WO2010118683A1 - 含索拉非尼的海藻酸钠靶向缓释微球血管拴塞剂及其制备和应用 - Google Patents

含索拉非尼的海藻酸钠靶向缓释微球血管拴塞剂及其制备和应用 Download PDF

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WO2010118683A1
WO2010118683A1 PCT/CN2010/071749 CN2010071749W WO2010118683A1 WO 2010118683 A1 WO2010118683 A1 WO 2010118683A1 CN 2010071749 W CN2010071749 W CN 2010071749W WO 2010118683 A1 WO2010118683 A1 WO 2010118683A1
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sodium alginate
sorafenib
solution
microspheres
drug
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PCT/CN2010/071749
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English (en)
French (fr)
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李新建
洪宏
鲁格
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北京圣医耀科技发展有限责任公司
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Priority to US13/264,709 priority Critical patent/US20120093932A1/en
Priority to CA2758820A priority patent/CA2758820C/en
Priority to EP10764096.3A priority patent/EP2420227B1/en
Priority to DK10764096.3T priority patent/DK2420227T3/en
Priority to JP2012505035A priority patent/JP5802193B2/ja
Publication of WO2010118683A1 publication Critical patent/WO2010118683A1/zh
Priority to HK12108089.1A priority patent/HK1167335A1/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to a microsphere vascular embolization agent containing an antitumor drug, and a preparation and application thereof, in particular to a sodium alginate-targeted sustained release microsphere vascular embolization agent containing sorafenib, and preparation and application thereof.
  • Sorafenib is a novel diaryl urea, chemical name 4- ⁇ 4-[3-(4-chloro-3-trifluoro-phenyl)-acyl urea]-phenoxy ⁇ - pyridine-2-carboxylic acid methylamine, molecular weight 464. 8g / mol.
  • Clinically used is the tosylate salt of sorafenib.
  • Molecular formula of sorafenib tosylate salt ( 21 6 ( ⁇ 0 3 - C 7 H 8 0 3 S, molecular weight: 637.0 g/mol.
  • the molecular structure is as follows:
  • Sorafenib tosylate has a melting point of 225-235 ° C and is an odorless solid between white and brown. Good thermal stability, no water absorption. The solubility in aqueous solution is low, the solubility is slightly increased under strong acidic conditions, slightly soluble in alcohol, and soluble in polyethylene glycerin 400. Sorafenib is a multi-targeted tumor-targeted therapeutic drug jointly developed by Bayer and ONYX since 1994. It is the first target approved by the US FDA for the treatment of metastatic renal cell carcinoma. medicine. In December 2005, the US FDA officially approved sorafenib for the treatment of advanced kidney cancer, becoming the world's first marketed oral multi-kinase inhibitor. At the end of November 2006, it was officially listed in China.
  • Sorafenib is a tyrosine kinase inhibitor, an angiogenesis inhibitor and a vascular endothelial growth inhibitor. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis.
  • the Ras (GTP-binding protein)/Raf signaling pathway is an important pathway for tumor cell proliferation and angiogenesis.
  • Raf is a serine/threonine (Ser/Thr) protein kinase that is a downstream effector of Ras.
  • sorafenib inhibits the RAS/RAF/MEK/ERK signaling pathway by directly inhibiting the growth of tumor cells by inhibiting the activity of RAF, and on the other hand by inhibiting several tyrosines involved in neovascularization and tumor development.
  • Kinase receptor activity including vascular endothelial growth factor receptor-2 (VEGFR-2), REGFR-3, platelet-derived growth factor receptor-beta (PDGFR- ⁇ ) and C-KIT proto-oncogene, blocks tumors The formation of new blood vessels and the cutting of the nutrient supply of tumor cells, and the inhibition of the growth of tumor cells indirectly, have a dual anti-tumor effect.
  • Sorafenib is mainly metabolized by hepatic CYP3A4 enzyme and glucuronidation of UGTIA9. Eight of its metabolites have been identified, five of which have been determined in blood. The main metabolite pyridinium oxide is shown in vitro. Rafini works similarly. This metabolite accounts for 9% to 16% of all metabolites. A single oral solution containing sorafenib lOOmg was excreted in the feces within 14 days, with 51% of the original drug. 19% is excreted in the urine by glucuronidation metabolites. Sorafenib is the first of its kind to enter clinical trials.
  • sorafenib is associated with solid tumors such as kidney cancer, liver cancer, melanoma, non-small cell lung cancer, gastric cancer and ovarian cancer. Have a certain anti-tumor effect.
  • sorafenib Common adverse reactions to sorafenib include redness of the skin, rash, itching, hair loss or patchy alopecia, frequent diarrhea and/or relaxation of bowel movements, nausea or vomiting, mouth ulcers, fatigue, loss of appetite (decreased), high Blood pressure, hand and foot syndrome, etc.
  • Skin toxicity and gastrointestinal reactions are common side effects of sorafenib and are a common cause of reduction or discontinuation of treatment.
  • the most common oral sorafenib in the course of treatment is the emergence of gastrointestinal side effects. Gastrointestinal reactions accounted for 95%, diarrhea accounted for 58%, nausea accounted for 30%, vomiting accounted for 24%, and dyspepsia loss of appetite accounted for 47%.
  • Sorafenib has a unique multi-target anti-tumor effect. It is a new drug based on the further clarification of the molecular biological mechanism of tumorigenesis. The successful clinical application has opened the biological targeted therapy for tumors. A new chapter. From the mechanism of action and clinical findings, sorafenib and chemotherapy drugs Differently, its role is mainly to inhibit the growth of tumor cells, rather than cytotoxic effects.
  • Sorafenib has a significant prolongation of PFS, OS and TTP in second-line treatment of advanced renal cell carcinoma; how to further improve the efficacy of sorafenib and to find markers that can predict the efficacy of sorafenib It is currently the most concerned issue in clinical trials.
  • Sorafenib is a novel multi-kinase inhibitor that inhibits the RAF-MEK-ERK pathway and inhibits tyrosine kinase receptors, thereby inhibiting tumor growth and angiogenesis.
  • Phase I clinical trials have found that oral sorafenib 400 mg is completely tolerated twice daily and also shows a certain effect. The most common side effects are diarrhea and skin damage.
  • phase II clinical trials have shown that sorafenib has certain anti-tumor activity against liver cancer and renal cancer.
  • Phase III clinical trials of advanced kidney cancer have demonstrated that most patients have significantly reduced tumors and a significant median survival.
  • phase III clinical trials underway.
  • China is conducting phase III clinical trials of sorafenib for liver cancer. It is believed that there will be more encouraging results and new hope for the treatment of cancer.
  • problems to be solved such as the difficulty in entering the tumor tissue due to drug treatment, and the difficulty in reaching the tumor tissue. The low concentration of the drug requires further clinical trials to answer. .
  • sorafenib alone has a certain effect on liver cancer.
  • the researchers believe that although the efficacy of sorafenib monotherapy for liver cancer is not very high, its efficacy is similar to that of combination chemotherapy, and its mechanism of action and less toxicity also support its use in combination with other anticancer drugs to further improve Efficacy.
  • the study is a multi-center, phase III clinical trial of the Asia- Pacific region for liver cancer that is incapable or unwilling to undergo surgery. With the elucidation of the pathogenesis of liver cancer and the study of new molecular targeted drugs, patients with advanced liver cancer are provided with opportunities for targeted therapy.
  • liver cancer Most patients with liver cancer have the basis of cirrhosis, their liver function and physical condition are poor, and chemotherapy and radiotherapy patients benefit very little.
  • the rapid development of molecular targeted drugs provides a new choice for the treatment of liver cancer.
  • molecular targeted therapy is highly targeted and less toxic, and has a promising future for advanced liver cancer.
  • These drugs may be one of the most promising and promising methods for the future treatment of liver cancer.
  • TACE Transcatheter chemoembolization
  • TACE for the treatment of liver cancer before surgery, may cause tumor tissue necrosis, absorption and fibrosis formation, and at the same time form a thick fibrous envelope, reduce the amount of bleeding in liver cancer surgery and prevent local surgical operations, squeezing caused by tumor cell dissemination Opportunity, and the liver can make certain drugs Inactivation of the substance, reduced toxicity, this advantage is not achieved by peripheral intravenous administration.
  • Tumor is one of the most deadly diseases in the world.
  • Clinical treatment such as chemoradiotherapy is an effective means to remove tumor tumors.
  • surgery can only remove macroscopic tumors, and can not remove invisible subclinical lesions and have passed.
  • Blood, lymphatic metastasis or tumor cells that infiltrate directly into surrounding normal tissues.
  • Radiotherapy is a partial irradiation that does not kill tumors in non-irradiated areas, and does not work for some insensitive tumor cells.
  • Chemotherapy is a method of total treatment, but selective inhibition of tumor cells is not strong, and it is less effective for dormant tumor cells. In view of this, in recent years, many new methods and new techniques for treating tumors have been developed.
  • Molecular targeted therapy refers to the molecular biology of tumors.
  • a tumor-specific specific molecule is used as a target, and a target molecule-specific preparation or a drug is used for treatment.
  • This treatment with diseased cells has the most thorough therapeutic effect compared to surgery, radiotherapy and chemotherapy.
  • tumor is a multi-factor-caused disease, and its therapeutic mechanism must be considered in many aspects.
  • Targeting therapy is a new technology for tumor treatment at present, which can inhibit tumor occurrence and development against a variety of mechanisms to eliminate tumors.
  • Sorafenib and sodium alginate have not been used as microspheres at home and abroad for local target vascular embolization for liver cancer, renal cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, prostate cancer, head and neck cancer, melanin Reports of solid tumors such as tumors.
  • One of the objects of the present invention is to provide a sustained release vascular embolization agent containing sorafenib sea-alginate microspheres.
  • a sodium alginate-targeted sustained-release microsphere vascular embolization agent containing sorafenib comprising: a natural carrier sodium alginate and an antitumor drug sorafenib, the sodium alginate wrapping the sora
  • the weight ratio of the sorafenib to the sodium alginate is 1:1 to 1:30.
  • Another object of the present invention is to provide a method for preparing a sodium alginate-targeted sustained-release microsphere vascular embolization agent containing sorafenib.
  • a method for preparing a sodium alginate-targeted sustained release microsphere vascular embolization agent containing sorafenib the steps of which are as follows:
  • Calcium lactate or calcium chloride is weighed and dissolved in physiological saline or water for injection to prepare a calcium lactate or calcium chloride solution having a concentration of 1 to 10% by weight;
  • sorafenib drug solution Using a solution of polyvinyl glycerol 400 or dimethyl sulfoxide (DMS0 solution), the proportioned sorafenib is completely dissolved to obtain a sorafenib drug solution;
  • the mixed solution obtained in the step (4) is reacted with the solidified liquid of the step (2) by a high-pressure electrostatic multi-head microsphere generating device to obtain microspheres (or microgel beads).
  • the high-voltage electrostatic multi-head microsphere generating device in the step (5) comprises: a high-voltage electrostatic generator, a multi-head electrode, a micro-injection pump, a syringe, a special needle, a lifting platform, and a sterilizing Glass collector.
  • the positive electrode interface of the high-voltage electrostatic generator is connected to the special needle of 2 ⁇ 12 syringes through the multi-head electrode; the negative electrode of the high-voltage electrostatic generator passes through the multi-head electrode and 2 ⁇ 12 "b" immersed in the solidifying liquid in the step (2) Forming an extension of the stainless steel wire loop; the special needle is located above the sterile glass collector, the sterile glass collector is placed on the lifting platform; the lower end of the special needle and the sterile glass collector The distance between the liquid surfaces is 5-20 cm; press the high voltage electrostatic generator and the micro-injection pump's opening button, and the sorafenib-containing sodium alginate mixture is dropped into the sterile glass collector for curing. In the liquid, a microsphere (or microbead) is obtained, which is called a wet bulb.
  • a preferred technical solution is characterized in that: the special needle is made of stainless steel and the end is flat.
  • a preferred technical solution is characterized in that: the obtained microspheres (or microbeads) are subjected to centrifugation or precipitation washing treatment, and stored in a preservation solution to obtain sodium alginate (or microbeads) containing sorafenib. , preservation period micro The ball is intact and the sorafenib drug does not ooze out.
  • a preferred technical solution is characterized in that: the preparation process of the preservation solution is as follows:
  • Calcium chloride or calcium lactate is weighed, dissolved in water for injection, and formulated into a solution having a concentration of 3 to 15% by weight to obtain a preservation solution.
  • the particle size range of the microspheres (or microbeads) stored in the preservation solution is: 50 ⁇ 100 ⁇ , 70 ⁇ 150 ⁇ , 100 ⁇ 200 ⁇ , 100 ⁇ 300 ⁇ , 150 ⁇ 450 ⁇ , 300—500 ⁇ , 500 ⁇ 700 ⁇ , 700 ⁇ 900 ⁇ .
  • a preferred technical solution is characterized in that: the obtained microspheres or microbeads are dried by freeze-drying (or oven drying) to obtain dry spheres having a particle size ranging from 20 to 60 ⁇ m, 30 to 75 ⁇ m, 50 to 50. 100 ⁇ , 70 ⁇ 150 ⁇ , 80 ⁇ 250 ⁇ , 150 ⁇ 300 ⁇ , 250 ⁇ 500 ⁇ , 300 ⁇ 500 ⁇ , 500 ⁇ 700 ⁇ .
  • a further object of the present invention is to provide a sodium alginate-containing sustained release microsphere vascular embolization agent containing sorafenib.
  • the sorafenib-containing sodium alginate-targeted sustained release microsphere vascular embolization agent is used as a medicament for treating solid tumors such as liver cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, melanoma and the like.
  • the specific application steps are as follows: Insert the catheter into the blood supply artery of the target organ by interventional or interventional ultrasound, and perform angiography.
  • the above sodium alginate-containing sustained release microsphere vascular embolization agent containing sorafenib is selected. Try to use a microcatheter for superselective embolization, use aseptically in use; use the sodium alginate microsphere (wet bulb) containing sorafenib, discard the preservation solution in the bottle with a syringe, add the same amount Rinse the microspheres three times with saline or pour the microspheres into the sterile bowl.
  • the microspheres Rinse the microspheres with 50 ⁇ 100ml saline for 1 ⁇ 3 times, discard the rinse solution, and add the appropriate amount or diluted contrast medium. (The microspheres are fully suspended in the contrast agent), and the catheter is slowly injected into the lesion according to the specific conditions under fluoroscopy, until the contrast agent flow rate is significantly slowed down, that is, the embolization is completed; the angiography is performed again to determine the embolization effect.
  • the sorafenib-containing sodium alginate of the invention is targeted to the sustained-release microsphere vascular embolization agent, so that the targeted drug can be directly in the local target area, fast, long-acting, fixed point by changing the dosage form and changing the administration route. It is highly targeted and effective in cancer tissues. It basically does not damage normal tissues when killing cancer cells. It has low toxic and side effects, low dosage, and low cost of treatment.
  • Sodium alginate-containing sustained-release microsphere vascular embolization agent containing sorafenib is a new drug using sorafenib
  • the technology enables the drug to rapidly localize the target area, long-term slow release, fixed around the cancer cells, reduce the circulation of the drug, reduce the dosage of the drug, reduce the normal cell damage, reduce the side effects, and improve the therapeutic effect.
  • sorafenib has a low bioavailability, a large dose required, and a large side effect, resulting in high medical cost, which is difficult for doctors and patients to accept.
  • the combined effect, local combination of antineoplastic agents and embolic agents produces the effects that the original two drugs cannot produce at the same time.
  • the target drug, sorafenib is encapsulated in the microspheres, and arterial vascular embolization allows for a longer period of drug concentration in the local tissue.
  • the effect is concentrated, avoiding the first pass effect of the drug through the systemic circulation, liver and kidney, and the destruction of excretion, reducing the probability of drug and plasma protein binding failure, prolonging the action time of the drug, overcoming the oral chemotherapy
  • the simple perfusion drug has short retention time in the tumor tissue, rapid clearance, and the drug and the tumor cell can not be fully contacted.
  • the clinical pharmacokinetic study shows that within a certain range, the concentration of the local tissue anticancer drug is doubled, killing The number of cancer cells can be increased by 10 to 100 times, which doubles the therapeutic effect.
  • the inventors have found that 2 to 12 microinjection devices in the high-voltage electrostatic multi-head microsphere generating device can make the prepared microspheres more uniform, increase the yield, and simultaneously make microspheres of different sizes.
  • Treatment of glassware Dry the cleaned glassware and bake it in a high temperature oven at 260 °C for 3 hours (sterilization to remove heat);
  • sorafenib 10 mg was weighed and placed in the above glassware, and an appropriate amount of polyethylene glycol 400 was added dropwise until all dissolved, and 20 ml of sorafenib solution was obtained.
  • Calcium chloride is weighed, dissolved in physiological saline, and formulated into a 3 wt% calcium chloride solution; 4 preservation solution preparation:
  • the calcium chloride is weighed, dissolved in water for injection, and formulated into a solution having a concentration of 3% by weight to obtain a preservation solution;
  • the positive electrode interface of the high-voltage electrostatic generator is connected to the special needle of two syringes through the multi-head electrode; the negative electrode of the high-voltage electrostatic generator passes through the multi-head electrode and two "b-shaped" stainless steel wires immersed in the solidified liquid in the step (2)
  • the extension of the loop is connected; the special needle is located above the sterile glass collector, the sterile glass collector is placed on the lifting platform; the lower end of the special needle and the liquid level in the sterile glass collector The distance between the two is 12 cm; press the high-voltage electrostatic generator and the micro-injection pump to open the button, the sodium alginate containing sodium soda is mixed into the solidified liquid of the sterile glass collector to obtain the microspheres. (or micro-beads), called wet balls.
  • the special needle is made of stainless steel and has a flat end.
  • the obtained microspheres are subjected to centrifugation or precipitation washing treatment, and stored in a 3 wt% concentration preservation solution.
  • the microspheres are intact during the storage period, and the sorafenib drug does not ooze out.
  • the particle size range of the microspheres (or microbeads) stored in the preservation solution is 70 to 15 (m.
  • sorafenib sodium alginate microspheres are dried by freeze-drying to obtain a dry sphere, and the particle size ranges from 30 to 30 minutes.
  • the microspheres are immersed in physiological saline for half an hour to reduce to a wet bulb.
  • the catheter is inserted into the blood supply artery of the target organ by interventional or interventional ultrasound, and the angiography is performed.
  • the above-mentioned sorafenib sodium alginate microsphere sustained-release vascular embolization agent is selected.
  • the sorafenib sodium alginate microspheres (wet bulbs) are used, and the calcium chloride solution in the bottle is removed by a syringe, and the microspheres are washed three times with an equal amount of physiological saline or the microspheres in the bottle are poured into the bottle.
  • Treatment of glassware Dry the cleaned glassware and bake it in a high temperature oven at 260 °C for 3 hours (sterilization to remove heat);
  • the calcium lactate was weighed and dissolved in physiological saline to prepare a calcium lactate solution having a concentration of 1% by weight.
  • Calcium chloride was weighed, dissolved in water for injection, and formulated into a solution having a concentration of 8 wt% to obtain a preservation solution.
  • the positive electrode interface of the high-voltage electrostatic generator is connected to the special needle of 12 syringes through the multi-head electrode; the negative electrode of the high-voltage electrostatic generator passes through the multi-head electrode and 12 "b-shaped" stainless steel wires immersed in the solidified liquid in the step (2)
  • the extension of the loop is connected; the special needle is located above the sterile glass collector, the sterile glass collector is placed on the lifting platform; the lower end of the special needle and the liquid level in the sterile glass collector The distance between the two is 5 cm; press the high voltage electrostatic generator and the micro button of the micro syringe pump, the sodium alginate containing sodium soda is mixed into the solidified liquid of the sterile glass collector to obtain the microsphere (or micro-beads), called wet balls.
  • the special needle is made of stainless steel and has a flat end.
  • the obtained microspheres (or microbeads) are subjected to centrifugation or precipitation washing treatment, and stored in a 8% by weight concentration preservation solution.
  • the microspheres are intact during the storage period, and the sorafenib drug does not ooze out.
  • the particle size range of the microspheres (or microbeads) stored in the preservation solution 300 to 50 (m.
  • sorafenib sodium alginate microspheres are obtained by freeze-drying (or oven drying) to obtain dry spheres having a particle diameter range of 150 to 30 (m.
  • microspheres are immersed in physiological saline for half an hour in advance to be reduced to a wet bulb for use.
  • the catheter is inserted into the blood supply artery of the target organ by interventional or interventional ultrasound, and the angiography is performed.
  • the above-mentioned sorafenib sodium alginate microspheres are used for sustained release vascular embolization.
  • Agent Use microcatheters as much as possible for superselective embolization, and use aseptically.
  • the sorafenib sodium alginate microspheres (wet bulbs) are used, and the calcium chloride solution in the bottle is removed by a syringe, and the microspheres are washed three times with an equal amount of physiological saline or the microspheres in the bottle are poured into the bottle.
  • Treatment of glassware Dry the cleaned glassware and bake it in a high temperature oven at 260 °C for 3 hours (sterilization to remove heat);
  • the sodium alginate solution was placed at a concentration of 7 wt% (with stirring while adding physiological saline) until all the sodium alginate was dissolved, and 2000 ml of sodium alginate solution was obtained;
  • the calcium lactate was weighed and dissolved in water for injection to prepare a calcium lactate solution having a concentration of 10% by weight.
  • the calcium lactate was weighed, dissolved in water for injection, and formulated into a solution having a concentration of 15% by weight to obtain a preservation solution.
  • the preparation method and steps of the sorafenib sodium alginate microspheres are as follows: 1 After connecting a special needle with 10 50 ml syringes, aspirate the mixture of sorafenib solution and sodium alginate solution into the syringe at least 4 times;
  • the positive electrode interface of the high-voltage electrostatic generator is connected to the special needle of 10 syringes through the multi-head electrode; the negative electrode of the high-voltage electrostatic generator passes through the multi-head electrode and 10 "b-shaped" stainless steel wires immersed in the solidified liquid in the step (2)
  • the extension of the loop is connected; the special needle is located above the sterile glass collector, the sterile glass collector is placed on the lifting platform; the lower end of the special needle and the liquid level in the sterile glass collector The distance between the two is 5 cm; press the high voltage electrostatic generator and the micro button of the micro syringe pump, the sodium alginate containing sodium soda is mixed into the solidified liquid of the sterile glass collector to obtain the microsphere (or micro-beads), called wet balls.
  • the special needle is made of stainless steel and has a flat end.
  • the obtained microspheres are subjected to centrifugation or precipitation washing treatment, and stored in a 15% by weight concentration preservation solution.
  • the microspheres are intact during the storage period, and the sorafenib drug does not ooze out.
  • the particle size range of the microspheres (or microbeads) stored in the preservation solution is 500 to 70 (m.
  • microspheres are immersed in physiological saline for half an hour in advance to be reduced to a wet bulb for use.
  • the catheter is inserted into the blood supply artery of the target organ by interventional or interventional ultrasound, and the angiography is performed.
  • the above-mentioned sorafenib sodium alginate microsphere sustained-release vascular embolization agent is selected.
  • the sorafenib sodium alginate microspheres (wet bulbs) are used, and the calcium chloride solution in the bottle is removed by a syringe, and the microspheres are washed three times with an equal amount of physiological saline or the microspheres in the bottle are poured into the bottle.

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Description

含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂及其制备和应用 技术领域
本发明涉及一种含抗肿瘤药物的微球血管栓塞剂及其制备和应用，特别涉及一 种含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂及其制备和应用。
背景技术
索拉非尼 （Sorafenib ) 是一种新颖的二芳基尿素， 化学名 4- { 4- 〔3- (4-氯 -3-三氟基-苯基） -酰脲〕 -苯氧基} -吡啶 -2-羧酸甲胺， 分子量 464. 8g/mol。 临床 使用的是索拉非尼的甲苯磺酸盐。 甲苯磺酸索拉非尼盐的分子式： ( 21 6(^ 03 - C7H803S, 分子量为 637. 0g/mol。 分子结构式如下：
Figure imgf000002_0001
甲苯磺酸索拉非尼熔点为 225-235°C， 是无味， 介于白色和棕色之间的固体。 热稳定性良好， 不吸水。 在水溶液中溶解度低， 在强酸性条件下溶解度稍增加， 略 溶于酒精， 溶于聚乙烯甘油 400。 索拉非尼是拜耳（Bayer )和 ONYX公司从 1994年 开始合作共同研制的一种多靶点的肿瘤靶向治疗药物， 是第一个经美国 FDA批准用 于转移性肾癌治疗的靶向治疗药物。 2005年 12月美国 FDA正式批准索拉非尼用于 晚期肾癌的治疗， 成为世界上第一个上市的口服多激酶抑制剂。 2006年 11月底正 式在我国上市。
索拉非尼为酪氨酸激酶抑制剂， 血管生成抑制剂和血管内皮生长抑制剂。 肿瘤 的生存、 生长和转移依赖于有效的肿瘤细胞增殖和肿瘤血管生成。 Ras (GTP结合蛋 白） /Raf信号途径是肿瘤细胞增殖和血管生成的一个重要途径， Raf是一种丝氨酸 /苏氨酸 （Ser/Thr) 蛋白激酶， 为 Ras下游效应器酶， 一旦被激活， 继而激活有丝 分裂原活化蛋白 （MEK) 1和 （MEK) 2激酶， （MKE) 1和 （MEK) 2又相继使细胞外 信号调节激酶 （ERK) 1 和 （ERK) 2 磷酸化及活化， 并易位至细胞核， 剌激转录启 动和转译激活途径， 导致细胞增殖。 此信号传导途径在人体各种肿瘤组织中直接调 节肿瘤的形成和发展。 索拉非尼一方面通过抑制 RAF 的活性而抑制了 RAS/RAF/MEK/ERK信号传导通路直接抑制肿瘤细胞的生长， 另一方面通过抑制几种 与新生血管生成和肿瘤发展有关的酪氨酸激酶受体的活性， 包括血管内皮生长因子 受体 -2 (VEGFR-2 ) , REGFR-3 , 血小板衍生的生长因子受体 - β (PDGFR- β )和 C-KIT 原癌基因， 阻断肿瘤新生血管的形成和切断肿瘤细胞的营养供应， 间接地抑制肿瘤 细胞的生长， 具有双重抗肿瘤作用。
索拉非尼主要经肝 CYP3A4酶氧化代谢和 UGTIA9的葡萄糖醛酸化代谢， 其代谢 产物已鉴定的有 8个， 其中 5个已在血中测定， 主要代谢产物吡啶 Ν氧化物在体外 显示与索拉非尼作用相似。 该代谢产物占所有代谢产物的 9%〜16%。 单次口服含索 拉非尼 lOOmg的溶液 14d内 77%经粪便排泄， 其中原形药物占 51%。 19%以葡萄糖醛 酸化代谢产物经尿排泄。 索拉非尼是本类化合物中第一个进入临床试验的， 临床研 究的初步结果表明， 索拉非尼对肾癌、 肝癌、 黑色素瘤、 非小细胞肺癌、 胃癌和卵 巢癌等实体瘤均有一定的抗肿瘤作用。
索拉非尼常见的不良反应包括皮肤发红、 皮疹、 瘙痒、 脱发或斑片性脱发、 频 繁的腹泻和 /或肠蠕动松弛、 恶心或呕吐、 口腔溃疡、 疲劳、 食欲缺乏 （下降）、 高 血压、 手足综合症等。 皮肤毒性和胃肠道反应是索拉非尼常见的不良反应， 是导致 减量或中断治疗的常见原因。 口服索拉非尼在治疗过程中最常见的就是出现胃肠道 毒副反应。 胃肠道反应占 95%、 腹泻占 58%、 恶心占 30%、 呕吐占 24%、 消化不良食 欲减退占 47%。
美国 FDA公布的用索拉非尼治疗的潜在不良反应包括可能引起胎儿出生缺陷或 死亡。 男性和女性在用药期间和停药后两周内， 都应采取避孕措施。 也可见手掌和 足底出现发红、 疼痛、 肿胀或水泡。 在用药的最初六周， 应每周检测血压。 如用药 时出现高血压应及时治疗， 由于可能引起心脏方面的不良反应， 有心脏方面潜在问 题者在用药前应告诉医生。
肿瘤发生发展过程中有很多基因和激酶参与靶向治疗已经成为当前最热门的 研究领域之一。 索拉非尼具有独特的多靶点抗肿瘤作用， 是基于对肿瘤发生的分子 生物学机制进一步明确的基础上研制成功的新药， 在临床上的成功应用为肿瘤的生 物靶向治疗翻开了新的篇章。 从作用机制和临床研究结果看， 索拉非尼与化疗药物 不同， 其作用主要为抑制肿瘤细胞的生长， 而非细胞毒效应。 临床研究结果已证实 索拉非尼对晚期肾细胞癌的二线治疗有明显延长 PFS、 OS及 TTP的作用； 如何进一 步提高索拉非尼的疗效以及寻找可以预测索拉非尼疗效的标志物无疑是目前临床 试验最关注的问题。索拉非尼是一种新型的多激酶抑制剂，不仅能抑制 RAF-MEK-ERK 通路， 还能抑制酪氨酸激酶受体， 从而达到抑制肿瘤生长和血管生成的效果。 I期 临床试验发现口服索拉非尼 400mg每日两次完全可以耐受， 也显示了一定的疗效， 出现最多的毒副反应是腹泻和皮肤损害。 II期临床试验分别显示索拉非尼对肝癌和 肾癌有一定的抗肿瘤活性。 晚期肾癌的 III期临床试验证明大部分患者的肿瘤都显著 缩小， 中位生存期也显著延长。 目前还有许多 III期临床试验正在进行中， 如我国正 在开展索拉非尼治疗肝癌的 III期临床试验， 相信会有更加鼓舞人心的结果， 给肿瘤 的治疗带来新的希望。 但是我们在看到希望的同时， 更应该注意到还存在许多问题 有待解决， 如药物治疗肿瘤存在进入肿瘤组织内部困难等问题， 药物难以到达肿瘤 组织， 低浓度的药物需要进一步的临床试验来解答。
Ghassan等进行的一项关于索拉非尼治疗肝癌的二期研究显示， 索拉非尼单药 对肝癌有一定疗效。 研究者认为尽管索拉非尼单药治疗肝癌的有效率不是很高， 但 其疗效与联合化疗的效果相近， 其作用机制和较小的毒性也支持其与其他抗癌药物 联用来进一步提高疗效。 该研究是一项针对中晚期不能或不愿进行手术治疗的肝癌 的亚太地区， 多中心三期临床试验。 随着对肝癌发病机制的阐明和新的分子靶向药 物的研究， 给晚期肝癌患者提供了靶向治疗的机会。 肝癌患者大多有肝硬化的疾病 基础， 其肝功能和体力状况较差， 化疗和放疗患者受益很少， 分子靶向药物的飞速 发展为肝癌的治疗提供了新的选择。 总体而言， 分子靶向治疗针对性强、 毒性小， 在晚期肝癌的应用前景很大。 这类药物可能是未来治疗肝癌最有潜力和最有希望的 方法之一。
原发性肝癌是一种恶性程度极高的肿瘤， 手术切除是首选治疗方法， 但约 70% 患者发现时已属于中晚期， 病变广泛或已有转移， 并多伴有肝硬化， 不能手术切除， 经导管化疗栓塞术（TACE )是治疗中晚期肝癌的重要方法之一。 TACE主要依靠化疗 药物及栓塞达到治疗目的。 肝癌血供约 90%〜95%来源于肝动脉， 通过肝动脉灌注化 疗加栓塞， 其目的是阻断肿瘤血供致肿瘤缺血坏死， 在此基础上延长高浓度的化疗 药物， 对肿瘤的局部作用时间， 从而提高疗效。 并且 TACE用于肝癌手术前的治疗， 可能使肿瘤组织坏死， 吸收及纤维化形成， 同时形成较厚的纤维包膜， 减少肝癌手 术中出血量和防止局部手术操作、 挤压造成肿瘤细胞播散机会， 且肝脏能使某些药 物减活， 毒性降低， 此优点经周围静脉给药是达不到的。
肿瘤是目前世界上死亡率最高的疾病之一， 手术放化疗等临床治疗是清除肿瘤 瘤体的有效手段， 但手术仅能切除肉眼可见的瘤体， 不能切除不可见的亚临床病灶 和已通过血路、 淋巴路转移或直接浸润到周围正常组织的肿瘤细胞。 放疗是局部照 射， 不能杀灭非照射部位的肿瘤， 对一些不敏感的肿瘤细胞也无能为力。 化疗是全 身治疗的方法， 但对肿瘤细胞的选择性抑制不强， 对休眠期的肿瘤细胞更无效果。 鉴于此， 近年来开发了不少治疗肿瘤的新方法、 新技术， 其中分子靶向治疗已成为 现阶段研究的热点和趋势， 分子靶向治疗是指在肿瘤分子生物学的基础上， 将与肿 瘤相关的特异分子作为靶点， 利用靶分子特异制剂或药物进行治疗的手段。 这种以 病变细胞为靶点的治疗， 相对于手术， 放化疗三大传统治疗手段具有最彻底的治本 功效。 但是肿瘤是一个多因素导致的疾病， 必须从多方面考虑其治疗机制， 定位靶 向治疗是现阶段肿瘤治疗的新技术， 可针对多种机制来抑制肿瘤的发生和发展消除 肿瘤。
目前国内外还没有将索拉非尼与海藻酸钠做成微球用于局部靶区血管栓塞治 疗肝癌、 肾癌、 非小细胞肺癌、 胃癌、 卵巢癌、 前列腺癌、 头颈部肿瘤、 黑色素瘤 等实体瘤的报道。
因此， 如何充分利用索拉非尼的作用， 将其用于肿瘤的治疗就成为该技术领域 急需要解决的技术难题。
发明内容
本发明的目的之一是提供一种含索拉非尼海-藻酸钠微球靶向缓释血管栓塞 剂。
本发明的上述目的是通过以下技术方案达到的：
一种含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂， 其特征在于： 包括天然 载体海藻酸钠和抗肿瘤药物索拉非尼， 所述海藻酸钠包裹所述索拉非尼； 所述索拉 非尼与所述海藻酸钠的重量比为 1 : 1〜1： 30。
本发明的另一目的是提供一种含索拉非尼的海藻酸钠靶向缓释微球血管栓塞 剂的制备方法。
本发明的上述目的是通过下述技术方案达到的：
一种含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂的制备方法， 其步骤如 下：
( 1 ) 载体溶液的配制 按比例将海藻酸钠用生理盐水或注射用水溶解，按 1〜7重量%浓度配制成溶液， 得海藻酸钠载体溶液；
( 2 ) 固化液的配制
将乳酸钙或氯化钙称重， 用生理盐水或注射用水溶解， 配制成 1〜10 重量%浓 度的乳酸钙或氯化钙溶液；
( 3 ) 药物溶液的配制
用聚乙烯甘油 400或二甲基亚砜 （DMS0溶液）， 将按比例称重的索拉非尼全部 溶解， 得索拉非尼药物溶液；
(4) 载体溶液和药物混合溶液的配制
用高速混合器将步骤 (3)所述索拉非尼药物溶液和步骤（1) 所述海藻酸钠载体 溶液混合， 得混合液；
( 5 ) 含索拉非尼的海藻酸钠靶向缓释微球的制备
将步骤 (4)所得混合液通过高压静电多头微球发生装置与步骤 （2 ) 所述固化液 反应得到微球 （或微胶珠）。
一种优选技术方案， 其特征在于： 所述步骤 （5 ) 中所述高压静电多头微球发 生装置包括： 高压静电发生器、 多头电极、 微量注射泵、 注射器、 特制针头、 升降 台、 无菌玻璃收集器。
一种优选技术方案， 其特征在于： 所述步骤 （5 ) 的具体制备过程如下：
①用 10〜60 毫升注射器连接特制针头后， 抽吸步骤 （4) 所得混合液 10〜60 毫升于注射器内；
②将步骤①所述的注射器， 固定在微量注射泵上的注射器推杆槽内；
③高压静电发生器的正极接口通过多头电极与 2〜12 个注射器的特制针头相 连； 高压静电发生器的负极通过多头电极与浸在所述步骤 （2 ) 固化液中的 2〜12 个 " b 形"不锈钢丝圈的延长部相连接； 所述特制针头位于无菌玻璃收集器上方， 所述无菌玻璃收集器置于升降台上； 所述特制针头的下端与所述无菌玻璃收集器中 的液面之间的距离为 5-20 厘米； 按下高压静电发生器和微量注射泵的开启电钮， 所述含索拉非尼的海藻酸钠混合液滴入无菌玻璃收集器的固化液中， 得微球 （或微 胶珠）， 称为湿球。
一种优选技术方案， 其特征在于： 所述特制针头由不锈钢制成， 其端头为平头。 一种优选技术方案， 其特征在于： 将所得微球 （或微胶珠） 经过离心或沉淀洗 涤处理， 储存在保存液中得含索拉非尼的海藻酸纳微球 （或微胶珠）， 保存期内微 球完整， 索拉非尼药物不渗出。
一种优选技术方案， 其特征在于： 所述保存液配制过程如下：
将氯化钙或乳酸钙称重， 用注射用水溶解， 配制成 3〜15 重量%浓度的溶液， 得保存液。
—种优选技术方案， 其特征在于： 所述储存在保存液中的微球 （或微胶珠） 的 粒径范围为： 50〜100μηι、 70〜150μηι、 100〜200μηι、 100〜300μηι、 150〜450μηι、 300— 500μηι、 500〜700μηι、 700〜900μηι。
一种优选技术方案， 其特征在于： 将所得微球或微胶珠， 用冷冻干燥 （或烘箱 干燥） 法干燥， 得干球， 其粒径范围为： 20〜60μηι、 30〜75μηι、 50〜100μηι、 70〜 150μηι、 80〜250μηι、 150〜300μηι、 250〜500μηι、 300〜500μηι、 500〜700μηι。
本发明的再一目的是提供一种含索拉非尼的海藻酸钠靶向缓释微球血管栓塞 剂的应用。
本发明的上述目的是通过以下技术方案达到的：
所述的含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂作为治疗肝癌、 肺癌、 卵巢癌、 前列腺癌、 头颈部肿瘤、 黑色素瘤等实体瘤药物的应用。
具体应用步骤如下： 采用介入放射或介入超声方法， 将导管插入靶器官供血动 脉， 进行动脉造影， 根据造影所见， 选用上述含索拉非尼的海藻酸钠靶向缓释微球 血管栓塞剂； 尽量使用微导管进行超选择栓塞， 使用时要无菌操作； 将所述含索拉 非尼的海藻酸钠微球 （湿球）， 用注射器将瓶中保存液弃掉， 加等量的生理盐水冲 洗微球三遍或将瓶中微球倒入无菌碗内， 用 50〜100ml生理盐水冲洗微球 1〜3遍， 弃掉冲洗液， 再加入适量或稀释后的造影剂混均 （使微球充分悬浮于造影剂中）， 透视下经导管视具体情况缓慢注入病灶部位， 直到造影剂流速明显减慢时， 即完成 栓塞； 再次进行动脉造影判定栓塞效果。
如果是干球， 使用时提前半小时将微球浸泡在生理盐水中还原成湿球即可使 用。
有益效果
本发明的含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂， 使将靶向药物通过 改变剂型、 改变投药途径的方法使药物直接在局部靶区、 快速、 长效、 定点在癌组 织中去， 具有针对性强、 效果显著， 在杀伤癌细胞时基本上不损伤正常组织， 毒副 作用低， 用药量少， 病人治疗费用少的优点。
含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂是运用索拉非尼药物通过新 技术使药物快速局部靶区， 长效缓释， 定点在癌细胞周围， 减少药物体循环过程， 减少药物用量， 减少正常细胞损伤， 减少毒副作用， 提高治疗效果。
目前索拉非尼口服给药存在生物利用度低， 所需剂量大， 毒副作用大的问题， 导致医疗成本高， 医生和患者难以接受。 组合效应， 抗肿瘤药和栓塞剂组合局部定 位产生原有两种药同时单用所不能产生的效果。 微球中包裹靶向药物索拉非尼， 动 脉血管栓塞可使局部组织内保持较长时间的药物浓度。 作用集中， 避免了药物首先 经过体循环、 肝肾等脏器， 而被破坏排泄的首过效应， 减少了药物与血浆蛋白结合 而失败的几率， 延长了药物的作用时间， 克服了口服药静脉化疗， 单纯灌注药物在 肿瘤组织内保留时间短、 清除快， 药物与肿瘤细胞不能充分接触的缺点， 临床药代 动力学研究表明， 在一定范围内， 局部组织抗癌药物浓度提高一倍， 杀灭癌细胞的 数量可增加 10〜100倍， 使疗效倍增。 含索拉非尼的海藻酸钠靶向缓释微球血管栓 塞剂的研究成功，改变着传统的产品投药途径，可让人们享受新型制剂带来的高效、 舒适和便捷， 是实体瘤治疗中具有不可缺少的作用。
本发明人发现， 所述高压静电多头微球发生装置中的 2〜12个微量注射装置可 使制备的微球更均匀、 增加产量和同时做不同规格粒径的微球。
下面通过实施例对本发明作进一步说明， 但不意味着对本发明保护范围的限 制。
具体实施方式
实施例 1
1、 包裹前的准备工作：
玻璃器皿的处理： 将清洗干净的玻璃器皿凉干， 放在高温烤箱内在 260摄氏度 下烘烤 3小时 （除菌去热源）；
2、 各种试剂的配制：
①抗肿瘤药物索拉非尼药液的配制：
称取 10毫克市售索拉非尼， 置于上述玻璃器皿内， 滴加适量聚乙烯甘油 400， 直至全部溶解， 得索拉非尼溶液 20毫升。
②海藻酸钠溶液的配制：
按 2重量％的浓度配置海藻酸钠溶液 （边搅拌， 边加入生理盐水）， 直至海藻酸 钠全部溶解， 得海藻酸钠溶液 3升；
③固化液配制：
将氯化钙称重， 用生理盐水溶解， 配制成 3重量%浓度的氯化钙溶液； ④保存液配制：
将氯化钙称重， 用注射用水溶解， 配制成 3重量%浓度的溶液， 得保存液；
⑤使用高速混合器将上述索拉非尼溶液 20毫升和海藻酸钠溶液 3升混合， 得 含索拉非尼的海藻酸钠混合溶液；
3、 含索拉非尼的海藻酸钠微球的制备方法及步骤如下：
①用 2个 10毫升注射器连接特制针头后， 至少 151次分别抽吸索拉非尼溶液 和海藻酸钠溶液混合液于注射器内；
②将微球制作过程步骤①所述的注射器固定在微量注射泵上的注射器推杆槽 内；
③高压静电发生器的正极接口通过多头电极与 2个注射器的特制针头相连； 高 压静电发生器的负极通过多头电极与浸在所述步骤（2 ) 固化液中的 2个 " b形"不 锈钢丝圈的延长部相连接； 所述特制针头位于无菌玻璃收集器上方， 所述无菌玻璃 收集器置于升降台上； 所述特制针头的下端与所述无菌玻璃收集器中的液面之间的 距离为 12 厘米； 按下高压静电发生器和微量注射泵的开启电钮， 所述含索拉非尼 的海藻酸钠混合液滴入无菌玻璃收集器的固化液中， 得微球 （或微胶珠）， 称为湿 球。 所述特制针头由不锈钢制成， 其端头为平头。
④洗涤处理： 将所得微球 （或微胶珠） 经过离心或沉淀洗涤处理， 储存在 3重 量%浓度的保存液中， 保存期内微球完整， 索拉非尼药物不渗出。
⑤所述储存在保存液中的微球 （或微胶珠） 的粒径范围： 70〜15( m。
⑥所得索拉非尼海藻酸钠微球， 用冷冻干燥法干燥得干球， 其粒径范围： 30〜 用时提前半小时将微球浸泡在生理盐水中还原成湿球即可使用。
4、 用于靶向血管栓塞治疗病人
对于患有肝癌的病人， 采用介入放射或介入超声的方法， 将导管插入靶器官供 血动脉， 行动脉造影， 根据造影所见， 选用上述含索拉非尼海藻酸钠微球缓释血管 栓塞剂。 尽量使用微导管进行超选择栓塞， 使用时要无菌操作。 将所述含索拉非尼 海藻酸钠微球 （湿球）， 用注射器将瓶中氯化钙溶液抽掉， 加等量的生理盐水冲洗 微球三遍或将瓶中微球倒入无菌碗内， 用 50〜100ml生理盐水冲洗微球 1〜3遍， 弃掉冲洗液， 再加入适量或稀释后的造影剂混均 （使微球充分悬浮于造影剂中）， 透视下经导管视具体情况缓慢注入病灶部位， 直到造影剂流速明显减慢时， 即完成 栓塞。 再次行动脉造影判定栓塞效果。 实施例 2
1、 包裹前的准备工作：
玻璃器皿的处理： 将清洗干净的玻璃器皿凉干， 放在高温烤箱内在 260摄氏度 下烘烤 3小时 （除菌去热源）；
2、 各种试剂的配制：
①抗肿瘤药物索拉非尼药液的配制：
称取 0. 62克市售索拉非尼， 置于上述玻璃器皿内， 滴加适量二甲基亚砜（DMS0 溶液）， 直至全部溶解， 得索拉非尼溶液 500毫升。
②海藻酸钠溶液的配制：
按 1重量％的浓度配置海藻酸钠溶液 （边搅拌， 边加入生理盐水）， 直至海藻酸 钠全部溶解， 得海藻酸钠溶液 45升；
③固化液配制：
将乳酸钙称重， 用生理盐水溶解， 配制成 1重量%浓度的乳酸钙溶液。
④保存液配制：
将氯化钙称重， 用注射用水溶解， 配制成 8重量%浓度的溶液， 得保存液。
⑤使用高速混合器将上述索拉非尼溶液 500毫升和海藻酸钠溶液 45升混合， 得含索拉非尼的海藻酸钠混合溶液；
3、 索拉非尼海藻酸钠微球的制备方法及步骤如下：
①用 12个 60毫升注射器连接特制针头后， 至少分 63次抽吸索拉非尼溶液和 海藻酸钠溶液混合液于注射器内；
②将微球制作过程步骤①所述的注射器杆固定在微量注射泵上的注射器推杆 槽内， 同时调节好微量注射泵上的参数；
③高压静电发生器的正极接口通过多头电极与 12 个注射器的特制针头相连； 高压静电发生器的负极通过多头电极与浸在所述步骤（2 ) 固化液中的 12个 " b形" 不锈钢丝圈的延长部相连接； 所述特制针头位于无菌玻璃收集器上方， 所述无菌玻 璃收集器置于升降台上； 所述特制针头的下端与所述无菌玻璃收集器中的液面之间 的距离为 5厘米； 按下高压静电发生器和微量注射泵的开启电钮， 所述含索拉非尼 的海藻酸钠混合液滴入无菌玻璃收集器的固化液中， 得微球 （或微胶珠）， 称为湿 球。 所述特制针头由不锈钢制成， 其端头为平头。
④洗涤处理： 将所得微球 （或微胶珠） 经过离心或沉淀洗涤处理， 储存在 8重 量%浓度的保存液中， 保存期内微球完整， 索拉非尼药物不渗出。 ⑤所述储存在保存液中的微球 （或微胶珠） 的粒径范围： 300〜50( m。
⑥ 所得索拉非尼海藻酸钠微球， 用冷冻干燥 （或烘箱干燥） 法得干球， 其粒 径范围： 150〜30( m。
用时提前半小时将微球浸泡在生理盐水中还原成湿球即可使用。
4、 用于靶向血管栓塞治疗病人
对于患有肾癌的病人， 采用介入放射或介入超声的方法， 将导管插入靶器官供 血动脉， 行动脉造影， 根据造影所见， 选用上述含索拉非尼海藻酸钠微球缓释血管 栓塞剂。 尽量使用微导管进行超选择栓塞， 使用时要无菌操作。 将所述含索拉非尼 海藻酸钠微球 （湿球）， 用注射器将瓶中氯化钙溶液抽掉， 加等量的生理盐水冲洗 微球三遍或将瓶中微球倒入无菌碗内， 用 50〜100ml生理盐水冲洗微球 1〜3遍， 弃掉冲洗液， 再加入适量或稀释后的造影剂混均 （使微球充分悬浮于造影剂中）， 透视下经导管视具体情况缓慢注入病灶部位， 直到造影剂流速明显减慢时， 即完成 栓塞。 再次行动脉造影判定栓塞效果。
实施例 3
1、 包裹前的准备工作：
玻璃器皿的处理： 将清洗干净的玻璃器皿凉干， 放在高温烤箱内在 260摄氏度 下烘烤 3小时 （除菌去热源）；
2、 各种试剂的配制：
①抗肿瘤药物索拉非尼药液的配制：
称取 6. 9毫克市售索拉非尼，置于上述玻璃器皿内，滴加适量二甲基亚砜（DMS0 溶液）， 直至全部溶解， 得索拉非尼溶液 30毫升。
②海藻酸钠溶液的配制：
按 7重量％的浓度配置海藻酸钠溶液 （边搅拌， 边加入生理盐水）， 直至海藻酸 钠全部溶解， 得海藻酸钠溶液 2000毫升；
③固化液配制：
将乳酸钙称重， 用注射用水溶解， 配制成 10重量%浓度的乳酸钙溶液。
④保存液配制：
将乳酸钙称重， 用注射用水溶解， 配制成 15重量%浓度的溶液， 得保存液。
⑤使用高速混合器将上述索拉非尼溶液 30 毫升和海藻酸钠溶液 2000 毫升混 合， 得含索拉非尼的海藻酸钠混合溶液；
3、 索拉非尼海藻酸钠微球的制备方法及步骤如下： ①用 10个 50毫升注射器连接特制针头后， 至少分 4次抽吸索拉非尼溶液和海 藻酸钠溶液混合液于注射器内；
②将微球制作过程步骤①所述的注射器固定在微量注射泵上的注射器推杆槽 内；
③高压静电发生器的正极接口通过多头电极与 10 个注射器的特制针头相连； 高压静电发生器的负极通过多头电极与浸在所述步骤（2 ) 固化液中的 10个 " b形" 不锈钢丝圈的延长部相连接； 所述特制针头位于无菌玻璃收集器上方， 所述无菌玻 璃收集器置于升降台上； 所述特制针头的下端与所述无菌玻璃收集器中的液面之间 的距离为 5厘米； 按下高压静电发生器和微量注射泵的开启电钮， 所述含索拉非尼 的海藻酸钠混合液滴入无菌玻璃收集器的固化液中， 得微球 （或微胶珠）， 称为湿 球。 所述特制针头由不锈钢制成， 其端头为平头。
④洗涤处理： 将所得微球 （或微胶珠） 经过离心或沉淀洗涤处理， 储存在 15 重量%浓度的保存液中， 保存期内微球完整， 索拉非尼药物不渗出。
⑤所述储存在保存液中的微球 （或微胶珠） 的粒径范围： 500〜70( m。
⑥ 所得索拉非尼海藻酸钠微球， 用烘箱干燥法得干球， 其粒径范围： 250〜
50( m。
用时提前半小时将微球浸泡在生理盐水中还原成湿球即可使用。
4、 用于靶向血管栓塞治疗病人
对于患有肺癌的病人， 采用介入放射或介入超声的方法， 将导管插入靶器官供 血动脉， 行动脉造影， 根据造影所见， 选用上述含索拉非尼海藻酸钠微球缓释血管 栓塞剂。 尽量使用微导管进行超选择栓塞， 使用时要无菌操作。 将所述含索拉非尼 海藻酸钠微球 （湿球）， 用注射器将瓶中氯化钙溶液抽掉， 加等量的生理盐水冲洗 微球三遍或将瓶中微球倒入无菌碗内， 用 50〜100ml生理盐水冲洗微球 1〜3遍， 弃掉冲洗液， 再加入适量或稀释后的造影剂混均 （使微球充分悬浮于造影剂中）， 透视下经导管视具体情况缓慢注入病灶部位， 直到造影剂流速明显减慢时， 即完成 栓塞。 再次行动脉造影判定栓塞效果。

Claims

权 利 要 求 书
1、 一种含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂， 其特征在于： 包括药 物载体海藻酸钠和抗肿瘤药物索拉非尼， 所述海藻酸钠包裹所述索拉非尼； 所述索 拉非尼和海藻酸钠的重量比为 1 : 1〜1： 30。
2、 一种如权利要求 1所述含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂的制 备方法， 其步骤如下：
( 1 ) 载体溶液的配制
按比例将海藻酸钠用生理盐水或注射用水溶解，按 1〜7重量%浓度配制成溶液， 得海藻酸钠载体溶液；
( 2 ) 固化液的配制
将乳酸钙或氯化钙称重， 用生理盐水或注射用水溶解， 配制成 1〜10 重量%浓 度的乳酸钙或氯化钙溶液；
( 3 ) 药物溶液的配制
用聚乙烯甘油 400或二甲基亚砜， 将按比例称重的索拉非尼全部溶解， 得索拉 非尼药物溶液；
(4) 载体溶液和药物混合溶液的配制
用高速混合器将步骤 (3)所述索拉非尼药物溶液和步骤（1) 所述海藻酸钠载体 溶液混合， 得混合液；
( 5 ) 含索拉非尼的海藻酸钠靶向缓释微球的制备
将步骤 (4)所得混合液通过高压静电多头微球发生装置与步骤 （2 ) 所述固化液 反应得到微球或微胶珠。
3、 根据权利要求 2所述的含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂的制 备方法， 其特征在于： 所述步骤 （5 ) 中所述高压静电多头微球发生装置包括： 高 压静电发生器、 多头电极、 微量注射泵、 注射器、 特制针头、 升降台、 无菌玻璃收 集器。
4、 根据权利要求 3 所述的含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂的 制备方法， 其特征在于： 所述步骤 （5 ) 的具体制备过程如下：
①用 10〜60 毫升注射器连接特制针头后， 抽吸步骤 （4) 所得混合液 10〜60 毫升于注射器内；
②将步骤①所述的注射器， 固定在微量注射泵上的注射器推杆槽内； ③高压静电发生器的正极接口通过多头电极与 2〜12 个注射器的特制针头相 连； 高压静电发生器的负极通过多头电极与浸在所述步骤 （2 ) 固化液中的 2〜12 个 " b 形"不锈钢丝圈的延长部相连接； 所述特制针头位于无菌玻璃收集器上方， 所述无菌玻璃收集器置于升降台上； 所述特制针头的下端与所述无菌玻璃收集器中 的液面之间的距离为 5-20 厘米； 按下高压静电发生器和微量注射泵的开启电钮， 所述含索拉非尼的海藻酸钠混合液滴入无菌玻璃收集器的固化液中， 得微球 （或微 胶珠）， 称为湿球。
5、 根据权利要求 4所述的含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂的 制备方法， 其特征在于： 所述特制针头由不锈钢制成， 其端头为平头。
6、 根据权利要求 5 所述的含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂的 制备方法， 其特征在于： 将所得微球或微胶珠经过离心或沉淀洗涤处理， 储存在保 存液中得含索拉非尼的海藻酸纳微球或微胶珠， 保存期内微球完整， 索拉非尼药物 不渗出。
7、 根据权利要求 6所述的含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂的 制备方法， 其特征在于： 所述保存液配制过程如下： 将氯化钙或乳酸钙称重， 用注 射用水溶解， 配制成 3〜15重量%浓度的溶液， 得保存液。
8、 根据权利要求 7所述的含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂的 制备方法， 其特征在于： 所述储存在保存液中的微球或微胶珠的粒径范围为： 50〜 ΙΟΟμηκ 70〜150μηι、 100〜200μηι、 100〜300μηι、 150〜450μηι、 300〜500μηι、 500— 700μηι、 700〜900μηι。
9、 根据权利要求 8 所述的含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂的 制备方法， 其特征在于： 将所得微球或微胶珠， 用冷冻干燥或烘箱干燥法干燥， 得 干球， 其粒径范围为： 20〜60μηι、 30〜75μηι、 50〜100μηι、 70〜150μηι、 80〜250μηι、 150〜300μηι、 250〜500μηι、 300〜500μηι、 500〜700μηι。
10、 按权利要求 1中所述含索拉非尼的海藻酸钠靶向缓释微球血管栓塞剂作为 制备治疗肝癌、 肺癌、 肾癌、 卵巢癌、 前列腺癌、 头颈部肿瘤实体瘤药物的应用。
PCT/CN2010/071749 2009-04-16 2010-04-14 含索拉非尼的海藻酸钠靶向缓释微球血管拴塞剂及其制备和应用 WO2010118683A1 (zh)

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