CN110123745B - Preparation method of paclitaxel injection resistant to terminal sterilization - Google Patents
Preparation method of paclitaxel injection resistant to terminal sterilization Download PDFInfo
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- CN110123745B CN110123745B CN201910566115.XA CN201910566115A CN110123745B CN 110123745 B CN110123745 B CN 110123745B CN 201910566115 A CN201910566115 A CN 201910566115A CN 110123745 B CN110123745 B CN 110123745B
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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Abstract
The invention relates to a preparation method of a paclitaxel injection tolerant to terminal sterilization, belonging to the technical field of pharmaceutical preparations. The preparation method of the paclitaxel injection comprises the following steps: (1) adding paclitaxel with prescription amount into polyoxyethylene (35) castor oil with prescription amount, and stirring and shearing at high speed; (2) adding anhydrous ethanol with the amount of the prescription into the solution, stirring until the solution is uniformly mixed, and deoxidizing; (3) and (3) performing sterilization filtration, filling and deoxidization, sealing and high-temperature sterilization on the solution obtained in the step (2). According to the preparation method of the paclitaxel injection, the polyoxyethylene (35) castor oil wraps paclitaxel by changing the feeding sequence, so that the substance degradation and decomposition of the paclitaxel in the terminal sterilization process can be reduced, and the finally obtained paclitaxel injection has good quality and high stability.
Description
Technical Field
The invention relates to a preparation method of a paclitaxel injection, in particular to a preparation method of a paclitaxel injection which is resistant to terminal sterilization, and belongs to the technical field of pharmaceutical preparations.
Background
Paclitaxel is an antitumor agent extracted and separated from Taxus chinensis of Taxus of Taxaceae. It has unique action mechanism, can inhibit the growth of tumor cells by inducing and promoting tubulin polymerization, assembly and stabilizing microtubule, has obvious curative effect on ovarian cancer, breast cancer, head and neck cancer, non-small cell lung cancer and prostatic cancer, and is a broad-spectrum anticancer drug. Paclitaxel and its injection were first developed by Bristol-Myers Squibb company and were first approved by the FDA in 1992 for entry into the U.S. market and are now widely used worldwide.
Because the paclitaxel has a complex structure, is unstable to heat, alkali and light, is easy to hydrolyze and the chiral center is easy to reverse, the degradation of the paclitaxel active substance is easy to cause by adopting a terminal high-temperature sterilization process, the content of the paclitaxel in the finally obtained injection is reduced, related substances are increased, and the quality is reduced. Therefore, at present, the mainstream sterilization process in the industry mainly adopts a sterilization filtration mode to sterilize the paclitaxel injection, and the terminal sterilization treatment is not performed on the paclitaxel injection, but the sterility guarantee level of the sterilization filtration is obviously lower than that of the terminal sterilization.
Disclosure of Invention
The invention aims to overcome the defects of poor thermal stability and incapability of terminal sterilization of the paclitaxel, and provides a preparation method of a paclitaxel injection tolerant to terminal sterilization, so that the sterility guarantee level of the paclitaxel injection is improved.
In order to achieve the above purpose, the invention provides the following technical scheme:
a preparation method of paclitaxel injection tolerant to terminal sterilization comprises the following steps:
(1) adding paclitaxel with prescription amount into polyoxyethylene (35) castor oil with prescription amount, and stirring and shearing at high speed of more than 4000rpm for more than 120min to obtain solution A;
(2) adding anhydrous ethanol with the formula amount into the solution A, and stirring until the solution is uniformly mixed to obtain a solution B;
(3) deoxidizing the solution B;
(4) and (4) performing sterilization filtration, filling and deoxidization, sealing and high-temperature sterilization on the solution B treated in the step (3).
In the preparation method of the paclitaxel injection, in the step (1), the paclitaxel is pretreated by shearing the mixed liquid of the paclitaxel and the polyoxyethylene (35) castor oil at a high speed of more than 4000rpm for more than 120min, so that the paclitaxel can be dissolved in the polyoxyethylene (35) castor oil, and the paclitaxel can be wrapped by the polyoxyethylene (35) castor oil. And then processing the pretreated paclitaxel and polyoxyethylene (35) castor oil according to the processes of the steps (2), (3) and (4) to obtain a finished product paclitaxel injection. Wherein, the steps (2), (3) and (4) can be any process which can realize the preparation of the paclitaxel injection and are not described herein again. Wherein, the high-temperature sterilization means that the sterilization temperature is within121High temperature sterilization process at above deg.C. Preparation of paclitaxel injection of the inventionAccording to the method, the paclitaxel is wrapped by the polyoxyethylene (35) castor oil before the anhydrous ethanol is added to dissolve the paclitaxel, so that the substance degradation and decomposition of the paclitaxel in a terminal sterilization process (namely the high-temperature sterilization step in the step (4)) can be reduced, and the finally obtained paclitaxel injection is good in quality and high in stability. Further, the solution B is deoxidized in the step (3) to reduce the oxygen content in the paclitaxel injection, so that the oxidation of oxygen to paclitaxel in the storage process can be reduced, and the storage time of the paclitaxel injection is further prolonged.
Preferably, in the step (1), the rotation speed of the high-speed shearing is 4000rpm, and the shearing time is 120 min.
Preferably, in the step (3), the oxygen removal is performed by introducing nitrogen into the solution B.
Preferably, in the step (3), the solution B is deoxygenated until the dissolved oxygen content in the solution is less than or equal to 0.5 mg/L. When the content of dissolved oxygen in the solution B is less than or equal to 0.5mg/L, the stability of the paclitaxel injection is better, and the storage time is obviously prolonged. More preferably, the solution B is deoxygenated to a dissolved oxygen content of less than or equal to 0.2mg/L in the solution.
Preferably, in the step (4), the sterile filtration step is to filter the solution B through a 2-channel 0.22 mu mVDF filter element. The risk of visible foreign matters in the paclitaxel injection filtered by the two filter elements is lower, the paclitaxel injection is not easy to have crystallized precipitates, and the quality of the injection is better.
Preferably, in the step (4), in the filling and oxygen removing step, oxygen is removed by introducing nitrogen into the filling liquid. The oxygen removal of the headspace of the filling bottle can further reduce the oxidation of the injection by oxygen during the storage period, the nitrogen is introduced to remove the oxygen, and a protective barrier can be further carried out on the paclitaxel injection, so that the storage time of the paclitaxel injection can be further prolonged.
Preferably, in the step (4), in the filling and oxygen removing step, oxygen is removed until the headspace oxygen content of the filling bottle is less than or equal to 10% (v/v), that is, the volume ratio of oxygen in the air is less than 10%. When the oxygen content of the headspace of the filling bottle is less than or equal to 10% (v/v), oxygen in the gas cannot be dissolved into the paclitaxel liquid, so that the paclitaxel injection has lower oxygen content, oxidation reaction is not easy to occur, and the paclitaxel injection has longer storage time. More preferably, in the step (4), in the filling and oxygen removing step, oxygen is removed until the headspace oxygen content of the filling bottle is less than or equal to 5% (v/v), that is, the volume ratio of oxygen in the air is less than 5%.
Preferably, in the step (4), the high-temperature sterilization step is to sterilize for 8-15 min at 121-125 ℃ by adopting a water bath sterilization cabinet. The sterilization temperature is easier to control by a water bath sterilization mode, the sterilization is carried out for 8-15 min at the temperature of 121-125 ℃, the temperature-sensitive taxol is not easy to degrade at high temperature, and the sterilization effect is good. More preferably, the sterilization is carried out for 12 minutes at 121 ℃ by using a water bath sterilization cabinet.
Preferably, the moisture content of the finished product obtained in the step (4) is controlled to be less than or equal to 0.6 wt.%. By controlling the moisture in the finished product to 0.6wt.% or less, the shelf life of the paclitaxel injection can be significantly extended. More preferably, the moisture content of the finished product obtained in the step (4) is controlled to be less than or equal to 0.4 wt.%.
Preferably, the moisture of the finished product obtained in the step (4) is controlled by washing the liquid preparation container and the pipeline with absolute ethyl alcohol 3 times or more before the step (1). The water content in the paclitaxel injection is controlled by the preparation process, so that the water removal process of the paclitaxel injection is simplified, and other quality risks introduced by the water removal process can be avoided.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the preparation method of the paclitaxel injection, the paclitaxel is wrapped by the polyoxyethylene (35) castor oil through a paclitaxel pretreatment process, so that the material degradation of the paclitaxel in a terminal high-temperature sterilization process can be avoided, and the finally obtained paclitaxel injection has good quality and high stability.
2. The paclitaxel injection preparation method of the invention, deoxygenize to below 0.5mg/L through preparing liquid; filling and deoxidizing to below 10% of headspace, and can obviously prolong the storage time of the paclitaxel injection.
3. According to the preparation method of the paclitaxel injection, the hydrolysis of the paclitaxel injection in the storage process can be reduced by controlling the water content of the paclitaxel injection, when the water content of the paclitaxel injection is lower than 0.6wt.%, the storage time of the paclitaxel injection is remarkably prolonged, and the quality of the paclitaxel injection is remarkably improved.
Description of the drawings:
FIG. 1 is a test pattern of substances related to example 1.
FIG. 2 is a test pattern of the relevant substances in comparative example 1.
Detailed Description
The present invention will be described in further detail with reference to test examples and specific embodiments. It should be understood that the scope of the above-described subject matter is not limited to the following examples, and any techniques implemented based on the disclosure of the present invention are within the scope of the present invention.
Test example:
prescription information
Example 1
The method of preparing a paclitaxel injection that is resistant to terminal sterilization of example 1, comprising the steps of:
(1) adding paclitaxel with prescription amount into polyoxyethylene (35) castor oil with prescription amount, and stirring and shearing at high speed of more than 4000rpm for more than 120min to obtain solution A; the method comprises the following specific steps:
the liquid preparation tank and the pipeline are washed by absolute ethyl alcohol for 3 times; adding a prescription amount of polyoxyethylene (35) castor oil into a liquid preparation tank; then adding the paclitaxel with the prescription amount into a liquid preparation tank, stirring and shearing at a high speed of 4000rpm for 120min, dissolving and wrapping the paclitaxel into polyoxyethylene (35) castor oil to obtain a solution A.
(2) Adding anhydrous ethanol with the formula amount into the solution A, and stirring until the solution is uniformly mixed to obtain a solution B;
(3) deoxidizing the solution B; the method comprises the following specific steps:
and introducing clean nitrogen into the solution B until the content of dissolved oxygen in the solution B is less than or equal to 0.2 mg/L.
(4) And (4) performing sterilization filtration, filling and deoxidization, sealing and high-temperature sterilization on the solution B treated in the step (3). The method comprises the following specific steps:
introducing clean nitrogen into the liquid preparation tank for pressurization, filtering the solution B by 2 filter elements of 0.22 mu m PVDF, filling the solution B into a medium borosilicate glass injection bottle, filling nitrogen to remove oxygen before and after filling, and controlling the content of oxygen in the headspace of the bottle to be less than or equal to 5% (v/v); then adding a plug and rolling a cover. And sterilizing the filled finished product in a water bath sterilization cabinet for 12 minutes at the temperature of 121-.
Example 2
The method of preparing the terminal sterilization resistant paclitaxel injection of example 2, comprising the steps of:
(1) adding paclitaxel with prescription amount into polyoxyethylene (35) castor oil with prescription amount, and stirring and shearing at high speed of more than 4000rpm for more than 120min to obtain solution A; the method comprises the following specific steps:
the liquid preparation tank and the pipeline are washed by absolute ethyl alcohol for 3 times; adding a prescription amount of polyoxyethylene (35) castor oil into a liquid preparation tank; then adding the paclitaxel with the prescription amount into a liquid preparation tank, stirring and shearing at a high speed of 4000rpm for 120min, dissolving and wrapping the paclitaxel into polyoxyethylene (35) castor oil to obtain a solution A.
(2) Adding anhydrous ethanol with the formula amount into the solution A, and stirring until the solution is uniformly mixed to obtain a solution B;
(3) deoxidizing the solution B; the method comprises the following specific steps:
and introducing clean nitrogen into the solution B until the content of dissolved oxygen in the solution B is less than or equal to 0.5 mg/L.
(4) And (4) performing sterilization filtration, filling and deoxidization, sealing and high-temperature sterilization on the solution B treated in the step (3). The method comprises the following specific steps:
introducing clean nitrogen into the liquid preparation tank for pressurization, filtering the solution B by 2 filter elements of 0.22 mu m PVDF, filling the solution B into a medium borosilicate glass injection bottle, filling nitrogen to remove oxygen before and after filling, and controlling the content of oxygen in the headspace of the bottle to be less than or equal to 10% (v/v); then adding a plug and rolling a cover. And sterilizing the filled finished product in a water bath sterilization cabinet for 12 minutes at the temperature of 121-.
Comparative example:
prescription information
Comparative example 1
The preparation method of paclitaxel injection of comparative example 1, comprising the following steps:
(1) adding paclitaxel with the prescription amount into anhydrous ethanol with the prescription amount, and stirring to uniformly mix the solution to obtain a solution A; the method comprises the following specific steps:
the liquid preparation tank and the pipeline are washed by absolute ethyl alcohol for 3 times; adding anhydrous ethanol of a prescription amount into a liquid preparation tank; then adding the paclitaxel with the prescription amount into a liquid preparation tank, and stirring to uniformly mix the solution.
(2) Adding the polyoxyethylene (35) castor oil with the prescription amount into the solution A, and continuously stirring until the solution is uniformly mixed to obtain a solution B;
adding a prescription amount of polyoxyethylene (35) castor oil into a liquid preparation tank; stirring and shearing at a high speed of 4000rpm for 120min until the solution is uniformly mixed to obtain a solution B;
(3) deoxidizing the solution B; the method comprises the following specific steps:
and introducing clean nitrogen into the solution B until the content of dissolved oxygen in the solution B is less than or equal to 0.2 mg/L.
(4) And (4) performing sterilization filtration, filling and deoxidization, sealing and high-temperature sterilization on the solution B treated in the step (3). The method comprises the following specific steps:
introducing clean nitrogen into the liquid preparation tank for pressurization, filtering the solution B by 2 filter elements of 0.22 mu m PVDF, filling the solution B into a medium borosilicate glass injection bottle, filling nitrogen to remove oxygen before and after filling, and controlling the content of oxygen in the headspace of the bottle to be less than or equal to 5% (v/v); then adding a plug and rolling a cover. And sterilizing the filled finished product in a water bath sterilization cabinet for 12 minutes at the temperature of 121-.
Comparative example 2
The method for preparing paclitaxel injection of comparative example 2, comprising the steps of:
(1) adding paclitaxel with prescription amount into polyoxyethylene (35) castor oil with prescription amount, and stirring and shearing at high speed of more than 4000rpm for more than 120min to obtain solution A; the method comprises the following specific steps:
the liquid preparation tank and the pipeline are washed by absolute ethyl alcohol for 3 times; adding a prescription amount of polyoxyethylene (35) castor oil into a liquid preparation tank; then adding the paclitaxel with the prescription amount into a liquid preparation tank, stirring and shearing at high speed of 4000rpm for 120min, and dissolving and coating the paclitaxel into polyoxyethylene (35) castor oil.
(2) Adding anhydrous ethanol with the formula amount into the solution A, and stirring until the solution is uniformly mixed to obtain a solution B;
(3) deoxidizing the solution B; the method comprises the following specific steps:
and introducing clean nitrogen into the solution B until the dissolved oxygen content in the solution B is about 5 mg/L.
(4) And (4) performing sterilization filtration, filling and deoxidization, sealing and high-temperature sterilization on the solution B treated in the step (3). The method comprises the following specific steps:
introducing clean nitrogen into the liquid preparation tank for pressurization, filtering the solution B by 2 filter elements of 0.22 mu m PVDF, filling the solution B into a medium borosilicate glass injection bottle, filling nitrogen to remove oxygen before and after filling, and controlling the content of oxygen in the headspace of the bottle to be less than or equal to 5% (v/v); then adding a plug and rolling a cover. And sterilizing the filled finished product in a water bath sterilization cabinet for 12 minutes at the temperature of 121-.
Comparative example 3
The method for preparing paclitaxel injection of comparative example 3, comprising the steps of:
(1) adding paclitaxel with prescription amount into polyoxyethylene (35) castor oil with prescription amount, and stirring and shearing at high speed of more than 4000rpm for more than 120min to obtain solution A; the method comprises the following specific steps:
the liquid preparation tank and the pipeline are washed by absolute ethyl alcohol for 3 times; adding a prescription amount of polyoxyethylene (35) castor oil into a liquid preparation tank; then adding the paclitaxel with the prescription amount into a liquid preparation tank, stirring and shearing at high speed of 4000rpm for 120min, and dissolving and coating the paclitaxel into polyoxyethylene (35) castor oil.
(2) Adding anhydrous ethanol with the formula amount into the solution A, and stirring until the solution is uniformly mixed to obtain a solution B;
(3) deoxidizing the solution B; the method comprises the following specific steps:
and introducing clean nitrogen into the solution B until the content of dissolved oxygen in the solution B is less than or equal to 0.2 mg/L.
(4) And (4) sterilizing, filtering, filling, sealing and sterilizing at high temperature the solution B treated in the step (3). The method comprises the following specific steps:
introducing clean nitrogen into the liquid preparation tank for pressurization, filtering the solution B by 2 channels of 0.22 mu m PVDF filter elements, and filling the solution B into a medium borosilicate glass injection bottle; then adding a plug and rolling a cover. And sterilizing the filled finished product in a water bath sterilization cabinet for 12 minutes at the temperature of 121-. (oxygen removal by nitrogen filling and approximately 20% of oxygen content in the headspace of the bottle were not carried out before and after filling)
Comparative example 4
The method of preparing paclitaxel injection of comparative example 4, comprising the steps of:
(1) adding paclitaxel with prescription amount into polyoxyethylene (35) castor oil with prescription amount, and stirring and shearing at high speed of more than 4000rpm for more than 120min to obtain solution A; the method comprises the following specific steps:
the liquid preparation tank and the pipeline are washed clean by injection water; adding a prescription amount of polyoxyethylene (35) castor oil into a liquid preparation tank; then adding the paclitaxel with the prescription amount into a liquid preparation tank, stirring and shearing at high speed of 4000rpm for 120min, and dissolving and coating the paclitaxel into polyoxyethylene (35) castor oil.
(2) Adding anhydrous ethanol with the formula amount into the solution A, and stirring until the solution is uniformly mixed to obtain a solution B;
(3) deoxidizing the solution B; the method comprises the following specific steps:
and introducing clean nitrogen into the solution B until the content of dissolved oxygen in the solution B is less than or equal to 0.2 mg/L.
(4) And (4) performing sterilization filtration, filling and deoxidization, sealing and high-temperature sterilization on the solution B treated in the step (3). The method comprises the following specific steps:
introducing clean nitrogen into the liquid preparation tank for pressurization, filtering the solution B by 2 filter elements of 0.22 mu m PVDF, filling the solution B into a medium borosilicate glass injection bottle, filling nitrogen to remove oxygen before and after filling, and controlling the content of oxygen in the headspace of the bottle to be less than or equal to 5% (v/v); then adding a plug and rolling a cover. And sterilizing the filled finished product in a water bath sterilization cabinet for 12 minutes at the temperature of 121-.
Experimental test results and analysis:
samples prepared in each example and comparative example were tested, and the following experimental data were obtained:
in table 1: in the experimental data of example 1, experimental test data before high temperature sterilization, the test sample was taken from the paclitaxel injection prepared according to the method of example 1 before high temperature sterilization. The remaining data are for the final paclitaxel injection prepared according to the preparation methods of the examples and comparative examples (after terminal autoclaving).
In table 2: the experimental test data of each example and comparative example are data after the test samples corresponding to those in Table 1 were left under high temperature (60 ℃ C.) conditions for 30 days.
TABLE 1 test items of paclitaxel injection prepared in each example and comparative example for 0 day
From the experimental data of table 1, it can be seen that:
in the detection results of the example 1 and the example 2, the content of related substances is obviously lower than the detection results of experimental data of each proportion.
Before and after high temperature sterilization, the paclitaxel injection prepared in example 1 has no great difference in detection indexes. The paclitaxel injection prepared according to the comparative example 1 is sterilized at high temperature, and the content of related substances in the injection is obviously increased compared with the experimental detection data of the example 1.
It can be seen from this that: the invention changes the solution system environment of the paclitaxel, controls the oxygen residual quantity in the preparation process and the water content in the preparation process and the finished product by the pretreatment process of the paclitaxel, adopts the terminal sterilization process of the paclitaxel, obviously improves the quality of the paclitaxel injection and improves the sterility assurance level of the paclitaxel.
TABLE 2 high temperature (60 deg.C) 30-day testing items of paclitaxel injection prepared in each example and comparative example
The experimental data in table 1 and table 2 are combined to show that:
the paclitaxel injection prepared in the examples 1 and 2 is placed at the high temperature of 60 ℃ for 30 days, the indexes have no obvious change, and the content of related substances is obviously lower than that of the related substances in each proportion.
In each proportion, the content of related substances shows a large increase. The shelf life of the paclitaxel injection prepared in each example is obviously longer than that of the paclitaxel injection prepared in each comparative example.
Therefore, the paclitaxel injection prepared by the paclitaxel preparation method of the invention has longer storage time.
Claims (5)
1. A preparation method of a paclitaxel injection tolerant to terminal sterilization is characterized by comprising the following steps:
(1) adding paclitaxel with prescription amount into polyoxyethylene (35) castor oil with prescription amount, and stirring and shearing at high speed of more than 4000rpm for more than 120min to obtain solution A;
(2) adding anhydrous ethanol with the formula amount into the solution A, and stirring until the solution is uniformly mixed to obtain a solution B;
(3) deoxidizing the solution B, namely deoxidizing the solution B by introducing nitrogen into the solution B until the content of dissolved oxygen in the solution is less than or equal to 0.5 mg/L;
(4) performing sterilization filtration, filling and deoxidization, sealing and high-temperature sterilization on the solution B treated in the step (3);
in the step (4), the sterilization filtration step is to filter the solution B through 2 paths of 0.22 mu m VDF filter elements;
in the step (4), in the step of filling and deoxidizing, deoxidizing is carried out until the oxygen content of the headspace of the filling bottle is less than or equal to 10% (v/v);
in the step (4), the high-temperature sterilization is a high-temperature sterilization process with the sterilization temperature of more than 121 ℃;
controlling the moisture content of the finished product obtained in the step (4) to be less than or equal to 0.6 wt.%.
2. The method for preparing paclitaxel injection according to claim 1, which is characterized in that: in the step (3), the solution B is deoxidized until the content of dissolved oxygen in the solution is less than or equal to 0.2 mg/L.
3. The method for preparing paclitaxel injection according to claim 1, which is characterized in that: in the step (4), in the step of filling and deoxidizing, deoxidizing is carried out until the oxygen content of the headspace of the filling bottle is less than or equal to 5% (v/v).
4. The method for preparing paclitaxel injection according to claim 1, which is characterized in that: controlling the moisture content of the finished product obtained in the step (4) to be less than or equal to 0.4 wt.%.
5. The method for preparing paclitaxel injection according to claim 1 or 4, wherein: and (3) controlling the moisture of the finished product obtained in the step (4), and washing the liquid preparation container and the pipeline for 3 times or more by using absolute ethyl alcohol before the step (1).
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| CN113712912A (en) * | 2021-09-17 | 2021-11-30 | 杭州上禾健康科技有限公司 | Terbutaline sulfate oral liquid and production method thereof |
| CN116983259A (en) * | 2023-09-27 | 2023-11-03 | 成都瑞尔医药科技有限公司 | Preparation method of etoposide injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101816644A (en) * | 2009-02-27 | 2010-09-01 | 海南四环医药有限公司 | Composition of taxol and phenylalanine and preparation method thereof |
| CN102552123A (en) * | 2011-12-31 | 2012-07-11 | 江苏奥赛康药业股份有限公司 | Paclitaxel composition for injection and preparation method thereof |
| CN104257607A (en) * | 2014-10-11 | 2015-01-07 | 海南通用康力制药有限公司 | Paclitaxel injection and preparation method thereof |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101816644A (en) * | 2009-02-27 | 2010-09-01 | 海南四环医药有限公司 | Composition of taxol and phenylalanine and preparation method thereof |
| CN102552123A (en) * | 2011-12-31 | 2012-07-11 | 江苏奥赛康药业股份有限公司 | Paclitaxel composition for injection and preparation method thereof |
| CN104257607A (en) * | 2014-10-11 | 2015-01-07 | 海南通用康力制药有限公司 | Paclitaxel injection and preparation method thereof |
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