WO2006029554A1 - Microcapsules d'alginate de sodium contenant du paclitaxel qui permet de traiter un embole vasculaire - Google Patents

Microcapsules d'alginate de sodium contenant du paclitaxel qui permet de traiter un embole vasculaire Download PDF

Info

Publication number
WO2006029554A1
WO2006029554A1 PCT/CN2005/000320 CN2005000320W WO2006029554A1 WO 2006029554 A1 WO2006029554 A1 WO 2006029554A1 CN 2005000320 W CN2005000320 W CN 2005000320W WO 2006029554 A1 WO2006029554 A1 WO 2006029554A1
Authority
WO
WIPO (PCT)
Prior art keywords
paclitaxel
sodium alginate
solution
microspheres
vascular embolization
Prior art date
Application number
PCT/CN2005/000320
Other languages
English (en)
French (fr)
Inventor
Xinjian Li
Hong Hong
Original Assignee
Beijing Hongyiyao Science & Technology Development Co. Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Hongyiyao Science & Technology Development Co. Ltd filed Critical Beijing Hongyiyao Science & Technology Development Co. Ltd
Priority to US11/660,553 priority Critical patent/US20080020052A1/en
Priority to ES05714849.6T priority patent/ES2553130T3/es
Priority to CA2577589A priority patent/CA2577589C/en
Priority to JP2007531568A priority patent/JP2008513381A/ja
Priority to EP05714849.6A priority patent/EP1797874B1/en
Publication of WO2006029554A1 publication Critical patent/WO2006029554A1/zh

Links

Classifications

    • 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
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Paclitaxel-alginate microsphere vascular embolization agent and preparation thereof
  • the invention relates to a paclitaxel-alginate microsphere blood vessel embolization agent and preparation thereof.
  • ovarian cancer According to the World Cancer Registry, the incidence of ovarian cancer is the highest in Chile, 21/100,000, Japan and India are the lowest, 3.1/100,000 and 3.3/100,000 respectively. degree.
  • ovarian tumors are also one of the common diseases of gynecology, of which malignant tumors account for about 10%, and 70% of patients with ovarian malignant tumors have entered advanced stage.
  • the mortality rate is the highest in female genital malignant tumors, and the 5-year survival rate Only 30%-40%, it is a great hazard to women's health and life.
  • the incidence has also increased year by year, and has increased three-fold in the past 40 years. Studies have shown that the cure rate of paclitaxel for this disease is as high as 30-60%.
  • the molecular weight of paclitaxel is 853.92, and the solubility in water is very low ( ⁇ 0.004 g/ml). Its structure is as follows:
  • Paclitaxel Although paclitaxel is highly active against model tumors, clinical trials have been delayed due to the extremely limited source of paclitaxel and the formulation problems due to the insoluble water of paclitaxel.
  • Susan B. Horwitz a professor at the Einstein College of Medicine in the United States, and colleagues discovered the unique anticancer mechanism of paclitaxel.
  • Paclitaxel entered Phase I clinical studies in the United States from 1983 to 1987, entered Phase II clinical studies from 1987 to 1990, and entered Phase III studies in 1990.
  • the US FDA officially approved paclitaxel as a new anticancer drug for the treatment of advanced ovarian cancer.
  • the trade name is Paclit aX ol. It has been listed in more than 40 countries including Europe, America and South Africa. The Institute of Materia Medica of China Academy of Medical Sciences and Haikou Pharmaceutical Factory have obtained new drug certificates.
  • Paclitaxel has a unique mechanism of action, promotes microtubule polymerization and inhibits its depolymerization, inhibits cell mitosis, arrests cell proliferation in G 2 /M phase, and induces apoptosis. It is a highly effective cytotoxic drug. Recently, studies have shown that paclitaxel also has anti-invasive and metastatic effects, so it is a promising new anticancer drug, but it has limited its wide application due to poor water solubility and f drug traits.
  • the mechanism mainly includes: 1 The cytotoxic drugs are low in the concentration of fine beer due to the decrease or decrease in intake; 2 multidrug resistance gene MDR, induced P-89, multidrug resistance gene related protein MRP, Overexpression of lung L-protein LRP,
  • Paclitaxel can cause tubulin and tubulin dimers that make up microtubules to lose their homeostasis, induce and promote tubulin polymerization, microtubule assembly, prevent depolymerization, stabilize microtubules, and thus prevent cancer cell growth, paclitaxel
  • the binding site is different from guanosine triphosphate, vinblastine and colchicine.
  • Taxol binds to the N-terminal 31 amino acids on the ⁇ -tubulin subunit of microtubules and does not bind to tubulin dimer.
  • Paclitaxel in the cell induces bundles of microtubules and forms a large number of stellates in the mitotic pituitary.
  • the former is a useful clinical indicator of the role of lethal drugs. In vitro, it may inhibit cell division, inhibit division and proliferation, stop in the most sensitive mitotic prephase (G 2 phase) and mitosis phase (M phase), increase the cytotoxic effect of ion irradiation, until death, and then play an anti-cancer effect. .
  • paclitaxel itself is almost insoluble in water
  • clinical paclitaxel preparations are mostly made from oil-based preparations using organic solvents and oils.
  • the carriers of these drugs cause some adverse reactions, so the medication process must be carefully observed.
  • some water-soluble macromolecular carriers have been linked to them and brought into water. This research has opened up a new way to solve the water solubility problem of paclitaxel. Generally, it is encapsulated by liposome, cyclodextrin is encapsulated, and polyethylene glycol derivative is used to prepare emulsion and powder injection.
  • sodium alginate as a drug carrier for paclitaxel and for the treatment of vascular interventional embolization in cancer patients.
  • One of the objects of the present invention is to provide a paclitaxel-containing alginate microsphere vascular embolization agent which is safe, non-toxic, teratogenic, non-reproductive, and non-carcinogenic.
  • Another object of the present invention is to provide a method for preparing the above-described paclitaxel-containing alginate microsphere vascular embolization agent.
  • a paclitaxel-containing alginate microsphere vascular embolization agent comprising: a pharmaceutical carrier sodium alginate and paclitaxel, said sodium alginate encapsulating said paclitaxel.
  • the weight ratio of the sodium alginate to the paclitaxel is 1:1 to 90:1.
  • the paclitaxel-containing alginate microsphere vascular embolic agent may be microbeads or microspheres stored in a divalent metal cation solidifying solution.
  • the paclitaxel-containing alginate microsphere vascular embolic agent may also be powdery microparticles.
  • the particle size of the microbeads or microspheres stored in the solidifying liquid ranges from 200 to 550 ⁇ m or 400 ⁇
  • the powdery particles have a particle size ranging from 100 to 350 ⁇ m or from 200 to 550 ⁇ m or from 400 to 750 ⁇ m.
  • the paclitaxel is weighed in proportion and dissolved in an organic solvent; a paclitaxel solution is obtained;
  • the high-voltage electrostatic microsphere droplet generating device comprises: an electrostatic generating device having positive and negative poles, a positive electrode connected to a needle of the micro injection device, and a negative electrode and a stainless steel wire immersed in the solidifying liquid 3 ⁇ 4, the injection device is filled with a mixed solution of paclitaxel and sodium alginate, and dropped into the solidified liquid to form microspheres.
  • the obtained paclitaxel-containing alginate microsphere vascular embolic agent is a microsphere stored in a solidified liquid, which is called a wet bulb.
  • the particle size may range from 200 to 550 ⁇ m or from 400 to 750 ⁇ m or from 600 to 950 ⁇ m.
  • the following microspheres are placed in an oven to be dried, and sealed to obtain powdery particles, which are called dry balls.
  • the particle size may range from 100 to 350 ⁇ m or from 200 to 550 ⁇ m or from 400 to 750 ⁇ m.
  • the catheter was inserted into the blood supply artery of the target organ by interventional or interventional ultrasound, and angiography was performed. According to the angiography, the diameter of the embolic microsphere was determined.
  • Unpack the bottle cap after standing still, use a syringe to remove the maintenance solution (ie, the solidified solution) from the bottle and rinse the microspheres three times with the same amount of normal saline or remove the maintenance liquid (ie, the solidified solution) from the bottle.
  • the same amount of normal saline, together with physiological saline and microspheres, is poured into a sterile bowl.
  • the dry bulb stored in the closed container is first dissolved in physiological saline to swell (wet bulb), and then an appropriate amount or diluted contrast agent is added and uniformly mixed. (Make the microspheres fully suspended in the contrast agent), and then super-selectively embolize the blood vessels in the lesion through the catheter under the monitoring of the imaging device, slowly or slowly multiple injections (not excessive embolization) until the contrast agent flow rate is significantly slowed down. , that is, the embolization is completed. The angiography was performed again to determine the embolization effect.
  • the cleaned glassware is dried and placed in a high temperature oven for 3 hours at 300 ° C (to remove heat from the bacteria);
  • the above mixture was aspirated by a disposable sterile syringe, and dropped into the above calcium-calcifying solution by a high-pressure electrostatic microsphere droplet generating device, and the obtained paclitaxel-containing sodium alginate microsphere was submerged under the container.
  • the particle size of the microspheres is between 200 and 550 ⁇ m.
  • the upper layer solution of the above container is decanted, and the underlying microbeads are placed in an oven to be dried and sealed, and the obtained dry spheres have a particle size ranging from 100 to 350 ⁇ .
  • the catheter is inserted into the blood supply artery of the target organ by interventional or interventional ultrasound, and the angiography is performed. According to the contrast, the size of the microspheres is between 200 and 550 ⁇ m.
  • Paclitaxel-containing alginate microspheres Use microcatheters as much as possible for superselective embolization, and use aseptically.
  • Paclitaxel-containing alginate microspheres (wet bulbs), use a syringe to remove the calcium chloride solution in the bottle, add the same amount of physiological saline to rinse the microspheres three times, or pump the calcium chloride solution in the bottle.
  • the above mixture was aspirated with a disposable sterile syringe, and dropped into the calcium chloride solution by a high-pressure electrostatic microsphere droplet generating device, and the obtained paclitaxel-containing sodium alginate microsphere was submerged under the container.
  • the particle size of the microspheres is between 400 and 750 ⁇ m.
  • the upper layer solution of the above container was decanted, and the lower microspheres were placed in an oven to be dried and sealed, and the obtained dry spheres had a particle diameter ranging from 200 to 550 ⁇ m. It is reduced to a wet bulb by soaking in physiological saline for a few minutes before use.
  • the catheter In patients with uterine fibroids, the catheter is inserted into the blood supply artery of the target organ by interventional or interventional ultrasound. The angiography is performed according to the contrast. The size of the microspheres is between 400 and 750 ⁇ m.
  • Paclitaxel sodium alginate microspheres Use microcatheters as much as possible for superselective embolization, and use aseptically.
  • the paclitaxel-containing alginate microspheres (wet bulbs) are pumped out of the bottle with a calcium chloride solution, and the microspheres are washed three times with an equal amount of physiological saline, or the calcium chloride solution in the bottle is removed.
  • the above mixed solution was aspirated by a disposable sterile syringe, and dropped into the above cerium chloride solution by a high-pressure electrostatic microsphere droplet generating device, and the obtained paclitaxel-containing sodium alginate microsphere was submerged under the container.
  • the obtained microspheres have a particle diameter ranging from 600 to 950 ⁇ m.
  • the upper layer solution of the above container was decanted, and the underlying microspheres were placed in an oven to be dried and sealed, and the obtained dry spheres had a particle size ranging from 400 to 750 ⁇ m. It is reduced to a wet bulb by soaking in physiological saline for a few minutes before use.
  • the catheter In patients with uterine fibroids, the catheter is inserted into the blood supply artery of the target organ by interventional or interventional ultrasound, and angiography is performed. According to the contrast, the above-mentioned microspheres containing paclitaxel ranging from 600 to 750 ⁇ m are selected.
  • Alginate microspheres Use microcatheters as much as possible for superselective embolization, and use aseptically.
  • the paclitaxel-containing alginate microspheres (wet bulbs) are pumped out of the bottle by a syringe, the microspheres are washed three times with an equal amount of physiological saline, or the cerium chloride solution in the bottle is removed.
  • the sodium alginate drug carrier of the invention is a natural extract, which is a polysaccharide sodium salt composed of a mixture of ⁇ -D-mannitol and ⁇ -L-gulose extracted from natural plant brown algae, is a linear macromolecule, molecular weight 50 , 000-100, 000 Daltons, strong hydration, soluble in water can form a viscous colloid, under the action of calcium ions to produce macromolecular chain cross-linking curing, can be processed into different sizes of round or class according to clinical needs Round solid microspheres.
  • the microspheres have good biocompatibility. In the living organism, calcium ions gradually precipitate, and the microspheres are detoxified in a molecularly de-chained form within 3-6 months.
  • Degradation does not produce debris, and can cause permanent embolization of the target organ blood vessels (when the embolic agent is in the blood vessel for 2 months, the thrombus formation in the patient's blood vessels to achieve permanent embolization)
  • the purpose of treatment In practice, use this "bio-multi-micro The ball "embossing material physically blocks the tumor or the small arteries around the treatment site, causing the corresponding vascular atresia, cutting off the blood supply and nutrition of the tissue at the site, causing it to shrink and necrosis due to ischemia and hypoxia.
  • the blood supply of the target organ creates favorable conditions for the surgical treatment.
  • microspheres are used as carriers for the gynecological treatment, and the localized lesions are slowly released in a timed, positioned, and directed manner, thereby greatly improving the therapeutic effect and reducing the toxic and side effects of the drug. It has dual therapeutic effects of embolization and drug.
  • the invention is based on the unique anticancer mechanism and clinical application of paclitaxel, according to the semi-interpenetrating network structure and degradable principle of the sodium alginate microsphere, combined with the actual application of the sodium alginate microsphere embolic agent, from the safety, non-toxic, Non-immunogenic, no genotoxicity, no reproductive toxicity, no carcinogenicity, etc.
  • Sodium alginate is used as a carrier to add an anti-tumor target drug, and the target drug is released at a timed, fixed-point, directed, and periodic basis to kill the tumor cells for therapeutic purposes.
  • the paclitaxel is insoluble in water, the encapsulated paclitaxel droplets are not precipitated, the microspheres are not formed, and the crystals are precipitated, and special mixing reagents are added. After adjusting the concentration, frequency and speed of the organic solvent, the encapsulation is very good, the microspheres are uniform, smooth, and the drug is evenly dispersed. After being carried by the microspheres, the drug protects the active group of the drug, maintains the stability in the internal environment, and prevents paclitaxel from leaking out too quickly from the body to meet the clinical application requirements.
  • the paclitaxel-containing alginate microsphere vascular embolization agent of the invention has the advantages that the drug microsphere has a large drug loading amount, has a long residence time in the body, and has the specificity of targeting, and is the most promising targeted drug release at present. system.
  • concentration of paclitaxel was lOmol/L
  • the prepared drug microspheres showed no accumulation of paclitaxel crystals and drug microspheres by phase contrast microscopy, and maintained good physical and chemical stability after storage at 4 °C for 30 days.
  • the concentration was 30 mol/L, most of the paclitaxel crystals and drug accumulation were observed under the microscope.
  • the surface of the microspheres prepared with sodium alginate has a certain negative charge, and the particles are repulsive.
  • the dose should be selected according to the condition of the lesion.
  • the catheter can be inserted by interventional radiology or surgery.
  • the target blood vessel is inserted, and after the contrast, the drug microspheres and the contrast agent are mixed by a syringe, and the injection is gradually performed, and the tube is not condensed in the catheter, and the tube is not blocked.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Description

紫杉醇-海藻酸钠微球血管栓塞剂及其制备 技术领域
本发明涉及一种紫杉醇-海藻酸钠微球血管栓塞剂及其制备。
背景技术
根据世界癌症登记的资料表明， 卵巢癌发病率智利的妇女最高， 为 21/10 万名， 日本和印度最低， 分别为 3.1 /10万名和 3.3/10万名， 可见这种疾病对 妇女的危害程度。 在我国， 卵巢肿瘤也是妇科常见疾病之一， 其中恶性肿瘤 占 10%左右， 而且卵巢恶性肿瘤在诊断时 70%的病人已进入晚期， 死亡率在 女性生殖器恶性肿瘤中占首位， 5年生存率仅为 30%-40%， 对妇女的健康和 生命造成极大的危害。 不幸的是， 发病还呈逐年上升的趋势， 近 40年增加了 3倍。 研究表明， 紫杉醇对这种疾病的治愈率高达 30-60%， 这怎能不引起许 多国家、 学者的关注呢？ 专家学者的研究报告以及临床应用表明： 紫杉醇不 仅对卵巢癌， 子宫癌和乳腺癌有较好的疗效， 而且对胰腺癌、 结肠癌、 前列 腺癌、 转移性肾癌、 急性胰腺癌、 视网膜瘤、 恶性黑色素瘤、 头颈部肿瘤等 多种癌症的疗效也十分明显。
国外对肝肾肿瘤， 前列腺癌， 膀胱癌， 乙状结肠癌， 宫颈癌， 卵巢癌等 进行微球栓塞疗效明显。 对不同分期的肿瘤进行药物微球栓塞治疗都是有益 的， 对能接受手术切除的肿瘤进行手术前后栓塞治疗， 不仅可以减少术中出 血， 而且可防止术后转移和扩散， 对不能手术切除的肿瘤进行药物微球栓塞 治疗, '一方面可减少全身化疗的副作用， 增强局部疗效， 另一方面阻断了肿 瘤血管， 抑制肿瘤生长， 有时还可重新获得手术切除的机会。
肿瘤的治疗在很大程度上依赖于抗肿瘤药的开发， 抗肿瘤药物研究方兴未艾。 自从 30多年前，在短叶红豆杉树皮或树叶中分离提纯出紫杉醇 (paclitaxol, Taxol) 以来， 国内外的研究人员从不同角度对紫杉醇抗癌机理， 治疗癌症的范围、紫杉醇 用量、用法以及如何与其他药物配合使用等方面进行了深入的研究， 由于其具有良 好的抗癌活性和独特的抗癌机理， 因而被认为是抗癌药物的 "明星"。
早在 1856年， Lucas H.就从欧洲红豆杉 （Taxus baccata) 叶中提取到粉末 状碱性组分， 即紫杉碱 axinej 但在随后的 100年间没有多大进展。 1958年 美国国家癌症研究所 （NCI) 组织化学、 生态、 药理和临床方面的专家对 35000种 植物提取物进行抗癌活性的筛选， 1964年， 化学家 Monre E. Wall和 M. C. Wani 首次从红豆杉树皮中提取得到，随后他又用细胞毒性实验证明了这一提取物对离体 培养的鼠肿瘤细胞有很高活性，直到 1971年 Wani发表了紫杉醇的结构： 四环二萜 类化合物。 紫杉醇在水中的溶解度（Z0. 004 g/ml)。 分子式： C47H51014N 分子量： 853. 92， 血浆蛋白结合率 89-98%， 人体内半衰期平均值为： 5. 3- 17. 4h 。 人工半 合成分子式： C43H53014N 分子量： 807. 9， 血浆蛋白结合率 93-94%， 人体内半衰期 平均值为： 11. lh。
紫杉醇分子量为 853.92，水中溶解度很低（ <0.004 g/ml )其结构如下：
Figure imgf000003_0001
尽管紫杉醇对模式肿瘤有很高的活性，但是由于紫杉醇来源极其有限，且由于 紫杉醇不溶于水而带来的制剂问题使其临床实验迟迟不能进行。 到 1979年， 美国 爱因斯坦医学院教授 Susan B. Horwitz 及其同事发现了紫杉醇独特的抗癌作用 机制。 1983- 1987年紫杉醇在美国进入 I期临床研究， 1987- 1990年进入 II期临床 研究， 1990年进入 III期 床研究。 1992年 12月 9日美国 FDA正式批准紫杉醇作为 治疗晚期卵巢癌的新抗癌药物， 商品名为： PaclitaXol。 现已在欧洲、 美洲、 南非 等 40多个国家上市， 中国医学科学院药物研究所和海口制药厂已取得新药证书。
紫杉醇具有独特的作用机制，促进微管聚合并抑制其解聚，抑制细胞有丝分裂， 使细胞增殖阻滞于 G2/M期， 进而诱导细胞凋亡， 是高效的细胞毒类药物。 最近还 有研究表明：紫杉醇还有抗侵袭转移作用， 因此它是一种很有发展前途的新型抗癌 药,但因'水溶性差以及 f药性等问题而限制了它的广泛应用，其耐药机理主要包括： ①细胞毒类药物因摄入减少或排出增加而导致药物在细啤内浓度偏低；②多药耐药 基因 MDR,诱导的 P- 89， 多药耐药基因相关蛋白 MRP、肺^隆蛋白 LRP的过度表达，
③与谷胱甘肽代谢有关的酶在耐药株中的表达明显升高。 .
紫杉醇可使微管蛋白和组成微管的微管蛋白二聚体失去动态平衡，诱导与促进 微管蛋白聚合， 微管装配， 防止解聚， 使微管稳定， 从而阻止癌细胞的生长， 紫杉 醇的结合部位与三磷酸鸟苷、长春花碱、秋水仙碱不同， 紫杉醇与微管中 β微管蛋 白亚单位上 N末端 31个氨基酸相结合， 并不与微管蛋白二聚体相结合。 在完整细 胞中紫杉醇可诱导微管成束及使有丝分裂纺垂体形成大量的星状体，前者是致死性 药物作用的一个有用的临床指标。在体外可能通过诱导细胞， 抑制分裂和增殖， 停 止于放射性最敏感的有丝分裂前期 （G2期） 与有丝分裂期 （M 期）， 增加离子照射 的细胞毒作用， 直至死亡， 进而起到抗癌作用。
中国医学科学院药物研究所等自 1984年以来对我国的紫杉植物进行了调查和 化学研究， 发现四川、 云南、 东北等地均有丰富的红豆杉植物资源， 从中提取到紫 杉醇， 并完成了临床前化学和药理研究， 10个单位于 1995年 3-8月根据协作组共 同制定的 II期临床试用计划， 用其对 121例中晚期癌症患者进行治疗。 紫杉醇因 其独特的抗癌机制，得到医学界及其相关行业的公认，但是紫杉醇的不溶水性和临 床应用中的毒副作用给紫杉醇的应用带来一定的困难。近年来，人们对紫杉醇的药 用剂型进行研究和探讨， 以便找到克服以上困难的突破口。
由于紫杉醇本身几乎不溶于水， 所以临床的紫杉醇制剂多是用有机溶剂 和油制成油剂型制剂， 这些药物的载体会引发一些不良反应， 所以必须谨慎 观测用药过程。 近年来， 人们将一些水溶性大分子载体与之相连接， 使之被 带入水中， 这一研究为解决紫杉醇的水溶性问题开辟了一条新的途径。 一般 采用脂质体包裹， 环糊精包合， 聚乙二醇衍生物， 制成乳剂和粉针剂等。
目前国内外还没有将海藻酸钠作为药物载体包裹紫杉醇并应用于肿瘤患者的 血管介入栓塞治疗的先例。
发明内容
本发明的目的之一在于提供一种安全、 无毒、 无致畸性、 无生殖毒性、 无致 癌性的含紫杉醇的海藻酸钠微球血管栓塞剂。
本发明的另一目的是提供上述含紫杉醇的海藻酸钠微球血管栓塞剂的制备方 法。 ―
本发明的目的是通过以下技术方案达到的：
一种含紫杉醇的海藻酸钠微球血管栓塞剂，其特征在于：包括药物载体海藻酸 钠和紫杉醇， 所述海藻酸钠包裹所述紫杉醇。
所述海藻酸钠与所述紫杉醇的重量比为 1 : 1〜90： 1。
所述含紫杉醇的海藻酸钠微球血管栓塞剂可以是储存在二价金属阳离子固 化液当中的微胶珠或微球。
所述含紫杉醇的海藻酸钠微球血管栓塞剂也可以是粉末状微粒。
所述储存在固化液中的微胶珠或微球的粒径范围在 200〜550μπι或 400〜
750μηι或 600〜950μπι。
所述粉末状微粒的粒径范围在 100〜350μπι或 200~550μιη或 400~750μπι。 一种含紫杉醇的海藻酸钠微球血管栓塞剂的制备方法， 其步骤如下：
( 1 ) 将紫杉醇按比例称重， 用有机溶剂溶解； 得紫杉醇溶液；
(2) 将海藻酸钠按比例称重， 溶解， 得海藻酸钠溶液；
(3) 将氯化钙或氯化钡称重， 配制成 1〜10%浓度的溶液， 得固化液；
(4) 将所得紫杉醇溶液和海藻酸钠溶液混合， 并通过高压静电微球液滴 发生装置与所述固化液混合固化成圆形或类圆形的微球或微胶珠， 得含 紫杉醇的海藻酸钠微球血管栓塞剂。
所述高压静电微球液滴发生装置包括： 一静电发生装置，所述静电发生装置上 有正负两极，正极与微量注射装置的针头相连，负极与浸在所述固化液中的不锈钢 钢丝相 ¾接，注射装置内装有紫杉醇和海藻酸钠的混合溶液， 滴入所述固化液中形 成微球。
所得含紫杉醇的海藻酸钠微球血管栓塞剂为储存在固化液中的微球， 称为湿 球。 其粒径范围可以是 200〜550μπι或 400〜750μιη或 600〜950μιη。
将所得含紫杉醇的海藻酸钠微球血管栓塞剂倾析后，将下面的微球放入烘箱干 燥，密闭保存，得粉末状颗粒，称为干球。其粒径范围可以是 100〜350μπι或 200〜 550μιη或 400〜750μπι。
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， 决定选用栓塞微球的直径。尽量使用微导管进行超选择栓塞， 使用 时要无菌操作。 将瓶盖开封， 静置沉淀后， 用注射器将瓶中保养液（即固化液）抽 掉加等量的生理盐水冲洗微球三遍或将瓶中保养 '液（即固化液）抽掉加等量生理盐 水， 连同生理盐水及微球倒入无菌碗内， 用 50〜60ml生理盐水冲洗微球一遍弃掉 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或缓慢多次注入 （切忌过量栓塞)， 裒到造影剂流速明显 减慢时， 即完成栓塞。 再次行动脉造影判定栓塞效果。
如果含紫杉醇的海藻酸钠微球血管栓塞剂是粉末状颗粒，则先将保存在密闭容 器中干球溶于在生理盐水中溶胀 （湿球)， 再加入适量或稀释后的造影剂混合均匀 (使微球充分悬浮于造影剂中）， 再在影像设备监视下通过导管超选择性栓塞在病 变部位的血管内缓慢或缓慢多次注入 （切忌过量栓塞）， 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。
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 :
含紫杉醇的海藻酸钠微球的制备 1、 包裹前的准备工作：
①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 300摄氏度下烘烤 3小时（除 菌去热源)；
②紫杉醇药液的配制- 称取 1. 5 千克市售紫杉醇， 置于上述玻璃器皿内， 滴加丙二醇， 直到全部溶 解为止； 得浓度为 lOmol/L紫杉醇药物溶液；
③海藻酸钠溶液的制备： - 称取 2千克市售海藻酸钠， 置于玻璃器皿内， 一边搅拌， 一边加入生理盐水， 直至海藻酸钠全部溶解， 得海藻酸钠溶液；
④配制 1%的氯化钙溶液；
⑤将上述紫杉醇溶液和海藻酸钠溶液混合， 得含紫杉醇的海藻酸钠混合溶液；
⑥用一次性无菌注射器吸取上述混合液， 通过高压静电微球液滴发生装置滴 入上述 化钙溶液中，所得含紫杉醇的海藻酸钠微球沉入容器下面。微球的粒径范 围在 200~550μιη之间。
将上述容器的上层溶液倾析， 将下面的微胶珠放入烘箱干燥， 密闭保存， 所 得干球的粒径范围为在 100〜350μΙη之间。使用前用生理盐水浸泡几分钟还原成湿 球。
也可以将上述容器的上层溶液倾析后， 用水冲洗两次， 即时使用。
对于患有子宫肌腺症的病人， 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， 选用上述微球粒径范围在 200〜 550μιη之间的含紫杉醇的海藻酸钠微球。 尽量使用微导管进行超选择栓塞， 使用 时要无菌操作。 将所述含紫杉醇的海藻酸钠微球 （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，或将瓶中氯化钙溶液抽掉加等量生理 盐水， 连同生理盐水及微球倒入无菌碗内， 用 50〜60ml生理盐水冲洗微球一遍弃 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或缓慢多次注入（切忌过量栓塞）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:
含紫杉醇的海藻酸钠微球的制备
1、 包裹前的准备工作：
①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 300摄氏度下烘烤 3小时（除 菌去热源）；
②紫杉醇药液的配制：
称取 2 千克市售紫杉醇， 置于上述玻璃器皿内， 滴加生理盐水和乙醇， 直到 全部溶解为止； 得紫杉醇药物溶液；
③海藻酸钠溶液的制备：
称取 20千克市售海藻酸钠， 置于玻璃器皿内， 一边搅拌， 一边加入生理盐水， 直至海藻酸钠全部溶解， 得海藻酸钠溶液；
④配制 10%的氯化钙溶液；
⑤将上述紫杉醇溶液和海藻酸钠溶液混合， 得含紫杉醇的海藻酸钠混合溶液;
⑥用一次性无菌注射器吸取上述混合液， 通过高压静电微球液滴发生装置滴 入上述氯化钙溶液中，所得含紫杉醇的海藻酸钠微球沉入容器下面。微球的粒径范 围在 400〜750μηι之间。
将上述容器的上层溶液倾析， 将下面的微球放入烘箱干燥， 密闭保存， 所得 干球的粒径范围为在 200〜550μιη之间。 使用前用生理盐水浸泡几分钟还原成湿 球。
也可以将上述容器的上层溶液倾析后， 用水冲洗两次， 即时使用。
患有子宫肌瘤的患者，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， 选用上述微球粒径范围在 400〜750μιη之间 的含紫杉醇的海藻酸钠微球。尽量使用微导管进行超选择栓塞，使用时要无菌操作。 将所述含紫杉醇的海藻酸钠微球 （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，或将瓶中氯化钙溶液抽掉加等量生理盐水，连同生理 盐水及微球倒入无菌碗内， 用 50〜60ml生理盐水冲洗微球一遍弃掉冲洗液， 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 体情况缓慢或缓慢多次注入（切忌过量栓塞）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。
实施例 3
含紫杉醇的海藻酸钠微球的制备
1、 包裹前的准备工作：
①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 300摄氏度下烘烤 3小时（除 菌去热源）； ②紫杉醇药液的配制：
称取 2 千克市售紫杉醇， 置于上述玻璃器皿内， 滴加丙酮， 直到全部溶解为 止； 得紫杉醇药物溶液；
③海藻酸钠溶液的制备：
称取 150千克市售海藻酸钠， 置于玻璃器皿内， 一边搅拌， 一边加入生理盐 水， 直至海藻酸钠全部溶解， 得海藻酸钠溶液；
④配制 6%的氯化钡溶液；
⑤将上述紫杉醇溶液和海藻酸钠溶液混合， 得含紫杉醇的海藻酸钠混合溶液；
⑥用一次性无菌注射器吸取上述混合液， 通过高压静电微球液滴发生装置滴 入上述氯化钡溶液中，所得含紫杉醇的海藻酸钠微球沉入容器下面。所得微球的粒 径范围在 600〜950μιη之间。
将上述容器的上层溶液倾析， 将下面的微球放入烘箱干燥， 密闭保存， 所得 干球的粒径范围为在 400〜750μιη 之间。 使用前用生理盐水浸泡几分钟还原成湿 球。
患有子宫肌瘤的患者， 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， 选用上述微球粒径范围在 600〜750μηι之间 的含紫杉醇的海藻酸钠微球。尽量使用微导管进行超选择栓塞，使用时要无菌操作。 将所述含紫杉醇的海藻酸钠微球 （湿球）， 用注射器将瓶中氯化钡溶液抽掉， 加等 量的生理盐水冲洗微球三遍，或将瓶中氯化钡溶液抽掉加等量生理盐水，连同生理 盐水及微球倒入无菌碗内， 用 50〜60ml生理盐水冲洗微球一遍弃掉冲洗液， 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 体情况缓慢或缓慢多次注入（切忌过量栓塞）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， 该患者还可以生育。
工业应用性
本发明的海藻酸钠药物载体为天然提取物， 是从天然植物褐藻中提取的 β -D 一甘露醇和 α— L一古罗糖混合组成的多糖钠盐， 是一种线性大分子， 分子量 50， 000-100， 000道尔顿， 水合力强， 溶于水可形成粘稠胶体， 在钙离子作用下产生 大分子链间交联固化，可根据临床需要加工成不同大小规格圆形或类圆形的固态微 球。 此种微球具有良好的生物相容性， 在生物机体内， 钙离子渐渐析出， 微球以分 子脱链的形式在 3— 6个月内无毒降解。 降解时不产生碎屑， 并可造成靶器官血管 的永久性栓塞（当栓塞剂在血管内长达 2个月之久时，病人血管内的血栓形成而达 到永久性栓塞的目的）， 而达到治疗的目的。 实际操作中， 用这种 "生物多功能微 球"栓塞材料通过物理堵塞肿瘤或治疗部位周围的小动脉血管，造成相应的血管闭 锁， 切断对该部位组织的血供与营养， 导致其因缺血缺氧而萎缩和坏死。 同时也可 通过减少靶器官的血供， 为手术治疗创造有利条件。将此种微球作为加入妇科治疗 用药的载体， 定时、 定位、 定向地对局部病灶组织缓慢释放， 从而大大提高疗效， 降低药物的毒副作用， 具有栓塞与药物双重治疗作用。
本发明根据紫杉醇独特的抗癌作用机制和临床应用情况，根据海藻酸钠微球的 半互穿网络结构和可降解原理， 结合以往海藻酸钠微球栓塞剂应用实际， 从安全， 无毒， 无免疫原性， 无遗传毒性， 无生殖毒性， 无致癌性等方面考虑。 选用海藻酸 钠作为载体加入抗肿瘤的靶药， 定时、 定点、 定向、 定期的局部释放靶药， 杀伤肿 瘤细胞， 达到治疗目的。在研究海藻酸钠紫杉醇微球靶向缓释血管栓塞剂过程中完 成了紫杉醇不溶于水，被包封的紫杉醇微滴不沉淀，形不成微球，析出结晶等步骤， 经加入特别混合试剂-有机溶剂等， 调整浓度、 频率及速度后， 包封非常好， 微球 均匀， 圆滑， 药物分散均匀。 药物经微球携带后， 保护药物的活性基团， 在内环境 中维持体内的稳定性，避免紫杉醇从体内过早过快地漏出，达到符合临床应用需要。
本发明的含紫杉醇的海藻酸钠微球血管栓塞剂，具有药物微球载药量大，在体 内滞留时间长， 又具有靶向专一性的优点， 成为目前最有前途的靶向释药系统。紫 杉醇浓度为 lOmol/L时,制成的药物微球经相差显微镜观察未见紫杉醇结晶和药物 微球积聚现象， 并且 4°C存放 30d 仍保持良好的物理和化学稳定性。 当浓度为 30mol/L 时时，镜下可见大部分紫杉醇结晶和药物积聚。 用海藻酸钠制作的微球颗 粒表面带有一定的负电荷， 其颗粒之间相斥， 在使用过程中， 应视病灶情况选择剂 量， 可选用介入放射或手术中插管的方法， 将导管插入靶血管， 造影后用注射器将 药物微球和造影剂混合， 缓缓注入， 在导管内不凝聚， 不堵管。

Claims

权 利 要 求 书
1、 一种含紫杉醇的海藻酸钠微球血管栓塞剂， 其特征在于： 包括药物载体海 藻酸钠和紫杉醇， 所述海藻酸钠包裹所述紫杉醇，
2、 按权利要求 1所述的含紫杉醇的海藻酸钠微球血管栓塞剂， 其特征在于： 所述海藻酸钠与所述紫杉醇的重量比为 1 : 1〜90： 1。
3、 按权利要求 1所述的含紫杉醇的海藻酸钠微球血管栓塞剂， 其特征在于： 所述含紫杉醇的海藻酸钠微球血管栓塞剂为储存在二价金属阳离子溶液中的微胶 珠或微球。
4、按权利要求 1所述的含紫杉醇的海藻酸钠微球血管栓塞剂，其特征在于： 所述含紫杉醇的海藻酸钠微球血管栓塞剂为粉末状微粒。
5、按权利要求 4所述的含紫杉醇的海藻酸钠微球血管栓塞剂，其特征在于： 所述储存在固化液中的微胶珠或微球的粒径范围为 300〜550μιη或 500〜750μιη 或 700〜950μιη。
6、按权利要求 4所述的含紫杉醇的海藻酸钠微球血管栓塞剂，其特征在于- 所述粉末状微粒的粒径范围为 100〜350μιη或 200〜550μιη或 400〜750μπι。
7、 一种含紫杉醇的海藻酸钠微球血管栓塞 j的制备方法， 其步骤如下：
( 1 ) 将紫杉醇按比例称重， 用有机溶剂溶解， 得紫杉醇溶液；
(2) 将海藻酸钠按比例称重， 溶解， 得海藻酸钠溶液；
(3 ) 将氯化钙或氯化钡称重， 配制成 1〜10%浓度的溶液， 得固化液；
(5) 将所得紫杉醇溶液和海藻酸钠溶液混合，并通过高压静电微球液滴发生 装置与所述固化液混合， 得含紫杉醇的海藻酸钠微球血管栓塞剂。
8、 按权利要求 7所述的含紫杉醇的海藻酸钠微球血管栓塞剂的制备方法， 其 特征在于： 所述高压静电微球液滴发生装置包 : 一静电发生装置， 所述静电发生 装置上有正负两极，正极与微量注射装置的针头相连，负极与浸在所述固化液中的 不锈钢钢丝相连接，注射装置内装有紫杉醇和涛藻酸钠的混合溶液，滴入所述固化 液中形成微球。
9、按权利要求 7或 8所述的含紫杉醇的海藻酸钠微球血管栓塞剂的制备方法， 其特征在于： 所得含紫杉醇的海藻酸钠微球经干燥， 得粉末状颗粒。
10、 按权利要求 1〜7中任一项所述的含紫杉醇的海藻酸钠微球血管栓塞剂的 应用， 其特征在于： 在影像设备监视下， 将所述含紫杉醇的海藻酸钠微球血管栓塞 剂通过导管超选择性栓塞在病变部位的血管内。 ·
PCT/CN2005/000320 2004-09-16 2005-03-16 Microcapsules d'alginate de sodium contenant du paclitaxel qui permet de traiter un embole vasculaire WO2006029554A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US11/660,553 US20080020052A1 (en) 2004-09-16 2005-03-16 Vascular Embolus Of Paclitaxel-Sodium Alginate Microsphere And Its Preparation
ES05714849.6T ES2553130T3 (es) 2004-09-16 2005-03-16 Émbolo vascular de microesferas de alginato de sodio-paclitaxel y su preparación
CA2577589A CA2577589C (en) 2004-09-16 2005-03-16 Vascular embolus of paclitaxel-sodium alginate microsphere and its preparation
JP2007531568A JP2008513381A (ja) 2004-09-16 2005-03-16 パクリタキセル−アルギン酸ナトリウムマイクロスフェア血管塞栓剤及びその製造方法
EP05714849.6A EP1797874B1 (en) 2004-09-16 2005-03-16 Vascular embolus of paclitaxel-sodium alginate microsphere and its preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB2004100744643A CN1319525C (zh) 2004-09-16 2004-09-16 紫杉醇－海藻酸钠微球血管栓塞剂及其制备
CN200410074464.3 2004-09-16

Publications (1)

Publication Number Publication Date
WO2006029554A1 true WO2006029554A1 (fr) 2006-03-23

Family

ID=34765357

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2005/000320 WO2006029554A1 (fr) 2004-09-16 2005-03-16 Microcapsules d'alginate de sodium contenant du paclitaxel qui permet de traiter un embole vasculaire

Country Status (8)

Country Link
US (1) US20080020052A1 (zh)
EP (1) EP1797874B1 (zh)
JP (1) JP2008513381A (zh)
KR (1) KR100915601B1 (zh)
CN (1) CN1319525C (zh)
CA (1) CA2577589C (zh)
ES (1) ES2553130T3 (zh)
WO (1) WO2006029554A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8168224B2 (en) * 2007-12-19 2012-05-01 Beijing Shengyiyao Science & Technology Development Co., Ltd. Sodium alginate microsphere vascular embolus containing water-soluble drug and preparation and application thereof
US8481075B2 (en) * 2007-12-13 2013-07-09 Beijing Shengyiyao Science & Technology Development Co. Ltd. Preparation and application of biodegradable-material-made microsphere vascular embolus containing liposome-encapsulated cytokines

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1870089A4 (en) * 2005-04-15 2012-10-03 Beijing Shengyiyao Science & Technology Dev Co Ltd GYNECOLOGIC DRUG-MOISTURIZED MICROBALL VASCULAR SUPPOSITORIUM FROM SODIUM ALGINATE AND ITS MANUFACTURING PROCESS
CN100518719C (zh) * 2006-07-05 2009-07-29 中国科学院大连化学物理研究所 一种复合基质的多功能动脉栓塞剂的制备方法
CN100438915C (zh) * 2006-08-08 2008-12-03 四川大学 靶向性纳米药物载体及其制备方法
CN101536986B (zh) * 2009-04-16 2011-05-04 北京圣医耀科技发展有限责任公司 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
CN101536987A (zh) * 2009-04-30 2009-09-23 北京圣医耀科技发展有限责任公司 含抗血管瘤药物海藻酸钠微球血管栓塞剂及制备方法和应用
CN102258477B (zh) * 2010-05-28 2014-09-03 北京宏医耀科技发展有限公司 一种抗移植免疫排斥反应的新型j2-海藻酸钠微球缓释免疫抑制剂、制备方法和用途
CN103861157A (zh) * 2012-12-17 2014-06-18 中国科学院大连化学物理研究所 一种基于海藻酸钆的mri显影栓塞微球
CN103432080A (zh) * 2013-05-07 2013-12-11 哈尔滨工程大学 可显影载药纳米银海藻酸钠微球血管栓塞剂及其制备方法
CN103536970B (zh) * 2013-10-25 2016-06-08 北京大学 一种栓塞材料及其制备方法和用途
CN111803698B (zh) * 2014-02-14 2022-05-27 波士顿科学国际有限公司 具有治疗剂释放的快速降解栓塞颗粒
WO2018038253A1 (ja) 2016-08-26 2018-03-01 哲治 奥野 微小ナノ化薬剤およびその利用
JP7198666B2 (ja) 2016-08-26 2023-01-04 哲治 奥野 微小血管血流低減剤およびその利用
CN108795921A (zh) * 2017-04-28 2018-11-13 南京理工大学 一种海藻酸钙多相微载体的制备方法
CN107185029A (zh) * 2017-05-24 2017-09-22 南京大学 一种包裹载药纳米材料的高分子水凝胶栓塞微球及其制备方法和应用
CN108452368A (zh) * 2018-05-08 2018-08-28 天津市肿瘤医院（天津医科大学肿瘤医院） 一种海藻酸钠载药栓塞微球及其制备方法和装置
CN108785733A (zh) * 2018-08-01 2018-11-13 江苏红豆杉药业有限公司 一种紫杉醇-无水乙醇肿瘤栓塞剂及其制备方法
CN108578758A (zh) * 2018-08-01 2018-09-28 江苏红豆杉药业有限公司 一种多西他赛-无水乙醇肿瘤栓塞剂及其制备方法
CN110292574A (zh) * 2019-08-02 2019-10-01 江苏红豆杉药业有限公司 一种抗肠癌药物组合物及其应用
CN110279671A (zh) * 2019-08-08 2019-09-27 江苏红豆杉药业有限公司 一种紫杉醇抗胃癌纳米微球胶囊剂及其制备方法
CN110507601B (zh) * 2019-08-28 2022-03-25 哈尔滨贝科德糖生物科技有限公司 一种紫杉醇负载红松松塔多糖-a凝胶及其制备方法与应用
KR102288833B1 (ko) * 2019-09-11 2021-08-13 주식회사 메피온 자가 팽창형 색전물질의 제조 방법
JP7430904B2 (ja) * 2020-04-07 2024-02-14 国立大学法人 岡山大学 塞栓物質の作製方法、塞栓物質および塞栓物質作製用キット
CN111454379B (zh) * 2020-04-22 2021-12-10 广东海洋大学 一种n-亚苄基海藻酸钠腙化合物及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003007914A2 (en) * 2001-07-19 2003-01-30 Guilford Pharmaceuticals, Inc. Biocompatible polymer containing composition for treatment of prostate cancers
CN1399958A (zh) * 2001-07-27 2003-03-05 潘君琦 一种紫杉醇纳米磁性靶向制剂及其制备方法
WO2003020210A2 (en) * 2001-08-29 2003-03-13 Umd, Inc. Vaginal delivery of chemotherapeutic agents and inhibitors of membrane efflux systems for cancer therapy

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4956128A (en) * 1984-05-25 1990-09-11 Connaught Laboratories Limited Droplet generation
JP3534780B2 (ja) * 1992-01-31 2004-06-07 テルモ株式会社 血管塞栓剤
US6749868B1 (en) * 1993-02-22 2004-06-15 American Bioscience, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
US5895757A (en) * 1993-06-30 1999-04-20 Pope; Edward J. A. Encapsulation of living tissue cells in inorganic microspheres prepared from an organosilicon
US5417982A (en) * 1994-02-17 1995-05-23 Modi; Pankaj Controlled release of drugs or hormones in biodegradable polymer microspheres
CA2253980C (en) * 1996-05-23 2004-08-17 Samyang Corporation Locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof
US6432449B1 (en) * 1998-05-18 2002-08-13 Amgen Inc. Biodegradable sustained-release alginate gels
US6124131A (en) * 1998-08-25 2000-09-26 The Johns Hopkins University School Of Medicine Mutant hypoxia inducible factor-1 HIF-1
KR20010002589A (ko) * 1999-06-16 2001-01-15 김윤 생리활성물질 함유 생분해성 고분자 마이크로스피어의 제조방법
IL152180A0 (en) * 2000-04-10 2003-05-29 Teva Pharma Method and composition for treating cancer by administration of apoptosis-inducing chemotherapeutic agents
US6881420B2 (en) * 2000-06-23 2005-04-19 Teva Pharmaceutical Industries Ltd. Compositions and dosage forms for gastric delivery of irinotecan and methods of treatment that use it to inhibit cancer cell proliferation
IL149030A0 (en) * 2000-08-09 2002-11-10 Panacea Biotec Ltd Pharmaceutical compositions containing rifampicin, isoniazid or combinations thereof
CN1106845C (zh) * 2000-08-17 2003-04-30 洪宏 海藻酸钠固态微球血管栓塞剂的生产工艺
EP1355566B1 (en) * 2000-12-18 2012-11-28 Board Of Regents, The University Of Texas System Local regional chemotherapy and radiotherapy using in situ hydrogel
KR20030023369A (ko) * 2001-09-13 2003-03-19 한국과학기술연구원 화학색전용 파클리탁셀 유성 조성물, 그의 제형 및 제조방법
US7622299B2 (en) * 2002-02-22 2009-11-24 University Of Washington Bioengineered tissue substitutes
US20040076582A1 (en) * 2002-08-30 2004-04-22 Dimatteo Kristian Agent delivery particle
JP2005535752A (ja) * 2002-08-09 2005-11-24 ボストン サイエンティフィック リミテッド 塞栓術
JP4686970B2 (ja) * 2002-10-29 2011-05-25 東レ株式会社 血管塞栓材料
KR20040066548A (ko) * 2003-01-20 2004-07-27 코오롱제약주식회사 생리활성펩타이드의 국소투여용 서방성 마이크로스피어 및그 제조방법

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003007914A2 (en) * 2001-07-19 2003-01-30 Guilford Pharmaceuticals, Inc. Biocompatible polymer containing composition for treatment of prostate cancers
CN1399958A (zh) * 2001-07-27 2003-03-05 潘君琦 一种紫杉醇纳米磁性靶向制剂及其制备方法
WO2003020210A2 (en) * 2001-08-29 2003-03-13 Umd, Inc. Vaginal delivery of chemotherapeutic agents and inhibitors of membrane efflux systems for cancer therapy

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DAI Z. ET AL: "Studies on cetyl-chitosan nanosphere as carriers for paclitaxel", CHINESE TRADITIONAL AND HERBAL DRUGS, vol. 34, no. 2, February 2003 (2003-02-01), pages 20 - 122, XP008112837 *
See also references of EP1797874A4 *
XIONG X. ET AL: "Preliminary study on preparation of paclitaxel microsphere", CHINES JOURNAL OF NEW DRUGS, vol. 10, no. 7, 2001, pages 517 - 519, XP008138004 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8481075B2 (en) * 2007-12-13 2013-07-09 Beijing Shengyiyao Science & Technology Development Co. Ltd. Preparation and application of biodegradable-material-made microsphere vascular embolus containing liposome-encapsulated cytokines
US8168224B2 (en) * 2007-12-19 2012-05-01 Beijing Shengyiyao Science & Technology Development Co., Ltd. Sodium alginate microsphere vascular embolus containing water-soluble drug and preparation and application thereof

Also Published As

Publication number Publication date
KR20070053350A (ko) 2007-05-23
EP1797874A4 (en) 2012-09-12
JP2008513381A (ja) 2008-05-01
CA2577589C (en) 2010-05-25
CA2577589A1 (en) 2006-03-23
CN1319525C (zh) 2007-06-06
US20080020052A1 (en) 2008-01-24
KR100915601B1 (ko) 2009-09-07
ES2553130T3 (es) 2015-12-04
EP1797874B1 (en) 2015-11-04
EP1797874A1 (en) 2007-06-20
CN1615841A (zh) 2005-05-18

Similar Documents

Publication Publication Date Title
WO2006029554A1 (fr) Microcapsules d&#39;alginate de sodium contenant du paclitaxel qui permet de traiter un embole vasculaire
US8673266B2 (en) Polyvinyl alcohol microspheres, injectable solutions and therapeutic uses of the same
CN100586480C (zh) 一种含水溶性药物的海藻酸钠微球血管栓塞剂和制备及应用
WO2021042778A1 (zh) 一种治疗肿瘤的温敏型凝胶药物组合物
JP6145513B2 (ja) アルブミン及びデキストランサルフェートを含む抗癌剤吸着能力の向上された生分解性マイクロビーズ及びその製造方法
CN1923189A (zh) 一种紫杉碱类抗癌药物的缓释注射剂
CN111803698B (zh) 具有治疗剂释放的快速降解栓塞颗粒
WO2010118683A1 (zh) 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
WO2008086756A1 (fr) Matériaux emboliques de vaisseau sanguin, microsphériques, biodégradables et développables
Han et al. Progress in research and application of PLGA embolic microspheres
US8168224B2 (en) Sodium alginate microsphere vascular embolus containing water-soluble drug and preparation and application thereof
CN101385696B (zh) 含依托泊苷的海藻酸钠微球血管栓塞剂及制备方法与用途
KR101614911B1 (ko) 제 1 및 제 2 생분해성 마이크로 비드를 포함하는 화학색전용 조성물 및 이의 제조방법
CA2602281C (en) Gynecological drugs encapsulated in sodium alginate microspheres for use in embolotherapy
CN108113976B (zh) Th-302制剂、制备方法及其用途
JP6976327B2 (ja) 化学塞栓用エマルジョン組成物およびその製造方法
CN1311818C (zh) 一种抗实体肿瘤的药物组合物
CN1299674C (zh) 一种缓慢释放的体内植入抗癌药物组合物
Liu et al. A Novel Coacervate Embolic Agent for Tumor Chemoembolization
CN100384419C (zh) 一种埃坡霉素缓释植入组合物及应用
CN101244030A (zh) 一种含雌激素受体拮抗剂的抗癌缓释注射剂

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2577589

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 11660553

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2007531568

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2005714849

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2715/DELNP/2007

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 1020077008633

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2005714849

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 11660553

Country of ref document: US