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WO2011047639A1 - Solution pharmaceutique de taxanes comprenant un agent chélatant et son procédé de préparation - Google Patents

Solution pharmaceutique de taxanes comprenant un agent chélatant et son procédé de préparation Download PDF

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Publication number
WO2011047639A1
WO2011047639A1 PCT/CN2010/077998 CN2010077998W WO2011047639A1 WO 2011047639 A1 WO2011047639 A1 WO 2011047639A1 CN 2010077998 W CN2010077998 W CN 2010077998W WO 2011047639 A1 WO2011047639 A1 WO 2011047639A1
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Prior art keywords
emulsion
drug solution
chelating agent
solution
injection
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Ceased
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PCT/CN2010/077998
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English (en)
Chinese (zh)
Inventor
陈建明
高保安
杨秋霞
邓莉
孙靖
顾芃
刘薇
张佳良
张莹莹
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Tianjin Tasly Group Co Ltd
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Tianjin Tasly Group Co Ltd
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Publication of WO2011047639A1 publication Critical patent/WO2011047639A1/fr
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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a pharmaceutical preparation technology, in particular to a docetaxel solution having a chelating agent and a preparation method thereof.
  • Taxanes include paclitaxel (trade name Taxol) and docetaxel (trade name Taxotem), two FDA-approved docetaxan anticancer drugs. Taxanes are a class of typical cytotoxic agents with broad-spectrum anti-tumor effects on breast cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma of the head and neck, and malignant melanoma. Both cancer and metastatic cancer have strong inhibitory effects.
  • Its anti-tumor mechanism is to stimulate the assembly of microtubules into microtubules by stimulating the bundle of microtubules, and to make the microtubules ultra-stable and inhibit the dynamic reorganization of microtubules, and finally stop the proliferation of cancer cells in the stationary phase of mitosis. The stage to achieve anti-tumor purposes.
  • Paclitaxel and docetaxel are very water-soluble, almost insoluble in water (about 4 g/ml), and the oral absorption rate is only 2% to 4%, so it can only be administered intravenously.
  • the clinical application of paclitaxel injection is a colorless viscous concentrated solution made of polyoxyethylene castor oil and absolute ethanol (50: 50, V / V), although the composite solvent is solved.
  • docetaxel formulations A similar problem exists with the available docetaxel formulations.
  • the clinical preparation of docetaxel is composed of Tween-80 solution and 13% ethanol solution. When it is used, it is dispersed intravenously in physiological saline. Although the dissolution of docetaxel is solved, the injection contains Tween-80, which has a hemolysis effect, is prone to a certain degree of hemolysis reaction in clinical use, and its safety is poor.
  • the research and development of docetaxel injections are active. In recent years, studies on docetaxel injections have focused on liposomes, fat emulsions, nanoparticles, albumin cross-linking precursors, and cyclodextrin inclusion complexes. The current technology focus is on the biocompatibility, in vivo tolerance, and stability of the formulation. Despite breakthroughs in some formulation studies, their use is still limited due to low drug loading and insufficient therapeutic drug concentrations.
  • BS Anderson's "non-intestinal stable non-toxic preparation of paclitaxel" (Chinese patent: 97196934.5)
  • the drug solvent part of the drug solution is composed of polyethylene glycol 400 and dimethylacetamide in a ratio of 3:1, Although methyl acetamide can increase the dissolution rate of the drug, it also increases the toxic side effects of the drug preparation.
  • Zhou Lisweeping et al (research progress in the toxic effects of dimethylacetamide [J].
  • Chinese Occupational Medicine, 2009, 36 (1): 66-67) reported that dimethylacetamide can cause weight loss and retinal atrophy in large mice. , brain wave changes and lung, stomach, liver, kidney and other damage.
  • the drug solvent in the drug solution portion is mainly composed of polyethylene glycol 400 and oleic acid.
  • R.C. Roche et al. (Handbook of Pharmaceutical Excipients [M]. Original 4th Edition: 476) showed that oleic acid can cause rupture of red blood cells, ie, it is hemolytic, and is only allowed in non-injectables in the UK.
  • the pharmaceutical solution portion contains a surfactant such as Tween-80, povidone, lecithin and the like. These ones Surfactants have certain hemolytic and stimulating properties.
  • the invention provides a docetaxan pharmaceutical composition, which is prepared from a docetaxel solution and an emulsion, wherein the drug solution or the emulsion contains a chelating agent, and the content is 0.05-2% (g/ml). Preferably, 0.1 to 1% (g/ml).
  • the preparation is to mix the drug solution and the emulsion in a ratio of from 1 : 10 to 1: 100 by volume, preferably in a ratio of from 1:20 to 1:50, most preferably in a ratio of 1:25.
  • composition of the present invention exhibits strong stability after being mixed with an injectable emulsion by adding a chelating agent to the docetaxel solution or emulsion prior to formulation.
  • the present invention provides a docetaxel solution containing a docetaxel, a chelating agent and a solvent.
  • the ratio of each component is:
  • the ratio of each component is:
  • the other medicinal excipients are added during the preparation of the solution, such as: cosolvents, isotonic regulators, surfactants, pH adjusters, etc., whether or not to add these medicinal excipients depends on the yew The nature of terpenoids, chelating agents and solvents.
  • the docetaxel is any of the docetaxel drugs, preferably paclitaxel or docetaxel which has been marketed.
  • the chelating agent is added to the drug solution, wherein the chelating agent is selected from the group consisting of: ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodium edetate One or a mixture of one or more of trisodium edetate and disodium citrate, preferably citric acid, lactic acid, ethylenediaminetetraacetic acid, disodium edetate, and most preferably ethylenediamine Disodium acetate.
  • the solvent in the pharmaceutical solution of the present invention is selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, propylene glycol, glycerin, absolute ethanol, water for injection or More than one mixture; polyethylene glycol 400 is preferred.
  • the present invention also includes a method for preparing a solution of the present invention, which comprises dissolving a docetaxel drug and a chelating agent in a solvent, and is necessary The step of adding other pharmaceutical excipients.
  • the preparation method of the present invention comprises the steps of: weighing paclitaxel or docetaxel, a chelating agent into a solvent, heating or stirring at 50-100 ° C or shear-dissolving, and then diluting with a solvent; adding 0.01% - The 3 g/ml needle is adsorbed by activated carbon at a heating temperature of 25-100 ° C for 15 - 120 minutes, then filtered, dispensed, sealed, and sterilized.
  • the present invention also provides a pharmaceutical combination package comprising the combination of a taxane drug solution and an emulsion according to the present invention, wherein the two agents are separately loaded in a container, placed separately, and packaged together.
  • the taxane drug solution and the medicinal emulsion of the present invention are respectively filled in a plastic bottle or a glass bottle, and the two drugs are combined in a volume ratio of 1:10-10:1. Packed together, preferably in a ratio of 1:1, packaged in the same large packaging container. It is advisable to pack in one use.
  • the emulsion according to the present invention is an oil-water mixed emulsified preparation, which is a non-uniform dispersion system in which an oil or an oil solution is dispersed in a dispersion state in a dispersion medium, and has an oral emulsion and an intravenous emulsion.
  • the present invention uses an intravenous emulsion, preferably a fat emulsion for intravenous injection, such as: 20% medium/long-chain fat emulsion, 20% long-chain fat emulsion, and the like.
  • the emulsion of the present invention is a commercially available emulsion product for injection or an emulsion product formulated according to the prior art. It generally contains an injection oil, an emulsifier, an antioxidant, an isotonic regulator, a pH adjuster, water for injection, and the like.
  • the invention is characterized in that a chelating agent can be added to the emulsion of the invention in an amount of 0.05-2% g/ml, preferably 0.1-
  • the chelating agent is selected from the group consisting of: ethylenediaminetetraacetic acid, citric acid, lactic acid, malic acid, tartaric acid, disodium edetate, trisodium ethylenediaminetetraacetate, disodium citrate One or more mixtures, preferably citric acid, lactic acid, ethylenediaminetetraacetic acid, disodium edetate, and most preferably disodium edetate.
  • the emulsion of the present invention wherein the oil for injection is selected from the group consisting of caprylic acid triglyceride, caprylic acid monoglyceride, caprylic acid diglyceride, caprylic acid triglyceride, ganoderma lucidum spore oil, capric acid monoglyceride, capric acid diglyceride , citric acid triglyceride, caprylic acid monoglyceride, coix seed oil, brucea oil, artemisin oil, caprylic acid diglyceride, soybean oil, fish oil, linseed oil, sunflower oil, evening primrose oil, A mixture of one or more of sea buckthorn oil, zedoary turmeric oil, safflower seed oil, sesame oil, corn oil, elemene oil, garlic oil, etc., in an amount of from 1 to 30% g/ml.
  • the concentration of oil in the emulsion is expressed in grams of oil per ml of emulsion.
  • Preferred injectable oils are selected from the group consisting of one or a mixture of caprylic acid triglyceride and soybean oil in an amount of 10-30% g/ml.
  • the emulsifier is selected from the group consisting of soybean phospholipids, egg yolk phospholipids, dimyristoyl phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, palmitoyl oil
  • One or more mixtures of acylphosphatidylcholine, distearoylphosphatidylethanolamine, poloxamer 188 in an amount of from 0.5 to 5% g/ml.
  • the preferred emulsifier is selected from the group consisting of one or a mixture of soybean phospholipids and egg yolk phospholipids in an amount of from 0.8 to 3% g/ml.
  • the concentration of the emulsifier in the emulsion is expressed in grams of emulsifier per ml of emulsion.
  • the antioxidant of the present invention is tocopherol, and its content is 0-0.5% g/ml. A preferred content is 0-0.3% g/ml.
  • the isotonicity adjusting agent of the present invention is one or more selected from the group consisting of glycerin, sorbitol, mannitol, glucose, and sodium chloride, preferably glycerin.
  • the pH adjusting agent of the present invention is selected from one or more of citric acid, malic acid, hydrochloric acid, acetic acid, lactic acid, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, preferably sodium hydroxide, and the pH is adjusted to 6.0. — 9.0. Preferably, the pH is adjusted to 6.5 8.5.
  • the preparation method of the intravenous emulsion is conventional techniques, such as mixing the injection oil and the antioxidant, heating to 50-90 V, adding an emulsifier, stirring or shearing to dissolve the emulsifier to obtain an oil phase;
  • the osmotic adjusting agent and the stabilizer are added to an appropriate amount of water for injection, heated to 50-90 ° C to be stirred and dissolved to obtain an aqueous phase;
  • the oil phase and the aqueous phase are mixed at a temperature of 50-90 ° C, and emulsified or stirred by a shear emulsifier.
  • the colostrum is further emulsified, then fixed to volume with water for injection, adjusted to pH 6.0-9.0 with a pH adjuster, filtered, dispensed, nitrogen-filled, sealed, and sterilized.
  • the preparation step of the emulsion includes: dissolving the emulsifier in the injectable oil or dissolving the emulsifier in the water.
  • further emulsification of the colostrum is carried out using a high pressure homogenizer at a pressure of 5,000 to 25,000 psi.
  • the disinfection in the preparation step of the emulsion is a sterilization method using a rotary high-pressure steam sterilization pot, a circulating steam or a microporous membrane, wherein the high temperature sterilization temperature is 100-121 ° C, and the time is 8 - 45 minutes.
  • the filtration device in the preparation step of the emulsion includes, but is not limited to, a microfiltration membrane, a sand filter rod, a funnel or a capsule filter.
  • the final emulsion is a white or off-white emulsion liquid with opalescence, an average particle size of 100-500 nm, and a pH of 6.0-9.0.
  • the present invention also provides a method for using a taxane drug solution, which comprises dispersing a drug solution by a ratio of a taxane drug solution and a medicinal emulsion in a volume ratio of 1:10 to 100, preferably 1:25.
  • a taxane drug solution which comprises dispersing a drug solution by a ratio of a taxane drug solution and a medicinal emulsion in a volume ratio of 1:10 to 100, preferably 1:25.
  • the emulsion-dispersed drug solution is added to physiological saline or glucose solution for injection.
  • the content and particle diameter of the dispersion at different time points are respectively determined by high performance liquid chromatography and particle size analyzer; when measuring the content, an appropriate amount of the dispersion is firstly extracted by a syringe through a microporous membrane of 0.45 ⁇ m. The content of the drug in the filtrate was measured, and the percentage of the label was calculated, and the content was used to evaluate whether the drug precipitated crystals; the particle diameter was directly measured, and the appearance was visually observed, and the results are shown in Table 1 and Table 2.
  • the chelating agent-containing dispersion is stable under the premise of the chelating agent (citric acid) prepared in the same manner as in Example 1 and the paclitaxel injection composition containing no chelating agent.
  • the time is up to 6 days, and the dispersion time without the chelating agent is about 3 days.
  • the dispersion containing the chelating agent has no oil floating phenomenon within 6 days, which is better and does not contain chelating.
  • the dispersion of the mixture has more oil, and with the prolongation of time, the oil gradually increases, and the appearance is poor; the particle size does not change much during the stabilization time, and the particle size becomes larger when the drug is precipitated.
  • the paclitaxel injection composition containing a chelating agent has a remarkable effect, which is advantageous in that the dispersion stability of the paclitaxel injection composition containing no chelating agent is remarkably improved, and the dispersion is unexpectedly overcome.
  • a chelating agent is a feature of the present invention having substantially excellent effects.
  • the composition containing the chelating agent disodium edetate
  • the chelating agent-free docetaxel injection we will pre-administer the composition containing the chelating agent (disodium edetate) and the chelating agent-free docetaxel injection. The stability of the dispersion is compared.
  • a docetaxel injection composition containing a chelating agent (disodium ethylenediaminetetraacetate) was prepared according to the embodiment described in Example 2 to obtain a test sample; according to the embodiment described in Example 2, the chelating agent was removed ( Ethylenediaminetetraacetic acid disodium)
  • the docetaxel injection composition containing no chelating agent was prepared to obtain a control sample; 4 ml of each of the drug solutions of the above test and control samples were aspirated, and dispersed in respective ones according to Example 2 In an embodiment of a self-made 100 ml emulsion, shake it to obtain a test sample.
  • the content and particle diameter of the dispersion at different time points are respectively determined by high performance liquid chromatography and particle size analyzer; when measuring the content, an appropriate amount of the dispersion is firstly extracted by a syringe through a microporous membrane of 0.45 ⁇ m. The content of the drug in the filtrate was measured, and the percentage of the label was calculated, and the content was used to evaluate whether the drug precipitated crystals; the particle size was directly measured, and the appearance was visually observed, and the results are shown in Table 3 and Table 4.
  • Table 3 The docetaxel injection composition containing the chelating agent (disodium edetate) represented by Example 2
  • the stability of the dispersion before the administration (the dispersion emulsion is a self-made emulsion)
  • the chelating agent-containing dispersion has a stabilization time of more than half a month, and the chelating agent-free dispersion has a stabilization time of about 6 days. From the apparent point of view, the chelating agent-containing dispersion has no oil floating in half a month. , good appearance, and no chelating agent, more oil, and with the extension of time, the floating oil gradually increased, the appearance is poor; the particle size does not change much during the stabilization time, when there is drug precipitation The diameter becomes larger.
  • the docetaxel injection composition containing a chelating agent (disodium edetate) has a remarkable effect, which is advantageous in that the dispersion stability of the docetaxel injection composition containing no chelating agent is greatly improved. Improved, and unexpectedly overcome the lack of dispersion oil. Therefore, it has been revealed that the inclusion of a chelating agent is a feature of the present invention having substantially excellent effects.
  • the drug solution is prepared as a control drug solution; the drug solution is prepared according to the embodiment described in Example 18 to obtain a test drug solution; 4 ml of the above reference drug solution and the test drug solution are respectively taken up and dispersed in the implementation.
  • the appropriate amount of the dispersion was firstly extracted with a microfiltration membrane of 0.45 ⁇ m by a syringe to determine the content of the drug in the filtrate, and the calculation was performed. The percentage content was indicated, and the content was used to evaluate whether the drug precipitated crystals; and the appearance was visually observed, and the results are shown in Table 5.
  • the preparation of the invention 100.4% 99.2% 100.1% 101.0% 97.9 %
  • the preparation of the present invention has no oil floating phenomenon within 24 hours; the control preparation has more oil.
  • the dispersion of the composition of the present invention containing a chelating agent is stable for up to 24 hours, and contains dimethylacetamide.
  • the control solution dispersion has a stabilization time of less than 6 Hour; from the apparent point of view, the dispersion of the preparation of the invention has no oil floating phenomenon, and the dispersion liquid containing the dimethylacetamide control preparation is more serious, and there is a large amount of oil stains hanging on the wall.
  • the addition of a chelating agent unexpectedly solved the problem. It can be seen that the formulation scheme of the present invention has significant advantages and unexpected effects compared to the control patent. Therefore, it has been revealed that the inclusion of a chelating agent is a feature of the present invention having substantially excellent effects.
  • oleic acid polyethylene glycol 400 solutions were separately prepared; and then the solution was used to prepare a paclitaxel solution having a paclitaxel content of 25 mg/ml as a control solution;
  • the drug solution is prepared to obtain a test solution; 4 ml of the above control solution and the test solution are respectively taken up and dispersed in 100 ml of the commercially available emulsion described in Example 19, and shaken to obtain a test sample.
  • the content of the drug at different time points was determined by high performance liquid chromatography.
  • the appropriate amount of the dispersion was firstly extracted with a microfiltration membrane of 0.45 ⁇ m by a syringe to determine the content of the drug in the filtrate, and the calculation was performed. The percentage content is indicated, and the content is used to evaluate whether the drug precipitates crystallization; and the appearance is visually observed, as shown in Table 6.
  • the preparation of the invention 101.5% 100.8% 99.3% 100.0% 97.7%
  • the dispersion of the composition of the present invention containing a chelating agent has a stabilization time of up to 20 hours, and the dispersion time of the oleic acid-containing control preparation dispersion Less than 6 hours, and the stability decreases with the increase of oleic acid; from the apparent point of view, the dispersion of the present invention has no oil floating phenomenon, and the oleic acid-containing series of controlled patent preparation dispersions are more serious, and there are a lot of oil stains. wall.
  • the addition of a chelating agent unexpectedly solved the problem. It can be seen that the formulation scheme of the present invention has significant advantages and unexpected effects compared to the control patent. Therefore, it has been revealed that the inclusion of a chelating agent is a feature of the present invention having substantially excellent effects.
  • the drug solution was prepared as a control solution; the drug solution was prepared according to the embodiment described in Example 20 to obtain a test solution; 4 ml of the above control solution and the test solution were separately aspirated, and dispersed in the method described in Example 20, respectively. In 100 ml of a commercially available emulsion, shake it to obtain a test sample.
  • the content of the drug at different time points is determined by high performance liquid chromatography; First, use a syringe to extract a proper amount of the dispersion through a 0.45 ⁇ m microporous membrane, determine the content of the drug in the filtrate, calculate the percentage of the label, and use this content to evaluate whether the drug precipitates crystallize; and visually observe the appearance, the results are shown in the table. 7.
  • the preparation of the invention has no oil floating phenomenon within 20 hours; the control preparation has more oil.
  • the dispersion of the composition of the present invention containing a chelating agent has a stabilization time of up to 20 hours, and the dispersion time of the surfactant-containing proprietary formulation dispersion is stabilized. Less than 8 hours; from the apparent point of view, the dispersion of the composition of the present invention has no oil floating phenomenon, and the dispersion of the control patent preparation containing surfactant is more serious, and there is a large amount of oil stains hanging on the wall.
  • the addition of a chelating agent unexpectedly solved the problem. It can be seen that the formulation scheme of the present invention has significant advantages and unexpected effects compared to the control patent. Therefore, it has been revealed that the inclusion of a chelating agent is a feature of the present invention which has substantially excellent effects.
  • the above paclitaxel solution and the medicinal emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume and packaged in the same large packaging container.
  • the paclitaxel solution and the emulsion are in a ratio of 1:25 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled; or the drug solution may be added to the emulsion first, and then a predetermined amount of physiological saline or A glucose solution is used for the injection.
  • docetaxel add to the appropriate amount of polyethylene glycol 400, heat shear at 90 ° C, then dilute to 100 ml with polyethylene glycol 400; add 0.3 g of needle with activated carbon, at 25 ° The mixture was adsorbed for 30 minutes at a temperature of C, then filtered through a microporous membrane, dispensed, sealed, and sterilized by a rotary autoclave at 115 ° C for 30 minutes, i.e., a paclitaxel solution.
  • the above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:25 by volume ratio, shaken, and intravenously dripped.
  • paclitaxel add to 90 g of polyethylene glycol 400, dissolve at 90 ° C with stirring, and obtain paclitaxel solution; weigh 1.2 g of disodium edetate, and dissolve it with 10 g of water for injection.
  • Chelating agent solution; chelating agent solution and drug The solution was mixed well, and the volume was adjusted to 100 ml with polyethylene glycol 400; 0.8 g of the needle was added to the activated carbon, and the mixture was adsorbed at 30 ° C for 120 minutes, then filtered with a microporous membrane, dispensed, sealed, and rotated. The autoclave was sterilized at 121 °C for 8 minutes to obtain a paclitaxel solution.
  • Colostrum further emulsification of colostrum with a high-pressure homogenizer (pressure 22000 psi), constant volume to 1000 ml with water for injection, pH 8.00 with sodium hydroxide solution, filtration with a capsule filter, dispensing, nitrogen filling , Sealed, sterilized in a rotary autoclave at 115 °C for 30 minutes to obtain an emulsion. It was determined to have an average particle diameter of 284.2 nm and a pH of 7.64.
  • the above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged in a ratio of 1:1 by volume and packaged in the same large packaging container.
  • the drug solution and the emulsion are in a ratio of 1:20 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously dripped.
  • the above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:25 by volume ratio, shaken, and intravenously dripped.
  • the above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged in a ratio of 1:1 by volume and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:80 by volume ratio, shaken, and intravenously dripped.
  • the above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:90 by volume, shaken, and intravenously dripped.
  • emulsion 100 g of octanoic acid monoester, 50 g of fish oil, 50 g of sesame oil, 3.0 g of tocopherol and mixed, heated to 83 ° C in a water bath, stirred and mixed to obtain an oil phase; 700 ml of water for injection was added, and ethylenediaminetetraacetic acid was added.
  • the above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged in a ratio of 1:1 by volume and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:40 by volume, shaken, and intravenously dripped.
  • docetaxel solution add to a mixed solvent of 60 g of absolute ethanol, 20 g of polyethylene glycol 200, 10 g of propylene glycol, stir at 55 ° C with stirring, and then make up to 100 ml with absolute ethanol; Add 0.6 g of needle to activated carbon, adsorb at 50 °C for 50 minutes, then filter with a capsule filter, dispense, seal, and sterilize in a rotary autoclave at 121 °C for 15 minutes. Docetaxel solution.
  • the pH is adjusted with sodium hydroxide solution. It is 7.14, filtered with a capsule filter, subpacked, nitrogen-filled, sealed, and sterilized at 121 °C for 15 minutes in a rotary autoclave to obtain an emulsion. It was determined to have an average particle diameter of 134.5 nm and a pH of 6.40.
  • the above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:50 by volume, shaken, and intravenously dripped.
  • zedoary turmeric oil 90 grams of sunflower oil, 25 grams of citric acid monoglyceride, 25 grams of caprylic acid diglyceride, 0.5 grams of tocopherol and mix, heated to 60 ° C in a water bath, stirred and mixed to obtain an oil phase; Take 800 ml of water for injection, add 6 g of dipalmitoylphosphatidylcholine (DPPC), 4 g of distearoylphosphatidylcholine (DSPC), 25 g of glycerin, shear dispersion, and heat to 70 V to obtain aqueous phase.
  • DPPC dipalmitoylphosphatidylcholine
  • DSPC distearoylphosphatidylcholine
  • the oil phase and the aqueous phase were mixed at a temperature of 60 ° C, emulsified by a shear emulsifier for 6 minutes (rotation speed of 30,000 rpm) to obtain colostrum, and the colostrum was further emulsified by a high-pressure homogenizer (pressure 10000 psi).
  • a high-pressure homogenizer pressure 10000 psi.
  • Make up to 1000 ml with water for injection adjust the pH to 8.10 with sodium hydroxide solution, filter with microporous membrane, dispens, nitrogen, seal, and sterilize in a rotary autoclave at 115 °C for 30 minutes. , that is, get the emulsion. It was determined to have an average particle diameter of 250 nm and a pH of 7.46.
  • the above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged in a ratio of 1:1 by volume and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:90 by volume, shaken, and intravenously dripped.
  • caprylic acid diglyceride 30 g of elemene oil, 34 g of safflower seed oil, 36 g of caprylic triglyceride, 5.0 g of tocopherol, heated to 75 ° C in water bath, and added soybean lecithin 2.0 for injection.
  • DOPC dioleoylphosphatidylcholine
  • POPC palmitoyl oleoylphosphatidylcholine
  • the above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:80 by volume ratio, shaken, and intravenously dripped.
  • the above paclitaxel solution and the emulsion are respectively filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:30 by volume, shaken, and intravenously dripped.
  • caprylic acid triglyceride for injection 20 g of soybean oil, 30 g of ganoderma spore oil, heat to 70 ° C in a water bath, add 12 g of egg yolk phospholipid for injection, shear to dissolve, stir and mix, obtain oil
  • take 850 ml of water for injection add 22.5 g of glycerin, stir to dissolve, and heat to 75 ° C to obtain an aqueous phase; mix the oil phase and the aqueous phase at 75 ° C, and emulsify with a shear emulsifier for 10 minutes
  • the colostrum was obtained by a high pressure homogenizer (pressure 15000 psi), the volume was adjusted to 1000 ml with water for injection, and the pH was adjusted to 7.81 with sodium hydroxide solution.
  • Membrane filtration aliquoting, nitrogen filling, sealing, sterilization in a rotary autoclave at 121 °C for 10 minutes to obtain an emulsion. It was determined to have an average particle diameter of 208 nm and a pH of 7.15.
  • the above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:70 by volume ratio, shaken, and intravenously instilled.
  • the average particle diameter is 179 nm
  • the pH is such that the above paclitaxel solution and the emulsion are respectively filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of a volume ratio of 1:1, and packaged in the same Large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:50 by volume, shaken, and intravenously dripped.
  • the pH was adjusted to 6.50 with sodium hydroxide solution, filtered through a microporous membrane, and dispensed. Nitrogen, sealed, and sterilized by rotary autoclaving at 121 °C for 12 minutes to obtain an emulsion. It was determined to have an average particle diameter of 227 nm and a pH of 6.01.
  • the above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:60 by volume, shaken, and intravenously dripped.
  • the above paclitaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged in a ratio of 1:1 by volume and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:60 by volume, shaken, and intravenously dripped.
  • the above docetaxel solution and the emulsion are separately filled in a plastic bottle or a glass bottle, and the two drugs are packaged together in a ratio of 1:1 by volume, and packaged in the same large packaging container.
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:40 by volume, shaken, and intravenously dripped.
  • paclitaxel add to 90 g of polyethylene glycol 400, dissolve at 85 °C with stirring, and obtain paclitaxel solution; weigh 0.5 g of disodium edetate, and dissolve it with 10 g of water for injection.
  • a chelating agent solution mixing the chelating agent solution with the drug solution uniformly, and diluting to 100 ml with polyethylene glycol 400; adding 0.5 g of the needle to the activated carbon at a temperature of 25 ° C After adsorption for 45 minutes, it was filtered with a microporous membrane, dispensed, sealed, and sterilized by a rotary autoclave at 121 °C for 15 minutes to obtain a paclitaxel solution.
  • the ratio of the drug solution to the commercially available emulsion is 1:15, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • paclitaxel add to the appropriate amount of polyethylene glycol 400, heat and shear at 80 ° C to dissolve, weigh 0.5 g of disodium edetate, and dissolve it with 10 g of water for injection to obtain a chelating agent solution; Mix the chelating agent solution with the drug solution and make up to 100 ml with polyethylene glycol 400. Add 0.5 g of the needle to the activated carbon, adsorb at 45 ° C for 45 minutes, then filter with a microporous membrane. Packed, sealed, and sterilized in a rotary autoclave at 121 °C for 15 minutes to obtain a paclitaxel solution.
  • the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the ratio of the drug solution to the commercially available emulsion is 1:60, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • paclitaxel add to 90 g of polyethylene glycol 400, dissolve at 90 ° C with stirring, and obtain paclitaxel solution; weigh 1.0 g of disodium edetate, and dissolve it with 5 g of water for injection. a chelating agent solution; mixing the chelating agent solution with the drug solution uniformly, and diluting to 100 ml with polyethylene glycol 400; adding 0.5 g of the needle to the activated carbon, adsorbing at 25 ° C for 30 minutes, and then using microporous filtration The membrane was filtered, subpacked, and sealed, and sterilized by a rotary autoclave at 121 °C for 12 minutes to obtain a paclitaxel solution.
  • the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the ratio of the drug solution to the commercially available emulsion is 1:40, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the ratio of the drug solution to the commercially available emulsion is 1:25, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

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  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention a pour objet une solution pharmaceutique de taxanes, son procédé de préparation, une composition comprenant ladite solution et son emballage pharmaceutique combiné. Ladite solution pharmaceutique comprend des taxanes, un agent chélatant et un solvant.
PCT/CN2010/077998 2009-10-23 2010-10-22 Solution pharmaceutique de taxanes comprenant un agent chélatant et son procédé de préparation Ceased WO2011047639A1 (fr)

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CN200910070932.2A CN102038636B (zh) 2009-10-23 2009-10-23 一种含有螯合剂的紫杉烷类药物溶液及其制备方法

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CN110496103B (zh) * 2018-05-18 2022-05-10 上海维洱生物医药科技有限公司 一种多西他赛棕榈酸酯脂质体及其制备方法
CN112933137A (zh) * 2021-02-22 2021-06-11 青岛康地恩动物药业有限公司 一种牛至精油和胍基乙酸组成的纳米乳剂及其制备方法

Citations (3)

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Publication number Priority date Publication date Assignee Title
CN1228022A (zh) * 1996-06-28 1999-09-08 德克萨斯州立大学董事会 紫杉醇的非肠道稳定无毒制剂
CN1382038A (zh) * 1999-10-25 2002-11-27 苏伯俭股份有限公司 新的和改进的紫杉醇制剂
CN1535679A (zh) * 2003-04-04 2004-10-13 齐鲁制药厂 含有紫杉醇类物质的药物组合物及其制备方法

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US8557861B2 (en) * 2004-09-28 2013-10-15 Mast Therapeutics, Inc. Low oil emulsion compositions for delivering taxoids and other insoluble drugs
EP2205215A2 (fr) * 2007-10-01 2010-07-14 Intas Pharmaceuticals Limited Composition injectable de docetaxel, étant absolument dépourvue d'éthanol
CN101288642B (zh) * 2007-11-07 2011-04-27 天津天士力集团有限公司 一种紫杉烷类药物静脉给药制剂及其制备方法

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Publication number Priority date Publication date Assignee Title
CN1228022A (zh) * 1996-06-28 1999-09-08 德克萨斯州立大学董事会 紫杉醇的非肠道稳定无毒制剂
CN1382038A (zh) * 1999-10-25 2002-11-27 苏伯俭股份有限公司 新的和改进的紫杉醇制剂
CN1535679A (zh) * 2003-04-04 2004-10-13 齐鲁制药厂 含有紫杉醇类物质的药物组合物及其制备方法

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