CN102579338B - Preparation method and application of paclitaxel intravenous fat emulsion - Google Patents
Preparation method and application of paclitaxel intravenous fat emulsion Download PDFInfo
- Publication number
- CN102579338B CN102579338B CN 201210054361 CN201210054361A CN102579338B CN 102579338 B CN102579338 B CN 102579338B CN 201210054361 CN201210054361 CN 201210054361 CN 201210054361 A CN201210054361 A CN 201210054361A CN 102579338 B CN102579338 B CN 102579338B
- Authority
- CN
- China
- Prior art keywords
- paclitaxel
- oil
- fat emulsion
- water
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 71
- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 71
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title claims abstract description 71
- 239000000468 intravenous fat emulsion Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000008215 water for injection Substances 0.000 claims abstract description 12
- 235000019198 oils Nutrition 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 239000012071 phase Substances 0.000 claims description 18
- 239000000839 emulsion Substances 0.000 claims description 11
- 210000000481 breast Anatomy 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 7
- 238000013019 agitation Methods 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 235000021323 fish oil Nutrition 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 5
- 238000010253 intravenous injection Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 235000019197 fats Nutrition 0.000 abstract description 34
- 239000003995 emulsifying agent Substances 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 7
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 235000020660 omega-3 fatty acid Nutrition 0.000 abstract description 5
- 241001465754 Metazoa Species 0.000 abstract description 2
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 abstract description 2
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 abstract description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 abstract description 2
- 230000002411 adverse Effects 0.000 abstract 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 abstract 1
- 239000002960 lipid emulsion Substances 0.000 abstract 1
- 229940012843 omega-3 fatty acid Drugs 0.000 abstract 1
- 235000013336 milk Nutrition 0.000 description 31
- 239000008267 milk Substances 0.000 description 31
- 210000004080 milk Anatomy 0.000 description 31
- 239000003921 oil Substances 0.000 description 27
- 239000003814 drug Substances 0.000 description 21
- 229940079593 drug Drugs 0.000 description 12
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 9
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 9
- 235000010445 lecithin Nutrition 0.000 description 9
- 239000000787 lecithin Substances 0.000 description 9
- 229940067606 lecithin Drugs 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 8
- -1 polyoxyethylene Polymers 0.000 description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 239000004359 castor oil Substances 0.000 description 5
- 235000019438 castor oil Nutrition 0.000 description 5
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 4
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 208000019065 cervical carcinoma Diseases 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 229940090044 injection Drugs 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 235000004626 essential fatty acids Nutrition 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- SUUGFZGMNNIKEE-NOSCCTPQSA-N paclitaxel ethanol Chemical compound CCO.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 SUUGFZGMNNIKEE-NOSCCTPQSA-N 0.000 description 1
- 229940108949 paclitaxel injection Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
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 preparation of the paclitaxel intravenous fat emulsion take seal oil as substrate.Relate generally to this fat milk to the application of 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 the 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, namely pharmaceutical pack is wrapped in interior phase or boundary layer.Compare with other particle type carriers, the advantage of vein breast is: pharmaceutical pack is wrapped in interior phase or 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 condition and the technology of carrying out large-scale production, is easier to realize commercialization; The long-term clinical application 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 in the last few years people to pay close attention to, and 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 seal oil as the oil phase of preparation fat milk, to obtaining good result.
At first paclitaxel was 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.At present this medicine has been classified as the first-line drug of kinds of tumors, be used for the treatment of 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 formula at present, namely 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, is mainly manifested in the serious adverse reaction that polyoxyethylene castor oil causes, as anaphylactic shock, bronchospasm etc.; In addition, the divinyl hexyl phthalate in polyoxyethylene castor oil solubilized PVC transfusion device causes toxic reaction, and the clinical safety that affects traditional Ramulus et folium taxi cuspidatae class medicine is used.
Summary of the invention
The objective of the invention is, the preparation method of the intravenous injection fatty breast that is loaded with paclitaxel is provided.
The present invention comprises that also with described paclitaxel intravenous fat emulsion drug sustained release system, wherein taxol content is 0.02%-12% (W/V), and all the other are the intravenous injection fatty breast.
Paclitaxel intravenous fat emulsion of the present invention, each component is composed as follows: oil phase 5%-30%, emulsifying agent: 0.5%-7.5%, glycerol: 1.5%-3.5%, pH adjusting 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 in polyoxyl 40 hydrogenated castor oil (HC0-40), lecithin, soybean phospholipid, Tween 80 or Pluronic F68, pH adjusting agent is selected from: sodium hydroxide or hydrochloric acid.
A kind of in seal oil or bathypelagic fish oil of the wherein said marine organisms fat that is rich in omega-3 unsaturated fatty acid.
Preferred paclitaxel intravenous fat emulsion 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%, pH adjusting agent is 0.1% sodium hydroxide or hydrochloric acid solution, paclitaxel: 0.02%-12%, all the other are water for injection.
Particularly preferred formula 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 formula consists of:
Paclitaxel 0.01g
1.0g in seal oil
HC0-400.25g
Glycerol 0.20g
Water for injection 10ml
0.1% sodium hydroxide is transferred pH to 8.5
Paclitaxel intravenous fat emulsion of the present invention, 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 fat emulsion preparation method of the present invention: take the recipe quantity paclitaxel and be dissolved in appropriate seal oil, as oil phase; The appropriate 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; Oil phase is slowly dripped and aqueous phase again, form just emulsion through magnetic agitation, under the pressure of the even 800-1200bar of high pressure breast, circulation is 5 times, namely obtains paclitaxel intravenous fat emulsion.
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 in clinical answering, polyoxyethylene castor oil brings, strengthen patient's compliance.
The present invention is through the screening of formula, selection is wrapped in paclitaxel in fat milk take seal oil as oil phase, add simultaneously HC0-40, solved the common stable low problem of fat milk, its quality outward appearance homogeneous after testing, stability is high, and preparation method is simple, and prepared paclitaxel fat milk has obvious antitumor action.According to general lipomul characteristics, paclitaxel lipomul of the present invention also has slow release, targeting, the effects such as energy and nutrition is provided for body.
Below data illustrate useful result of the present invention (testing take embodiment 1 as representative) by experiment:
1, the stability of paclitaxel intravenous fat emulsion
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 is by monitoring it under high temperature, illumination condition and the physical and chemical stability of accelerated test and long term test is evaluated.Result illustrate 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 vitro release of paclitaxel intravenous fat emulsion
Be loaded with the drug 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, is placed in the wide mouthed bottle that contains 50mL dialysis medium.Wide mouthed bottle is put into 37 ℃ of air isothermal vibration devices, 100 times/minutes 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 compares.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 the S180 ascites tumor, body weight 18-22g, administering mode: tail vein injection, dosage 8mg/kg.Experiment grouping: 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 after 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 tumor heavy, calculate tumour inhibiting rate.The results are shown in accompanying drawing 7.
4, the killing effect in vitro of paclitaxel fat milk to human cervical carcinoma Hela cell system
Estimating curative effect of medication realizes in the following manner: select the human cervical carcinoma Hela cell to be, be inoculated in 96 orifice plates, 5000, every hole cell, 37 ℃, 5%CO
2Cultivate in incubator.Experiment is divided into paclitaxel fat milk group and paclitaxel suspension group, sets five concentration for every group, 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.After cell culture 24h (this moment, cell monolayer was paved with 80% left and right at the bottom of the hole), add the medicine of each Concentraton gradient, cultivate respectively 24h, 48h, 72h.After cultivating end, each hole adds 5mg/ml MTT solution 20ul, hatch 4h, abandon supernatant, every hole adds 150ulDMSO, fully shook 10 minutes on oscillator, crystallization is fully dissolved, measure the optical density value in each hole at enzyme-linked immunosorbent assay instrument OD570nm (630nm calibration), calculate cell survival rate.The results are shown in accompanying drawing 8.
Description of drawings
Accompanying drawing 1 has been described the scanning electron microscope (SEM) photograph of paclitaxel fat milk.
Accompanying drawing 2 has been described the transmission electron microscope picture of paclitaxel fat milk.
Paclitaxel fat milk (Emulsion A) take polyoxyl 40 hydrogenated castor oil as emulsifying agent when Fig. 3 has described 25 ℃ of storages of room temperature and particle diameter and the Zeta potential of the paclitaxel fat milk take lecithin as emulsifying agent (Emulsion B) change.
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.
Fig. 6 has described the drug release in vitro curve of paclitaxel in paclitaxel fat milk take polyoxyl 40 hydrogenated castor oil as emulsifying agent.
Fig. 7 has described the drug release in vitro curve of paclitaxel in paclitaxel fat milk take lecithin as emulsifying agent.
Fig. 8 has described paclitaxel fat milk take polyoxyl 40 hydrogenated castor oil as emulsifying agent and the anti-tumor in vivo effect of the paclitaxel fat milk take lecithin as emulsifying agent.
Fig. 9 has described paclitaxel fat milk take polyoxyl 40 hydrogenated castor oil as emulsifying agent and the paclitaxel fat milk take lecithin as emulsifying agent to human cervical carcinoma Hela cell's killing effect in vitro.
The specific embodiment
In order further to set forth the present invention, the below provides a series of embodiment.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Embodiment one: take seal oil as the preparation as the paclitaxel fat milk of emulsifying agent of oil phase, polyoxyl 40 hydrogenated castor oil
Accurately taking 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; Oil phase is slowly dripped and aqueous phase again, form just emulsion through magnetic agitation 30min, under the pressure of the even 800-1200bar of high pressure breast, circulation is 5 times, namely obtains paclitaxel intravenous fat emulsion.
Embodiment two: take seal oil as the preparation as the paclitaxel fat milk of emulsifying agent of oil phase, lecithin
Accurately taking 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; Oil phase is slowly dripped and aqueous phase again, form just emulsion through magnetic agitation 30min, under the pressure of the even 800-1200bar of high pressure breast, circulation is 5 times, namely obtains paclitaxel intravenous fat emulsion.
Embodiment three: the microscopic pattern of paclitaxel fat milk is observed
Get paclitaxel fat milk sample solution, use distilled water diluting, get 10ul and be placed in the copper mesh surface, lower lining filter paper after naturally volatilizing, is prepared transmission electron microscope observing.Fixedly the Electronic Speculum electron-beam voltage is 80kV, and moving coordinate is regulated amplification, seeks and observes particle and take pictures.See accompanying drawing 1.Simultaneously with the dilution sample drop 20ul on coverslip, after naturally volatilizing, metal spraying carries out scanning electron microscopic observation.See accompanying drawing 2.
The present invention can find out by transmission electron microscope, and single nano structured lipid carrier is 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 (4)
1. a paclitaxel intravenous fat emulsion, is characterized in that, each component forms according to following percentage by weight:
Paclitaxel 0.02%-12%
Seal oil or bathypelagic fish oil 5%-30%
HC0-40?0.5%-7.5%
Glycerol 1.5%-3.5%
0.1% sodium hydroxide is transferred pH to 8.5
All the other are water for injection.
2. paclitaxel intravenous fat emulsion claimed in claim 1, is characterized in that, each component is composed as follows:
Paclitaxel 0.01g
Seal oil 1.0g
HC0-40?0.25g
Glycerol 0.20g
Water for injection 10ml
0.1% sodium hydroxide is transferred pH to 8.5.
3. the preparation method of intravenous injection fatty breast claimed in claim 1, is characterized in that, step is as follows: take the recipe quantity paclitaxel and be dissolved in 5%-30% seal oil or bathypelagic fish oil, as oil phase; Weighing 0.5%-7.5% HC0-40 and 1.5%-3.5% glycerol are transferred pH to 8.5 in water for injection with sodium hydroxide, and mix homogeneously is as water; Oil phase is slowly dripped and aqueous phase again, form just emulsion through magnetic agitation 30min, under the pressure of the even 800-1200bar of high pressure breast, circulation is 5 times, namely obtains paclitaxel intravenous fat emulsion.
4. according to claim 3 preparation method, is characterized in that, step is as follows: take paclitaxel and be dissolved in the 1.0g seal oil, as oil phase; Weighing 0.25g HC0-40 and 0.20g glycerol are transferred pH value of solution to 8.5 with 0.1% sodium hydroxide in 10ml water for injection, mix homogeneously is as water; Oil phase is slowly dripped and aqueous phase again, form just emulsion through magnetic agitation 30min, under the pressure of the even 800-1200bar of high pressure breast, circulation is 5 times, namely obtains paclitaxel intravenous fat emulsion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210054361 CN102579338B (en) | 2012-03-02 | 2012-03-02 | Preparation method and application of paclitaxel intravenous fat emulsion |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210054361 CN102579338B (en) | 2012-03-02 | 2012-03-02 | Preparation method and application of paclitaxel intravenous fat emulsion |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102579338A CN102579338A (en) | 2012-07-18 |
| CN102579338B true CN102579338B (en) | 2013-06-19 |
Family
ID=46468951
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201210054361 Expired - Fee Related CN102579338B (en) | 2012-03-02 | 2012-03-02 | Preparation method and application of paclitaxel intravenous fat emulsion |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102579338B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110824122B (en) * | 2019-10-29 | 2021-05-25 | 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 |
| CN113116811A (en) * | 2020-01-14 | 2021-07-16 | 中国科学院上海药物研究所 | Injectable long-acting analgesic pharmaceutical composition and preparation method and application thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003055323A1 (en) * | 2001-12-27 | 2003-07-10 | Genesis Group Inc. | Seal oil based lipid emulsions and uses thereof |
| US20080128314A1 (en) * | 2005-03-14 | 2008-06-05 | Koichi Takeda | Pharmaceutical Composition Containing Hardly Water Soluble Medicament |
| CN101006997B (en) * | 2006-01-26 | 2011-07-20 | 董英杰 | Compound taxol and its derivative docetaxel fat emulsion and preparation method |
| CN101288642B (en) * | 2007-11-07 | 2011-04-27 | 天津天士力集团有限公司 | Taxanes medicine preparation for intravenous injection and preparation method thereof |
| CN101366697A (en) * | 2008-08-14 | 2009-02-18 | 沈阳万爱普利德医药科技有限公司 | Novel nano-lipid carrier for injection embodying paclitaxel series substances and preparation method thereof |
| CN101822839B (en) * | 2010-03-31 | 2012-01-04 | 首都医科大学 | Preparation of nanometer structure lipid carrier by using seal oil as liquid-phase substrate and application |
| CN101926757B (en) * | 2010-09-01 | 2013-01-02 | 北京大学 | Liquid composition of indissolvable medicines and preparation method thereof |
-
2012
- 2012-03-02 CN CN 201210054361 patent/CN102579338B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN102579338A (en) | 2012-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104224711B (en) | Paclitaxel submicron emulsion taking steroid compound as intermediate vector | |
| CN104337851B (en) | The preparation method of brucea fruit oil nano structured lipid carrier and its freeze-dried powder | |
| CN102133190A (en) | Transferrin nanoparticles and preparation method and application thereof | |
| CN104306333B (en) | A kind of Cabazitaxel lipide microsphere injection and preparation method thereof | |
| CN102579338B (en) | Preparation method and application of paclitaxel intravenous fat emulsion | |
| CN104042567A (en) | Ampelopsin nano-micelle and application thereof | |
| CN100496609C (en) | Stable liposome composition | |
| CN104826122A (en) | Lipid-modified substance of chlorogenic acid and derivative thereof, preparation method and purification method of the lipid-modified substance | |
| CN110025593A (en) | Cell microcapsule, the cell microcapsule for being loaded with anticancer drug, preparation method and application | |
| CN102552137B (en) | Triptolide fat emulsion injection and preparation method thereof | |
| CN108853056B (en) | Folic acid targeted modification carried doxorubicin hydrochloride and gambogic acid nano-structure lipid carrier preparation and preparation method thereof | |
| CN104352566A (en) | Oil-in-water compound chlortetracycline nanoemulsion | |
| CN102641311B (en) | Kiwi fruit seed oil liposome oral liquid and preparation method thereof | |
| CN105748409A (en) | Protopanoxadiol submicroemulsion preparation as well as preparation method and application thereof | |
| CN108158997A (en) | Using rhamnolipid as liposome of membrane material and its preparation method and application | |
| CN101810577A (en) | Gossypol intravenous injection fatty emulsion for curing tumors | |
| CN110478379B (en) | Selaginella chinensis total biflavone precursor liposome and preparation method thereof | |
| CN101822839B (en) | Preparation of nanometer structure lipid carrier by using seal oil as liquid-phase substrate and application | |
| CN107334745A (en) | Multifunctional nano pharmaceutical carrier and taxanes lipid nano particle and preparation method thereof | |
| CN108186573B (en) | Hydroxycamptothecin liver targeting preparation using lipid-coated mesoporous silica as carrier and preparation method thereof | |
| Sangwai et al. | Effect of decisive formulation variables on bioencapsulation efficiency and integrity of yeast biocapsules for oral itraconazole delivery | |
| CN109044991A (en) | Macrophage carrying medicine and preparation method thereof | |
| CN102973508A (en) | Compound astragalus polysaccharide liposome long-acting injection and preparation method thereof | |
| CN114652820A (en) | Cationic liposome nanoparticle and preparation method and application thereof | |
| CN108619098A (en) | A kind of Raltitrexed pH sensitive liposomes and preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130619 Termination date: 20170302 |