CN102579338A - Preparation method and application of paclitaxel intravenous fat emulsion - Google Patents
Preparation method and application of paclitaxel intravenous fat emulsion Download PDFInfo
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- CN102579338A CN102579338A CN2012100543615A CN201210054361A CN102579338A CN 102579338 A CN102579338 A CN 102579338A CN 2012100543615 A CN2012100543615 A CN 2012100543615A CN 201210054361 A CN201210054361 A CN 201210054361A CN 102579338 A CN102579338 A CN 102579338A
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Abstract
The invention relates to a preparation method and application of paclitaxel intravenous fat emulsion. The paclitaxel fat emulsion comprises (1) 5-30% of marine organism fat rich in omega-3 fatty acid, (2) 0.5-7.5% of emulsifying agents, (3) 1.5-3.5% of glycerol, (4) 0.02-12% of paclitaxel and the balance of water for injection. The paclitaxel intravenous fat emulsion has good stability and slow release effect, shows excellent anti-tumor effects inside and outside the animal bodies, avoids the adverse effects caused by cremophor EL in the paclitaxel preparations clinically applied at present and provides a good carrier for paclitaxel.
Description
Technical field
The invention belongs to field of medicaments, relate to the seal oil preparation of the paclitaxel intravenous injection fatty breast that is substrate.Relate generally to of the application of this fat milk to solubilization, stability and the anti-tumor aspect of medicine.
Background technology
For a long time; Fat milk mainly is applied to clinical with the form of auxotype fat milk; But have advantages such as volume is little, energy is high, the little peripheral vein administration of vein irritating because of this Emulsion; Increasing attention has been invested and has been selected the vein breast as a kind of new pharmaceutical carrier, promptly is wrapped in pharmaceutical pack in inner phase or the boundary layer.Compare with other particle type carriers, the advantage of vein breast is: pharmaceutical pack is wrapped in inner phase or the boundary layer, and envelop rate is high, improves medicine stability and reduces medicine irritation and toxicity; Drug loading is high; Have slow release and targeting; Oneself possesses the condition and the technology of carrying out large-scale production, is easier to realize commercialization; The long-term clinical experience is arranged; Need not harsh accumulating condition, easy to use.In addition, fat milk can provide heat energy and essential fatty acid, can be fully by organism metabolism and utilization.So as pharmaceutical carrier, make the patient in drug application fat milk, also can replenish certain energy and nutrition.
Seal oil is the animal oil that is rich in omega-3 unsaturated fatty acid that enjoyed people to pay close attention in the last few years, is used to body-care and immunomodulating.It is rich in a high proportion of omega-3 unsaturated fatty acid, EPA, DPA and DHA.And seal oil can be used as the good solvent of insoluble medicine.Based on its above characteristics, we consider to select for use the oil phase of seal oil as the preparation fat milk, in the hope of obtaining good result.
Paclitaxel was at first gone on the market by FDA (Food and Drug Adminstration) (FDA) approval in 1992, was used for the treatment of ovarian cancer.Approval treatment breast carcinoma in 1994.This medicine has been classified at present as a line medicine of kinds of tumors, be used to treat nonsmall-cell lung cancer, the esophageal carcinoma, hepatocarcinoma, carcinoma of prostate, incidence scale cancer etc.But taxol soluble extreme difference; In order to increase its dissolubility, domestic and international commercial formulation for paclitaxel all adopts same prescription at present, promptly at paclitaxel ethanol; Be about to paclitaxel be dissolved in polyoxyethylene castor oil (cremophor EL) and dehydrated alcohol (50: 50, in oil solution v/v).But self there are many defectives in this taxoid preparation, mainly shows the serious adverse reaction that polyoxyethylene castor oil causes, like anaphylactic shock, bronchospasm etc.; In addition, the divinyl hexyl phthalate in the polyoxyethylene castor oil solubilized PVC transfusion device causes toxic reaction, and the clinical safety that influences traditional Ramulus et folium taxi cuspidatae class medicine is used.
Summary of the invention
The objective of the invention is, the method for preparing of the intravenous injection fatty breast that is loaded with paclitaxel is provided.
The present invention comprises that also wherein taxol content is 0.02%-12% (W/V) with described paclitaxel intravenous injection fatty breast drug sustained release system, and all the other are the intravenous injection fatty breast.
Paclitaxel intravenous injection fatty breast of the present invention, each component is formed as follows: oil phase 5%-30%, emulsifying agent: 0.5%-7.5%; Glycerol: 1.5%-3.5%, pH regulator agent 0.1%, paclitaxel 0.02%-12%; All the other are water for injection, and percentage ratio wherein is mass percent.
Wherein oil phase is the marine organisms fat that is rich in omega-3 unsaturated fatty acid; Emulsifying agent is selected from: one or more among polyoxyl 40 hydrogenated castor oil (HC0-40), lecithin, soybean phospholipid, Tween 80 or the pluronic F68, the pH regulator agent is selected from: sodium hydroxide or hydrochloric acid.
A kind of in seal oil or the bathypelagic fish oil of the wherein said marine organisms fat that is rich in omega-3 unsaturated fatty acid.
Preferred paclitaxel intravenous injection fatty breast of the present invention; Consisting of of each component: seal oil or bathypelagic fish oil: 5%-30%; Emulsifying agent: 0.5%-7.5%, glycerol: 1.5%-3.5%, the pH regulator agent is 0.1% sodium hydroxide or hydrochloric acid solution; Paclitaxel: 0.02%-12%, all the other are water for injection.
Preferred especially prescription consists of:
Paclitaxel 0.02%-12%
Seal oil or bathypelagic fish oil 5%-30%
HC0-400.5％-7.5％
Glycerol 1.5%-3.5%
0.1% sodium hydroxide is transferred pH to 8.5
All the other are water for injection
Most preferred prescription consists of:
Paclitaxel 0.01g
1.0g in the seal oil
HC0-400.25g
Glycerol 0.20g
Water for injection 10ml
0.1% sodium hydroxide is transferred pH to 8.5
Paclitaxel intravenous injection fatty of the present invention breast, its particle diameter be at 180-250nm, and PI is between 0.15-0.25, and Zeta potential is at-30mV--50mV, Ke＜0.5, and pH value is at 7-8.
Paclitaxel intravenous injection fatty breast method for preparing of the present invention: take by weighing the recipe quantity paclitaxel and be dissolved in an amount of seal oil, as oil phase; An amount of emulsifying agent of weighing and glycerol is mix homogeneously in a certain amount of water for injection (0.1% sodium hydroxide is transferred pH to 8.5), as water; With slow dropping of oil phase and aqueous phase, form emulsion just again, circulate 5 times under the pressure of the even 800-1200bar of high pressure breast, promptly obtain paclitaxel intravenous injection fatty breast through magnetic agitation.
The invention provides a kind of cosolvent polyoxyethylene castor oil formulation for paclitaxel that do not contain, solved a series of application limitations such as serious adverse reaction that polyoxyethylene castor oil brings in clinical the answering, strengthen patient's compliance.
The present invention is through the screening of prescription; It is in the fat milk of oil phase that selection is wrapped in paclitaxel with the seal oil, adds HC0-40 simultaneously, has solved the common stable low problem of fat milk; Through detecting its quality outward appearance homogeneous; Stability is high, and method for preparing is simple, and prepared paclitaxel fat milk has obvious antineoplastic.According to general lipomul characteristics, paclitaxel lipomul of the present invention also has slow release, targeting, effects such as energy and nutrition is provided for body.
Below through experimental data useful result of the present invention (is that representative experimentizes with embodiment 1) is described:
1, the stability of paclitaxel intravenous injection fatty breast
The invention belongs to the injection nano-emulsion, belong to thermodynamic unstable system, decentralized photo is easy to merge and destroys.The quality of Emulsion and the physical and chemical stability of Emulsion are in close relations, and the stability of research Emulsion is to improve the important step of its quality.The present invention through monitor its under high temperature, illumination condition and the physical and chemical stability of accelerated test and long term test evaluate.The result explain that the paclitaxel fat milk of preparation has good stability, and low tempertaure storage is more favourable referring to accompanying drawing 3,4,5.
2, the release in vitro degree of paclitaxel intravenous injection fatty breast
Be loaded with the medicine release in vitro of the fat milk of paclitaxel; Realize in the following manner: the preparation drug loading is the paclitaxel fat milk of 800mg/L; The accurate 3mL that draws is in the bag filter of handling well, and step up with dialysis clamp at two ends, places the wide mouthed bottle that contains 50mL dialysis medium.Wide mouthed bottle is put into 37 ℃ of air isothermal vibration devices, 100 times/minute vibrations, in 1h, 2h, 4h, 8h, 12h, 24h, 36h, 48h, the 60h sampling, and change the fresh dialysis medium of 50mL.The sample that takes out with 0.45 μ m filtering with microporous membrane after sample introduction, the concentration of HPLC analysis TAX.Release with free drug simultaneously contrasts.The result is referring to accompanying drawing 6.
3, the anti-tumor in vivo of paclitaxel fat milk is active
Estimating curative effect of medication realizes in the following manner: laboratory animal adopts the Male Kunming strain mice that the oxter is inoculated has the S180 ascites tumor, body weight 18-22g, administering mode: tail vein injection, dosage 8mg/kg.Experiment is divided into groups: 1 paclitaxel fat milk group, 2 paclitaxel injection groups, 3 paclitaxel suspension groups, 4 blank fat milk groups, 5 normal saline groups.Each is organized mice and normally raises, 24 hours beginning intravenous injection said medicine 0.2ml behind the inoculated tumour, and in administration in 1,3,5,7 day, totally 4 times.After 7 days each group tumor-bearing mice is put to death, dissect, get tumor, take by weighing tumor and weigh, calculate tumour inhibiting rate.The result sees accompanying drawing 7.
4, the paclitaxel fat milk is to the external lethal effect of human cervical carcinoma Hela cell system
Estimating curative effect of medication realizes in the following manner: select for use the human cervical carcinoma Hela cell to be, be inoculated in 96 orifice plates, 5000 cells in every hole, 37 ℃, 5%CO
2Cultivate in the incubator.Experiment is divided into paclitaxel fat milk group and paclitaxel suspension group, five concentration of every settings, and content of taxol is respectively: 80.00mg/L, 8.00mg/L, 8.00 * 10
-1Mg/L, 8.00 * 10
-2Mg/L, 8.00 * 10
-3Mg/L.Behind the cell culture 24h (this moment cell monolayer be paved with at the bottom of the hole about 80%), add the medicine of each Concentraton gradient, cultivate 24h respectively, 48h, 72h.Cultivate and finish each hole adding 5mg/ml MTT solution 20ul of back, hatch 4h, abandon supernatant; Every hole adds 150ulDMSO, fully shakes 10 minutes on the oscillator, and crystallization is fully dissolved; Measure the OD value in each hole at enzyme-linked immunosorbent assay instrument OD570nm (630nm calibration), calculate cell survival rate.The result sees accompanying drawing 8.
Description of drawings
Accompanying drawing 1 has been described the sem photograph of paclitaxel fat milk.
Accompanying drawing 2 has been described the transmission electron microscope picture of paclitaxel fat milk.
When Fig. 3 has described 25 ℃ of room temperatures and stores be the paclitaxel fat milk (Emulsion A) of emulsifying agent and be the particle diameter and Zeta potential variation of the paclitaxel fat milk (Emulsion B) of emulsifying agent with lecithin with the polyoxyl 40 hydrogenated castor oil.
When Fig. 4 has described 25 ℃ of room temperatures and has stored with the pH value of polyoxyl 40 hydrogenated castor oil and lecithin and the variation of centrifugal stability constant.
Osmotic pressure and content of taxol with polyoxyl 40 hydrogenated castor oil and lecithin when Fig. 5 has described 25 ℃ of storages of room temperature change.
It is the medicine release in vitro curve of paclitaxel in the paclitaxel fat milk of emulsifying agent with the polyoxyl 40 hydrogenated castor oil that Fig. 6 has described.
It is the medicine release in vitro curve of paclitaxel in the paclitaxel fat milk of emulsifying agent with lecithin that Fig. 7 has described.
Fig. 8 has described to be the paclitaxel fat milk of emulsifying agent with the polyoxyl 40 hydrogenated castor oil and to be the anti-tumor in vivo effect of the paclitaxel fat milk of emulsifying agent with lecithin.
Fig. 9 has described to be the paclitaxel fat milk of emulsifying agent with the polyoxyl 40 hydrogenated castor oil and to be the external lethal effect of the paclitaxel fat milk of emulsifying agent to the human cervical carcinoma Hela cell with lecithin.
The specific embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
Embodiment one: with seal oil is the preparation of the paclitaxel fat milk of emulsifying agent as oil phase, polyoxyl 40 hydrogenated castor oil
Accurately taking by weighing the 0.1g paclitaxel is dissolved in the 1.0g seal oil, as oil phase; Weighing 0.25g polyoxyl 40 hydrogenated castor oil (HC0-40) and 0.20g glycerol mix homogeneously in 10ml water for injection (0.1% sodium hydroxide is transferred pH to 8.5) are as water; With slow dropping of oil phase and aqueous phase, form emulsion just again, circulate 5 times under the pressure of the even 800-1200bar of high pressure breast, promptly obtain paclitaxel intravenous injection fatty breast through magnetic agitation 30min.
Embodiment two: with seal oil is the preparation of the paclitaxel fat milk of emulsifying agent as oil phase, lecithin
Accurately taking by weighing the 0.02g paclitaxel is dissolved in the 1.0g seal oil, as oil phase; Weighing 0.25g lecithin and 0.225g glycerol is mix homogeneously in 10ml water for injection (0.1% sodium hydroxide is transferred pH to 8.5), as water; With slow dropping of oil phase and aqueous phase, form emulsion just again, circulate 5 times under the pressure of the even 800-1200bar of high pressure breast, promptly obtain paclitaxel intravenous injection fatty breast through magnetic agitation 30min.
Embodiment three: the microscopic pattern of paclitaxel fat milk is observed
Get paclitaxel fat milk sample solution, use distilled water diluting, get 10ul and place the copper mesh surface, following lining filter paper after volatilizing naturally, is prepared transmission electron microscope observing.Fixedly the Electronic Speculum electron-beam voltage is 80kV, and moving coordinate is regulated amplification, and searching is observed particle and taken pictures.See accompanying drawing 1.Simultaneously with the dilution sample drop 20ul on coverslip, after volatilizing naturally, metal spraying carries out scanning electron microscopic observation.See accompanying drawing 2.
The present invention can find out that through transmission electron microscope single nano structured lipid carrier is a spheroidal particle, and size is homogeneous relatively, and it is more even to distribute; Also confirmed The above results in the scanning electron microscope visual field.
Claims (9)
1. a paclitaxel intravenous injection fatty is newborn, it is characterized in that, each component is formed as follows: oil phase 5%-30%, and emulsifying agent: 0.5%-7.5%, glycerol: 1.5%-3.5%, pH regulator agent 0.1%, paclitaxel 0.02%-12%, all the other are water for injection.
2. the described paclitaxel intravenous injection fatty of claim 1 is newborn; It is characterized in that; Wherein oil phase is the marine organisms fat that is rich in omega-3 unsaturated fatty acid; Emulsifying agent is selected from: one or more among polyoxyl 40 hydrogenated castor oil, lecithin, soybean phospholipid, Tween 80 or the pluronic F68, pH regulator agent are sodium hydroxide or hydrochloric acid.
3. the described paclitaxel intravenous injection fatty of claim 2 breast is characterized in that, a kind of in seal oil or the bathypelagic fish oil of the described marine organisms fat that is rich in omega-3 unsaturated fatty acid.
4. the described paclitaxel intravenous injection fatty of claim 3 is newborn; It is characterized in that each component is formed as follows: seal oil or bathypelagic fish oil: 5%-30%, emulsifying agent: 0.5%-7.5%; Glycerol: 1.5%-3.5%; The pH regulator agent is 0.1% sodium hydroxide or hydrochloric acid solution, paclitaxel: 0.02%-12%, and all the other are water for injection.
5. the described paclitaxel intravenous injection fatty of claim 4 breast is characterized in that particle diameter at 180-250nm, and PI is between 0.15-0.25, and Zeta potential is at-30mV--50mV, Ke＜0.5, and pH value is 7-8.
6. the described paclitaxel intravenous injection fatty of claim 4 is newborn, it is characterized in that, each component is formed as follows:
Paclitaxel 0.02%-12%
Seal oil or bathypelagic fish oil 5%-30%
HC0-400.5％-7.5％
Glycerol 1.5%-3.5%
0.1% sodium hydroxide is transferred pH to 8.5
All the other are water for injection.
7. the described paclitaxel intravenous injection fatty of claim 6 is newborn, it is characterized in that, each component is formed as follows:
Paclitaxel 0.01g
1.0g in the seal oil
HC0-400.25g
Glycerol 0.20g
Water for injection 10ml
0.1% sodium hydroxide is transferred pH to 8.5.
8. the method for preparing of the described intravenous injection fatty breast of claim 1 is characterized in that step is following: take by weighing the recipe quantity paclitaxel and be dissolved in the 5%-30% seal oil, as oil phase; Weighing 0.5%-7.5% emulsifying agent and 1.5%-3.5% glycerol are transferred pH to 8-9 in water for injection with sodium hydroxide, and mix homogeneously is as water; With slow dropping of oil phase and aqueous phase, form emulsion just again, circulate 5 times under the pressure of the even 800-1200bar of high pressure breast, promptly obtain paclitaxel intravenous injection fatty breast through magnetic agitation 30min.
9. according to the method for preparing of claim 9, it is characterized in that step is following: take by weighing paclitaxel and be dissolved in the 1.0g seal oil, as oil phase; Weighing 0.25g HC0-40 and 0.20g glycerol is mix homogeneously in 10ml water for injection (0.1% sodium hydroxide is transferred pH to 8.5), as water; With slow dropping of oil phase and aqueous phase, form emulsion just again, circulate 5 times under the pressure of the even 800-1200bar of high pressure breast, promptly obtain paclitaxel intravenous injection fatty breast through magnetic agitation 30min.
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| CN105147609A (en) * | 2015-10-28 | 2015-12-16 | 辅必成（上海）医药科技有限公司 | Diethylstilbestrol fat emulsion injection |
| CN110824122A (en) * | 2019-10-29 | 2020-02-21 | 江苏盈科生物制药有限公司 | In-vitro release model and in-vitro release method of propofol fat emulsion injection |
| WO2021143751A1 (en) * | 2020-01-14 | 2021-07-22 | 中国科学院上海药物研究所 | Injectable long-acting analgesic pharmaceutical composition, preparation method therefor, and application thereof |
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