CN109044969B - Preparation method of paclitaxel injection - Google Patents
Preparation method of paclitaxel injection Download PDFInfo
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- CN109044969B CN109044969B CN201811236777.2A CN201811236777A CN109044969B CN 109044969 B CN109044969 B CN 109044969B CN 201811236777 A CN201811236777 A CN 201811236777A CN 109044969 B CN109044969 B CN 109044969B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses a preparation method of a paclitaxel injection, which comprises the following components of 30 parts by weight of paclitaxel, 1000 parts by volume of anhydrous ethanol, 18-24 parts by volume of lactic acid and 1000 parts by volume of castor oil polyoxyl ester (35). Compared with the prior art, the paclitaxel injection prepared by the invention has the advantages of good solubility, uniform concentration, stable quality and low acute adverse reaction, and the preparation process provided by the invention is simple and easy to control, and has high production efficiency and low production energy consumption.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method of a paclitaxel injection.
Background
Paclitaxel is a natural plant extract antitumor drug for effectively treating various cancers, is widely used for treating various tumors such as ovarian cancer, breast cancer, lung cancer and the like, has outstanding curative effects on the breast cancer and the ovarian cancer, also has certain curative effects on liver cancer, lung cancer, esophageal cancer, head and neck cancer and prostate cancer, can be further improved in curative effect when combined with other common antitumor drugs, and is very widely used in clinic due to a unique anticancer mechanism. However, paclitaxel has poor water solubility, is difficult to dissolve in water, and has low bioavailability, so that the preparation of the paclitaxel into intravenous injection or infusion preparations has great technical difficulty. The paclitaxel injection which is currently marketed is a colorless transparent or yellowish viscous solution, namely a polyoxyethylene castor oil-absolute ethyl alcohol (V: V ═ 50:50) solution of paclitaxel, and is diluted to 0.35-1.4mmol/L before use for intravenous injection. The polyoxyethylene castor oil has obvious toxicity, the clinical manifestation is serious anaphylactic reaction, the combination of ethanol can cause the release of in vivo histamine, several minutes after the administration can cause the hypersensitivity reactions of drug eruption, tachypnea, bronchospasm, hypotension and the like of partial patients, and 5-10mg (milligram) of dexamethasone and 300mg of cimetidine are required to be injected in advance in an intravenous way 30 minutes before the use in order to avoid the anaphylactic reaction; or 50mg diphenhydramine is injected intramuscularly and clinical monitoring is required, although desensitization is generally performed by using antihistamine medicines such as hormone in clinic at present, partial prevention is still achieved, and due to the inconvenience of the medication process, the clinical application of the existing paclitaxel injection is severely limited.
In view of the disadvantages of paclitaxel injection, over the last decade, intensive and extensive research has been carried out by preparation workers at home and abroad, and a large number of new paclitaxel preparations have been developed. For example, nanoparticles prepared by modifying polyethylene glycol, polyvinyl alcohol, povidone, heparin, etc. or paclitaxel albumin nanosuspension ABI-007. And then for example, paclitaxel is encapsulated in liposome of phospholipid, cholesterol and other membrane materials, or hydroxypropyl cyclodextrin is used for loading paclitaxel to form a complex, so as to achieve the effects of solubilization and the like. However, the preparation also has the defect of generating paclitaxel precipitation when being diluted by a solution, even has adverse reactions such as erythrocyte lysis and the like caused by overhigh concentration of a membrane material; or easy delamination, low encapsulation efficiency, easy leakage, poor stability and the like. These insurmountable drawbacks have seriously hampered the industrial development and practical clinical application of the above-mentioned novel formulations.
In order to solve the technical problems of the paclitaxel preparation on the market at present, for many years, research and development personnel in the prior art develop a large amount of research and development aiming at adverse reactions caused by polyoxyethylene castor oil, increasing the solubility and stability of paclitaxel, reducing toxicity and increasing bioavailability, and are dedicated to preparing a low-toxicity and stable paclitaxel injection. Chinese patent application CN101816644A discloses a composition injection containing paclitaxel and phenylalanine, wherein the weight ratio of paclitaxel to phenylalanine is 1:0.01-0.8, the solubilizer in the injection is polyoxyethylene castor oil, the solvent is absolute ethyl alcohol, the volume ratio of the polyoxyethylene castor oil to ethyl alcohol is 1:2, the dosage of the polyoxyethylene castor oil in the injection is properly reduced, but the phenylalanine is used and the dosage of the polyoxyethylene castor oil is still higher. CN101574318A discloses a paclitaxel injection, which comprises, by weight, 0.6% of paclitaxel raw material, 55% of polyoxyethylene castor oil, 43% of absolute ethyl alcohol, and 1% of a mixture of oleic acid and sodium glycocholate, wherein in the preparation process, a 4A type molecular sieve is added into the polyoxyethylene castor oil to remove organic impurities. However, the polyoxyethylene castor oil in the above technology is still high in usage amount, and is easy to cause adverse reactions. Therefore, the applicant is dedicated to research a preparation method of a paclitaxel injection with low usage amount of polyoxyethylene castor oil, high solubility, strong stability and high bioavailability of paclitaxel.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the technical defect that the existing paclitaxel injection is easy to cause hypersensitivity, so that the paclitaxel injection with low polyoxyethylene castor oil dosage, stable product, good solubility and low side effect and the preparation method thereof are provided.
Therefore, the invention provides a paclitaxel injection which comprises paclitaxel, absolute ethyl alcohol, lactic acid and castor oil polyoxyl ester (35),
wherein the components are as follows:
preferably, the paclitaxel injection comprises the following components:
the invention also provides a preparation method of the paclitaxel injection, which comprises the following steps:
A. preparing materials according to a production prescription, and weighing the raw materials and the auxiliary materials according to the prescription respectively for later use;
B. adding one third of anhydrous ethanol and one half of lactic acid into paclitaxel, performing ultrasonic treatment, adding four fifths of polyoxyethylene castor oil and one half of lactic acid, and mixing;
C. freeze-drying the solution, and performing pre-freezing, sublimation drying and re-drying to obtain taxol freeze-dried powder;
D. and D, adding the rest of absolute ethyl alcohol into the taxol freeze-dried powder obtained in the step C, ultrasonically dissolving, adding the rest of polyoxyethylene castor oil and the rest of acetic acid, and stirring for 30min to obtain the taxol injection.
Preferably, the freeze-drying procedure is that the solution is pre-frozen for 3 hours at-50 ℃; then carrying out sublimation drying for 12 hours at the temperature of-15 ℃; the temperature was then raised to 30 ℃ and re-dried for 6 hours.
Compared with the prior art, the technical scheme of the invention has the following advantages that partial raw materials are subjected to freeze-drying treatment, so that paclitaxel can be completely dissolved in a small amount of anhydrous ethanol and polyoxyethylene castor oil, and meanwhile, the direct effect of most of the polyoxyethylene castor oil on a human body is reduced through freeze-drying, so that the paclitaxel injection which is good in solubility, good in stability, stable in quality and reduced in side effect caused by the polyoxyethylene castor oil can be obtained by adopting a simple preparation process. In the preparation process, activated carbon filtration is not needed, so that the use of activated carbon is avoided, the environmental pollution is reduced, and the yield is improved. The product prepared by the invention has good stability, the stability of various project indexes such as impurities is obviously superior to that of the existing product, and the preparation process provided by the invention is simple and easy to control, the production efficiency is high, and the production energy consumption is low.
Detailed Description
In the present invention, all parts and percentages are by weight or volume, and all equipment and raw materials are commercially available or commonly used in the industry, if not specified. The methods in the following examples are conventional in the art unless otherwise specified.
Example 1: paclitaxel injection
The preparation method comprises the following steps:
A. preparing materials according to a production prescription, and weighing the raw materials and the auxiliary materials according to the prescription respectively for later use;
B. adding one third of anhydrous ethanol and one half of lactic acid into paclitaxel, performing ultrasonic treatment, adding four fifths of polyoxyethylene castor oil and one half of lactic acid, and mixing;
C. pre-freezing the solution at-50 deg.C for 3 hr; then carrying out sublimation drying for 12 hours at the temperature of-15 ℃; then raising the temperature to 30 ℃ for re-drying for 6 hours to obtain taxol freeze-dried powder through prefreezing, sublimation drying and re-drying stages;
D. and D, adding the rest of absolute ethyl alcohol into the taxol freeze-dried powder obtained in the step C, ultrasonically dissolving, adding the rest of polyoxyethylene castor oil and the rest of acetic acid, and stirring for 30min to obtain the taxol injection.
Comparative example 1:
(1) adding polyoxyethylene castor oil and 4A type molecular sieve into the liquid preparation tank, stirring for 30 minutes, fully mixing, sealing, and filtering.
(2) And (2) carrying out sterile pressure filtration on the feed liquid prepared in the step (1) through a filter membrane of 0.22 mu m.
(3) Accurately weighing paclitaxel according to the prescription amount, adding 10 times of anhydrous ethanol according to the mass ratio, uniformly mixing, adding a mixture of sodium bisulfite and lactic acid (the mass ratio is 2: 1) as a stabilizer, stirring until the paclitaxel and the stabilizer are completely dissolved, and adding the anhydrous ethanol to the prescription amount.
(4) And (4) carrying out sterile pressure filtration on the prepared solution in the step (3) through a filter membrane of 0.22 mu m.
(5) Mixing the above two prepared solutions, and performing aseptic pressure filtration.
Comparative example 2:
(1) preparing auxiliary liquid: adding polyoxyethylene castor oil into dried molecular sieve, charging nitrogen, and sealing for three days; activated by activated carbon, and sealed in a dryer for later use; washing the molecular sieve with anhydrous ethanol until the ethanol is transparent, volatilizing the ethanol, drying, cooling, and sealing in a dryer for later use; the polyoxyethylated castor oil, ethanol and activated carbon were mixed (stainless steel container) and stirred ultrasonically.
(2) Auxiliary liquid sterile pressure filtration: sterile filter pressing with a microporous filter membrane, weighing, and calculating the amount of absolute ethyl alcohol to be supplemented;
(3) dissolving main drugs: drying the main drugs in a vacuum drying oven, precisely weighing the main drugs, adding the main drugs into the filtrate obtained in the step (2), supplementing absolute ethyl alcohol for flushing, filling high-purity nitrogen, sealing, slightly shaking and carrying out ultrasonic treatment until the sample is completely dissolved;
(4) sterile pressure filtration of the solution: the solution was sonicated and sterile filter-pressed with a microporous membrane.
Experimental example 1 stability comparative study results
The paclitaxel injection in the embodiment 1 of the invention and the products prepared in the comparative examples 1 and 2 are examined in accelerated tests and long-term tests to determine various indexes.
Accelerated test
Taking a test sample, placing the test sample under the condition of 40 +/-2 ℃/RH75 +/-5 percent for 6 months to carry out accelerated test investigation. Sampling once at the end of 1, 2, 3 and 6 months, detecting each item according to the research method of the national standard WS1- (X-026) -2001Z of the paclitaxel injection, and comparing the result with 0 month. The results are given in table 1 below:
long-term test A test sample is taken and placed under the conditions of the temperature of 25 +/-2 ℃ and the relative humidity of 60 +/-10 percent for long-term test. Sampling once at the end of each of 0 th and 6 th month, detecting each item according to the research method of the national standard WS1- (X-026) -2001Z of the paclitaxel injection, and comparing with the result of 0 month. The results are given in table 2 below:
the paclitaxel injection of example 1, comparative example 1 and comparative example 2 were added to 0.9% sodium chloride solution for drug stability test, and the results are shown in table 3:
experimental example 2 allergy test
Animal experiments were carried out using the injection solution prepared in example 1 of the present invention and the injection solutions in comparative examples 1 to 2, and the same effective amount of paclitaxel was converted for use.
The allergy test method comprises the following steps: 18 guinea pigs were selected and randomly divided into three groups, and were intraperitoneally injected with 6mg/mL paclitaxel injection at a dose of 3 mg/guinea pig, 1 time every other day, 3 times continuously, 14 days and 21 days after the first injection, 3 guinea pigs were selected for each group, and were challenged by intravenous injection at a dose of 6 mg/guinea pig, and the allergy score was determined according to the systemic anaphylaxis rating scale of Table 4.
The results are shown in table 5 (average):
the results in Table 5 show that the anaphylaxis of the paclitaxel injection of the present invention ranges from 0 to 1 grade, and the anaphylaxis of the paclitaxel injection in the comparative examples 1 to 2 ranges from 1 to 2 grade, which indicates that the present invention significantly reduces the severe anaphylaxis of the original paclitaxel injection.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (1)
1. A paclitaxel injection is characterized by comprising paclitaxel, absolute ethyl alcohol, lactic acid and castor oil polyoxyl ester (35),
wherein the components are as follows:
the preparation method of the paclitaxel injection comprises the following steps:
A. preparing materials according to a production prescription, and weighing the raw materials and the auxiliary materials according to the prescription respectively for later use;
B. adding one third of anhydrous ethanol and one half of lactic acid into paclitaxel, performing ultrasonic treatment, and adding four fifths of polyoxyethylene castor oil and one half of lactic acid;
C. the solution is freeze-dried and the solution is dried,
the freeze-drying procedure is as follows: pre-freezing the solution at-50 deg.C for 3 hr; then carrying out sublimation drying for 12 hours at the temperature of-15 ℃; then the temperature is raised to 30 ℃ for drying again for 6 hours,
pre-freezing, sublimation drying, and re-drying to obtain taxol lyophilized powder;
D. and D, adding the rest of absolute ethyl alcohol into the taxol freeze-dried powder obtained in the step C, ultrasonically dissolving, adding the rest of polyoxyethylene castor oil and the rest of lactic acid, and stirring for 30min to obtain the taxol injection.
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| CN201811236777.2A CN109044969B (en) | 2018-10-23 | 2018-10-23 | Preparation method of paclitaxel injection |
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| CN201811236777.2A CN109044969B (en) | 2018-10-23 | 2018-10-23 | Preparation method of paclitaxel injection |
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| CN109044969B true CN109044969B (en) | 2020-04-10 |
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| CN110882213B (en) * | 2019-11-21 | 2021-05-04 | 海南紫杉园制药有限公司 | Paclitaxel injection and preparation method thereof |
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 |
| CN103833693A (en) * | 2014-03-04 | 2014-06-04 | 悦康药业集团有限公司 | Taxol compound and medicine composition containing same |
| 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 |
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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 |
| CN103833693A (en) * | 2014-03-04 | 2014-06-04 | 悦康药业集团有限公司 | Taxol compound and medicine composition containing same |
| 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 |
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Denomination of invention: A preparation method of paclitaxel injection Effective date of registration: 20230317 Granted publication date: 20200410 Pledgee: Industrial Bank Co.,Ltd. Haikou Branch Pledgor: HAINAN CHOITEC PHARMACEUTICAL CO.,LTD. Registration number: Y2023980034716 |
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