CN102552123A - Paclitaxel composition for injection and preparation method thereof - Google Patents
Paclitaxel composition for injection and preparation method thereof Download PDFInfo
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- CN102552123A CN102552123A CN2011104570852A CN201110457085A CN102552123A CN 102552123 A CN102552123 A CN 102552123A CN 2011104570852 A CN2011104570852 A CN 2011104570852A CN 201110457085 A CN201110457085 A CN 201110457085A CN 102552123 A CN102552123 A CN 102552123A
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Abstract
The invention provides a paclitaxel composition for injection. The composition comprises the following components in percentage by weight: 0.200-1.087% of paclitaxel, 95.000-99.200% of polyoxyethylenated castor oil and ethanol as well as 0.200-1.500% of organic acid. The paclitaxel composition for injection, provided by the invention, can be directly administrated after being diluted by an infusion solution. By using the paclitaxel composition for injection, provided by the invention, the damage caused by terminal sterilization of the product to the main component is avoided because a sterile production process is adopted in the preparation process; meanwhile, the sterile level of the product is more preferably guaranteed because an polyoxyethylenated castor oil sterilizing process is additionally increased in the process. Compared with the prior art, the paclitaxel composition for injection, provided by the invention, has the advantages of reducing the content of the preparation related substances, improving the product stability, reducing the occurring rate of the adverse reaction and improving the safety in clinical use.
Description
Technical field
The present invention relates to medical preparation field, particularly relate to the medical preparation field of compositions.
Background technology
The paclitaxel chemical name is: (2S, 5R, 7S, 10R, 13S)-10, two (the acetoxyl group)-2-benzoyloxys-1 of 20-, 7-dihydroxy-9-oxo-5,20-epoxy taxane-11-alkene-13-base (3S)-3-benzamido-3-phenyl-D-lactic acid fat.
Its structural formula is:
Molecular formula: C
47H
51NO
14
Molecular weight: 853.92
Paclitaxel is a novel anti microtubule medicine, can act on cell microtubule/tubulin system, promotes that tubulin is assembled into microtubule; But suppress the depolymerization of microtubule, thereby cause the arrangement of microtubule fasolculus unusual, form aster; Make spindle lose normal function, thereby cause microcell dead.This medicine also can be induced under the condition that lacks GTP (GTP) and MAP (MAP) and formed non-functional microtubule.
Paclitaxel is a line and the second line treatment medicine of ovarian cancer and breast carcinoma and nonsmall-cell lung cancer (NSCLC), for head and neck cancer, the esophageal carcinoma, and spermocytoma, recurrence Fei Hejin lymphomas etc. has certain curative effect.Belong to the broad-spectrum anti-tumor medicine, also effective to cisplatin, this medicine of amycin drug resistance person.
Polyoxyethylene castor oil (Cremphor EL) in the bibliographical information paclitaxel injection prescription is arranged: dehydrated alcohol (V: V=50: 50) solution is diluted to 0.3～1.2 gL
-1Intravenous injection, the Cremphor EL in the prescription can cause that in-vivo tissue amine discharges, and after the administration several minutes, causes the part patient anaphylaxiss such as medicine property erythra, rapid breathing, bronchospasm, hypotension to occur.Reduce untoward reaction so need inject hormone medicine simultaneously.But the Cremphor EL in the injection contacts lixiviate with pvc tube and goes out a large amount of plasticiser phthalic acid diethyl ethyl phosphonate (DEHP) with transfusion bag in addition, causes toxicity.Therefore my company gives abundant concern to the quality of the adjuvant polyoxy ethyl Oleum Ricini that uses, drafts the sterilization process that in production technology, adds polyoxyethylene castor oil, to improve the quality of products, reduces clinical application risk.
In the sterilization process research of polyoxyethylene castor oil, find; Pressure sterilizing, when sterilising temp is higher than 120 ℃, the time is when reaching more than 20 minutes; Polyoxyethylene castor oil color after the sterilization is deepened to some extent; Cause final injection color dark partially, and the pH value rising, the quality of final products is shone into influence.
Find that through experimental study paclitaxel has degraded in various degree under illumination, alkali, acid, high-temperature situation; Especially particularly evident in high basicity and high heat affecting; Thereby make its related substances raise, therefore the terminal sterilization technology (generally adopting 115 ℃, 30 minutes) after injection preparation fill is accomplished just may impact product quality; Principal agent catabolite (related substance) is increased, bring the risk of clinical use.
Mentioned a kind of paclitaxel Injectable composition among the CN1248680C; Quality evaluation and stability to the paclitaxel Injectable composition in this technology are explained; Mainly be from content of taxol, dilution back particle size; Aspects such as product toxicity are described, to the own catabolite of product (related substance), and clinical compatibility stability; And Injectable composition preparing process aspect do not have detailed description, and the advantage of this topmost untoward reaction of the clinical anaphylaxis of paclitaxel Injectable composition in said composition do not embody.
In sum, how to produce quality controllable, its related substances is low, stablize, the clinical compatibility good stability, the injection paclitaxel compositions that can effectively reduce the anaphylaxis incidence rate becomes present problem demanding prompt solution.
Summary of the invention
The objective of the invention is toSet about by adjuvant polyoxy ethyl Oleum Ricini, produce quality controllable, its related substances is low, stablize, the clinical compatibility good stability, can effectively reduce the injection paclitaxel compositions of anaphylaxis incidence rate.
In order to realize the foregoing invention purpose, the invention discloses following technical scheme:
A kind of injection paclitaxel compositions comprises: paclitaxel 0.200%～1.087%, the polyoxyethylene castor oil of sterilization and alcohol mixeding liquid 95.000%～99.200%, organic acid 0.200%～1.500%.Thereby sterilization process is advanceed in the middle of the production technology by terminal sterilization, added the sterilization process of polyoxyethylene castor oil, the degraded of the paclitaxel that has caused when having avoided terminal sterilization has improved product quality.
As a kind of improvement of the present invention, the polyoxyethylene castor oil of said sterilization is polyoxyethylene-35-Oleum Ricini.
As further improvement of the present invention, polyoxyethylene-35-Oleum Ricini is to be generated by the reacting ethylene oxide of 1mol Oleum Ricini and 35 ~ 40 mol.
As improvement further of the present invention, the polyoxyethylene castor oil of said sterilization is the polyoxyethylene castor oil of 105 ℃ of sterilizations
As organic acid optimal way among the present invention, described organic acid is selected from citric acid, lactic acid.
More preferred mode is that described organic acid is selected from citric acid in citric acid and lactic acid.
The pH value of paclitaxel composition solution is 3.0～5.0.
Supporting method for preparing as paclitaxel compositions disclosed by the invention may further comprise the steps:
(1) polyoxyethylene castor oil, pressure sterilizing puts that to be chilled to room temperature subsequent use;
(2) polyoxyethylene-35-Oleum Ricini of getting after the sterilization is put in the stainless steel cask, and paclitaxel is added, and is stirred to the supplementary material uniform mixing, adds 80% ethanol; Continue to stir 15 minutes, add citric acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure medicinal liquid content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
In the method for preparing disclosed by the invention, be after polyoxyethylene castor oil is sterilized in advance, to join in the middle of the paclitaxel compositions, so, the sterilising temp of terminal sterilization can reduce again, thus the influence of having avoided sterilization process to bring to final products.
And polyoxyethylene castor oil sterilized separately, can also further reduce sterilising temp targetedly, adopt to prolong sterilization time, the mode of batch (-type) sterilization repeatedly guarantees the color and the pH value of polyoxyethylene castor oil.
As the preferred sterilization method of polyoxyethylene castor oil, the sterilising temp of said polyoxyethylene castor oil is 105 ℃, and sterilization time is 30 minutes, is cooled to 40 ℃, repeats said process twice, and it is subsequent use to be cooled to room temperature.
This preparation of compositions process adopts sterile production technology, thereby has avoided the terminal sterilization of product, has improved the stability of product than prior art, has reduced the preparation its related substances, reduces incidence rate of adverse reaction, can improve the safety of clinical use.
Preparation technology of the present invention is simple, and cost is lower, is fit to industrialized great production, the product quality homogeneous, and good reproducibility can bring favorable economic benefit and social benefit.
The specific embodiment
Embodiment 1
Conventional method is carried out disinfecting action to polyoxyethylene-35-Oleum Ricini
Prescription
Paclitaxel 30g
Polyoxyethylene-35-Oleum Ricini 2650g
Citric acid 10g
Ethanol adds to 5000ml
Process 1000 bottles altogether
Polyoxyethylene-35-Oleum Ricini, pressure sterilizing temperature are 120 ℃, and sterilization time is 20 minutes, and it is subsequent use to be cooled to room temperature.
Get polyoxyethylene-35-Oleum Ricini and put in the stainless steel cask, paclitaxel is added wherein, stir and made the supplementary material uniform mixing in 30 minutes, at the ethanol that adds 80%; Continue to stir 15 minutes, add citric acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure solution content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
Embodiment 2
Conventional method is carried out disinfecting action to polyoxyethylene-35-Oleum Ricini
Prescription
Paclitaxel 30g
Polyoxyethylene-35-Oleum Ricini 2650g
Citric acid 10g
Ethanol adds to 5000ml
Process 1000 bottles altogether
Polyoxyethylene-35-Oleum Ricini, pressure sterilizing temperature are 115 ℃, and sterilization time is 30 minutes, and it is subsequent use to be cooled to room temperature.
Get polyoxyethylene-35-Oleum Ricini and put in the stainless steel cask, paclitaxel is added wherein, stir and made the supplementary material uniform mixing in 30 minutes, at the ethanol that adds 80%; Continue to stir 15 minutes, add citric acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure solution content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
Embodiment 3
Prescription
Paclitaxel 30g
Polyoxyethylene-35-Oleum Ricini 2600g
Citric acid 10g
Ethanol adds to 5000ml
Process 1000 bottles altogether
Polyoxyethylene-35-Oleum Ricini, pressure sterilizing temperature are 105 ℃, and sterilization time is 30 minutes, are cooled to 40 ℃, repeat said process twice, and it is subsequent use to be cooled to room temperature.
Get polyoxyethylene-35-Oleum Ricini and put in the stainless steel cask, paclitaxel is added wherein, stir and made the supplementary material uniform mixing in 30 minutes, at the ethanol that adds 80%; Continue to stir 15 minutes, add citric acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure solution content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
Embodiment 4
Prescription
Paclitaxel 30g
Polyoxyethylene-35-Oleum Ricini 2600
Citric acid 10g
Ethanol adds to 5000ml
Process 1000 bottles altogether
Polyoxyethylene-35-Oleum Ricini, pressure sterilizing temperature are 105 ℃, and sterilization time is 30 minutes, are cooled to 40 ℃, repeat said process twice, and it is subsequent use to be cooled to room temperature.
Get polyoxyethylene-35-Oleum Ricini and put in the stainless steel cask, paclitaxel is added wherein, stir and made the supplementary material uniform mixing in 30 minutes, add 80% ethanol; Continue to stir 15 minutes, add citric acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure solution content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
Embodiment 5
Prescription
Paclitaxel 30g
Polyoxyethylene-35-Oleum Ricini 2600g
Citric acid 12g
Ethanol adds to 5000ml
Process 1000 bottles altogether
The pressure sterilizing temperature is 105 ℃, and sterilization time is 30 minutes, is cooled to 40 ℃, repeats said process twice, and it is subsequent use to be cooled to room temperature.
Get polyoxyethylene-35-Oleum Ricini and put in the stainless steel cask, paclitaxel is added wherein, stir and made the supplementary material uniform mixing in 30 minutes, add 80% ethanol; Continue to stir 15 minutes, add citric acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure solution content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
Embodiment 6
Prescription
Paclitaxel 30g
Polyoxyethylene-35-Oleum Ricini 2650g
Citric acid 10g
Ethanol adds to 5000ml
Process 1000 bottles altogether
Polyoxyethylene-35-Oleum Ricini through 121 ℃ of pressure sterilizings, 40 minutes, puts that to be chilled to room temperature subsequent use.
Get polyoxyethylene-35-Oleum Ricini and put in the stainless steel cask, paclitaxel is added wherein, stir and made the supplementary material uniform mixing in 30 minutes, add 80% ethanol; Continue to stir 15 minutes, add citric acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure solution content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
Embodiment 7
Prescription
Paclitaxel 30g
Polyoxyethylene-35-Oleum Ricini 2650g
Citric acid 10g
Ethanol adds to 5000ml
Process 1000 bottles altogether
Polyoxyethylene-35-Oleum Ricini, pressure sterilizing temperature are 105 ℃, and sterilization time is 30 minutes, are cooled to 40 ℃, repeat said process twice, and it is subsequent use to be cooled to room temperature.
Get polyoxyethylene-35-Oleum Ricini and put in the stainless steel cask, paclitaxel is added wherein, stir and made the supplementary material uniform mixing in 30 minutes, add 80% ethanol; Continue to stir 15 minutes, add citric acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure solution content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
Embodiment 8
Prescription
Paclitaxel 30g
Polyoxyethylene-35-Oleum Ricini 2650g
Lactic acid 43ml
Ethanol adds to 5000ml
Process 1000 bottles altogether
Polyoxyethylene-35-Oleum Ricini, pressure sterilizing temperature are 105 ℃, and sterilization time is 30 minutes, are cooled to 40 ℃, repeat said process twice, and it is subsequent use to be cooled to room temperature.
Get polyoxyethylene-35-Oleum Ricini and put in the stainless steel cask, paclitaxel is added wherein, stir and made the supplementary material uniform mixing in 30 minutes, add 80% ethanol; Continue to stir 15 minutes, add lactic acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure solution content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
Embodiment 9
Prescription
Paclitaxel 600g
Polyoxyethylene-35-Oleum Ricini 53000g
Citric acid 200g
Ethanol adds to 100000ml
Process 20000 bottles altogether
Polyoxyethylene-35-Oleum Ricini, pressure sterilizing temperature are 105 ℃, and sterilization time is 30 minutes, are cooled to 40 ℃, repeat said process twice, and it is subsequent use to be cooled to room temperature.
Get polyoxyethylene-35-Oleum Ricini and put in the stainless steel cask, paclitaxel is added wherein, stir and made the supplementary material uniform mixing in 30 minutes, add 80% ethanol; Continue to stir 15 minutes, add citric acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure solution content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
Embodiment 10
Get the paclitaxel injection of embodiment 1～9 preparation, check its character, pH value, clarity of solution, visible foreign matters, particulate matter, related substance, aseptic, content respectively,
Detection method is following:
The paclitaxel injection determination of related substances
Measure according to HPLC (2010 editions two ones of Chinese Pharmacopoeias)
These article of getting add ethanol and process the solution that contains 0.5mg among every 1ml approximately, as need testing solution; Precision is measured in right amount; Add ethanol dilution respectively and become the solution that contains 2.5 μ g, 0.5 μ g among every 1ml approximately, as contrast solution
and contrast solution
; Other gets paclitaxel, paclitaxel impurity A (the peaceful alkali of three China firs point), paclitaxel impurity B (7-table 10-deacetylate paclitaxel) is an amount of with paclitaxel impurity C (7-table-paclitaxel) reference substance, uses dissolve with ethanol and dilution to process every 1ml and contains paclitaxel 0.5mg, paclitaxel impurity A, paclitaxel impurity B respectively 2.5 μ g and paclitaxel impurity C are that the solution of 25 μ g is as system suitability solution.Measure according to HPLC (appendix
D), use octadecylsilane chemically bonded silica to be filler (column length is 250mm); With the acetonitrile-water is that mobile phase is carried out gradient elution, and initial flow is acetonitrile-water (40:60) mutually, is eluted to main peak and has gone out (about 35 minutes); Increase the ratio of acetonitrile then with the speed of per minute 1.6%, after 25 minutes, the ratio of acetonitrile increases to 80%; Reduce the ratio of acetonitrile again with the speed of per minute 4%; After 10 minutes, the ratio of acetonitrile reduces to 40%, keeps this ratio 10 minutes; Flow velocity is 1.5ml/min; Column temperature is 30 ℃; The detection wavelength is 227nm.Get each 10 μ l of system suitability solution and contrast solution
and inject chromatograph of liquid; Paclitaxel peak and the peak-to-peak separating degree of paclitaxel impurity B should be greater than 1.2, and signal to noise ratio should be greater than 10 for contrast solution
.Get contrast solution
10 μ l and inject chromatograph of liquid; Regulate detection sensitivity; Make the peak height of main constituent chromatographic peak be about 10%～20% of full scale; Precision is measured need testing solution and each 10 μ l of contrast solution
; Inject chromatograph of liquid respectively; 0.12 minute chromatographic peak in the past of RRT is disregarded in the need testing solution chromatogram; The chromatographic peak of retention time after paclitaxel impurity C be integration not; In the need testing solution chromatogram if any impurity peaks; Paclitaxel impurity A (correction factor is 1.26) and other single impurity peak area all must not be greater than the main peak areas (0.5%) of contrast solution
, the peak area of each impurity with must not be greater than 4 times (2.0%) of the main peak area of contrast solution
.
The paclitaxel injection assay
Measure according to HPLC (2010 editions two ones of Chinese Pharmacopoeias)
Chromatographic condition and system suitability test use octadecylsilane to be filler; With methanol-water-acetonitrile (23:41:36) is mobile phase, and the detection wavelength is 227nm.Get system suitability solution 10 μ l injection chromatograph of liquid under the related substance item, the separating degree at paclitaxel peak and paclitaxel impurity A, B peak answers >=1.0.
Algoscopy is used the inner capacities pipet, and precision is measured these article 2ml, puts in the 100ml measuring bottle, adds ethanol dilution to scale, shakes up, and precision is measured 10 μ l and injected chromatograph of liquid, the record chromatogram; It is an amount of that other gets the paclitaxel reference substance, and accurate the title decides, and measures with method., promptly get with calculated by peak area by external standard method.
Add up above-mentioned test, the result is as shown in the table,
Embodiment 11
According to the method for preparing of embodiment 9, produce on a large scale, the clinical compatibility stability of sample is investigated.Paclitaxel injection is diluted to 0.3～1.2mg/ml solution with normal saline, 5% glucose or 5% G/NS, in 0～8 hour, investigates stability, concrete outcome sees the following form.
Embodiment 12
To embodiment 9, the paclitaxel injection of large-scale production is placed investigation for a long time, and the result is as shown in the table.
Embodiment 13 anaphylaxiss test
For being designated as A, embodiment 9 prepared injection paclitaxel compositionss are for being designated as B with prepared injection paclitaxel compositions among the embodiment 1.Two groups of medicines are parallel to carry out the anaphylaxis test.
Behind three intraperitoneal injections of injection group the 14th day and the 21st day; The intravenous injection original liquid is attacked; The result is A group Cavia porcellus after three lumbar injection sensitization the 14th day and the 21st day; The intravenous injection original liquid is attacked, and Cavia porcellus began to occur severe allergic reaction symptoms such as dyspnea, tic, gatism in 2-3 minute after intravenous injection.Slight symptoms of allergic such as B group administration Cavia porcellus has cough, grabs nose, trembles, perpendicular hair; This shows that B organizes the paclitaxel compositions and can significantly improve symptoms of allergic, concrete outcome sees the following form.
Cavia porcellus anaphylaxis standards of grading
| Score value | Reaction symptom |
| 0 | No significant reaction |
| 1 | Have only and slightly grab nose, tremble or perpendicular hair |
| 2 | Cough is several times arranged, grab nose, tremble or perpendicular hair |
| 3 | Repeatedly or continuously cough, with dyspnea or spasm or tic etc. |
| 4 | Spasm is twitched gatism, shock death |
Paclitaxel injection anaphylaxis result of the test
Claims (8)
1. an injection paclitaxel compositions is characterized in that described paclitaxel compositions comprises: paclitaxel 0.200%～1.087%, the polyoxyethylene castor oil of sterilization and alcohol mixeding liquid 95.000%～99.200%, organic acid 0.200%～1.500%.
2. according to the described injection paclitaxel of claim 1 compositions, it is characterized in that: the polyoxyethylene castor oil of said sterilization is polyoxyethylene-35-Oleum Ricini.
3. according to the described polyoxyethylene castor oil of claim 2, it is characterized in that polyoxyethylene-35-Oleum Ricini is to be generated by the reacting ethylene oxide of 1mol Oleum Ricini and 35 ~ 40 mol.
4. according to the described injection paclitaxel of claim 1 compositions, it is characterized in that: the polyoxyethylene castor oil of said sterilization is the polyoxyethylene castor oil of 105 ℃ of sterilizations
According to the described injection paclitaxel of claim 1 compositions, it is characterized in that: described organic acid is selected from citric acid, lactic acid.
5. according to the described injection paclitaxel of claim 1 compositions, it is characterized in that: described organic acid is selected from citric acid.
6. according to the described injection paclitaxel of claim 1 compositions, it is characterized in that the pH value of said compositions is 3.0～5.0.
7. one kind prepares like any described injection paclitaxel method for compositions in the claim 1 to 7, it is characterized in that may further comprise the steps:
(1) polyoxyethylene castor oil, pressure sterilizing puts that to be chilled to room temperature subsequent use;
(2) polyoxyethylene-35-Oleum Ricini of getting after the sterilization is put in the stainless steel cask, and paclitaxel is added, and is stirred to the supplementary material uniform mixing, adds 80% ethanol; Continue to stir 15 minutes, add citric acid again, continue to stir 5 minutes, add ethanol to full dose; Filter through two-stage 0.22um politef bag type filter, measure medicinal liquid content and pH value, the inspection medicinal liquid clarity, qualified after; Liquid medicine filling in glass ampoule, is sealed, and lamp inspection forms injection paclitaxel compositions.
8. according to the pressure sterilizing method described in the claim 8, it is characterized in that: the sterilising temp of said polyoxyethylene castor oil is 105 ℃, and sterilization time is 30 minutes, is cooled to 40 ℃, repeats said process twice, and it is subsequent use to be cooled to room temperature.
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| CN106880589A (en) * | 2017-03-07 | 2017-06-23 | 华北制药股份有限公司 | A kind of paclitaxel injection and preparation method thereof |
| CN110123745A (en) * | 2019-06-27 | 2019-08-16 | 四川汇宇制药有限公司 | A kind of Taxol injection liquid and preparation method thereof being resistant to terminal sterilization |
| CN112778513A (en) * | 2020-12-30 | 2021-05-11 | 江苏优仿医药科技有限公司 | Refining method and application of polyoxyethylene castor oil |
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Application publication date: 20120711 |