CN111329838A - Paclitaxel liposome pharmaceutical composition and preparation method thereof - Google Patents
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Abstract
The invention relates to the field of pharmaceutical preparations, in particular to a paclitaxel liposome and a preparation method thereof. The invention also provides a preparation method of the paclitaxel liposome, which is characterized in that the yolk lecithin with low cost is selected and contains the phosphatidylcholine and the phosphatidylethanolamine which meet the requirement in a certain proportion and content.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a paclitaxel liposome pharmaceutical composition and a preparation method thereof.
Background
Paclitaxel is a natural anticancer drug which is discovered at present, and is widely used for treating breast cancer, ovarian cancer and partial head and neck cancer and lung cancer in clinic. Paclitaxel is difficult to dissolve in water, the paclitaxel injection which is sold on the market at the earliest uses polyoxyethylated castor oil and ethanol as solvents to improve the solubility of paclitaxel, but the polyoxyethylated castor oil can influence the effect of the medicament and produce serious adverse reactions, such as histamine release by in vivo degradation, allergy and the like, and the paclitaxel liposome which is sold on the market later is the first paclitaxel liposome which is approved in the world, compared with the injection, the common solvent 5% glucose is used, so that toxic and side reactions are obviously reduced, the clinical effect is good, and the paclitaxel injection is also suitable for patients allergic to paclitaxel solvents.
CN1291474A provides a paclitaxel liposome preparation which has good water solubility, low preparation toxicity and improved stability compared with paclitaxel injection, and the liposome preparation takes the following medicines in parts by weight as raw materials: 2-5 parts of paclitaxel, 20-200 parts of phospholipid, 2-30 parts of cholesterol, 0.4-4 parts of amino acid and 10-75 parts of mannitol or glucose. The phospholipid is lecithin or soybean phospholipid.
The four parts of the 'Chinese pharmacopoeia' 2015 edition stipulates that 'the content of phosphatidylcholine and phosphatidylethanolamine in egg yolk lecithin (for injection) should not be less than 68%, the content of phosphatidylethanolamine should not be more than 20.0%, and the total content of phosphatidylcholine and phosphatidylethanolamine should not be less than 80%', and the stipulation of the pharmacopoeia can show that the content of phosphatidylcholine and phosphatidylethanolamine in egg yolk lecithin is a key factor influencing liposome; WO8803797a1 provides a phospholipid composition comprising 97% to 98% phosphatidylcholine and the like without phosphatidylethanolamine, which can form more stable liposomes with ingredients including anti-tumor active compounds.
The invention further researches the yolk lecithin for preparing the paclitaxel liposome, limits the content range of phosphatidylcholine and phosphatidylethanolamine, and further prepares the paclitaxel liposome with good film forming property, uniform particle size, high encapsulation rate and good stability.
Disclosure of Invention
The invention provides a paclitaxel liposome pharmaceutical composition, which comprises the following components in percentage by weight: 1 part of paclitaxel, 15-40 parts of yolk lecithin, 0.5-10 parts of cholesterol, 0.2-2 parts of amino acid and 10-37.5 parts of glucose, and is characterized in that: the content of phosphatidylcholine in the egg yolk lecithin is 85-95 wt%, and the content of phosphatidylethanolamine in the egg yolk lecithin is 1-6 wt%.
Preferably, the content of phosphatidylethanolamine in the egg yolk lecithin is 1-3%, 3-6%, 1-1.4% or 1.4-3% by weight.
The amino acid may be lysine, methionine, glutamic acid, or threonine.
The paclitaxel liposome pharmaceutical composition provided by the invention is administered in an injection form, and is preferably a freeze-dried powder injection.
The invention provides a preparation method of a paclitaxel liposome freeze-dried preparation for injection, which comprises the following steps: weighing paclitaxel, yolk lecithin and cholesterol according to the proportion of the prescription, dissolving in ethanol until completely dissolving into clear solution, sterilizing and filtering with a 0.22um filter core, adding into a rotary bottle, placing in constant temperature water bath (53 ℃ +/-2 ℃) and decompressing into dry lipid membrane; adding 5% glucose solution containing amino acids into the above rotary bottle to form lipid membrane, hydrating in water bath at 20-40 deg.C until the suspension has no insoluble substances, grading the hydrated liquid with extrusion device to obtain paclitaxel liposome suspension with required particle size, and freeze drying the liposome suspension.
The amino acid may be lysine, methionine, glutamic acid or threonine.
The paclitaxel liposome pharmaceutical composition provided by the invention is used for preparing a medicament for treating ovarian cancer, breast cancer or non-small cell lung cancer.
The paclitaxel liposome prepared from the specific content of phosphatidylcholine and phosphatidylethanolamine in the egg yolk lecithin provided by the invention has uniform particle size, better moldability and higher encapsulation efficiency, so that the paclitaxel liposome has better stability.
Drawings
FIG. 1 is a graph showing the particle size of one of paclitaxel liposomes obtained in test example 1 with PE content of 0 over 0h
FIG. 2 is a graph showing the particle size of two paclitaxel liposomes obtained in test example 1 with PE content of 0 in 0h
FIG. 3 is a graph showing the particle size of one of paclitaxel liposomes obtained in test example 1 with PE content of 0 over 2 hours
FIG. 4 is a graph showing the particle size of two paclitaxel liposomes obtained in test example 1 with PE content of 0 in 2 hours
FIG. 5 is a graph showing the particle size of one of paclitaxel liposomes obtained in test example 1, in which PE content is 1%, at 0h
FIG. 6 is a graph showing the particle size of two paclitaxel liposomes obtained in test example 1, which has a PE content of 1%, at 0h
FIG. 7 is a graph showing the particle size of one of paclitaxel liposomes obtained in Experimental example 1, in which the PE content is 1%, over 2 hours
FIG. 8 is a graph showing the particle size of paclitaxel liposome II obtained with PE content of 1% in test example 1 over 2 hours
FIG. 9 is a graph showing the particle size of one of paclitaxel liposomes obtained in Experimental example 1, in which PE content is 3%, at 0h
FIG. 10 is a graph showing the particle size of two paclitaxel liposomes obtained in test example 1, which has a PE content of 3%, at 0h
FIG. 11 is a graph showing the particle size of one of paclitaxel liposomes obtained in Experimental example 1, in which the PE content is 3%, over 2 hours
FIG. 12 is a graph showing the particle size of paclitaxel liposome having PE content of 3% obtained in test example 1 at 2h
FIG. 13 is a graph showing the particle size of one of paclitaxel liposomes obtained with PE content of 6% in test example 1 at 0h
FIG. 14 is a graph showing the particle size of two paclitaxel liposomes obtained in test example 1 and having a PE content of 6% at 0h
FIG. 15 is a graph showing the particle size of one of paclitaxel liposomes obtained in Experimental example 1, in which the PE content is 6%, over 2 hours
FIG. 16 is a graph showing the particle size of two paclitaxel liposomes obtained in test example 1, which has a PE content of 6%, in 2 hours
FIG. 17 is a graph showing the particle size of one of paclitaxel liposomes obtained in test example 1, in which PE content is 8%, at 0h
FIG. 18 is a graph showing the particle size of two paclitaxel liposomes obtained in test example 1, which has a PE content of 8%, at 0h
FIG. 19 is a graph showing the particle size of one of paclitaxel liposomes obtained in Experimental example 1, in which the PE content is 8%, over 2 hours
FIG. 20 is a graph showing the particle size of two paclitaxel liposomes obtained in test example 1, which has a PE content of 8%, in 2 hours
FIG. 21 is a graph showing the particle size of one of paclitaxel liposomes obtained in Experimental example 1, in which the PE content is 10%, at 0h
FIG. 22 is a graph showing the particle size of paclitaxel liposome II obtained in test example 1, in which the PE content is 10%, in 0h
FIG. 23 is a graph showing the particle size of one of paclitaxel liposomes obtained in Experimental example 1, in which the PE content is 10%, over 2 hours
FIG. 24 is a graph showing the particle size of paclitaxel liposome II obtained in test example 1, in which the PE content is 10%, in 2 hours
Detailed Description
Experimental example 1 comparison of film Forming Properties and particle diameters of paclitaxel liposomes prepared from phosphatidylethanolamines of different contents
1. Instruments and materials:
phosphatidylcholine (PC): purchased from kyoto corporation, lot number: AL18001 content 99.0%, wherein PE content is less than 0.1%
Phosphatidylethanolamine (PE): purchased from Avanti, lot number: 840021P-500MG-261 content 99.0%
Biological microscope: olympus, japan, model: olympus CX31
NANO particle size analyzer: malvern, model number: malvern NANO-ZS
2. The test process comprises the following steps:
2.1 preparation of paclitaxel liposome:
test groups 1-6: selecting phospholipid consisting of Phosphatidylcholine (PC) and Phosphatidylethanolamine (PE) with different weight percentage contents, and the other preparation and test processes are the same:
weighing 180mg of taxol, 7.2g of phospholipid and 90mg of cholesterol, dissolving in ethanol until the taxol, the phospholipid and the cholesterol are completely dissolved into clear solution, sterilizing and filtering by using a 0.22um filter core, adding into a rotary bottle, and placing in a constant-temperature water bath (53 +/-2 ℃) to reduce pressure to obtain a dry lipid membrane; and adding 40ml of 5% glucose solution containing 72mg of threonine into the rotary bottle for forming the lipid membrane, hydrolyzing the mixture into milky liposome suspension in a water bath at the temperature of 30 ℃, and grading the particles by an extrusion device to obtain the paclitaxel liposome suspension with the particle size meeting the requirement.
2.2 detection Process
Observing the microscopic morphology of the liposome by using a biological microscope, performing particle size detection by using a NANO particle size analyzer, wherein particle size graphs of the obtained paclitaxel liposome with different PC and PE contents at 0h and 2h are shown in the accompanying drawings 1-24, and the average value of two particle size detections is taken as the corresponding particle size, and the specific observation and detection results are shown in the following table 1:
TABLE 1
2.3 test results
As can be seen from fig. 1 to 24: after the particle size of the paclitaxel liposome prepared without PE is 2 hours, the particle size is obviously increased, and PDI is also increased; when the PE content is in the range of 1-6%, the grain size of 2 hours is not obviously different from that of 0 hour; when the PE content is more than 6%, the particle size of the prepared paclitaxel liposome after 2 hours is obviously increased compared with that of the prepared paclitaxel liposome when 0 hour, and the peak shape has double peaks which are not normally distributed.
From the results in table 1 above, it can be seen that: the paclitaxel liposome prepared without PE has a small amount of precipitation when observed under microscopic examination at 0 hour, and the paclitaxel liposome can be observed to have more precipitation and agglomeration after being placed for 2 hours; when the PE content is higher than 6%, precipitation is observed in microscopic examination at 0, precipitation is observed in microscopic examination after the paclitaxel liposome is placed for 2 hours, aggregation occurs, and the uniformity of the particle size of the prepared liposome is poor; the paclitaxel liposome prepared with PE content of 1-6% has no precipitation phenomenon in microscopic examination at 0 hr and 2 hr, and the obtained liposome has good particle diameter uniformity.
Experimental example 2 comparison of encapsulation efficiency of paclitaxel liposome prepared from phosphatidylethanolamine with different contents in phospholipid
1. Instruments and materials:
phosphatidylcholine (PC): purchased from kyoto corporation, lot number: AL18001, content 99.0%, wherein PE content is less than 0.1%
Phosphatidylethanolamine (PE): purchased from Avanti, lot number: 840021P-500MG-263 content of 99.0%
Biological microscope: olympus, japan, model: olympus CX31
NANO particle size analyzer: malvern, model number: malvern NANO-ZS
2. The test process comprises the following steps:
2.1 preparation of paclitaxel liposome:
test groups 1-6: selecting phospholipid consisting of Phosphatidylcholine (PC) and Phosphatidylethanolamine (PE) with different weight percentage contents, and the other preparation and test processes are the same:
weighing 180mg of taxol, 7.2g of phospholipid and 90mg of cholesterol, dissolving in ethanol until the taxol, the phospholipid and the cholesterol are completely dissolved into clear solution, adding the clear solution into a rotating bottle after sterilizing and filtering by a 0.22um filter core, and decompressing to form a dry liposome membrane in a constant-temperature water bath (53 +/-2 ℃); and adding 40ml of 5% glucose solution containing 72mg of lysine into the rotary bottle for forming the lipid membrane, carrying out water synthesis in a water bath at 35 ℃ to obtain a milky-white liposome solution, and finishing the particles by an extrusion device to obtain the paclitaxel liposome suspension with the particle size meeting the requirement.
2.2 detection Process
Observing the microscopic morphology of the liposome by using a biological microscope; carrying out granularity detection by using a NANO tester;
the encapsulation efficiency was determined using the following method:
3ml extraction column hollow tube with 9mm diameter and cotton end-capped bottom. And filling the macroporous resin which is fully washed by water, wherein the filling height is 2 cm.
Precisely measuring 0.1ml of liposome, adding the liposome to the surface of the small column filler, and pressurizing to make the sample enter the gel column. The eluate was first eluted with water and 5ml (envelope fraction) was collected quantitatively, then eluted with 75% ethanol and 10ml (free fraction) of the eluate was collected quantitatively.
Total amount of solution: accurately weighing paclitaxel solution 0.1ml to 50ml, adding 75% ethanol, diluting and fixing volume.
Paclitaxel solution encapsulated in liposomes: precisely measuring the packaging part in a measuring flask of 1.0ml to 10ml, adding 1.5ml of water, and diluting with ethanol to a constant volume.
Free paclitaxel solution: taking the free part for direct injection analysis.
Chromatographic conditions are as follows:
octadecylsilane chemically bonded silica is used as a filling agent; taking 40% acetonitrile as a mobile phase; the injection volume is 20 mul; the flow rate is 1.0 ml/min; the column temperature was 25 ℃; the detection wavelength was 227 nm.
Calculating the formula:
in the formula: a. theE: is the major peak area of paclitaxel solution encapsulated in liposomes;
AF: is the major peak area of free paclitaxel solution;
AT: the area of the main peak of the total solution;
VE: is the dilution factor of the paclitaxel solution encapsulated in the liposome;
VF: is the dilution factor of the free paclitaxel solution;
VT: is the dilution multiple of the total solution.
Specific observation and detection results are shown in table 2 below:
TABLE 2
2.3 test results
From the above test results, it can be seen that: the paclitaxel liposome prepared without PE has a small amount of precipitation when observed under microscopic examination at 0 hour, and can be observed to have more precipitation and agglomeration after being placed for 2 hours, and the encapsulation rate is extremely low; when the PE content is higher than 6%, precipitation is observed at 0 hours by microscopic examination, and after the paclitaxel liposome is placed for 2 hours, precipitation is observed at microscopic examination, and agglomeration occurs, and the encapsulation rate of the prepared liposome is not high and cannot meet the requirements of pharmacopoeia; the paclitaxel liposome prepared with the PE content of 1-6% has no precipitation phenomenon in microscopic examination at 0 hour and 2 hours after placement, and the obtained liposome has good particle size uniformity and high entrapment rate.
Experimental example 3 film Forming Properties and particle size comparison of paclitaxel liposomes prepared from phosphatidylethanolamine with different contents in egg yolk lecithin
1. Instruments and materials:
egg yolk lecithin: manufactured by Nanjing green leaf pharmaceutical Co., Ltd, batch number: s110307, wherein: the content of Phosphatidylcholine (PC) is 90%, and the content of Phosphatidylethanolamine (PE) is 0.11%;
egg yolk lecithin: manufactured by Nanjing green leaf pharmaceutical Co., Ltd, batch number: s110314, wherein: the content of Phosphatidylcholine (PC) is 92.7%, and the content of Phosphatidylethanolamine (PE) is 0%;
egg yolk lecithin: manufactured by Nanjing green leaf pharmaceutical Co., Ltd, batch number: s110301, wherein: the content of Phosphatidylcholine (PC) is 90.80%, and the content of Phosphatidylethanolamine (PE) is 2.99%.
Biological microscope: olympus, japan, model: olympus CX31
NANO particle size analyzer: malvern, model number: malvern NANO-ZS
2. The test process comprises the following steps:
2.1 preparation of paclitaxel liposome:
the procedure for preparing paclitaxel liposome was the same as in test example 1.
2.2 detection Process
Observing the microscopic morphology of the liposome by using a biological microscope; particle size detection was performed using a NANO meter, and the specific observation and detection results are shown in table 3 below:
TABLE 3
2.3 test results
From the above test results, it can be seen that: the yolk lecithin produced by Nanjing green leaf pharmaceutical Co., Ltd is free of PE when the content of phosphatidylcholine in the yolk lecithin is more than 85%, and paclitaxel liposome prepared by the PE with the content of 0.11%, although the sample state is good and uniform and is not separated out when the sample is observed by microscopic examination at 0, the phenomenon that more separated out is generated and a small amount of agglomeration and fine crystal cluster structure occur can be observed when the sample is placed for 2 hours, which indicates that the sample is poor in stability and dispersibility when the yolk lecithin does not contain PE or the content of PE is 0.11%; when the PE content is 2.99%, the sample has good stability, no precipitation in microscopic examination and good dispersibility.
Experimental example 4 film Forming Properties and particle size comparison of paclitaxel liposomes prepared from phosphatidylethanolamine with different contents in egg yolk lecithin
1. Instruments and materials:
egg yolk lecithin: manufactured by Nanjing green leaf pharmaceutical Co., Ltd, batch number: 19070107, wherein: the content of Phosphatidylcholine (PC) was 93.0%, and the content of Phosphatidylethanolamine (PE) was 1.4%.
Phosphatidylethanolamine (PE): purchased from Avanti, lot number: 840021P-500MG-263, content 99.0%;
biological microscope: olympus, japan, model: olympus CX31
NANO particle size analyzer: malvern, model number: malvern NANO-ZS
2. The test process comprises the following steps:
2.1 preparation of paclitaxel liposome:
and adding Phosphatidylethanolamine (PE) into the egg yolk lecithin to ensure that the PE content of the egg yolk lecithin reaches 7%, then preparing paclitaxel liposome, and inspecting the sample dispersibility and stability.
The procedure for preparing paclitaxel liposome was the same as in test example 1.
2.2 detection Process
Observing the microscopic morphology of the liposome by using a biological microscope; particle size detection was performed using a NANO meter, and the specific observation and detection results are shown in table 4 below:
TABLE 4
2.3 test results
From the above test results, it can be seen that: when the content of phosphatidylcholine in the egg yolk lecithin is more than 85 percent and the content of PE is 7 percent, the prepared paclitaxel liposome has poor stability, poor microscopic examination dispersibility, large particle size change and low entrapment rate, and cannot meet the requirements of liposome preparations; when the PE content in the egg yolk lecithin is 1.4, the prepared paclitaxel liposome has good stability, uniform particle size and high encapsulation efficiency.
Test example 5 Long-term stability test of paclitaxel liposome for injection
1. Material
Egg yolk lecithin: the Nanjing green leaf pharmaceutical Co Ltd produces the following batch numbers and contents:
17120407: phosphatidylcholine (PC) content 87.3%, Phosphatidylethanolamine (PE) 1.4%
17120507: phosphatidylcholine (PC) content 87.7% Phosphatidylethanolamine (PE) content 1.4%
17120607: phosphatidylcholine (PC) content 88.5%, Phosphatidylethanolamine (PE) content 1.6%
2. The test process comprises the following steps:
2.1 preparation of paclitaxel liposomes
Three batches of paclitaxel liposomes were prepared according to the preparation method of test example 1 by selecting the above three batches of egg yolk lecithin, and the long-term stability (2-8 ℃) was examined, and the specific experimental results are shown in table 5:
TABLE 5
According to the stability result, the three batches of samples have good stability, all indexes of the samples accord with the quality standard, and the batch-to-batch consistency is good.
Example 1 preparation of egg yolk lecithin
Weighing 380kg of refined egg yolk (wet powder), adding 950L of absolute ethyl alcohol, homogenizing for 30min, centrifuging after homogenizing, collecting an extracting solution, keeping a filter cake, repeatedly extracting for four times, and combining the obtained collecting extracting solutions;
adding neutral alumina into the filtered extractive solution at a ratio of refined yolk (wet powder) and neutral alumina of 1kg:0.5kg, homogenizing for 50min, centrifuging, and collecting centrifugate to obtain adsorption solution;
adding activated carbon for injection into the adsorption solution at a ratio of 1Kg to 0.01Kg of the refined yolk (wet powder) to the activated carbon for injection, homogenizing for 50min, and centrifuging to obtain decolorized solution;
absorbing the decolorized solution into a concentrator for vacuum concentration to obtain a concentrated solution; filtering the concentrated solution, and collecting filtrate; distilling the filtrate under reduced pressure with a rotary evaporator, and removing ethanol to obtain egg yolk lecithin for injection. The content of PC is 89.0% and the content of PE is 1.4% by HPLC-ELSD detection.
Example 2 preparation of egg yolk lecithin
Weighing 380kg of refined egg yolk (wet powder), adding 950L of absolute ethyl alcohol, homogenizing for 30min, centrifuging after homogenizing, collecting an extracting solution, keeping a filter cake, repeatedly extracting for four times, and combining the obtained collecting extracting solutions;
adding neutral alumina into the filtered extractive solution at a ratio of refined yolk (wet powder) and neutral alumina of 1kg:0.4kg, homogenizing for 50min, centrifuging, and collecting centrifugate to obtain adsorption solution;
adding activated carbon for injection into the adsorption solution at a ratio of 1Kg to 0.01Kg of the refined yolk (wet powder) to the activated carbon for injection, homogenizing for 50min, and centrifuging to obtain decolorized solution;
absorbing the decolorized solution into a concentrator for vacuum concentration to obtain a concentrated solution; filtering the concentrated solution, and collecting filtrate; distilling the filtrate under reduced pressure with a rotary evaporator, and removing ethanol to obtain egg yolk lecithin for injection. The content of PC is 85.0% and the content of PE is 5.6% by HPLC-ELSD detection.
Example 3 preparation of egg yolk lecithin
Weighing 380kg of refined egg yolk (wet powder), adding 950L of absolute ethyl alcohol, homogenizing for 30min, centrifuging after homogenizing, collecting an extracting solution, keeping a filter cake, repeatedly extracting for four times, and combining the obtained collecting extracting solutions;
adding neutral alumina into the filtered extractive solution at a ratio of refined yolk (wet powder) and neutral alumina of 1kg:0.6kg, homogenizing for 50min, centrifuging, and collecting centrifugate to obtain adsorption solution;
adding activated carbon for injection into the adsorption solution at a ratio of 1Kg to 0.01Kg of the refined yolk (wet powder) to the activated carbon for injection, homogenizing for 50min, and centrifuging to obtain decolorized solution;
absorbing the decolorized solution into a concentrator for vacuum concentration to obtain a concentrated solution; filtering the concentrated solution, and collecting filtrate; distilling the filtrate under reduced pressure with a rotary evaporator, and removing ethanol to obtain egg yolk lecithin for injection. The content of PC is 95.0% and the content of PE is 1.1% by HPLC-ELSD detection.
EXAMPLE 4 preparation of paclitaxel liposome for injection
Weighing 1.2kg of paclitaxel raw material, 30kg of egg yolk lecithin (wherein, the content of PC is 93.4 percent, the content of PE is 1.42 percent) and 4.12kg of cholesterol, dissolving in a proper amount of ethanol until the mixture is completely dissolved into clear solution, adding the clear solution into a plurality of rotary bottles after sterilizing and filtering by a 0.22um filter core, and placing the rotary bottles in a thermostatic water bath (53 +/-2 ℃) for decompressing into dry lipid membranes; adding 280L of 480g threonine-containing 5% glucose solution into the rotary bottle, hydrating in 35 deg.C water bath to obtain milky white liposome solution, grading with an extrusion device to obtain paclitaxel liposome with required particle size, packaging in penicillin bottles to make each bottle contain 30mg paclitaxel, and freeze drying to obtain loose block paclitaxel liposome for injection.
EXAMPLE 5 preparation of paclitaxel liposome for injection
Weighing 1.2kg of paclitaxel raw material, 48kg of yolk lecithin (wherein, the content of PC is 90.1%, the content of PE is 2.35%), 2.4kg of cholesterol, dissolving in a proper amount of ethanol until the mixture is completely dissolved into clear solution, sterilizing and filtering by a 0.22um filter core, adding into a plurality of rotary bottles, and placing in a thermostatic water bath (53 +/-2 ℃) for decompressing into dry lipid membranes; adding 264L of 480g lysine-containing 5% glucose solution into the rotary bottle, hydrating in 30 deg.C water bath to obtain milky white liposome solution, grading with an extrusion device to obtain paclitaxel liposome with required particle size, packaging in penicillin bottles to make each bottle contain 30mg paclitaxel, and freeze drying to obtain loose block paclitaxel liposome for injection.
EXAMPLE 6 preparation of paclitaxel liposome for injection
Weighing 1.2kg of paclitaxel raw material, 20kg of refined egg yolk lecithin (wherein, the content of PC is 88.3 percent, the content of PE is 3.19 percent) and 1.2kg of cholesterol, dissolving in a proper amount of ethanol until the mixture is completely dissolved into clear solution, adding the clear solution into a plurality of rotary bottles after sterilizing and filtering by a 0.22um filter core, and placing the rotary bottles in a thermostatic water bath (53 +/-2 ℃) for decompressing into dry lipid membranes; adding 480g of methionine into the rotary bottle with the lipid film formed, adding 260L of 5% glucose solution, hydrating to obtain milk white liposome solution under the condition of water bath at 25 ℃, grading by an extrusion device to obtain paclitaxel liposome with the particle size meeting the requirement, subpackaging in penicillin bottles so that each bottle contains 30mg of paclitaxel, and freeze-drying to obtain loose and blocky paclitaxel liposome for injection.
Example 7 preparation of paclitaxel liposome for injection
Weighing 1.2kg of paclitaxel raw material, 36kg of refined egg yolk lecithin (wherein, the content of PC is 86.5 percent, the content of PE is 5.02 percent) and 3.6kg of cholesterol, dissolving in a proper amount of ethanol until the mixture is completely dissolved into clear solution, sterilizing and filtering by a 0.22um filter core, adding into a rotary bottle, placing in a constant temperature water bath (53 +/-2 ℃) for decompression and film forming, and drying; adding 480g of 5% glucose solution 272L containing glutamic acid into the rotary bottle forming the lipid film, hydrating into milk white liposome solution under the condition of 40 ℃ water bath, grading by an extrusion device to obtain paclitaxel liposome with the particle size meeting the requirement, subpackaging in penicillin bottles to ensure that each bottle contains 30mg of paclitaxel, and freeze-drying to obtain loose blocky paclitaxel liposome for injection.
Claims (10)
1. A paclitaxel liposome pharmaceutical composition comprises the following components in parts by weight: 1 part of paclitaxel, 15-40 parts of yolk lecithin, 0.5-10 parts of cholesterol, 0.2-2 parts of amino acid and 10-37.5 parts of glucose, and is characterized in that: the content of phosphatidylcholine in the egg yolk lecithin is 85-95 wt%, and the content of phosphatidylethanolamine in the egg yolk lecithin is 1-6 wt%.
2. The paclitaxel liposome pharmaceutical composition according to claim 1, wherein: the content of phosphatidylethanolamine in the egg yolk lecithin is 1-3% by weight.
3. The paclitaxel liposome pharmaceutical composition according to claim 1, wherein: the content of phosphatidylethanolamine in the egg yolk lecithin is 3-6% by weight.
4. The paclitaxel liposome pharmaceutical composition according to claim 1, wherein: the content of phosphatidylethanolamine in the egg yolk lecithin is 1-1.4% by weight.
5. The paclitaxel liposome pharmaceutical composition according to claim 1, wherein: the content of phosphatidylethanolamine in the egg yolk lecithin is 1.4-3% by weight.
6. The paclitaxel liposome pharmaceutical composition according to claim 1, wherein: the amino acid is selected from threonine, lysine, methionine or glutamic acid.
7. The paclitaxel liposome pharmaceutical composition according to any one of claims 1 to 6, wherein: the pharmaceutical composition is in a freeze-dried powder injection for injection.
8. The method for preparing a paclitaxel liposome pharmaceutical composition according to any one of claims 1 to 6, wherein the paclitaxel liposome pharmaceutical composition comprises: weighing paclitaxel, yolk lecithin and cholesterol according to the proportion of the prescription, dissolving in ethanol until completely dissolving into clear solution, sterilizing and filtering with a 0.22um filter core, adding into a rotary bottle, placing in constant temperature water bath (53 ℃ +/-2 ℃) and decompressing into dry lipid membrane; adding 5% glucose solution containing amino acids into the above rotary bottle to form lipid membrane, hydrating in water bath at 20-40 deg.C until the suspension has no insoluble substances, grading the hydrated liquid with extrusion device to obtain paclitaxel liposome suspension with required particle size, and freeze drying the liposome suspension.
9. The production method according to claim 8, characterized in that: the amino acid is selected from threonine, lysine, methionine or glutamic acid.
10. Use of the paclitaxel liposome pharmaceutical composition of any of claims 1-6 in the preparation of a medicament for treating ovarian cancer, breast cancer or non-small cell lung cancer.
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