CN101972493B - Visualized iodized oil-5-fluorouracil loaded polylactic acid microsphere preparation and preparation method thereof - Google Patents
Visualized iodized oil-5-fluorouracil loaded polylactic acid microsphere preparation and preparation method thereof Download PDFInfo
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- CN101972493B CN101972493B CN2010105086689A CN201010508668A CN101972493B CN 101972493 B CN101972493 B CN 101972493B CN 2010105086689 A CN2010105086689 A CN 2010105086689A CN 201010508668 A CN201010508668 A CN 201010508668A CN 101972493 B CN101972493 B CN 101972493B
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Abstract
The invention belongs to the technical field of medicine, and discloses a visualized iodized oil-5-fluorouracil loaded polylactic acid microsphere preparation with a controlled-release effect and a preparation method thereof. The preparation comprises the main components of 5-fluorouracil, iodized oil injecta, polyvinyl alcohol and polylactic acid, and is characterized in that the preparation process is simple, the drug-loading rate is large, the drug release is stable and lasts for a long time, and the in-vitro continuous effective drug release time can be longer than 4 weeks. In the invention, the liquid preparation is prepared into solid microsphere preparation, thus compared with the traditional method, the invention has the advantages that controlled-release drug administration is realized; the toxic and side effect of chemotherapeutic drugs is reduced; the embolism time is prolonged; the microsphere preparation can durably act on focus; the drug therapy effect is enhanced; and the curative effect can be tracked according to the visualized position of the iodized oil in the later stage, thus waste of drugs can be reduced, and the physical damage and economic burden of patients can be lightened.
Description
Technical field
The present invention relates to medical technical field, is a kind of developed iodized oil with slow releasing function-5-fluorouracil polylactic acid microsphere preparation and preparation method thereof.
Background technology
Iodized oil is a kind of organic iodine injection, has viscosity, because it can develop under X-light, the positive suppository that is otherwise known as in the interventional therapy (hepatic artery embolism art) of clinical hepatocarcinoma, often is used as the hepatic artery embolism agent and uses.5-fluorouracil is a kind of chemotherapeutics injection, is clinical cancer therapy drug commonly used, has the wide characteristics of anticancer spectrum, is the choice drug for the treatment of entity tumor.
At present the main usage in clinical interventional therapy is to mix after directly iodized oil and two medicines of 5-fluorouracil (5-FU) being sucked same syringe, the conduit that inserts through femoral artery directly injects the focus happening part, thromboembolism is in the arteries around the cancerous cell, iodized oil utilizes the blood supply of viscosity blocking-up cancerous cell, make cancerous cell lack nutrition and death, the Chemotherapy of 5-fluorouracil performance medicine kills and wounds cancerous cell.Though thisly face the time spent injecting method of two kinds of medicament mixed had preferably therapeutic effect, but because the two is liquid, more liquid, easily washed away by blood, cause at lesions position drug treating time weak point, add that the half-life of 5-fluorouracil is short, effectively treatment time can only continue 3～4 hours usually, and after the injection, early stage is also larger because of the large toxic and side effects of chemotherapeutics concentration.
Summary of the invention
The invention provides that a kind of effective treatment longer duration, toxic and side effects are little, developed iodized oil with slow releasing function-5-fluorouracil polylactic acid microsphere preparation and preparation method thereof.
The present invention adopts multi-emulsion method to prepare the iodized oil-5-fluorouracil polylactic acid microsphere preparation that can develop, and main component and the proportioning of preparation are as follows:
Contents of Main Components
5-fluorouracil (5-FU) 20～80mg
Iodinate oil injection 0.02～0.5ml
1～5% polyvinyl alcohol (PVA), 10～80mg
Polylactic acid (PLA) 10～100mg
Said polylactic acid molecule amount is 70000 dalton, and specificity viscosity is 0.7～0.8dl/g.
Preparation process is:
1. preparation oil phase
By proportioning polylactic acid (PLA) and iodinate oil injection are dissolved in organic solvent, said organic solvent is selected from dichloromethane or acetonitrile, oil phase;
2. water in preparing
By proportioning 5-fluorouracil is dissolved in the 1mol/LNaOH aqueous solution, in water;
3. preparation colostrum
Above-mentioned oil phase is mixed with interior water, make w/o type emulsion, be colostrum;
4. prepare outer water
As continuous phase, preparation 5-FU saturated aqueous solution is outer water with 1～5% polyvinyl alcohol (PVA);
5. preparation emulsion
Under stirring colostrum is at the uniform velocity splashed into outer aqueous phase, with 400～1200rpm high-speed stirred emulsifying 5～20 minutes, namely get emulsion;
6. preparation dry microspheres
Above-mentioned emulsion is continued to stir with 300～600rpm, make organic solvent volatilization and solidified microsphere, centrifugal, distilled water wash, lyophilization namely gets microsphere of the present invention.
After testing, the iodized oil that develops of the present invention-5-fluorouracil polylactic acid microsphere outward appearance rounding, particle size distribution is between 50-250 μ m, and suspension ability is good, and envelop rate is more than 80%.Through extracorporeal releasing experiment, slow-release time reached more than 4 weeks, and development effect is good under X-ray.
The present invention's iodized oil-5-fluorouracil polylactic acid microsphere preparation process thereof that can develop is simple, and drug loading is large, release steadily and longer duration, its external continuous and effective drug release time can reach more than 4 weeks.The present invention makes the microspheres with solid preparation with liquid preparation, compare with traditional method, realized sustained-release administration, reduce the toxic and side effects of chemotherapeutic, prolonged the thromboembolism time, but the dauer effect focus, improved medication effect, and the later stage can be followed the tracks of curative effect according to the developing location of iodized oil, reduces drug waste, alleviates patient's somatic damage and financial burden.
Description of drawings
Fig. 1 is microball preparation cumulative in vitro release～time plot of the present invention.
The specific embodiment
Embodiment 1: adopt 2% polyvinyl alcohol to prepare microball preparation of the present invention
1. preparation oil phase: PLA60mg is dissolved in the 2ml dichloromethane, adds iodinate oil injection 0.06ml, 3 minutes mix homogeneously of vortex, and as oil phase, iodinate oil injection is street drug, by French GUERBET company's production (together lower);
2. water in the preparation: the concentration of preparing 5-FU with 1mol/L NaOH aqueous solution be the 5-FU solution of 50g/L as interior water, the purity of cancer therapy drug 5-FU is not less than 95%;
3. preparation colostrum: the interior aqueous phase solution of getting 0.4ml injects above-mentioned oil phase, under the ice bath with 400W power ultrasonic 2 minutes, colostrum;
4. prepare outer water: as continuous phase, preparation 5-FU saturated aqueous solution is outer water with 2% polyvinyl alcohol (PVA);
5. preparation emulsion: under 600r/min stirs, above-mentioned colostrum at the uniform velocity is injected into aqueous phase outside the 80ml with syringe, stirred 10 minutes, get emulsion;
6. prepare the dry microspheres preparation: above-mentioned emulsion is continued to stir with 300～600rpm, make organic solvent volatilization and solidified microsphere, centrifugal, distilled water wash, lyophilization namely gets microball preparation of the present invention.
Embodiment 2: adopt 2.5% polyvinyl alcohol to prepare microball preparation of the present invention
1. preparation oil phase: PLA60mg is dissolved in the 2ml acetonitrile, adds iodinate oil injection 0.06ml, and 3 minutes mix homogeneously of vortex are as oil phase;
2. water in the preparation: the concentration of preparing 5-FU with the 1mol/LNaOH aqueous solution is that the 5-FU of 60g/L is as interior water;
3. preparation colostrum: method is with embodiment 1;
4. prepare outer water: as continuous phase, preparation 5-FU saturated aqueous solution is outer water with 2.5% polyvinyl alcohol (PVA);
5. preparation emulsion: under 600r/min, above-mentioned colostrum at the uniform velocity is injected into aqueous phase outside the 80ml with syringe, stirred 10 minutes, get emulsion;
6. prepare the dry microspheres preparation: with embodiment 1.
Embodiment 3: adopt 3% polyvinyl alcohol to prepare microball preparation of the present invention
1. preparation oil phase: with embodiment 1;
2. water in the preparation: the concentration of preparing 5-FU with the 1mol/LNaOH aqueous solution is that the 5-FU of 70g/L is as interior water;
3. preparation colostrum: with embodiment 1;
4. prepare outer water: as continuous phase, preparation 5-FU saturated aqueous solution is outer water with 3% polyvinyl alcohol (PVA);
5. preparation emulsion: under 600r/min, above-mentioned colostrum is at the uniform velocity injected aqueous phase outside the 80ml with syringe, stirred 10 minutes, get emulsion;
6. prepare the dry microspheres preparation: with embodiment 1.
The extracorporeal releasing experiment of microball preparation:
The medicine-containing microsphere 30mg that gets respectively embodiment 1,2,3 preparations puts in the bag filter, add 50ml pH 7.4 phosphate buffer solutions (containing 0.02% sodium azide as antibacterial) as release medium, place the water bath with thermostatic control shaking table, under 100rpm hunting speed, 37 ℃ ± 0.5 ℃ temperature conditions, carry out drug release determination outside the microsphere.Respectively take out 2ml solution during respectively at the 2nd, 3,4,5,6,7,8,10,12,15,20,25,30 day, and the synthermal pH7.4 phosphate buffer of adding immediately equivalent is in bag filter, every 1ml sample is diluted to respectively 10ml, measures respectively the release amount.
Take the sampling natural law as abscissa, take corresponding 5-Fu cumulative release percentage ratio as vertical coordinate, make the drug release curve, the microball preparation release profiles of above-mentioned three embodiment preparation is basically identical, sees Fig. 1.As seen from Figure 1, prepared the developed iodized oil of the present invention-5-fluorouracil polylactic acid microsphere preparation is effectively more than 4 weeks of release.
Claims (2)
1. the preparation method of the iodized oil that can develop-5-fluorouracil polylactic acid microsphere preparation, main component and the proportioning of preparation are as follows:
Contents of Main Components
5-fluorouracil 20～80mg
Iodinate oil injection 0.02～0.5ml
1～5% polyvinyl alcohol, 10～80mg
Polylactic acid 10～100mg
Said polylactic acid molecule amount is 70000 dalton, and specificity viscosity is 0.7～0.8dl/g;
Preparation process is:
1) preparation oil phase
By proportioning polylactic acid and iodinate oil injection are dissolved in organic solvent, said organic solvent is selected from dichloromethane or acetonitrile, oil phase;
2) water in the preparation
By proportioning 5-fluorouracil is dissolved in 1mol/L NaOH aqueous solution, in water;
3) preparation colostrum
Above-mentioned oil phase is mixed with interior water, make w/o type emulsion, be colostrum;
4) the outer water of preparation
As continuous phase, preparation 5-FU saturated aqueous solution is outer water with 1～5% polyvinyl alcohol;
5) preparation emulsion
Under stirring colostrum is at the uniform velocity splashed into outer aqueous phase, with 400～1200rpm high-speed stirred emulsifying 5～20 minutes, namely get emulsion;
6) preparation dry microspheres preparation
Above-mentioned emulsion is continued to stir with 300～600rpm, make organic solvent volatilization and solidified microsphere, centrifugal, distilled water wash, lyophilization namely gets microball preparation.
2. the developed iodized oil of the described method of claim 1 preparation-5-fluorouracil polylactic acid microsphere preparation.
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| CN102258812B (en) * | 2011-07-08 | 2013-11-27 | 杨杨 | Phase-change-controllable embolic material and preparation method thereof |
| CN102503897B (en) * | 2011-10-25 | 2015-01-07 | 同济大学附属第十人民医院 | 5-fluorouracil iodized oil derivative as well as preparation method and application thereof |
| CN102397593B (en) * | 2011-11-11 | 2013-12-18 | 北京大学 | Embolization particles developable under X-rays and preparation method and application thereof |
| CN111298189A (en) * | 2018-12-11 | 2020-06-19 | 陈传果 | Iodized oil suppository easy to inject and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1969823A (en) * | 2006-09-28 | 2007-05-30 | 山东蓝金生物工程有限公司 | Sustained release agent containing fluorouracil and synergist thereof |
| CN101234084A (en) * | 2006-07-25 | 2008-08-06 | 济南帅华医药科技有限公司 | Fluorouracil containing anti-cancer sustained-release injection |
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| KR100573289B1 (en) * | 2002-07-20 | 2006-04-24 | 대화제약 주식회사 | Paclitaxel composition for the intravesical treatment of bladder tumor and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101234084A (en) * | 2006-07-25 | 2008-08-06 | 济南帅华医药科技有限公司 | Fluorouracil containing anti-cancer sustained-release injection |
| CN1969823A (en) * | 2006-09-28 | 2007-05-30 | 山东蓝金生物工程有限公司 | Sustained release agent containing fluorouracil and synergist thereof |
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