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WO2008098415A1 - Composition pharmaceutique contenant du taxane et son procédé de préparation et d'application - Google Patents

Composition pharmaceutique contenant du taxane et son procédé de préparation et d'application Download PDF

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Publication number
WO2008098415A1
WO2008098415A1 PCT/CN2007/000529 CN2007000529W WO2008098415A1 WO 2008098415 A1 WO2008098415 A1 WO 2008098415A1 CN 2007000529 W CN2007000529 W CN 2007000529W WO 2008098415 A1 WO2008098415 A1 WO 2008098415A1
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WIPO (PCT)
Prior art keywords
acid
pharmaceutical composition
composition according
salt
tween
Prior art date
Application number
PCT/CN2007/000529
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English (en)
Chinese (zh)
Inventor
Shouzhu Hao
Original Assignee
Beijing Century Biocom Pharmaceutical Technology Co., Ltd.
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Application filed by Beijing Century Biocom Pharmaceutical Technology Co., Ltd. filed Critical Beijing Century Biocom Pharmaceutical Technology Co., Ltd.
Priority to PCT/CN2007/000529 priority Critical patent/WO2008098415A1/fr
Publication of WO2008098415A1 publication Critical patent/WO2008098415A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid

Definitions

  • composition of taxane compound preparation method and use thereof
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a docetaxel compound as an active ingredient, a process for the preparation of the composition and use thereof.
  • Taxanes are a class of anticancer compounds with a taxane structure. The mechanism of action is to stimulate the polymerization of cathelicidin, promote the assembly of microtubules into microtubules, and stabilize microtubules and inhibit microtubules. Reticulum reorganization, which ultimately stops cell proliferation in the quiescent phase of mitosis, and thus acts as a cytotoxic agent.
  • the most widely used taxanes are paclitaxel and docetaxel (ie, docetaxel), which have been widely used in breast cancer, ovarian cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SC.LC).
  • Taxol polyoxyethylated castor oil
  • Euthanol ethanol
  • Oxyethylated castor oil can cause severe allergic reactions, so the instructions for paclitaxel injections clearly state - "To prevent serious allergic reactions, all patients receiving paclitaxel should take precautionary medications in advance.
  • Oral administration of dexamethasone 20 mg, usually 12 and 6 hours before paclitaxel, diphenhydramine (or its analog) 50 mg intravenously 30 to 60 minutes before paclitaxel, and 30 to 60 minutes before paclitaxel injection Cimetidine (300mg) or ranitidine (50mg). making the preparation extremely inconvenient for clinical use; the same marketed docetaxel injection (trade name Taxotere), its preparation (concentrate Contains high concentrations (nearly 100%) of Tween 80 (TWEEN 80 or Polysorbate 80), containing 40 mg of docetaxel and 1040 mg of Tween 80 per ml of concentrate.
  • the concentrate is equipped with a special solvent, 13% ethanol, which can be injected after diluting the concentrate
  • a taxane compound is added to a mixed solution of Tween and glycerin, or a mixed solution of Tween and polyethylene glycol is added, or three substances of Tween, glycerin and polyethylene glycol are added.
  • the bile acid or its salt is added at the same time, on the one hand, the solubility of the taxane compound in water can be further improved, and on the other hand, the stability of the solution of the taxane compound can be remarkably enhanced.
  • the taxane compound is a compound having a taxane skeleton structure, preferably paclitaxel and docetaxel, and most preferably paclitaxel.
  • the bile acid in the present invention is selected from the group consisting of free bile acids, bound bile acids or a mixture of the two, and the free bile acids include cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and pigs.
  • Oxycholic acid, etc. preferably cholic acid, deoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid; combined bile acid is a carboxaldehyde and glycine (H 2 NCH 2 COOH) or taurin in the above free bile acid a product of an acid (H 2 NCH 2 CH 2 S0 3 H) or an amino group in a compound containing an amino group to form an amide bond, preferably glycocholic acid, glycodeoxycholic acid, glycine chenodeoxycholic acid, Glycine ursodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid; bile acid salt is the above-mentioned free bile acid or combined with bile acid salt Subsequent products include, but are not limited to, potassium salts, sodium salts, calcium salts, magnesium salts, zinc salts, seleni
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a taxane compound comprising a therapeutically effective amount of a taxane compound, a Tween-based surfactant, a co-solvent glycerin or polyethylene glycol, and a bile acid or a salt thereof.
  • the Tween-based surfactant is selected from one or more of Tween-20, Tween-40, Tween-60 and Tween-80, preferably Tween-80.
  • the cosolvent is selected from the group consisting of glycerin, polyethylene glycol or a mixture of the two, wherein the polyethylene glycol has an average molecular weight of from 200 to 10,000, preferably PEG200, PEG400, PEG800, and most preferably PEG400.
  • the bile acid is selected from the group consisting of free bile acids, bound bile acids or a mixture of the two, wherein the free bile acids include cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, bear Deoxycholic acid, hyodeoxycholic acid, etc., preferably cholic acid, deoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid; combined bile acid is carboxaldehyde and glycine (H 2 NCH) in the above free bile acid 2 COOH) or taurine (H 2 NCH 2 CH 2 S0 3 H) or an amino group-containing compound in which the amino group forms an amide bond, preferably glycocholic acid, glycodeoxycholic acid, glycine Chenodeoxycholic acid, glycine bear deoxyacid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid
  • the weight ratio of the docetaxel compound to the Tween-based surfactant, the solubilizing agent, and the bile acid or the salt thereof in the pharmaceutical composition of the present invention is 1: 5-150: 2-100: 0.1-100, preferably 1: 15 -80: 5-50: 0.5-50, particularly preferably I: 25-65: 10-30: 1-30, most preferably 1:50-65: 10-30: 30.
  • the pharmaceutical composition of the present invention may be in the form of an injection or a frozen powder for injection.
  • concentration of the taxane compound in the solution of the present invention or before the freeze-dried powder freeze-drying is 0.1 mg to 80 mg/m, preferably 1 mg to 50 mg/ml, and the concentration of the solubilizing agent is 5 mg to 500 mg. / ml, preferably 30mg ⁇ 200mg / ml, a concentration of Tween surfactant is 20mg ⁇ 500mg / ml, preferably 30mg ⁇ 300m g / ml, the concentration of bile acid or salt thereof 0.2mg ⁇ 400mg / ml, It is preferably from 1 mg to 200 mg/ml.
  • the pharmaceutical composition of the present invention may further comprise other conventional adjuvants for injection or lyophilized powder for injection.
  • These conventional adjuvants include, but are not limited to, lyophilized excipients, preservatives, stabilizers, pH adjusters, isotonic agents.
  • the excipient may be selected from one or more selected from the group consisting of, but not limited to, mannitol, lactose, glucose, sorbitol, sodium chloride, hydrolyzed gelatin, dextran, sucrose, glycine, polyvinylpyrrolidone; For mannitol or glucose.
  • the preservative may be selected from, but not limited to, one or more of phenol, cresol, tri-tert-butanol, benzyl alcohol, and paraben.
  • the stabilizer may be selected from, but not limited to, sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, sodium thiosulfate, thiourea, vitamin C, tert-butyl p-hydroxyanisole, dibutyl phenol, propyl gallate, tocopherol, One of methionine, cysteine hydrochloride, acetylcysteine, N-acetyl-DL-methionine, ascorbyl palmitate, ethylenediaminetetraacetic acid, disodium edetate Or several.
  • PH regulators include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, metaphosphoric acid, polymetaphosphoric acid, carbonic acid, sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium hydrogencarbonate, hydrogencarbonate Potassium, amine carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ethanolamine, diethanolamine, triethanolamine, 1,2-hexanediamine, sodium carbonate, potassium sodium tartrate, potassium metaphosphate, potassium polymetaphosphate, sodium metaphosphate One or several of them.
  • the taxane pharmaceutical composition of the present invention should have a pH of 8 or less, preferably a pH of 3-5, and the pH adjusting agent includes, but not limited to, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, and partiality.
  • the pH adjusting agent includes, but not limited to, hydrochloric acid, citric acid, tartaric acid, phosphoric acid, and partiality.
  • phosphoric acid and polymetaphosphoric acid preferably citric acid or tartaric acid.
  • the amount of the docetaxan compound is not particularly limited and may be any dose which is usually used in the injection liquid.
  • “Therapeutically effective amount” means the usual amount of the therapeutic effect of the taxane, and the doctor can make appropriate adjustments depending on the patient's condition and other conditions.
  • the taxane compound is present in the composition of the present invention in an amount of from 0.1 to 80 mg/ml.
  • the pharmaceutical composition of the taxane compound of the present invention may be in the form of a clear injectable aqueous solution, or In the form of a lyophilized powder for injection.
  • the lyophilized powder can be directly dissolved in water for injection, 5% or 10% glucose solution or 0.9% sodium chloride solution to obtain a clear injection.
  • the powder injection is a dry solid mass or powder, which can prevent the oxidation, hydrolysis and other factors of the taxane compound in the solution, and improve the stability during storage of the product.
  • the powder injection preparation process is simple, the quality control is simple, the product stability is good, and the industrial production is convenient.
  • the lowest eutectic point of the content of the present invention is high, and it can be pre-frozen at a temperature of -4 (TC), and the appearance is good.
  • the powder injection can have a moisture content of less than 1%, and is generally controlled within 5%.
  • the prepared solution and the equivalent turbidity standard solution were placed in a paired turbidity glass tube, respectively, after 5 minutes of preparation of the turbidity standard solution, Vertically placed under the umbrella shed lamp in the dark room, the illuminance is lOOOLx. When viewed from the horizontal direction, the prepared solution should be clarified and not deeper than the No. 1 turbidity standard solution.
  • the present invention provides a method for improving the solubility of a taxane compound, comprising the steps of mixing and stirring a taxane compound and a co-solvent, a Tween-based surfactant, and a bile acid (or a salt thereof).
  • the cosolvent is selected from the group consisting of glycerin, polyethylene glycol or a mixture of the two.
  • the method may further comprise the step of preparing the above mixture into an injection solution, specifically comprising adding an aqueous solvent to the mixture, for example, distilled water, water for injection, aqueous mannitol solution, or an aqueous solution containing any other adjuvant, and adding activated carbon after mixing After stirring, decarburization was carried out by coarse filtration through a 0.8 ⁇ filter, and then sterilized by a 0.22 ⁇ m ⁇ filter, and dispensed.
  • an aqueous solvent for example, distilled water, water for injection, aqueous mannitol solution, or an aqueous solution containing any other adjuvant
  • the concentration of the taxane compound in the composition is 0.1 mg to 80 mg/ml
  • the concentration of the cosolvent is 5 mg to 500 mg/ml
  • the concentration of the tween surfactant is 20 mg to 500 mg/ml
  • the bile acid or The concentration of the salt is from 0.2 mg to 400 mg/ml.
  • the method may further comprise the step of freeze-drying the above-mentioned injection solution to form a lyophilized powder needle, wherein the freeze-drying adopts a conventional freeze-drying technique of a freeze-dried injection in the field of pharmaceuticals, and the person skilled in the art according to the prior art and the textbook The technical teaching in it can be done without creative labor.
  • the Tween-based surfactant is selected from one or more of Tween-20, Tween-40, Tween-60 and Tween-80, preferably Tween-80.
  • the co-solvent is selected from the group consisting of glycerin, polyethylene glycol or a mixture of the two, wherein the polyethylene glycol
  • the average molecular weight of the alcohol is from 200 to 10,000, preferably PEG 200, PEG 400, PEG 800, most preferably PEG 400.
  • the bile acid is selected from the group consisting of free bile acids, bound bile acids or a mixture of the two, wherein the free bile acids include cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, and bear deoxygenation.
  • Cholic acid, hyodeoxycholic acid, etc. preferably cholic acid, deoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid;
  • combined bile acid is the carboxaldehyde and glycine (3 ⁇ 4NCH 2 COOH) in the above free bile acid or a product of an amide bond in the taurine (H 2 NC3 ⁇ 4CH 2 S0 3 H) or other amino group-containing compound, preferably glycocholic acid, glycodeoxycholic acid, glycine chenodeoxycholic acid, Glycine ursodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid;
  • bile acid salt is the above-mentioned free bile acid or combined with bile acid salt Subsequent products include, but are not limited to, potassium salts, sodium salts, calcium salts, magnesium salts, zinc salts
  • the weight ratio of the docetaxel compound to the Tween surfactant, the co-solvent, and the bile acid or a salt thereof is 1: 5-150: 2-100: 0.1-100, preferably 1: 15-80: 5-50: 0.5-50, particularly preferably 1: 25-65: 10-30: 1-30, most preferably 1:50-65: 10-30: 1-30.
  • the taxane compound is docetaxel and paclitaxel, with paclitaxel being most preferred.
  • a third aspect of the invention is the use of the paclitaxel or docetaxel composition of the invention for the treatment of proliferative diseases, in particular for cancer, such as breast cancer, non-small cell lung cancer, ovarian cancer, AIDS-related Treatment of Kaposi's sarcoma, pancreatic cancer, colorectal cancer, melanoma, head and neck cancer, lymphoma, brain tumor, stomach cancer, etc.
  • cancer such as breast cancer, non-small cell lung cancer, ovarian cancer, AIDS-related Treatment of Kaposi's sarcoma, pancreatic cancer, colorectal cancer, melanoma, head and neck cancer, lymphoma, brain tumor, stomach cancer, etc.
  • the prepared solution and the equivalent amount of turbidity standard solution were placed in the paired turbidity glass tube, after 5 minutes of preparation of the turbidity standard solution, Vertically placed under the umbrella shed lamp in the dark room, the illuminance is lOOOLx. When viewed from the horizontal direction, the prepared solution is clarified and not deeper than the No. 1 turbidity standard solution. After standing at room temperature for 8 hours, the solution remained clear.
  • Paclitaxel and polyethylene glycol 200, Tween 80, and glycocholic acid were mixed and stirred, added to a mannitol aqueous solution, mixed, adjusted to pH 4 with a tartaric acid solution, and the solution was added to 0.1% activated carbon for 20 minutes.
  • the solution was de-carbonized by coarse filtration through a 0.8 ⁇ m filter, then sterilized by a 0.22 m filter and dispensed into a vial.
  • the paclitaxel injection was prepared according to the method of Example 1. According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbid glass tube. After the turbidity standard solution was prepared for 5 minutes, it was placed vertically under the umbrella lamp in the dark room, and the illuminance was lOOOLx. The prepared solution was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution. After standing at room temperature for 8 hours, the solution remained clear.
  • the prepared solution and the equal amount of the turbidity standard solution are separately placed in the paired turbidity glass tube, and after being prepared for 5 minutes in the turbidity standard solution, they are vertically placed under the umbrella shed lamp in the dark room.
  • Illuminance is lOOOLx, from horizontal Observe, compare, and prepare the solution to be clear, not deeper than the 1 turbidity standard. After standing at room temperature for 8 hours, the solution remained clear.
  • the docetaxel injection was prepared according to the method of Example 1. According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbidity. In the glass tube, after the turbidity standard solution is prepared for 5 minutes, it is placed vertically under the umbrella lamp in the dark room, and the illuminance is lOOOLx. The solution is clarified from the horizontal direction and compared, and the solution is not deeper than the No. 1 turbidity standard. liquid. After standing at room temperature for 8 hours, the solution remained clear.
  • the paclitaxel injection was prepared according to the method of Example 1. According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbid glass tube. After the turbidity standard solution was prepared for 5 minutes, it was placed vertically under the umbrella lamp in the dark room, and the illuminance was 1000 LX. The solution prepared was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution. After standing at room temperature for 8 hours, the solution remained clear.
  • the paclitaxel injection was prepared according to the method of Example 1. According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbid glass tube. After the turbidity standard solution was prepared for 5 minutes, it was placed vertically under the umbrella lamp in the dark room, and the illuminance was lOOOLx. The prepared solution was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution. After standing at room temperature for 5 hours, the solution remained clear.
  • the paclitaxel injection was prepared according to the method of Example 1. According to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2), the prepared solution and the equivalent turbidity standard solution were respectively placed in the paired turbid glass tube. After the turbidity standard solution was prepared for 5 minutes, it was placed vertically under the umbrella lamp in the dark room, and the illuminance was lOOOLx. The prepared solution was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution. After standing at room temperature for 8 hours, the solution remained clear.
  • Paclitaxel and polyethylene glycol 400, Tween 80, sodium deoxycholate were mixed and stirred, and an aqueous solution of mannitol was added, mixed, and the solution was added to 0.1% activated carbon and stirred for 20 minutes.
  • the solution was de-carbonized by coarse filtration through a 0.8 ⁇ filter, and then sterilized by a 0.22 ⁇ m filter and dispensed into a vial.
  • the prepared solution and the equivalent amount of turbidity standard solution were placed in the paired turbidity glass tube, after 5 minutes of preparation of the turbidity standard solution, Vertically placed under the umbrella lamp in the dark room, the illuminance is lOOOLx, and the prepared solution is clarified from the horizontal direction and compared, and is not deeper than the No. 1 turbidity standard solution. After standing at room temperature for 6 hours, the solution remained clear.
  • the paclitaxel injection was prepared according to the method of Example 18, and the "Chinese Pharmacopoeia 2005 Edition (Part 2)" Appendix IX
  • the prepared solution and the equal amount of the turbidity standard solution are respectively placed in the paired turbidity glass tube, and after being prepared for 5 minutes in the turbidity standard solution, the illuminance is vertically placed in the dark room, and the illuminance is vertically
  • the prepared solution was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution. After standing at room temperature for 8 hours, the solution remained clear.
  • the paclitaxel injection was prepared according to the method of Example 18, and the prepared solution and the equivalent amount of the turbidity standard solution were respectively placed in the paired turbidity glass tubes according to the method of Appendix IX B of the Chinese Pharmacopoeia 2005 Edition (Part 2).
  • the turbidity standard solution was prepared for 5 minutes, it was placed vertically under the umbrella lamp in the dark room, and the illuminance was lOOOLx.
  • the prepared solution was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution. After standing at room temperature for 8 hours, the solution remained clear.
  • the solutions prepared in Examples 3, 5, 6, 8, 9, 13, 14, 17, 19, 20 were freeze-dried as follows: Pre-freezing: The temperature of the product was lowered to a temperature of 45 ⁇ , and sublimation was carried out after 3 hours of heat preservation. Dry
  • Sublimation drying temperature is controlled below 12 ⁇ ;
  • Re-drying The final temperature in the re-drying stage is controlled at 35 °C, and the weight loss on drying should meet the requirements;
  • the rubber plug is pressed in the box, and the aluminum cover is released from the box. After the finished product is inspected, the package is obtained.
  • the lyophilized product is further dissolved by adding 3 ⁇ 15ml of water for injection.
  • the prepared solution and the equivalent turbidity standard solution are respectively placed in the paired turbid glass tube. After 5 minutes of preparation of the turbidity standard solution, it was placed vertically under the umbrella lamp in the dark room, and the illuminance was lOOOLx. The solution prepared was clarified from the horizontal direction and compared, and was not deeper than the No. 1 turbidity standard solution. After the solution was allowed to stand at room temperature for 8 hours, it remained clear. Comparative example 1
  • Paclitaxel and glycerin and Tween 80 were mixed and stirred, and an aqueous solution of mannitol was added, mixed, and the solution was added to 0.1% activated carbon and stirred for 20 minutes.
  • the solution was de-carbonized by a coarse filtration through a 0.8 ⁇ m filter, then sterilized by a 0.22 ⁇ filter, and dispensed into a vial. One part was placed at room temperature and the other part was freeze-dried. After 1 hour at room temperature, the solution became cloudy. The frozen dry sample was reconstituted with water for injection, and the solution was cloudy after 1 hour.
  • the lyophilized product obtained by the method of Examples 1-20 has the properties required for the lyophilized composition of the present invention.
  • Each sample was stored under accelerated experimental conditions for 6 months, and the changes in the contents and related substances were measured. The results are shown in Table 1.
  • the lyophilized product prepared according to the methods of Examples 5, 6, 8, 9, 13, 14, 17, 19, 20 was subjected to animal blood vessel irritation.
  • the method was to take 6 healthy rabbits with no ear damage and randomly divided into two groups according to body weight, namely, injection of docetaxel or paclitaxel injection test group and sodium chloride injection control group. Rabbits were dosed according to the clinical adult dose, and were injected slowly from the left ear vein of rabbits. The control group was given an equal volume of sodium chloride injection for 5 consecutive days.
  • the results of the test showed that, compared with the sodium chloride injection group, intravenous bolus injection of docetaxel for injection or paclitaxel for injection, after the administration and 24 hours after the last administration, no red blood vessels and surrounding tissues were observed by the naked eye.
  • the tissue section examination showed that the structure of the rabbit ear vein was clear, the individual blood vessels were dilated, the wall thickness was uniform, the inner wall was smooth, and there was no inflammatory exudate around the tube. It indicated that docetaxel or injection paclitaxel had no obvious stimulating effect on rabbit ear veins under experimental conditions.

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Abstract

La présente invention concerne une composition pharmaceutique et sa préparation. La composition injectable comporte une quantité thérapeutiquement efficace de texane, de tensioactif Tween, de solvant auxiliaire et d'acide cholique et ses sels, le solvant auxiliaire étant sélectionné parmi PEG et glycérol. La combinaison de Tween avec un solvant auxilaire (et acide cholique ou ses sels) améliore l'hydrosolubilité et la stabilité du taxane.
PCT/CN2007/000529 2007-02-14 2007-02-14 Composition pharmaceutique contenant du taxane et son procédé de préparation et d'application WO2008098415A1 (fr)

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