WO2012000253A1 - 一种供注射用的多西他赛组合物及其制备方法 - Google Patents

一种供注射用的多西他赛组合物及其制备方法 Download PDF

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Publication number
WO2012000253A1
WO2012000253A1 PCT/CN2010/077940 CN2010077940W WO2012000253A1 WO 2012000253 A1 WO2012000253 A1 WO 2012000253A1 CN 2010077940 W CN2010077940 W CN 2010077940W WO 2012000253 A1 WO2012000253 A1 WO 2012000253A1
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Prior art keywords
temperature
front box
docetaxel
vacuum
box
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PCT/CN2010/077940
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English (en)
French (fr)
Inventor
陈庆财
赵俊
赵小伟
戴建国
叶东
戴艳
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江苏奥赛康药业有限公司
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Publication of WO2012000253A1 publication Critical patent/WO2012000253A1/zh

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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
    • A61K9/14—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

Definitions

  • the present invention relates to a docetaxel composition for injection and a process for the preparation thereof, and the docetaxel composition prepared by the method can be used for the treatment of non-small cell lung cancer.
  • Docetaxel is a semi-synthetic paclitaxel derivative developed by Rhone-Poulenc Rorer, a microtubule depolymerization inhibitor that promotes the aggregation of tubules into stable microtubules. And inhibit its depolymerization so that the number of free tubules is significantly reduced.
  • Rhone-Poulenc Rorer a microtubule depolymerization inhibitor that promotes the aggregation of tubules into stable microtubules. And inhibit its depolymerization so that the number of free tubules is significantly reduced.
  • Rhone-Poulenc Rorer a microtubule depolymerization inhibitor that promotes the aggregation of tubules into stable microtubules. And inhibit its depolymerization so that the number of free tubules is significantly reduced.
  • the recommended dosing regimen is once every 3 weeks, with an intravenous infusion of 100 mg/m 2 for 1 hour.
  • docetaxel [2aR-(2a ⁇ , 4 ⁇ , 4a ⁇ , 6 ⁇ , 9 a , ( a R*, ⁇ S*), ll ⁇ , 12 a , 12a a , 12b a ) ]- p -[[(l, l dimethylethoxy)carbonyl]amino]- a-hydroxyphenylpropionic acid [12b-acetoxy-12-benzoyloxy-2a,3, 4,4a,5 ,6,9,10, ll, 12, 12a, 12b-dodecyl-4,6,11-trihydroxy-4a,8, 13, 13-tetramethyl-5-oxo-7, 11-Asia Methyl-1H-cyclopentapenta[3,4]benzo[1,2-b]oxabutan-9-yl]ester trihydrate, molecular formula: C 43 H 53 N0 14 ⁇ 33 ⁇ 40, The molecular weight
  • the prior art uses polysorbate 80 as a solvent to prepare an injection thereof, but because of the high viscosity of the solvent such as polysorbate 80, the fluidity is poor and cannot be accurately filled, usually more Tetraxel is dissolved in ethanol and mixed with polysorbate 80, and then ethanol is removed by vacuum drying to prepare docetaxel injection.
  • the best way is to vacuum dry the filled docetaxel solution in a sterile environment using a freeze dryer. Achieve sterility protection and remove ethanol.
  • CN200910304453.2 The invention discloses a docetaxel pharmaceutical composition injection, which can ensure that no docetaxel precipitates in a long time, but the final product contains a large amount of ethanol, and the clinical use has more on the human body. Excessive irritability, and the presence of ethanol has made the stability of docetaxel injection worse, and the above technical defects have not been solved.
  • a pharmaceutical composition containing docetaxel and a preparation method thereof are disclosed, the preparation process thereof is cumbersome, and there is no guarantee that no docetaxel precipitation in the process of removing anhydrous ethanol, and the remaining purified polysorbate is added.
  • the operation of 80 also increases the difficulty of quality control. Due to the high viscosity of the final solution, sterilization filtration and filling are difficult, and the difference in loading is large, which does not solve the above technical defects.
  • CN200710038470.7 A docetaxel preparation and a preparation method thereof are disclosed.
  • the active ingredient of the formulation is a docetaxel phospholipid dispersion and there is no suggestion to improve the above defects.
  • a pharmaceutical composition of docetaxel comprising a therapeutically effective amount of docetaxel, a Tween surfactant and a cosolvent, wherein the cosolvent is selected from the group consisting of glycerin or polyethylene glycol One or more, there is no suggestion to improve the above defects.
  • a preparation process of an antitumor drug docetaxel injection for use in the field of chemical preparations is disclosed, wherein ethanol is removed by a conventional vacuum drying process, and ethanol is largely volatilized under vacuum conditions, and the temperature of the docetaxel solution is sharp Decreased, which led to the precipitation of docetaxel. After vacuum drying to remove the ethanol, the precipitated docetaxel could not be dissolved again in the remaining polysorbate 80, resulting in discoloration of foreign bodies and insoluble particles in docetaxel injection. There are major flaws.
  • CN200680054069.6 discloses a pharmaceutical composition comprising polysorbate 80, anhydrous docetaxel (I) or a trihydrate thereof and an organic acid having a pKa of 2.5 to 4.5 as a degradation inhibitor, and there is no suggestion for improving the above defects.
  • a stable pharmaceutical composition for injection containing docetaxel and a system thereof are disclosed Preparation method.
  • docetaxel a water-insoluble compound
  • CD cyclodextrin
  • HPMC hydroxypropyl methylcellulose
  • PEG polyethylene glycol
  • PVP vinylpyrrolidone
  • the object of the present invention is to provide a docetaxel composition for injection and a preparation method thereof for the above disadvantages, by which docetaxel injection can be appropriately flowable for precise dispensing. Achieve stable evaporation of ethanol in a vacuum environment, and avoid a sharp drop in the temperature of docetaxel solution. Docetaxel does not precipitate in the whole process, reducing or even completely eliminating the unacceptable foreign matter and insoluble particles in docetaxel injection. phenomenon. Therefore, it is not necessary to increase the lamp inspection workload and the lamp inspection labor cost due to the large amount of rejecting waste products, and the production rate is greatly improved, the production cost is reduced, and the hidden dangers caused by the failure of visible foreign matter and insoluble particulates to the patient for clinical safety medication are also avoided. .
  • the inventors of the present invention discovered through experiments that changing the dissolution scheme of docetaxel, especially the idea of dissolving docetaxel in absolute ethanol and then mixing with polysorbate 80, directly Sorbate 80 is mixed with absolute ethanol to obtain a mother liquor of a specific density.
  • the mother liquor has appropriate viscosity and volatility of ethanol. Dissolving docetaxel in the mother liquor can create a good solution basis for the subsequent stable volatile ethanol process. .
  • the inventors of the present invention have found through research and experiments that the conventional technique cannot produce a product of uniform quality and uniformity, and the problem is solved by controlling the mother liquor density by an appropriate preparation process.
  • preset the front box temperature Place the dispensed docetaxel solution in the lyophilizer, set the front box temperature to 7.5 ⁇ 9.5°C, and keep it for 45 ⁇ 60 minutes. Insulation for 45 ⁇ 60 minutes can make the temperature of all laminating products To achieve uniformity, set the front box temperature to 7.5 ⁇ 9.5 °C to make the product have good chemical and physical properties, chemical degradation rate is very slow, physical layering will not appear delamination and precipitation. More critically, this preset temperature allows the docetaxel solution of the present invention to have a suitable viscosity and ethanol volatility. In the subsequent volatile ethanol process, the temperature of the docetaxel solution fluctuates on this basis. Also the smallest.
  • the compressor is used to cool the cold trap in the back box, and the temperature of the cold trap in the back box is maintained at -58 ⁇ -62 °C.
  • This condition is most beneficial for the evaporation of ethanol and the control of the vacuum of the front box.
  • the pressure difference is inconvenient to control, the front box pressure is too small, the first stage ethanol evaporation rate is too fast and the docetaxel solution temperature drops too much.
  • the vacuum pump and the septum valve are opened, and vacuum drying is performed to remove the ethanol in stages.
  • the vacuum of the front box is controlled at 80 to 100 Pa, and the temperature of the front tank is set to 7.5 to 9.5 ° C, and the temperature of the cold trap is maintained at -58 ⁇ - 62°C for 4 hours.
  • the gas convection in the front tank is stable, the heat transfer is uniform, and the ethanol can be volatilized uniformly and uniformly from the product.
  • the temperature fluctuation of the docetaxel solution is extremely small, and no precipitation occurs, and the ethanol in the back box is rapidly condensed. Stable, while ensuring efficient evaporation of ethanol, the vacuum pump has a small and stable working load, and the amount of ethanol entering is extremely small, and the equipment is well protected.
  • the vacuum of the front box is controlled at 40 to 80 Pa, and the temperature of the front box is set to 7.5 to 9.5 ° C. The temperature is maintained at -58 ⁇ - 62 °C for 2 hours.
  • the front box vacuum is controlled at 10 ⁇ 40Pa, the front box temperature is set to 7.5 ⁇ 9.5 °C, and the cold trap temperature is maintained at -62°. Below C, lasts for 2 hours.
  • the front box vacuum is controlled below 10Pa, the front box temperature is set to 10.5 ⁇ 12.5 °C, and the cold trap temperature is kept below -65 °C for 3 ⁇ 4 hours to close the septum.
  • the plug is plugged out and out of the box. Since the ethanol content in the late stage is very small, it is no longer necessary to maintain good convection. Therefore, the vacuum of the front box is controlled below 10 Pa to ensure the maximum evaporation of ethanol, supplemented by a certain heating, and the temperature of the front box is set.
  • the docetaxel composition for injection provided by the present invention is specifically as follows:
  • a docetaxel composition for injection the main ingredients are docetaxel and polysorbate 80, and The use of anhydrous ethanol as a solvent in the preparation process was prepared as follows:
  • step 2) Sterile filtration and dispensing:
  • the docetaxel solution obtained by step 2) is sterilized by 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile room, and placed in a vial, half-plugged;
  • a, preset front box temperature will step 3) Dispensed Docetaxel solution into the lyophilizer, set the front box temperature to 7.5 ⁇ 9.5 °C, keep warm for 45 ⁇ 60 minutes;
  • the compressor is used to cool the back box cold trap, and the temperature of the back box cold trap is -58 ⁇ -62 °C;
  • the front box vacuum is controlled at 40 to 80 Pa, the front box temperature is set to 7.5 to 9.5 ° C, and the cold trap temperature is maintained at -58 to - 62 ° C for 2 hours.
  • the front box vacuum is controlled to 10 ⁇ 40Pa, the front box temperature is set to 7.5 ⁇ 9.5°C, and the cold trap temperature is kept below -62°C for 2 hours.
  • the front box vacuum is controlled below 10Pa, the front box temperature is set to 10.5 ⁇ 12.5°C, and the cold trap temperature is kept below -65°C for 3 ⁇ 4 hours, until the middle compartment valve box is closed.
  • the plug is pressed out, out of the box, and the aluminum-plastic composite is used to cover the mouth. After passing the quality inspection, the package is obtained.
  • a docetaxel composition for injection which is prepared by:
  • step 2) Sterile filtration and dispensing:
  • the docetaxel solution obtained in step 2) is sterilized by 0.22 ⁇ m polytetrafluoroethylene filter and placed in a sterile room, and placed in a vial, half-plugged;
  • Vacuum drying in addition to ethanol is sterilized by 0.22 ⁇ m polytetrafluoroethylene filter and placed in a sterile room, and placed in a vial, half-plugged;
  • a, preset front box temperature will step 3) Dispensed Docetaxel solution into the lyophilizer, set the front box temperature to 7.5 ⁇ 9.5 °C, keep warm for 45 ⁇ 60 minutes;
  • the compressor is used to cool the back box cold trap, and the temperature of the back box cold trap is -58 ⁇ -62 °C;
  • the front box vacuum is controlled at 40 ⁇ 80Pa, the front box temperature is set to 7.5 ⁇ 9.5 °C, and the cold trap temperature is maintained at -58 ⁇ - 62 °C for 2 hours.
  • the front box vacuum is controlled to 10 ⁇ 40Pa, the front box temperature is set to 7.5 ⁇ 9.5 °C, and the cold trap temperature is kept below -62 °C for 2 hours.
  • the front box vacuum is controlled below 10Pa, the front box temperature is set to 10.5 ⁇ 12.5 °C, and the cold trap temperature is kept below -65 °C for 3 ⁇ 4 hours, until the middle compartment valve box is closed.
  • the plug is pressed out, out of the box, and the aluminum-plastic composite is used to cover the mouth. After passing the quality inspection, the package is obtained.
  • the present invention provides a docetaxel composition for injection and a preparation method thereof, by which the docetaxel injection can be stably volatilized in a vacuum environment under the condition of proper fluidity and precise dispensing, and
  • the temperature of the docetaxel solution is drastically reduced, and the whole process of docetaxel does not precipitate, reducing or even completely eliminating the phenomenon that the visible foreign matter and insoluble particles in the docetaxel injection are unqualified. Therefore, it is not necessary to increase the lamp inspection workload and the lamp inspection labor cost due to the large number of rejects of waste products, and the production rate is greatly improved, the production cost is reduced, and the hidden dangers caused by the failure of visible foreign matter and insoluble particulates to the patient for clinical safety medication are also avoided. .
  • the invention greatly improves the stability of the docetaxel composition for injection in the preparation process, and the prepared docetaxel composition for injection has lower content of related substances, uniform quality, and complete drying of ethanol, in transportation And stability during storage is better.
  • the preparation method has the advantages of simple preparation process, convenient and feasible, good repeatability, low production cost, and easy industrialized large production, thereby generating considerable economic and social benefits. detailed description
  • Docetaxel is added to the mother liquor, stirred to completely dissolve and mix well.
  • the completely dissolved and uniformly mixed docetaxel solution was sterilized by a 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile chamber, and placed in a vial, half-plugged, loaded, placed in a lyophilizer, before setting.
  • the box temperature was 8.0 ° C and kept for 50 minutes.
  • the compressor is used to cool the rear tank cold trap, and the temperature of the back tank cold trap is maintained at -58 to -62 °C.
  • the temperature is 7.5 ° C
  • the cold trap temperature is kept below -62 ° C, after 2 hours
  • the front box vacuum is controlled below 10 Pa
  • the front box temperature is set to 10.5 ° C
  • the cold trap temperature is maintained at -65 ° C below, for 4 hours, until the vacuum of the front box is closed, the pressure is not changed significantly, the plug is plugged out, the box is closed, and the aluminum-plastic composite is used to cover the mouth. After passing the quality inspection, the package is ready for injection. Match composition.
  • docetaxel 100 g of docetaxel, 2.675 kg of polysorbate 80 were weighed, polysorbate 80 was added to the dosing tank, anhydrous ethanol was slowly added under stirring, and the mother liquor density was measured by a hydrometer until the mother liquor density was 0.896 g/ Ml.
  • Docetaxel is added to the mother liquor, stirred to completely dissolve and mix well.
  • the completely dissolved and uniformly mixed docetaxel solution was sterilized by a 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile chamber, and placed in a vial, half-plugged, loaded, placed in a lyophilizer, before setting.
  • the box temperature is 8.5 ° C and is kept for 50 minutes.
  • the compressor is used to cool the rear tank cold trap, and the temperature of the back tank cold trap is maintained at -58 to -62 °C.
  • Open true Empty pump and septum valve the front box vacuum is controlled at 80 ⁇ 100Pa, the front box temperature is set to 9.5 °C, the cold trap temperature is maintained at -58 ⁇ - 62 °C, and the front box vacuum is maintained for 4 hours.
  • the degree is controlled at 40 ⁇ 80Pa, the front box temperature is set to 9.0°C, the cold trap temperature is kept at -58 ⁇ - 62 °C, and after 2 hours, the front box vacuum is controlled at 10 ⁇ 40Pa, and the front box is set.
  • the temperature is 9.0 ° C
  • the cold trap temperature is kept below -62 ° C, after 2 hours, the front box vacuum is controlled below 10 Pa, the front box temperature is set to 12.0 ° C, and the cold trap temperature is maintained at -65 ° Below C, for 3 hours, until the vacuum of the front box is closed, the pressure is not changed significantly, the plug is plugged out, the box is closed, and the aluminum-plastic composite is used to cover the mouth. After passing the quality inspection, the package is ready for injection. Match composition.
  • Docetaxel is added to the mother liquor, stirred to completely dissolve and mix well.
  • the completely dissolved and uniformly mixed docetaxel solution was sterilized by a 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile chamber, and placed in a vial, half-plugged, loaded, placed in a lyophilizer, before setting.
  • the box temperature is 8.5 °C and is kept for 55 minutes.
  • the compressor is used to cool the rear tank cold trap, and the temperature of the back tank cold trap is maintained at -58 to -62 °C.
  • control the vacuum of the front box to 80 ⁇ 100Pa, set the temperature of the front box to 8.5 °C, and keep the temperature of the cold trap at -58 ⁇ - 62 °C. After 4 hours, vacuum the front box. The degree is controlled at 40 ⁇ 80Pa, the front box temperature is set to 8.5 °C, the cold trap temperature is kept at -58 ⁇ - 62 °C, and after 2 hours, the front box vacuum is controlled at 10 ⁇ 40Pa, and the front box is set. The temperature is 8.5 °C, the temperature of the cold trap is kept below -62 °C.
  • the vacuum of the front box is controlled below 10Pa, the temperature of the front box is set to 11.5 °C, and the temperature of the cold trap is kept at -65 °. Below C, for 3.5 hours, until the vacuum of the front box is closed, the pressure is not changed significantly, the plug is plugged out, the box is closed, and the aluminum-plastic composite is used to cover the mouth. After passing the quality inspection, the package is ready for injection. Match composition.
  • docetaxel 100 g of docetaxel, 2.675 kg of polysorbate 80 were weighed, polysorbate 80 was added to the dosing tank, anhydrous ethanol was slowly added under stirring, and the mother liquor density was measured by a hydrometer until the mother liquor density was 0.888 g/ Ml.
  • Docetaxel is added to the mother liquor, stirred to completely dissolve and mix well.
  • the completely dissolved and uniformly mixed docetaxel solution was sterilized by a 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile chamber, and placed in a vial, half-plugged, loaded, placed in a lyophilizer, before setting.
  • the box temperature is 9.5 °C and is kept for 60 minutes.
  • the compressor is used to cool the rear tank cold trap, and the temperature of the back tank cold trap is maintained at -58 to -62 °C.
  • Open the vacuum pump and the septum valve control the front box vacuum to 80 ⁇ 100Pa, set the front box temperature to 7.5 °C, cold trap The temperature is maintained at -58 ⁇ - 62 °C.
  • the vacuum of the front box is controlled at 40 ⁇ 80Pa, the front box temperature is set to 8.0 °C, and the cold trap temperature is maintained at -58 ⁇ - 62 °C.
  • the front box vacuum is controlled at 10 ⁇ 40Pa, the front box temperature is set to 8.0°C, and the cold trap temperature is kept below -62°C.
  • the front box vacuum is controlled at 10Pa.
  • the front box temperature is set to 12.5 °C
  • the cold trap temperature is kept below -65 °C for 3 hours
  • the vacuum of the front box is closed after the shut-off valve is closed.
  • the gauze mouth is packaged after passing the quality inspection, that is, the docetaxel composition for injection.
  • Docetaxel is added to the mother liquor, stirred to completely dissolve and mix well.
  • the completely dissolved and uniformly mixed docetaxel solution was sterilized by a 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile chamber, and placed in a vial, half-plugged, loaded, placed in a lyophilizer, before setting.
  • the box temperature was 7.5 °C and held for 45 minutes.
  • the compressor is used to cool the rear tank cold trap, and the temperature of the back tank cold trap is maintained at -58 to -62 °C.
  • the vacuum of the front box is controlled below 10Pa, the temperature of the front box is set to 11.0 °C, and the temperature of the cold trap is kept at -65 °. C below, for 4 hours, until the vacuum of the front box is closed, the pressure is not changed significantly, the plug is plugged out, the box is closed, and the aluminum-plastic composite is used to cover the mouth. After passing the quality inspection, the package is ready for injection. Match composition.
  • docetaxel 100 g of docetaxel, 2.675 kg of polysorbate 80 were weighed, polysorbate 80 was added to the dosing tank, anhydrous ethanol was slowly added under stirring, and the mother liquor density was measured by a hydrometer until the mother liquor density was 0.894 g/ Ml.
  • Docetaxel is added to the mother liquor, stirred to completely dissolve and mix well.
  • the completely dissolved and uniformly mixed docetaxel solution was sterilized by a 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile chamber, and placed in a vial, half-plugged, loaded, placed in a lyophilizer, before setting.
  • the box temperature is 9.0 ° C and is kept for 60 minutes.
  • the compressor is used to cool the rear tank cold trap, and the temperature of the back tank cold trap is maintained at -58 to -62 °C.
  • Open the vacuum pump and the septum valve control the vacuum of the front box to 80 ⁇ 100Pa, set the temperature of the front box to 9.0°C, and keep the temperature of the cold trap at -58 ⁇ - 62 °C. After 4 hours, vacuum the front box.
  • Degree control at 40 ⁇ 80Pa set The front box temperature is 9.0 ° C
  • the cold trap temperature is maintained at -58 ⁇ - 62 °C
  • the front box vacuum is controlled at 10 ⁇ 40Pa
  • the front box temperature is set to 9.0 °C, the cold trap temperature.
  • Docetaxel is added to the mother liquor, stirred to completely dissolve and mix well.
  • the completely dissolved and uniformly mixed docetaxel solution was sterilized by a 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile chamber, and placed in a vial, half-plugged, loaded, placed in a lyophilizer, before setting.
  • the box temperature is 8.5 °C and is kept for 50 minutes.
  • the compressor is used to cool the rear tank cold trap, and the temperature of the back tank cold trap is maintained at -58 to -62 °C.
  • control the vacuum of the front box to 80 ⁇ 100Pa, set the temperature of the front box to 8.5 °C, and keep the temperature of the cold trap at -58 ⁇ - 62 °C. After 4 hours, vacuum the front box. The degree is controlled at 40 ⁇ 80Pa, the front box temperature is set to 8.5 °C, the cold trap temperature is kept at -58 ⁇ - 62 °C, and after 2 hours, the front box vacuum is controlled at 10 ⁇ 40Pa, and the front box is set.
  • the temperature is 8.5 °C
  • the cold trap temperature is kept below -62 °C
  • the front box vacuum is controlled below 10Pa
  • the front box temperature is set to 12.5 °C
  • the cold trap temperature is kept at -65 ° Below C, for 3 hours, until the vacuum of the front box is closed, the pressure is not changed significantly, the plug is plugged out, the box is closed, and the aluminum-plastic composite is used to cover the mouth. After passing the quality inspection, the package is ready for injection. Match composition.
  • docetaxel 100 g of docetaxel, 2.675 kg of polysorbate 80 were weighed, polysorbate 80 was added to the dosing tank, anhydrous ethanol was slowly added under stirring, and the mother liquor density was measured by a hydrometer until the mother liquor density was 0.890 g/ Ml.
  • Docetaxel is added to the mother liquor, stirred to completely dissolve and mix well.
  • the completely dissolved and uniformly mixed docetaxel solution was sterilized by a 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile chamber, and placed in a vial, half-plugged, loaded, placed in a lyophilizer, before setting.
  • the box temperature is 7.5 °C and is kept for 60 minutes.
  • the compressor is used to cool the rear tank cold trap, and the temperature of the back tank cold trap is maintained at -58 to -62 °C. Open the vacuum pump and the septum valve, control the vacuum of the front box to 80 ⁇ 100Pa, set the temperature of the front box to 7.5 °C, and keep the temperature of the cold trap at -58 ⁇ - 62 °C. After 4 hours, vacuum the front box. The degree is controlled at 40 ⁇ 80Pa, the front box temperature is set to 7.5 °C, the cold trap temperature is maintained at -58 ⁇ - 62 °C, and the front box vacuum is maintained for 2 hours.
  • the control is at 10 ⁇ 40Pa, the front box temperature is set to 7.5 °C, the cold trap temperature is kept below -62 °C, and after 2 hours, the front box vacuum is controlled below 10Pa, and the front box temperature is set to 10.5 °. C, the temperature of the cold trap is kept below -65 °C for 4 hours.
  • the vacuum of the front box is closed, there is no significant change in the vacuum.
  • the plug is plugged out, and the box is closed with aluminum-plastic composite. After passing the quality inspection, the package is qualified. , that is, a docetaxel composition for injection.
  • Docetaxel is added to the mother liquor, stirred to completely dissolve and mix well.
  • the completely dissolved and uniformly mixed docetaxel solution was sterilized by a 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile chamber, and placed in a vial, half-plugged, loaded, placed in a lyophilizer, before setting.
  • the box temperature is 9.5 °C and is kept for 45 minutes.
  • the compressor is used to cool the rear tank cold trap, and the temperature of the back tank cold trap is maintained at -58 to -62 °C.
  • the vacuum of the front box is controlled below 10Pa, the temperature of the front box is set to 12.5 °C, and the temperature of the cold trap is kept at -65 °. Below C, for 3 hours, until the vacuum of the front box is closed, the pressure is not changed significantly, the plug is plugged out, the box is closed, and the aluminum-plastic composite is used to cover the mouth. After passing the quality inspection, the package is ready for injection. Match composition.
  • docetaxel 100 g of docetaxel, 2.675 kg of polysorbate 80 were weighed, polysorbate 80 was added to the dosing tank, anhydrous ethanol was slowly added under stirring, and the mother liquor density was measured by a hydrometer until the mother liquor density was 0.893 g/ Ml.
  • Docetaxel is added to the mother liquor, stirred to completely dissolve and mix well.
  • the completely dissolved and uniformly mixed docetaxel solution was sterilized by a 0.22 ⁇ polytetrafluoroethylene filter and placed in a sterile chamber, and placed in a vial, half-plugged, loaded, placed in a lyophilizer, before setting.
  • the box temperature was 8.0 ° C and was kept for 60 minutes.
  • the compressor is used to cool the rear tank cold trap, and the temperature of the back tank cold trap is maintained at -58 to -62 °C. Open the vacuum pump and the septum valve, control the vacuum of the front box to 80 ⁇ 100Pa, set the temperature of the front box to 8.0°C, and keep the temperature of the cold trap at -58 ⁇ - 62 °C. After 4 hours, vacuum the front box. The degree is controlled at 40 ⁇ 80Pa, the front box temperature is set to 8.0°C, the cold trap temperature is kept at -58 ⁇ - 62 °C, and after 2 hours, the front box vacuum is controlled at 10 ⁇ 40Pa, and the front box is set.
  • the temperature is 8.0 ° C
  • the cold trap temperature is kept below -62 ° C, lasting 2
  • the front box vacuum is controlled below 10Pa
  • the front box temperature is set to 11.5°C
  • the cold trap temperature is kept below -65°C for 3.5 hours, until the vacuum of the front box is closed and there is no significant change in vacuum.
  • the docetaxel composition for injection was prepared according to each of Examples 1 to 12, and the visible foreign matter, insoluble particles, content, related substances and residual ethanol amount were separately examined, and the rejection rate was statistically calculated. The results are shown in Table 1. .

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一种供注射用的多西他赛组合物及其制备方法 技术领域
本发明涉及的是一种供注射用的多西他赛组合物及其制备方法，通过该方法 制备的多西他赛组合物可以用于非小细胞肺癌的治疗。
背景技术
多西他赛 （Docetaxel) 是由罗纳普朗克 ·乐安 （Rhone-Poulenc Rorer) 公司 开发的一个半合成紫杉醇衍生物， 属微管解聚抑制剂，通过促进小管聚合成稳定 的微管并抑制其解聚从而使游离小管的数量显著减少。 于 1995年 4月在墨西哥 首次上市， 并随即在英、 美、 法、 意、 德、 日等主要国家上市， 用于经蒽环类抗 肿瘤药物治疗无效或仍复发的晚期和转移性乳腺癌及曾经治疗无效的非小细胞 肺癌。 推荐给药方案为每 3周 1次， 1小时静脉输注 100mg/m2。 多西他赛为白 色或类白色粉末， 具亲脂性， 几乎不溶于水。
多西他赛的化学名称为： [2aR-(2a α ,4 β ,4a β ,6 β ,9 a ,(aR*， β S*), l l α , 12 a , 12a a , 12b a )]- p -[[(l, l二甲基乙氧基)羰基]氨基]- a -羟基苯丙酸 [12b-乙酰氧 -12-苯甲酰氧 -2a,3， 4,4a,5,6,9, 10, l l, 12, 12a, 12b-十二氢 -4,6, 11-三羟基 -4a,8, 13, 13- 四甲基 -5-氧代 -7， 11-亚甲基 -1H-环癸五烯并 [3,4]苯并 [1,2-b]氧杂丁环 -9-基]酯三 水合物， 分子式为： C43H53N014 · 3¾0， 分子量为： 861.94。
因多西他赛在水中溶解性极差， 现有技术采用聚山梨酯 80等作为溶剂制备 其注射液， 但由于聚山梨酯 80等溶剂粘度高， 流动性差， 无法准确灌装， 通常 将多西他赛溶于乙醇后与聚山梨酯 80混匀， 再通过减压干燥的方法除去乙醇来 制备多西他赛注射液。对于制药领域来说， 要有充分的无菌保证， 又要进行减压 干燥，最好的办法即是在无菌环境下利用冻干机对灌装好的多西他赛溶液进行真 空干燥， 达到无菌保障和除去乙醇的目的。但在实际的工业化生产中发现， 真空 条件下乙醇大量挥发， 多西他赛溶液温度急剧下降， 从而导致多西他赛析出， 真 空干燥除去乙醇结束后，析出的多西他赛无法再次溶解在余留的聚山梨酯 80中， 导致多西他赛注射液可见异物和不溶性微粒不合格，大量的废品增加了灯检工作 量和灯检人力成本， 并使得成品率大幅下降， 生产成本也随之增加。 另外， 由于 除去乙醇后的多西他赛注射液流动性很差，试图通过灯检检出所有废品极其困难 甚至是不可能的， 这就给患者临床安全用药带来了隐患。
CN200910304453.2 公布了一种多西他赛药物组合物注射剂， 该方法虽然可 以保证较长时间内没有多西他赛析出，但其最终产品中含有较多量的乙醇， 临床 使用时对人体有更多的剌激性， 且乙醇的存在对使得多西他赛注射液稳定性变 差， 没有解决上述技术缺陷。
CN200910154685.4 公布了一种含多西他赛的药物组合物及其制备方法， 其 其制备过程繁琐， 且无法保证去除无水乙醇过程中无多西他赛析出，加入剩余的 精制聚山梨酯 80的操作也增加了质量控制的难度， 由于最终溶液粘度大， 除菌 过滤和灌装均很困难， 装量差异较大， 没有解决上述技术缺陷。
CN200610032942.3 公布了一种稳定的多西他赛注射剂。 通过加入一定量的 抗氧剂改善多西他赛注射剂的稳定性， 没有改善以上缺陷的建议。
CN200710038470.7 公布了一种多西他赛制剂及其制备方法。 其制剂的活性 成份是多西他赛磷脂分散物， 没有改善以上缺陷的建议。
CN200780000695.1 公布了一种多西他赛的药物组合物， 包含治疗有效量的 多西他赛、吐温类表面活性剂以及助溶剂，其中助溶剂选自甘油或聚乙二醇中的 一种或多种， 没有改善以上缺陷的建议。
CN200710049357.9 公布了一种以多西他赛原料药制成的供注射用的注射液 及其工艺制备方法。在注射液中加入路易斯酸， 使多西他赛处于酸性条件下， 增 加了多西他赛的稳定性， 但没有改善以上缺陷的建议。
CN200810012588.7 公布了一种应用于化学药制剂领域中的抗肿瘤药多西他 赛注射液的制备工艺，采用传统真空干燥工艺除去乙醇，真空条件下乙醇大量挥 发， 多西他赛溶液温度急剧下降， 从而导致多西他赛析出， 真空干燥除去乙醇结 束后， 析出的多西他赛无法再次溶解在余留的聚山梨酯 80中， 导致多西他赛注 射液可见异物和不溶性微粒不合格， 存在重大的缺陷。
CN200680054069.6公布了含聚山梨酯 80， 无水多西他赛 (I)或其三水合物和 pKa为 2.5-4.5 作为降解抑制剂的有机酸的药物组合物， 没有改善以上缺陷的建 议。
CN200780024837.8 公布了包含多西他赛的稳定的注射用药物组合物及其制 备方法。通过将多西他赛 (一种不溶于水的化合物)与环糊精 (CD)和水溶性聚合物 例如羟丙基甲基纤维素 (HPMC)、聚乙二醇 （PEG；)、或聚乙烯吡咯烷酮 (PVP)混合 之后， 将其溶解于蒸熘水中， 最后将混合物冻干， 没有提出任何改善以上缺陷的 建议。
现有公知技术均没有对以上缺陷提出改善的建议。
发明内容
本发明的目的是针对以上不足之处提供供注射用的多西他赛组合物及其制 备方法，通过该方法可以使多西他赛注射液在具有适当流动性以精确分装的条件 下， 实现真空环境中乙醇的稳定挥发， 并避免了多西他赛溶液温度急剧下降， 全 过程多西他赛不会析出，减少甚至完全消除了多西他赛注射液可见异物和不溶性 微粒不合格的现象。从而无需因大量剔除废品所增加了灯检工作量和灯检人力成 本， 加之成品率大幅提高， 生产成本得到降低， 也避免了因可见异物和不溶性微 粒不合格给患者临床安全用药带来的隐患。
本发明的发明人通过研究实验发现， 改变多西他赛的溶解方案，特别是脱离 原有先将多西他赛溶解于无水乙醇， 再与聚山梨酯 80混合的思路， 直接先将聚 山梨酯 80与无水乙醇混合均匀获得特定密度的母液， 该母液有适当的粘度和乙 醇挥发性能， 再将多西他赛溶解于母液当中，可以为后续的稳定挥发乙醇过程创 造良好的溶液基础。 通过研究实验发现， 将聚山梨酯 80加入到配液罐中， 搅拌 状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为 0.886〜 0.896g/ml，此时获得的母液具有最适当的粘度和乙醇挥发性能，而多西他赛的加 入对其密度无明显改变，即溶解多西他赛后的溶液同样也具有最适当的粘度和乙 醇挥发性能， 在后续的挥发乙醇过程中， 配合适当的生产工艺， 可以获得稳定的 挥发速度，无乙醇急剧挥发造成的喷瓶现象，多西他赛溶液温度也不会急剧下降， 避免了多西他赛析出导致的可见异物及不溶性微粒废品。
在制备工艺方面，本发明的发明人通过研究实验发现，传统技术无法制备出 质量稳定均一的产品， 而通过恰当的制备工艺，通过控制母液密度来解决这一难 题。
首先， 预置前箱温度： 将分装好的多西他赛药液置冻干机内， 设定前箱温度 为 7.5〜9.5°C， 并保温 45〜60分钟。 保温 45〜60分钟可以使全体板层制品温度 达到均一， 设定前箱温度为 7.5〜9.5 °C可以使制品具有良好的化学和物理性能， 化学降解速度很慢， 物理性状上也不会出现分层和析出。更关键的是， 这一预置 温度使得本发明的多西他赛溶液具有适宜的粘度和乙醇挥发性能，在后续的挥发 乙醇过程中， 多西他赛溶液温度在这一基础上的波动幅度也最小。
其次， 利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C， 该 条件最有利于乙醇的挥发和前箱真空度的控制， 温度过低则前后箱压差不便控 制， 前箱压力过小， 第一阶段乙醇挥发速度过快而多西他赛溶液温度下降过多。
接下来， 开启真空泵和中隔阀， 分阶段进行真空干燥去除乙醇， 第一阶段， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 7.5〜9.5 °C， 冷阱温度保持在 -58〜- 62°C， 持续 4小时。 在这样的条件下， 前箱气体对流稳定， 传热均一， 乙 醇可以稳定均匀的从制品中挥发出来， 多西他赛溶液温度波动极小， 不会出现析 出现象， 后箱乙醇凝结迅速， 压力稳定， 在保证乙醇高效挥发的同时真空泵工作 负担小而稳定， 乙醇进入量极小， 设备也得到了很好的保护。
随着乙醇挥发，制品的粘度和乙醇挥发性能发生改变，需相应调整制备工艺， 第二阶段， 将前箱真空度控制在 40〜80Pa， 设定前箱温度为 7.5〜9.5 °C， 冷阱温 度保持在 -58〜- 62 °C， 持续 2小时， 第三阶段， 将前箱真空度控制在 10〜40Pa， 设定前箱温度为 7.5〜9.5 °C， 冷阱温度保持在 -62°C以下， 持续 2小时。 这些制 备工艺调整使得前箱气体对流始终保持稳定，传热均一， 乙醇可以稳定均匀的从 制品中挥发出来， 整个过程多西他赛溶液温度波动极小， 不会出现析出现象， 后 箱乙醇凝结迅速， 压力稳定， 乙醇挥发一直保持高效。
最后，在第四阶段，将前箱真空度控制在 10Pa以下，设定前箱温度为 10.5〜 12.5 °C， 冷阱温度保持在 -65 °C以下， 持续 3〜4小时， 至关闭中隔阀前箱真空无 显著变化后， 压塞， 出箱。 由于后期乙醇含量已经很少， 不再需要维持较好的对 流， 因此将前箱真空度控制在 10Pa以下， 以保证乙醇最大限度的挥发出来， 并 辅以一定的供热， 将前箱温度设定为 10.5〜12.5 °C， 提高后箱冷阱捕捉能力， 大 幅将冷阱温度降低至 -65 °C以下。 这些制备工艺， 使得最终成品具有很低的乙醇 含量， 极大的提高了供注射用多西他赛组合物的稳定性。
本发明提供的供注射用的多西他赛组合物， 具体如下：
一种供注射用的多西他赛组合物， 主要成分为多西他赛和聚山梨酯 80， 并 在配制过程中使用无水乙醇作为溶剂， 是按照如下方法制备：
1 )母液配制： 将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙 醇， 通过比重计检测母液密度， 直至母液密度为 0.886〜0.896g/ml;
2) 溶解： 按多西他赛和聚山梨酯 80的质量比为 1 :26.75的配比； 将多西他 赛加入到步聚 1 ) 制得的母液中， 搅拌使之完全溶解并混合均匀；
3 )无菌过滤、 分装： 将步聚 2)得到的多西他赛溶液经 0.22μιη聚四氟乙烯 滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞；
4) 真空干燥除乙醇：
a、 预置前箱温度： 将步聚 3 ) 分装好的多西他赛药液置冻干机内， 设定前 箱温度为 7.5〜9.5°C， 保温 45〜60分钟；
b、 后箱制冷： 利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜 -62 °C ;
c、 除乙醇： 开启真空泵和中隔阀， 分阶段进行真空干燥去除乙醇， 第一阶段， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 7.5〜9.5°C， 冷阱温度保持在 -58〜- 62 °C， 持续 4小时，
第二阶段， 将前箱真空度控制在 40〜80Pa， 设定前箱温度为 7.5〜9.5°C， 冷 阱温度保持在 -58〜- 62 °C， 持续 2小时，
第三阶段， 将前箱真空度控制在 10〜40Pa， 设定前箱温度为 7.5〜9.5°C， 冷 阱温度保持在 -62°C以下， 持续 2小时，
第四阶段， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 10.5〜12.5°C， 冷阱温度保持在 -65°C以下， 持续 3〜4小时， 至关闭中隔阀前箱真空无显著变化 后， 压塞， 出箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得。
一种供注射用的多西他赛组合物， 其制备方法为：
1 )母液配制： 将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙 醇， 通过比重计检测母液密度， 直至母液密度为 0.886〜0.896g/ml;
2) 溶解： 按多西他赛和聚山梨酯 80的质量比为 1 :26.75的配比； 将多西他 赛加入到步聚 1 ) 制得的母液中， 搅拌使之完全溶解并混合均匀；
3 )无菌过滤、 分装： 将步聚 2)得到的多西他赛溶液经 0.22μιη聚四氟乙烯 滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞； 4) 真空干燥除乙醇：
a、 预置前箱温度： 将步聚 3 ) 分装好的多西他赛药液置冻干机内， 设定前 箱温度为 7.5〜9.5 °C， 保温 45〜60分钟；
b、 后箱制冷： 利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜 -62 °C ;
c、 除乙醇： 开启真空泵和中隔阀， 分阶段进行真空干燥去除乙醇， 第一阶段， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 7.5〜9.5 °C， 冷阱温度保持在 -58〜- 62 °C， 持续 4小时，
第二阶段， 将前箱真空度控制在 40〜80Pa， 设定前箱温度为 7.5〜9.5 °C， 冷 阱温度保持在 -58〜- 62 °C， 持续 2小时，
第三阶段， 将前箱真空度控制在 10〜40Pa， 设定前箱温度为 7.5〜9.5 °C， 冷 阱温度保持在 -62°C以下， 持续 2小时，
第四阶段， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 10.5〜12.5 °C， 冷阱温度保持在 -65 °C以下， 持续 3〜4小时， 至关闭中隔阀前箱真空无显著变化 后， 压塞， 出箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得。
本发明供注射用的多西他赛组合物及其制备方法，通过该方法使多西他赛注 射液在具有适当流动性以精确分装的条件下， 实现真空环境中乙醇的稳定挥发， 并避免了多西他赛溶液温度急剧下降，全过程多西他赛不会析出，减少甚至完全 消除了多西他赛注射液可见异物和不溶性微粒不合格的现象。从而无需因大量剔 除废品所增加了灯检工作量和灯检人力成本，加之成品率大幅提高， 生产成本得 到降低，也避免了因可见异物和不溶性微粒不合格给患者临床安全用药带来的隐 患。本发明大大提高了供注射用的多西他赛组合物在制备过程的稳定性， 制备的 供注射用的多西他赛组合物有关物质含量更低， 质量均一稳定， 乙醇干燥彻底， 在运输和贮存过程中的稳定性更好。本发明制备工艺简单，方便可行，重复性好， 生产成本较低，很容易实现工业化大生产，从而可以产生可观的经济和社会效益。 具体实施方式
下面通过实施例来进一步说明本发明。应该正确理解的是： 本发明的实施例 仅仅是用于说明本发明而给出， 而不是对本发明的限制， 所以， 在本发明的方法 前提下对本发明的简单改进均属本发明要求保护的范围。 实施例 1 :
称取 lOOg多西他赛、 2.675kg聚山梨酯 80、 5.850kg无水乙醇， 将无水乙醇 加入到配液罐中， 搅拌状态下加入多西他赛， 搅拌使之完全溶解。加入聚山梨酯 80， 继续搅拌使之完全混合均匀， 将混合均匀的多西他赛溶液经 0.22μιη聚四氟 乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 利用压缩机对后箱冷阱制冷， 开启真空泵和中隔阀， 对制品中乙醇进行挥发， 持 续 12小时， 压塞， 出箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得供注射 用的多西他赛组合物。
实施例 2:
称取 100g多西他赛、 2.675kg聚山梨酯 80，将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为
0.890g/ml。将多西他赛加入到母液中， 搅拌使之完全溶解并混合均匀。将完全溶 解并混合均匀的多西他赛溶液经 0.22μιη聚四氟乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 设定前箱温度为 8.0°C， 保温 50 分钟。利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C。 开启真 空泵和中隔阀， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 8.5°C， 冷阱 温度保持在 -58〜- 62 °C， 持续 4小时后， 将前箱真空度控制在 40〜80Pa， 设定 前箱温度为 9.5°C， 冷阱温度保持在 -58〜- 62 °C， 持续 2小时后， 将前箱真空度 控制在 10〜40Pa， 设定前箱温度为 7.5°C， 冷阱温度保持在 -62°C以下， 持续 2 小时后， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 10.5°C， 冷阱温度保 持在 -65°C以下， 持续 4小时， 至关闭中隔阀前箱真空无显著变化后， 压塞， 出 箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得供注射用的多西他赛组合物。
实施例 3 :
称取 100g多西他赛、 2.675kg聚山梨酯 80，将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为 0.896g/ml。将多西他赛加入到母液中， 搅拌使之完全溶解并混合均匀。将完全溶 解并混合均匀的多西他赛溶液经 0.22μιη聚四氟乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 设定前箱温度为 8.5°C， 保温 50 分钟。利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C。 开启真 空泵和中隔阀， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 9.5 °C， 冷阱 温度保持在 -58〜- 62 °C， 持续 4小时后， 将前箱真空度控制在 40〜80Pa， 设定 前箱温度为 9.0°C， 冷阱温度保持在 -58〜- 62 °C， 持续 2小时后， 将前箱真空度 控制在 10〜40Pa， 设定前箱温度为 9.0°C， 冷阱温度保持在 -62°C以下， 持续 2 小时后， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 12.0°C， 冷阱温度保 持在 -65 °C以下， 持续 3小时， 至关闭中隔阀前箱真空无显著变化后， 压塞， 出 箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得供注射用的多西他赛组合物。
实施例 4:
称取 100g多西他赛、 2.675kg聚山梨酯 80，将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为
0.892g/ml。将多西他赛加入到母液中， 搅拌使之完全溶解并混合均匀。将完全溶 解并混合均匀的多西他赛溶液经 0.22μιη聚四氟乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 设定前箱温度为 8.5 °C， 保温 55 分钟。利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C。 开启真 空泵和中隔阀， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 8.5 °C， 冷阱 温度保持在 -58〜- 62 °C， 持续 4小时后， 将前箱真空度控制在 40〜80Pa， 设定 前箱温度为 8.5 °C， 冷阱温度保持在 -58〜- 62 °C， 持续 2小时后， 将前箱真空度 控制在 10〜40Pa， 设定前箱温度为 8.5 °C， 冷阱温度保持在 -62°C以下， 持续 2 小时后， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 11.5 °C， 冷阱温度保 持在 -65 °C以下， 持续 3.5 小时， 至关闭中隔阀前箱真空无显著变化后， 压塞， 出箱，用铝塑组合盖扎口，经质检合格后包装，即得供注射用的多西他赛组合物。
实施例 5 :
称取 100g多西他赛、 2.675kg聚山梨酯 80，将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为 0.888g/ml。将多西他赛加入到母液中， 搅拌使之完全溶解并混合均匀。将完全溶 解并混合均匀的多西他赛溶液经 0.22μιη聚四氟乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 设定前箱温度为 9.5 °C， 保温 60 分钟。利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C。 开启真 空泵和中隔阀， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 7.5 °C， 冷阱 温度保持在 -58〜- 62 °C， 持续 4小时后， 将前箱真空度控制在 40〜80Pa， 设定 前箱温度为 8.0°C， 冷阱温度保持在 -58〜- 62 °C， 持续 2小时后， 将前箱真空度 控制在 10〜40Pa， 设定前箱温度为 8.0°C， 冷阱温度保持在 -62°C以下， 持续 2 小时后， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 12.5 °C， 冷阱温度保 持在 -65 °C以下， 持续 3小时， 至关闭中隔阀前箱真空无显著变化后， 压塞， 出 箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得供注射用的多西他赛组合物。
实施例 6:
称取 100g多西他赛、 2.675kg聚山梨酯 80，将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为
0.886g/ml。将多西他赛加入到母液中， 搅拌使之完全溶解并混合均匀。将完全溶 解并混合均匀的多西他赛溶液经 0.22μιη聚四氟乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 设定前箱温度为 7.5 °C， 保温 45 分钟。利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C。 开启真 空泵和中隔阀， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 8.0°C， 冷阱 温度保持在 -58〜- 62 °C， 持续 4小时后， 将前箱真空度控制在 40〜80Pa， 设定 前箱温度为 7.5 °C， 冷阱温度保持在 -58〜- 62 °C， 持续 2小时后， 将前箱真空度 控制在 10〜40Pa， 设定前箱温度为 9.5 °C， 冷阱温度保持在 -62°C以下， 持续 2 小时后， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 11.0°C， 冷阱温度保 持在 -65 °C以下， 持续 4小时， 至关闭中隔阀前箱真空无显著变化后， 压塞， 出 箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得供注射用的多西他赛组合物。
实施例 7:
称取 100g多西他赛、 2.675kg聚山梨酯 80，将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为 0.894g/ml。将多西他赛加入到母液中， 搅拌使之完全溶解并混合均匀。将完全溶 解并混合均匀的多西他赛溶液经 0.22μιη聚四氟乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 设定前箱温度为 9.0°C， 保温 60 分钟。利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C。 开启真 空泵和中隔阀， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 9.0°C， 冷阱 温度保持在 -58〜- 62 °C， 持续 4小时后， 将前箱真空度控制在 40〜80Pa， 设定 前箱温度为 9.0°C， 冷阱温度保持在 -58〜- 62 °C， 持续 2小时后， 将前箱真空度 控制在 10〜40Pa， 设定前箱温度为 9.0°C， 冷阱温度保持在 -62°C以下， 持续 2 小时后， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 12.0°C， 冷阱温度保 持在 -65 °C以下， 持续 3.5 小时， 至关闭中隔阀前箱真空无显著变化后， 压塞， 出箱，用铝塑组合盖扎口，经质检合格后包装，即得供注射用的多西他赛组合物。
实施例 8:
称取 100g多西他赛、 2.675kg聚山梨酯 80，将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为
0.891g/ml。将多西他赛加入到母液中， 搅拌使之完全溶解并混合均匀。将完全溶 解并混合均匀的多西他赛溶液经 0.22μιη聚四氟乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 设定前箱温度为 8.5 °C， 保温 50 分钟。利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C。 开启真 空泵和中隔阀， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 8.5 °C， 冷阱 温度保持在 -58〜- 62 °C， 持续 4小时后， 将前箱真空度控制在 40〜80Pa， 设定 前箱温度为 8.5 °C， 冷阱温度保持在 -58〜- 62 °C， 持续 2小时后， 将前箱真空度 控制在 10〜40Pa， 设定前箱温度为 8.5 °C， 冷阱温度保持在 -62°C以下， 持续 2 小时后， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 12.5 °C， 冷阱温度保 持在 -65 °C以下， 持续 3小时， 至关闭中隔阀前箱真空无显著变化后， 压塞， 出 箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得供注射用的多西他赛组合物。
实施例 9:
称取 100g多西他赛、 2.675kg聚山梨酯 80，将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为 0.890g/ml。将多西他赛加入到母液中， 搅拌使之完全溶解并混合均匀。将完全溶 解并混合均匀的多西他赛溶液经 0.22μιη聚四氟乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 设定前箱温度为 7.5 °C， 保温 60 分钟。利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C。 开启真 空泵和中隔阀， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 7.5 °C， 冷阱 温度保持在 -58〜- 62 °C， 持续 4小时后， 将前箱真空度控制在 40〜80Pa， 设定 前箱温度为 7.5 °C， 冷阱温度保持在 -58〜- 62 °C， 持续 2小时后， 将前箱真空度 控制在 10〜40Pa， 设定前箱温度为 7.5 °C， 冷阱温度保持在 -62°C以下， 持续 2 小时后， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 10.5 °C， 冷阱温度保 持在 -65 °C以下， 持续 4小时， 至关闭中隔阀前箱真空无显著变化后， 压塞， 出 箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得供注射用的多西他赛组合物。
实施例 10:
称取 100g多西他赛、 2.675kg聚山梨酯 80，将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为
0.889g/ml。将多西他赛加入到母液中， 搅拌使之完全溶解并混合均匀。将完全溶 解并混合均匀的多西他赛溶液经 0.22μιη聚四氟乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 设定前箱温度为 9.5 °C， 保温 45 分钟。利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C。 开启真 空泵和中隔阀， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 9.5 °C， 冷阱 温度保持在 -58〜- 62 °C， 持续 4小时后， 将前箱真空度控制在 40〜80Pa， 设定 前箱温度为 9.5 °C， 冷阱温度保持在 -58〜- 62 °C， 持续 2小时后， 将前箱真空度 控制在 10〜40Pa， 设定前箱温度为 9.5 °C， 冷阱温度保持在 -62°C以下， 持续 2 小时后， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 12.5 °C， 冷阱温度保 持在 -65 °C以下， 持续 3小时， 至关闭中隔阀前箱真空无显著变化后， 压塞， 出 箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得供注射用的多西他赛组合物。
实施例 11 :
称取 100g多西他赛、 2.675kg聚山梨酯 80，将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙醇， 通过比重计检测母液密度， 直至母液密度为 0.893g/ml。将多西他赛加入到母液中， 搅拌使之完全溶解并混合均匀。将完全溶 解并混合均匀的多西他赛溶液经 0.22μιη聚四氟乙烯滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞， 装盘， 置冻干机内， 设定前箱温度为 8.0°C， 保温 60 分钟。利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜- 62 °C。 开启真 空泵和中隔阀， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 8.0°C， 冷阱 温度保持在 -58〜- 62 °C， 持续 4小时后， 将前箱真空度控制在 40〜80Pa， 设定 前箱温度为 8.0°C， 冷阱温度保持在 -58〜- 62 °C， 持续 2小时后， 将前箱真空度 控制在 10〜40Pa， 设定前箱温度为 8.0°C， 冷阱温度保持在 -62°C以下， 持续 2 小时后， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 11.5°C， 冷阱温度保 持在 -65°C以下， 持续 3.5 小时， 至关闭中隔阀前箱真空无显著变化后， 压塞， 出箱，用铝塑组合盖扎口，经质检合格后包装，即得供注射用的多西他赛组合物。
实施例 12:
按实施例 1〜12各分别制备供注射用的多西他赛组合物，再分别检查可见异 物、 不溶性微粒、 含量、 有关物质和乙醇残留量， 并统计计算其废品率， 其结果 见表 1。
表 1 供注射用的多西他赛组合物检查结果 废品率 不溶性微粒 有关物质 乙醇残留 实施例 可见异物 含 g(%)
( ) 1 Ομτη 25 μΐΏ e/。）
1 8.75 部分不合格 4780 376 98.88 0.87 7.19
2 0.21 均符合规定 620 3 99.14 0.21 0.52
3 0.12 均符合规定 480 0 99.39 0.23 0.38
4 0.18 均符合规定 550 0 99.18 0.15 0.75
5 0.07 均符合规定 730 6 98.92 0.24 0.66
6 0.09 均符合规定 820 6 98.67 0.17 0.47
7 0.18 均符合规定 440 0 99.26 0.14 0.49
8 0.15 均符合规定 520 0 100.1 0.23 0.56
9 0.14 均符合规定 460 0 99.94 0.18 0.44
10 0.17 均符合规定 390 0 100.5 0.21 0.48
11 0.10 均符合规定 510 0 99.78 0.22 0.57 从表 1可以看出， 本发明的技术方案 （实施例 2〜11 ) 较现有技术 （实施例 1 ) 废品率显著降低， 可见异物及不溶性微粒更有保障， 有关物质 （即杂质） 更 低， 乙醇残留量小， 具有明显优势。

Claims

权 利 要 求 书
1、 一种供注射用的多西他赛组合物， 其特征在于主要成分为多西他赛和聚 山梨酯 80， 并在配制过程中使用无水乙醇作为溶剂， 是按照如下方法制备：
1 )母液配制： 将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙 醇， 通过比重计检测母液密度， 直至母液密度为 0.886〜0.896g/ml;
2) 溶解： 按多西他赛和聚山梨酯 80的质量比为 1 :26.75的配比； 将多西他 赛加入到步聚 1 ) 制得的母液中， 搅拌使之完全溶解并混合均匀；
3 )无菌过滤、 分装： 将步聚 2)得到的多西他赛溶液经 0.22μιη聚四氟乙烯 滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞；
4) 真空干燥除乙醇：
a、 预置前箱温度： 将步聚 3 ) 分装好的多西他赛药液置冻干机内， 设定前 箱温度为 7.5〜9.5 °C， 保温 45〜60分钟；
b、 后箱制冷： 利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜 -62 °C ;
c、 除乙醇： 开启真空泵和中隔阀， 分阶段进行真空干燥去除乙醇， 第一阶段， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 7.5〜9.5 °C， 冷阱温度保持在 -58〜- 62 °C， 持续 4小时，
第二阶段， 将前箱真空度控制在 40〜80Pa， 设定前箱温度为 7.5〜9.5 °C， 冷 阱温度保持在 -58〜- 62 °C， 持续 2小时，
第三阶段， 将前箱真空度控制在 10〜40Pa， 设定前箱温度为 7.5〜9.5 °C， 冷 阱温度保持在 -62°C以下， 持续 2小时，
第四阶段， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 10.5〜12.5 °C， 冷阱温度保持在 -65 °C以下， 持续 3〜4小时， 至关闭中隔阀前箱真空无显著变化 后， 压塞， 出箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得。
2、 一种权利要求 1所述的供注射用的多西他赛组合物的制备方法， 其特征 在于制备方法为：
1 )母液配制： 将聚山梨酯 80加入到配液罐中， 搅拌状态下缓慢添加无水乙 醇， 通过比重计检测母液密度， 直至母液密度为 0.886〜0.896g/ml; 2) 溶解： 按多西他赛和聚山梨酯 80的质量比为 1 :26.75的配比； 将多西他 赛加入到步聚 1 ) 制得的母液中， 搅拌使之完全溶解并混合均匀；
3 )无菌过滤、 分装： 将步聚 2)得到的多西他赛溶液经 0.22μιη聚四氟乙烯 滤器除菌过滤置无菌室内， 分装于西林瓶内， 半加塞；
4) 真空干燥除乙醇：
a、 预置前箱温度： 将步聚 3 ) 分装好的多西他赛药液置冻干机内， 设定前 箱温度为 7.5〜9.5 °C， 保温 45〜60分钟；
b、 后箱制冷： 利用压缩机对后箱冷阱制冷， 并保持后箱冷阱温度为 -58〜 -62 °C ;
c、 除乙醇： 开启真空泵和中隔阀， 分阶段进行真空干燥去除乙醇， 第一阶段， 将前箱真空度控制在 80〜100Pa， 设定前箱温度为 7.5〜9.5 °C， 冷阱温度保持在 -58〜- 62 °C， 持续 4小时，
第二阶段， 将前箱真空度控制在 40〜80Pa， 设定前箱温度为 7.5〜9.5 °C， 冷 阱温度保持在 -58〜- 62 °C， 持续 2小时，
第三阶段， 将前箱真空度控制在 10〜40Pa， 设定前箱温度为 7.5〜9.5 °C， 冷 阱温度保持在 -62°C以下， 持续 2小时，
第四阶段， 将前箱真空度控制在 10Pa以下， 设定前箱温度为 10.5〜12.5 °C， 冷阱温度保持在 -65 °C以下， 持续 3〜4小时， 至关闭中隔阀前箱真空无显著变化 后， 压塞， 出箱， 用铝塑组合盖扎口， 经质检合格后包装， 即得。
PCT/CN2010/077940 2010-06-28 2010-10-21 一种供注射用的多西他赛组合物及其制备方法 WO2012000253A1 (zh)

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