WO2011047636A1 - Solution pharmaceutique de taxanes comprenant un solubilisant et procédé de préparation de celle-ci - Google Patents

Solution pharmaceutique de taxanes comprenant un solubilisant et procédé de préparation de celle-ci Download PDF

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WO2011047636A1
WO2011047636A1 PCT/CN2010/077995 CN2010077995W WO2011047636A1 WO 2011047636 A1 WO2011047636 A1 WO 2011047636A1 CN 2010077995 W CN2010077995 W CN 2010077995W WO 2011047636 A1 WO2011047636 A1 WO 2011047636A1
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emulsion
drug solution
solution
injection
preparation
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PCT/CN2010/077995
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Chinese (zh)
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陈建明
高保安
孙靖
邓莉
杨秋霞
刘薇
顾芃
张莹莹
张佳良
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天津天士力集团有限公司
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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
    • 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
    • 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
    • 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 containing a co-solvent and a preparation method thereof.
  • Taxanes include paclitaxel (trade name Taxol) and docetaxel (trade name Taxotem), two FDA-approved docetaxan anticancer drugs, which are both poorly water soluble. The drug is 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. The problem of dissolution of paclitaxel, but the injection contains polyoxyethylene castor oil which is easy to cause allergic reaction.
  • 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,
  • methyl acetamide can improve the solubility of the drug, it also increases the toxic side effects of the drug preparation.
  • the addition of dimethylacetamide increases the toxic side effects of the formulation.
  • 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. Brainwave changes and damage to the lungs, stomach, liver, kidneys, etc.
  • the pharmaceutical solvent part of the drug solution is mainly composed of polyethylene glycol 400 and oleic acid, RC Roche et al. [M].
  • the fourth edition of the original: 476) indicates that oleic acid can cause rupture of red blood cells, that is, hemolysis, and is only allowed in non-injectables in the United Kingdom.
  • Hu Yufang's "Concentrated emulsifier containing paclitaxel compound and its use method” contains a surfactant such as Tween-80, povidone, lecithin and the like in the drug solution portion. These surfactants have certain hemolytic and irritating properties, and the drug solution is dispersed in the emulsion for a short period of time.
  • Lactic acid is widely distributed in the body as a product of anaerobic metabolism of sugar. Luo Mingsheng et al (Chinese Pharmaceutical Excipients [M]. 2006, 1st edition: 740) Studies have shown that lactic acid can be used as a cosolvent in pharmaceuticals. This product is non-toxic, GRAS, ADI has no restrictions (FDA, 184.1061.1985), has been used in China's listed injection preparations, is a safe and non-toxic pharmaceutical excipients. Since the solvent for injection such as polyethylene glycol 400 or propylene glycol has a certain viscosity, the water-insoluble drug such as paclitaxel or docetaxel has a long dissolution time therein.
  • the present invention employs lactic acid as a co-solvent to overcome the toxic side effects of existing cosolvents such as dimethylacetamide, oleic acid and Tween-80.
  • Lactic acid makes dissolution easier, which is beneficial to industrial production and avoids the occurrence of by-products when the drug is heated for too long.
  • the addition of lactic acid significantly prolongs the stabilization time of the drug solution dispersed in the emulsion, and overcomes the problem that the drug solution is dispersed in the emulsion in the dispersion without lactic acid, further improving the safety of the clinical drug. And effectiveness.
  • the invention provides a taxane-like pharmaceutical composition, which is prepared from a taxane drug solution and an emulsion two-part agent, wherein the drug solution contains a co-solvent.
  • the preparation is to mix the drug solution and the emulsion in a ratio of a volume ratio of 1:10 to 100, preferably in a ratio of the ratio of 1:20 to 1:50, and most preferably a ratio of 1:25.
  • composition of the present invention exhibits strong stability after being mixed with an emulsion for injection because a co-solvent is added to the taxane solution before preparation.
  • the present invention provides a taxane drug solution containing a taxane drug, a co-solvent 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: isotonicity adjusting agent, surfactant, pH adjusting agent, chelating agent, etc., whether or not to add these medicinal excipients depends on the yew The nature of alkanes, cosolvents and solvents.
  • the taxane is any taxane, preferably a yew that has been marketed Alcohol or docetaxel.
  • the co-solvent is lactic acid.
  • the solvent is selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, propylene glycol, glycerin, absolute ethanol, and water for injection.
  • polyethylene glycol 400 is preferred.
  • the present invention also encompasses a process for the preparation of a solution of the present invention comprising the steps of dissolving a taxane-based drug and a co-solvent in a solvent, optionally adding other pharmaceutically acceptable excipients.
  • the preparation method of the present invention comprises the steps of: weighing paclitaxel or docetaxel, a co-solvent 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 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, capric acid triglyceride Ester, caprylic acid monoglyceride, coix seed oil, brucea oil, artemisin oil, caprylic acid diglyceride, soybean oil, fish oil, linseed oil, sunflower oil, evening primrose oil, sea buckthorn oil, zedoary oil A mixture of one or more of 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 milliliter of emulsion.
  • a preferred injectable oil is 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.
  • Preferred is glycerol.
  • 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 emulsion for intravenous injection of the present invention is a conventional conventional technique, such as mixing oil for injection and antioxidant, heating to 50-90 ° C, adding an emulsifier, stirring or shearing to dissolve the emulsifier, and obtaining an oil.
  • the isotonicity adjusting agent and the stabilizer are added to an appropriate amount of water for injection, heated to 50-90 ° C and stirred to obtain an aqueous phase; the oil phase and the aqueous phase are mixed at a temperature of 50-90 ° C, and emulsified by shearing.
  • 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 carried out by a sterilization method such as 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 microporous membrane, a sand filter, a funnel or a capsule.
  • the final emulsion is a white or off-white emulsion containing opalescence with 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.
  • Example 1 Taking the preparation method and the preparation amount of the drug solution described in Example 1 as an example, the time required for the dissolution of paclitaxel in the polyethylene glycol 400 when lactic acid was added and no lactic acid was added was compared, and the results are shown in Table 1.
  • the lactic acid-containing drug solution is prepared to obtain a test drug solution; according to the embodiment described in the embodiment 1, the co-solvent lactic acid is removed, and the lactic acid-free drug solution is prepared to obtain a control drug solution; 4 ml of each of the above test drug solution and the control drug solution was aspirated, and dispersed in 100 ml of the self-made emulsion described in Example 1, and shaken to obtain a test sample.
  • the content and particle diameter of the dispersion at different time points were measured by high performance liquid chromatography and particle size analyzer. When measuring the content, a proper amount of the dispersion was firstly extracted by a syringe through a microfiltration membrane of 0.45 ⁇ m.
  • the content of the drug in the filtrate is calculated as the percentage of the label, and the content is used to evaluate whether the drug precipitates crystallize; the particle size is directly determined; the appearance is observed by the naked eye, and the results are shown in Table 2 and Table 3.
  • Table 2 The stability of the dispersion before the administration of the lactic acid-containing paclitaxel injection represented by Example 1 (dispersed emulsion is a self-made emulsion)
  • Example 3 Stability of the dispersion before the administration of the lactic acid-free paclitaxel injection represented by Example 1 (dispersion emulsion is a self-made emulsion)
  • the lactic acid-containing dispersion has a stabilization time of up to 9 days without the lactic acid-containing and lactic acid-free paclitaxel injection prepared in the same manner as in Example 1, without The lactic acid-containing dispersion has a stabilization time of about 3 days. From the apparent point of view, the dispersion containing the co-solvent lactic acid has no oil floating phenomenon within 9 days, which is superior, and the lactic acid-free dispersion has more oil, and As time goes on, the floating 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 results showed that the paclitaxel injection containing the co-solvent lactic acid had a remarkable effect, and the advantage was that the stability of the dispersion of the paclitaxel injection without lactic acid was remarkably improved, and the shortage of the dispersion oil was unexpectedly overcome. Therefore, it has been revealed that the lactic acid containing the co-solvent is a feature of the present invention having substantially excellent effects.
  • a lactic acid-containing drug solution is prepared to obtain a test drug solution;
  • the solvent lactic acid is removed, and the drug solution containing no lactic acid is prepared to obtain a control drug solution; 4 ml of each of the test drug solution and the control drug solution are aspirated, and 100 ml of the self-made emulsion described in Example 2 are separately dispersed.
  • the content and particle diameter of the dispersion at different time points were measured by high performance liquid chromatography and particle size analyzer.
  • a proper amount of the dispersion was firstly extracted by a syringe through a microfiltration membrane of 0.45 ⁇ m.
  • the content of the drug in the filtrate was calculated as the percentage of the label, and the content was used to evaluate whether the drug precipitated crystals; the particle size was directly determined; the appearance was observed with the naked eye, and the results are shown in Table 4 and Table 5.
  • Table 4 The stability of the dispersion before the administration of the lactic acid-containing docetaxel injection represented by Example 2 (the dispersion emulsion is a self-made emulsion)
  • the lactic acid-containing dispersion liquid was stable for up to 20 days without The dispersion time of the dispersion containing the co-solvent lactic acid is about 3 days; from the apparent point of view, the dispersion containing the co-solvent lactic acid has no oil floating phenomenon within 20 days, and the appearance is good, and the oil containing no co-solvent lactic acid is more And with the extension of time, the floating oil gradually increases, 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 stability comparison test of the present invention containing the co-solvent lactic acid and the dimethylacetamide-containing patent embodiment is shown in the patent (Chinese Patent: 97196934.5), and the patent is mainly added on the basis of polyethylene glycol 400.
  • Dimethylacetamide has a ratio of 1:3 to polyethylene glycol 400 and a drug loading of 25 mg/ml.
  • the drug solution is prepared as a control solution; the drug solution is prepared according to the embodiment described in Example 14 to obtain a test solution; 4 ml of the above control solution and the test solution are separately aspirated, and dispersed in the same manner as in Example 14 In a 100 ml commercial emulsion, shake it to obtain a test sample.
  • the drug content of the dispersion at different time points was determined by high performance liquid chromatography.
  • the results are shown in Table 6.
  • the preparation of the present invention has no oil floating phenomenon within 24 hours; the control preparation has more oil.
  • the dispersion of the injection of the present invention containing the cosolvent lactic acid has a stabilization time of up to 24 hours, and the dispersion time of the dispersion containing the sample of the dimethylacetamide control preparation is stable. Less than 6 hours; from the apparent point of view, the dispersion of the present invention has no oil floating phenomenon, and the dispersion of dimethylacetamide added is more serious, and there is a large amount of oil stains hanging on the wall.
  • the addition of the cosolvent lactic acid 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 lactic acid containing the co-solvent is a feature of the present invention having substantially excellent effects.
  • the drug content of the dispersion at different time points was determined by high performance liquid chromatography.
  • the dispersion of the inventive injection containing the co-solvent lactic acid has a stabilization time of up to 24 hours, and the dispersion of the oleic acid-containing series of control preparations has a stabilization time of less than 6 hours.
  • 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 series of oleic acid-containing control
  • the dispersion of the preparation preparation is more serious, and there is a large amount of oil stains hanging on the wall.
  • the addition of the cosolvent lactic acid unexpectedly solved the problem. It can be seen that the formulation scheme of the present invention has significant advantages and unexpected effects compared with the control patent.
  • the drug solution was prepared as a control solution; the drug solution of paclitaxel was prepared according to the embodiment described in Example 14 to obtain a test solution; 4 ml of the above control solution and the test solution were separately aspirated, respectively, and dispersed in Example 14 In 100 ml of the commercially available emulsion, shake it to obtain a test sample.
  • the drug content of the dispersion at different time points was determined by high performance liquid chromatography.
  • the preparation of the present invention has no oil floating phenomenon within 24 hours; the control preparation has more oil.
  • the dispersion of the inventive injection containing the co-solvent lactic acid has a stabilization time of more than 24 hours, and the dispersion time of the dispersion containing the surfactant control preparation is less than 8 hours; From the apparent point of view, the dispersion of the present invention has no oil floating phenomenon, and the dispersion of the control patent preparation containing the surfactant is more serious, and there is a large amount of oil stains hanging on the wall.
  • the addition of the cosolvent lactic acid unexpectedly solved the problem. It can be seen that the formulation of the present invention has significant advantages and unexpected effects compared to the control patent.
  • 1Safety Does not contain any toxic co-solvent, such as polyoxyethylene castor oil, Tween-80, dimethylacetamide, oleic acid, povidone, etc., so the side effects are correspondingly reduced; Oxyethylene castor oil and Tween-80 have severe hemolysis and allergic reactions, and are less safe; dimethylacetamide mice are given LD 5 orally. It is 4.620 g/kg, and the preferred injectable solvent of the present invention is polyethylene glycol 400, which is non-toxic and non-irritating, and its mouse is orally administered with LD 5 . Up to 28.9g/kg, LD 5 year-on-year.
  • any toxic co-solvent such as polyoxyethylene castor oil, Tween-80, dimethylacetamide, oleic acid, povidone, etc.
  • Membrane filtration aliquoting, nitrogen filling, sealing, sterilization in a rotary autoclave at 121 °C for 15 minutes to obtain an emulsion. It was determined to have an average particle diameter of 139 nm and a pH of 6.78.
  • 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 paclitaxel solution and the medicinal emulsion are dispersed in the emulsion in a ratio of 1:25 by volume, shaken, and intravenously instilled; the drug solution may be first added to the emulsion, and then a predetermined amount of physiologically added A saline or glucose solution is used for the injection.
  • 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 instilled.
  • 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 1:50 by volume, shaken, and intravenously dripped.
  • the colostrum is further emulsified by a high-pressure homogenizer (pressure 25000 psi), and the volume is adjusted to 1000 ml with water for injection.
  • the pH is adjusted with sodium hydroxide. It is 8.11, filtered with a sand filter, subpacked, nitrogen-filled, sealed, and sterilized by circulating steam at 100 ° C for 45 minutes to obtain an emulsion. It was determined to have an average particle diameter of 300.8 nm and a pH of 7.48.
  • 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 in a ratio of 1:40 by volume, the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the oil phase and the aqueous phase were mixed at 60 ° C, emulsified by a shear emulsifier for 15 minutes (rotation speed 22000 rpm) to obtain colostrum; the colostrum was further emulsified by a high pressure homogenizer (pressure 12000 psi), Make up to 1000 ml of water for injection, adjust the pH to 6.58 with sodium hydroxide solution, filter with a fused funnel, dispense, fill with nitrogen, seal, and sterilize in a rotary autoclave at 121 °C for 15 minutes. Get an emulsion. It was determined to have an average particle diameter of 224 nm and a pH of 6.10.
  • 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 1:100 by volume, and shaken. Intravenous drip, just fine.
  • paclitaxel 0.05 g of lactic acid
  • the needle was adsorbed by activated carbon at a temperature of 45 ° C for 110 minutes, then filtered through a funnel, packed, sealed, and sterilized by circulating steam at 100 ° C for 45 minutes to obtain a paclitaxel solution containing a cosolvent.
  • soybean oil 100 grams of soybean oil, 50 grams of coix seed oil, 50 grams of Brucea javanica oil, 0.5 g of tocopherol, mixed in a water bath to 90 V, stirred and mixed to obtain an oil phase; 720 ml of water for injection, 6 g of egg yolk phospholipid 22.5 g of glycerin, shear-dispersed, heated to 90 ° C to obtain an aqueous phase; the oil phase and the aqueous phase were mixed at a temperature of 90 ° C, and emulsified by a shear emulsifier for 25 minutes (speed 7000 rpm).
  • Colostrum further emulsification of colostrum with a high-pressure homogenizer (pressure 9000 psi), constant volume to 1000 ml with water for injection, pH 8.88 with sodium hydroxide solution, filtration with microporous membrane, partitioning, 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 234.2 nm and a pH of 8.11.
  • 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 1:10 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 1:15 by volume, shaken, and intravenously instilled.
  • 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 1:100 by volume, shaken, and intravenously instilled.
  • citric acid diglyceride 10 grams of corn oil, 30 grams of caprylic acid monoglyceride, 20 grams of safflower seed oil, 10 grams of fish oil, 80 grams of sesame oil, heated to 50 ° C in a water bath, and added egg yolk for injection.
  • 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 100 g of soybean oil, heat to 70 ° C in a water bath, add 20 g of soy lecithin for injection, shear to dissolve, stir and mix to obtain oil phase; 750 ml, adding 22.5 g of glycerin, stirring to dissolve, heating to 70 ° C to obtain an aqueous phase; mixing the oil phase and the aqueous phase at 70 ° C, and emulsifying with a shear emulsifier for 20 minutes (speed 10,000 rpm) Get colostrum; further emulsification of colostrum with high pressure homogenizer (pressure 15000 psi), make up to 1000 ml with water for injection, adjust the pH to 7.05 with sodium hydroxide solution, filter with microporous membrane, dispense, Nitrogen, seal, and sterilize in a rotary autoclave at 121 °C for 15 minutes to obtain an emulsion. It was determined to have an average particle
  • the drug solution and the emulsion are dispersed in the emulsion in a ratio of 1:70 by volume ratio, shaken, and intravenously instilled.
  • caprylic acid triglyceride for injection 150 g of soybean oil, heat to 90 ° C in a water bath, add 12 g of soybean phospholipid for injection, shear to dissolve, stir and mix to obtain oil phase; 650 ml, adding 22.5 g of glycerin, stirring to dissolve, heating to 75 ° C to obtain an aqueous phase; mixing the oil phase and the aqueous phase at 90 ° C, and emulsifying with a shear emulsifier for 15 minutes (speed 10,000 rpm)
  • the colostrum is further emulsified by a high-pressure homogenizer (pressure 7000 psi), adjusted to 1000 ml with water for injection, and adjusted to pH 7.30 with sodium hydroxide solution, filtered through a microporous membrane, and dispensed.
  • 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.
  • caprylic acid triglyceride for injection 150 g of soybean oil, heat to 70 ° C in a water bath, add 10 g of egg yolk phospholipid for injection, shear to dissolve, stir and mix to obtain oil phase; 650 ml, adding 2 g of distearoylphosphatidylcholine (DSPC), 22.5 g of glycerin, stirring to dissolve, heating to 70 ° C to obtain an aqueous phase; mixing the oil phase and the aqueous phase at 70 ° C, using The shearing emulsifier is emulsified for 15 minutes (speed: 10,000 rpm) to obtain colostrum; the colostrum is further emulsified by a high-pressure homogenizer (pressure 10000 psi), and the volume is adjusted to 1000 ml with water for injection, and the solution is adjusted with sodium hydroxide solution.
  • a high-pressure homogenizer pressure 10000 psi
  • the pH was 8.02, filtered with a capsule filter, subpacked, nitrogen-filled, sealed, and sterilized by a rotary autoclave at 121 °C for 12 minutes to obtain an emulsion. It was measured to have an average particle diameter of 402 nm and a pH of 7.35.
  • 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 1:50 by volume, shaken, and intravenously dripped.
  • paclitaxel 0.5 g of lactic acid
  • polyethylene glycol 400 heat and shear at 80 ° C
  • dilute to 100 ml with polyethylene glycol 400 add 0.2 g of needle with activated carbon
  • the solution was adsorbed for 30 minutes at a temperature of 25 ° C, then filtered through a microporous membrane, dispensed, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes to obtain a paclitaxel solution containing a cosolvent.
  • the drug solution and the commercially available emulsion are in a ratio of 1:25 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • Preparation of drug solution Weigh 4.0 g of paclitaxel and 0.3 g of lactic acid, add to the appropriate amount of polyethylene glycol 400, heat and shear at 90 ° C, then dilute to 100 ml with polyethylene glycol 400; add 0.15 g of needle with activated carbon, After adsorption at a temperature of 25 ° C for 45 minutes, it was filtered with a capsule filter, dispensed, sealed, and sterilized by a rotary autoclave at 121 ° C for 15 minutes to obtain a paclitaxel solution containing a cosolvent.
  • the drug solution and the commercially available emulsion are in a ratio of 1:45 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the drug solution and the commercially available emulsion are in a ratio of 1:80 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the drug solution and the commercially available emulsion are in a ratio of 1:70 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the drug solution and the commercially available emulsion are in a ratio of 1:25 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the drug solution and the commercially available emulsion are in a ratio of 1:25 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the drug solution and the commercially available emulsion are in a ratio of 1:25 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the drug solution and the commercially available emulsion are in a ratio of 1:60 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the drug solution and the commercially available emulsion are in a ratio of 1:70 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the drug solution and the commercially available emulsion are in a ratio of 1:100 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.
  • the drug solution and the commercially available emulsion are in a ratio of 1:10 by volume, and the drug solution is dispersed in the emulsion, shaken, and intravenously instilled.

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

Abstract

La présente invention concerne une solution pharmaceutique de taxanes, son procédé de préparation, une composition comprenant ladite solution et son emballage de combinaison pharmaceutique. Ladite solution pharmaceutique comprend des taxanes, un solubilisant et un solvant, où le solubilisant est l'acide lactique.
PCT/CN2010/077995 2009-10-23 2010-10-22 Solution pharmaceutique de taxanes comprenant un solubilisant et procédé de préparation de celle-ci WO2011047636A1 (fr)

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CN200910070930.3A CN102038634B (zh) 2009-10-23 2009-10-23 一种含有助溶剂的紫杉烷类药物溶液及其制备方法

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Citations (3)

* Cited by examiner, † Cited by third party
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

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1771932A (zh) * 2005-11-04 2006-05-17 张伟 低含量聚氧乙烯醚蓖麻油和低含量乙醇的紫杉醇静脉注射溶液剂
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
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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