CN117180201A - Etoposide liposome pharmaceutical composition with low cholesterol content and preparation method thereof - Google Patents
Etoposide liposome pharmaceutical composition with low cholesterol content and preparation method thereof Download PDFInfo
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- CN117180201A CN117180201A CN202311266140.9A CN202311266140A CN117180201A CN 117180201 A CN117180201 A CN 117180201A CN 202311266140 A CN202311266140 A CN 202311266140A CN 117180201 A CN117180201 A CN 117180201A
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- etoposide
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- lecithin
- cholesterol
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- 239000002502 liposome Substances 0.000 title claims abstract description 85
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 title claims abstract description 67
- 229960005420 etoposide Drugs 0.000 title claims abstract description 67
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title claims abstract description 62
- 235000012000 cholesterol Nutrition 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 19
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 18
- 239000000787 lecithin Substances 0.000 claims abstract description 18
- 229940067606 lecithin Drugs 0.000 claims abstract description 18
- 235000010445 lecithin Nutrition 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- 239000000725 suspension Substances 0.000 claims abstract description 13
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- 239000000203 mixture Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 6
- 238000001125 extrusion Methods 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 229940083466 soybean lecithin Drugs 0.000 claims description 6
- 229930006000 Sucrose Natural products 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 4
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 4
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 125000000185 sucrose group Chemical group 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 19
- 239000002904 solvent Substances 0.000 abstract description 5
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 210000001185 bone marrow Anatomy 0.000 abstract description 4
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- 231100000331 toxic Toxicity 0.000 abstract description 4
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- 229940075383 etoposide injection Drugs 0.000 description 18
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- 206010028980 Neoplasm Diseases 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 210000003743 erythrocyte Anatomy 0.000 description 5
- 238000005538 encapsulation Methods 0.000 description 4
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- 102000001554 Hemoglobins Human genes 0.000 description 3
- 108010054147 Hemoglobins Proteins 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
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- 238000011580 nude mouse model Methods 0.000 description 3
- 239000008279 sol Substances 0.000 description 3
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- 238000012449 Kunming mouse Methods 0.000 description 2
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- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 238000001704 evaporation Methods 0.000 description 1
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- 238000003760 magnetic stirring Methods 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses an etoposide liposome pharmaceutical composition with low cholesterol content and a preparation method thereof, which belong to the field of pharmaceutical liposome preparations, wherein etoposide, lecithin, DSPE-PEG2000 and cholesterol are weighed according to a mass ratio of 1-4:78-98:1-10:0-8 by adopting a film dispersion method, then are dissolved in an organic solvent, then are placed in a rotary bottle, the organic solvent is distilled under reduced pressure to form a film, then water is added for hydration, liposome suspension is formed, then the particle size of the liposome is reduced by homogenization treatment, and then a freeze-drying protective agent is added, thus obtaining the preparation after freeze drying; the liposome prepared by the invention can avoid the addition of organic solvents and solubilizers in the commercial preparation, can reduce the irritation of the medicine, reduce the toxic and side effects of the medicine, has a certain slow release effect, can improve the anti-tumor effect of the medicine, lightens the bone marrow suppression side effects of the medicine, and has stronger clinical application value.
Description
Technical Field
The invention relates to the field of pharmaceutical liposome preparations, in particular to an etoposide liposome pharmaceutical composition with low cholesterol content and a preparation method thereof.
Background
Etoposide is a kind of antitumor medicine widely applied to clinic, and the present commercial injection is common solution type preparation, because etoposide is difficult to dissolve in water, in order to increase the solubility of the medicine, the commercial etoposide injection is added with organic solvent ethanol and polyethylene glycol, and with the addition of solubilizing agent tween, the addition of the organic solvent and the solubilizing agent increases the irritation of the medicine. In addition, the specification of the commercial preparation clearly indicates that etoposide injection is prone to dilution and precipitation, and must be diluted to less than 0.25mg/ml for intravenous administration, thus increasing the infusion volume of the patient. Therefore, the etoposide liposome prepared by the invention can avoid the addition of an organic solvent and a solubilizer in a commercial preparation, reduce the irritation of the medicine, reduce the toxic and side effects of the medicine, and can be directly administered intravenously without dilution so as to reduce the administration volume of patients. The liposome prepared by the invention has a certain slow release effect, can improve the anti-tumor effect of the medicine, lighten the bone marrow suppression side effect of the medicine, and has great clinical application value.
Disclosure of Invention
Accordingly, it is an object of the present invention to provide a method for preparing an etoposide liposome pharmaceutical composition with low cholesterol content; the second object of the invention is to provide an etoposide liposome pharmaceutical composition prepared by the method.
In order to achieve the above purpose, the present invention provides the following technical solutions:
1. a method for preparing an etoposide liposome pharmaceutical composition with low cholesterol content, which comprises the following steps:
and (3) weighing etoposide, lecithin, DSPE-PEG2000 and cholesterol according to a proportion by adopting a film dispersion method, dissolving in an organic solvent, then placing in a rotary bottle, distilling under reduced pressure to remove the organic solvent to form a film, adding water for hydration to form a liposome suspension, reducing the particle size of the liposome by adopting an ultrasonic treatment or extrusion finishing or ultrahigh pressure homogenization method, adding a freeze-drying protective agent, and freeze-drying to obtain the preparation.
Preferably, the mass ratio of etoposide to lecithin to DSPE-PEG2000 to cholesterol is 1-4:78-98:1-10:0-8.
Preferably, the lecithin is soybean lecithin or egg yolk lecithin.
Preferably, the organic solvent is selected from one or more of ethanol, methanol, chloroform and dichloromethane.
Preferably, the drug concentration in the liposome suspension is 0.5-4 mg/ml.
Preferably, the homogenizing treatment is ultrasonic, extrusion finishing or high-pressure homogenizing.
Preferably, the lyoprotectant is sucrose, lactose or trehalose.
Preferably, the optimum amount of the lyoprotectant is 10% (w/v).
2. The etoposide liposome pharmaceutical composition prepared by the method has the mass ratio of etoposide, lecithin, DSPE-PEG2000 to cholesterol of 1-4:78-98:1-10:0-8.
The invention has the beneficial effects that: the invention prepares etoposide into liposome dosage forms, wherein the mass ratio of etoposide to lecithin to DSPE-PEG2000 to cholesterol is 1-4:78-98:1-10:0-8, which can avoid the addition of organic solvents and solubilizers in the commercial preparations, reduce the irritation of the drugs, reduce the toxic and side effects of the drugs, and can be directly administered intravenously without dilution, thereby reducing the administration volume of patients. The liposome prepared by the invention has a certain slow release effect, can improve the anti-tumor effect of the medicine, lighten the bone marrow suppression side effect of the medicine, and has stronger clinical application value.
Drawings
In order to make the objects, technical solutions and advantageous effects of the present invention more clear, the present invention provides the following drawings for description:
FIG. 1 is an in vitro release profile of a commercial etoposide injection and an etoposide liposome of the invention;
FIG. 2 is a graph of body weight of mice after intravenous injection of a commercially available etoposide injection and etoposide liposomes of the invention;
FIG. 3 shows the blood normals of mice after intravenous injection of PBS, commercially available etoposide injection and etoposide liposomes of the invention (pictures from left to right, sequentially from top to bottom, WBC: white blood count, neu: neutrophil, lym: lymphocyte, RBC: red blood cell count, HGB: hemoglobin, HCT: hematocrit, MCV: mean red blood cell volume, MCHC: mean red blood cell hemoglobin concentration, PLT: platelet count, MPV: mean platelet volume);
FIG. 4 is a graph showing tumor volume increase in nude mice following intravenous injection of PBS, commercially available etoposide injection, and etoposide liposomes of the invention;
FIG. 5 is the tumor weight of nude mice after intravenous injection of PBS, commercially available etoposide injection, and etoposide liposome of the invention (sol: commercially available etoposide injection, LPs: etoposide liposome).
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to limit the invention, so that those skilled in the art may better understand the invention and practice it.
Etoposide bulk drug is WUHANXIN Jiali Biotechnology Co., ltd., batch number: 20210106-2; lecithin: shenyang Tianfeng biopharmaceutical Co., ltd, production lot SY-SO-200801; DSPE-PEG2000: ai Weita Shanghai pharmaceutical technologies Co., ltd., lot number: c00486; cholesterol: ai Weita Shanghai pharmaceutical technologies Co., ltd., lot number: c10780; etoposide injection: qilu pharmaceutical (Hainan) Co., ltd., lot number: BB1K2045.
And (3) weighing etoposide, lecithin, DSPE-PEG2000 and cholesterol in a specific proportion by adopting a film dispersion method, and dissolving the etoposide, the lecithin, the DSPE-PEG2000 and the cholesterol in an organic solvent, wherein the organic solvent can be one or a mixture of more of ethanol, methanol, chloroform and dichloromethane. Then placing the liposome into a rotary bottle, distilling under reduced pressure to remove the organic solvent to form a film, then adding water for hydration, wherein the dosage of the water can influence the encapsulation rate of the liposome, the dosage of the water is such that the concentration of the drug in the water is in the range of 0.5-4 mg/ml, forming milky liposome suspension, reducing the particle size of the liposome by an ultrasonic treatment or extrusion finishing or over-high pressure homogenization method, adding a freeze-drying protective agent, and freeze-drying to obtain the liposome.
The lyoprotectant can be selected from sucrose, lactose and trehalose, and the dosage is 1% -15% (w/v) of the volume of etoposide plastid suspension, preferably sucrose, and the optimal dosage is 10% (w/v).
In the invention, the proportion of etoposide in the liposome medicine composition is preferably 1-4%, and more than 4% of the etoposide can cause precipitation.
Preferably, the amount of cholesterol used in the present invention should be less than 8%, more than 8% precipitation occurs, preferably no cholesterol is added, and the liposome composition can increase the stability of the liposome, reduce the intake of cholesterol in patients, and reduce the toxic and side effects of the drug.
The proportion of DSPE-PEG2000 in the liposome pharmaceutical composition should be greater than 1%, and proper amount of DSPE-PEG2000 is added to help improve stability, and economic cost is considered, preferably 5%.
The proportion of lecithin in the liposome pharmaceutical composition is 78% -98%, and the lecithin can be soybean lecithin and egg yolk lecithin, preferably soybean lecithin.
Example 1
The effect of cholesterol on the appearance state of the prepared liposome was examined, wherein etoposide was 3% (w/w) in the liposome composition, DSPE-PEG2000 was 5% (w/w) in the liposome composition, and the effect of cholesterol was examined at 0,2%,5%,8%,10% and 15% respectively on the appearance state of the prepared liposome, wherein the amount of lecithin was adjusted accordingly according to the amounts of the other components, and the appearance state of the prepared liposome was shown in the following table, and it was found that precipitation phenomenon occurred in the prepared liposome when the amount of cholesterol was 10% or more.
TABLE 1 Effect of cholesterol usage on Etoposide Liposome appearance status
| Cholesterol ratio (w/w) | 0 | 2％ | 5％ | 8％ | 10％ | 15％ |
| Appearance state | Clarifying | Clarifying | Clarifying | Clarifying | Precipitation | Precipitation |
Example 2
The influence of etoposide dosage on the appearance state of the prepared etoposide liposome is examined, wherein DSPE-PEG2000 accounts for 5 percent (w/w) of the liposome composition, the cholesterol dosage is 0, and the influence of etoposide accounts for 1 percent, 2 percent, 3 percent, 4 percent and 5 percent (w/w) of the liposome composition on the appearance state of the prepared liposome is examined respectively, and the dosage of lecithin is adjusted according to the dosage of other components, so that the prepared liposome can be precipitated when the etoposide dosage is more than 5 percent.
TABLE 2 Effect of etoposide dosage on etoposide liposome appearance status
| Etoposide ratio (w/w) | 1％ | 2％ | 3％ | 4％ | 5％ |
| Appearance state | Clarifying | Clarifying | Clarifying | Clarifying | Precipitation |
Example 3
The effect of the amount of DSPE-PEG2000 on the appearance of the prepared liposomes was examined, wherein etoposide was 3% (w/w) in the liposome composition and cholesterol was 0, and the effect of DSPE-PEG2000 was 0,0.5%,1%,2%,5%,10% and 15% (w/w) in the liposome composition, respectively, on the appearance of the prepared liposomes. The amount of lecithin was adjusted according to the amount of other components, and it was found that precipitation occurred in the prepared liposome when the amount of DSPE-PEG2000 was less than 1%.
TABLE 3 Effect of DSPE-PEG2000 usage on Etoposide Liposome appearance status
Example 4
30mg of etoposide, 870mg of soybean lecithin, 50mg of cholesterol and 2000 50mg of DSPE-PEG are dissolved in ethanol and then are put into a rotary bottle, reduced pressure evaporation is carried out in a constant-temperature water bath at 37 ℃ to form a film, 20ml of water for injection is added, the film is hydrated into milky liposome suspension, the milky liposome suspension is granulated by an extrusion device, the etoposide liposome suspension with the particle size meeting the requirement is obtained, the concentration of the etoposide in the obtained liposome preparation is 1.5mg/ml, finally citric acid is added to adjust the pH value to 4-4.5, 10% (w/v) sucrose is added, the mixture is pre-frozen at-80 ℃ for 12h, then the mixture is put into a freeze dryer for reduced pressure freeze-drying for 24h, the etoposide freeze-dried liposome can be rapidly dispersed and re-obtained after the water is added, the average particle size is 100nm, and the encapsulation rate is 91.3%.
Example 5
30mg of etoposide, 870mg of soybean lecithin, 50mg of cholesterol and 2000 50mg of DSPE-PEG are dissolved in a mixed solvent (chloroform: methanol=2:1) and then are added into a rotary bottle, a film is formed by decompression in a constant-temperature water bath, 20ml of water for injection is added, the film is hydrated into milky liposome suspension, granules are formed by an extrusion device, etoposide liposome with the particle size meeting the requirement is obtained, the concentration of etoposide in the obtained liposome preparation is 1.5mg/ml, finally citric acid is added to adjust the pH to 4-4.5, 10% (w/v) trehalose is added, then the mixture is placed in a freeze dryer for decompression and freeze-drying for 24 hours, and the etoposide freeze-dried liposome can be quickly dispersed and re-obtained after water addition, the average particle size is 90nm, and the encapsulation rate is 90.5%.
Example 6
30mg of etoposide, 870mg of egg yolk lecithin, 50mg of cholesterol and 2000 50mg of DSPE-PEG are dissolved in dichloromethane and then are put into a rotary bottle, reduced pressure is carried out in a constant-temperature water bath to form a film, 20mL of water for injection is added, the film is hydrated into milky liposome suspension, high-pressure homogenization is carried out to reduce the particle size, the etoposide liposome with the particle size meeting the requirement is obtained, the concentration of the etoposide in the obtained liposome preparation is 1.5mg/mL, 10% (w/v) lactose is added, the mixture is pre-frozen for 12 hours at-80 ℃, then the mixture is placed into a freeze dryer for reduced pressure and freeze-dried for 24 hours, the obtained etoposide freeze-dried liposome can be rapidly dispersed and re-obtained after water is added, and the average particle size is measured to be 400nm, and the encapsulation rate is 92.6%.
Example 7
Evaluating the in vitro release behavior of etoposide liposome by adopting a dialysis bag method, respectively sucking 500 μl of etoposide injection and etoposide liposome suspension with the concentration of 1.5mg/ml, placing into a dialysis bag, then placing the dialysis bag into 40ml of phosphate buffer (pH 7.4) release medium, keeping the temperature at 37+ -0.5 ℃, collecting 500 μl of samples respectively at 30min,1h,2h,4h,6h,8h,12h and 24h under magnetic stirring, and replacing with the blank release medium with the same volume. And finally, measuring the concentration of etoposide in the release medium by HPLC, and calculating the accumulated release rate. The accumulated release rate results are shown in figure 1, and compared with etoposide injection, the accumulated release rate results show that the medicament in the liposome has slow release rate and obvious slow release effect.
Example 8
The Kunming mice (6-8 weeks) are selected and divided into two groups (n=5), and the commercial etoposide injection and the etoposide liposome are respectively injected into tail veins, the dosage is 15mg/kg, and the etoposide liposome is administrated once every two days, so that a weight curve is shown in the following figure 2, the weight of the commercial etoposide injection is obviously reduced, and the result shows that compared with the commercial etoposide injection, the etoposide liposome prepared by the invention can reduce the toxicity of the medicament.
Example 9
The Kunming mice (6-8 weeks) were selected and divided into three groups (n=5), and Phosphate Buffer Solution (PBS), commercially available etoposide injection (VP 16-sol) and etoposide liposome (VP 16-LPs) were injected into tail veins respectively at a dose of 15mg/kg, once every two days, and blood was taken after 2 weeks of continuous administration for blood routine analysis, and the results are shown in fig. 3, which indicate that the numbers of white blood cells, neutrophils, lymphocytes, erythrocytes, hemoglobin and platelets in the liposome group were significantly higher than those in the solution group, and the results indicate that the etoposide liposome prepared by the invention can significantly reduce the bone marrow suppression effect of the drug compared with the commercially available etoposide injection.
Example 10
Pharmacodynamic experiments, human classical small cell lung cancer cells NCI-H1688 are injected into a nude mice to form a tumor model, and are divided into three groups (n=5), and Phosphate Buffer Solution (PBS), commercially available etoposide injection (VP 16-sol) and etoposide liposome (VP 16-LPs) are respectively injected into tail veins, and the obtained tumor volume increase curve (figure 4) and tumor weight (figure 5) are dosed at a dose of 15mg/kg, so that the result shows that compared with the commercially available etoposide injection, the etoposide liposome prepared by the invention can obviously inhibit tumor increase.
The above-described embodiments are merely preferred embodiments for fully explaining the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions and modifications will occur to those skilled in the art based on the present invention, and are intended to be within the scope of the present invention. The protection scope of the invention is subject to the claims.
Claims (9)
1. A preparation method of an etoposide liposome pharmaceutical composition with low cholesterol content, which is characterized by comprising the following steps: comprises the following steps: and (3) weighing etoposide, lecithin, distearoyl phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG 2000) and cholesterol according to a proportion by adopting a film dispersion method, dissolving in an organic solvent, then placing in a rotary bottle, distilling under reduced pressure to remove the organic solvent, forming a film, adding water for hydration to form a liposome suspension, homogenizing to reduce the particle size of the liposome, adding a freeze-drying protective agent, and freeze-drying to obtain the liposome.
2. The method according to claim 1, characterized in that: the mass ratio of etoposide, lecithin, DSPE-PEG2000 and cholesterol is 1-4:78-98:1-10:0-8.
3. The method according to claim 1, characterized in that: the lecithin is soybean lecithin or egg yolk lecithin.
4. The method according to claim 1, characterized in that: the organic solvent is selected from one or more of ethanol, methanol, chloroform and dichloromethane.
5. The method according to claim 1, characterized in that: the drug concentration in the liposome suspension is 0.5-4 mg/mL.
6. The method according to claim 1, characterized in that: the homogenization treatment is ultrasonic, extrusion finishing or high-pressure homogenization.
7. The method according to claim 1, characterized in that: the freeze-drying protective agent is sucrose, lactose or trehalose.
8. The method according to claim 1, characterized in that: the optimum amount of the lyoprotectant is 10% (w/v).
9. The etoposide liposome pharmaceutical composition prepared by the method of any one of claims 1 to 8, wherein the mass ratio of etoposide, lecithin, DSPE-PEG2000 and cholesterol in the composition is 1-4:78-98:1-10:0-8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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