CN1299685C - Fluorouracil medicine carrier microsphere and production thereof - Google Patents
Fluorouracil medicine carrier microsphere and production thereof Download PDFInfo
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- CN1299685C CN1299685C CNB2005100235811A CN200510023581A CN1299685C CN 1299685 C CN1299685 C CN 1299685C CN B2005100235811 A CNB2005100235811 A CN B2005100235811A CN 200510023581 A CN200510023581 A CN 200510023581A CN 1299685 C CN1299685 C CN 1299685C
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Abstract
The present invention relates to a fluorouracil medicine carrying microsphere and a preparation method thereof. The fluorouracil medicine carrying microsphere is prepared by using polylactic acid as a coating material, using nanometer silicon dioxide or mesoporous silicon dioxide as a carrier and using the adsorption function of silicon dioxide to adsorb fluorouracil, wherein the medicine carrying quantity is from 18.7% to 32.6%; the average grain size is from 13.25 to 40.01 mum. The preparation method of the medicine carrying microsphere comprises the following steps: polylactic acid (PLA) is added to methylene chloride, and SiO2 is uniformly dispersed in the PLA solution to form a suspension; the suspension is injected in gelatin water solution under the condition of stirring to form an oil-in-water type O/W emulsion which is stirred to volatilize methylene chloride, microspheres are solidified, collected by centrifugation and washed by redistilled water, and then, vacuum drying is carried out at the temperature of 20 to 50DEGC to obtain SiO2-PLA microspheres; the microspheres are dipped in fluorouracil hydrochlric solution for 1 hour, the microspheres in the suspension are centrifugated, collected and washed by redistilled water, and then, freeze drying is carried out to obtain the medicine carrying microsphere. The medicine carrying quantity of the fluorouracil medicine carrying microsphere of the present invention is obviously increased. The surface of the microsphere is smooth and is not adhered. The size of the microsphere is from 13.25 to 40.01 mum. The microsphere has uniform diameter distribution, obvious and long-time sustained release action, and tissue targeting.
Description
Technical field
The present invention relates to a kind of fluorouracil medicine carrier microsphere and preparation method thereof, particularly a kind of biodegradable macromolecular material parcel fluorouracil medicine carrier microsphere and preparation method thereof.
Background technology
Fluorouracil is the pyrimidines antimetabolic medicine, and mainly the competition effect of logical enzyme suppresses the formation of thymidylic acid and the biosynthesis of DNA, thereby suppresses tumor growth.Its anticancer spectrum is wider, and is effective to colon cancer, rectal cancer, gastric cancer and breast carcinoma etc., is the choice drug of treatment entity tumor.Though the curative effect of fluorouracil is good, toxicity is also big, can cause side effect such as serious digestive tract reaction and bone marrow depression, and disappears blood plasma t from blood plasma very soon after the intravenous injection
1/2About 10～20 minutes.For the toxic and side effects that reduces fluorouracil and improve utilization ratio of drug, can make it to mix with the biodegradable macromolecular material, make medicine carrying microballoons with slow releasing function, and by control particle diameter size make it to have targeting, thereby improve the local concentration of organizing Chinese medicine, effectively killing pathogenic bacteria.Reduce dosage and number of times simultaneously, reduce systemic drug concentration, reduce toxic and side effects.
Less about the research of biodegradable polyphosphazene polymer ester material parcel fluorouracil microglobule at present, Xiong Subin, Lu Bin have delivered " Preparation Techniques of Fluorouracil Microspheres " Chinese Journal of Pharmaceuticals, 2003,34 (7): 330-332.This research is carrier with polylactic acid (PLA), adopt O/O type and O/W type emulsifying volatility process and spray drying method for preparation fluorouracil polylactic acid microsphere respectively, wherein, the actual drug loading of microsphere that O/O type emulsifying volatility process makes is less than 2.0%, and the microsphere drug loading of two kinds of method preparations is respectively 10.25% and 26.18% in addition.Its weak point is that the microsphere drug loading for preparing with O/O type and O/W type emulsifying volatility process is low, and spray drying method is had relatively high expectations to preparation condition.
Summary of the invention
One of purpose of the present invention is to adopt has excellent biological compatibility and biodegradable polylactic acid (PLA) as clad material, utilizes the adsorption of silicon dioxide, and a kind of smooth surface is provided, and diameter is even, and can control; The fluorouracil medicine carrier microsphere that drug loading obviously improves.
Two of purpose of the present invention is to provide a kind of method that adopts oil-in-water O/W emulsion-solvent evaporation method to prepare fluorouracil medicine carrier microsphere.
For achieving the above object, the present invention adopts following technical scheme:
A kind of fluorouracil medicine carrier microsphere, it is characterized in that, this medicine carrying microballoons is as clad material with polylactic acid, with nano silicon or mesoporous type silicon dioxide is carrier, utilize the adsorption of silicon dioxide, the fluorouracil medicine carrier microsphere that adsorbs fluorouracil and form, this medicine carrying microballoons prepares as follows:
A. be solvent with the dichloromethane, polylactic acid PLA fully be dissolved in the dichloromethane, under sonic oscillation with SiO
2Be dispersed in the PLA solution, form suspension, the used PLA and the quality of silicon dioxide are 15-45: 1; This suspension under agitation is injected in the aqueous gelatin solution of 1-4%, the volume ratio of aqueous gelatin solution and suspension is 50-100: 10, and emulsifying 10 minutes forms oil-in-water type O/W emulsion, restir volatilization in 4 hours dichloromethane, solidified microsphere; With the centrifugal collection of microsphere in the suspension that obtains and with after the second distillation water washing at 20-50 ℃ of vacuum drying, obtain SiO
2-PLA microsphere;
B. fluorouracil is dissolved in the hydrochloric acid solution that concentration is 0.1mol/L, forming concentration is the fluorouracil hydrochloric acid solution of 4g/L, again with the SiO of above-mentioned preparation
2-PLA microsphere is pressed fluorouracil and SiO
2The mass ratio of-PLA microsphere is 8: 5 a ratio, is soaked in the fluorouracil hydrochloric acid solution, soaks 1 hour, and the microsphere in this suspension is centrifugal, collects, and with second distillation water washing postlyophilization, promptly gets fluorouracil medicine carrier microsphere.。
The drug loading of above-mentioned medicine carrying microballoons is 18.7%-32.6%, and mean diameter is 13.25-40.01 μ m, and the molecular weight of used polylactic acid is 67000 gram/mol, and the particle diameter of nano silicon is 10-30nm.
Compare with prior art, because it is clad material that the present invention selects polylactic acid PLA for use, utilize the adsorption of nanometer SiO2 or many skies property raising drug loading of mesoporous type SiO2, thereby can control and regulate the content of silicon dioxide in the carrier material by the ingredient proportion of regulating PLA and silicon dioxide, finally control the drug loading of microsphere; Can control microsphere size and pattern by control medicine microspheres preparation technology simultaneously.
The fluorouracil medicine carrier microsphere of the present invention's preparation, the drug loading of fluorouracil reaches more than the 18.7%-32.63%, compares with above-mentioned bibliographical information, and drug loading is significantly improved.And microsphere features smooth surface, adhesion, microsphere are of a size of 13.25～40.01 μ m, and diameter Distribution is even, and has long-acting significantly, slow releasing function and tissue target tropism.
Medicine fluorouracil of the present invention is the uracil antimetabolite, and anticancer spectrum is wide, is subjected to the enzyme effect to suppress the formation of thymidylic acid and the biosynthesis of DNA, thereby suppresses tumor growth.Its character is a white crystalline powder, and odorless, tasteless is slightly water-soluble, is slightly soluble in ethanol, is insoluble to chloroform, dissolves in dilute hydrochloric acid or sodium hydroxide solution.Stable under the room temperature, relatively stable to heat.
The specific embodiment
Embodiment one: (Mn=67,000g/mol) 0.4g is dissolved in the dichloromethane of 10ml, the nanometer SiO of 0.02g10nm under sonic oscillation with PLA
2Be dispersed in the PLA solution.This solution under agitation is injected in the aqueous gelatin solution of 75ml 1.5%, emulsifying 10 minutes forms the O/W emulsion, restir volatilization in 4 hours dichloromethane, solidified microsphere.With the centrifugal collection of microsphere in the suspension that obtains and with 37 ℃ of vacuum dryings after the second distillation water washing, obtain SiO
2-PLA microsphere.Accurately take by weighing the SiO that 50mg makes
2-PLA microsphere is soaked in the fluorouracil hydrochloric acid solution of 20ml4g/L, and is after one hour that the microsphere in this suspension is centrifugal, collect, and with second distillation water washing postlyophilization.Fluorouracil content is 27.54% in the microsphere, and microsphere average grain diameter is 21.59 μ m.
Embodiment two: present embodiment and embodiment one are basic identical, and that different is the SiO that adopts
2Particle diameter be 30nm, fluorouracil content is 30.9% in the resulting medicine carrying microballoons, mean diameter is 30.42 μ m.
Embodiment three: present embodiment and embodiment one are basic identical, and that different is the SiO that adopts
2Be mesoporous type SiO
2, fluorouracil content is 29.58% in the resulting medicine carrying microballoons, mean diameter is 40.01 μ m.
Embodiment four: (Mn=67,000g/mol) 0.3g is dissolved in the dichloromethane of 10ml, the nanometer SiO of 0.02g10nm under sonic oscillation with PLA
2Be dispersed in the PLA solution.This solution under agitation is injected in the aqueous gelatin solution of 75ml 2.5%, emulsifying 10min forms the O/W emulsion, restir volatilization in 4 hours dichloromethane, solidified microsphere.With the centrifugal collection of microsphere in the suspension that obtains and with 50 ℃ of vacuum dryings after the second distillation water washing, obtain SiO
2-PLA microsphere.Accurately take by weighing the SiO that 50mg makes
2-PLA microsphere is soaked in the fluorouracil hydrochloric acid solution of 20ml4g/L, and is after one hour that the microsphere in this suspension is centrifugal, collects, and with second distillation water washing postlyophilization, obtains fluorouracil medicine carrier microsphere.Fluorouracil content is 32.63% in the microsphere, and microsphere average grain diameter is 13.25 μ m.
Embodiment five: present embodiment and embodiment four are basic identical, and the amount of different is used polylactic acid is 0.6g, and fluorouracil content is 28.3% in the resulting microsphere, and microsphere average grain diameter is 27.50 μ m.
Embodiment six: present embodiment and embodiment four are basic identical, and the amount of different is used polylactic acid is 0.9g, and fluorouracil content is 18.7% in the gained medicine carrying microballoons, and microsphere average grain diameter is 35.30 μ m.
Embodiment seven: (Mn=67,000g/mol) 0.4g is dissolved in the dichloromethane of 10ml, the SiO of 0.02g30nm under sonic oscillation with PLA
2Be dispersed in the PLA solution.This solution under agitation is injected in the aqueous gelatin solution of 100ml1.0%, emulsifying 10min forms the O/W emulsion, the restir 4h dichloromethane that volatilizees, solidified microsphere.With the centrifugal collection of microsphere in the suspension that obtains and with 20 ℃ of vacuum dryings after the second distillation water washing, obtain SiO
2-PLA microsphere.Accurately take by weighing the SiO that 50mg makes
2-PLA microsphere is soaked in the fluorouracil hydrochloric acid solution of 20ml4g/L, and is after one hour that the microsphere in this suspension is centrifugal, collects, and with second distillation water washing postlyophilization, obtains fluorouracil medicine carrier microsphere.Fluorouracil content is 26.52% in the microsphere, and microsphere average grain diameter is 32.25 μ m.
Embodiment eight: present embodiment and embodiment seven are basic identical, and different is to adopt 2.5% aqueous gelatin solution, and gained medicine carrying microballoons mean diameter is 27.13 μ m, and drug loading is 30.08%.
Embodiment nine: present embodiment and embodiment seven are basic identical, and different is to adopt 4.0% aqueous gelatin solution, and gained medicine carrying microballoons smooth surface, mean diameter are 23.85 μ m, and drug loading is 30.17%.
Claims (2)
1. fluorouracil medicine carrier microsphere, it is characterized in that, this medicine carrying microballoons is as clad material with polylactic acid, with nano silicon or mesoporous type silicon dioxide is carrier, utilize the adsorption of silicon dioxide, the fluorouracil medicine carrier microsphere that adsorbs fluorouracil and form, this medicine carrying microballoons prepares as follows:
A. be solvent with the dichloromethane, polylactic acid PLA fully be dissolved in the dichloromethane, under sonic oscillation with SiO
2Be dispersed in the PLA solution, form suspension, the used PLA and the quality of silicon dioxide are 15-45: 1; Described suspension under agitation is injected in the aqueous gelatin solution of 1-4%, the volume ratio of described aqueous gelatin solution and described suspension is 50-100: 10, and emulsifying 10 minutes forms oil-in-water type O/W emulsion, restir volatilization in 4 hours dichloromethane, solidified microsphere; With the centrifugal collection of microsphere in the suspension that obtains and with after the second distillation water washing at 20-50 ℃ of vacuum drying, obtain SiO
2-PLA microsphere;
B. fluorouracil is dissolved in the hydrochloric acid solution that concentration is 0.1mol/L, forming concentration is the fluorouracil hydrochloric acid solution of 4g/L, again with the SiO of above-mentioned preparation
2-PLA microsphere is pressed fluorouracil and SiO
2The mass ratio of-PLA microsphere is 8: 5 a ratio, is soaked in the fluorouracil hydrochloric acid solution, soaks 1 hour, and the microsphere in this suspension is centrifugal, collects, and with second distillation water washing postlyophilization, promptly gets fluorouracil medicine carrier microsphere.
2. fluorouracil medicine carrier microsphere according to claim 1, it is characterized in that the molecular weight of used polylactic acid is 67000 gram/mol, the particle diameter of nano silicon is 10-30nm, the drug loading of prepared medicine carrying microballoons is 18.7%-32.6%, and mean diameter is 13.25-40.01 μ m.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100465229C (en) * | 2006-10-19 | 2009-03-04 | 上海大学 | Process for preparing biologically degradable SiO2/poly lactic acid nano composite material |
| CN101885905B (en) * | 2009-05-12 | 2013-08-21 | 无锡纳奥新材料科技有限公司 | Polymer/ inorganic nano particle composite nano-particle and preparation method thereof and uses |
| CN103751857A (en) * | 2014-01-22 | 2014-04-30 | 同济大学 | Drug-loaded silica embolism microsphere and preparation method thereof |
| CN104958767A (en) * | 2015-07-08 | 2015-10-07 | 金陵科技学院 | Preparation method of pH-sensitive cyclodextrin nanoparticles having biocompatibility |
| CN105131066B (en) * | 2015-07-31 | 2018-08-03 | 四川大学 | A kind of pyrimidine derivatives and preparation method thereof and purposes |
| CN106177968A (en) * | 2016-07-15 | 2016-12-07 | 河南中帅医药科技股份有限公司 | The preparation of the medicinal microsphere of a kind of silicon dioxide and in the application of pharmaceutical field |
| CN106730033B (en) * | 2016-11-14 | 2020-03-06 | 中国人民解放军第四军医大学 | Double-effect drug-loaded nanoparticle microsphere with antibacterial and growth promoting functions and preparation method and application thereof |
| CN113577031A (en) * | 2021-08-02 | 2021-11-02 | 郑州大学第一附属医院 | Preparation method of drug sustained-release body and drug sustained-release body |
| CN113694029A (en) * | 2021-08-02 | 2021-11-26 | 郑州大学第一附属医院 | Preparation method of porous drug sustained-release body and porous drug sustained-release body |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6235313B1 (en) * | 1992-04-24 | 2001-05-22 | Brown University Research Foundation | Bioadhesive microspheres and their use as drug delivery and imaging systems |
| CN1356892A (en) * | 1999-05-17 | 2002-07-03 | 埃迪克埃迪法姆药品实验室 | Use of biodegradable microspheres for delivery of anticancer for treatment of glioblastoma |
| CN1546006A (en) * | 2003-12-11 | 2004-11-17 | 同济大学 | Preparation method of biodegradable polymer pharmaceutical microsphere |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6235313B1 (en) * | 1992-04-24 | 2001-05-22 | Brown University Research Foundation | Bioadhesive microspheres and their use as drug delivery and imaging systems |
| CN1356892A (en) * | 1999-05-17 | 2002-07-03 | 埃迪克埃迪法姆药品实验室 | Use of biodegradable microspheres for delivery of anticancer for treatment of glioblastoma |
| CN1546006A (en) * | 2003-12-11 | 2004-11-17 | 同济大学 | Preparation method of biodegradable polymer pharmaceutical microsphere |
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