WO2016008401A1 - 一种含多西他赛的药物组合物 - Google Patents

一种含多西他赛的药物组合物 Download PDF

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WO2016008401A1
WO2016008401A1 PCT/CN2015/083928 CN2015083928W WO2016008401A1 WO 2016008401 A1 WO2016008401 A1 WO 2016008401A1 CN 2015083928 W CN2015083928 W CN 2015083928W WO 2016008401 A1 WO2016008401 A1 WO 2016008401A1
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docetaxel
pharmaceutical composition
polyethylene glycol
methyl ether
glycol methyl
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PCT/CN2015/083928
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English (en)
French (fr)
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WO2016008401A8 (zh
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腾鑫
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腾鑫
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Priority claimed from CN201410336638.2A external-priority patent/CN105267158A/zh
Priority claimed from CN201410336415.6A external-priority patent/CN105287397A/zh
Priority claimed from CN201410336424.5A external-priority patent/CN105287398A/zh
Priority claimed from CN201410336464.XA external-priority patent/CN105310987A/zh
Application filed by 腾鑫 filed Critical 腾鑫
Priority to GB1700560.4A priority Critical patent/GB2542092B/en
Priority to US15/325,939 priority patent/US10080720B2/en
Publication of WO2016008401A1 publication Critical patent/WO2016008401A1/zh
Priority to ZA2017/00278A priority patent/ZA201700278B/en
Publication of WO2016008401A8 publication Critical patent/WO2016008401A8/zh

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • 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 invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing docetaxel.
  • Docetaxel (Docetaxel, C 43 H 53 NO 14 ) is a new antitumor drug based on the structure of the natural antitumor drug paclitaxel. Its anti-spectrum and paclitaxel Similarly, the mechanism of action is to promote tubulin polymerization and prevent microtubule depolymerization, thereby inhibiting mitosis and proliferation of cancer cells, and is more potent than paclitaxel.
  • IC50 is 9 times lower in human breast, colon, bladder and epithelial-like cell lines than paclitaxel.
  • docetaxel has a high anti-tumor activity, and tumors and mouse transplanted tumors can completely resolve after administration. More importantly, docetaxel does not spontaneously produce cross-resistance to docetaxel in paclitaxel-resistant cell lines.
  • Docetaxel is a white or off-white powder and is a highly fat-soluble and water-insoluble drug having a solubility in water of 6-7 ⁇ g/ml.
  • Tween 80 is added as a surfactant in the formulation of currently available docetaxel formulations. The use of Tween 80 has two major drawbacks.
  • the first drawback is that it brings a strong adverse reaction to the patient.
  • Tween 80 may cause adverse reactions including allergic reactions, hemolysis, cardiovascular adverse reactions, and fluid retention.
  • the second drawback is that the method of administration is more complicated and increases the difficulty of use.
  • Taxotere Take Taxotere as an example: firstly, the concentrated drug and the diluted solution are mixed to prepare a premixed solution, and then the premixed solution is diluted with 0.9% physiological saline to prepare a premixed mixture within 4 hours after the premixed diluent is prepared. The dilution was administered for about 1 hour. During this process, the concentrated drug mixed with the diluted solution needs to be carefully inverted for 45 seconds without stirring, so that bubbles may be formed in the resulting solution, so the solution needs to be allowed to stand for 5 minutes to allow the bubbles to escape.
  • the polymer micelle is a core-shell structure spontaneously formed from an amphiphilic block copolymer having a nanometer-sized particle size.
  • Polymer micelles were first proposed as a delivery vehicle by Bader et al. in 1984.
  • the amphiphilic block copolymer is used to encapsulate the drug in the hydrophobic core of the micelle to achieve the effect of further solubilizing the poorly soluble drug to further improve bioavailability.
  • good polymer micelles can prolong drug circulation time, reduce drug toxicity, and achieve passive targeting through EPR effects.
  • docetaxel micelles can overcome the shortcomings of commercially available docetaxel medicinal agents, but the current research on micelles in docetaxel generally lacks practical value.
  • the main disadvantages are that the particle size is too large to be The EPR effect is exerted, the drug loading is too low, and the stability of the preparation is poor.
  • Pluronic F68 as a micelle carrier
  • vitamin ETPGS as a solubilizer
  • wrapped docetaxel was only 0.923%.
  • the average particle size is as high as 135.1 ⁇ 3.42 nm (Yu Kezhen, "Research on Docetaxel Polymer Micelle").
  • Lyophilized powder is an effective method for preserving drugs.
  • the product to be dried is frozen at a low temperature, and then dried in a vacuum environment to allow the moisture to be directly sublimated from the solid state into water vapor and removed from the product to make the product active and dry.
  • the method effectively prevents the physical and chemical changes of the product and the change of the biological properties, and effectively protects the stability of the active ingredient of the heat sensitive drug; the lyophilized product has a loose shape and no change in color after drying, and can be quickly dissolved after adding water or a hydrophilic organic solvent.
  • the prescription is simple, safe and reliable.
  • the dosage of docetaxel in this pharmaceutical composition is the highest. It can exceed 25%, and the lyophilized powder has a smaller particle size and higher stability after reconstitution.
  • a pharmaceutical composition comprising docetaxel consisting of docetaxel and a polyethylene glycol methyl ether-polylactide block copolymer having an amino acid end group, wherein
  • the molecular formula of the polyethylene glycol methyl ether-polylactide block copolymer having an amino acid end group is:
  • the amino acid group R is Wherein R 1 is H, CH 3 , (CH 3 ) 2 CH, PhCH 2 or (CH 2 ) 3 NHC(NH)NH 2 .
  • Polyethylene glycol in polyethylene glycol methyl ether-polylactide block copolymer with amino acid end groups is highly stable and difficult to be degraded; polyethylene glycol methyl ether-polylactide having amino acid end groups
  • the polylactide in the block copolymer is susceptible to degradation only under strongly acidic conditions; the grafted amino acid reacts under neutral conditions. Therefore, the polyethylene glycol methyl ether-polylactide block copolymer having an amino acid end group has high stability in a normal body fluid environment.
  • the polyethylene glycol methyl ether block and the polylactide block in the polyethylene glycol methyl ether-polylactide block copolymer having an amino acid end group can be obtained by mass spectrometry or the like to obtain different triblock copolymers.
  • the above docetaxel-containing pharmaceutical composition is a lyophilized powder preparation which can be prepared by lyophilization.
  • the docetaxel refers to an anhydrous docetaxel bulk drug having a purity of 98.0% or more in terms of C 43 H 53 NO 14 .
  • polyethylene glycol methyl ether-polylactide block copolymer having amino acid end groups has no obvious carcinogenicity, no reproductive toxicity, no teratogenicity, mutagenicity, and can be degraded into lactic acid in vivo.
  • amino acid PEG can be directly excreted.
  • the cytotoxicity test showed that the cytotoxicity of the triblock copolymer was lower than the currently recognized non-toxic block copolymer mPEG-PLA, wherein Tables 1 to 4 respectively represent polyethylene glycols with different amino acid end groups. MTT method hepatotoxicity test results of methyl ether-polylactide block copolymer.
  • the present invention has the following beneficial effects:
  • the composition can be prepared into a solid lyophilized powder by a common freeze-drying process in the pharmaceutical industry, and can be quickly reconstituted by using ordinary physiological saline, water for injection or glucose for injection, and the preparation, transportation, storage and use of the drug are simpler.
  • the docetaxel content can reach more than 20%, the preparation process is simple, and it is easy for industrial application.
  • the molecular formula of the polyethylene glycol methyl ether-polylactide block copolymer having an amino acid end group is:
  • R is an amino acid group
  • a 10 to 200
  • b 3 to 30
  • the average molecular weight of the polyethylene glycol methyl ether block is 1000 to 3,500
  • the average molecular weight of the polylactide block is 450. ⁇ 5500.
  • R 1 is H, CH 3 , (CH 3 ) 2 CH, PhCH 2 or (CH 2 ) 3 NHC(NH)NH 2 .
  • Docetaxel is an anhydrous docetaxel API (CAS: 114977-28-5), produced by Xi'an Tianfeng Biotechnology Co., Ltd.;
  • the average molecular weight of the polylactide block is 505 to 4982 and the average molecular weight of the polyethylene glycol methyl ether block is 1017 to 2992. It was prepared by the inventors in accordance with the process described in Patent No. PCT-CN-2013000453. The average molecular weight of the different blocks was determined by mass spectrometry combined with the molecular weight of the starting materials.
  • the above raw materials are put into a container, and an organic solvent is added until completely dissolved.
  • the types of the organic solvent include ethanol, acetonitrile and the like.
  • the mixed membrane was placed in a water bath at 40-60 ° C until it was transparent, and ultra-pure water or physiological saline or phosphate buffer solution preheated at the same temperature was added thereto, and the mixture was shaken and hydrated to obtain a transparent drug-loaded micelle solution.
  • the drug-loaded micelle solution was filtered through a 0.45 ⁇ m microporous membrane to obtain a micelle.
  • the above drug-loaded micelle solution was prepared into a solid dry powder by a conventional lyophilization process without adding any excipients.
  • the separator temperature setting is raised from -45 ° C to -25 ° C for more than 12 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the separator temperature setting is raised from -25 ° C to 0 ° C for more than 8 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the separator temperature setting is raised from 0 ° C to 5 ° C for more than 3 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the temperature of the separator is raised from 5 ° C to 20 ° C, and after the product temperature reaches 20 ° C, it is maintained for more than 4 h, and then lyophilized to obtain a loose block of docetaxel lyophilized powder.
  • a docetaxel lyophilized powder formulation wherein: the excipient is selected from one or more of the group consisting of lactose, mannitol, dextran, glycine, and glucose.
  • the organic solvent described in the step 2 is ethanol or acetonitrile.
  • excipient in the lyophilization process is primarily to promote a solution that is difficult to solidify to ultimately yield a solid powder.
  • excipients can also improve the appearance, morphology, solubility, stability and other performance indicators of the lyophilized preparation to varying degrees.
  • Carrier polyethylene glycol methyl ether - polylactide - lysine
  • Example (1-7) The docetaxel lyophilized powder and water prepared in Example (1-7) were weighed according to the concentration of docetaxel at a concentration of 3 mg/ml, and the lyophilized powder was placed in water for injection, physiological saline or glucose injection. All docetaxel lyophilized powders were completely dissolved after 60 seconds of shaking, indicating good solubility.
  • the particle size distribution was measured by dynamic light scattering, and the particle size distribution of the reconstituted solution was measured to be between 10 and 100 nm, and the average particle diameter was between 20 and 29.2 nm, as shown in Table 6.
  • Example (1-7) The docetaxel micelles obtained in Example (1-7) were diluted with water to obtain a solution having a docetaxel concentration of about 3 mg/ml, respectively, at 15 ° C, 25 ° C, 30 ° C under normal indoor lighting conditions. The solution was visually observed for sedimentation or turbidity every 2 hours. If precipitation or turbidity occurs, the solution ends in a steady state.
  • the stability test results are shown in Table 7.
  • Tumor inhibition tests were performed using physiological saline, commercially available docetaxel injection (taxotere), and docetaxel micelle solution (obtained by the examples of the present invention), respectively.
  • Balb/c mice transplanted with L7912 tumor strain were used as test subjects.
  • the administration route was intravenous administration, and administration was performed every 3 days for 30 days.
  • the concentration of Taxotere and the docetaxel of the present invention is also 10 mg/kg.
  • the tumor volume of the mice was measured twice a week, and the results are shown in Table 8.
  • mice instilled with saline increased rapidly; the tumor volume growth rate of mice instilled with Taxotere was controlled, but the tumor volume still increased; the tumor volume of mice instilled in this invention was controlled and rapidly Reduced, see Table 8. It is proved that the present invention has a remarkable inhibitory effect on mouse T cell leukemia xenografts.
  • docetaxel is an anhydrous docetaxel bulk drug (CAS: 114977-28-5), which is produced by Xi'an Tianfeng Biotechnology Co., Ltd.;
  • the polyethylene glycol methyl ether-polylactide block copolymer having an amino acid end group is polyethylene glycol methyl ether-polylactide-aspartic acid, and its molecular formula is:
  • the average molecular weight of the polylactide block is 495 to 4996 and the average molecular weight of the polyethylene glycol methyl ether block is 987 to 3020. It was prepared by the inventors in accordance with the process described in Patent No. PCT-CN-2013000453. The average molecular weight of the different blocks was determined by mass spectrometry combined with the molecular weight of the starting materials.
  • the above raw materials are put into a container, and an organic solvent is added until completely dissolved.
  • the types of the organic solvent include ethanol, acetonitrile and the like. After rotary evaporation at 30-50 ° C for 2 h until evaporation of the organic solvent, vacuum drying at 10-60 ° C for > 12 h to remove residual organic solvent to obtain a polymer mixture film containing docetaxel.
  • the mixed membrane was placed in a water bath at 40-60 ° C until it was transparent, and ultra-pure water or physiological saline or phosphate buffer solution preheated at the same temperature was added thereto, and the mixture was shaken and hydrated to obtain a transparent drug-loaded micelle solution.
  • the drug-loaded micelle solution was filtered through a 0.45 ⁇ m microporous membrane to obtain a micelle.
  • the above drug-loaded micelle solution was prepared into a solid dry powder by a conventional lyophilization process without adding any excipients.
  • the separator temperature setting is raised from -45 ° C to -25 ° C for more than 12 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the separator temperature setting is raised from -25 ° C to 0 ° C for more than 8 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the separator temperature setting is raised from 0 ° C to 5 ° C for more than 3 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the temperature of the separator is raised from 5 ° C to 20 ° C, and after the product temperature reaches 20 ° C, it is maintained for more than 4 h, and then lyophilized to obtain a loose block of docetaxel lyophilized powder.
  • a docetaxel lyophilized powder formulation wherein: the excipient is selected from one or more of the group consisting of lactose, mannitol, dextran, glycine, and glucose.
  • the organic solvent described in the step 2 is ethanol or acetonitrile.
  • excipient in the lyophilization process is primarily to promote a solution that is difficult to solidify to ultimately yield a solid powder.
  • excipients can also improve the appearance, morphology, solubility, stability and other performance indicators of the lyophilized preparation to varying degrees.
  • Carrier polyethylene glycol methyl ether-polylactide-aspartate
  • the docetaxel lyophilized powder prepared in Example (9-15) was weighed according to the concentration of docetaxel at a concentration of 3 mg/ml. Water, the above lyophilized powder was put into water for injection, physiological saline or glucose injection, and all the docetaxel lyophilized powder was completely dissolved after shaking for 60 seconds, indicating good solubility. The particle size distribution was measured by dynamic light scattering, and the particle size distribution of the reconstituted solution was measured to be between 10 and 100 nm, and the average particle diameter was between 20 and 29.2 nm, as shown in Table 10.
  • Example (9-15) The docetaxel micelles obtained in Example (9-15) were diluted with water to obtain a solution having a docetaxel concentration of about 3 mg/ml, respectively, at 15 ° C, 25 ° C, 30 ° C under normal indoor lighting conditions. The solution was visually observed for sedimentation or turbidity every 2 hours. If precipitation or turbidity occurs, the solution ends in a steady state.
  • the stability test results are shown in Table 11.
  • Tumor inhibition tests were performed using physiological saline, commercially available docetaxel injection (taxotere), and docetaxel micelle solution (obtained by the examples of the present invention), respectively.
  • Balb/c mice transplanted with L7912 tumor strain were used as test subjects.
  • the administration route was intravenous administration, and administration was performed every 3 days for 30 days.
  • the concentration of Taxotere and the docetaxel of the present invention is also 10 mg/kg.
  • the tumor volume of the mice was measured twice a week, and the results are shown in Table 12.
  • mice instilled with saline increased rapidly; the tumor volume growth rate of mice instilled with Taxotere was controlled, but the tumor volume still increased; the tumor volume of mice instilled in this invention was controlled and rapidly Reduced, see Table 12. It is proved that the present invention has a remarkable inhibitory effect on mouse T cell leukemia xenografts.
  • docetaxel is an anhydrous docetaxel bulk drug (CAS: 114977-28-5), produced by Xi'an Tianfeng Biotechnology Co., Ltd.;
  • the polyethylene glycol methyl ether-polylactide block copolymer having an amino acid end group is polyethylene glycol methyl ether-polylactide-glutamic acid, and the molecular formula is:
  • a 10 ⁇ 200
  • b 3 ⁇ 30.
  • the average molecular weight of the polylactide block is 504 to 4985 and the average molecular weight of the polyethylene glycol methyl ether block is 1003 to 3015. It was prepared by the inventors in accordance with the process described in Patent No. PCT-CN-2013000453. The average molecular weight of the different blocks was determined by mass spectrometry combined with the molecular weight of the starting materials.
  • the above raw materials are put into a container, and an organic solvent is added until completely dissolved.
  • the types of the organic solvent include ethanol, acetonitrile and the like. After rotary evaporation at 30-50 ° C for 2 h until evaporation of the organic solvent, vacuum drying at 10-60 ° C for > 12 h to remove residual organic solvent to obtain a polymer mixture film containing docetaxel.
  • the mixed membrane was placed in a water bath at 40-60 ° C until it was transparent, and ultra-pure water or physiological saline or phosphate buffer solution preheated at the same temperature was added thereto, and the mixture was shaken and hydrated to obtain a transparent drug-loaded micelle solution.
  • the drug-loaded micelle solution was filtered through a 0.45 ⁇ m microporous membrane to obtain a micelle.
  • the above drug-loaded micelle solution was prepared into a solid dry powder by a conventional lyophilization process without adding any excipients.
  • the separator temperature setting is raised from -45 ° C to -25 ° C for more than 12 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the separator temperature setting is raised from -25 ° C to 0 ° C for more than 8 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the separator temperature setting is raised from 0 ° C to 5 ° C for more than 3 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the temperature of the separator is raised from 5 ° C to 20 ° C, and after the product temperature reaches 20 ° C, it is maintained for more than 4 h, and then lyophilized to obtain a loose block of docetaxel lyophilized powder.
  • step of adding 6 excipients to prepare a solid dry powder is as follows.
  • a docetaxel lyophilized powder preparation wherein: the excipient is selected from the group consisting of lactose, mannitol, dextran, glycine, glucose or A variety.
  • the organic solvent described in the step 2 is ethanol or acetonitrile.
  • excipient in the lyophilization process is primarily to promote a solution that is difficult to solidify to ultimately yield a solid powder.
  • excipients can also improve the appearance, morphology, solubility, stability and other performance indicators of the lyophilized preparation to varying degrees.
  • Table 13 shows the measured drug loading and particle size in different examples.
  • Carrier polyethylene glycol methyl ether - polylactide - glutamic acid
  • the docetaxel lyophilized powder prepared in Example (17-23) and water were weighed according to the concentration of docetaxel at a concentration of 3 mg/ml, and the lyophilized powder was placed in water for injection, physiological saline or glucose injection. All docetaxel lyophilized powders were completely dissolved after 60 seconds of shaking, indicating good solubility.
  • the particle size distribution was measured by dynamic light scattering, and the particle size distribution of the reconstituted solution was measured to be between 10 and 100 nm, and the average particle diameter was between 20 and 29.2 nm, as shown in Table 14.
  • the docetaxel micelle obtained in Example (17-23) was diluted with water to obtain a solution having a docetaxel concentration of about 3 mg/ml, respectively, at 15 ° C, 25 ° C, 30 ° C under normal indoor lighting conditions.
  • the solution was visually observed for sedimentation or turbidity every 2 hours. If precipitation or turbidity occurs, the solution ends in a steady state.
  • the stability test results are shown in Table 15.
  • Tumor inhibition tests were performed using physiological saline, commercially available docetaxel injection (taxotere), and docetaxel micelle solution (obtained by the examples of the present invention), respectively.
  • Balb/c mice transplanted with L7912 tumor strain were used as test subjects.
  • the administration route was intravenous administration, and administration was performed every 3 days for 30 days.
  • the concentration of Taxotere and the docetaxel of the present invention is also 10 mg/kg.
  • the tumor volume of the mice was measured twice a week, and the results are shown in Table 16.
  • mice instilled with saline increased rapidly; the tumor volume growth rate of mice instilled with Taxotere was controlled, but the tumor volume still increased; the tumor volume of mice instilled in this invention was controlled and rapidly Reduced. It is proved that the present invention has a remarkable inhibitory effect on mouse T cell leukemia xenografts.
  • docetaxel is an anhydrous docetaxel bulk drug (CAS: 114977-28-5), produced by Xi'an Tianfeng Biotechnology Co., Ltd.;
  • the polyethylene glycol methyl ether-polylactide block copolymer having an amino acid end group is polyethylene glycol methyl ether-polylactide-phenylalanine, and the molecular formula is:
  • the average molecular weight of the polylactide block is 502 to 4962 and the average molecular weight of the polyethylene glycol methyl ether block is 998 to 2998.
  • the above raw materials are put into a container, and an organic solvent is added until completely dissolved.
  • the types of the organic solvent include ethanol, acetonitrile and the like.
  • the mixed membrane was placed in a water bath at 40-60 ° C until it was transparent, and ultra-pure water or physiological saline or phosphate buffer solution preheated at the same temperature was added thereto, and the mixture was shaken and hydrated to obtain a transparent drug-loaded micelle solution.
  • the drug-loaded micelle solution was filtered through a 0.45 ⁇ m microporous membrane to obtain a micelle.
  • the above drug-loaded micelle solution was prepared into a solid dry powder by a conventional lyophilization process without adding any excipients.
  • the separator temperature setting is raised from -45 ° C to -25 ° C for more than 12 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the separator temperature setting is raised from -25 ° C to 0 ° C for more than 8 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the separator temperature setting is raised from 0 ° C to 5 ° C for more than 3 h.
  • the ultimate vacuum is set to 0.013 Bar.
  • the temperature of the separator is raised from 5 ° C to 20 ° C, and after the product temperature reaches 20 ° C, it is maintained for more than 4 h, and then lyophilized to obtain a loose block of docetaxel lyophilized powder.
  • a docetaxel lyophilized powder formulation wherein: the excipient is selected from one or more of the group consisting of lactose, mannitol, dextran, glycine, and glucose.
  • the organic solvent described in the step 2 is ethanol or acetonitrile.
  • excipient in the lyophilization process is primarily to promote a solution that is difficult to solidify to ultimately yield a solid powder.
  • excipients can also improve the appearance, morphology, solubility, stability and other performance indicators of the lyophilized preparation to varying degrees.
  • Carrier polyethylene glycol methyl ether-polylactide-phenyl endoline
  • the docetaxel lyophilized powder prepared in Example 25-31 and water were weighed according to the concentration of docetaxel at a concentration of 3 mg/ml, and the lyophilized powder was placed in water for injection, physiological saline or glucose injection, and shaken 60. After the second, all the docetaxel lyophilized powder was completely dissolved, indicating good solubility.
  • the particle size distribution was measured by dynamic light scattering, and the particle size distribution of the reconstituted solution was measured to be between 10 and 100 nm, and the average particle diameter was between 20 and 29.2 nm, as shown in Table 18.
  • Tumor inhibition tests were performed using physiological saline, commercially available docetaxel injection (taxotere), and docetaxel micelle solution (obtained by the examples of the present invention), respectively.
  • Balb/c mice transplanted with L7912 tumor strain were used as test subjects.
  • the administration route was intravenous administration, and administration was performed every 3 days for 30 days.
  • the concentration of Taxotere and the docetaxel of the present invention is also 10 mg/kg.
  • the tumor volume of the mice was measured twice a week, and the results are shown in Table 16.
  • mice instilled with saline increased rapidly; the tumor volume growth rate of mice instilled with Taxotere was controlled, but the tumor volume still increased; the tumor volume of mice instilled in this invention was controlled and rapidly Reduced, see Table 20. It is proved that the present invention has a remarkable inhibitory effect on mouse T cell leukemia xenografts.

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Abstract

一种含多西他赛的药物组合物，由多西他赛和具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物所组成。其采用毒性更低的三嵌段共聚物为载体，除了药物有效成分和载体外不含其它添加物，其组分更简单、安全性更高，多西他赛含量可达20%以上。具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物与多西他赛形成的胶束，粒径较小，稳定性较高，且制剂中无需添加其它辅助成分，安全性更高，制备工艺简单易于工业应用。

Description

一种含多西他赛的药物组合物 技术领域
本发明属于医药制剂技术领域，具体涉及一种含多西他赛的药物组合物。
背景技术
多西他赛(多烯紫杉醇，Docetaxel，C43H53NO14)，是在天然抗肿瘤药物紫杉醇的结构基础上，经结构修饰后获得的一种新的抗肿瘤药物，其抗谱与紫杉醇类似，作用机制是促进微管蛋白聚合和阻止微管解聚，从而抑制癌细胞的有丝***和增殖，药效比紫杉醇强。
体外的研究表明，在人乳腺、结肠、膀胱和上皮样的细胞株，其IC50比紫杉醇低9倍。体内研究表明，多西他赛具有有高度抗肿瘤活性，用药后鼠肿瘤和小鼠移植肿瘤可完全消退。更重要的是，多西他赛对紫杉醇耐药的细胞株不会自发地产生对多西他赛的交叉耐药性。
多西他赛为白色或类白色的粉末，是高度脂溶性且难溶于水的药物，其在水中的溶解度为6-7μg/ml。为了增加其溶解性，目前市售的多西他赛制剂均配方中均需添加吐温80作为表面活性剂。而采用吐温80有两大缺点。
第一个缺点是给患者带来较强的不良反应。吐温80可能引起包括过敏反应、溶血作用、心血管不良反应和体液潴留等在内的不良反应。(《吐温-80引起动物类过敏反应的原因初步探索》，《毒理学杂志》2007年04期；《药用辅料吐温80的药理、药动学及分析方法研究进展》，《中国药事》2008年第22卷第8期)。因此需要提前给患者口服糖皮质激素类药物进行脱敏，对已经发生过敏反应的病人需要注射肾上腺素，这无疑加重了患者的负担。
第二个缺点是给药方法比较复杂，增加了使用的难度。以泰索帝为例：需要首先混合浓缩药物与稀释溶液以制备预混合溶液，然后用0.9％的生理盐水将预混合溶液稀释，制得预混合稀释液后的4小时内对得到的预混合稀释液进行约1小时的滴注。此过程中需要小心地将混合了稀释溶液的浓缩药物颠倒45秒，而不进行搅拌，这样得到的溶液中可能形成气泡，因此需要将该溶液静置5分钟以使气泡排出。齐鲁制药生产的多西他赛注射液“多帕菲”的产品说明书中有如下的说明文字：“每瓶 标示量为1ml∶20mg的多帕菲，实际装有1.2ml浓度为20mg/ml的多西他赛溶液，相当于24mg的多西他赛。此容积已经对在准备过程中由于药液粘稠导致的药液粘着瓶壁及不能抽出的“死容积”等原因造成的液体损失进行了补充。使用时，用注射器将每瓶溶液抽取干净并稀释到5％葡萄糖注射液或0.9％氯化钠注射液中。为避免药物过量引起毒副反应。切勿用溶剂洗涮西林瓶和注射器！”。
聚合物胶束是由两亲性嵌段共聚物自发形成的一种核壳结构，具有纳米级粒径。聚合物胶束作为一种给药载体由Bader等在1984年首次提出。使用两亲性嵌段共聚物将药物包封在胶束的疏水内核内，达到增溶难溶性药物进一步提高生物利用度的效果。此外，良好的聚合物胶束能延长药物体内循环时间，降低药物毒性，及能通过EPR效应达到被动靶向作用。
采用聚合物制成多西他赛胶束能克服市售多西他赛药剂的缺点，但目前对于多西他赛的胶束研究成果普遍缺乏实用价值，主要的缺点包括粒径太大而无法发挥EPR效应，载药量过低、制剂稳定性差等。例如山东大学的于克炜采用普朗尼克F68作为胶束载体，维生素ETPGS做增溶剂，对多西他赛进行包裹，结果制得的多西他赛胶束平均载药量仅有0.923％，而平均粒径高达135.1±3.42nm(于克炜，《多西他赛聚合物胶束的研究》)。山东大学翟光喜等人采用TPGS、MPEG-PLA、CSO-SA为胶束载体材料得到多西他赛胶束，载药量不超过5.2％《一种载多烯紫杉醇混合胶束及其制备方法》，专利申请号：201210372072.X)。
冻干粉是一种保藏药物的有效方法。将需要干燥的制品在低温下使其所含的水分冻结，然后放在真空的环境下干燥，让水分由固体状态直接升华为水蒸气并从制品中排除而使制品活性干燥。该方法有效地防止了制品理化及生物特性的改变，有效保护热敏性药物有效成份的稳定性；冻干制品在干燥后形态疏松、颜色基本不发生改变，加水或者亲水性有机溶剂后能够快速溶解并恢复原有水溶液的理化特性和生物活性；由于干燥在真空条件下进行，对于一些易氧化的物质具有很好的保护作用；制品经过冻干后水份含量非常低，使制品的稳定性提高，受污染的机会减小，这不仅方便了运输还延长了制品保存期限。
目前对于多西他赛冻干粉的研究成果并未取得突破，尤其在组分、复溶后的粒径和载药量等方面。郝守祝公开了一种多西他赛冻干粉的制备方法(《一种多西他赛的药用组合物、制备方法及用途》专利申请号：200780000695.1)，但在冻干粉中依 然含有吐温80。山东大学张娜等利用PLA-PEG共聚物得到多西他赛胶束冻干粉，但复溶后的粒径在200nm以上(《载多烯紫杉醇纳米粒混合胶束及冻干剂的制备方法》，专利申请号：201010151501.1)。
发明内容
本发明的目的在于克服现有技术的不足，提供一种含多西他赛的药物组合物。其采用具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物作为载体材料与多西他赛制成，处方简单安全可靠，此药物组合物中多西他赛载药量最高可超过25％，冻干粉复溶后的粒径较小、稳定性较高。
本发明的技术解决方案如下。
一种含多西他赛的药物组合物，由多西他赛及具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物所组成，其中
具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物的分子式为：：
Figure PCTCN2015083928-appb-000001
在式(I)中，R为氨基酸基a＝10～200，b＝3～30，聚乙二醇甲醚嵌段的平均分子量为1000～3500，聚丙交酯嵌段的平均分子量为450～5500及多西他赛的重量组份为3.21～27.75份和具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物的重量组份为100。
在上式(I)中，氨基酸基R為
Figure PCTCN2015083928-appb-000002
其中R1为H、CH3、(CH3)2CH、PhCH2或(CH2)3NHC(NH)NH2。
具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物中的聚乙二醇稳定性很高，较难被降解；具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物中的聚丙交酯只有在强酸性条件下才易发生降解；接枝氨基酸在中性条件下反应。因此具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物在正常体液环境中的稳定性较高。在具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物中的聚乙二醇甲醚嵌段以及聚丙交酯嵌段可以通过质谱分析等手段得到不同的三嵌段共聚物中不同的嵌段平均分子量的数值。
上述含多西他赛的药物组合物为冻干粉制剂，其可以采用冻干法制备。
本发明中，所述的多西他赛是指无水多西他赛原料药，按照C43H53NO14计，纯度在98.0％以上。
本发明中，研究表明，具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物无明显的致癌性，无生殖毒性，无致畸、致突变性，在体内可降解为乳酸、氨基酸PEG，均可直接排出体外。对小鼠进行急性毒性试验，小鼠的LD50＞2.00g/kg；长毒试验中，1.00g/kg剂量，1次/天，每周连续给药2天，停药5天，连续给药13周后，恢复4周后观察，未见明显毒副作用。
经细胞毒性测试表明，三嵌段共聚物的的细胞毒性比目前公认无毒的嵌段共聚物mPEG-PLA更低，其中表1-表4分别表示具有不同的氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物的MTT法肝细胞毒性测试结果。
表1 MTT法肝细胞毒性测试结果-聚乙二醇甲醚-聚丙交酯-赖氨酸
Figure PCTCN2015083928-appb-000003
表2 MTT法肝细胞毒性测试结果-聚乙二醇甲醚-聚丙交酯-天冬氨酸
Figure PCTCN2015083928-appb-000004
表3 MTT法肝细胞毒性测试结果-聚乙二醇甲醚-聚丙交酯-谷氨酸
Figure PCTCN2015083928-appb-000005
表4 MTT法肝细胞毒性测试结果-聚乙二醇甲醚-聚丙交酯-苯丙氨酸
Figure PCTCN2015083928-appb-000006
与现有技术相比，本发明具有以下有益效果：
1.采用毒性更低的具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物做为载体，除了药物有效成分和载体外，不含其他添加物，处方更简单、安全性更高。
2.组合物可通过制药业普通冻干工艺制成固态冻干粉的形态，使用普通生理盐水、注射用水或注射用葡萄糖即可迅速复溶，药物的制备、运输、储存、使用更简便。
3.含多西他赛的药物组合物中，多西他赛含量可达20％以上，制备工艺简单，易于工业应用。
具体实施方式
下面结合实施例对本发明做详细的说明，本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业 途径得到。
在本发明中，具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物的分子式为：
Figure PCTCN2015083928-appb-000007
在式(I)中，R为氨基酸基，a＝10～200，b＝3～30，聚乙二醇甲醚嵌段的平均分子量为1000～3500，聚丙交酯嵌段的平均分子量为450～5500。
上述的氨基酸基R为
Figure PCTCN2015083928-appb-000008
其中R1为H、CH3、(CH3)2CH、PhCH2或(CH2)3NHC(NH)NH2。
实施例(1-7)
多西他赛为无水多西他赛原料药(CAS：114977-28-5)，由西安天风生物科技有限公司生产；
在实施例(1-7)，具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物为聚乙二醇甲醚-聚丙交酯-赖氨酸，其分子式为
Figure PCTCN2015083928-appb-000009
其中a＝10～200，b＝3～30。在聚乙二醇甲醚-聚丙交酯-赖氨酸中，聚丙交酯嵌段的平均分子量为505～4982及聚乙二醇甲醚嵌段的平均分子量为1017～2992。由发明人按照专利号PCT-CN-2013000453所述的工艺自行制备。采用质谱分析并结合反应原料的分子量确定不同嵌段的平均分子量。
实施例(1-7)中的含多西他赛的药物组合物，药物组合物为胶束，采用薄膜水化法制备得到，包括：
①按照不同的投料比称量多西他赛和聚乙二醇甲醚-聚丙交酯-赖氨酸(见表5)；
②将上述原料投入容器中，加入有机溶剂至完全溶解，有机溶剂的种类包括乙醇、乙腈等。30-50℃旋转蒸发2h至有机溶剂蒸干为止，10-60℃下真空干燥＞12h 去除残留的有机溶剂，得到含多西他赛的聚合物混合膜。
③混合膜于40-60℃水浴至透明状，加入相同温度预热的超纯水或生理盐水、磷酸盐缓冲液，充分振摇水化，得透明的载药胶束溶液。
④将所述载药胶束溶液用0.45μm微孔滤膜过滤，得到胶束。
⑤将上述载药胶束溶液采用常规的，不添加任何赋形剂的冻干工艺制得固态干粉。
制备固态干粉的步骤如下：
a.搁板预降温至0℃后放入载多西他赛的胶束，降温至-45℃以下，确保溶液温度降至-45℃，维持2-4h。
b.上述步骤结束后开启真空泵。抽真空1-1.5h。
c.隔板温度设定由-45℃升至-25℃，维持12h以上。极限真空度设定为0.013Bar。
d.隔板温度设定由-25℃升至0℃，维持8h以上。极限真空度设定为0.013Bar。
e.隔板温度设定由0℃升至5℃，维持3h以上。极限真空度设定为0.013Bar。
f.隔板温度设定由5℃升至20℃，制品温度达到20℃后，维持4h以上，然后结束冻干，得到疏松块状的多西他赛冻干粉。
或⑥添加赋形剂制备固态干粉的步骤如下：
向多西他赛的胶束中添加不超过步骤①投料总重量5％的赋形剂，并使之充分溶解，再将得到的上述混合胶束溶液按步骤⑤所述工艺冻干，制得多西他赛冻干粉制剂；其中：所述赋形剂选自乳糖、甘露醇、右旋糖苷、甘氨酸、葡萄糖中的一种或多种。
上述制备方法中，步骤②所述的有机溶剂是乙醇或乙腈。
赋形剂在冻干工艺中的作用主要是促使难于固态化的溶液最终得到固态粉末。而各种赋形剂也可不同程度的改善冻干制剂的外观、形态、溶解性、稳定性等性能指标。
实施例(1-7)分别选择不同的投料比，以及分别选用不同嵌段分子量的聚乙二醇甲醚-聚丙交酯-赖氨酸，按照上述步骤制得多西他赛冻干粉。采用高效液相色谱测定其载药量，用动态光散射测定复溶后溶液的平均粒径，见表5。
表5不同实施例实测载药量及粒径
Figure PCTCN2015083928-appb-000010
载体＝聚乙二醇甲醚-聚丙交酯-赖氨酸
按照多西他赛浓度3mg/ml的比例称量实施例(1-7)制得的多西他赛冻干粉和水，将上述冻干粉投入注射用水、生理盐水或葡萄糖注射液中，振荡60秒后所有多西他赛冻干粉均完全溶解，说明具有良好的溶解性。用动态光散射测定粒径分布，测得复溶溶液的粒径分布在10-100nm之间，平均粒径在20-29.2nm之间，见表6。分别于15℃、25℃、30℃，正常室内光照条件下，每隔2h肉眼观察溶液，直至发现溶液出现浑浊或者发现有沉淀析出，则说明溶液结束了稳定状态。结果见表6，说明本发明具有良好的稳定性。
表6不同实施例复溶后平均粒径和稳定性测试结果
Figure PCTCN2015083928-appb-000011
稳定性测试：
用水将实施例(1-7)得到的多西他赛胶束稀释得到多西他赛浓度约为3mg/ml的溶液，分别于15℃、25℃、30℃，正常室内光照条件下，每隔2h肉眼观察溶液是否有沉淀或浑浊产生。如果有沉淀或者浑浊产生，则说明溶液结束了稳定状态。稳定性测试结果见表7。
表7不同实施例稳定性测试结果
Figure PCTCN2015083928-appb-000012
实验例8
分别利用生理盐水、市售多西他赛注射液(泰索帝)和多西他赛胶束溶液(通过本发明实施例得到)分别进行肿瘤抑制试验。采用移植L7912瘤株的Balb/c小鼠为试验对象。给药途径为静脉给药，每3天给药一次，连续给药30天。泰索帝与本发明的多西他赛药物浓度同样为10mg/kg。每周测量小鼠的肿瘤体积2次，其结果如表8所示。结果表明：滴注生理盐水的小鼠肿瘤体积迅速增长；滴注泰索帝的小鼠肿瘤体积增长速度得到一定控制，但肿瘤体积依然增长；滴注本发明的小鼠肿瘤体积得到控制并迅速减小，见表8。证明本发明对小鼠T细胞性白血病移植瘤的抑制效果显著。
表8小鼠肿瘤体积测量结果
Figure PCTCN2015083928-appb-000013
实施例(9-15)
于实施例(9-15)中，多西他赛为无水多西他赛原料药(CAS：114977-28-5)，由西安天风生物科技有限公司生产；
于实例(9-15)，具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物为聚乙二醇甲醚-聚丙交酯-天冬氨酸，其分子式为：
Figure PCTCN2015083928-appb-000014
其中a＝10～200，b＝3～30。在聚乙二醇甲醚-聚丙交酯-天冬氨酸中，聚丙交酯嵌段的平均分子量为495～4996及聚乙二醇甲醚嵌段的平均分子量为987～3020。由发明人按照专利号PCT-CN-2013000453所述的工艺自行制备。采用质谱分析并结合反应原料的分子量确定不同嵌段的平均分子量。
实施例(9-15)中的含多西他赛的药物组合物，药物组合物为胶束，采用薄膜水化法制备得到，包括：
①按照不同的投料比称量多西他赛和聚乙二醇甲醚-聚丙交酯-天冬氨酸(见表7)：
②将上述原料投入容器中，加入有机溶剂至完全溶解，有机溶剂的种类包括乙醇、乙腈等。30-50℃旋转蒸发2h至有机溶剂蒸干为止，10-60℃下真空干燥＞12h去除残留的有机溶剂，得到含多西他赛的聚合物混合膜。
③混合膜于40-60℃水浴至透明状，加入相同温度预热的超纯水或生理盐水、磷酸盐缓冲液，充分振摇水化，得透明的载药胶束溶液。
④将所述载药胶束溶液用0.45μm微孔滤膜过滤，得到胶束。
⑤将上述载药胶束溶液采用常规的，不添加任何赋形剂的冻干工艺制得固态干粉。
制备固态干粉，步骤如下：
a.搁板预降温至0℃后放入载多西他赛的胶束，降温至-45℃以下，确保溶液温 度降至-45℃，维持2-4h。
b.上述步骤结束后开启真空泵。抽真空1-1.5h。
c.隔板温度设定由-45℃升至-25℃，维持12h以上。极限真空度设定为0.013Bar。
d.隔板温度设定由-25℃升至0℃，维持8h以上。极限真空度设定为0.013Bar。
e.隔板温度设定由0℃升至5℃，维持3h以上。极限真空度设定为0.013Bar。
f.隔板温度设定由5℃升至20℃，制品温度达到20℃后，维持4h以上，然后结束冻干，得到疏松块状的多西他赛冻干粉。
或⑥添加赋形剂制备固态干粉的步骤如下：
向多西他赛的胶束中添加不超过步骤①投料总重量5％的赋形剂，并使之充分溶解，再将得到的上述混合胶束溶液按步骤⑤所述工艺冻干，制得多西他赛冻干粉制剂；其中：所述赋形剂选自乳糖、甘露醇、右旋糖苷、甘氨酸、葡萄糖中的一种或多种。
上述制备方法中，步骤②所述的有机溶剂是乙醇或乙腈。
赋形剂在冻干工艺中的作用主要是促使难于固态化的溶液最终得到固态粉末。而各种赋形剂也可不同程度的改善冻干制剂的外观、形态、溶解性、稳定性等性能指标。
实施例(9-15)分别选择不同的投料比，以及分别选用不同嵌段分子量的聚乙二醇甲醚-聚丙交酯-天冬氨酸，按照上述步骤制得多西他赛冻干粉。采用高效液相色谱测定其载药量，用动态光散射测定复溶后溶液的平均粒径，见表9。
表9不同实施例实测载药量及粒径
Figure PCTCN2015083928-appb-000015
载体＝聚乙二醇甲醚-聚丙交酯-天冬氨酸
按照多西他赛浓度3mg/ml的比例称量实施例(9-15)制得的多西他赛冻干粉和 水，将上述冻干粉投入注射用水、生理盐水或葡萄糖注射液中，振荡60秒后所有多西他赛冻干粉均完全溶解，说明具有良好的溶解性。用动态光散射测定粒径分布，测得复溶溶液的粒径分布在10-100nm之间，平均粒径在20-29.2nm之间，见表10。分别于15℃、25℃、30℃，正常室内光照条件下，每隔2h肉眼观察溶液，直至发现溶液出现浑浊或者发现有沉淀析出，则说明溶液结束了稳定状态，结果见表10，说明本发明具有良好的稳定性。
表10不同实施例复溶后平均粒径和稳定性测试结果
Figure PCTCN2015083928-appb-000016
稳定性测试：
用水将实施例(9-15)得到的多西他赛胶束稀释得到多西他赛浓度约为3mg/ml的溶液，分别于15℃、25℃、30℃，正常室内光照条件下，每隔2h肉眼观察溶液是否有沉淀或浑浊产生。如果有沉淀或者浑浊产生，则说明溶液结束了稳定状态。稳定性测试结果见表11。
表11不同实施例稳定性测试结果
Figure PCTCN2015083928-appb-000017
Figure PCTCN2015083928-appb-000018
实验例16
分别利用生理盐水、市售多西他赛注射液(泰索帝)和多西他赛胶束溶液(通过本发明实施例得到)分别进行肿瘤抑制试验。采用移植L7912瘤株的Balb/c小鼠为试验对象。给药途径为静脉给药，每3天给药一次，连续给药30天。泰索帝与本发明的多西他赛药物浓度同样为10mg/kg。每周测量小鼠的肿瘤体积2次，其结果如表12所示。结果表明：滴注生理盐水的小鼠肿瘤体积迅速增长；滴注泰索帝的小鼠肿瘤体积增长速度得到一定控制，但肿瘤体积依然增长；滴注本发明的小鼠肿瘤体积得到控制并迅速减小，见表12。证明本发明对小鼠T细胞性白血病移植瘤的抑制效果显著。
表12小鼠肿瘤体积测量结果
Figure PCTCN2015083928-appb-000019
实施例(17-23)
在实施例(17-23)中，多西他赛为无水多西他赛原料药(CAS：114977-28-5)，由西安天风生物科技有限公司生产；
于实施例(17-23)，具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物为聚乙二醇甲醚-聚丙交酯-谷氨酸，其分子式为：
Figure PCTCN2015083928-appb-000020
其中 a＝10～200，b＝3～30。在聚乙二醇甲醚-聚丙交酯-谷氨酸中，聚丙交酯嵌段的平均分子量为504～4985及聚乙二醇甲醚嵌段的平均分子量为1003～3015。由发明人按照专利号PCT-CN-2013000453所述的工艺自行制备。采用质谱分析并结合反应原料的分子量确定不同嵌段的平均分子量。
实施例(17-23)中的含多西他赛的药物组合物，药物组合物为胶束，采用薄膜水化法制备得到，包括：
①按照不同的投料比称量多西他赛和聚乙二醇甲醚-聚丙交酯-谷氨酸(见表13)：
②将上述原料投入容器中，加入有机溶剂至完全溶解，有机溶剂的种类包括乙醇、乙腈等。30-50℃旋转蒸发2h至有机溶剂蒸干为止，10-60℃下真空干燥＞12h去除残留的有机溶剂，得到含多西他赛的聚合物混合膜。
③混合膜于40-60℃水浴至透明状，加入相同温度预热的超纯水或生理盐水、磷酸盐缓冲液，充分振摇水化，得透明的载药胶束溶液。
④将所述载药胶束溶液用0.45μm微孔滤膜过滤，得到胶束。
⑤将上述载药胶束溶液采用常规的，不添加任何赋形剂的冻干工艺制得固态干粉。
制备固态干粉，步骤如下：
a.搁板预降温至0℃后放入载多西他赛的胶束，降温至-45℃以下，确保溶液温度降至-45℃，维持2-4h。
b.上述步骤结束后开启真空泵。抽真空1-1.5h。
c.隔板温度设定由-45℃升至-25℃，维持12h以上。极限真空度设定为0.013Bar。
d.隔板温度设定由-25℃升至0℃，维持8h以上。极限真空度设定为0.013Bar。
e.隔板温度设定由0℃升至5℃，维持3h以上。极限真空度设定为0.013Bar。
f.隔板温度设定由5℃升至20℃，制品温度达到20℃后，维持4h以上，然后结束冻干，得到疏松块状的多西他赛冻干粉。
或⑥添加赋形剂制备固态干粉的步骤如下。
向多西他赛的胶束中添加不超过步骤①投料总重量5％的赋形剂，并使之充分溶解，再将得到的上述混合胶束溶液按步骤⑤所述工艺冻干，制得多西他赛冻干粉制剂；其中：所述赋形剂选自乳糖、甘露醇、右旋糖苷、甘氨酸、葡萄糖中的一种或 多种。
上述制备方法中，步骤②所述的有机溶剂是乙醇或乙腈。
赋形剂在冻干工艺中的作用主要是促使难于固态化的溶液最终得到固态粉末。而各种赋形剂也可不同程度的改善冻干制剂的外观、形态、溶解性、稳定性等性能指标。
实施例(17-23)分别选择不同的投料比，以及分别选用不同嵌段分子量的聚乙二醇甲醚-聚丙交酯-谷氨酸，按照上述步骤制得多西他赛冻干粉。采用高效液相色谱测定其载药量，用动态光散射测定复溶后溶液的平均粒径，见表13。
表13不同实施例实测载药量及粒径
Figure PCTCN2015083928-appb-000021
载体＝聚乙二醇甲醚-聚丙交酯-谷氨酸
按照多西他赛浓度3mg/ml的比例称量实施例(17-23)制得的多西他赛冻干粉和水，将上述冻干粉投入注射用水、生理盐水或葡萄糖注射液中，振荡60秒后所有多西他赛冻干粉均完全溶解，说明具有良好的溶解性。用动态光散射测定粒径分布，测得复溶溶液的粒径分布在10-100nm之间，平均粒径在20-29.2nm之间，见表14。分别于15℃、25℃、30℃，正常室内光照条件下，每隔2h肉眼观察溶液，直至发现溶液出现浑浊或者发现有沉淀析出，则说明溶液结束了稳定状态。结果见表14，说明本发明具有良好的稳定性。
表14不同实施例复溶后平均粒径和稳定性测试结果
Figure PCTCN2015083928-appb-000022
Figure PCTCN2015083928-appb-000023
稳定性测试：
用水将实施例(17-23)得到的多西他赛胶束稀释得到多西他赛浓度约为3mg/ml的溶液，分别于15℃、25℃、30℃，正常室内光照条件下，每隔2h肉眼观察溶液是否有沉淀或浑浊产生。如果有沉淀或者浑浊产生，则说明溶液结束了稳定状态。稳定性测试结果见表15。
表15不同实施例稳定性测试结果
Figure PCTCN2015083928-appb-000024
实验例24
分别利用生理盐水、市售多西他赛注射液(泰索帝)和多西他赛胶束溶液(通过本发明实施例得到)分别进行肿瘤抑制试验。采用移植L7912瘤株的Balb/c小鼠为试验对象。给药途径为静脉给药，每3天给药一次，连续给药30天。泰索帝与本发明的多西他赛药物浓度同样为10mg/kg。每周测量小鼠的肿瘤体积2次，其结果如表16所示。结果表明：滴注生理盐水的小鼠肿瘤体积迅速增长；滴注泰索帝的小鼠肿瘤体积增长速度得到一定控制，但肿瘤体积依然增长；滴注本发明的小鼠肿瘤体积得到控制并迅速减小。证明本发明对小鼠T细胞性白血病移植瘤的抑制效果显著。表16小鼠肿瘤体积测量结果
Figure PCTCN2015083928-appb-000025
Figure PCTCN2015083928-appb-000026
实施例(25-31)
在实施例(25-31)中，多西他赛为无水多西他赛原料药(CAS：114977-28-5)，由西安天风生物科技有限公司生产；
于实施例(25-31)，具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物为聚乙二醇甲醚-聚丙交酯-苯丙氨酸，其分子式为：
Figure PCTCN2015083928-appb-000027
其中a＝10～200，b＝3～30。在聚乙二醇甲醚-聚丙交酯-苯丙氨酸中，聚丙交酯嵌段的平均分子量为502～4962及聚乙二醇甲醚嵌段的平均分子量为998～2998。
由发明人按照专利号PCT-CN-2013000453所述的工艺自行制备。采用质谱分析并结合反应原料的分子量确定不同嵌段的平均分子量。
实施例(25-31)中的含多西他赛的药物组合物，药物组合物为胶束，采用薄膜水化法制备得到，包括：
①按照不同的投料比称量多西他赛和聚乙二醇甲醚-聚丙交酯-苯丙氨酸(见表17)；
②将上述原料投入容器中，加入有机溶剂至完全溶解，有机溶剂的种类包括乙醇、乙腈等。30-50℃旋转蒸发2h至有机溶剂蒸干为止，10-60℃下真空干燥＞12h 去除残留的有机溶剂，得到含多西他赛的聚合物混合膜。
③混合膜于40-60℃水浴至透明状，加入相同温度预热的超纯水或生理盐水、磷酸盐缓冲液，充分振摇水化，得透明的载药胶束溶液。
④将所述载药胶束溶液用0.45μm微孔滤膜过滤，得到胶束。
⑤将上述载药胶束溶液采用常规的，不添加任何赋形剂的冻干工艺制得固态干粉。
制备固态干粉，步骤如下：
a.搁板预降温至0℃后放入载多西他赛的胶束，降温至-45℃以下，确保溶液温度降至-45℃，维持2-4h。
b.上述步骤结束后开启真空泵。抽真空1-1.5h。
c.隔板温度设定由-45℃升至-25℃，维持12h以上。极限真空度设定为0.013Bar。
d.隔板温度设定由-25℃升至0℃，维持8h以上。极限真空度设定为0.013Bar。
e.隔板温度设定由0℃升至5℃，维持3h以上。极限真空度设定为0.013Bar。
f.隔板温度设定由5℃升至20℃，制品温度达到20℃后，维持4h以上，然后结束冻干，得到疏松块状的多西他赛冻干粉。
或⑥添加赋形剂制备固态干粉的步骤如下：
向多西他赛的胶束中添加不超过步骤①投料总重量5％的赋形剂，并使之充分溶解，再将得到的上述混合胶束溶液按步骤⑤所述工艺冻干，制得多西他赛冻干粉制剂；其中：所述赋形剂选自乳糖、甘露醇、右旋糖苷、甘氨酸、葡萄糖中的一种或多种。
上述制备方法中，步骤②所述的有机溶剂是乙醇或乙腈。
赋形剂在冻干工艺中的作用主要是促使难于固态化的溶液最终得到固态粉末。而各种赋形剂也可不同程度的改善冻干制剂的外观、形态、溶解性、稳定性等性能指标。
实施例(25-31)分别选择不同的投料比，以及分别选用不同嵌段分子量的聚乙二醇甲醚-聚丙交酯-苯丙氨酸，按照上述步骤制得多西他赛冻干粉。采用高效液相色谱测定其载药量，用动态光散射测定复溶后溶液的平均粒径，见表17。
表17不同实施例实测载药量及粒径
Figure PCTCN2015083928-appb-000028
载体＝聚乙二醇甲醚-聚丙交酯-苯内氨酸
按照多西他赛浓度3mg/ml的比例称量实施例25-31制得的多西他赛冻干粉和水，将上述冻干粉投入注射用水、生理盐水或葡萄糖注射液中，振荡60秒后所有多西他赛冻干粉均完全溶解，说明具有良好的溶解性。用动态光散射测定粒径分布，测得复溶溶液的粒径分布在10-100nm之间，平均粒径在20-29.2nm之间，见表18。分别于15℃、25℃、30℃，正常室内光照条件下，每隔2h肉眼观察溶液，直至发现溶液出现浑浊或者发现有沉淀析出，则说明溶液结束了稳定状态。结果见表18，说明本发明具有良好的稳定性。
表18不同实施例复溶后平均粒径和稳定性测试结果
Figure PCTCN2015083928-appb-000029
稳定性测试。用水将实施例25-31得到的多西他赛胶束稀释得到多西他赛浓度约为3mg/ml的溶液，分别于15℃、25℃、30℃，正常室内光照条件下，每隔2h肉眼观察溶液是否有沉淀或浑浊产生。如果有沉淀或者浑浊产生，则说明溶液结束了稳定状态。稳定性测试结果见表19。
表19不同实施例稳定性测试结果
Figure PCTCN2015083928-appb-000030
实验例32
分别利用生理盐水、市售多西他赛注射液(泰索帝)和多西他赛胶束溶液(通过本发明实施例得到)分别进行肿瘤抑制试验。采用移植L7912瘤株的Balb/c小鼠为试验对象。给药途径为静脉给药，每3天给药一次，连续给药30天。泰索帝与本发明的多西他赛药物浓度同样为10mg/kg。每周测量小鼠的肿瘤体积2次，其结果如表16所示。结果表明：滴注生理盐水的小鼠肿瘤体积迅速增长；滴注泰索帝的小鼠肿瘤体积增长速度得到一定控制，但肿瘤体积依然增长；滴注本发明的小鼠肿瘤体积得到控制并迅速减小，见表20。证明本发明对小鼠T细胞性白血病移植瘤的抑制效果显著。
表20小鼠肿瘤体积测量结果
Figure PCTCN2015083928-appb-000031

Claims (7)

  1. 一种含多西他赛的药物组合物，其特征在于，所述药物组合物由多西他赛和具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物所组成，其中所述多西他赛的重量组份为3.21～27.75份和所述具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物的重量组份为100份，且所述具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物的分子式为：
    Figure PCTCN2015083928-appb-100001
    在式(I)中，R为氨基酸基a＝10～200，b＝3～30，聚乙二醇甲醚嵌段的平均分子量为1000～3500，聚丙交酯嵌段的平均分子量为450～5500。
  2. 根据权利要求1所述的含多西他赛的药物组合物，其特征在于，所述氨基酸基R
    为
    Figure PCTCN2015083928-appb-100002
    其中R1为H、CH3、(CH3)2CH、PhCH2或(CH2)3NHC(NH)NH2。
  3. 根据权利要求1所述的含多西他赛的药物组合物，其特征在于，所述药物组合物为冻干粉制剂。
  4. 根据权利要求3所述的含多西他赛的药物组合物，其特征在于，所述冻干粉制剂复溶后在溶液中胶束的平均粒径为18.5～29.5nm。
  5. 根据权利要求3所述的含多西他赛的药物组合物，其特征在于，所述冻干粉制剂由冻干法制备，所述冻干法包括：
    a.搁板预降温至0℃后放入载有所述多西他赛的所述胶束，降温至-45℃以下，确保载药胶束溶液温度降至-45℃，维持2-4h；
    b.上述步骤结束后开启真空泵，抽真空1-1.5h；
    c.隔板温度设定由-45℃升至-25℃，维持12h以上，极限真空度设定为0.013Bar；
    d.隔板温度设定由-25℃升至0℃，维持8h以上，极限真空度设定为0.013Bar；
    e.隔板温度设定由0℃升至5℃，维持3h以上，极限真空度设定为0.013Bar；以及
    f.隔板温度设定由5℃升至20℃，制品温度达到20℃后，维持4h以上，然后结束冻干，得到疏松块状的多西他赛冻干粉。
  6. 根据权利要求1所述的含多西他赛的药物组合物，其特征在于，所述药物组合物为胶束，采用薄膜水化法制备得到，包括：①按照不同的投料比称取所述多西他赛和所述具有氨基酸端基的聚乙二醇甲醚-聚丙交酯嵌段共聚物；②将上述原料投入容器中，加入乙醇或乙腈至完全溶解；③30-50℃温度下，旋转蒸发2h至有机溶剂蒸干为止，再10-60℃下真空干燥12h以上去除残留的有机溶剂，得到含多西他赛的聚合物混合膜；④混合膜于40-60℃温度水浴至透明状，加入相同温度预热的超纯水或生理盐水、磷酸盐缓冲液，充分振摇水化，得透明的载药胶束溶液；⑤将所述载药胶束溶液用0.45μm微孔滤膜过滤，得到所述胶束。
  7. 根据权利要求1所述的含多西他赛的药物组合物，其特征在于，在所述胶束中，胶束的平均粒径为18.0～29.5nm。
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