WO2014063549A1 - 一种两亲性嵌段共聚物及其制备方法、以及该共聚物与抗肿瘤药物形成的胶束载药系统 - Google Patents
一种两亲性嵌段共聚物及其制备方法、以及该共聚物与抗肿瘤药物形成的胶束载药系统 Download PDFInfo
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Definitions
- the invention relates to an amphiphilic block copolymer, a preparation method thereof, and a stable micelle drug-loading system formed by the copolymer and the antitumor drug, and belongs to the field of nano drug preparations.
- Tumors are a type of disease that seriously threatens the safety of human life. Studying safe and effective anti-tumor drugs is of great significance for improving the quality of life of human beings.
- Taxanes (mainly including paclitaxel, PTX, docetaxel, DTX, cabazitaxel, and larotaxel) are a very effective and broad-spectrum anti-tumor
- the mechanism of action of the drug is mainly to polymerize and stabilize the microtubules, which can cause the rapidly dividing tumor cells to be fixed in the mitotic stage, and the cancer cell replication is blocked and died.
- the taxane has a significant radiosensitizing effect, allowing the cells to stop in the G2 and M phases that are sensitive to radiotherapy.
- almost all of the taxanes are highly hydrophobic and their oral absorption is poor, and currently only the route of administration is administered.
- Doxorubicin is an anti-tumor antibiotic. It is a cytotoxic drug like taxanes. It inhibits the synthesis of RNA and DNA. It has the strongest inhibitory effect on RA and has a wide anti-tumor spectrum. It is a non-specific drug that has a killing effect on tumor cells of various growth cycles. Mainly used for acute leukemia, for acute lymphocytic leukemia and myeloid leukemia. Conventional doxorubicin preparations have significant side effects such as cardiotoxicity and myelosuppression.
- Epirubicin is an isomer of doxorubicin, which is equivalent or slightly higher than doxorubicin, but less toxic to the heart.
- Curcumin is a non-cytotoxic drug with potential anti-tumor activity that has received extensive attention in recent years. Its greatest feature is that it has almost no side effects, and at the same time has anti-inflammatory, anti-oxidation and other auxiliary therapeutic effects. Its biggest drawback is water soluble Very poor performance, the preparation of stable aqueous curcumin preparation is currently a hot topic.
- Polymer micelles are a new type of drug delivery system that has been developed in recent years.
- the micelles usually consist of a large number of amphiphilic block copolymer molecular chains oriented, and their hydrophobic segments enclose the drug in the nucleus through weak interaction with the drug molecules, and the hydrophilic chains stabilize the micelles outward. Core-shell structure. Polymer micelles not only increase the solubility of the drug, but also increase the therapeutic dose, and the drug is wrapped therein to avoid degradation and reduce side effects.
- the micelle size is usually below 100 nm, and the periphery is a hydrophilic PEG segment, so it can avoid the phagocytosis of the reticuloendothelial system (RES), prolong the system circulation time, and pass the EPR effect (high permeability and retention effect). And retention effect) achieves the effect of passive targeting of tumors.
- RES reticuloendothelial system
- EPR high permeability and retention effect
- retention effect achieves the effect of passive targeting of tumors.
- due to the high molecular weight of the polymer micelles renal clearance can also be prevented.
- the polymer micelles have very low CMC values (critical micelle concentrations) and maintain the stability of the micelle structure when the drug micelles are diluted.
- the micelle delivery system can carry up to 25% of the drug, fully meeting the needs of clinical use, while the polymer material has biodegradability and good biocompatibility.
- polymer micelles are considered to be a promising new drug delivery system, especially for some poorly soluble antitumor drugs, their low stability in solution has been affecting this new drug delivery system.
- the solution has a stabilization time of no more than 24 hours at room temperature (Lee SW, et al, Ionically Fixed Polymeric Nanoparticles as a Novel Drug Carrier, Pharmaceutical). Research, 2007, 24: 1508-1516).
- the micelles can only be stabilized for about 6 hours at room temperature (Lee SW, et al, Development of docetaxel-loaded intravenous formulation, Nanoxel-PMTM using colymer-based delivery system, Journal of Controlled Release, 2011, 155: 262-271).
- the micelles quickly disintegrate after entering the body, and the drug immediately binds to proteins in the blood (such as albumin), so the EPR effect of the micelles cannot be exerted.
- the results of animal experiments show that the drug is no different from docetaxel injection.
- the tolerated dose has not increased, so the advantage is not obvious.
- the stability of its mPEG-PLA micelles is similar.
- Taxanes are one of the greatest discoveries in the field of oncology drug discovery in the past 20 years, and will be the mainstream anti-tumor drugs for the next 20 years. Due to its dose-limiting toxicity, the full use of the drug has been a hot topic. As a promising drug delivery system for taxanes, the instability of micelles has become the biggest drawback of this drug delivery system, and the cause of this instability is still not fully understood. In order to improve the stability of the taxane drug bundle, a lot of efforts have been made. For example, patent 201010001047 discloses a method for adding amino acids to a micelle solution to improve its stability.
- the amino acid is added during micelle formation, and the position of the amino acid in the micelle (only as a physical barrier of micelles)
- the agent or the synergistic drug molecule together in the hydrophobic core of the micelle is not mentioned, and it is not known whether the amino acid as an auxiliary additive can maintain the stability of the micelle after being diluted by the blood after entering the body, so that it is used in vivo.
- the effect is still unclear; it has been reported that the inclusion of paclitaxel and docetaxel in the copolymer micelle can significantly increase the drug loading and stability of the micelle, but the composite drug micelle has not been used clinically.
- amphiphilic block copolymer of the present invention is based on a polyethylene glycol monomethyl ether (or polyethylene glycol)-polyester block copolymer having a recognized safety, and the terminal hydroxyl group of the polyester segment Modification with a hydrophobic group, introduction of a hydrophobic group having a large spatial structure such as a tert-butoxycarbonyl group or an amino acid having a benzene ring and a derivative thereof, not only improving hydrophobicity in drug molecules and block copolymers
- the compatibility of the segments increases the interaction between them, and the introduced hydrophobic groups have a larger spatial structure, which provides more space for the drug molecules to enter the core of the micelles, making them less soluble.
- the greatest significance of the invention is to improve the stability of the micelles in solution state, especially in vivo, thereby exerting the EPR effect of the micelles, achieving higher bioavailability and better therapeutic effects.
- amphiphilic block copolymer characterized in that: the hydrophilic segment is polyethylene glycol (PEG) or polyethylene glycol monomethyl ether (mPEG) having a number average molecular weight between 400 and 20,000, which is hydrophobic
- the sexual segment is selected from the group consisting of polylactide (PLA), polyglycolide (PGA), polyglycolide (PLGA), and polycaprolactone having a number average molecular weight of 500,000,000 capped with a hydrophobic group.
- PCL polycarbonate
- PTMC polycarbonate
- PPDO polydioxanone
- the amino acid derivative is preferably an amino acid derivative protected by ⁇ -benzyl glutamic acid, ⁇ -benzyl aspartic acid or amino group.
- the amino acid derivative is further preferably an amino acid comprising a benzyl protected or a tert-butoxycarbonyl (Boc) protected.
- the amino acid derivative is more preferably t-butoxycarbonylphenylalanine.
- the hydrophobic segment is preferably polylactide (PLA), polyglycolide (PGA), poly(ethylene lactide) (PLGA), polycaprolactone having a number average molecular weight of 1000 50000. (PCL), polycarbonate (PTMC) or a derivative thereof, or polydioxanone (PPDO) or a derivative thereof; preferably, the hydrophilic segment is a polyethylene having a number average molecular weight of 750 5000 Glycol or polyethylene glycol monomethyl ether.
- Another object of the present invention is to provide a process for the preparation of the above amphiphilic block copolymer.
- the preparation method of the above amphiphilic block copolymer comprises the following steps:
- hydrophilic segment with a number average molecular weight between 400 and 20,000 is added to the polymerization bottle, heated to 100 ° C ⁇ 130 °, vacuum dehydrated for 2 h ⁇ 4 h, and then added to form a hydrophobic segment of the polymer monomer and The monomer weight is 0.3%. _1%.
- Another object of the present invention is to provide a micellar drug delivery system formed from the above amphiphilic block copolymer and an antitumor drug.
- the technical solution provided by the present invention is as follows:
- micellar drug delivery system formed by the above amphiphilic block copolymer and an antitumor drug, the micellar drug delivery system comprising at least one of the above amphiphilic block copolymers, a therapeutically effective amount of at least one antitumor drug, and A pharmaceutically acceptable pharmaceutical excipient.
- the pharmaceutical excipient is a lyophilized excipient.
- the lyophilized excipient is at least one of lactose, mannitol, sucrose, trehalose, fructose, glucose, sodium alginate or gelatin.
- the pharmaceutical auxiliary material further includes an antioxidant, a metal ion complexing agent, a pH adjusting agent or an isotonic adjusting agent, etc.
- the antioxidant is sodium sulfite, sodium hydrogen sulfite or sodium metabisulfite
- the metal ion complexing agent is Disodium glutamate, calcium edetate or sodium cyclohexanediamine tetraacetate
- pH regulator is citric acid, sodium bicarbonate, disodium hydrogen phosphate or sodium dihydrogen phosphate
- isotonic regulator is chlorinated Sodium or glucose, etc.
- the anti-tumor drug is the taxane paclitaxel (PTX), docetaxel (DTX), cabazit axe l, larotaxel, and turmeric At least one of a vegetarian, doxorubicin or epirubicin.
- PTX taxane paclitaxel
- DTX docetaxel
- cabazit axe l larotaxel
- turmeric At least one of a vegetarian, doxorubicin or epirubicin.
- the weight ratio of the amphiphilic block copolymer to the drug in the amphiphilic block copolymer is between 99.5:0.5 and 50:50, preferably between 99:1 and 75:25.
- the weight ratio of the lyophilized excipient to the entire system is between 0 and 99.9%, preferably between 10.0 and 80.0%.
- the antitumor drug polymer micelle preparation prepared by the present invention can be used for the treatment of cancer, preferably for the treatment of breast cancer, prostate cancer, ovarian cancer, intestinal cancer, lung cancer, liver cancer, head and neck cancer and the like.
- the therapeutically effective amount referred to in the present invention means that the amount of the antitumor drug contained in the above micellar drug-loading system can effectively treat cancer (specifically, it can be referred to as breast cancer, prostate cancer, ovarian cancer, intestinal cancer, lung cancer, liver cancer). , head and neck cancer, etc.).
- the micelle drug-loading system of the present invention can be administered by an injection route, and is generally prepared as a lyophilized powder preparation. Further, those skilled in the art can determine the dose to be administered according to the dosage of the existing anti-tumor drug, and according to the individual situation. Different up and down adjustments.
- the invention also provides a preparation method of a micellar drug-loading system formed by an amphiphilic block copolymer and an antitumor drug, comprising a dialysis method, a direct dissolution method, a film hydration method, a solid dispersion method, a high energy homogeneous emulsification method, A film hydration method and a solid dispersion method are preferred.
- the specific steps of the film hydration method are as follows: dissolving the polymer adjuvant and the drug in an organic solvent, removing the solvent by rotary evaporation, adding the water for injection to dissolve the drug film to obtain a drug-loaded micelle solution, and lyophilizing the gel to obtain a micelle Dry powder.
- the specific steps of the solid dispersion method are as follows: dissolving the drug in a molten polymer material after heating (this process may be appropriately added with a small amount of an organic solvent to help dissolve) to obtain a clear mixture, and then adding water for injection to dissolve the micelle solution, After filtration and sterilization, the micelles are freeze-dried to obtain a lyophilized powder.
- the present invention has the following features:
- the present invention modifies the terminal hydroxyl group of the polyester segment with a hydrophobic group according to the hydrophobicity of the structure of most antitumor drugs and a large spatial structure, by improving the hydrophobicity of the drug molecule and the block copolymer.
- the compatibility of the sexual segments increases the interaction between them, and at the same time increases the space in the micelle nucleus that can accommodate the drug molecules, and limits the drug molecules to the core of the micelles, making it difficult to dissolve, thus obtaining a series of Highly stable drug-loaded micelles both in vitro and in vivo, the drug-loaded micelles can be made into a lyophilized preparation;
- the test results prove that: the reconstituted lyophilized preparation of the antitumor drug-loaded micelle prepared by the amphiphilic block copolymer of the invention can be rapidly dispersed to form a clear solution with a blueish opalescence.
- the solution is stable for at least 24 hours at room temperature without significant precipitation of the drug, and the EPR effect can be effectively exerted in the body after injection, and has a good industrial application prospect.
- Figure 3 is mPEG 2 . . . -PLA 18 . . Nuclear magnetic resonance spectrum of -BP;
- Figure 8 is a nuclear magnetic resonance spectrum of mPEGsooo-PC ooo-BP
- Figure 9 is mPEG 5 . . . -PCL 4 . . . -BP/paclitaxel micelle particle size map
- Figure 10 is a graph of mPEG 2 ( KKrPLA 18Q (r BP / docetaxel micelle size;
- Figure 11 3 ⁇ 4mPEG 2 ooo-PLGA 20 oo-TB / cabazitaxel micelle particle size map;
- Figure 12 is a result of stability test of mPEG 2GGG -PLA 18Q () -BP / docetaxel micelle solution;
- Figure 13 is a graph showing the stability test results of the mPEG ⁇ o-PLGA ⁇ o-TB / cabazitaxel micelle solution
- Figure 14 is a tumor suppressing effect of docetaxel injection and docetaxel micelle injection on H460;
- Figure 15 is a tumor suppressive effect of docetaxel injection and docetaxel micelle injection on H460;
- Figure 16 is a graph showing the inhibitory effect of docetaxel injection and docetaxel micelle injection on MDA-MB-231 tumor;
- Figure 17 is a tumor suppressive effect of docetaxel injection and docetaxel micelle injection on MDA-MB-231;
- Figure 18 is a plasma drug concentration of iv-administered docetaxel micelle (5 mg/kg). Time-dependent curve;
- Figure 19 is a graph showing the plasma drug concentration over time in iv administration of cabazitaxel micelles (5 mg/kg);
- Figure 20 is a graph showing the time-dependent change in the total amount of plasma drug and the concentration of the encapsulated drug in rats given iv to docetaxel micelles (5 mg/kg);
- Figure 21 is a graph showing the time-dependent change in the total amount of plasma drug and the concentration of the encapsulated drug in rats by iv administration of cabazitaxel micelles (5 mg/kg);
- Figure 22 is a graph showing the time-dependent change of docetaxel drug concentration in tumor-bearing (MX-1) nude mice (iv 10 mg/kg) ;
- Figure 23 mPEG 2 . . . -PLA 18 . . -BP/paclitaxel micelles and benzoyl terminated mPEG 2 . . . -PLA 18 . .
- the drug time curve of paclitaxel micelles The drug time curve of paclitaxel micelles.
- TB is an abbreviation for tert-butanoyl.
- the polymer structure was determined by deuterated chloroform as solvent and 400MBruker NMR.
- the NMR data of mPEG 2Q(K )-PLGA 2()()Q -TB was as follows:
- BP is an abbreviation for tert-butoxycarbonylphenylalanine residue.
- the polymer structure, mPEG 2 was determined by deuterated chloroform as a solvent and 400 MBruker NMR. . . -PLA 18 . . -
- the nuclear magnetic resonance spectrum of BP is shown in Figure 3, and its nuclear magnetic resonance spectrum data is as follows:
- the mPEG oo-PLA ⁇ oo synthesis method is the same as in Example 1 (2).
- the polymer structure was determined by deuterated chloroform as solvent and 400MBruker NMR.
- the NMR data of mPEG oo-PLA ⁇ oo-Asp are as follows:
- Example 1 (1) The synthesis method was the same as in Example 1 (1).
- TS is an abbreviation for a tyrosine residue.
- the polymer structure was determined by deuterated chloroform as solvent and 400MBruker NMR.
- the nuclear magnetic resonance data of mPEG 2 ooo-PLGA 20 oo-TS are as follows:
- Example 1 The synthesis method is referred to in Example 1 (1).
- TS is an abbreviation for a tyrosine residue.
- BP is an abbreviation for tert-butoxycarbonylphenylalanine residue.
- the polymer structure, mPEG 2 was determined by deuterated chloroform as a solvent and 400 MBruker NMR. . . -PLA 18 . . -
- the nuclear magnetic resonance spectrum of BP is shown in Figure 8, and its nuclear magnetic resonance spectrum data is as follows:
- paclitaxel micelle lyophilized powder 150 mg of mPEG 5 prepared in Example 1 was taken. . . -PCL 4 . . . -BP and 30 mg of paclitaxel were dissolved in 2 ml of tetrahydrofuran, and 5 ml of ultrapure water was slowly added dropwise with stirring. After the addition was completed, the solution was stirred at room temperature overnight to remove the organic solvent to obtain a clear paclitaxel micelle solution with obvious blue opalescence. 120 mg of mannitol was added, and the resulting solution was filtered through a 0.22 ⁇ sterilizing membrane and lyophilized to obtain a paclitaxel micelle lyophilized powder.
- the drug encapsulation efficiency was 98.6%, and the drug loading was greater than 11.2%, the particle size measurement result is as shown in Fig. 9, and the average particle diameter was 33.8 nm, and the dispersion coefficient PDI was 0.1.
- the stabilization time at room temperature was more than 7 days, which was significantly higher than that of the acetoxy group and the benzoyl terminated polymer micelle.
- the micelle lyophilized powder is reconstituted into a solution having a concentration of 5 mg/mL by physiological saline, the docetaxel content in the dissolved state is greater than 90% in the solution for 90 days at room temperature.
- Example 1 1.9 g of mPEG 2 obtained in Example 1 was taken. . . -PLGA 2 . . . -TB is heated to 50 ° C to melt it, then add 100 mg of cabazitaxel, dissolved in the polymer with stirring to obtain a clear and transparent mixture, add 25 ml of physiological saline preheated to 50 ° C to dissolve the polymer / drug The mixture obtained a micelle solution, and then 400 mg of sucrose was added, and the solution was filtered through a 0.22 sterilizing membrane and then freeze-dried to obtain a freeze-dried powder of cabazitaxel.
- the drug encapsulation efficiency was 96.2%, and the drug loading was more than 4.82%.
- the particle size measurement results are shown in Fig. 11, and the average particle diameter was 24.2 nm, and the dispersion coefficient PDI was 0.02.
- the content of the cabazitaxel in the dissolved state is more than 90% in the solution stored at room temperature for 90 days.
- the micelle lyophilized powder is reconstituted into a solution of 5 mg/mL concentration by physiological saline, the content of curcumin in the dissolved state is more than 90% in the solution stored at room temperature for 7 days.
- mPEG 2 prepared in Example 1 was taken.
- . . -PLGA 2 . . . -TB and 40mg doxorubicin hydrochloride were dissolved in chloroform at 40 ° C, added with 0.1 ml of triethylamine at room temperature for 1 h, and the organic solvent was removed by rotary evaporation, and 50 ml of a concentration of 10 mM was added.
- the HBS buffer solution dissolves the drug film, and after removing the triethylamine hydrochloride by dialysis or ultrafiltration, 250 mg of gelatin solution is added and filtered through a 0.22 ⁇ filter, and then freeze-dried to obtain a doxorubicin micelle lyophilized powder.
- the drug encapsulation efficiency was 94.7%
- the drug loading was more than 22.47%
- the average particle size was 19.4 nm
- the micelle lyophilized powder is reconstituted into a solution of 2 mg/mL concentration by physiological saline, the doxorubicin content in the dissolved state is greater than 90% in the solution stored at room temperature for 24 hours.
- the drug content in the dissolved state changes with time as shown in Figure 12: mPEG 2 . . . -PLA 18 . . -
- the drug in the dissolved state of BP/Docetaxel micelle solution showed a certain degree of decline in the first 15 days, and the dissolution of the drug in the late stage was very slow, even if the drug in the dissolved state remained above 90% within 90 days.
- the drug content in the dissolved state changes with time as shown in Figure 13: mPEG 2 . . . -PLGA 2 . . .
- the drug in the dissolved state of the -TB/carbamazee micelle solution showed a certain degree of decline in the first 3 days, and the dissolution of the drug in the late stage was very slow, even if the drug in the dissolved state remained above 90% within 90 days.
- the docetaxel micelle lyophilized powder prepared in Example 2 was provided by Shandong Target Drug Research Co., Ltd., and dissolved in 0.9% physiological saline;
- Docetaxel Injection 0.5ml per bottle: 20mg, produced by Qilu Pharmaceutical Co., Ltd. Blank solvent control (blank micelles, 10 mg/kg), supplied by Shandong Target Drug Research Co., Ltd., dissolved in 0.9% physiological saline.
- Human lung cancer H460 cells were obtained from ATCC, cultured in vitro by the laboratory, inoculated into nude mice for tumor formation, and subcultured.
- the H460 tumor was selected to grow well, and the tumor-bearing animals were better in systemic condition, and the cervical vertebrae were killed by dislocation. Tumors were removed under aseptic conditions, and scalpels were used to cut tumors with a diameter of 2 to 3 mm.
- the trocars were inoculated subcutaneously into the ankle of nude mice. On the 7th to 8th day after inoculation, the average tumor volume of the tumor-bearing mice reached 110 ⁇ 120mm 3 , and the animals were divided into groups according to the size of the tumor, 8 in each group.
- the tumor of the negative control group grew naturally.
- the blank solvent control group used the same volume of solvent as the docetaxel micelle freeze-dried powder group, and the docetaxel injection was also diluted to the same level as the docetaxel micelle freeze-dried powder group. Volume administration, each administration group was intravenously administered simultaneously.
- each group of animals was administered intravenously once every three days as planned, for a total of three doses. The observation was terminated when the average tumor volume of the negative control group reached about 2000 mm 3 .
- TV is the tumor volume.
- T/C The evaluation index of antitumor activity is the relative tumor growth rate T/C (%) is calculated as:
- Docetaxel injection group (10mg/kg/time) and docetaxel micelle freeze-dried powder administration group (10mg/kg/time) had obvious tumor growth inhibition effect on H460 nude mice, and the tumor volume was obvious. Reduced. Among them, the docetaxel micelle freeze-dried powder administration group (10 mg/kg/time) gradually reduced the tumor volume during the administration period and maintained the average value less than the pre-dose average for nearly 10 days. Compared with the docetaxel injection group (10 mg/kg/time), the same dose of docetaxel micelle injection significantly improved the tumor inhibition rate, the tumor weight inhibition rate was 68.35%, and the latter 97.5%. The relative tumor growth rate is 25.25% in the former, and the latter is only 3.78%, and the curative effect is improved.
- the inhibitory effect of docetaxel injection and docetaxel micelle freeze-dried powder on H460 tumors is shown in Figure 14 and Figure 15.
- the tumor inhibition rate and relative tumor proliferation rate of docetaxel injection and docetaxel micelle freeze-dried powder on H460 tumors are shown in Tables 1 and 2.
- Solvent control group 8 20.9 ⁇ 1.39 24.1 soil 1.76 1.62 soil 0.510 5.81 Docetaxel injection (10 8 8 21.3 ⁇ 0.97 23.1 ⁇ 2.20 0.545 ⁇ 0.166* 68.35 mg/kg)
- Docetaxel micelles 10 8 8 21.6 ⁇ 1.11 21.6 ⁇ 2.34 0.04 soil 0.018* 97.5 mg/kg
- Human breast cancer MAD-MB-231 cells were obtained from ATCC, cultured in vitro by the laboratory, inoculated into nude mice for tumor formation, and subcultured. E, test method
- the MDA-MB-231 tumor was selected to grow well, and the tumor-bearing animals were better in systemic condition, and the cervical vertebrae were dislocated and sacrificed.
- the tumor pieces were taken out under aseptic conditions, and the tumor pieces were cut into 2 to 3 mm in diameter with a scalpel, and the trocars were inoculated subcutaneously into the ankle of the nude mice.
- the average tumor volume of the tumor-bearing mice reached 110 ⁇ 120mm 3 , and the animals were divided into groups according to the size of the tumor, 8-9 per group.
- the tumor of the negative control group grew naturally.
- the blank solvent control group used the same volume of solvent as the docetaxel micelle 10 mg/kg dose group, and the docetaxel injection was also diluted into the docetaxel micelle freeze-dried powder group. The same volume was administered, and each administration group was intravenously administered at the same time.
- T/C The evaluation index of antitumor activity is the relative tumor growth rate T/C (%) is calculated as:
- Body column rate (%) control group average tumor weight X 100
- the docetaxel injection group (10 mg/kg/time) and the docetaxel micelle lyophilized powder administration group (10 mg/kg/time) were administered to the MDA-MB-231 mouse intermittent vein. After 3 injections, the drug showed a significant inhibitory effect on tumor growth in nude mice. After 3 doses, the tumor volume of mice was progressively reduced compared with before administration. Docetaxel micelle freeze-dried powder administration group
- the tumor suppressive effect of MDA-MB-231 was better than that of the docetaxel injection group of the same dose.
- the tumor inhibition rate and relative tumor proliferation rate of Docetaxel injection and docetaxel micelle freeze-dried powder on MDA-MB-231 tumors are shown in Table 3 and Table 4.
- Solvent control group 8 17.3 soil 0.99 20.8 soil 1.92 2.48 soil 0.886 12.3 Docetaxel injection (10 8 15.8 ⁇ 1.16 21.0 ⁇ 1.63 1.08 soil 0.646* 61.8 mg/kg)
- Solvent control group 107 soil 27.9 2472 soil 904.9 27.26 soil 11.779 94.41 docetaxel injection (10 mg/kg) 107 soil 30.7 1054 soil 620.5 10.62 soil 5.295* 36.78 docetaxel micelles (10 mg/kg) 101 soil 42.4 0 1.96 soil 1.48** 6.79
- mice Male Sprague-Dawley rats weighing 240 ⁇ 20 g were randomly divided into 4 groups: I, II, III and IV, with 6 in each group.
- Docetaxel micelle lyophilized powder (a), prepared according to the method of Example 2. (2), lot number 20120907, specification: containing docetaxel 20 mg / bottle;
- Cabazitaxel micelle lyophilized powder (b), prepared according to the method of Example 2. (3), batch number 20120830, Specifications: containing cabazitaxel 20 mg / bottle;
- Dopafi Docetaxel Injection, c
- Qilu Pharmaceutical Co., Ltd. Lot 1120312TA, Specification 0.5 ml: 20 mg;
- the experimental preparation was dissolved and diluted to a suitable concentration before use.
- docetaxel micelles (a) and cabazitaxel micelles (b) were given to rats in groups I and II by tail vein injection at a dose of 5 mg/kg (each in docetaxel, cabazitaxel).
- Docetaxel injection (c) and cabazitaxel lyophilized powder (d) were administered to rats in groups III and IV via tail vein at a dose of 5 mg/kg.
- Blood samples were collected from the orbital venous plexus of the rats at different times after administration, and the plasma was separated by centrifugation, and stored in an ultra-low temperature freezer at -80 °C for testing.
- Plasma samples were deproteinized by methanol precipitation and analyzed by LC-MS/MS. The total drug concentration of docetaxel or cabazitaxel was determined. The plasma drug concentration of each drug-administered group was plotted over time. The results are shown in Figure 18 ( Rats were given intravenous docetaxel lyophilized powder (a) and docetaxel injection (c) plasma drug time curve), Figure 19 (rat intravenous administration of cabazitaxel micelle lyophilized powder (b) ) and the plasma drug time curve of the cabazitaxel lyophilized powder (d).
- the plasma AUC of the docetaxel micelle administration group and the cabazitaxel micelle administration group were 8.56 times and 8.91 times that of the corresponding injection administration groups, respectively.
- both docetaxel micelles and cabazitaxel micelles were intravenously encapsulated in the form of micelles 24 hours after administration.
- the plasma pharmacokinetic characteristics exhibited by micelle administration reflect the superior stability and unique in vivo release characteristics of the micelles prepared by the present invention.
- mice Female nude mice were inoculated with human breast cancer MX-1 cells at a density of 5 X 10 6 under the armpits until the tumor grew to ⁇ 500 mm 3 and randomly divided into two groups (Group I: docetaxel micelles).
- the body weight of the two groups of tumor-bearing mice were 24.9 ⁇ 1.2 g and 25.0 ⁇ 1.3 g, respectively, no significant difference (P > 0.05). Every big The group was evenly divided into 7 groups, each of which had 10 tumor-bearing mice, which were reserved.
- Docetaxel micelle lyophilized powder prepared according to the method of Example 2. 2), batch number 20120907, specification: 20 mg / bottle; Dopafi (Docetaxel Injection), Qilu Pharmaceutical Co., Ltd., batch number 1120312TA , size 0.5 ml: 20mg.
- Docetaxel injection and docetaxel micelle lyophilized powder were dissolved and diluted to the appropriate concentration before use, and administered to the group I and II via tail vein injection at a dose of 10 mg/kg (based on docetaxel). Animals were sacrificed at 5 min, 15 min, 30 min 1 h, 3 h, 8 h and 24 h after administration, and the tumor tissues were excised, and then weighed and stored in an ultra-low temperature freezer at -80 °C for testing. .
- LC-MS/MS analysis was performed to determine the drug concentration of docetaxel, and the drug concentration of the tumor tissue in each administration group was plotted as shown in Fig. 22 .
- the AUC of docetaxel in the tumor tissue of group II and micelle group was 45.528 mg/L for 24 h. h and 57.089 mg/L h.
- the results showed that the distribution of docetaxel in the tumor tissue of the micelle group was significantly higher than that of the injection group (( ⁇ 0.01), and the difference was 25.4%.
- Example 6 Comparison of in vitro and in vivo stability of Boc-phenylalanine-terminated mPEG 2flflfl- PLA 18flfl copolymer/paclitaxel micelles and benzoyl-terminated mPEG 2flflfl- PLA 18flfl copolymer/paclitaxel micelles
- mPEG ⁇ o-PLA ⁇ o-BP/paclitaxel micelles had no drug precipitation for at least 48h, while benzoyl terminated mPEG 2QQQ- PLA 18()() copolymer/paclitaxel micelles showed significant drug precipitation at 17h, mPEG 2 . . . -PLA 18 . .
- the stability of the -BP/paclitaxel micelles was significantly higher than that of the benzoyl terminated mPEG 2 . . . Paclitaxel micelles prepared by -PLA 18 (K) .
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JP2015534992A (ja) | 2015-12-07 |
US20150283246A1 (en) | 2015-10-08 |
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CA2889518A1 (en) | 2014-05-01 |
CA2889518C (en) | 2016-12-13 |
US9393312B2 (en) | 2016-07-19 |
CN103772686B (zh) | 2015-01-07 |
ES2613876T3 (es) | 2017-05-26 |
PT2913353T (pt) | 2017-04-05 |
CN103772686A (zh) | 2014-05-07 |
EP2913353B1 (en) | 2017-01-11 |
AU2013334301A1 (en) | 2015-05-07 |
EP2913353A4 (en) | 2015-12-16 |
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