CN1555799A - Fatly emulsion of camptothecin kind antitumour medicine and its preparation method - Google Patents
Fatly emulsion of camptothecin kind antitumour medicine and its preparation method Download PDFInfo
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- CN1555799A CN1555799A CNA2003101128131A CN200310112813A CN1555799A CN 1555799 A CN1555799 A CN 1555799A CN A2003101128131 A CNA2003101128131 A CN A2003101128131A CN 200310112813 A CN200310112813 A CN 200310112813A CN 1555799 A CN1555799 A CN 1555799A
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Abstract
An antineoplastic camptothecin kind of medicines in the form of lipoemulsion is prepared from camptothecin, oil for injection, surfactant and water phase. Its advantages are high curative effect, low toxin and low cost.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to lipomul of camptothecin antineoplastic agents and preparation method thereof
Background technology
(Campotothecin CPT) is a kind of alkaloid that Americanized scholar Wall ME and Wani MC at first extracted in 1966 to camptothecine from Chinese Nyssaceae plant camptotheca acuminata (Campotheca acuminata).Test shows that it has active anticancer to many solid tumors.Yet camptothecine water solublity extreme difference, therefore early stage clinical water solublity sodium salt with camptothecine, and the sodium salt that will prepare camptothecine must make the camptothecine open loop, and it is poor that regrettably camptothecine open loop form produces serious toxic and side effects and active anticancer, causes the clinical interruption of II phase.Oncologist is the mechanism of action that comes from it to the interest again of camptothecine, discovering of the later stage eighties 20th century, the anti-tumor activity of camptothecine is to suppress duplicating and transcribing of DNA by acting on topology isomerase I, thereby makes the research of camptothecine enter a brand-new stage.
In recent years, successively go on the market with respect to some water soluble camptothecin derivatives such as irinotecan, topotecan etc., (10-Hydroxycampotothecin, research HCPT) but is to rarely have progress to the camptothecine of indissoluble and derivant thereof such as 10-hydroxycamptothecine.Though in China's listing, preparation also is its water solublity sodium salt to 10-hydroxycamptothecine, anti-tumor activity is lower and toxicity is bigger.Discover, Alpha-hydroxy lactonic ring on the camptothecine E ring is the key position of its anti-tumor activity, and the anti-tumor activity of (sodium salt) only is 1/10 (progress of natural antitumor medicine camptothecin derivative, an Acta Pharmaceutica Sinica of lactone form after the open loop, 2003,38 (9): 715-720).Therefore, do not make sodium salt and the camptothecine and the derivant thereof of indissoluble prepared ejection preparation, have crucial meaning, not only brought new hope, and had very vast market prospect for numerous cancer patients for the research and development of camptothecine.
Summary of the invention
The invention discloses lipomul (also claiming Emulsion) of camptothecin antineoplastic agents and preparation method thereof.The invention solves camptothecin antineoplastic agents and when its injection of preparation, can only prepare the difficult problem that its sodium salt causes active reduction owing to be insoluble in water, the slightly solubility camptothecin antineoplastic agents is prepared into lipomul, with lactone form camptothecine and derivant thereof are prepared into intravenous formulations, can improve the anti-tumor activity of these medicines; In addition, Emulsion is the drug particles transmission system, have tangible lymphsystem and mononuclear phagocyte system (mononuclear phagocyte system as pharmaceutical carrier, MPS) targeting, be that medicine in the Emulsion is transported to lymphsystem along with emulsion droplet or is engulfed by reticuloendothelial cell and concentrate at lymph fluid and the organs and tissues that is rich in MPS, utilize this characteristics, in the infatmul agent, add cancer therapy drug, can obviously increase cancer therapy drug after injecting in the body liver, spleen, the concentration at position such as lung and lymph, thereby can improve curative effect, reduce untoward reaction; And higher lymph drug level can prevent effectively that cancerous cell from shifting from the lymph approach.
The lipomul of camptothecin antineoplastic agents of the present invention, form by following component and weight:
Camptothecin antineoplastic agents 0.001-1%
Oil for injection 0.5-50%
Surfactant 0.5-50%
Water 40-98%
Antioxidant 0-0.01%
More than each percentage ratio be weight/volume percent.
Preferred ingredients and weight are formed:
Camptothecin antineoplastic agents 0.005-0.1%
Oil for injection 1-30%
Surfactant 1-10%
Water 70-95%
Vitamin E or vitamin C 0-0.001%
More than each percentage ratio be weight/volume percent.
The lipomul of above-mentioned camptothecin antineoplastic agents, wherein camptothecin antineoplastic agents can be: camptothecine, 10-hydroxycamptothecine, 9-nitrocamptothecin, 9-aminocamptothecin or other slightly solubility camptothecin antineoplastic agents.
The lipomul of above-mentioned camptothecin antineoplastic agents, the wherein preferred injection soybean oil of oil for injection, injection medium chain length fatty acid triglyceride or its mixture.Fatty acid preferably contains the medium-chain fatty acid of 6 to 14 carbon atoms in the medium chain length fatty acid triglyceride.
The lipomul of above-mentioned camptothecin antineoplastic agents, wherein one or more in the preferred phospholipid of surfactant, pluronic F-68, polyoxyethylene sorbitan monoleate, polyoxyethylene castor oil, the NaTDC.Wherein preferred fabaceous lecithin of phospholipid or lecithin.
The lipomul of above-mentioned camptothecin antineoplastic agents, wherein water is sodium-chloride water solution, sodium lactate aqueous solution, glycerine water solution, Osmitrol, sorbitol aqueous solution, dextran aqueous solution, HP-beta-schardinger dextrin-aqueous solution, starch derivatives aqueous solution, aqueous gelatin solution, polyvidone aqueous solution.
The preparation method of the lipomul of camptothecin antineoplastic agents of the present invention: take by weighing recipe quantity medicine, emulsifying agent and oil phase, dissolving obtains oil phase; Oil phase and water vortex or mix and make colostrum; Colostrum makes Emulsion through high pressure homogenize.But clarify oil phase heating for dissolving medicine in order to prepare, also available organic solvent dissolution, reduction vaporization is removed organic solvent and must be clarified oil phase then, described organic solvent particular methanol, ethanol, isopropyl alcohol, ether, chloroform, dichloromethane or their mixture.
Camptothecin antineoplastic agents Emulsion steady quality of the present invention need not to add stabilizing agent and cosolvent, so not only effectively reduces cost, and has removed the toxicity that adds stabilizing agent and cosolvent in addition and produced, better efficacy.For reducing phospholipid and greasy oxidation, can add antioxidant, antioxidant preferred vitamin E and/or vitamin C, consumption are the 0-0.01% (w/v) of Emulsion.Hydroxy camptothecin lipomul of the present invention can be directly used in intravenous injection.
Comparing with commercial preparation (hydroxy camptothecin liquid drugs injection) with the prepared camptothecin antineoplastic agents Emulsion of the present invention and can significantly improve drug effect, is part pharmacology test data below.
1 hydroxy camptothecin Emulsion and commercially available light water are at the inhibiting comparison of S180 cancerous cell
Adopt mtt assay.The S180 cell of exponential phase is by every hole 2 * 10
4Be inoculated in 96 orifice plates, 5%CO
2Cultivate after 12 hours for 37 ℃ and be divided into 3 groups, add respectively common liquid drugs injection of hydroxy camptothecin (HCPT) and microemulsion diluent (concentration is respectively 0.125,0.5,2,8,32,128 μ g/ml) each 50 μ l, negative control group adds equal-volume serum-free 1640 culture medium 50 μ l, each concentration is established 6 multiple holes, 5%CO
2Cultivate after 36 hours for 37 ℃, adding MTT solution (5mg/ml) 20 μ l continues to cultivate, every hole adds acidifying SDS solution (10%SDS-0.01MHCl) after 4 hours, effect product Jia Za dissolving with cell and MTT, measure absorbance in the 570nm place with enzyme-linked immunosorbent assay instrument immediately behind the mixing, calculate cell growth rate.
Cell growth curve is seen accompanying drawing 1.Calculate the IC of HCPT Emulsion and commercial preparation
50Be respectively 1.31 and 45.5 μ mol/L.This shows, be prepared into the ability that has improved its anticancer behind the Emulsion greatly.
2 hydroxy camptothecin Emulsions and commercial preparation are to the inhibiting comparison of mice-transplanted tumor Heps
Get 30 of kunming mices, (under the sterile working, get the tumor piece by transplanted tumor organon inoculation Heps solid type, weigh, grind with the glass Potter-Elvehjem Tissue Grinders, put in people's sterile chamber after mill is even, add the cell suspension that normal saline is diluted to 1: 3, container is put on the ice cube, with the empty needle suction, each suction is preceding with the cell mixing, every mice right fore liquid nest subcutaneous vaccination 0.2ml), inoculate back 24 hours and claim Mus heavy, and being divided into 3 groups at random, blank group and hydroxy camptothecin liquid drugs injection group are respectively the positive and negative matched group, hydroxy camptothecin Emulsion group.The iv administration, per 2 days are once, and administration is 4 times altogether, and execution in the 2nd day is weighed after the drug withdrawal, and separates the tumor piece and weigh, and the gained data are carried out statistical procedures (t check).
Table 1 hydroxy camptothecin Emulsion iv is to inhibitory action (X ± SD) (n=10) of mice-transplanted tumor Heps
The heavy tumour inhibiting rate of dosage body weight (g) tumor
Group
(mg/kg) (g) (%) after the administration before the administration
Matched group 19.6 ± 1.4 25.2 ± 1.0 1.70 ± 0.23
HCPT liquid drugs injection 3 19.4 ± 1.2 25.4 ± 1.2 1.02 ± 0.23
a40.1
HCPT Emulsion 3 19.7 ± 1.3 25.2 ± 1.0 0.77 ± 0.18
A, b54.6
aP＜0.01: compare with the normal saline matched group;
bP＜0.05: compare with hydroxy camptothecin liquid drugs injection group
Result of the test sees Table 1.The result shows, compares with the normal saline matched group, and hydroxy camptothecin Emulsion group and hydroxy camptothecin liquid drugs injection group all have the tumor growth effect (P＜0.01) that suppresses Heps significantly, and both all do not have obvious influence to weight of mice; Compare with hydroxy camptothecin liquid drugs injection group, the tumor growth effect that hydroxy camptothecin Emulsion suppresses Heps can significantly increase (P＜0.05), has increased by 14.5%.
Description of drawings
Fig. 1 is that hydroxy camptothecin Emulsion and commercially available hydroxy camptothecin hydro-acupuncture preparation are to the inhibiting comparison of S180 cancerous cell.Wherein ▲ and representing blank Emulsion, ■ represents the commercial preparation, ● expression pastille Emulsion.
The specific embodiment
Take by weighing HCPT, injection soybean oil and injection fabaceous lecithin by the listed mass percent of table 2,60 ℃ of heating for dissolving get oil phase; Take by weighing the water-soluble water that gets of recipe quantity glycerol.Water is heated to 60 ℃, and water is poured oil phase into, and high-speed stirred makes colostrum.Colostrum through high pressure homogenizer (Microfluidics Corp., Newton, MA, U.S.A.) breast even submicron emulsion, 0.45 μ m membrane filtration, canned in ampoule, the 2ml/ ampoule.
Table 2
Composition weight (g)
HCPT 0.1
Injection fabaceous lecithin 2
Glycerol 2.25
Water for injection 85.65
Measure the Emulsion particle diameter with the Ma Erwen particle size analyzer, measure Emulsion Chinese medicine content with the high performance liquid chromatogram fluorescence detection.4 ℃ of testing results that keep sample of gained Emulsion see Table 3.
4 ℃ of reserved sample observing results of table 3 Emulsion
Time (moon) 01236
Particle diameter 223 220 230 232 235
Content 100.4 100.5 99.8 100.0 99.5
Embodiment 2
Take by weighing HCPT, injection soybean oil and injection fabaceous lecithin by the listed percentage by weight of table 4, with anhydrous alcohol solution, 60 ℃ of reduction vaporizations are removed dehydrated alcohol and are got oil phase; Take by weighing the water-soluble water that gets of recipe quantity pluronic F-68 and sorbitol.Water is heated to 60 ℃, and water is poured oil phase into, and high-speed stirred makes colostrum.Colostrum through high pressure homogenizer breast even submicron emulsion, the 0.22m membrane filtration, canned in ampoule, the 5ml/ ampoule.
Table 4
Composition weight (g)
HCPT 0.1
Injection soybean oil 5
Injection fabaceous lecithin 2
Pluronic F-68 1
Sorbitol 5
Water for injection 86.9
Measure the Emulsion particle diameter with the Ma Erwen particle size analyzer, measure Emulsion Chinese medicine content with high performance liquid chromatogram fluorescence prison detection method.4 ℃ of testing results that keep sample of gained Emulsion see Table 5.
4 ℃ of reserved sample observing results of table 5 Emulsion
Time (moon) 01236
Particle diameter 89 94 91 95 97
Content 100.3 99.7 99.9 99.3 99.5
Embodiment 3
Take by weighing HCPT, injection soybean oil, vitamin E, injection medium chain length fatty acid triglyceride, vitamin E and injection fabaceous lecithin by the listed percentage by weight of table 6,60 ℃ of heating for dissolving get oil phase; Take by weighing the water-soluble water that gets of recipe quantity glycerol.Water is heated to 60 ℃, and water is poured oil phase into, and high-speed stirred makes colostrum.Colostrum through high pressure homogenizer breast even submicron emulsion, 0.45 μ m membrane filtration, canned in the 100ml infusion bottle.
Table 6
Composition weight (g)
HCPT 0.005
Injection soybean oil: injection medium chain length fatty acid triglyceride (1: 1) 10
Injection fabaceous lecithin 2
Vitamin E 0.005
Glycerol 2.25
Water for injection 85.74
Measure the Emulsion particle diameter with the Ma Erwen particle size analyzer, measure Emulsion Chinese medicine content with the high performance liquid chromatogram fluorescence detection.4 ℃ of testing results that keep sample of gained Emulsion see Table 7.
4 ℃ of reserved sample observing results of table 7 Emulsion
Time (moon) 01236
Particle diameter 189 191 195 196 203
Content 100.1 99.9 100.2 99.7 99.5
Embodiment 4
Take by weighing HCPT, injection soybean oil, vitamin E, injection medium chain length fatty acid triglyceride, vitamin E and injection fabaceous lecithin by the listed percentage by weight of table 8, with anhydrous alcohol solution, 60 ℃ of reduction vaporizations are removed dehydrated alcohol and are got oil phase; Take by weighing the water-soluble water that gets of recipe quantity pluronic F-68 and glycerol.Water is heated to 60 ℃, and water is poured oil phase into, and high-speed stirred makes colostrum.Colostrum through high pressure homogenizer breast even microemulsion, 0.22 μ m membrane filtration, canned in the 100ml infusion bottle.
Table 8
Composition weight (g)
HCPT 0.005
Injection soybean oil: injection medium chain length fatty acid triglyceride (1: 1) 5
Injection fabaceous lecithin 2
Vitamin E 0.005
Pluronic F-68 0.5
HP-beta-schardinger dextrin-1
Glycerol 2.25
Water for injection 89.69
Measure the Emulsion particle diameter with the Ma Erwen particle size analyzer, measure Emulsion Chinese medicine content with high performance liquid chromatogram fluorescence monitoring method.4 ℃ of testing results that keep sample of gained Emulsion see Table 9.
4 ℃ of reserved sample observing results of table 9 Emulsion
Time (moon) 01236
Particle diameter 79 83 85 84 89
Content 100.1 99.7 99.8 100.0 99.8
Claims (10)
1, the lipomul of camptothecin antineoplastic agents, form by following component and weight:
Camptothecin antineoplastic agents 0.001-1%
Oil for injection 0.5-50%
Surfactant 0.5-50%
Water 40-98%
Antioxidant 0-0.01%
More than each percentage ratio be weight/volume percent.
2, the lipomul of the described camptothecin antineoplastic agents of claim 1, form by following component and weight:
Camptothecin antineoplastic agents 0.005-0.1%
Oil for injection 1-30%
Surfactant 1-10%
Water 70-95%
Vitamin E or vitamin C 0-0.001%
More than each percentage ratio be weight/volume percent.
3, the lipomul of claim 1 or 2 described camptothecin antineoplastic agents, wherein camptothecin antineoplastic agents is: camptothecine, 10-hydroxycamptothecine, 9-nitrocamptothecin, 9-aminocamptothecin or other slightly solubility camptothecin antineoplastic agents.
4, the lipomul of claim 1 or 2 described camptothecin antineoplastic agents, wherein oil for injection is injection soybean oil, injection medium chain length fatty acid triglyceride or its mixture.
5, the lipomul of the described camptothecin antineoplastic agents of claim 4, wherein fatty acid is the medium-chain fatty acid that contains 6 to 14 carbon atoms in the medium chain length fatty acid triglyceride.
6, the lipomul of claim 1 or 2 described camptothecin antineoplastic agents, wherein surfactant is selected from one or more in phospholipid, pluronic F-68, polyoxyethylene sorbitan monoleate, polyoxyethylene castor oil, the NaTDC.
7, the lipomul of the described camptothecin antineoplastic agents of claim 6, wherein phospholipid is fabaceous lecithin or lecithin.
8, the lipomul of claim 1 or 2 described camptothecin antineoplastic agents, wherein water is sodium-chloride water solution, sodium lactate aqueous solution, glycerine water solution, Osmitrol, sorbitol aqueous solution, dextran aqueous solution, HP-beta-schardinger dextrin-aqueous solution, starch derivatives aqueous solution, aqueous gelatin solution or polyvidone aqueous solution.
9, the preparation method of the lipomul of each described camptothecin antineoplastic agents in the claim 1 to 8: take by weighing recipe quantity medicine, emulsifying agent and oil phase, dissolving obtains oil phase; Oil phase and water vortex or mix and make colostrum; Colostrum makes Emulsion through high pressure homogenize.
10, the described preparation method of claim 9, but wherein in order to prepare clarification oil phase heating for dissolving medicine or to use organic solvent dissolution, reduction vaporization is removed organic solvent and must be clarified oil phase then, and described organic solvent is methanol, ethanol, isopropyl alcohol, ether, chloroform, dichloromethane or their mixture.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100349570C (en) * | 2004-11-26 | 2007-11-21 | 复旦大学 | 10-hydoxy camptothecin self micro emulsifieation composition |
| CN1951367B (en) * | 2006-08-08 | 2012-05-30 | 沈阳药科大学 | Fat emulsion containing hydroxycamptothecine and preparation method thereof |
-
2003
- 2003-12-30 CN CNA2003101128131A patent/CN1555799A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100349570C (en) * | 2004-11-26 | 2007-11-21 | 复旦大学 | 10-hydoxy camptothecin self micro emulsifieation composition |
| CN1951367B (en) * | 2006-08-08 | 2012-05-30 | 沈阳药科大学 | Fat emulsion containing hydroxycamptothecine and preparation method thereof |
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