is preferably the medicine of slow release formulation owing to its very strong whole body toxic and side effects and short biological half-life.Such as cisplatin, 5-fluorouracil, the microsphere preparation and the research of inside and outside drug release behavior of medicines such as amycin all have many paper publishings.It should be noted that wherein 5-fluorouracil/poly-(lactide-co-glycolide) microsphere as anti-glioma carries out clinical trial at research group of France.By making sustained-release micro-spheres, cancer therapy drug can release have slowly increased bioavailability of medicament and has improved therapeutic effect in that tumor locus is local, has reduced the whole body toxic and side effects simultaneously.
Preparation water soluble drug microsphere has three kinds of methods at present.First method is O/w emulsion-solvent evaporation method.But because the water solublity of medicine, this method is difficult to obtain the microsphere (embedding rate generally is lower than 10%) of high embedding rate.Second method is water bag (Water-In-Oil) or water bag (oil bag powder) emulsion-solvent evaporates/extraction method.Many reports are pointed out the embedding rate that is loaded with the 5-fluorouracil microsphere generally very low (＜10%) that water bag (Water-In-Oil) method obtains.Although also the someone reports the microsphere that has obtained containing 5-fluorouracil by water bag (Water-In-Oil) solvent evaporation method, and embedding rate higher (70%), in fact this is only at 5-fluorouracil drug loading extremely low (3.9 * 10
-6The mg/mg polymer) just possible the time.Emulsion-solvent extraction method has prepared 5-fluorouracil/poly-(lactide-co-glycolide) microsphere to people such as Menei, and embedding rate higher (40～53%) with water bag (oil bag powder).But owing to the first step of water bag (oil bag powder) solvent evaporates/extraction method is to disperse the 5-fluorouracil powder to wrap powder suspension to form oil in the dichloromethane solution that contains polymer, thereby the particle diameter of this method thus obtained microsphere generally 40 μ m or more than, so be difficult to obtain than the small particle diameter microsphere with this method.The third method is oil bag fat liquor-solvent evaporates/extraction method.People such as Chiang are interior oil phase with dichloromethane, and liquid paraffin has prepared 5-fluorouracil/poly-(lactide-co-glycolide) microsphere as outer oil phase, although obtained the microsphere that particle diameter is little and embedding rate is high (～76%).But the used emulsifying agent of this method is a lecithin, and when using commonly used and cheap span as emulsifying agent, perhaps thus obtained microsphere embedding rate very low (～21%) perhaps can not get microsphere at all.Simultaneously, the release in vitro time of the microsphere that they make is about 21 days, and this slow-release time to the microsphere that water bag (oil bag powder) method obtains is similar.The antitumaous effect of medicines such as (especially) 5-fluorouracil depends primarily on the blood drug level of pharmaceutical release time and lesions position because cancer therapy drug, so wish to obtain high drug load and can slow release microball preparation for more time.
Summary of the invention
The preparation method that the purpose of this invention is to provide a kind of water soluble anticancer medical microsphere.
The preparation method of water solublity antitumor drug microsphere is at first polymer and water soluble drug to be dissolved in N, obtains interior oil phase in the mixed solvent of dinethylformamide or acetone and acetonitrile or dichloromethane; Span or lecithin is dissolved in obtains outer oil phase in liquid paraffin or the vegetable oil.Then oil phase in the gained is placed stirred vessel, form oil bag fat liquor in the oil phase outside being emulsifiable under stirring in room temperature with per minute 800～4000 commentaries on classics middling speeds.This emulsion is the oil phase solvent in 30～100 ℃ of following electromagnetic agitation evaporations, treat that microsphere hardens after, petroleum ether is used in centrifugalize, vacuum drying gets final product.
The present invention adopts N, the mixed solvent of dinethylformamide or acetone and acetonitrile or dichloromethane has prepared the polylactic acid that is surrounded by water soluble anti-cancer medicine, poly-(lactide-co-glycolide), poly-(lactide-be total to-carbonic ester) control-release microsphere as interior oil phase with oil bag fat liquor-solvent evaporates technology.
The major advantage of this method is: first, cosolvent is as interior oil phase both solubilized medicine, soluble polymeric thing again, and used interior oil phase soluble polymeric thing and can not dissolved substance usually, thereby this method can obtain medicine and be uniformly dispersed in polymer, and the microsphere of particle diameter easy-regulating; The second, compare with common oil bag fat liquor solvent evaporation method, use mixed solvent can improve the embedding rate (bringing up to 70～90%) of medicine; The 3rd, use commonly used and cheap span series emulsifying agent can realize the successful embedding of medicine, and need not be with emulsifying agents such as lecithin; The 4th, the microsphere that this method obtains has obviously prolonged the release time of medicine, and the external lasting release of medicine reached about 40 days when using polylactic acid as carrier material; When being lapping, the 5-fluorouracil release in vitro time can reach about 60 days to adopt poly-(lactide-be total to-carbonic ester).
The specific embodiment
Oil phase adopts N, the mixed solvent of dinethylformamide or acetone and acetonitrile or dichloromethane in the present invention.N, the volumetric concentration of dinethylformamide or acetone is 0～100%, and drug level is 1～50mg/ml, and polylactic acid, poly-(lactide-co-glycolide) or poly-(lactide-be total to-carbonic ester) concentration are 1～200mg/ml.Outer oil phase adopts liquid paraffin or vegetable oil, and other model of sorbester p17 or span series or lecithin are as emulsifying agent, and the w/v of emulsifying agent and liquid paraffin or vegetable oil is 0.1～15%.During preparation, interior oil phase is placed stirred vessel, form oil bag fat liquor in the oil phase outside being emulsifiable under stirring in room temperature with per minute 800～4000 commentaries on classics middling speeds.This emulsion is the oil phase solvent in 30～100 ℃ of following electromagnetic agitation evaporations, treat that microsphere hardens after, petroleum ether is used in centrifugalize, vacuum drying.
Oil phase is N in said, the mixed solvent of dinethylformamide or acetone and acetonitrile or dichloromethane, N wherein, dinethylformamide or acetone body volume concentrations are 0～100%, drug level is 1～100mg/ml, the concentration of polylactic acid or poly-(lactide-co-glycolide) or poly-(lactide-be total to-trimethylene carbonate) or poly-(lactide-be total to-2,2-dimethyl trimethylene carbonate) is 1～200mg/ml.
The w/v of span or lecithin and liquid paraffin or lecithin is 0.1-15% in the outer oil phase.
Water soluble anti-cancer medicine be mustine hydrochlcride, cyclophosphamide, plug for group, cisplatin, 5-fluorouracil, cytarabine hydrochloride, actinomycin D, bleomycin, doxorubicin hydrochloride, daunorubicin, epirubicin,
Embodiment 1
Interior oil phase adopts 3mlN, and the cosolvent of dinethylformamide and acetonitrile, the volumn concentration of acetonitrile are 75%.Wherein dissolving 5-fluorouracil is 22.5mg, and the dissolving molecular weight is 2.83 * 10
4Poly-(L-lactide) 300mg.Outer oil phase is the 50ml liquid paraffin, and sorbester p17 is as emulsifying agent, and its concentration is 3%.During preparation interior oil phase is emulsifiable under 800rpm stirs and forms oil bag fat liquor in the outer oil phase, this emulsion is the oil phase solvent in 40～45 ℃ of following electromagnetic agitation are evaporated; Treat microsphere sclerosis back centrifugalize and use petroleum ether, vacuum drying.The embedding rate of the 5-fluorouracil of thus obtained microsphere is 86.5%, and the microsphere number average bead diameter is 69.8 μ m.The vitro drug release time can reach 40 days.
Embodiment 2
Interior oil phase adopts 3mlN, and the mixed solvent of dinethylformamide and acetonitrile, the volumn concentration of acetonitrile are 75%.Wherein dissolve 5-fluorouracil 22.55mg, the dissolving molecular weight is 2.57 * 10
4Poly-(trimethylene carbonate-altogether-lactide) 300mg.Outer oil phase is the 50ml liquid paraffin, and sorbester p17 is as emulsifying agent, and its concentration is 7%.All the other are with embodiment 1.The embedding rate of thus obtained microsphere 5-fluorouracil is 76.4%, number average bead diameter 23.7 μ m.The vitro drug release time can reach 50 days.
Embodiment 3
Interior oil phase adopts 3mlN, and the cosolvent of dinethylformamide and acetonitrile, the volumn concentration of acetonitrile are 75%.Wherein dissolve 5-fluorouracil 22.5mg, the dissolving molecular weight is 2.48 * 10
4Poly-(2,2-dimethyl trimethylene carbonate-altogether-lactide) 300mg.Outer oil phase is the 50ml liquid paraffin, and sorbester p17 is as emulsifying agent, and its concentration is 10%.All the other are with embodiment 1.The embedding rate of the 5-fluorouracil of thus obtained microsphere is 70.4%, number average bead diameter 13.7 μ m.The vitro drug release time can reach more than 60 days.
Embodiment 4
Interior oil phase adopts 5ml acetone, and wherein dissolved 5-fluorouracil is 25mg, dissolving poly-(lactide-co-glycolide) (mole ratio of components 50/50, molecular weight 9000) 300mg, and outer oil phase is the 50ml liquid paraffin, and lecithin is as emulsifying agent, and its concentration is 1%.During preparation interior oil phase is emulsifiable under 1500rpm stirs and forms oil bag fat liquor in the outer oil phase, this emulsion is the oil phase solvent in 30～35 ℃ of following electromagnetic agitation are evaporated; Treat microsphere sclerosis back centrifugalize and use petroleum ether, vacuum drying.The embedding rate of the 5-fluorouracil of thus obtained microsphere is 76.8%, and the microsphere number average bead diameter is 2.7 μ m.The vitro drug release time can reach 20 days.
Claims (4)
1. the preparation method of a water solublity antitumor drug microsphere is characterized in that: at first polymer and water soluble drug are dissolved in N, obtain interior oil phase in the mixed solvent of dinethylformamide or acetone and acetonitrile or dichloromethane; Span or lecithin is dissolved in obtains outer oil phase in liquid paraffin or the vegetable oil; Then oil phase in the gained is placed stirred vessel, form oil bag fat liquor in the oil phase outside being emulsifiable under stirring in room temperature with per minute 800～4000 commentaries on classics middling speeds.This emulsion is the oil phase solvent in 30～100 ℃ of following electromagnetic agitation evaporations, treat that microsphere hardens after, petroleum ether is used in centrifugalize, vacuum drying gets final product.
2. the preparation method of a kind of water soluble anticancer medical microsphere according to claim 1, it is characterized in that said interior oil phase is N, the mixed solvent of dinethylformamide or acetone and acetonitrile or dichloromethane, N wherein, dinethylformamide or acetone body volume concentrations are 0～100%, drug level is 1～100mg/ml, the concentration of polylactic acid or poly-(lactide-co-glycolide) or poly-(lactide-be total to-trimethylene carbonate) or poly-(lactide-be total to-2,2-dimethyl trimethylene carbonate) is 1～200mg/ml.
3. the preparation method of a kind of water soluble anticancer medical microsphere according to claim 1 is characterized in that the w/v of span in the said outer oil phase or lecithin and liquid paraffin or lecithin is 0.1-15%.
4. the preparation method of a kind of water soluble anticancer medical microsphere according to claim 1 is characterized in that said water soluble anti-cancer medicine is that mustine hydrochlcride, cyclophosphamide, plug are for group, cisplatin, 5-fluorouracil, cytarabine hydrochloride, actinomycin D, bleomycin, doxorubicin hydrochloride, daunorubicin, epirubicin, zorubicin, aclarubicin.
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| CNB021377812A CN1193741C (en) | 2002-10-29 | 2002-10-29 | Preparation method of water soluble anticancer medical microsphere |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100344277C (en) * | 2005-03-30 | 2007-10-24 | 深圳市人民医院 | Nano-magnetic medicinal microglobule, its preparation method and application |
| CN100355418C (en) * | 2005-10-14 | 2007-12-19 | 中山大学 | Magnetic nano-balls carried with cisplatin and its prepn. method |
| CN100438913C (en) * | 2004-11-22 | 2008-12-03 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition |
| CN100464783C (en) * | 2004-11-22 | 2009-03-04 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition containing antineoplastic antibiotics |
| CN102580109A (en) * | 2012-03-02 | 2012-07-18 | 河南师范大学 | Anti-cancer drug carrier and method for producing same |
| CN101461785B (en) * | 2009-01-08 | 2012-10-17 | 上海交通大学 | Oil in water-oil in oil-water in oil method for preparing microballoons |
| CN107684547A (en) * | 2016-09-30 | 2018-02-13 | 青岛大学 | A kind of preparation method of analgin microballoon |
-
2002
- 2002-10-29 CN CNB021377812A patent/CN1193741C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100438913C (en) * | 2004-11-22 | 2008-12-03 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition |
| CN100464783C (en) * | 2004-11-22 | 2009-03-04 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition containing antineoplastic antibiotics |
| CN100344277C (en) * | 2005-03-30 | 2007-10-24 | 深圳市人民医院 | Nano-magnetic medicinal microglobule, its preparation method and application |
| CN100355418C (en) * | 2005-10-14 | 2007-12-19 | 中山大学 | Magnetic nano-balls carried with cisplatin and its prepn. method |
| CN101461785B (en) * | 2009-01-08 | 2012-10-17 | 上海交通大学 | Oil in water-oil in oil-water in oil method for preparing microballoons |
| CN102580109A (en) * | 2012-03-02 | 2012-07-18 | 河南师范大学 | Anti-cancer drug carrier and method for producing same |
| CN102580109B (en) * | 2012-03-02 | 2013-11-06 | 河南师范大学 | Anti-cancer drug carrier and method for producing same |
| CN107684547A (en) * | 2016-09-30 | 2018-02-13 | 青岛大学 | A kind of preparation method of analgin microballoon |
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