CN104368016A - Method for preparation of ultrasound micro bubbles carrying docetaxel lipid - Google Patents
Method for preparation of ultrasound micro bubbles carrying docetaxel lipid Download PDFInfo
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- CN104368016A CN104368016A CN201310688779.6A CN201310688779A CN104368016A CN 104368016 A CN104368016 A CN 104368016A CN 201310688779 A CN201310688779 A CN 201310688779A CN 104368016 A CN104368016 A CN 104368016A
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Abstract
The invention relates to a method for preparation of ultrasound micro bubbles carrying docetaxel lipid, main chemical reagent used in the method are DPPC (dipalmitoyl phosphatidylcholine), DPPE (dipalmitoyl phosphoethanolamine), DSPA, cholesterol and PBS solution, and a novel and efficient drug administration route for the treatment of liver cancer is ultimately provided.
Description
Technical field
The present invention relates to a kind of method preparing year Docetaxel lipid ultrasonic microvesicle, belong to pharmaceutical preparations technology field.
Background technology
Primary hepatocarcinoma is the sixth-largest common malignant tumor in the world, annual approximately newly-increased hepatocarcinoma patient 1,000,000 people in worldwide, 5 years survival rates of patient are less than 10%, its median survival time of patient losing surgical engine meeting is only 4-6 month, poor prognosis, occupies the 3rd of the cause of death that cancer causes.Population of China due to HBV, HCV infection rate high, onset of liver cancer rate and mortality rate occupy first of the whole world, and therefore, the research for liver cancer treatment seems and to be even more important and necessary.The therapeutic scheme of current hepatocarcinoma first-selection is still excision, but only the patient of 10%-15% has surgical engine meeting making a definite diagnosis fashion, and Resection Rate is low, and Postoperative recurrent rate is high; Chemotherapy is usually alternative primary treatments and means, but chemotherapeutics is mostly cytotoxic drug, lacks targeting, have larger toxic and side effects to tumor tissues and normal structure; Selectivity TACE (TACE) because of the relatively little application of its whole body toxic and side effects more extensive, but curative effect is still not good enough, and postoperatively cause serious post embolizatiou syndrome, upper gastrointestinal hemorrhage, gallbladder thromboembolism, serious vascular spasm, the even serious side reaction such as acute hepatic failure, make patient tolerability and compliance poor, and can not adhere to treatment, and TACE all has radiological hazard to patient and medical worker, should not carry out repetitive therapy.Therefore, a kind of effective, that safety, targeting are high, toxic and side effects is little treatment means is sought extremely urgent.
Taxone is the antitumor drug that a class is new, there is unique anti-tumor activity, be considered to one of potential anti-malignant tumor medicine of most in recent years, have Docetaxel and paclitaxel two kinds clinically at present, both antineoplastic mechanism is identical, is all act on microtubule/microtubuli system, by strengthening tubulin polymerization and microtubule depolymerization effect of drawing up, make microtubule stabilization, tumoricidal mitosis, impels apoptosis of tumor cells.And the anti-tumor activity of Docetaxel (being called for short DOC) is better than paclitaxel, Docetaxel can be used for the treatment of breast carcinoma, nonsmall-cell lung cancer, ovarian cancer, hepatocarcinoma, carcinoma of prostate etc. by other chemotherapeutics alone or in combination.But due to the poorly water-soluble of Docetaxel, better fat-soluble, limited in Clinical practice.
Liposome forms by by phospholipid and cholesterol, there is the structure of similar biomembrane bilayer, alternate intervals aqueous phase and lipid bilayer, hydrophilic medicament can be encapsulated in aqueous phase by this kind of structure, again can by lipophilic drug encapsulation in lipid bilayer, therefore, liposome can be used as the carrier of fat-soluble better medicine, overcomes the technical problem that Clinical practice is limited.
From nineteen sixty-eight Gramiak reported first since the application of acoustic contrast agent, its acoustic characteristic is constantly by people are familiar with and be applied to practice.People, while utilizing microbubble contrast agent Enhance ultrasonography, also find that microvesicle has targeting delivery effect, utilizes the cavitation effect of microvesicle under ultrasonic mediation, can targeting delivery gene or medicine, reach the object of disease therapy.This has greatly expanded the application of acoustic contrast agent undoubtedly, and may set up a kind of safe, effective, noninvasive ultrasonic mediation targeting delivery system.
In recent years, the research about acoustic contrast agent targeting drug delivery is increasing.By adjusting the characteristic of microvesicle itself, can medicine or therapeutic genes be integrated in microvesicle, the antibody of high special or other parts be connected to microbubble surface simultaneously.After the microvesicle of medicine is taken in vein injection, with the specific position of ultrasonic irradiation, the targeted release of medicine or therapeutic genes can be realized.Ultrasonic microbubble drug delivery system serves important function in thromboembolism treatment and antineoplaston.Ultrasound targeted microbubble explosion is a kind of emerging target administration and gene delivery method, and using the carrier that ultrasound microbubble contrast agent passes on as medicine or gene, main mechanism is sonoporation, the instantaneous hole namely after birth formed.Ultrasonic irradiation is in target tissue or target organ, and after target site carries gene or medicine-carrying microvesicle, Targeting delivery goes out gene and medicine, improves medicine and gene transfection rate.
The biological characteristics of ultrasonic microbubble becomes a kind of desirable gene or drug delivery vehicle.By carrying the microvesicle of gene or medicine on a small quantity after peripheral vein or local injection, carrying out ultrasonic examination when microvesicle flows through targeting moiety, namely obtaining ultrasonic image.When ultrasonic image figure prove ultrasonic be accurately positioned targeting moiety time, increase acoustic pressure to make it to reach some strength, microbubble ruptures can be made to produce cavitation effect, cavitation effect refers to that the small cavity be present in liquid is excited under the effect of high strength supersonic, cavitation nucleus sharply expands and shrinks until burst, this process cavitation core absorbs a large amount of acoustic energy, and by centralized release energy in minimum region, in core, local temperature and pressure sharply raise, produce powerful shock wave thereupon, interior shear force, the quadratic effects such as high speed microbeam jet and free radical, not only make microvascular, vascular endothelial cell shrinks, Dilated intercellular space, the permeability of wall of micrangium increases, the integrity of cell membrane also can be made to be destroyed, produce temporary, reversible aperture, add membrane passage, all can strengthen the transfer of medicine-carrying microvesicle to gene or medicine.
Between this, the present invention is intended to carry Docetaxel lipid ultrasonic microvesicle by preparation, and by investigating its performance, evaluate, the chemotherapy for hepatocarcinoma provides a kind of novel, efficient route of administration.
Summary of the invention
The object of the invention is to, provide a kind of and prepare the method for carrying Docetaxel lipid ultrasonic microvesicle, the method has science, efficiently feature.
Another object of the present invention is, the final prepared Docetaxel lipid ultrasonic microvesicle that carries is being used for the treatment of the application in liver-cancer medicine.
Technical scheme of the present invention, the method that Docetaxel lipid ultrasonic microvesicle is carried in preparation is:
Get Docetaxel 1-5mg, DPPC reagent 0.5-2mg, DPPE reagent 1-4mg, DSPA reagent 3-10mg and cholesterol appropriate, add organic solvent fully to dissolve, be cooled to room temperature, add the PBS solution 200-800 μ l of pH value≤7.0, glycerol 40-60 μ l, cholesterol is appropriate, fully sealing after mixing, the thermostatic equipment being placed in 40-60 DEG C hatches into thin film, be filled with perfluoropropane and substitute air in hermetic container, be airtightly placed in Ag and Hg mixer vibration 45s, to obtain final product.
Wherein, preferred preparation method is:
Get Docetaxel 2mg, DPPC reagent 1mg, DPPE reagent 2mg, DSPA reagent 5mg and cholesterol appropriate, add organic solvent fully to dissolve, be cooled to room temperature, add the PBS solution 450 μ l that pH value equals 7.0, glycerol 50 μ l, cholesterol are appropriate, fully sealing after mixing, the thermostatic equipment being placed in 50 DEG C hatches into thin film, be filled with perfluoropropane and substitute air in hermetic container, be airtightly placed in Ag and Hg mixer vibration 45s, to obtain final product.
Above-mentioned prepared year Docetaxel lipid ultrasonic microvesicle, is used in the application prepared in Hepatoma therapy medicine.
Beneficial effect
For technical solutions according to the invention, we have carried out comprehensive research comparison to the novelty that this technology is brought, and it can significantly improve ultrasonic ablation in the process of applications of ultrasound, and summing up beneficial effect has following 2 points:
1. radiography function: the microvesicle mean diameter that this kind of method prepares is 350nm-750nm, and the neat rounding of profile, is evenly distributed.Give this microvesicle of animal doses in ultrasonic contrast pattern, obvious radiography function can be seen, demonstrate the profile of liver tumor more clearly.
2. Targeting delivery medicine: HIFU is conbined usage with it, can reach the function of directional blasting, and drug utilization more can be made to reach maximization, is that a step important on treatment level is brought up in ultrasonic diagnosis.
Specific embodiment
Below the specific embodiment of content of the present invention, for set forth in present specification want the technical scheme of technical solution problem, contributes to those skilled in the art and understand content of the present invention, but the realization of technical solution of the present invention is not limited to these embodiments.Embodiment 1
Get Docetaxel 2mg, DPPC reagent 1mg, DPPE reagent 2mg, DSPA reagent 5mg and cholesterol appropriate, add organic solvent fully to dissolve, be cooled to room temperature, add the PBS solution 450 μ l that pH value is 5.0, glycerol 50 μ l, cholesterol are appropriate, fully sealing after mixing, the thermostatic equipment being placed in 50 DEG C hatches into thin film, be filled with perfluoropropane and substitute air in hermetic container, be airtightly placed in Ag and Hg mixer vibration 30s, to obtain final product.
Embodiment 2
Get Docetaxel 1mg, DPPC reagent 0.5mg, DPPE reagent 1mg, DSPA reagent 3mg and cholesterol appropriate, add organic solvent fully to dissolve, be cooled to room temperature, add the PBS solution 200 μ l that pH value is less than 4.0, glycerol 40 μ l, cholesterol are appropriate, fully sealing after mixing, the thermostatic equipment being placed in 60 DEG C hatches into thin film, be filled with perfluoropropane and substitute air in hermetic container, be airtightly placed in Ag and Hg mixer vibration 35s, to obtain final product.
Embodiment 3
Get Docetaxel 5mg, DPPC reagent 2mg, DPPE reagent 4mg, DSPA reagent 10mg and cholesterol appropriate, add organic solvent fully to dissolve, be cooled to room temperature, add the PBS solution 800 μ l that pH value is less than 3.0, glycerol 60 μ l, cholesterol are appropriate, fully sealing after mixing, the thermostatic equipment being placed in 40 DEG C hatches into thin film, be filled with perfluoropropane and substitute air in hermetic container, be airtightly placed in Ag and Hg mixer vibration 40s, to obtain final product.
Embodiment 4
Get Docetaxel 2mg, DPPC reagent 1mg, DPPE reagent 2mg, DSPA reagent 5mg and cholesterol appropriate, add organic solvent fully to dissolve, be cooled to room temperature, add the PBS solution 450 μ l that pH value is 2.5, glycerol 50 μ l, cholesterol are appropriate, fully sealing after mixing, the thermostatic equipment being placed in 55 DEG C hatches into thin film, be filled with perfluoropropane and substitute air in hermetic container, be airtightly placed in Ag and Hg mixer vibration 45s, to obtain final product.
Embodiment 5
Get Docetaxel 2mg, DPPC reagent 1mg, DPPE reagent 2mg, DSPA reagent 5mg and cholesterol appropriate, add organic solvent fully to dissolve, be cooled to room temperature, add the PBS solution 450 μ l that pH value is 6.5, glycerol 55 μ l, cholesterol are appropriate, fully sealing after mixing, the thermostatic equipment being placed in 50 DEG C hatches into thin film, be filled with perfluoropropane and substitute air in hermetic container, be airtightly placed in Ag and Hg mixer vibration 50s, to obtain final product.
Above in all technical schemes of the present invention, described DPPC is: dipalmitoyl phosphatidyl choline, DPPE: dipalmitoylphosphatidylethanoiamine, DSPA: DSPA, PBS solution: phosphate buffered solution, HIFU: high intensity focused ultrasound.
Claims (3)
1. prepare a method of carrying Docetaxel lipid ultrasonic microvesicle, it is characterized in that:
Get Docetaxel 1-5mg, DPPC reagent 0.5-2mg, DPPE reagent 1-4mg, DSPA reagent 3-10mg and cholesterol appropriate, add organic solvent fully to dissolve, be cooled to room temperature, add the PBS solution 200-800 μ l of pH value≤7.0, glycerol 40-60 μ l, cholesterol is appropriate, fully sealing after mixing, the thermostatic equipment being placed in 40-60 DEG C hatches into thin film, be filled with perfluoropropane and substitute air in hermetic container, be airtightly placed in Ag and Hg mixer vibration 45s, to obtain final product.
2. preparation method as claimed in claim 1, is characterized in that:
Get Docetaxel 2mg, DPPC reagent 1mg, DPPE reagent 2mg, DSPA reagent 5mg and cholesterol appropriate, add organic solvent fully to dissolve, be cooled to room temperature, add the PBS solution 450 μ l that pH value is 7.0, glycerol 50 μ l, cholesterol are appropriate, fully sealing after mixing, the thermostatic equipment being placed in 50 DEG C hatches into thin film, be filled with perfluoropropane and substitute air in hermetic container, be airtightly placed in Ag and Hg mixer vibration 45s, to obtain final product.
3. preparation method as claimed in claim 1 or 2, is characterized in that: the final made Docetaxel lipid ultrasonic microvesicle that carries is preparing the application in Hepatoma therapy medicine.
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| CN201310688779.6A CN104368016A (en) | 2013-12-12 | 2013-12-12 | Method for preparation of ultrasound micro bubbles carrying docetaxel lipid |
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| CN201310688779.6A CN104368016A (en) | 2013-12-12 | 2013-12-12 | Method for preparation of ultrasound micro bubbles carrying docetaxel lipid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019051752A1 (en) * | 2017-09-14 | 2019-03-21 | 吴金凤 | Method for preparing lipidosome nano-bubble ultrasound contrast agent |
| CN115154472A (en) * | 2022-07-27 | 2022-10-11 | 北京大学第三医院（北京大学第三临床医学院） | Hydrocortisone multifunctional ultrasonic microbubble with targeting function for treating cerebral apoplexy |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103100093A (en) * | 2013-01-23 | 2013-05-15 | 中山大学附属第三医院 | Load small interfering RNA nanoscale lipid microbubble ultrasonic contrast agent and preparation method |
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2013
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103100093A (en) * | 2013-01-23 | 2013-05-15 | 中山大学附属第三医院 | Load small interfering RNA nanoscale lipid microbubble ultrasonic contrast agent and preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 郑宏志等: ""载多西紫杉醇脂质微泡对人肝癌HepG2细胞抑制作用的体外研究"", 《现代生物医学进展》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019051752A1 (en) * | 2017-09-14 | 2019-03-21 | 吴金凤 | Method for preparing lipidosome nano-bubble ultrasound contrast agent |
| CN115154472A (en) * | 2022-07-27 | 2022-10-11 | 北京大学第三医院（北京大学第三临床医学院） | Hydrocortisone multifunctional ultrasonic microbubble with targeting function for treating cerebral apoplexy |
| CN115154472B (en) * | 2022-07-27 | 2024-05-07 | 北京大学第三医院（北京大学第三临床医学院） | Hydrocortisone multifunctional ultrasonic microbubble with targeting function for treating cerebral apoplexy |
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Application publication date: 20150225 |