CN101889982B - Novel long-circulating liposome composition and preparation method thereof - Google Patents
Novel long-circulating liposome composition and preparation method thereof Download PDFInfo
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- CN101889982B CN101889982B CN2010101470307A CN201010147030A CN101889982B CN 101889982 B CN101889982 B CN 101889982B CN 2010101470307 A CN2010101470307 A CN 2010101470307A CN 201010147030 A CN201010147030 A CN 201010147030A CN 101889982 B CN101889982 B CN 101889982B
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Abstract
The invention relates to a novel long-circulating liposome composition and an application method thereof. The long-circulating liposome composition is mainly prepared from phospholipid, cholesterol, an electronegative material and a long-circulating material serving as main raw materials, wherein tocopheryl acetate succinate or cholesterol succinate is used as the electronegative material particularly, and tocopheryl acetate polyethylene glycol succinate (TPGS) is used as the long-circulating material particularly, so that the stability of combining the long-circulating liposome composition and medicaments is improved; the long-circulating liposome composition can be used as a carrier of anti-tumor medicaments such as paclitaxel, docetaxel and 10-hydroxycamptothecine, and simultaneously, the tolerance is improved; and when the long-circulating liposome composition is used as the medicinal carrier, the circulating time of the carried medicaments in vivo is longer than that of various carriers sold on the market obviously, and the long-circulating liposome composition has the advantages of low cost and suitability for wide popularization and application.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of novel long-circulating liposome composition and application thereof.
Background technology
Paclitaxel (Paclitaxel) is the natural product that from bark, dry root and the branch and leaf of yewtree (Taxus brevifolia Nutt.), extracts, and clinically is used to treat ovarian cancer, breast carcinoma and nonsmall-cell lung cancer.Its chemical constitution is following:
Chemical name is: 5 β, 20-epoxy-1,2 α, 4,7 β, 10 β, 13 α-hexahydroxy taxane-11-alkene-9-ketone-4,10-diacetate esters-2-benzoate-13 [(2 ' R, 3 ' S)-N-benzoyl-3-phenylisoserine ester].
Because of its dissolubility in water atomic (about 0.1 μ g/ml),, thereby bring great difficulty for the intravenously administrable of paclitaxel only at organic solvent dissolutions such as methanol, ethanol, dimethyl sulfoxide.Paclitaxel injection employing surfactant polyoxyethylene Oleum Ricini (Cremophor EL) and dehydrated alcohol (55: 45, v/v) as the dissolution with solvents paclitaxel.Paclitaxel injection (U.S. Bristol-Myers Squibb Co., trade name: Taxol, taxol) like drugs approved by FDA in 1992.Though Cremorphor EL can increase the water solublity of paclitaxel, owing to can promote after its degraded in vivo that body discharges histamine, thus possibly cause the serious quick reaction that surpasses.Therefore, for the Polyglucan reaction, 30min before the intravenous drip paclitaxel injection, patient need accept antianaphylactic pretreatment: the intravenous drip glucocorticoid like dexamethasone, also has H
1And H
2The antagonist of receptor is like diphenhydramine, cimetidine or ranitidine.The time of intravenous drip will be not less than 3h.Nonetheless handle, still can run into during the clinical practice of paclitaxel injection because allergy, and can not continue the case of medication.In addition, as antitumor drug, taxol drug itself also exists toxic reactions such as bone marrow depression, leukopenia, thrombocytopenia, anemia, has limited the application of its antitumaous effect.
Also there is the mode that adopts paclitaxel albumin nano granular injection suspension to solve the problems referred to above in the prior art; But cost is too high; Be more than 5 times of present commercially available paclitaxel injection; And up to now, the preparation liposome remains a kind of good selection that solves paclitaxel injection solvent problem as paclitaxel intravenously administrable carrier.Ideal Paclitaxel liposome can be brought into play following effect: avoid paclitaxel injection to surpass quick reaction owing to what solvent caused; Reduce the peripheral circulation toxic reaction, improve the toleration of body paclitaxel; Have bank effect and passive target effect.Based on identical reason; Much antitumor drug such as the Docetaxel as paclitaxel also all can adopt liposome as carrier with 10-hydroxycamptothecine, is issued in the prerequisite of avoiding surpassing quick reaction, reducing toxic action and improves dosage, raising drug effect.
But the liposome that uses now; Exist stable difference of vitro stability and the low shortcoming of drug loading: be dispersed in the influence that paclitaxel in the liposome phospholipid bilayer receives factors such as drug loading, temperature easily; Self intermolecular gathering takes place; And then generate acicular drug crystallization, precipitate in the aqueous solution; In the Paclitaxel liposome of stability range, the mol ratio of general medicine and phospholipid material is 1: 30, makes the drug loading of liposome reduce greatly simultaneously.
For solve the above problems research be employed in add electronegative phospholipid material such as Ovum Gallus domesticus Flavus lecithin acyl glycerol (ePG), four myristoyl cuorins (Cardiolipin) in the liposome prescription, DOTAP waits the stability that improves Paclitaxel liposome; But the Ovum Gallus domesticus Flavus lecithin acyl glycerol (ePG) that is adopted, four myristoyl cuorins (Cardiolipin), DOTAP are artificial the purification and synthetic phospholipid material, therefore exist expensive shortcoming.Usually these charge phospholipid material consumptions be generally 1: 10 of mol ratio of phospholipid, and the drug loading of paclitaxel are lower, and the mol ratio of medicine and phospholipid is 1: 30.Therefore the consumption of charge phospholipid material is 3 times of paclitaxel mol ratio, and consumption is higher relatively, and this has just further increased the production cost of Paclitaxel liposome; And for drug loading is crossed low this technical problem, also do not have technical scheme to solve in the prior art.
In addition; For improve liposome in blood plasma with the best measure of body internal stability; It is exactly the designing and preparing long circulating liposomes; This is because long circulating liposomes owing to the modification and the protective effect of long recycled material PEG formed material, disturbs conditioning and lipid exchange in the body inner blood, thereby can obviously improve liposome body internal stability, extension body internal recycle time.In order to reach the purpose of preparation long circulating liposomes, key is to PEG material chosen and application, and Macrogol 2000-DSPE (PEG2000-DSPE) is the PEGization phospholipid material that present long circulating liposomes adopts usually; Adopt in the amycin long circulating liposomes DOXIL prescription of listing and promptly adopt this material, but PEG2000-DSPE is artificial synthetic phospholipid material, the synthetic route relative complex; Production cost is high; Commercially available costing an arm and a leg, in the prescription of long circulating liposomes, the PEG2000-DSPE consumption is at least 5% (mol ratio) of phospholipid total amount; Just can play long preferably circulating effect; But because its molecular weight is 2790, so its actual mass ratio is relatively large, has increased the production cost of long circulating liposomes like this with regard to a step.And there are some researches show that also the someone adopts Polyethylene Glycol or gathers the mountain forest alcohol ester or the PEGization cholesterol is used as long recycled material, all do not obtain good effect.
This shows; How to select the basic preparation material of long circulating liposomes; Production and use for long circulating liposomes have very important effect, and how a kind of insufficient liposome material that can remedy the above-mentioned technical scheme of mentioning is provided, and also are the technical problems that continues solution now.
Summary of the invention
The present invention is directed to many deficiencies that technique scheme exists; A kind of novel long-circulating liposome composition and application process thereof are provided, mainly adopt phospholipid, cholesterol, elecrtonegativity material, long recycled material as primary raw material, wherein having adopted vitamin e succinate or cholesterol succinate especially is the elecrtonegativity material; Vitamin E polyethylene glycol succinic acid ester (TPGS) is as long recycled material; Improved the bonded stability of this long-circulating liposome composition and medicine, can be used as the carrier of antitumor drug paclitaxel, Docetaxel, 10-hydroxycamptothecine, its toleration improves simultaneously; During as pharmaceutical carrier; Its contained medicine circulation time in vivo obviously is longer than commercially available various carriers, and cost is lower, is suitable for applying widely.
The concrete technical scheme that the present invention adopted is:
A kind of long-circulating liposome composition; Comprise the filmogen that constitutes by phospholipid and cholesterol; Elecrtonegativity material and long recycled material, the elecrtonegativity material that is adopted is one or more in vitamin E succinum ester, cholesterol succinum ester, NaTDC, the cholesterol sodium sulfate; The long recycled material that is adopted is a vitamin E polyethylene glycol succinic acid ester, and the molecular weight ranges of Polyethylene Glycol is 500-5000 in its molecular structure; The mol ratio of said phospholipid, cholesterol, elecrtonegativity material, long recycled material is: 100: 10-50: 0.1-10: 2-10.
Owing in prescription, used new elecrtonegativity material, in the Zeta potential of liposome dispersion is remained on-15 to-35mV the scope, help keeping the stability of liposome dispersion; And, prolonged the medicine Circulation time in vivo owing to adopted vitamin E polyethylene glycol succinic acid ester (TPGS) as long recycled material, reached and improved stability and macrocyclic purpose.
In order to improve stability of drug, also contain the negative electricity material in the liposome composition of the present invention, but in order to overcome deficiency of the prior art, the inventor selects according to following principle: the stability of liposome is good; Safety is good, and is biodegradable in the body, and has the precedent of aspect pharmaceutic adjuvant, using; Cheap, market is originated secure.And selected negative electricity material has exactly satisfied these requirements among the present invention; Thereby equilibrium treatment has been accomplished in the aspects such as stability at the safety of intravenously administrable approach, cost factor, liposome; Obtained ideal effect; Except adopt reported cholesterol sodium sulfate as the negative electricity material, inventor of the present invention has also selected following negative electricity material:
Vitamin e succinate be vitamin E succinate derivative (d-α-tocopherol acid succinate, VES), chemical structural formula is following:
Formula I
Vitamin e succinate has the natural Vitamin E physiological active functions; Stability improves than vitamin E greatly; Become the raw material of VE quasi drugs widespread usage; Be widely used, the vitamin E that uses in nearly all tablet, capsule class medicine and the supplementary is vitamin e succinate or its calcium salt.The extensive antitumor characteristic that vitamin e succinate has, to improve immunity active, can be effective as the auxiliary treatment means of cancer.Be used in the antitumor medicinal liposome, can utilize its extensive inhibitory action, improve the curative effect of antitumor drug such as paclitaxel tumors such as ovarian cancer, breast carcinoma.
Vitamin e succinate is under blood plasma physiology condition of neutral pH, and the carboxyl of the succinic acid in its molecular structure dissociates, and molecule is electronegative.Also can be converted into water miscible vitamin E succinum ester (sodium salt, ammonium salt) in use, improve its water solublity, dissociating property, charging performance.Simultaneously, vitamin e succinate also has reducing property, can improve the stability of Liposomal formulation Chinese medicine.Vitamin e succinate, biodegradable in the body, there is not security risks, therefore can be used as alternative elecrtonegativity material of the present invention.
(cholesterol hemisuccinate is the succinum ester derivant of cholesterol CHS) to cholesterol succinate, has another name called Cholesteryl hemisuccinate, and cholesterol hemisuccinate is a kind of crude drug of arteriosclerosis.
Chemical constitution is following:
Formula II
Under blood plasma physiology condition of neutral pH, the carboxyl of the succinic acid in its molecular structure dissociates, and molecule is electronegative.Also can be converted into water miscible cholesterol succinum vinegar (sodium salt) in use.Cholesterol succinum ester also has liposome membrane Stabilization preferably except the bear electric charge.The succinic acid derivative of this cholesterol, biodegradable in the body, there is not security risks, can safe using as the elecrtonegativity material.
(sodium deoxycholate is a kind of cholate that exists in the human body bile SDC) to NaTDC, is a kind of anion surfactant.Chemical structural formula is following:
Formula III
Therefore bear electric charge after NaTDC dissociates can utilize this character to increase the stability of liposome.In the prescription of amphotericin B injection, mol ratio NaTDC and amphotericin B formation complex such as employing improve its water solublity.Therefore, many bibliographical informations adopt NaTDC as the elecrtonegativity material, add in the liposome, improve stability.Biodegradable in this material bodies, there is not the risk of safety yet.
Above-mentioned three kinds of elecrtonegativity materials add cholesterol sodium sulfate, can mix use, also can use separately, in order to reach best effect, can select vitamin e succinate separately for use.
The long recycled material that the front had been described in the prescription of liposome is successfully to prepare the long circulating liposomes key; Be directed against the expensive shortcoming of PEGization phospholipid material PEG2000-DSPE of present extensive use in the present invention; The inventor attempts to select for use the source to be easy to get; Relative low price, the material that has long cycle performance equally replaces PEG2000-DSPE.The inventor contrasts the long recycled material that adopts in present patent and the document; Analyze its pluses and minuses; (DL-α-Tocopherol polyethylene glycol succinate TPGS) is applied in the preparation of long circulating liposomes, in the prescription design with vitamin E polyethylene glycol succinum ester; Through measures such as the selecting for use of elecrtonegativity material, cholesterol are stable; Cooperate the effect of vitamin E polyethylene glycol succinum ester successfully to prepare the long circulating liposomes of inside and outside function admirable, thereby reached technical purpose of the present invention, improved stability and long circulatory function.
The chemical constitution of TPGS is following:
Formula IV
Vitamin E polyethylene glycol succinum ester is called watermiscible vitamin E again, at present applied research concentrate on mostly its to the solubilising aspect of insoluble drug with as New-type emulsifier, improve the stability of Emulsion.TPGS 1000 has been widely used in medicine, health care, cosmetic field, and TPGS is recorded by American Pharmacopeia, so the source of material, safety aspect do not have difficulties.The synthetic route of TPGS is simple relatively, and synthetic route is seen patent CN101232871A, and raw material sources are abundant, are raw material with vitamin e succinate and Polyethylene Glycol (PEG), promptly gets through esterification process is synthetic, therefore has tangible price advantage.And to it aspect the applied research of long circulating liposomes, do not cause enough attention.The Polyethylene Glycol of TPGS (PEG) chain along with the difference of the degree of polymerization, has many specifications.Usually use as emulsifying agent, solubilizing agent; When especially the administration of administered through oral route of administration is used; It is generally acknowledged that TPGS 1000 is only (Collnot EM; Baldes C.Influence of vitamin E TPGSpoly (ethylene glycol) chain length on apical.efflux transporters in Caco-2 cellmonolayers [J] .Journal of Controlled Release.2006,111 (1-2): 35-40).But long recycled material as liposome; When the PEG molecular weight ranges was 500-5000, the PEG long-chain can play screening effect preferably on the surface of liposome, and particularly the PEG molecular weight is 2000 o'clock; Its chain length is identical with the chain length of PEG2000-DSPE; Therefore preferred TPGS 2000 so just greatly reduces cost as long recycled material, has played good long circulating effect simultaneously.
Employing has added the long-circulating liposome composition of above-mentioned negative electricity material and long recycled material preparation; Be used for sealing antitumor drug; The liposome composition bear of gained of the present invention is electric, the quantity of electric charge is low, and quality is highly stable, has tangible long cycle characteristics; The prospect that possesses industrial applications has remedied the deficiency of existing liposome technology.
Except such scheme, in order to accomplish the liposome material that this invention is prepared into shaping, also be added with the filmogen that constitutes by phospholipid and cholesterol in the prescription, the phospholipid that is wherein adopted is unsaturated phospholipid or saturated phospholipid or its mixture; Wherein said unsaturated phospholipid is soybean phospholipid or Ovum Gallus domesticus Flavus lecithin or its mixture; Described saturated phospholipid is that the carbon number of hydrogenated soya phosphatide or hydrogenation egg yolk lecithin or fatty acid chain is the saturated phospholipid of 14-18; Like dipalmitoyl phosphatidyl choline (DPPC), DSPC (DSPC); But consider the then preferred saturated soybean phospholipid of hydrogenation, the saturated lecithin of hydrogenation from production cost.The preferred purity of the saturated soybean phospholipid of hydrogenation is more than 97%, and its main component is a phosphatidylcholine, also contains a spot of PHOSPHATIDYL ETHANOLAMINE and phosphatidylinositols.Because its aliphatic chain hydrogenation is saturated, therefore can prevent the hydrolysis oxidation of phospholipid, the stability of raising liposome.
And another must component be a cholesterol, and C/PL is regulated the flowability of lipid bilayer together as filmogen.Contain a certain amount of cholesterol in the prescription and can avoid the lipoprotein in liposome and the blood plasma to carry out lipid exchange, and destroyed, thus the body internal stability ability of raising liposome.
In order to reach best effect, the inventor is that the mol ratio of phospholipid, cholesterol, elecrtonegativity material, long recycled material is with the limited proportion of above-mentioned substance: 100: 10-50: 0.1-10: 2-10.Then employing mol ratio more preferably is: 100: 20-35: 0.5-5: 3-6, can better bring into play the effect of negative electricity material and long recycled material like this, and prepared long-circulating liposome composition is more stable.
In order to improve final effect, on the basis of above-mentioned prescription, also contain antioxidant and freeze drying protectant in the described long-circulating liposome composition, wherein antioxidant is selected from vitamin E, and the mol ratio of itself and phospholipid is 0.1-2: 100; And in daily production, the liposome that contains reactive compound can be stablized with lyophilization, to process the suitable compositions form; In this process, need to add freeze drying protectant, rely on the stabilising membrane effect of its glassy state; Protect the structural intergrity of liposome; Of the present invention freezing in protective agent is selected from sucrose, trehalose, the lactose one or more, its consumption be phospholipid weight 1-8 doubly, wherein more preferably adopt sucrose.
The front said that the purposes of the long-circulating liposome composition that the present invention is prepared was the medicine as preparing carriers coating active composition, and described active component is an antitumor drug, comprises paclitaxel or Docetaxel or 10-hydroxycamptothecine etc.; When the active substance of parcel was paclitaxel, the mol ratio of paclitaxel and phospholipid was: 1-5: 100.Preferred employing 2-5: 100.
And, comprise that thin film disperses with the method for long-circulating liposome composition as the lyophilized preparation of preparing carriers coating active composition, and high pressure homogenize, aseptic filtration, the step of freeze-drying, its concrete steps are following:
Active substance, phospholipid, cholesterol, elecrtonegativity material, long recycled material and antioxidant are dissolved in the dehydrated alcohol, decompression rotary evaporation film forming under 31-50 ℃ water bath condition, vacuum drying is fully taken out dehydrated alcohol;
Add the frozen-dried protective agent solution, aquation under 50-55 ℃ the water bath condition; High pressure homogenize or prepare the liposome of mean diameter 80nm-300nm with the mode that microporous membrane is extruded;
Adopt the polyvinylidene fluoride film aseptic filtration of 0.22 μ m;
In being sub-packed in the container, feed noble gas after the lyophilization, gland promptly gets.
In order to make the liposome of preparation practical more, the liposome mean diameter that may command high pressure homogenize or the mode of using microporous membrane to extrude prepare is 100nm.
In above-mentioned method for preparing, The suitable solvent is the solvent of nonpolar or low pole, and can after evaporation, not stay toxic residue.Common employed organic solvent is selected from methanol, ethanol, chloroform or their mixture.In the present invention, preferred dehydrated alcohol.The noble gas that adopts among the present invention is selected from a kind of in nitrogen, helium, the argon.The frozen-dried protective agent solution that is adopted is its aqueous solution, like aqueous sucrose solution etc.
When the active substance of parcel is paclitaxel; The paclitaxel long-circulating liposome composition that the present invention prepares gained is a paclitaxel drug administration by injection novel form; Owing to do not contain polyoxyethylene castor oil in the prescription, thereby avoided the allergy that causes thus, compare with conventional liposome with conventional paclitaxel injection; Improve toleration, improved curative effect.In order to verify the effect of the long circulating liposomes that the present invention prepares, the inventor has carried out the test of performance with above-mentioned paclitaxel long-circulating liposome composition, has obtained following beneficial effect:
(1) semi-finished product and stability of formulation
The novel paclitaxel long-circulating liposome composition of the present invention preparation was measured its particle diameter, Zeta potential before lyophilizing, for-15mV between-the 35mV, room temperature condition held 12h measures its particle diameter, Zeta potential during this period, remains unchanged basically.Liposome keeps homodisperse, does not take place to assemble and deposition under suspension.After the lyophilization, redissolve with sterilized water for injection, room temperature condition held 12h measures its particle diameter, Zeta potential during this period, remains unchanged basically, and liposome keeps homogeneously dispersed state under suspension, does not take place to assemble and deposited phenomenon.The particle size determination result of redissolution sample shows that its particle size distribution is in the 80nm-300nm scope after preceding sample of lyophilizing and the lyophilization.
(2) the intravital tolerance test of animal, pharmacokinetics experiment and pharmacodynamics test
In animal experiment, novel paclitaxel long circulating liposomes administration group mice does not show toxicity, and each item physical signs is normal, and of short duration stupor appears in isodose paclitaxel injection treated animal after administration.The pharmacokinetics result of the test shows that the novel same paclitaxel injection of paclitaxel long circulating liposomes, commercially available paclitaxel conventional liposome are compared, and the holdup time in the ability significant prolongation body, has tangible long cycle characteristics.Results of pharmacodynamic test shows that novel paclitaxel long circulating liposomes is compared with isodose paclitaxel injection, and tumour inhibiting rate improves, and significant difference is arranged.Hence one can see that, and novel paclitaxel long circulating liposomes of the present invention can improve the interior holdup time of toleration, extension body of animal, improves curative effect.
(3) feasibility of industrialization
Liposome composition of the present invention; The phospholipid that adopts in the prescription, cholesterol, elecrtonegativity material (vitamin E succinum ester, cholesterol succinum ester, NaTDC), long recycled material (vitamin E polyethylene glycol succinic acid ester TPGS) wait each constituent to be available pharmaceutical formulation material on the market; The source is easy to get, relative low price; The precedent of in other drug preparation, especially injection, using is all arranged, and security performance is good.Preparation technology of the present invention is easy, and the preparation equipment of employing is the liposome preparation common equipment, is convenient to amplify the suitability for industrialized production scale that is applied to.
As the novel long-circulating liposome composition that active component makes, avoided the quick reaction that surpasses that the polyoxyethylene castor oil in the paclitaxel injection (Cremophor EL) caused with paclitaxel.Liposome The acute toxicity tests through after redissolving can be known, can reduce the general toxicity of paclitaxel behind the novel paclitaxel long-circulating liposome composition intravenous administration, improves toleration.The pharmacokinetics experimental result can be known; Prolong the holdup time of liposome in blood plasma behind the novel paclitaxel long-circulating liposome composition intravenous administration; Has long cycle characteristics; Thereby more liposome medicament is arranged through infiltration and retention effect (EPR effect), arrive tumor tissues, thereby improve drug effect.
In sum, can see the long-circulating liposome composition of using technical scheme preparation according to the invention, improve the bonded stability of this long-circulating liposome composition and medicine; Can be used as the carrier of antitumor drug paclitaxel, Docetaxel, 10-hydroxycamptothecine; Its toleration improves simultaneously, and during as pharmaceutical carrier, its contained medicine circulation time in vivo obviously is longer than commercially available various carriers; And cost is lower, is suitable for applying widely.
Description of drawings:
The transmission electron microscope photo of the liposome that Fig. 1 makes for embodiment 1;
The lipidosome freeze-dried preceding particle size distribution that Fig. 2 makes for embodiment 1;
The lipidosome freeze-dried redissolution back particle size distribution that Fig. 3 makes for embodiment 1;
The liposome that Fig. 4 makes for embodiment 1, paclitaxel injection, the release profiles of paclitaxel conventional liposome in human plasma;
The liposome that Fig. 5 makes for embodiment 1, paclitaxel injection, paclitaxel conventional liposome are at the intravital plasma concentration curve of rat.
The specific embodiment
Below, foregoing of the present invention is done further detailed description, but should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance through the specific embodiment of embodiment form.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention;
The quality of the material that is obtained by the mol ratio conversion among the embodiment feeds intake, because mostly phospholipid is mixture, so when calculating, get its about molecular weight.The molecular weight of the material that relates to is following:
Soybean phospholipid (SPC): 750 Ovum Gallus domesticus Flavus lecithins (ePC): 780
The saturated soybean phospholipid of hydrogenation (HSPC): the saturated lecithin of 762 hydrogenations (HEPC): 782
Dipalmitoyl phosphatidyl choline (DPPC): 740 DSPCs (DSPC): 760
Cholesterol: 386.6 cholesterol succinates (CHS): 486.7
Vitamin e succinate (VES): 531 NaTDCs (SDC): 414.6
Cholesterol sodium sulfate (CS-Na): 489
Vitamin E polyethylene glycol succinic acid ester (TPGS 500)
Vitamin E polyethylene glycol succinic acid ester (TPGS 1000): 1510
Vitamin E polyethylene glycol succinic acid ester (TPGS 2000): 2500
Vitamin E polyethylene glycol succinic acid ester (TPGS 5000): 5500
Macrogol 2000-DSPE (PEG2000-DSPE): 2790
Vitamin E: 430.7 paclitaxels: 853.9
Docetaxel: 807.9 10-hydroxycamptothecines: 364.3
Raw materials used or equipment all can obtain from market among the embodiment.Wherein soybean phospholipid (SPC), Ovum Gallus domesticus Flavus lecithin (ePC), the saturated soybean phospholipid of hydrogenation (HSPC Lipoid S PC-3), the saturated lecithin of hydrogenation (HEPC), dipalmitoyl phosphatidyl choline (DPPC), DSPC (DSPC), NaTDC (SDC), Macrogol 2000-DSPE (PEG2000-DSPE) are all available from sharp precious beneficial (Lipoid) company (agency of Shanghai Dong Shang Industrial Co., Ltd.) of Germany; Cholesterol, cholesterol sodium sulfate (CS-Na) are available from Xian Libang Pharmaceutical Co., Ltd.; Vitamin e succinate (VES) closes mesophytization pharmaceutical Co. Ltd available from Wuhan; Cholesterol succinate (CHS) is available from the sharp big biochemical industry company limited in Zhengzhou; The vitamin E polyoxyethylene succinate (TPGS) of different size is available from Zhejiang Medicine Co; Vitamin E is available from Shandong Boshan Pharmaceutical Co., Ltd.; Paclitaxel, Docetaxel, hydroxy camptothecin are available from Chengdu Tian Yuan natural product company limited; Sucrose is available from Distributions in Liaocheng of Shandong Province peace letter pharmaceutic adjuvant company limited; Trehalose, lactose are available from Wuhan Yuancheng Technology Development Co., Ltd.;
Rotary Evaporators is available from Shanghai Yarong Biochemical Instrument Plant; The recirculated water vacuum pump is available from Yuhua Instrument Co., Ltd., Gongyi City; EmulsiFlex-C3 high pressure homogenizer (join and extrude device, heat pipe) is available from Canadian Avis spit of fland company; The water bath with thermostatic control Ultrasound Instrument is led the Ultrasound Instrument company limited available from Shanghai section; Nicomp388/ZetaPALS laser granulometry (U.S. Nicomp company); The desk-top freezer dryer of Labco (U.S. Labco company); Lyophilization cillin bottle, plug are available from peak, Thousand-Island Lake, Chunan vial factory; The XSP-10C biological microscope is available from the optical instrument factory, Shanghai; Microporous filter membrane (100nm, 200nm), 0.22 μ m Kynoar (PVDF) aseptic filter membrane is available from Hai Haoxia nucleopore membranes scientific and technological development company limited; (the molecular retention quality is 8000～14400u) available from Beijing Xia Si biotech company to bag filter.
The preparation of embodiment 1 novel paclitaxel long circulating liposomes
Paclitaxel 0.60g hydrogenated soya phosphatide 16g
Cholesterol 2.5g vitamin e succinate 0.1g
Vitamin E polyethylene glycol succinic acid ester (TPGS 2000) 2.5g
Vitamin E 0.05g
Sucrose 20g
Water for injection 200ml
Take by weighing paclitaxel, hydrogenated soya phosphatide, cholesterol, vitamin e succinate (VES), vitamin E polyethylene glycol succinic acid ester (TPGS 2000), the vitamin E of recipe quantity respectively, add the 100ml dehydrated alcohol, after the dissolving; Put Rotary Evaporators, under the nitrogen current protective condition, 50 ℃ of constant temperature water baths; Drain solvent; The preparation film forming is put in the vacuum desiccator and is placed, and fully removes residual solvent.Add with the dissolved sucrose solution of water for injection, 55 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Use the high pressure homogenizer homogenizing, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds nitrogen, gland seal after the lyophilizing.
According to method among 2005 editions two appendix XIX E of middle pharmacopeia, the envelop rate that records sample is 96.5%.
According to method among two appendix XIX of Chinese Pharmacopoeia version E, measure lyophilizing proliposome sample with laser particle size determination appearance, mean diameter is 110.5nm.Freeze drying example uses the sample average particle diameter that water for injection redissolves to be 123.2nm.
Its transmission electron microscope photo is seen Fig. 1, and particle size distribution figure sees Fig. 2 and Fig. 3.
Embodiment 2: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.15g hydrogenated soya phosphatide 16g
Cholesterol 4.5g vitamin e succinate 0.5g
Vitamin E polyethylene glycol succinic acid ester (TPGS 1000) 2.5g
Vitamin E 0.08g
Trehalose 20g
Water for injection 200ml
Take by weighing paclitaxel, hydrogenated soya phosphatide, cholesterol, vitamin e succinate (VES), vitamin E polyethylene glycol succinic acid ester (TPGS 1000), the vitamin E of recipe quantity respectively, add the 100ml dehydrated alcohol, after the dissolving; Put Rotary Evaporators, under the nitrogen current protective condition, 50 ℃ of constant temperature water baths; Drain solvent; The preparation film forming is put in the vacuum desiccator and is placed, and fully removes residual solvent.Add with the dissolved sucrose solution of water for injection, 55 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Extrude with extruding device 100nm microporous membrane, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds nitrogen, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 108.5nm before the lyophilizing, and envelop rate is 99.5%.
Embodiment 3: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.90g hydrogenated soya phosphatide 16g
Cholesterol 1.25g vitamin e succinate 1.0g
Vitamin E polyethylene glycol succinic acid ester (TPGS 500) 2.0g
Vitamin E 0.1g
Lactose 15g
Water for injection 200ml
Take by weighing paclitaxel, hydrogenated soya phosphatide, cholesterol, vitamin e succinate, vitamin E polyethylene glycol succinic acid ester (TPGS 2000), the vitamin E of recipe quantity respectively, add the 100ml dehydrated alcohol, after the dissolving; Put Rotary Evaporators, under the nitrogen current protective condition, 50 ℃ of constant temperature water baths; Drain solvent; The preparation film forming is put in the vacuum desiccator and is placed, and fully removes residual solvent.Add with the dissolved sucrose solution of water for injection, 55 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Use the high pressure homogenizer homogenizing, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds nitrogen, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 86.3% for the 115.2nm envelop rate before the lyophilizing.
Embodiment 4: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.60g hydrogenated soya phosphatide 16g
Cholesterol 2.5g cholesterol succinate 1.0g
Vitamin E polyethylene glycol succinic acid ester (TPGS 2000) 4.5g
Vitamin E 0.05g
Sucrose 20g
Water for injection 200ml
The paclitaxel, hydrogenated soya phosphatide, cholesterol, cholesterol succinate, vitamin E polyethylene glycol succinic acid ester (TPGS 2000), the vitamin E that take by weighing recipe quantity respectively add, and the 100ml dehydrated alcohol is after the dissolving; Put Rotary Evaporators, under the nitrogen current protective condition, 50 ℃ of constant temperature water baths; Drain solvent; The preparation film forming is put in the vacuum desiccator and is placed, and fully removes residual solvent.Add with the dissolved sucrose solution of water for injection, 55 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Use the high pressure homogenizer homogenizing, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds nitrogen, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 114.1nm before the lyophilizing, and envelop rate is 96.6%.
Embodiment 5: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.30g hydrolecithin 16g
Cholesterol 4.0g cholesterol succinate 1.0g
Vitamin E polyethylene glycol succinic acid ester (TPGS 5000) 2.3g
Vitamin E 0.05g
Lactose 15g
Water for injection 200ml
Take by weighing paclitaxel, hydrolecithin, cholesterol, cholesterol succinate, vitamin E polyethylene glycol succinic acid ester (TPGS 1000), the vitamin E of recipe quantity respectively, add the 100ml dehydrated alcohol, after the dissolving; Put Rotary Evaporators, under the nitrogen current protective condition, 50 ℃ of constant temperature water baths; Drain solvent; The preparation film forming is put in the vacuum desiccator and is placed, and fully removes residual solvent.Add with the dissolved sucrose solution of water for injection, 55 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Extrude with extruding device 100nm microporous membrane, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds argon, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 116.2nm before the lyophilizing, and envelop rate is 94.3%.
Embodiment 6: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.6g dipalmitoyl phosphatidyl choline 15.5g
Cholesterol 2.5g NaTDC 0.45g
Vitamin E polyethylene glycol succinic acid ester (TPGS 2000) 4.8g
Vitamin E 0.05g
Sucrose 15g
Water for injection 200ml
Take by weighing paclitaxel, dipalmitoyl phosphatidyl choline, cholesterol, NaTDC, vitamin E polyethylene glycol succinic acid ester (TPGS 2000), the vitamin E of recipe quantity respectively, add the 100ml dehydrated alcohol, after the dissolving; Put Rotary Evaporators, under the nitrogen current protective condition, 50 ℃ of constant temperature water baths; Drain solvent; The preparation film forming is put in the vacuum desiccator and is placed, and fully removes residual solvent.Add with the dissolved sucrose solution of water for injection, 55 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Use the high pressure homogenizer homogenizing, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds Kazakhstan, helium, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 102.1nm before the lyophilizing, and envelop rate is 95.3%.
Embodiment 7: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.2g DSPC 16g
Cholesterol 3.5g cholesterol sodium sulfate 0.05g
Vitamin E polyethylene glycol succinic acid ester (TPGS 1000) 1.6g
Vitamin E 0.05g
Trehalose 20g
Water for injection 200ml
Take by weighing paclitaxel, hydrogenated soya phosphatide, cholesterol, vitamin e succinate, vitamin E polyethylene glycol succinic acid ester (TPGS 1000), the vitamin E of recipe quantity respectively, add the 100ml dehydrated alcohol, after the dissolving; Put Rotary Evaporators, under the nitrogen current protective condition, 50 ℃ of constant temperature water baths; Drain solvent; The preparation film forming is put in the vacuum desiccator and is placed, and fully removes residual solvent.Add with the dissolved sucrose solution of water for injection, 55 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Extrude with extruding device 100nm microporous membrane, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds nitrogen, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 116.3nm before the lyophilizing, and envelop rate is 94.2%.
Embodiment 8: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.40g hydrogenated soya phosphatide 16g
Cholesterol 2.0g vitamin e succinate 1.0g
Macrogol 2000-DSPE 3.0g
Vitamin E 0.1g
Lactose 15g
Water for injection 200ml
The paclitaxel, hydrogenated soya phosphatide, cholesterol, vitamin e succinate, Macrogol 2000-DSPE, the vitamin E that take by weighing recipe quantity respectively add the 100ml dehydrated alcohol, after the dissolving, put Rotary Evaporators; Under the nitrogen current protective condition; 50 ℃ of constant temperature water baths are drained solvent, the preparation film forming; Put in the vacuum desiccator and place, fully remove residual molten profit.Add with the dissolved sucrose solution of water for injection, 55 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Use the high pressure homogenizer homogenizing, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds argon, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 103.2nm before the lyophilizing, and envelop rate is 96.5%.
Embodiment 9: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.36g hydrogenation egg yolk lecithin 16g
Cholesterol 3.2g cholesterol succinate 1.6g
Macrogol 2000-DSPE 5.8g
Vitamin E 0.10g
Sucrose 20g
Water for injection 200ml
The paclitaxel, hydrogenation egg yolk lecithin, cholesterol, cholesterol E succinate, Macrogol 2000-DSPE, the vitamin E that take by weighing recipe quantity respectively add the 100ml dehydrated alcohol, after the dissolving, put Rotary Evaporators; Under the nitrogen current protective condition; 50 ℃ of constant temperature water baths are drained solvent, the preparation film forming; Put in the vacuum desiccator and place, fully remove residual solvent.Add with the dissolved sucrose solution of water for injection, 55 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Extrude with extruding device 100nm microporous membrane, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds nitrogen, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 101.6nm before the lyophilizing, and envelop rate is 94.3%.
Embodiment 10: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.2g dipalmitoyl phosphatidyl choline 16g
Cholesterol 2.4g cholesterol sodium sulfate 0.03g
Macrogol 2000-DSPE 1.25g
Vitamin E 0.05g
Sucrose 15g
Water for injection 200ml
The paclitaxel, hydrogenated soya phosphatide, cholesterol, cholesterol sodium sulfate, Macrogol 2000-DSPE, the vitamin E that take by weighing recipe quantity respectively add the 100ml dehydrated alcohol, after the dissolving, put Rotary Evaporators; Under the nitrogen current protective condition; 50 ℃ of constant temperature water baths are drained solvent, the preparation film forming; Put in the vacuum desiccator and place, fully remove residual solvent.Add with the dissolved sucrose solution of water for injection, 55 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Extrude with extruding device 100nm microporous membrane, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds argon, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 120.6nm before the lyophilizing, and envelop rate is 96.7%.
Embodiment 11: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.6g soybean phospholipid (SPC) 16g
Cholesterol 2.4g vitamin e succinate 1.2g
Vitamin E polyethylene glycol succinic acid ester (TPGS1000) 0.65g
Vitamin E 0.05g
Trehalose 10g
Water for injection 200ml
The paclitaxel, soybean phospholipid, cholesterol, vitamin e succinate, vitamin E polyethylene glycol succinic acid ester (TPGS 1000), the vitamin E that take by weighing recipe quantity respectively add the 100ml dehydrated alcohol, after the dissolving, put Rotary Evaporators; Under the nitrogen current protective condition; 40 ℃ of constant temperature water baths are drained solvent, the preparation film forming; Put in the vacuum desiccator and place, fully remove residual solvent.Add with the dissolved aqueous trehalose of water for injection, 40 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Use the high pressure homogenizer homogenizing, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds nitrogen, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 116.5nm before the lyophilizing, and envelop rate is 93.7%.
Embodiment 12: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.2g Ovum Gallus domesticus Flavus lecithin (ePC) 16.5g
Cholesterol 0.8g cholesterol succinate 1.5g
Vitamin E polyethylene glycol succinic acid ester (TPGS 2000) 2.5g
Vitamin E 0.04g
Lactose 15g
Water for injection 200ml
The paclitaxel, Ovum Gallus domesticus Flavus lecithin, cholesterol, cholesterol succinate, vitamin E polyethylene glycol succinic acid ester (TPGS 2000), the vitamin E that take by weighing recipe quantity respectively add the 100ml dehydrated alcohol, after the dissolving, put Rotary Evaporators; Under the nitrogen current protective condition; 40 ℃ of constant temperature water baths are drained solvent, the preparation film forming; Put in the vacuum desiccator and place, fully remove residual solvent.Add with the dissolved sucrose solution of water for injection, 40 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Extrude with extruding device 100nm microporous membrane, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds nitrogen, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 114.0nm before the lyophilizing, and envelop rate is 95.5%.
Embodiment 13: the preparation of novel paclitaxel long circulating liposomes
Paclitaxel 0.30g soybean phospholipid 16g
Cholesterol 2.5g NaTDC 0.25g
Vitamin E polyethylene glycol succinic acid ester (TPGS 5000) 2.3g
Vitamin E 0.1g
Sucrose 20g
Water for injection 200ml
The paclitaxel, soybean phospholipid, cholesterol, NaTDC, vitamin E polyethylene glycol succinic acid ester (TPGS 5000), the vitamin E that take by weighing recipe quantity respectively add the 100ml dehydrated alcohol, after the dissolving, put Rotary Evaporators; Under the nitrogen current protective condition; 40 ℃ of constant temperature water baths are drained solvent, the preparation film forming; Put in the vacuum desiccator and place, fully remove residual solvent.Add with the dissolved sucrose solution of water for injection, 40 ℃ of constant temperature, magnetic agitation 30min, the water-bath ultra-sonic dispersion is even; Use the high pressure homogenizer homogenizing, 0.22 μ m PVDF filter membrane aseptic filtration is sub-packed in the lyophilizing cillin bottle; Lyophilization feeds nitrogen, gland seal after the lyophilizing.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 123.4nm before the lyophilizing, and envelop rate is 91.2%.
Embodiment 14: the preparation of novel Docetaxel long circulating liposomes
Docetaxel 1.20g hydrogenated soya phosphatide 16g
Cholesterol 2.0g vitamin e succinate 0.1g
Vitamin E polyethylene glycol succinic acid ester (TPGS 2000) 3.0g
Vitamin E 0.10g
Sucrose 20g
Water for injection 200ml
The Docetaxel, hydrogenated soya phosphatide, cholesterol, vitamin e succinate, vitamin E polyethylene glycol succinic acid ester (TPGS 2000), the vitamin E that take by weighing recipe quantity respectively add the 100ml dehydrated alcohol, after the dissolving, put Rotary Evaporators; Under the nitrogen current protective condition; 50 ℃ of constant temperature water baths are drained solvent, the preparation film forming; Put in the vacuum desiccator and place, fully remove residual solvent.Add with the dissolved sucrose solution of water for injection 55 ℃ of constant temperature, magnetic agitation 30min; The water-bath ultra-sonic dispersion is even, extrudes 0.22 μ m PVDF filter membrane aseptic filtration with extruding device 100nm microporous membrane; Be sub-packed in the lyophilizing cillin bottle, lyophilization feeds nitrogen after the lyophilizing; Gland seal promptly gets the lyophilizing long circulating liposome preparation of Docetaxel.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 107.1nm before the lyophilizing, and envelop rate is 93.3%.
Embodiment 15: the preparation of novel 10-hydroxycamptothecine long circulating liposomes
10-hydroxycamptothecine 0.50g hydrogenated soya phosphatide 16g
Cholesterol 4.0g vitamin e succinate 0.1g
Vitamin E polyethylene glycol succinic acid ester (TPGS 2000) 3.0g
Vitamin E 0.10g
Sucrose 30g
Water for injection 300ml
The 10-hydroxycamptothecine, hydrogenated soya phosphatide, cholesterol, vitamin e succinate, vitamin E polyethylene glycol succinic acid ester (TPGS 2000), the vitamin E that take by weighing recipe quantity respectively add the 100ml dehydrated alcohol, after the dissolving, put Rotary Evaporators; Under the nitrogen current protective condition; 50 ℃ of constant temperature water baths are drained solvent, the preparation film forming; Put in the vacuum desiccator and place, fully remove residual solvent.Add with the dissolved sucrose solution of water for injection 55 ℃ of constant temperature, magnetic agitation 30min; The water-bath ultra-sonic dispersion is even, uses the high pressure homogenizer homogenizing, 0.22 μ m PVDF filter membrane aseptic filtration; Be sub-packed in the lyophilizing cillin bottle, lyophilization feeds nitrogen after the lyophilizing; Gland seal promptly gets the lyophilizing long circulating liposome preparation of 10-hydroxycamptothecine.
Measure with quadrat method with embodiment 1, the mean diameter of sample is 109.4nm before the lyophilizing, and envelop rate is 95.3%.
Embodiment 16: the stability test of the compositions of novel paclitaxel long circulating liposomes
This test is intended to investigate the bin stability and the stability in use of the liposomal samples for preparing among the embodiment.
The exsiccant paclitaxel long-circulating liposome composition that embodiment 1,4,6 is made in sampling in 0,1,3,6,12 month, is observed its outward appearance 2-10 ℃ of preservation, redissolves with water for injection, uses microscopy, and the result sees table 1.
Solution room temperature condition held after the exsiccant paclitaxel long-circulating liposome composition that embodiment 1,4,6 is made redissolves in sampling in 0,1,4,8,12 hour, is observed outward appearance, uses microscopy, and the result sees table 2.
The exsiccant paclitaxel long-circulating liposome composition that embodiment 1,4,6 is made redissolves with water for injection, and 5% glucose injection with 8 times of volumes dilutes the room temperature condition held then; In sampling in 0,1,2,3,4 hour; Observe outward appearance, use microscopy, the result sees table 3.
Can know that by the result paclitaxel long-circulating liposome composition lyophilized preparation, is not assembled after the redissolution after 12 months 2-10 ℃ of preservation, does not have paclitaxel acicular crystal to separate out.Solution room temperature condition held is 12 hours after redissolving, and does not assemble, and does not have the paclitaxel crystallization to separate out.Redissolve the back with 8 times of 5% glucose injection dilutions, and room temperature condition held 4 hours is not assembled, and does not have the paclitaxel crystallization to separate out.
The novel paclitaxel long circulating liposomes of table 1 low temperature is placed (2-10 ℃) shelf-stability result of the test
Room temperature shelf-stability result of the test after the novel paclitaxel long-circulating liposome composition of table 2 redissolves
5% glucose injection with 8 times of volumes after the novel paclitaxel long-circulating liposome composition of table 3 redissolves dilutes room temperature shelf-stability result of the test
The human plasma stability test of Test Example 1 novel paclitaxel long-circulating liposome composition
Test specimen: (1) paclitaxel injection (taxol, Bristol-Myers Squibb Co., 30mg/5ml); (2) paclitaxel conventional liposome (power is pounced on element, injection Paclitaxel liposome, Nanjing Sike Pharmaceutical Co., Ltd, specification 30mg/ bottle); (3) paclitaxel long-circulating liposome composition (the paclitaxel long-circulating liposome composition of embodiment 1 preparation, specification 15mg/ bottle).
Precision is measured paclitaxel injection 1ml, with normal saline 2ml dilution, as the diluent of paclitaxel injection.Paclitaxel conventional liposome, paclitaxel long-circulating liposome composition are used 15ml respectively, and 10ml water for injection redissolves, and promptly gets paclitaxel conventional liposome and paclitaxel long circulating liposomes redissolution liquid.Precision is measured the diluent of paclitaxel injection; Paclitaxel conventional liposome and each 1ml of paclitaxel long circulating liposomes redissolution liquid; Add human plasma 2ml, put (molecular retention amount 1.4 ten thousand) in the tubular bag filter, seal; Place the beaker that 200ml pH7.4PBS (0.05mol/L) is housed, 37 ℃ of water-bath magnetic agitation.Respectively at 0.5,1,2,4,6,8,10,24h sampling 1ml (replenishing equality of temperature blank medium 1ml simultaneously).The HPLC method is measured the medication amount of the liposome cumulative release of calculating each time period.Following formula calculates the release degree.
Total amount * 100% of the cumulative release amount/bag filter Chinese medicine of release degree %=extracellular fluid dialysis.
The stability test result shows in the blood plasma; The paclitaxel conventional liposome is rapid in blood plasma Chinese medicine seepage, and 24h discharges 46.72%, and is faster than the rate of release (15.96%) of paclitaxel injection; The good stability of paclitaxel long circulating liposomes in blood plasma; Drug release is slow, and 24h discharges and is merely 4.4%, demonstrates good slow release characteristic.Stability test result in the blood plasma sees Fig. 4.
The acute toxicity test of Test Example 2 novel paclitaxel long-circulating liposome compositions
Test objective: investigate instant toxic reaction and the toleration of multiple dosing of paclitaxel long circulating liposomes of the present invention after by the usual manner administration.
Test is divided into groups and sample: (1) negative control group: blank liposome; (2) positive controls: paclitaxel injection (taxol, Bristol Myers Squibb, specification 30mg/5ml); (3) low dosage, high dose test group: paclitaxel long circulating liposomes (the paclitaxel long-circulating liposome composition of embodiment 1 preparation, specification 15mg/ bottle redissolves with water for injection).
Experimental animal: Kunming kind female mice, body weight 18-20g is divided into 4 groups at random, 5 every group.Negative control group is given the blank liposome of the maximum amount lipid that test group contains.Positive controls gives paclitaxel injection.Test group gives the paclitaxel long circulating liposomes, and the 1st, 4,7 days to each group tail vein injection administration.
Result of the test: (1) instant toxic reaction is observed: each organizes immediate observation after the mice administration, and negative control group and low dosage, all no overt toxicity of high dose test group react.Rapid breathing, of short duration stupor phenomenon appear in the mice that has in the paclitaxel injection group.(2) mice body weight change: negative control group mice body weight progressively rises.
Result of the test is seen table 4.
The weight of animals changes in the acute toxicity test of the novel paclitaxel long circulating liposomes of table 4 body
The pharmacokinetics test of the preparation compositions of Test Example 3 novel paclitaxel long circulating liposomess
Get 15 of SD rats, be divided into 3 groups at random, give paclitaxel injection (taxol, Bristol Myers Squibb, specification 30mg/5ml) respectively, (power is pounced on element to the paclitaxel conventional liposome; Injection Paclitaxel liposome, Nanjing Sike Pharmaceutical Co., Ltd, specification 30mg/ bottle), paclitaxel long circulating liposomes (embodiment 1 preparation, specification 15mg/ bottle); (liposome redissolves with water for injection) slowly injects through rat tail vein with 15mg/kg dosage, respectively at after the administration 5, and 30min; 1,2,4,6; 8,12,16,24h eyeground vein clump is got blood 0.5ml in the heparinization centrifuge tube; Centrifugal 5min separated plasma, after blood sample was handled, HPLC analyzed, and the standard curve external standard method is calculated plasma drug level.
Chromatographic column: ODS-C18 post (200mm * 4.6mm, 5 μ m); Mobile phase: methanol-water (65: 35), flow velocity: 1.0ml/min, detect wavelength: 227nm, column temperature: 30 ℃, sampling volume: 20 μ l.
Blood sample is handled: essence is got blood plasma 100 μ l to be measured, adds t-butyl methyl ether 2ml and on vortex mixer, mixes 3min, and the centrifugal 10min of 3000r/min draws supernatant 1.5ml and puts in another centrifuge tube, in 35 ℃ of water-baths, volatilizes under the nitrogen current.Residue is with mobile phase 100 μ l dissolving, 20 μ l sample introductions.
Date processing: gained rat serum concentration data are handled with the 3P87 pharmacokinetics program that mathematics pharmacology committee of Chinese Pharmacological Society writes.With handling, try to achieve the pharmacokinetic parameter of respectively writing out a prescription.
The result: paclitaxel injection, commercially available paclitaxel conventional liposome, paclitaxel long circulating liposomes plasma concentration curve all meet two-compartment model, t
1/2 βBe respectively 1.685h, 1.882h and 17.829h, AUC
0-48Be respectively 123.84,168.598 and 1028.896 μ gh/ml.The result sees Fig. 5.
Conclusion: the moving scholarship and moral conduct of the rat body giving drugs into nose of paclitaxel long circulating liposomes is for there being tangible change; Compare with commercially available paclitaxel injection, conventional liposome; The circulation time of eliminating in half-life, the blood all has prolongation in various degree, and AUC increases, and has tangible long cycle characteristics.
The pharmacodynamics test of Test Example 4 novel paclitaxel long circulating liposomes liposome compositions
Experimental animal: adopt the black mice of C57BL/6, male, body weight 19-22g, random packet, 10 every group.
Grouping and administration situation are following:
(1) matched group: blank liposome;
(2) paclitaxel injection (taxol, Bristol Myers Squibb, specification 30mg/5ml);
(3) paclitaxel conventional liposome administration group: injection Paclitaxel liposome (power is pounced on element, Nanjing Sike Pharmaceutical Co., Ltd, specification 30mg/ bottle);
(4) the paclitaxel long-circulating liposome composition (specification 15mg/ bottle) of paclitaxel long circulating liposomes administration group: embodiment 1 preparation
Test method:
Get B16 melanoma source, adopt the homogenate method, be prepared into tumor cell suspension at 1: 6 with normal saline, right axil subcutaneous vaccination B16 melanoma, 24h behind the tumor inoculation, immediate reaction and body weight change are observed in the mouse tail vein injection administration.After the off-test, cut open and get tumor and weigh, be calculated as follows tumor control rate.
Tumor control rate %=(the average tumor of the average tumor weight-administration of matched group group the is heavy)/average tumor of matched group heavy * 100%.Result of the test is seen table 5, and visible by table, the tumour inhibiting rate of novel Paclitaxel liposome is apparently higher than paclitaxel conventional liposome and paclitaxel injection.
The pharmacodynamics test of the novel paclitaxel long circulating liposomes of table 5
It is thus clear that the paclitaxel long-circulating liposome composition tumour inhibiting rate of embodiment 1 preparation obviously improves.
Claims (9)
1. a long-circulating liposome composition comprises the filmogen that is made up of phospholipid and cholesterol, elecrtonegativity material and long recycled material, and it is characterized in that: the elecrtonegativity material that is adopted is a vitamin e succinate; The long recycled material that is adopted is a vitamin E polyethylene glycol succinic acid ester, and the molecular weight of Polyethylene Glycol is 2000 in its molecular structure; The mol ratio of said phospholipid, cholesterol, elecrtonegativity material, long recycled material is: 100: 10-50: 0.1-10: 2-10.
2. long-circulating liposome composition according to claim 1 is characterized in that: described phospholipid is unsaturated phospholipid or saturated phospholipid or its mixture; Wherein said unsaturated phospholipid is soybean phospholipid or Ovum Gallus domesticus Flavus lecithin or its mixture; Described saturated phospholipid is that the carbon number of hydrogenated soya phosphatide or hydrogenation egg yolk lecithin or fatty acid chain is saturated phospholipid or its mixture of 14-18.
3. long-circulating liposome composition according to claim 2 is characterized in that: the carbon number of described fatty acid chain is that the saturated phospholipid of 14-18 is two palmityl phosphatidyl choline or DSPCs.
4. long-circulating liposome composition according to claim 1; It is characterized in that: also contain antioxidant and freeze drying protectant in the said liposome composition; Wherein antioxidant is selected from vitamin E; The mol ratio of itself and phospholipid is 0.1-2: 100, freeze drying protectant is selected from one or more in sucrose, trehalose, the lactose, its consumption be phospholipid weight 1-8 doubly.
5. will long-circulating liposome composition to be as the purposes of the medicine of preparing carriers coating active composition according to claim 1, wherein said active component is an antitumor drug, comprises paclitaxel or Docetaxel or 10-hydroxycamptothecine.
6. purposes according to claim 5 is characterized in that: when the active substance of parcel was paclitaxel, the mol ratio of paclitaxel and phospholipid was: 1-5: 100.
7. purposes according to claim 6 is characterized in that: the mol ratio of said paclitaxel and phospholipid is: 2-5: 100.
8. with the method for long-circulating liposome composition as claimed in claim 4, comprise that thin film disperses as the lyophilized preparation of preparing carriers coating active composition, high pressure homogenize, aseptic filtration, the step of freeze-drying, its concrete steps are following:
Active substance, phospholipid, cholesterol, elecrtonegativity material, long recycled material and antioxidant are dissolved in the dehydrated alcohol, decompression rotary evaporation film forming under 30-50 ℃ water bath condition, vacuum drying is fully taken out dehydrated alcohol;
Add the freeze drying protectant aqueous solution, aquation under 50-55 ℃ the water bath condition; High pressure homogenize or prepare the liposome of mean diameter 80nm-300nm with the mode that microporous membrane is extruded;
Adopt the polyvinylidene fluoride film aseptic filtration of 0.22 μ m;
Be sub-packed in the container, feed noble gas after the lyophilization, gland promptly gets.
9. method for preparing according to claim 8 is characterized in that: the mean diameter of the liposome that high pressure homogenize or the mode of using microporous membrane to extrude prepare is 100nm.
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| CN103690556B (en) * | 2014-01-06 | 2016-04-20 | 济南大学 | A kind of hydroxy camptothecin long cyclic liposome |
| CN111803698B (en) | 2014-02-14 | 2022-05-27 | 波士顿科学国际有限公司 | Rapidly degrading embolic particles with therapeutic agent release |
| CN104473873B (en) * | 2014-11-14 | 2018-07-03 | 南京华威医药科技集团有限公司 | A kind of Cabazitaxel long circulating liposome injection and preparation method thereof |
| HK1252369A1 (en) * | 2015-02-13 | 2019-05-24 | 友杏生技医药股份有限公司 | Compositions and methods of tumor treatment utilizing nanoparticles |
| CN104799430A (en) * | 2015-03-26 | 2015-07-29 | 江南大学 | Long-circulating lipidosome as well as preparation method and application thereof |
| CN107158395B (en) * | 2016-03-07 | 2020-04-07 | 中国科学院上海药物研究所 | Cabazitaxel phospholipid composition and preparation method and application thereof |
| CN111372570A (en) * | 2017-11-30 | 2020-07-03 | 希尔帕医疗保健有限公司 | High drug-loading docetaxel liposome injection composition |
| CN110575549B (en) * | 2018-06-08 | 2021-11-05 | 四川大学华西医院 | A tbFGF ligand-modified liposome with active tumor targeting function and its preparation method and use |
| CN116459224A (en) * | 2023-05-15 | 2023-07-21 | 济南大学 | Butylphthalide nano liposome freeze-dried powder injection and preparation method thereof |
| CN118490567A (en) * | 2024-05-11 | 2024-08-16 | 广州品赫化妆品有限公司 | A firming and anti-wrinkle composition containing bosine and preparation method thereof |
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