CN102871963A - Paclitaxel lipid nanoparticle injection liquid with anti-tumor activity - Google Patents
Paclitaxel lipid nanoparticle injection liquid with anti-tumor activity Download PDFInfo
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- CN102871963A CN102871963A CN2012103999598A CN201210399959A CN102871963A CN 102871963 A CN102871963 A CN 102871963A CN 2012103999598 A CN2012103999598 A CN 2012103999598A CN 201210399959 A CN201210399959 A CN 201210399959A CN 102871963 A CN102871963 A CN 102871963A
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Abstract
The invention provides paclitaxel lipid nanoparticle injection liquid, which comprises paclitaxel medicine, lipid materials, water for injection, surfactant, stabilizers and metal ion chelating agents. Most medicine is wrapped inside lipid, the direct contact between the medicine and blood or other liquid is avoided, and the local irritation of the medicine on the injection position is reduced, and the toxicity is reduced. No any organic solvents are contained, no solvents with toxicity and irritation on human bodies are contained, and no irritation and no sensitization are caused on the human bodies. The adverse reaction of the existing preparation caused by the recipe problem can be eliminated, and the goals of safety and efficiency are reached. Meanwhile, the paclitaxel lipid nanoparticle injection liquid has the excellent characteristic that the tumor medicine resistance is overcome, and the cure efficiency of the paclitaxel on the existing various tumors is greatly improved.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of taxusol-lipid nanoparticle injection, relate in particular to a kind of preparation method that contains the novel lipid nano particle preparations of paclitaxel and vitamin E, have highly effective antineoplastic activity and overcome drug resistance of tumor.
Background technology
Paclitaxel is to separate the native compound that obtains in the slower aiphyllium of this growth of taxaceae.It has more obvious and unique antitumor curative effect.Paclitaxel is blocked mitosis by acting on intracellular canaliculus albumen, makes the cancer cell death of quick division.Simultaneously, but paclitaxel trigger cell apoptosis, regulation and control immunity is killed and wounded tumor cell or suppresses.Powerful and unique antitumor mechanism so that paclitaxel become already now in the world the most popular, be in great demand most, the most in short supply, the most expensive, also be the most widely antitumor drug of clinical practice simultaneously.Paclitaxel mainly is applicable to ovarian cancer and breast carcinoma at present, and pulmonary carcinoma, colorectal cancer etc. is also had certain curative effect.
The powerful antitumor curative effect of paclitaxel is the happiness of extensive patients, but its atomic little dissolubility has restricted clinical practice.Paclitaxel is water insoluble, is dissolved in the organic solvents such as chloroform, acetone, ethanol.Present commercial formulation for paclitaxel is it to be dissolved in the solvent (floating breast) of polyoxyethylene castor oil (Cremophor) and ethanol 1:1 thin up during use.Yet polyoxyethylene castor oil can cause more serious untoward reaction, such as neutrophilic granulocyte minimizing, bone marrow depression etc.Simultaneously, polyoxyethylene castor oil contacts with polrvinyl chloride (PVC) and can produce pyrocarbonic acid diethyl ester, easily causes allergy.Therefore, said preparation can not contact with the container that contains polrvinyl chloride, syringe etc., and this has greatly limited its use.In view of this, improve the dissolubility of paclitaxel, seeking safer, hypotoxic cosolvent is the large requirement that present paclitaxel uses.
Research finds that vitamin E has the tumor growth of inhibition, reduces or delay tumorigenic effect.Epidemiologic data shows that body vitamin E intake and tumor are negative correlativing relation.The people that Vitamin E levels is low in the body gets the dangerous high 2.5 times of pulmonary carcinoma than the people of normal level.Mice takes can obviously reduce skin carcinoma that carcinogen induces and the probability of breast carcinoma behind the vitamin E.The Semen Tritici aestivi germ oil of containing the higher concentration vitamin E for the experiment mice feeding can obviously reduce the sickness rate of the skin carcinoma that the lumbar injection methyl cholanthrene causes.
This mainly is because vitamin E is a kind of stronger antioxidant, can suppress and remove interior free yl, and the formation of blocking-up Carcinogenic Nitrosamines, the normal activity of Cell protection.And the number of chemical carcinogen belongs to strong oxidizer, and the antioxidant properties of vitamin E can prevent effectively that this type of carcinogen is to the damage of body.Secondly, vitamin E is to immune protective effect.Vitamin E can obviously strengthen the immunoreation of animal body, and experimental result shows that vitamin E can make the passive immunity of chickling strengthen, and mouse spleen weight is increased, and helper T cell is active obviously to be strengthened.When vitamin E deficiency, lymphocyte reduces the post-stimulatory competence for added value of mitogen, and delayed hypersensitive reaction reduces; If picked-up cushion 2-10 vitamin E doubly can strengthen delayed hypersensitive reaction, strengthen monokaryon-mononuclear phagocyte system to the removing of particulate matter antigen, improve host's immunity.Simultaneously, vitamin E can be grown by inhibition tumor cell, and experimental data shows that vitamin E has significant inhibitory action to the propagation of mice neuroblastoma, murine melanoma, rat neurogliocytoma cell.Vitamin E can also the inducing mouse neuroblastoma, the generation Morphological Differentiation of rat neurogliocytoma cell, and cell volume is increased.Experiment in vitro shows that vitamin E can directly suppress the growth of prostate tumor cells, and can strengthen the curative effect of antitumor drug (for example amycin), reduces toxic and side effects.Again, but the interior vitamin A of vitamin E protective and the not oxidized destruction of vitamin C, and the existence of these vitamin can be kept body immune system and carry out normal physiological activity, keeps normal immunologic function.By this process, vitamin E has played the indirect protection body, has prevented the effect of canceration.In addition, it is very large that vitamin E and other kinds antineoplastic agent merge the potentiality of using, and may reach the effect that strengthens anticancer therapeutic, reduces toxicity.
Above result of study can show, vitamin E is kept normal immunologic function, strengthens the body drag, resisted canceration positive effect is arranged human body.Simultaneously, vitamin E is a kind of oily lipid, and its dissolubility to paclitaxel is better.Can satisfy clinical administration to the requirement of medicament contg.
Tumor cell produces cross resistance to the number of chemical medicine, claims multidrug resistance (MDR), is to cause the failed main cause of tumor chemotherapy (chemotherapy).Statistics shows, in the tumor annual death rate, belongs to the tumor of inwardness multidrug resistance (intrinsic MDR), and what comprise that digestive organs, respiratory system, urinary system and central nerve neuroma cause accounts for 61%; Belong to the tumor of acquired multidrug resistance (acquired MDR), comprise skin carcinoma, breast carcinoma, anogenital cancer, endocrine tumors, leukemia and lymphoma, account for 33%.In other words, the 90% above tumor patient cause of the death is all relevant with drug resistance.On the other hand, newfound medicine such as paclitaxel and the leukemic STI-571. of the chronic graininess for the treatment of are just to be used for clinical just the discovery drug resistance is arranged, and this makes problem more serious.Therefore, the research of the expression of tumor drug resistance gene and reversion MDR becomes the oncotherapy problem demanding prompt solution.
Illustrate not yet fully about the reason that the tumor natural bacterial drug resistance produces.According to the drug resistance characteristics of tumor cell, drug resistance can be divided into primary resistance (PDR) and MDR two large classes.The former refers to only induced drug be produced drug resistance and other drug is not produced cross resistance, such as antimetabolite methotrexate (MTX), 5-fluorouracil (5-Fu) etc.; Latter refers to tumor cell in case certain chemotherapeutics is produced drug resistance, and simultaneously to irrelevant on other structures, the mechanism of action also different medicine also produces cross resistance, and this is a kind of wide spectrum drug resistance phenomenon of uniqueness.The antitumor drug of many natural origins such as alkaloid anticarcinogen (colchicine, vinblastine, harringtonine and paclitaxel etc.), anthracycline antitumor antibiotic (amycin and daunorubicin), multidrug resistance all very easily occurs in podophillotoxines and synthetic drug (mitoxantrone and amsacrine).Relevant multidrug resistance forms mechanism and has become in recent years one of focus of Chinese scholars research.Think that at present tumor drug resistance mechanism mainly contains:
(1) pharmacology drug resistance: refer to the drug resistance that the impact of medicine caused by body, as medicine enter organism metabolism enhancing or activated disfunction, tumor blood for not enough, medicine tissue penetration is poor, the formation of pharmacological sanctuaries etc., causes the outer medicine effective concentration of tumor cell to reduce.
(2) biochemical drug resistance: refer to that complicated variation occurs for the heritability of tumor cell and biochemical characteristic, cause cell by different approaches medicine to be produced drug resistance, mainly contain: (1) cell membrane/nuclear membrane albumen, be the medicine rear pump: such as P-glycoprotein (P-gp), multidrug-associated protein (MRP), lung resistance-related protein (LRP) and breast drug-resistance protein (BCRP), can make drug efflux increase or vesicle isolation in the cell, cause drug concentration to reduce or the drug distribution change.。Wherein medicine " pump " goes out the main mechanism that mechanism is the generation tumor multi-medicine drug-resistant in the cell of P-gp mediation.P-gp is that a kind of relative molecular mass is the strand transmembrane glycoprotein of 170kD, also claims P170, by multidrug resistance gene 1(multidrug resistance gene1, MDR1) coding, the overexpression meeting of MDR1 causes the generation of tumor multi-medicine drug-resistant.(2) Cytoplasm/nuclear protein, i.e. medicine target enzyme activity change: be the target enzyme of MTX such as dihydrofolate reductase (DHFR), the DNA topoisomerase II is the target enzyme of anthracycline and podophillotoxines medicine, and their content and activity decreased also can cause drug resistance; Tyrosine kinase BCR-Abl is the target enzyme of STI-571, and its amplification and sudden change can both produce drug resistance; Glutathion-S transferring enzyme (GST) active metabolism and binding ability strengthen, and catalysis glutathion (GSH) is combined with medicine and metabolite thereof; Intracellular protein kinases (PKC) activity change accelerates the Pgp phosphorylation; Q6 methyl guanine-dnmt rna increased activity causes DNA repair function enhancing etc.But no matter be with what resistance mechanism to work, all be reduced to its feature with drug level in the tumor cell.
(3) apoptosis drug resistance: most of antitumor drug causes that cell death is by apoptosis, and the disappearance of short apoptogene or the overexpression of anti-apoptotic genes expression Bcl-2 all will correspondingly cause tumor cell that chemotherapeutics is produced drug resistance.
(4) microenvironment drug resistance: the survival and growth of tumor cell depends on the organ microenvironment, and the organ microenvironment can affect tumor cell to the sensitivity of chemotherapeutics by regulating different expression of drug resistance genes.Experiment showed, that drug-resistant phenotype is polygenic, it is different with the medicine of inducing, the difference of tumor kind, differentiation degree and host's microenvironment and show one or more drug resistant genes and express simultaneously.
Overcome at present tumor multi-medicine drug-resistant and mainly contain 3 kinds of strategies: the one, the ingestion of medicines amount of increase tumor cell; The 2nd, reduce drug efflux; The 3rd, adopt the relevant reversal method of biotechnology.
The 1st kind of approach can realize overcoming tumor multi-medicine drug-resistant by using the nano drug-carrying technology.Nano medicament carrying system is because the little surface area of particle diameter is large, and the surface adsorption characteristic is strong, and medicine has obvious different at the performance of the aspects such as physicochemical property, pharmacokinetics and pharmacodynamics and conventional formulation, and this is the material base that nano medicament carrying system can overcome tumor multi-medicine drug-resistant.It is generally acknowledged, nano-carrier is as the delivery vector of antitumor drug or various Multidrug resistance moderators, why can reverse multiple drug resistance of tumor, and be because it can be by initiatively or passive mode, increase medicine in intracellular accumulation or reduce effluxing of medicine, thus the reversing tumor drug resistance.Nano-carrier enters cell by endocytosis, and endocytosis can be divided into engulfs and pinocytosis, and wherein latter's effect is more general.Particularly many targets modifications of modification by to nano-carrier can make medicine initiatively be targeted to more accurately specific part or cell.Nano-carrier can be attached to surface of cell membrane and by internalization by the absorption of non-specific and receptor-mediated pinocytosis.Nano medicament carrying system after the internalization is discharging medicine under the effect of desmoenzyme or under the slightly acidic pH environment.Numerous studies show that uses nano-carrier to overcome the power of drug resistance of tumor, and with the size of nano-carrier, surface physicochemical property and carrier constituent exist great dependency.
The strategy of the 2nd kind of reverse multiple drug resistance of tumor is chemotherapeutic sensitizer and the Multidrug resistance moderator that uses for P-gp or other drug-resistant proteins mostly: such as verapamil, the full element of ring etc., but these drug intoxication dosage are close with effective dose, be difficult to reach the valid density that can reverse, but also exist action target spot single, the problem such as selectivity is low.The RNA perturbation technique is the focus of Recent study, particularly by the reticent coding of microRNA fragment (siRNA) P-gp, for the tumor multi-medicine drug-resistant of reversing tumor brings new dawn.The RNA perturbation technique also has the characteristics such as high degree of specificity, high efficiency, high success rate simultaneously.But siRNA body internal stability and cell targeted poor can make gene silent technology better use by nano-carrier.
The method of the 3rd kind of reverse multiple drug resistance of tumor adopts the realizations such as biotechnology, gene technology to overcome the effect of drug resistance.Such as gene therapy, Antisense OligodeoxynucleotideTechnique Technique etc.There is document to show, utilizes the RNA of siRNA mediation to disturb means, can reduce specific gene and express, cause the target gene inactivation.Utilize the method can realize now making drug-resistant leukemia that the sensitivity of vincristine and doxorubicin is strengthened.Ribozyme is to rouse the RNA molecule that there is catalytic activity in the territory, can identify special nucleotide sequence, and by being combined with purpose RNA, and the mRNA of cutting Disease-causing gene coding and reduce its expression has become a kind of promising molecular targeted therapy instrument.Utilize the ribozyme technology,, 6 anti-MDR1 are earned credit for the next world after hammerhead ribozyme is transfected in the human leukemia medicine-resistant cell line of overexpression P-gp, find that the expression of this cell P-gp descends the efflux pump miopragia of P-gp.Improve the medicament contg that enters cell interior, reach the effect that overcomes drug resistance.
1961, the Wretlind of Sweden first at clinical use fat milk as the intravenous injection nutrient.Started the history of lipomul, the development of lipomul has had semicentennial course to today.In this process, fat milk is in conjunction with liposome, nano material etc., develop into the instantly Nano grade administering mode of study hotspot by single administering mode, several route of administration that differ from one another such as solid lipid nanoparticle (SLN), nano structured lipid carrier (NLC) and medicine fat conjugate (LDC).Enriched this category of lipomul.
The preparation method of SLN is: with medicine dissolution or be scattered in the molten lipid, the molten lipid is scattered in the aqueous phase of heat under rapid stirring, make colostrum, and colostrum carries out homogenizing and processes being higher than under the melting temperature environment, obtain solid lipid nanoparticle.Perhaps colostrum is joined the aqueous phase of lower temperature, its cooling is separated out.Yet the crystal behavior is different because of the change of grain size.Such as, phase transition temperature can reduce to reduce according to lattice; The lipid of crystal form irregular arrangement can more easily carry out phase inversion.In the preservation process, in the time of several days or several hours, major part has solid lipid nanoparticle that neat crystal form arranges and has all produced drug leakage or drug crystallization in various degree separate out in disperse medium.In addition, comparatively orderly crystal arrangement has obviously restricted the drug encapsulation ability.And the concordance of lipid molecular on chemical constitution also depended in the formation of crystal form in order.For example, use highly purified tromethane to prepare the product that lipid granule can access the crystal form marshalling in commercial production.
One of essential condition that medicine is had good bag loading capability is in lipidic matrix, between the fatty acid chain of lipid and the crystals space enough large distance will be arranged, to hold the drug molecule of unformed shape.And the distance between the fatty acid chain can increase by the glyceride that forms with different fatty acids, and for example glyceride contains respectively saturated and undersaturated fatty acid chain.
SLN has more clear superiority: employed lipid has good biocompatibility mostly; Be applicable to the number of ways administration; Simultaneously, solid lipid substrate is solid-state under room temperature environment, and the inner lattice form that forms marshalling has overcome unsettled shortcoming under external environment.But Just because of this, the confined space between the crystal of marshalling has limited the Drug loading capacity of SLN.In addition, SLN still has a lot of potential problems: limited drug delivery amount, drug release curve changeable, deposit drug leakage in the process etc.These problems have greatly limited the use of SLN.
The good news is that these shortcomings can be weakened or avoid to a certain extent, this has benefited from the lipid nanometer drug-supplying system of a new generation---have the appearance of the nano structured lipid carrier (NLC) of good drug encapsulation ability.NLC develops on the SLN basis, and it is to mix the lipid with special construction of formation as the novel lipid nanoparticle of matrix composition with the inconsistent solid of several space structure or liquid fatty.Obtain a kind of novel lipid particle by the liquid fatty of mixing variety classes solid lipid and different chemical structures, be used for replacing using the SLN of solid lipid making.The mixing of different phase lipid, so that be difficult to form the lattice form of marshalling in the nanoparticle, this is so that the interior drug storage space of lipid obviously increases, the spatial content of medicine increases, and effectively improves drug loading, reduces drug leakage.The preparation method of NLC has: mini-emulsion process, high pressure homogenization method, solvent diffusion method and solvent emulsion evaporation.The selection of concrete grammar will be depended on the physicochemical property of medicine.Select the parameters such as different temperatures, response time all can affect the physicochemical property of product in the Same Way.
Studies show that, distribute, discharge that behavior all has a better role in the bodies such as duration, targeting at nanoparticle finishing PEG in to the body of preparation.After DSPE-PEG2000 carries out finishing to nanoparticle, the DSPE of one end (DSPE) lipotropy is stronger, can be inserted into the nanoparticle the inside, the PEG chain of the other end is pliable and tough and the long-chain of good hydrophilic property, can adsorb large quantity of moisture, form one deck hydration shell on the nanoparticle surface, the space structure of nanoparticle is changed constantly, and make macrophage be difficult to it is produced effectively identification, thereby the absorption of mononuclear phagocyte system (MPS) and the opsonic action of plasma protein have been avoided, increased the circulation time in blood, reached long circulation, be conducive to simultaneously medicine and arrive smoothly targeting moiety.
Summary of the invention
The taxusol-lipid nanoparticle injection that the purpose of this invention is to provide a kind of tool anti-tumor activity, lipid nanoparticle injection formula provided by the invention comprises taxol drug, matrix material, water for injection, surfactant, stabilizing agent, metal ion chelation agent, and concrete percentage by weight composition is:
Paclitaxel 0.1%-5%
Stabilizing agent 5%-20%
Metal ion chelation agent 0.1%-1%
All the other are water for injection.
In order to realize better the present invention, the prescription composition of injection is adjusted into:
Paclitaxel 0.1%-4%
Stabilizing agent 5%-15%
Metal ion chelation agent 0.1%-1%
All the other are water for injection.
Injection preferred version of the present invention is:
Paclitaxel 0.5%-3%
Stabilizing agent 5%-15%
Metal ion chelation agent 0.1%-0.5%
All the other are water for injection.
Matrix material among the present invention is selected a kind of in vitamin E, refined plant oil, the animal oil or is wherein appointed several mixture; Surfactant is selected a kind of in phospholipid, polyethyleneglycol modified phospholipid (DSPE-PEG2000), tween, poloxamer, span, oleic acid, the enuatrol or is wherein appointed several mixture; Stabilizing agent is selected a kind of of sucrose, trehalose, mannose, glycine, glutamic acid, sorbitol, mannitol or is wherein appointed several mixture; Metal ion chelation agent is selected a kind of or its mixture in disodium EDTA (EDTA), the calcium disodium salt of EDTA.
Second purpose of the present invention provides a kind of preparation method of taxusol-lipid nanoparticle injection, realizes by following steps:
(1) preparation of lipid phase: the lipid of recipe quantity, the surfactant that is dissolved in lipid, polyethyleneglycol modified phospholipid, paclitaxel are dissolved in an amount of dehydrated alcohol, and reduction vaporization is removed ethanol, gets the lipid phase;
(2) preparation of water: the surfactant, stabilizing agent, the metal ion chelation agent that are soluble in the aqueous phase are mixed in water for injection, stir until the each several part dissolving gets water;
(3) preparation of colostrum: under 60 ℃ of heated and stirred of lipid phase, water dropwise adds oil phase, gets the milky colostrum;
(4) preparation of lipid nanoparticle: with colostrum as in the high pressure dispersing emulsification machine, under 0-10 ℃, circulate with 1000-1500bar pressure homogenizing 15-30, to mean diameter about 150nm, get lipid nanoparticle, with this Emulsion embedding in infusion bottle, fill nitrogen, place the steam rotating sterilizer, sterilization gets effect of nano-paclitaxel.
The effect of nano-paclitaxel that the present invention is prepared is wrapped in lipid inside with most of pharmaceutical pack, has avoided medicine to contact with the direct of blood or other body fluid, has reduced local irritation, the reduction toxicity of medicine to the injection site.Because the present invention does not contain polyoxyethylene castor oil and other any organic solvents, has avoided contingent anaphylaxis or toxic reaction.The vitamin E that wherein contains (tocopherol) has good dissolubility to paclitaxel, has again the immune function of human body of raising and anti-cancer and kill cancer action simultaneously, share with paclitaxel and can play the effect that heightens the effect of a treatment.Polyethyleneglycol modified phospholipid in the prescription can form one deck hydrone film on the nanoparticle surface, reduce phagocyte to the elimination effect of nanoparticle, prolongs preparation circulation time in vivo, reaches long circulation purpose.Simultaneously, this preparation has the stronger feature that overcomes tumor drug resistance, presents stronger oncotherapy effect.The present invention is according to the existing product of tradition, and in conjunction with pharmaceutics frontier development achievement, the characteristics such as provide collection science, practicality, novelty, be easy to produce are the preparation of the whole body.
A kind of novel paclitaxel vein lipid nanoparticle injection provided by the invention (injection), overcome the shortcoming of existing paclitaxel injection preparation, this preparation does not contain any organic solvent, do not contain the solvent toxic, irritating to human body, to the human body nonirritant, without sensitization.Can eliminate existing preparation because the untoward reaction that the prescription problem is brought reaches safety, efficient therapeutic purposes.Simultaneously, this novel paclitaxel vein lipid nanoparticle injection has the good characteristics that overcome drug resistance of tumor, and this will greatly promote paclitaxel to the effect of present numerous oncotherapys.
Description of drawings
Fig. 1 is the particle sketch map, and wherein 1 is hydrated sheath, and 2 is the hydrophilic long-chain of Polyethylene Glycol, and 3 is the oiliness kernel, and 4 is taxol drug; Wherein 1 is hydrated sheath, and 2 is the hydrophilic long-chain of Polyethylene Glycol, and 3 is the oiliness kernel, and 4 is taxol drug.
Fig. 2 is preparation technology figure.
Fig. 3 is nanoparticle particle size distribution figure.
Fig. 4 is the interior distribution collection of illustrative plates of the 96h body of drug-carrying nanometer particle.
Fig. 5 be after the administration 96h animal drug disposition in the distribution of each organ.
Fig. 6 is animal pattern SKOV-3 cell tumour volume rheological parameters' change with time.
Fig. 7 is the average weight of the solid tumor that animal pattern was taken out after experiment finished.
Fig. 8 is that the free paclitaxel medicine is to the toxicity of SKOV-3 and mdr cell ST-30.
Fig. 9 carries effect of nano-paclitaxel to the toxicity of SKOV-3 and ST-30 cell.
The specific embodiment
The present invention is further described in conjunction with the accompanying drawings and embodiments.
Prescription and the preparation technology of embodiment 1 formulation for paclitaxel
Prescription 1:
Oleic acid 0.8%
Phosphatidase 12 %
DSPE-PEG2000 0.5%
EDTA 0.5%
All the other are water for injection.
Preparation method 1:
(1) vitamin E, phospholipid, oleic acid, cholesterol, DSPE-PEG2000, the paclitaxel with recipe quantity is dissolved in an amount of dehydrated alcohol, and the decompression rotary evaporation is removed ethanol, gets the lipid phase;
(2) with sucrose, EDTA, be mixed in water for injection, magnetic agitation is until each several part dissolving gets water;
(3) under 60 ℃ of heated and stirred of lipid phase, water dropwise adds the lipid phase, and rapid stirring 10min gets the milky colostrum;
(4) with colostrum as in the high pressure dispersing emulsification machine, under 4 ℃, with 1500bar pressure homogenizing 20 times circulation, to mean diameter about 150nm, this Emulsion embedding in infusion bottle, is filled nitrogen, place the steam rotating sterilizer, sterilization gets effect of nano-paclitaxel.The particle sketch map is referring to Fig. 1, and preparation technology figure is referring to Fig. 2.
Physicochemical property:
Recording lipid nanoparticle particle diameter result by particle instrument is: Size:94.2nm, figure is referring to Fig. 3 for the nanoparticle particle size distribution.
Show (Fig. 4) according to the result who distributes in the mark fluorescent dyestuff indication body, most of medicine concentrates on tumor locus, illustrates that this product has tumor-targeting.Along with the time lengthening dose concentrates gradually at tumor locus, and still have a large amount of medicines to be present in tumor locus at 96 hours, illustrate that medicine do not removed by phagocyte, reached macrocyclic effect in the body.Medicine further specifies the present invention in the distribution results of Different Organs can make medicine concentrate at the tumor locus targeting, referring to Fig. 5.
Pharmacodynamic result shows in the body of animal pattern: than commercially available formulation for paclitaxel, this preparation can suppress tumor growth better, and has slow release effect, referring to Fig. 6, Fig. 7.
Overcoming the drug resistance of tumor experimental result shows: preparation of the present invention can overcome the drug resistance of tumor cell more significantly, so that this preparation obviously reduces (Fig. 8, Fig. 9) to the drug resistance multiple of mdr cell.
Prescription 2:
Paclitaxel 0.5%
Oleic acid 0.65%
Lecithin 2.6%
DSPE-PEG2000 1%
Sucrose 10.4%
Sodium cholate 0.7%
EDTA 0.1%
All the other are water for injection.
Preparation method 2:
(1) vitamin E, lecithin, oleic acid, paclitaxel, the DSPE-PEG2000 with recipe quantity is dissolved in an amount of dehydrated alcohol, and the decompression rotary evaporation is removed ethanol, gets the lipid phase;
(2) sucrose, sodium cholate, EDTA are mixed in water for injection, magnetic agitation is until the each several part dissolving gets water;
(3) under 60 ℃ of heated and stirred of lipid phase, water dropwise adds oil phase, and rapid stirring 10min gets the milky colostrum;
(4) with colostrum as in the high pressure dispersing emulsification machine, with 1100-1200bar pressure homogenizing 15-30 circulation, to mean diameter about 150nm, this Emulsion embedding in infusion bottle, is filled nitrogen, place the steam rotating sterilizer, sterilization gets effect of nano-paclitaxel.
Prescription 3:
Oleic acid 2.4%
Cholesterol 1.2%
DSPE-PEG2000 1%
Sucrose 10.05%
Sodium cholate 0.7%
EDTA 0.5%
All the other are water for injection.
Preparation method 3:
(1) vitamin E, lecithin, oleic acid, paclitaxel, cholesterol, the DSPE-PEG2000 with recipe quantity is dissolved in an amount of dehydrated alcohol, and the decompression rotary evaporation is removed ethanol, gets the lipid phase;
(2) sucrose, sodium cholate, EDTA are mixed in water for injection, magnetic agitation is until the each several part dissolving gets water;
(3) under 60 ℃ of heated and stirred of lipid phase, water dropwise adds oil phase, and rapid stirring 10min gets the milky colostrum;
(4) with colostrum as in the high pressure dispersing emulsification machine, with 1100-1200bar pressure homogenizing 15-30 circulation, to mean diameter about 150nm, this Emulsion embedding in infusion bottle, is filled nitrogen, place the steam rotating sterilizer, sterilization gets effect of nano-paclitaxel.
Prescription 4:
Lecithin 5.44%
Vitamin E 6.4%
Cholesterol 0.5%
DSPE-PEG2000 2%
Sucrose 11.8%
Sodium cholate 2.2%
PLURONICS F87 4.4%
EDTA 0.5%
All the other are water for injection.
Preparation method 4:
(1) vitamin E, lecithin, oleic acid, paclitaxel, the DSPE-PEG2000 with recipe quantity is dissolved in an amount of dehydrated alcohol, and the decompression rotary evaporation is removed ethanol, gets the lipid phase;
(2) sucrose, sodium cholate, PLURONICS F87, EDTA are mixed in water for injection, magnetic agitation is until the each several part dissolving gets water;
(3) under 60 ℃ of heated and stirred of lipid phase, water dropwise adds oil phase, and rapid stirring 10min gets the milky colostrum;
(4) with colostrum as in the high pressure dispersing emulsification machine, with 1100-1200bar pressure homogenizing 15-30 circulation, to mean diameter about 150nm, this Emulsion embedding in infusion bottle, is filled nitrogen, place the steam rotating sterilizer, sterilization gets effect of nano-paclitaxel.
Prescription 5:
Lecithin 2.5%
Soybean oil 5.2%
DSPE-PEG2000 0.5%
Sodium cholate 0.7%
EDTA 0.1%
All the other are water for injection.
Preparation method 5:
(1) soybean oil, lecithin, oleic acid, paclitaxel, the DSPE-PEG2000 with recipe quantity is dissolved in an amount of dehydrated alcohol, and the decompression rotary evaporation is removed ethanol, gets the lipid phase;
(2) sucrose, sodium cholate, EDTA are mixed in water for injection, magnetic agitation is until the each several part dissolving gets water;
(3) under 60 ℃ of heated and stirred of lipid phase, water dropwise adds oil phase, and rapid stirring 10min gets the milky colostrum;
(4) with colostrum as in the high pressure dispersing emulsification machine, with 1100-1200bar pressure homogenizing 15-30 circulation, to mean diameter about 150nm, this Emulsion embedding in infusion bottle, is filled nitrogen, place the steam rotating sterilizer, sterilization gets effect of nano-paclitaxel.
The sample physicochemical property index of above-described embodiment 2-5 formula preparation is as follows:
| Example 2 | Example 3 | Example 4 | Example 5 | |
| Particle diameter | 87.3nm | 153.2nm | 137.4nm | 90.5nm |
| Current potential | -20.5 | -22.7 | -19.5 | -21.1 |
Claims (4)
1. the taxusol-lipid nanoparticle injection of a tool anti-tumor activity is characterized in that, the percentage by weight composition of this injection is:
Paclitaxel 0.1%-5%
Matrix material 5%-50%
Surfactant 1%-25%
Stabilizing agent 5%-20%
Metal ion chelation agent 0.1%-1%
All the other are water for injection;
Wherein: matrix material is selected a kind of in vitamin E, refined plant oil, the animal oil or is wherein appointed several mixture; Surfactant is selected a kind of in phospholipid, polyethyleneglycol modified phospholipid, tween, poloxamer, span, oleic acid, the enuatrol or is wherein appointed several mixture; Stabilizing agent is selected a kind of of sucrose, trehalose, mannose, glycine, glutamic acid, sorbitol, mannitol or is wherein appointed several mixture; Metal ion chelation agent is selected a kind of or its mixture in disodium EDTA, the calcium disodium salt of EDTA.
2. the taxusol-lipid nanoparticle injection of a kind of tool anti-tumor activity according to claim 1 is characterized in that, the percentage by weight composition of this injection is:
Paclitaxel 0.1%-4%
Matrix material 5%-30%
Surfactant 3%-15%
Stabilizing agent 5%-15%
Metal ion chelation agent 0.1%-1%
All the other are water for injection;
Wherein the definition of matrix material, surfactant, stabilizing agent, metal ion chelation agent is with claim 1.
3. the taxusol-lipid nanoparticle injection of a kind of tool anti-tumor activity according to claim 1 is characterized in that, the percentage by weight composition of this injection is:
Paclitaxel 0.5%-3%
Matrix material 5%-25%
Surfactant 3%-15%
Stabilizing agent 5%-15%
Metal ion chelation agent 0.1%-0.5%
All the other are water for injection;
Wherein the definition of matrix material, surfactant, stabilizing agent, metal ion chelation agent is with claim 1.
4. the preparation method of the taxusol-lipid nanoparticle injection of arbitrary described a kind of tool anti-tumor activity according to claim 1-3, realize by following steps:
(1) preparation of lipid phase: the lipid of recipe quantity, the surfactant that is dissolved in lipid, polyethyleneglycol modified phospholipid, paclitaxel are dissolved in an amount of dehydrated alcohol, and reduction vaporization is removed ethanol, gets the lipid phase;
(2) preparation of water: the surfactant, stabilizing agent, the metal ion chelation agent that are soluble in the aqueous phase are mixed in water for injection, stir until the each several part dissolving gets water;
(3) preparation of colostrum: under 60 ℃ of heated and stirred of lipid phase, water dropwise adds oil phase, gets the milky colostrum;
(4) preparation of lipid nanoparticle: with colostrum as in the high pressure dispersing emulsification machine, under 0-10 ℃, circulate with 1000-1500bar pressure homogenizing 15-30, to mean diameter about 150nm, get lipid nanoparticle, with this Emulsion embedding in infusion bottle, fill nitrogen, place the steam rotating sterilizer, sterilization gets effect of nano-paclitaxel.
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| CN105560182A (en) * | 2016-02-04 | 2016-05-11 | 索安克（上海）投资有限公司 | Cabazitaxel composition for injection and preparing method thereof |
| WO2021077990A1 (en) * | 2019-10-24 | 2021-04-29 | 慧禹康成(杭州)医药科技有限公司 | Use of vitamin e compound |
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| WO2011062420A2 (en) * | 2009-11-20 | 2011-05-26 | Yuhan Corporation | Nanoparticles for tumor-targeting and processes for the preparation thereof |
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| CN105560182A (en) * | 2016-02-04 | 2016-05-11 | 索安克（上海）投资有限公司 | Cabazitaxel composition for injection and preparing method thereof |
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| CN105534903B (en) * | 2016-02-04 | 2017-10-20 | 索安克（上海）投资有限公司 | Injection paclitaxel composition and preparation method thereof |
| WO2021077990A1 (en) * | 2019-10-24 | 2021-04-29 | 慧禹康成(杭州)医药科技有限公司 | Use of vitamin e compound |
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