CN100364525C - Docetaxel liposome containing chitosan derivative, lyophiled preparation and preparation method thereof - Google Patents
Docetaxel liposome containing chitosan derivative, lyophiled preparation and preparation method thereof Download PDFInfo
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- CN100364525C CN100364525C CNB2006100394757A CN200610039475A CN100364525C CN 100364525 C CN100364525 C CN 100364525C CN B2006100394757 A CNB2006100394757 A CN B2006100394757A CN 200610039475 A CN200610039475 A CN 200610039475A CN 100364525 C CN100364525 C CN 100364525C
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Abstract
The present invention relates to a docetaxel liposome modified by a chitosan derivative, a freeze-dried preparation and a preparation method, which belongs to the field of medicinal preparations. The present invention is characterized in that the docetaxel liposome contains 1 share of docetaxel, 1 to 10 shares of a chitosan derivative, 10 to 50 shares of phospholipid and 1 to 10 shares of cholesterol. The docetaxel liposome of the present invention has the advantages of stable quality, high encapsulation efficiency and better medical effect than ordinary liposomes.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to many Xi Tasai liposome, lyophilized formulations and preparation method that a kind of chitosan derivatives is modified.
Background technology
Many Xi Tasai (having another name called Docetaxel, English name docetaxel) are the derivants of paclitaxel, are used for the treatment of breast carcinoma and non-small cell carcinoma clinically, and are effective to pulmonary carcinoma, ovarian cancer, cancer of pancreas, gastric cancer and head and neck cancer.The late period that is used for late period of the failure of chemotherapy in advance or metastatic breast cancer and fails based on the chemotherapy of cisplatin or the treatment of transitivity nonsmall-cell lung cancer.U.S. FDA is ratified many Xi Tasaijia cisplatin on July 15th, 2002 and is applied to the nonsmall-cell lung cancer in late period as a line scheme.The mechanism of action of many Xi Tasai is to strengthen the tubulin polymerization effect and suppress the tubulin depolymerisation, causes forming stable non-functional microtubule fasolculus, thereby tumoricidal mitosis.The IC of this product is higher 3 times than paclitaxel, and in cell the holdup time long, to the cell strain of cisplatin, etoposide, 5Fu or taxol resistance, many Xi Tasai do not produce cross resistance.
The poorly water-soluble of many Xi Tasai, have well fat-solublely, at present the double solvent be made up of Tween 80 and ethanol of commercially available injection is made, and some cases after intravenous injection severe allergic reaction may take place, it is characterized by hypotension and bronchospasm, need therapy discontinued.Slight anaphylaxis also may take place in some cases, as blush, with or without the erythema of Pruritus, uncomfortable in chest, backache, dyspnea, drug fever or shiver.Also have some cases that fluid retention may take place.All patients are all necessary oral glucocorticoid class before accepting the docetaxel treatment phase, with Polyglucan reaction and fluid retention.Present docetaxel injection is before use earlier with 5% the glucose solution of 250ml or 0.9% normal saline solution dilution, this dilution injection later must use immediately, and use at the appointed time, promptly there are many Xi Tasai to separate out otherwise place a few hours.Except the problem of double solvent, itself also has very strong toxicity many Xi Tasai, and is common such as bone marrow depression, neurotoxicity, hypotension etc., so wish under situation about not lessening the curative effect, can reduce amount of drug to lower side effects of pharmaceutical drugs.
Liposome has targeting, can improve curative effect of medication and lower toxic and side effects.People such as Maria laura Immordino have reported a kind of many Xi Tasai liposome, but because this liposome stability of technical reason is poor, just revealed in one day for 4 ℃ and surpass 50%, its liposome production method is not suitable for industrialized great production (Maria laura Immordino, Paola Brusa, J.Journal ofControlled Release, 91 (2003) 417-429), more be not suitable for clinical.
Summary of the invention
The invention discloses a kind of stable many Xi Tasai liposome composition, by chitosan derivatives being dissolved in the preparation process of liposome, the chitosan derivatives of preparation is modified many Xi Tasai liposome and is fit to industrialized great production and stability height.Because what use all is that Biodegradable material obviously reduces than existing injection toxicity.Compare with traditional injection that is prepared into by Tween 80 and alcoholic solution, chitosan-modified many Xi Tasai liposome has reduced the unsafe factor in the clinical use.The animal experiment proof is because the adding of chitosan derivatives, it is compared with traditional liposomal and has improved the killing effect of medicine to tumor cell, and make medicine in blood, continue to discharge, prolonged the circulation time of medicine in blood, thereby can reduce amount of drug, improve the curative effect of medicine, reduce the toxic and side effects of medicine.
Many Xi Tasai liposome composition of the present invention, contain following components in part by weight:
1 part of many Xi Tasai
Chitosan derivatives 1-10 part
Phosphatidase 11 0-50 part
Cholesterol 1-10 part.
The preferred weight ratio of each component is:
1 part of many Xi Tasai
Chitosan derivatives 4-6 part
Phosphatidase 12 3-30 part
Cholesterol 2-5 part.
Above component is the key component of many Xi Tasai liposome composition, and the combination of each component and proportioning make many Xi Tasai liposome composition show good especially stability and very high envelop rate.The substrate of liposome is water, and a medicine is generally wanted 1-500 part water.If make the liposome precursor lyophilized products, then moisture content volatilizees in freeze-drying process.
In above-mentioned many Xi Tasai liposome composition, wherein the preferred substitution value of chitosan derivatives is n-caproic acid acylation chitosan, lauric acid acylation chitosan, oleic acid acylation chitosan, stearic acid acylation chitosan, Palmic acid acylation chitosan or the succinic acid acylation chitosan of 0.1-1.
In sour phosphatidyl amine derivative (PEG-DSPE) of the distearyl of phospholipid preferably lecithin, soybean phospholipid, Polyethylene Glycol or the two Palmic acid phosphatidylcholines (DPPC) one or more.
Above-mentioned chitosan-modified many Xi Tasai liposome can further be prepared into injection (little pin) and transfusion, can add other pharmaceutic adjuvant such as isoosmotic adjusting agent etc. as required when being prepared into injection or transfusion.The lipidosome freeze-dried one-tenth freeze-dried powder of chitosan-modified many Xi Tasai preferably can also be added excipient during lyophilizing, the amount of excipient is freeze-dried powder gross weight 50-80%.
Excipient preferably is made up of a and b two parts, wherein a be that mannitol, sucrose, dextrose are sweet, sorbitol, glucose or trehalose; B is Polyethylene Glycol stearic acid 15 (preferred Solutol
HS 15) or the poly-hydrocarbon oxygen fat 35 of Oleum Ricini (preferred Cremophor
ELP).
Medicine (being many Xi Tasai), the preferred weight ratio of a, b are 1: 30-60: 10-25.
The preparation method of chitosan-modified many Xi Tasai liposome of the present invention is simple, can use film dispersion method, alcohol injection, reverse phase evaporation, ether injection method and Mechanical Method etc., wherein Mechanical Method comprises and uses homogenizer, Ultrasound Instrument, supercritical fluid instrument and extrude the method that machinery equipment such as instrument prepares liposome.In proportion many Xi Tasai, phospholipid and cholesterol are made liposome turbid liquor with film dispersion method, alcohol injection, reverse phase evaporation or ether injection method, the acetum dissolving of chitosan derivatives with PH6.0-6.8 is uniformly dispersed, liposome turbid liquor is poured nitrogen at room temperature slowly to be stirred, chitosan derivative solution is splashed in the liposome turbid liquor, hatching at room temperature after dropwising, the phosphate buffer of PH7-8 joined in the suspension mix, regulate about the PH to 7.4 of suspension, promptly.For the chitosan derivatives that obtains small particle diameter is modified many Xi Tasai liposome, the chitosan derivatives that obtains is modified many Xi Tasai liposome use homogenizer or extrude instrument and carry out second homogenate or extruding.
The more excellent preparation method of chitosan-modified many Xi Tasai liposome may further comprise the steps:
The preparation of the common many Xi Tasai liposome turbid liquor before 1) chitosan derivatives is modified: the many Xi Tasai, phospholipid and the cholesterol that take by weighing recipe quantity are dissolved in the adequate amount of ethanol solution, feeding behind the nitrogen mix homogeneously drains ethanol with Rotary Evaporators (toxicity is little in the water-bath of 45 ℃ of temperature, needn't worry organic solvent residual), form the immobilized artificial membrane of homogeneous, use the phosphate buffer eluting immobilized artificial membrane of PH7.4.The liposome turbid liquor that obtains is poured in the APV2000 homogenizer, and homogenizing is 5 times under the pressure of a step valve 1760bar and secondary valve 270bar, and the filter membrane with 200nm pushes out by extruding instrument then.
2) prepare liposome turbid liquor after, chitosan derivatives is uniformly dispersed with the dissolving of the acetum of PH6.8, acid moieties carbon is greater than the acetate dissolution of 10 use PH6.5.Liposome turbid liquor is poured nitrogen at room temperature slowly stir, chitosan derivative solution is splashed in the liposome turbid liquor with constant speed, at room temperature hatched after dropwising 1 hour, it is standby to obtain suspension.
3) phosphate buffer of use PH7-8 joins in the suspension and mixes, and regulates about the PH to 7.4 of suspension, obtains stable chitosan derivatives and modifies many Xi Tasai liposome.
4) modify the more Xi Tasai liposome for the chitosan derivatives that obtains small particle diameter, the chitosan derivatives that obtains is modified many Xi Tasai liposome use homogenizer or extrude instrument and carry out second homogenate or extruding.
The preparation method of described chitosan-modified many Xi Tasai lipidosome freeze-dried preparation may further comprise the steps: excipient is soluble in water, and the liposome turbid liquor with method for preparing splashes in the excipient solution again, lyophilizing, promptly.
More specifically preferred preparation method is as follows:
The excipient that takes by weighing recipe quantity is dissolved in an amount of water, behind the mix homogeneously, the chitosan derivatives for preparing is modified many Xi Tasai liposome slowly to splash in the solution, stir while splashing into, obtain putting into ultra cold storage freezer after the filtering with microporous membrane sterilization by 0.15 μ m behind the stable suspension, placed one day down at subzero 70 ℃, putting into freeze dryer then carries out lyophilizing, pours nitrogen after lyophilizing finishes and seals.
Liposome after chitosan-modified many Xi Tasai liposome of the present invention and the lyophilized powder hydration, its envelop rate is 80%-99%, particle diameter is 20nm-5 μ m.
Chitosan derivatives of the present invention is modified many Xi Tasai liposome stability height, and chitosan-modified many Xi Tasai liposome lucifuge of the present invention is placed on the physical stability of observation after its 1 month in 4 ℃ of refrigerators.The mean diameter of placing proliposome is 22.3nm, and the zeta current potential is-30.1mv that envelop rate is 92.2 ± 1.48.The mean diameter of placing the back liposome is 29.9nm, and the zeta current potential is-29.1mv that envelop rate is 91.1% ± 2.18 (n=5).Envelop rate, particle diameter and zeta current potential all do not have significant change.Chitosan derivatives is modified many Xi Tasai lipid freeze-dry powder and was placed 9 months under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10%, and every index of detection meets quality standard, and wherein a collection of sample result sees the following form 1.
Table 1 chitosan derivatives is modified many Xi Tasai lipid freeze-dry powder long-term test results
| Time (moon) | Appearance character | Check | Assay (%) | ||||
| Particle diameter | Basicity | Envelop rate (%) | Related substance (%) | Aseptic | |||
| 0 | Little yellow loose powder | 221nm | 8.51 | 99.80 | 1.13 | Up to specification | 102.2 |
| 3 | Little yellow loose powder | 223nm | 8.47 | 99.15 | 1.18 | -- | 101.5 |
| 6 | Little yellow loose powder | 225nm | 8.58 | 98.89 | 1.28 | -- | 102.3 |
| 9 | Little yellow loose powder | 229nm | 8.48 | 98.61 | 1.27 | Up to specification | 103.1 |
Find that in the research process of many Xi Tasai liposome the adding of chitosan derivatives can make the quality of liposome more stable.The inventor has prepared in early-stage Study and has not used chitosan-modified common many Xi Tasai liposome.Concrete preparation process is: take by weighing the many Xi Tasai of 10mg, 300mg lecithin and 20mg cholesterol and be dissolved in the 15ml chloroform, place under the condition of 35-40 ℃ of water-bath with Rotary Evaporators 100rpm and decompression and remove chloroform, make mixture in eggplant-shape bottle, form the lipid membrane of homogeneous, with 20ml pure water eluting lipid material, obtain milky liposome turbid liquor, pour liposome turbid liquor into the APV2000 homogenizer, homogenizing is 5 times under the pressure of a step valve 1760bar and secondary valve 270bar, obtains the many Xi Tasai liposome solutions (liposome B) than clear.Prepared liposome encapsulation is 91%, and particle diameter is 311nm (a Ma Erwen zetasize3000 mensuration), but the less stable of liposome, places that particle diameter is increased to 1.1 μ m after 12 hours, and envelop rate drops to 75%.Can improve the stabilization time of liposome behind the adding surfactant.And use the same method, adding again that the gained liposome encapsulation is 97% behind the chitosan derivatives 50mg, particle diameter is 301nm (a Ma Erwen zetasize3000 mensuration), places that particle is increased to 305nm after 12 hours, envelop rate is 97%.
It is higher than the common Xi Tasai of manying liposome curative effect that research finds that also chitosan derivatives of the present invention is modified many Xi Tasai liposome, is pharmacology test and data below:
The S that the choosing inoculation is back 7 days
180The ascitic type mice with tumor, extract ascites inoculation nude mice, after inoculation is finished and is turned out to be the white mice sarcoma, nude mice is divided into 4 groups at random, every group more than 10, tail vein injection awards normal saline, commercially available injection, conventional liposome (liposome B) and liposome of the present invention (embodiment 1 makes) respectively, and the dosage of medicine is according to people 70mg/m
2Be converted into the dosage of mice.Liposome of the present invention, conventional liposome and the commercially available prod of same dose be to after the tumor-bearing rat injection, and after the drug withdrawal 5 days, put to death animal and weigh, peel tumor and weigh, be contrast with the normal saline group, calculate by following formula: S
180The average tumor of average tumor weight/matched group heavy * 100% is organized in the average tumor weight-treatment of tumour inhibiting rate %=matched group of tumor bearing nude mice.The result shows: liposome of the present invention is higher than conventional liposome to the tumor-inhibiting action of rat, and the effect of conventional liposome is higher than commercially available injection, the results are shown in Table 2.
Table 2 different dosage form is to S
180The tumour inhibiting rate % of tumor bearing nude mice
| Group | n | Average tumor weight/g | Tumour inhibiting rate % |
| The commercially available injection liposome of normal saline B | 10 10 10 | 2.51±0.31 1.27±0.32 0.98±0.28 | -- 49.4％ 60.9％ |
| Liposome of the present invention | 10 | 0.79±0.26 | 68.5％ |
Choose 18 of rats, divide three groups of tail vein injection liposome of the present invention (embodiment 2 makes), conventional liposome (liposome B) and commercially available prod respectively.Dosage is the same.Respectively at 1,5,10,20,100,200,250,500,1500min gets blood in the optical fundus after the administration, and blood sample is with anticoagulant heparin and centrifugal separation plasma, with the many Xi Tasai concentration in the liquid matter method mensuration blood plasma.In the present invention, medicine continues to discharge in the chitosan derivatives modified liposome, significantly improved blood drug level, significant prolongation the action time of medicine in blood (medicine of the chitosan-modified many Xi Tasai liposome of rat intravenous injection, conventional liposome and commercially available injection in blood through the time curve, pharmacokinetic parameters sees Table 3, the results are shown in Figure 1).
Table 3 through the time curve pharmacokinetic parameters
| AUC | t 1/2α | t 1/2β | MRT | |
| Liposomal lipid plastid B of the present invention | 15.6 6.11 | 2.29 1.54 | 667 259 | 953 369 |
| The commercially available prod | 0.218 | 1.16 | 53.4 | 50.2 |
This product adopts natural biologic material to have improved the safety of medication in the heavy dose of and long-time clinically use with arbitrarily than mixing with common transfusion.Owing to prolonged the action time of medicine in blood, improved killing action to tumor cell, so can reduce amount of drug, reduce of the injury of his turunda thing of many west itself to patient.
Description of drawings
Fig. 1 be the medicine of the chitosan-modified many Xi Tasai liposome of rat intravenous injection, conventional liposome and commercially available injection in blood through the time curve
The specific embodiment
Embodiment 1
Taking by weighing the many Xi Tasai of 15mg, 375mg lecithin and 45mg cholesterol is dissolved in the 10ml alcoholic solution, mix homogeneously is drained ethanol with Rotary Evaporators after feeding nitrogen in the water-bath of 45 ℃ of temperature, after forming the immobilized artificial membrane of homogeneous, use the phosphate buffer eluting immobilized artificial membrane 10ml of PH7.4.The liposome turbid liquor that obtains is poured in the APV2000 homogenizer, and homogenizing is 5 times under the pressure of a step valve 1760bar and secondary valve 270bar, and the filter membrane with 200nm pushes out by extruding instrument then.After preparing liposome turbid liquor, Palmic acid acylation chitosan 50mg is uniformly dispersed with the acetum dissolving of PH6.5.Liposome turbid liquor is poured nitrogen at room temperature slowly stir, splash in the liposome turbid liquor with constant speed, at room temperature hatched after dropwising 1 hour, it is standby to obtain suspension.The phosphate buffer of PH7.5 joined in the suspension mix, regulate about the PH to 7.4 of suspension, obtain stable chitosan derivatives and modify many Xi Tasai liposome.Chitosan derivatives is modified many Xi Tasai liposome use the homogenizer second homogenate.The chitosan derivatives modified liposome envelop rate of preparation is 98.4%, and particle diameter is 20nm (a Ma Erwen zetasize3000 mensuration).
Embodiment 2
Take by weighing the many Xi Tasai of 10mg, 200mg fabaceous lecithin, 50mgPEG-DSPE and 30mg cholesterol and be dissolved in the 10ml diethyl ether solution, solution is slowly hanged down in the phosphate buffer of 10mlPH7.4, at room temperature volatilize ether.The liposome turbid liquor that obtains is poured in the APV2000 homogenizer, and homogenizing is 5 times under the pressure of a step valve 1760bar and secondary valve 270bar, and the filter membrane with 200nm pushes out by extruding instrument then.After preparing liposome turbid liquor, stearic acid acylation chitosan 40mg is uniformly dispersed with the acetum dissolving of PH6.5.Liposome turbid liquor is poured nitrogen at room temperature slowly stir, splash in the liposome turbid liquor with constant speed, at room temperature hatched after dropwising 1 hour, it is standby to obtain suspension.The phosphate buffer of PH7.5 joined in the suspension mix, regulate about the PH to 7.4 of suspension, obtain stable chitosan derivatives and modify many Xi Tasai liposome.Chitosan derivatives is modified many Xi Tasai liposome use the homogenizer second homogenate.The chitosan derivatives modified liposome envelop rate of preparation is 99.6%, and particle diameter is 22nm (a Ma Erwen zetasize3000 mensuration).
Embodiment 3
Take by weighing the many Xi Tasai of 10mg, 500mg lecithin and 40mg cholesterol and be dissolved in the 15ml alcoholic solution, solution is splashed at the uniform velocity slowly among the phosphate buffer 8ml of PH7.4, at room temperature volatilize ethanol.The liposome turbid liquor that obtains is poured in the APV2000 homogenizer, and homogenizing is 5 times under the pressure of a step valve 1760bar and secondary valve 270bar, and the filter membrane with 200nm pushes out by extruding instrument then.After preparing liposome turbid liquor, lauric acid acylation chitosan 40mg is uniformly dispersed with the acetum 5ml dissolving of PH6.8.Liposome turbid liquor is poured nitrogen at room temperature slowly stir, splash in the liposome turbid liquor with constant speed, at room temperature hatched after dropwising 2 hours, it is standby to obtain suspension.The phosphate buffer of PH7.5 joined in the suspension mix, regulate about the PH to 7.4 of suspension, obtain stable chitosan derivatives and modify many Xi Tasai liposome.Chitosan derivatives is modified many Xi Tasai liposome use the homogenizer second homogenate.Take by weighing 500mg mannitol and 100mg Cremophor
ELP is dissolved in the 10ml water, behind the mix homogeneously, the chitosan derivatives for preparing is modified many Xi Tasai liposome slowly to splash in the solution, stir while splashing into, obtain putting into ultra cold storage freezer after the filtering with microporous membrane sterilization by 0.15 μ m behind the stable suspension, after placing one day under subzero 70 ℃, put into freeze dryer and carry out lyophilizing, pour nitrogen after lyophilizing finishes and seal.Liposome encapsulation after the chitosan derivatives modified liposome lyophilized powder hydration of preparation is 97.5%, and particle diameter is 216nm (a Ma Erwen zetasize3000 mensuration).
Embodiment 4
Take by weighing the many Xi Tasai of 20mg, 350mg lecithin, 100mgPEG-DSPE and 90mg cholesterol and be dissolved in the 20ml diethyl ether solution, solution is splashed at the uniform velocity slowly among the phosphate buffer 8ml of PH7.4, at room temperature volatilize ether.The liposome turbid liquor that obtains is poured in the bottle, with cell Ultrasound Instrument ultrasonic 10min under 240v.After preparing liposome turbid liquor, succinic acid acylation chitosan 60mg is uniformly dispersed with the acetum 5ml dissolving of PH6.5.Liposome turbid liquor is poured nitrogen at room temperature slowly stir, splash in the liposome turbid liquor with constant speed, at room temperature hatched after dropwising 2 hours, it is standby to obtain suspension.The phosphate buffer of PH7.8 joined in the suspension mix, regulate about the PH to 7.4 of suspension, obtain stable chitosan derivatives and modify many Xi Tasai liposome.Chitosan derivatives is modified many Xi Tasai liposome use the homogenizer second homogenate.Take by weighing 1200mg sucrose and 200mg Solutol
HS 15 is dissolved in the 25ml water, behind the mix homogeneously, the chitosan derivatives for preparing is modified many Xi Tasai liposome slowly to splash in the solution, stir while splashing into, obtain putting into ultra cold storage freezer after the filtering with microporous membrane sterilization by 0.15 μ m behind the stable suspension, after placing one day under subzero 70 ℃, put into freeze dryer and carry out lyophilizing, pour nitrogen after lyophilizing finishes and seal.Liposome encapsulation after the chitosan derivatives modified liposome lyophilized powder hydration of preparation is 99.8%, and particle diameter is 196nm (a Ma Erwen zetasize3000 mensuration).
Embodiment 5
Take by weighing the many Xi Tasai of 25mg, 400mg fabaceous lecithin, 100mgPEG-DSPE and 70mg cholesterol and be dissolved in the 20ml alcoholic solution, solution is splashed at the uniform velocity slowly among the phosphate buffer 8ml of PH7.4, at room temperature volatilize ethanol.The liposome turbid liquor that obtains is poured in the bottle, disperseed with the supercritical fluid instrument.After preparing liposome turbid liquor, oleic acid acylation chitosan 40mg and n-caproic acid acylation chitosan 30mg are uniformly dispersed with the acetum 5ml dissolving of PH6.5.Liposome turbid liquor is poured nitrogen at room temperature slowly stir, splash in the liposome turbid liquor with constant speed, at room temperature hatched after dropwising 2 hours, it is standby to obtain suspension.The phosphate buffer of PH7.7 joined in the suspension mix, regulate about the PH to 7.4 of suspension, obtain stable chitosan derivatives and modify many Xi Tasai liposome.Chitosan derivatives is modified many Xi Tasai liposome use the homogenizer second homogenate.Take by weighing 1200mg dextran and 200mg Solutol
HS 15 is dissolved in the 20ml water, behind the mix homogeneously, the chitosan derivatives for preparing is modified many Xi Tasai liposome slowly to splash in the solution, stir while splashing into, obtain putting into ultra cold storage freezer after the filtering with microporous membrane sterilization by 0.15 μ m behind the stable suspension, after placing one day under subzero 70 ℃, put into freeze dryer and carry out lyophilizing, pour nitrogen after lyophilizing finishes and seal.Liposome encapsulation after the chitosan derivatives modified liposome lyophilized powder hydration of preparation is 98.2%, and particle diameter is 201nm (a Ma Erwen zetasize3000 mensuration).
Claims (8)
1. Xi Tasai liposome composition more than a kind is characterized in that containing following components in part by weight:
1 part of many Xi Tasai
Chitosan derivatives 1-10 part
Phosphatidase 11 0-50 part
Cholesterol 1-10 part
Wherein chitosan derivatives is that substitution value is n-caproic acid acylation chitosan, lauric acid acylation chitosan, oleic acid acylation chitosan, stearic acid acylation chitosan, Palmic acid acylation chitosan or the succinic acid acylation chitosan of 0.1-1.
2. many Xi Tasai of claim 1 liposome composition, the weight ratio of each component is:
1 part of many Xi Tasai
Chitosan derivatives 4-6 part
Phosphatidase 12 3-30 part
Cholesterol 2-5 part.
3. claim 1 or many Xi Tasai liposome composition of 2, wherein phospholipid is one or more in lecithin, soybean phospholipid or the two Palmic acid phosphatidylcholines.
4. claim 1 or many Xi Tasai liposome composition of 2 also contain excipient.
5. many Xi Tasai of claim 4 liposome composition, wherein excipient is made up of a and b, and wherein a is mannitol, sucrose, dextran, sorbitol, glucose or trehalose; B is the poly-hydrocarbon oxygen fat 35 of Polyethylene Glycol stearic acid 15 or Oleum Ricini.
6. many Xi Tasai of claim 5 liposome composition, the weight ratio of wherein many Xi Tasai, a, b is 1: 30-60: 10-25.
7. the preparation method of each many Xi Tasai liposome composition in the claim 1 to 3 comprises:
Many Xi Tasai, phospholipid and cholesterol are made liposome turbid liquor with film dispersion method, alcohol injection, reverse phase evaporation or ether injection method, the acetum dissolving of chitosan derivatives with PH6.0-6.8 is uniformly dispersed, liposome turbid liquor is poured nitrogen at room temperature slowly to be stirred, chitosan derivative solution is splashed in the liposome turbid liquor, hatching at room temperature after dropwising, the phosphate buffer of PH7-8 joined in the suspension mix, regulate the PH to 7.4 of suspension, promptly.
8. the preparation method of many Xi Tasai of claim 4 liposome composition, comprising: excipient is soluble in water, and the liposome turbid liquor that claim 7 method is made splashes in the excipient solution again, lyophilizing, promptly.
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| CN101584663B (en) * | 2008-05-22 | 2013-02-20 | 广州瑞济生物技术有限公司 | Novel delivery system of Duoxitasai lipidosome for injection and preparation method thereof |
| CN101406454B (en) * | 2008-11-14 | 2014-04-09 | 沈阳药科大学 | Low molecular weight chitosan modified liposomes and preparation method thereof |
| CN107400179B (en) * | 2017-07-27 | 2019-06-28 | 大连民族大学 | Double fat chain substituent phosphatidyl-ethanolamine chitosans and its preparation method and application |
| CN107714707B (en) * | 2017-11-21 | 2020-09-22 | 青岛大学附属医院 | Doxycycline controlled-release quaternary ammonium salt chitosan-liposome composite nanoparticle with pH responsiveness and preparation method thereof |
| CN112641950B (en) * | 2021-01-12 | 2022-12-16 | 北京德立福瑞医药科技有限公司 | Pharmaceutical composition containing insoluble antitumor active agent and preparation method thereof |
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| 羟基喜树碱包衣纳米脂质体的处方及制备工艺研究. 吴燕.中国药学杂志，第40卷第2期. 2005 * |
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