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WO2011113301A1 - Formulation de taxanes auto-émulsifiante et procédé de préparation associé - Google Patents

Formulation de taxanes auto-émulsifiante et procédé de préparation associé Download PDF

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Publication number
WO2011113301A1
WO2011113301A1 PCT/CN2011/000398 CN2011000398W WO2011113301A1 WO 2011113301 A1 WO2011113301 A1 WO 2011113301A1 CN 2011000398 W CN2011000398 W CN 2011000398W WO 2011113301 A1 WO2011113301 A1 WO 2011113301A1
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Prior art keywords
oil
pharmaceutical composition
paclitaxel
composition according
lecithin
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Ceased
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PCT/CN2011/000398
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English (en)
Chinese (zh)
Inventor
王国强
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BEIJING YINGU CENTURY PHARMACY CO Ltd
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BEIJING YINGU CENTURY PHARMACY CO Ltd
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Publication of WO2011113301A1 publication Critical patent/WO2011113301A1/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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a self-emulsifying pharmaceutical composition of a taxane compound, and more particularly to a docetaxel self-emulsifying pharmaceutical composition which can be administered intravenously.
  • Taxanes a class of taxoids and molecularly similar isomers of taxoids, isoforms, analogs and derivatives of taxoids, are currently used for the treatment of metastatic ovarian cancer, lung cancer, esophagus First-line treatment for cancer, including paclitaxel, docetaxel, erythromycin, erythromycin diacetate, paclitaxel B, etc.
  • paclitaxel the most commonly used taxanes in the clinic are paclitaxel and docetaxel. Paclitaxel.
  • Paclitaxel has the structure of formula I, is a white crystalline powder, odorless, tasteless, its English name is Paclitaxel or Taxol, and its molecular formula is C 47 H 51 N0 14 , molecule
  • Docetaxel is a semi-synthetic taxane, also known as taxotere, docetaxel, English name Docetaxel or Taxotere, molecular formula C 43 H 53 N0 14 , white powder, insoluble in water, soluble In methylene chloride, methanol, with the structure of formula II:
  • paclitaxel injection is a colorless, transparent or slightly yellow viscous solution containing 6 mg of paclitaxel, 527 mg of polyoxyethylene castor oil (or polyoxyethylated castor oil, per gram of paclitaxel injection, Cremophor).
  • EL polyoxyethylene castor oil
  • Cremophor polyoxyethylated castor oil
  • EL 49.7% absolute ethanol
  • the problems of the preparation are mainly: 1
  • the toxicity and sensitization of the solvent cause a high proportion of allergic reactions, including bronchospasm caused by allergic reaction caused by the auxiliary polyoxyethylene castor oil. Shortness of breath, fatigue, hypotension, etc.
  • Paclitaxel injection is unstable after dilution: When the preparation is diluted, if it exceeds 24 h, a granular precipitate will appear, and the analysis indicates that the precipitate is not paclitaxel, so a filter is used in the infusion set during intravenous drip.
  • 3 compatibility changes 60 commonly used drugs in combination with paclitaxel injection can cause infusion turbidity, some drugs and paclitaxel competition with plasma protein will increase toxicity. 4 severe pain at the injection site, severe or potential permanent damage at the injection site or surrounding blood vessels.
  • paclitaxel injection in order to prevent the above adverse reactions, oral dexamethasone was given 12 hours and 6 hours before the paclitaxel injection treatment, diphenhydramine was administered 30 to 60 minutes before the treatment, and cimetidine was given intravenously. 300mg or ranitidine 50mg.
  • the single dose of paclitaxel injection is controlled to 135 ⁇ 200mg/m 2 , and the dose can reach 250mg/m 2 with the support of granulocyte colony stimulating factor, and the paclitaxel injection is diluted to the final concentration with normal saline or 5% glucose saline.
  • the skilled person has carried out extensive research on the adverse reactions caused by polyoxyethylene castor oil, increasing the solubility and stability of paclitaxel, reducing toxicity, and increasing bioavailability for many years.
  • the methods tried include prodrug method, emulsification method, and preparation of micelles, liposomes, nanoparticles, microemulsions, microspheres, cyclodextrin inclusion compounds, and topical administration, among which promising Paclitaxel is made into microemulsion.
  • the current paclitaxel microemulsion is still in the laboratory stage, and some have strict requirements on the production machinery and equipment, especially the need for high pressure emulsification, or the need for high temperature emulsification, or the need for high speed stirring emulsification, this method is complicated, high cost It is not conducive to industrial production, and the prepared emulsion has poor stability and cannot meet clinical needs.
  • WO2006037089 discloses a paclitaxel emulsion comprising paclitaxel, vegetable oil, medium chain triglyceride, glycerin, phospholipid, water, etc., however, it requires a high shear mixer to be stirred during preparation, and then at 18,000-23000 psi.
  • the microfluidizer homogenizer is operated 5 times under the operating pressure, and the process cost is high, and industrial production cannot be performed.
  • Chinese patent application CN101450040A also discloses a taxane emulsion containing paclitaxel, PEG-(CH 2 ) n-cholesterol, soybean oil, oleic acid, poloxamer, glycerin, phospholipid and water, in preparation,
  • the colostrum needs to be stirred at a high speed at 50 ° C - 80 ° C, then transferred to a high pressure milk homogenizer, repeatedly emulsified to a droplet of an average particle size of 1 ⁇ m, and the production process needs to be filled with nitrogen for protection.
  • the preparation method of the emulsion is also complicated, and industrial production is difficult.
  • Chinese patent application CN100341485C discloses a self-emulsifying preconcentrate of paclitaxel, which is composed of a surfactant such as paclitaxel, polyoxyethylene castor oil, an oil phase such as medium chain triglyceride, ethanol or propylene glycol, however, the technology implemented therefrom It can be seen that the product prepared is unstable after forming an emulsion, and therefore can only be administered orally and cannot be administered to a patient in the form of intravenous injection.
  • a surfactant such as paclitaxel, polyoxyethylene castor oil
  • an oil phase such as medium chain triglyceride, ethanol or propylene glycol
  • Chinese patent application CN1822859A also discloses a self-emulsifying preparation of paclitaxel, which comprises paclitaxel, POE hydrogen Castor oil, medium chain triglyceride and co-surfactant, wherein the co-surfactant is glycerol monooleate, PG monolaurate or the like.
  • the formulation cannot be stabilized for a long period of time after the addition of water to form an emulsion, and therefore it can only be administered orally and cannot be used as an intravenous product.
  • Chinese patent application CN1602854A discloses a self-emulsifying preparation comprising paclitaxel, Cremophor EL, Pluronic F68, phospholipid, soybean oil and ethanol, which can be self-emulsified after being added to glucose injection. An emulsion is formed. However, after the emulsion is formed, the stabilization time is not long, paclitaxel is easily precipitated from the solution, affecting clinical use, and since the amount of the surfactant is large, the irritation is still large when used.
  • the inventors of the present invention have developed a delivery system of docetaxan compounds through repeated experiments under the circumstance of a lot of creative labor.
  • the preparation is a clear liquid, simple to prepare, easy to industrialize, and the preparation is added to the water. Thereafter, the emulsion can be self-emulsified, and the formed emulsion can be kept stable for a long period of time, and can be safely and conveniently used in the clinic, thereby completing the present invention.
  • the composition of the present invention has the following advantages: (1) for clinical injectable use; (2) the formed emulsion can be used directly and maintains stability of >24 hours; (3) can be filtered and sterilized; 4)
  • the ingredients used are all the components for intravenous injection allowed by FSDA; (5)
  • the production process is simple, no high-speed shearing device is adopted, and it is easy to industrialize production; (6) It does not stimulate blood vessels; (7) Hypoallergenicity (8) no hemolysis; (9) adverse reactions are lower than existing paclitaxel preparations.
  • the present invention provides a pharmaceutical composition for delivering a taxane drug, which is a self-emulsifying preparation comprising an effective amount of a taxane compound, an oil component, a surfactant, and Ethanol, wherein the surfactant is a combination of a phospholipid and a polyoxyethylene castor oil (Cremophor EL).
  • a taxane drug which is a self-emulsifying preparation comprising an effective amount of a taxane compound, an oil component, a surfactant, and Ethanol, wherein the surfactant is a combination of a phospholipid and a polyoxyethylene castor oil (Cremophor EL).
  • the weight ratio of the taxane compound, the oil component, the phospholipid and the polyoxyethylene castor oil is within a certain range, so as to achieve the technical effect described in the present application, otherwise, after the emulsification, the microemulsion The stability is poor, and it is difficult to satisfy the effect of clinical use.
  • the weight ratio of the taxane compound, the oil component, the phospholipid to the polyoxyethylene castor oil is 1:3-10:30-80:20-50, preferably 1:3-8:30-50:20-40, particularly preferably 1: 4-6: 35-45: 25-30.
  • the taxane compound of the present invention encompasses isomers, analogs or derivatives of taxoid drugs or taxane drugs, including but not limited to paclitaxel, docetaxel, paclitaxel, taxane , snake chrysanthemum, cedarol, paclitaxel-2,13-dione, 5 ⁇ , 9 ⁇ , 10 ⁇ -trihydroxy-cyclo-9,10-acetal with acetone or acetate, paclitaxel-2 ,13-dione, 5 ⁇ ,9 ⁇ ,] 0 ⁇ -trihydroxy-cyclo-9, 10-acetal with acetone or acetate, paclitaxel-2 ⁇ , 15 ⁇ , 9 ⁇ , 10 ⁇ -tetraol -cyclo- 9,10-acetal with acetone or acetate, hydrazine-debenzoyl valerate, paclitaxel, cephalosporin-7-xyloside, 7-
  • paclitaxel B cyclic paclitaxel, 10-deacetyl-7-cyclopaclavin, 0-deacetylpaclitaxel, 10-deacetylpacificol 8 Or, 7-xylose-10-deacetylpaclitaxel and 10-deacetylpaclitaxel-7-xyloside.
  • preferred docetaxel compounds of the present invention are paclitaxel and docetaxel, and most preferably paclitaxel.
  • compositions have suitable viscosities and can be conveniently packaged for clinical use.
  • the composition of the present invention is added to a glucose injection solution to form a microemulsion by self-emulsification, and the microemulsion has a particle diameter of In-100 nm, preferably has a particle diameter of 10 to 800 nm, more preferably 50.
  • the particle size of -500 nm, most preferably having a particle size of 50-300 nm can be directly used for patient administration.
  • the formed microemulsion can be precipitated without precipitation at room temperature, and is stable for 8 hours or more, preferably for 12 hours or more, more preferably for 18 hours or more, most preferably for 24 hours or more, and particularly preferably for 30 hours or more.
  • the oil component of the present invention may be selected from pharmaceutically conventional oil phase ingredients including, but not limited to, monoglycerides, diglycerides, triglycerides, or mixtures thereof.
  • the oil component is a "vegetable oil.”
  • the vegetable oil is an oil derived from plant seeds or nuts. Vegetable oils are usually "long-chain triglycerides" which consist of tri-fatty acids (typically from about 14 to about 22 carbons in length, depending on the source of the oil, with different numbers and positions of unsaturated bonds) and three on glycerol. The hydroxyl group is formed by forming an ester bond.
  • Vegetable oils include, but are not limited to, soybean oil, almond oil, borage oil, blackcurrant seed oil, castor oil, corn oil, safflower oil, sesame oil, cottonseed oil, peanut oil, olive oil, rapeseed oil, cocoa butter, palm oil , canola oil, linseed oil, tea oil, safflower oil, cottonseed oil, evening primrose oil, etc., preferably soybean oil.
  • high purity vegetable oils are typically used to ensure the safety and stability of the formulation.
  • hydrogenated vegetable oils can also be used, which are prepared by controlled hydrogenation of vegetable oils.
  • the oil refers to "medium chain triglycerides”.
  • Medium chain triglycerides are another type of triglyceride oil, which may be natural or synthetic, made from fatty acids typically having a length of from about 8 to about 2 carbons.
  • MCT's have been widely used in emulsions designed for injection as a source of calories for patients requiring parenteral nutrition.
  • oils are commercially available, such as Miglyol 210 and Miglyol 812, CRODAMOL GTCC-PN, Neobees M-5 oil, and the like.
  • the oil component can also be an oil from an animal. It also includes triglycerides, but the length of its three fatty acid chains differs from the unsaturated bonds in it and vegetable oils.
  • the animal fat obtained from solid oil sources at room temperature eg, butter, lard, etc.
  • Other forms of animal fat which are liquid at room temperature include various fish oils, for example, ordinary fish oil, salmon oil, salmon oil or tuna oil, and the like.
  • the phospholipid in the present invention may be a phospholipid or a mixture of two or more phospholipids.
  • the phospholipid refers to a triglyceride having two fatty acids and one phosphate ion.
  • Phospholipids useful in the present invention include, but are not limited to, lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, having from about 4 to about 22 carbon atoms, and more typically from about 10 to about 18 carbon atoms. And different degrees of saturation of phosphatidic acid.
  • the phospholipids useful in the present invention may be phospholipids of natural origin.
  • Naturally occurring phospholipids include soy lecithin, egg Phospholipids, hydrogenated soy lecithin, hydrogenated egg lecithin, sphingosine, gangliosides and phytosphingosine, and combinations thereof.
  • Natural lecithin is a mixture of choline esters of stearic acid, palmitic acid and oleic acid linked to phosphoric acid, commonly known as phosphatidylcholine, and is available from a variety of sources, such as eggs and soy beans.
  • Soy lecithin and egg lecithin have a long history of safety, have comprehensive emulsification and solubility characteristics, and are more likely to disintegrate into harmless substances faster than most synthetic surfactants. Products are commercially available.
  • a preferred phospholipid of the invention is egg lecithin.
  • the phospholipid may also be a synthetic phospholipid, including but not limited to: diglycerides, such as 1, 2. Dilauroyl-sn-glycerol (DLG), 1 , 2- 2 S Decanoyl-sn-glycerol (DMG), 1,2-dipalmitoyl-sn-glycerol (DPG), 1,2-distearoyl-s-glycerol (DSG); phosphatidic acid, such as 1, 2- Decanoyl-sn-glycerol-3-phosphatidic acid, sodium salt (DMPA, Na), 1,2-dipalmitoyl-sn-glycerol-3-phosphatidic acid, sodium salt (DPPA, Na), 1, 2- Stearic-sn-glycerol-3-phosphatidic acid, sodium salt (DSPA, Na) ; phosphocholine, such as 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1, 2-S-decanoyl
  • DMG Dilau
  • the ethanol in the composition of the present invention acts to adjust the viscosity of the composition, making the composition easy to dispense and filter for sterilization.
  • the compositions of the present invention further comprise lactic acid.
  • the applicant has found through extensive experimental research that the addition of lactic acid to the composition of the present invention can not only be used to adjust the pH value, increase the stability of paclitaxel, reduce the degradation of paclitaxel and the production of related substances, and more importantly, in the system of the present invention.
  • the addition of lactic acid allows the composition to be stabilized for a longer period of time after the addition of the glucose injection to form an emulsion than the addition of other pharmaceutically acceptable acids, resulting in those skilled in the art. Unexpected effect.
  • the present invention also provides a pharmaceutical composition for delivering a docetaxel drug, which is a self-emulsifying formulation, comprising or consisting essentially of the following ingredients: an effective amount of a taxane compound An oil component, a surfactant, ethanol, and lactic acid, wherein the surfactant is a combination of a phospholipid and a polyoxyethylene castor oil.
  • a pharmaceutical composition for delivering a docetaxel drug which is a self-emulsifying formulation, comprising or consisting essentially of the following ingredients: an effective amount of a taxane compound An oil component, a surfactant, ethanol, and lactic acid, wherein the surfactant is a combination of a phospholipid and a polyoxyethylene castor oil.
  • the above pharmaceutical compositions have suitable viscosities and can be conveniently dispensed for clinical use.
  • the composition of the present invention is added to a glucose injection solution to form a microemulsion by self-emulsification, the microemulsion having a particle size of In-100 nm, preferably having a particle diameter of 10 to 800 nm, more preferably 50.
  • the particle size of -500 nm, most preferably having a particle size of 50-300 nm, can be directly used for patient injection administration.
  • the pharmaceutical composition containing the taxane compound, the oil component, the phospholipid, the polyoxyethylene castor oil, the ethanol and the lactic acid provided by the invention has excellent stability after forming the microemulsion, and can be used at room temperature.
  • the precipitate precipitates and remains stable for 12 hours or more, preferably for 18 hours or more, more preferably for 24 hours or more, and most preferably for 30 hours or more, far exceeding the formulation formed using other organic or inorganic acids, which is greatly advantageous for clinical use.
  • the weight ratio of the taxane compound, the oil component, the phospholipid to the polyoxyethylene castor oil is 1:3-10:30-80:20-50, preferably 1:3-8:30- 50: 20-40, particularly preferably 1: 4-6: 35-45: 25-30.
  • the taxane compound is preferably paclitaxel and docetaxel, most preferably paclitaxel.
  • the self-emulsifying composition of the taxane compound of the present invention comprises or consists of the following components, wherein each component is in weight percent:
  • the self-emulsifying composition of the taxane compound of the present invention comprises or consists of the following components, wherein each component is in a percentage by weight - a taxane compound 0.1 to 1%
  • the self-emulsifying composition of the taxane compound of the present invention comprises or consists of the following components, wherein each component is in weight percent:
  • Taxane compound 0.1 ⁇ 1% Soybean oil 2 to 3%
  • the taxane compound is preferably paclitaxel and docetaxel, most preferably paclitaxel.
  • the compositions of the present invention may further comprise other suitable pharmaceutically acceptable excipients including, but not limited to, acidification, alkalizing, buffering, chelating, complexing and stabilizing agents, antioxidants, and antimicrobial properties. Preservatives, suspending and / or viscosity modifiers, and other biocompatible substances or therapeutic agents.
  • the stabilizer may be selected from one or more of glycerin, oleic acid, linoleic acid, sodium cholate, sodium deoxycholate, monoglyceryl stearate, ethyl oleate, ethyl linoleate.
  • the antioxidant includes one or more of ascorbyl palmitate, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT); the chelating agent includes but is not limited to EDTA, three One or more of an amine pentaacetic acid and a sulfite.
  • the paclitaxel self-microemulsion composition of the present invention can be prepared by injecting various media such as physiological saline or glucose into an injection, intravenous, subcutaneous, intramuscular, intrathecal, etc.; or can be further prepared into other types of liquid preparations. , solid preparations, suppositories, external preparations, or lyophilized preparations, and the like.
  • Specific dosage forms include, but are not limited to, injectable solutions, lyophilized powders, capsules, soft capsules, pills, emulsions, transdermal patches, and the like.
  • the present invention provides a microemulsion comprising an effective amount of a taxane compound, an oil component, a surfactant, an aqueous solution of ethanol and glucose, wherein the surfactant is a phospholipid and a polyoxyethylene castor oil. mixture.
  • the microemulsion of the invention further contains lactic acid.
  • the lactic acid contained in the emulsion of the present invention can be used not only to adjust the pH value, to increase the stability of the taxane compound, to reduce the degradation of the taxane compound and the production of related substances, and more importantly, with other pharmacies.
  • the addition of lactic acid stabilizes the microemulsion for a longer period of time than conventionally used acids, yielding unexpected effects to those skilled in the art.
  • the emulsion of the present invention can be precipitated without precipitation at room temperature, and is stable for 12 hours or more, preferably for 18 hours or more, more preferably for 24 hours or more, and most preferably for more than 30 hours, which is far more than that formed by using other organic or inorganic acids.
  • the preparation is greatly beneficial to clinical use.
  • the docetaxan compound of the present invention is preferably paclitaxel and docetaxel, and most preferably paclitaxel.
  • the oil component of the above emulsion may be selected from pharmaceutically conventional oil phase ingredients including, but not limited to, monoglycerides, diglycerides, triglycerides, or mixtures thereof.
  • the oil component is a "vegetable oil.”
  • the vegetable oil is an oil derived from plant seeds or nuts. Vegetable oils are usually "long-chain triglycerides" which consist of tri-fatty acids (typically from about 14 to about 22 carbons in length, depending on the source of the oil, with different numbers and positions of unsaturated bonds) and three on glycerol. The hydroxyl group is formed by forming an ester bond.
  • Vegetable oils include, but are not limited to, soybean oil, almond oil, borage oil, blackcurrant seed oil, castor oil, corn oil, safflower oil, sesame oil, cottonseed oil, peanut oil, olive oil, rapeseed oil, cocoa butter, palm oil , canola oil, sub
  • soybean oil, tea oil, safflower oil, cottonseed oil, evening primrose oil, and the like are preferred.
  • high purity vegetable oils are typically used to ensure the safety and stability of the formulation.
  • hydrogenated vegetable oils can also be used, which are prepared by controlled hydrogenation of vegetable oils.
  • the oil refers to "medium chain triglycerides”.
  • Medium chain triglycerides are another class of triglyceride oils, which may be natural or synthetic, made from fatty acids typically having a length of from about 8 to about 12 carbons.
  • MCT's have been widely used in emulsions designed for injection as a source of calories for patients requiring parenteral nutrition.
  • oils are commercially available, such as Mi g ⁇ yoI 210 and Mig yo 812N , CRODAMOL GTCC-PN , Neobees M-5 oil and the like.
  • the oil component can also be an oil from an animal. It also includes triglycerides, but the length of its three fatty acid chains differs from the unsaturated bonds in it and vegetable oils.
  • the animal fat obtained from a solid source of oil at room temperature eg, butter, lard, etc.
  • Other forms of animal fat which are liquid at room temperature include various fish oils, for example, ordinary fish oil, oyster sauce, salmon oil or tuna oil, and the like.
  • the phospholipid may be a phospholipid or a mixture of two or more phospholipids.
  • Phospholipid refers to a triglyceride having two fatty acids and one phosphate ion.
  • Phospholipids useful in the present invention include, but are not limited to, lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, having from about 4 to about 22 carbon atoms, and more typically from about 10 to about 18 carbon atoms. And different degrees of saturation of phosphatidic acid.
  • the phospholipids useful in the present invention may be phospholipids of natural origin.
  • Naturally occurring phospholipids include soy lecithin, egg lecithin, hydrogenated soy lecithin, hydrogenated egg lecithin, sphingosine, gangliosides and phytosphingosine, and combinations thereof.
  • Natural lecithin is a mixture of choline esters of stearic acid, palmitic acid and oleic acid linked to phosphoric acid, commonly known as phosphatidylcholine, and is available from a variety of sources, such as eggs and soy beans.
  • Soy lecithin and egg lecithin have a long history of safety, have comprehensive emulsification and solubility characteristics, and are more likely to disintegrate into harmless substances faster than most synthetic surfactants. Products are commercially available.
  • a preferred phospholipid of the invention is egg lecithin.
  • the phospholipid may also be a synthetic phospholipid, including but not limited to: diglycerides, such as 1, 2. Dilauroyl-sn-glycerol (DLG), 1, 2-di Decanoyl-sn-glycerol (DMG), 1,2-dipalmitoyl-sn-glycerol (DPG), 1,2-distearoyl-s-glycerol (DSG); phosphatidic acid, for example 1, 2 ⁇ Decanoyl-sn-glycerol-3-picuric acid, sodium salt (DMPA, Na), 1,2-dipalmitoyl-sn-glycerol-3-phosphatidic acid, sodium salt (DPPA, Na), 1 , 2- Stearic-sn-glycerol-3-ylic acid, sodium salt (DSPA, Na) ; phosphorylcholine, such as 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1, 2-decanoyl
  • DMG Dilau
  • the weight ratio of the taxane compound, the oil component, the phospholipid to the polyoxyethylene castor oil is 1:3-10:30-80:20-50, preferably 1:3-8:30 -50: 20-40, particularly preferably 1:4-6:35-45:25-30. .
  • the emulsions of the present invention may further comprise other suitable pharmaceutically acceptable excipients including, but not limited to, acidification, alkalizing, buffering, chelating, complexing and stabilizing agents, antioxidants, and antimicrobial properties. Preservatives, suspending and / or viscosity modifiers, and other biocompatible substances or therapeutic agents.
  • the emulsion of the present invention can be formed by self-emulsification by adding the above-mentioned self-emulsifying composition containing an effective amount of a taxane compound, an oil component, a surfactant, and ethanol to a glucose injection solution, and does not require a high shearing device.
  • the surfactant is a phospholipid and a polyoxyethylene castor oil.
  • the emulsion of the present invention can be formed by self-emulsification by adding the above-mentioned self-emulsified composition containing an effective amount of a taxane compound, an oil component, a surfactant, ethanol, or lactic acid to a glucose injection solution, without requiring high Shearing device.
  • the surfactant is a phospholipid and a polyoxyethylene castor oil.
  • taxane compound is preferably paclitaxel and docetaxel, most preferably paclitaxel.
  • the emulsion has a particle size of Inm-100 Onm, preferably has a particle size of 10-800 nm, more preferably has a particle size of 50-500 nm, and most preferably has a particle size of 50-300 nm.
  • the emulsion has an average diameter of less than about 500 nm, 400 nm, 300 ran, 200 nm, 150 nm or 100 nm, preferably less than 400 nm, more preferably less than 300 nm, and most preferably less than 200 nm.
  • the present invention also provides a method for preparing the above-mentioned paclitaxel self-emulsifying composition, comprising the steps of: mixing paclitaxel, oil component, phospholipid, polyoxyethylene castor oil, ethanol and lactic acid, stirring and hooking, filtering, Dispense.
  • the composition of the composition of the present invention may have a paclitaxel content of 10 to 300 mg, preferably 20 to 200 mg, more preferably 30 to 100 mg.
  • the composition of the composition of the present invention may have a paclitaxel content of 10, 20, 30, 50, 60, 100, 150, 180, 200, 300 mg.
  • the volume of the unit preparation may be 2 to 60 ml, preferably 3 to 30 ml, and most preferably 5 to 20 ml.
  • the volume of the composition unit preparation of the present invention may be 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 20, 30, 40, 50, 60 ml.
  • the amount of polyoxyethylene castor oil is greatly reduced compared with the original paclitaxel injection, which is only 50% or less of the original paclitaxel injection, preferably less than 30% of the original paclitaxel injection, and soybean oil and lecithin are both It has good biocompatibility and is widely used as a main component of fat emulsion for injection. No serious side effects have been reported. Therefore, this prescription is expected to greatly reduce the probability and extent of allergic reactions.
  • composition of the present invention can be used for the treatment of cancer, and preferably the cancer to be treated is ovarian cancer, breast cancer, non-small cell cancer, head cancer or neck cancer.
  • Example 1 A particle size measurement chart of an emulsion formed by self-emulsification of a composition.
  • Fig. 2 is a graph showing the stability after dilution of each composition in Experimental Example 1 of the present invention.
  • Figure 3 is a quantitative standard for the observation of paclitaxel crystals used in Experimental Example 5 of the present invention. detailed description
  • the lecithin is egg lecithin unless otherwise specified.
  • the lecithin used in the specific embodiment of the present invention is commercially available Lipod E80.
  • other commercially available lecithins and lecithins prepared by those skilled in the art according to the prior art can also be used in the present invention and achieve the same.
  • Technical effects The particle size of the emulsion formed from the emulsification of the product of the following examples was measured by a laser scatterometer.
  • the above ingredients were mixed, stirred well, and then filtered through a microporous membrane having a pore size of 0.22 ⁇ m, and dispensed.
  • the product is a clear liquid.
  • the above ingredients are mixed, stirred and hooked, and then filtered through a microporous membrane having a pore size of 0.22 ⁇ m, and dispensed.
  • the product is a clear liquid.
  • the above components were mixed, stirred well, and then filtered through a microporous membrane having a pore size of 0.22 ⁇ m, and separately obtained.
  • the product is a clear liquid.
  • the above ingredients were mixed and stirred uniformly, and then filtered through a microporous membrane having a pore size of 0.22 ⁇ m to be dispensed.
  • the product is a clear liquid.
  • the above ingredients are mixed: After stirring uniformly, the membrane is filtered through a microporous membrane having a pore size of 0.22 ⁇ m, and is obtained by dispensing. The product is a clear liquid.
  • the above ingredients were mixed, stirred well, and then filtered through a microporous membrane having a pore size of 0.22 m, and dispensed.
  • the product is a clear liquid.
  • the above ingredients are mixed: After stirring uniformly, the mixture is filtered through a microporous membrane having a pore size of 0.22 ⁇ m, and is obtained by dispensing. The product is a clear liquid.
  • Example 10 After stirring uniformly, the membrane is filtered through a microporous membrane having a pore size of 0.22 ⁇ m, and is obtained by dispensing. The product is a clear liquid.
  • Example 10 After stirring uniformly, the membrane is filtered through a microporous membrane having a pore size of 0.22 ⁇ m, and is obtained by dispensing. The product is a clear liquid.
  • the above ingredients are mixed, after mixing with a pore size microporous membrane 0.22 ⁇ filtration, dispensing, i.e. for t as a clear liquid product.
  • the above components were mixed, stirred well, and then filtered through a microporous membrane having a pore size of 0.22 ⁇ m, and separately obtained.
  • the product is a clear liquid.
  • the above ingredients were mixed, stirred well, and then filtered through a microporous membrane having a pore size of 0.22 ⁇ m, and dispensed.
  • the product is a clear liquid.
  • Soybean oil for injection 90g Soybean oil for injection 90g
  • the above ingredients were mixed, stirred well, and then filtered through a microporous membrane having a pore size of 0.22 ⁇ m to be dispensed.
  • the product is a clear liquid.
  • the above components were mixed, stirred well, and then filtered through a microporous membrane having a pore size of 0.22 ⁇ !, and then dispensed. Production The product is a clear liquid.
  • the composition of the composition was indicated by the constant volume of anhydrous ethanol instead of the weight of ethanol.
  • the weight of the ethanol added in the above examples was not significantly changed, and was about 3000 g depending on the actual situation.
  • the ingredients and ultrasonic were stirred and dissolved at 35 ° C and mixed.
  • compositions of Examples 1-3, Comparative Examples 1 and 2, and 5 ml of each commercially available Taxol were emulsified by injecting into 50 ml of a 5 % glucose solution, and the concentration of paclitaxel in the microemulsion was measured as a control. Leave at 25 ° C for 24 hours, respectively, at 1.5, 6, The above microemulsion was taken at 9, 12, and 24 hours, and the content of paclitaxel in the microemulsion was measured after filtration, and compared with the control, the change of paclitaxel content was calculated. The results are shown in Figure 2. Experimental Example 2 Tolerance of the compositions of the present invention to various harsh environments
  • Example 1 The composition prepared in Example 1 was placed under the exposure of 4500 luminescence, and the appearance color of the injection after 5 days and 10 days (before emulsification, after emulsification), pH value, clarity before emulsification, related substances, peroxide value, emulsification There was no significant change in 24-hour stability, main drug content, etc. compared to 0 days.
  • Appearance color (before emulsification) Yellow clear viscous liquid Yellow clear viscous liquid Yellow clear viscous liquid Appearance color (after emulsification;) Milky white liquid Milky white liquid Milky white liquid
  • Example II The composition prepared in Example I was placed at a high temperature of 60 ° C, and was measured after 0 days, 5 days, and 10 days. The data are shown in Table 2. Table 2. The tolerance of paclitaxel microemulsion injection to high temperature (6(TC)
  • Appearance color (before emulsification) Yellow clear viscous liquid Dark yellow clear viscous liquid Brown clear viscous liquid Appearance color (after emulsification) Milky white liquid Milky white liquid Milky white liquid Acidity 4.01 3.80 3.72
  • Microemulsion particle size (nm;) 155 154 153 Emulsification 24 hours stability 99.0 99.4 99.3
  • Example 3 Tolerance of paclitaxel microemulsion injection to low temperature
  • Appearance color (before emulsification) Yellow clear viscous liquid Yellow clear viscous liquid Yellow clear viscous liquid Appearance color (after emulsification) Milky white liquid Milky white liquid Milky white liquid
  • compositions of Examples 1-3 were placed in a 2-8 hr cold room, and the relevant indexes were measured at 0, 3, 6, 9, and 24 months.
  • Male guinea pigs were randomly divided into 4 groups, 7 in each group, respectively, commercially available paclitaxel injection (Taxol®), the self-emulsified paclitaxel microemulsion injection of the composition of Example 1, and the composition of Comparative Example 3.
  • the sensitized dose of the emulsified paclitaxel microemulsion injection, the negative control (5% glucose solution), the commercially available paclitaxel injection, and the paclitaxel microemulsion injection was 2 mg/kg, and the excitation dose was 5 mg/kg.
  • the sensitization was performed by intraperitoneal injection for 3 times, 0, 2, and 4 days, respectively, and the 14th sputum after the last injection was stimulated by the anterior iliac vein of the guinea pig.
  • the crystals of paclitaxel in microemulsions are usually needle-like or cluster-like, have obvious characteristics, and are easily distinguished from other substances under a microscope. According to this characteristic, the microscopic observation standard of paclitaxel crystal was established, and the degree of crystallization of paclitaxel was quantified as "-, +/-, +, ++ , +++ , ++++ ", and "+” was judged to be positive. In order to avoid sampling differences and miss detection as much as possible, the observation area was enlarged by about 25 fields of view, the number of observed crystals was counted, and the grades were classified according to the criteria shown in Table 8 and Figure 3. The results are shown in Table 9.
  • the number is less than the number of crystals in a single field of view.
  • the number is between 3-8, 8-20, more than 20, equal to 10, less than 3, and the stability of the microemulsion.
  • the self-emulsified pharmaceutical composition for transporting a taxane drug mainly comprises a taxane compound, an oil component, a surfactant, ethanol and lactic acid, has a safe composition, is simple to prepare, and is easy to be industrially produced. After being added to water, it can be self-emulsifying to form an emulsion, and it can be used for clinical use safely and conveniently for a long time.
  • the composition of the present invention can be used for cancers such as ovarian cancer, breast cancer, non-small cell cancer, head cancer or neck cancer. Treatment.

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Abstract

La présente invention concerne une composition pharmaceutique auto-émulsifiante destinée à délivrer des taxanes. Ladite composition comprend un taxane, une huile, un surfactant et de l'éthanol, ainsi que, de préférence, de l'acide lactique. Le surfactant est un phospholipide ou une huile de ricin polyoxyéthylénée. Lorsque la composition pharmaceutique auto-émulsifiante est ajoutée dans l'injection de glucose, elle forme immédiatement une microémulsion avec une taille de particules de 50 à 300 nm. La microémulsion est stable pendant plus de 12 heures à température ambiante.
PCT/CN2011/000398 2010-03-16 2011-03-14 Formulation de taxanes auto-émulsifiante et procédé de préparation associé Ceased WO2011113301A1 (fr)

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CN104706585A (zh) * 2013-12-16 2015-06-17 天津迈迪瑞康生物医药科技有限公司 一种重酒石酸长春瑞滨脂肪乳浓缩液、其制备方法及用途
WO2016071365A1 (fr) * 2014-11-03 2016-05-12 Spherium Biomed, S.L. Compositions pharmaceutiques topiques de paclitaxel
CN109589305B (zh) * 2018-12-03 2021-03-19 昆明积大制药股份有限公司 多西他赛-环孢素a共包载自乳化制剂及其制备方法
CN113425683B (zh) * 2021-08-19 2022-09-20 谢彩华 一种三氮脒缓释注射剂及其制备方法

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