WO2018028644A1 - 医用磷酸钇碳微球及其制备方法 - Google Patents

医用磷酸钇碳微球及其制备方法 Download PDF

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WO2018028644A1
WO2018028644A1 PCT/CN2017/096892 CN2017096892W WO2018028644A1 WO 2018028644 A1 WO2018028644 A1 WO 2018028644A1 CN 2017096892 W CN2017096892 W CN 2017096892W WO 2018028644 A1 WO2018028644 A1 WO 2018028644A1
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medical
carbon
solution
phosphate
microspheres
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李茂良
蔡继鸣
胡学正
郭强
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成都纽瑞特医疗科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A61K51/1251—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention relates to a tumor radiotherapy medicine and a preparation method thereof, in particular to a medical yttrium phosphate [ 90 Y 32 PO 4 ] carbon microsphere and a preparation method thereof.
  • liver cancer patients in China are late in the discovery [Wu Mengchao. Current status and prospects of liver resection technology development in China. Chinese Journal of Surgery, 2010.48(3): 161-162], and affected by various factors, only about 20% Can be surgically removed [Tang Wei, Yang Binghui. Research and progress of primary liver cancer. Shanghai, Shanghai Medical University Press, 1990, 1-19]. Therefore, non-surgical interventional therapy has become an important tool for the treatment of liver cancer [Lencioni R, Crocetti L, De Simone P, et al. Loco-regional interventional treatment of hepatocellular carcinoma: techniques, advantages, and future prospects. Transpl Int, 2010, 23(7): 698-703].
  • transarterial radioactive embolization of microspheres is a very effective method for the treatment of malignant tumors.
  • ⁇ -90 ( 90 Y) and phosphorus-32 ( 32 P) are the two most commonly used therapeutic nuclides in nuclear medicine. They can be prepared into radioactive glass microspheres for tumor treatment, ⁇ -90( 90 Y) glass micro The specific activity of the sphere is high, but the half-life of ⁇ -90 ( 90 Y) is shorter (64h), while the specific activity of phosphorus-32 ( 32 P) glass microsphere is lower, but phosphorus-32 ( 32 P) Long half-life (about 14d), there are advantages and disadvantages in the treatment of tumors.
  • the object of the present invention is to provide a medical yttrium phosphate [ 90 Y 32 PO 4 ] carbon having a simple process, a high nuclide adsorption rate and a low release rate while having ⁇ -90 ( 90 Y) and phosphorus-32 ( 32 P). Microspheres and methods for their preparation.
  • the invention utilizes carbon microspheres as a carrier to adsorb a radioactive complex ( 90 Y-tartaric acid) formed by a radioactive 90 YCl 3 solution and a tartaric acid solution, and then reacts with a radioactive sodium phosphate (Na 3 32 PO 4 ) solution.
  • the radioactive strontium phosphate (Y 32 PO 4 ) precipitates in the carbon microspheres to solidify the strontium-90 ( 90 Y) and phosphorus-32 ( 32 P) nuclides, and then further purifies to form medical strontium phosphate ( 90 Y 32 PO 4 ) Carbon microspheres.
  • the adsorption rate of the medical yttrium phosphate ( 90 Y 32 PO 4 ) carbon microspheres prepared by the invention is higher than 95% for the yttrium-90 ( 90 Y) nuclides, and the adsorption efficiency for the phosphorus-32 ( 32 P) nuclides is higher than 99%, while the release rates of both ⁇ -90 ( 90 Y) and phosphorus-32 ( 32 P) are less than 0.01%, because the total activity is higher than the activity, and the treatment time for the tumor is longer and more Suitable for tumor radiation therapy.
  • the carbon microsphere adsorption of the present invention is physical adsorption, since the phosphorus-32 ( 32P ) nuclides are in the form of Na 3 32 PO 4 compounds and cannot be directly adsorbed by carbon microspheres, but 32 PO 4 3- ions (including non-radioactive)
  • the radioactive PO 4 3- ion reacts with radioactive 90 Y 3+ ions (including non-radioactive Y 3+ ions) to form insoluble precipitates of yttrium phosphate [ 90 Y 32 PO 4 ] (including non-radioactive YPO 4 ), so
  • the radioactive 90 Y 3+ ion (including the non-radioactive Y 3+ ion) is adsorbed in the carbon microsphere, and then the yttrium phosphate [ 90 Y 32 PO 4 ] precipitate is formed in the carbon microsphere, and the ruthenium is solidified in the carbon microsphere.
  • ⁇ -90( 90 Y) is a positive trivalent cation ( 90 Y 3+ ) in solution
  • the acidity is high, the amount of direct physical adsorption by the carbon microspheres is small ( ⁇ 30mgY/g microspheres).
  • the pH value of the solution is greater than 1, the 90 Y 3+ ions are easily hydrolyzed to form a precipitate, so in order to improve the adsorption of carbon microspheres.
  • the specific method is to select a complexing agent to form a stable complex with 90 Y 3+ ions, prevent hydrolysis of 90 Y 3+ ions and firmly adsorb the complex by carbon microspheres, and then use Na 3 32 PO 4 .
  • the solution reacts with the 90 Y 3+ ions adsorbed by the carbon microspheres to form a poorly soluble yttrium phosphate [ 90 Y 32 PO 4 ] precipitate.
  • the ruthenium-90 and phosphorus-32 nuclides are simultaneously solidified in the carbon microspheres, and then Further purification can be prepared into medical yttrium phosphate [ 90 Y 32 PO 4 ] carbon microspheres.
  • the carbon microspheres have a release rate of less than 0.01% for both sputum-90 and phosphorus-32, which meets the requirements for treating tumors.
  • the present invention finds that the complexing agent tartaric acid can be complexed with 90 Y 3+ to form a 90 Y 3+ -tartaric acid complex adsorbed by carbon microspheres, and 32 PO 4 3+ can react with 90 Y 3+ to form phosphoric acid. ⁇ [ 90 Y 32 PO 4 ] precipitates, and both ⁇ -90 and phosphorus-32 radionuclides are solidified in carbon microspheres, so that yttrium phosphate [ 90 Y 32 PO 4 ] carbon microspheres can be prepared.
  • the specific preparation method is as follows:
  • a medical strontium phosphate [ 90 Y 32 PO 4 ] carbon microsphere consisting mainly of carbon microspheres and radionuclides ⁇ -90 and phosphorus-32 which are precipitated and solidified in carbon microspheres.
  • the medical strontium phosphate microspheres are prepared by the following method: 90 Y-tartaric acid complex formed by adsorption of 90 YCl 3 solution and tartaric acid solution by carbon microspheres, and then with radioactive sodium phosphate Na 3 32 PO 4 The solution reacts to form yttrium phosphate [ 90 Y 32 PO 4 ] precipitate and solidifies, and then is further purified.
  • a method for preparing medical yttrium phosphate [ 90 Y 32 PO 4 ] carbon microspheres comprises the following steps:
  • the radioactive Na 3 32 PO 4 solution is prepared by sealing magnesium hydrogen phosphate or aluminum phosphate in a quartz glass tube and irradiating the nuclear reactor with a thermal neutron flux higher than 5 ⁇ 10 13 n/cm 2 .s. by 31 P (n, r) 32 P radioactivity generated MgH 32 PO Al 32 PO 4, 32 P nuclear purity of not less than 4, or 99.9% of the radioactivity, specific radioactivity of greater than 148G Bq (4Ci) / gP, Dissolved with hydrochloric acid, and precipitated Mg 2+ ions and Al 3+ ions with NaOH solution, converted MgH 32 PO 4 or Al 32 PO 4 to produce radioactive Na 3 32 PO 4 , the radiochemical purity of Na 3 32 PO 4 solution is not low At 95%, the concentration of the activity of the Na 3 32 PO 4 solution per ml is not less than 14.8 GBq (400 mCi) / mL, and is diluted to the desired concentration according to the use requirements.
  • the 90 Y-tartaric acid complex is prepared by mixing a 90 YCl 3 solution with a tartaric acid solution in a molar ratio of 1:2-2.5 to form a 90 Y-tartaric acid complex having a pH of 1.0-2.0.
  • the 90 YCl 3 solution is prepared by sealing Y 2 O 3 in a quartz glass tube and irradiating a nuclear reactor with a thermal neutron flux higher than 5 ⁇ 10 13 n/cm 2 .s, after 89 Y(n,r) 90 Y reaction produces 90 Y 2 O 3 , specific activity is greater than 370G Bq (10Ci) / gY, dissolved in hydrochloric acid, the Y 3 + ion concentration of the 90 YCl 3 solution is 40mg / mL - 60mg / mL, the pH of the solution values below 1.0, the core 90 YCl 3 solution purity 90 Y is not less than 99.9%, and the radiochemical purity of not less than 95% of chemical, radioactivity per ml concentration of not less than 18.5GBq (500mCi) / mL, using It is then diluted to the desired radioactive concentration according to the requirements of use.
  • the tartaric acid solution is prepared by dissolving tartaric acid in purified water at a concentration of 0.1 g/mL.
  • the preparation method of the medical yttrium phosphate [ 90 Y 32 PO 4 ] carbon microsphere further comprises the purification treatment of carbon microspheres, specifically: soaking the carbon microspheres with ethyl acetate, acetone or ethanol to remove fat, using sodium hydroxide The solution is soaked to remove alkali-soluble impurities, and repeatedly washed with purified water to weakly alkaline, and then soaked with acid to dissolve the acid-soluble impurities, and washed with purified water to a pH of 1-2 for use.
  • the carbon microsphere refers to a microsphere prepared by carbon-rich organic material, which is carbonized at a high temperature, and then degreased, alkali washed, acid washed, etc. to remove various impurities, thereby preparing a spherical body which is non-toxic and biocompatible to the human body. particle.
  • the carbon microspheres have a diameter of 20-30 ⁇ m.
  • the carbon microspheres have a diameter of 30 to 100 ⁇ m.
  • the carbon microspheres have a diameter greater than 100 ⁇ m.
  • the carbon microspheres have a diameter of 10 to 100 nm.
  • the carbon microspheres have a diameter of 100 to 150 nm.
  • the adsorption rate of the carbon microspheres to the 32 P nuclide in the medical phosphonium carbon microspheres is higher than 99%, and the adsorption rate to the 90 Y nuclide is higher than 95%.
  • the release rates of 90 Y nuclide and 32 P nuclide in the medical yttrium phosphate [ 90 Y 32 PO 4 ] carbon microspheres were all less than 0.01%.
  • a preparation for use in in vivo tumor radiation therapy prepared from the medical phosphonium carbon microspheres.
  • the radioactivity of ⁇ -90 ( 90 Y) used in the preparation of tumor radiotherapy in vivo is 1.85 GBq-14.8 GBq (50 mCi-400 mCi)
  • the activity of P-32 ( 32 P) is 1.85 GBq-7.4 GBq. (50mCi-200mCi)
  • the size of carbon microspheres depends on the application: medical yttrium phosphate [ 90 Y 32 PO 4 ] carbon microspheres with a particle size of 20-30 ⁇ m are mainly used for arterial perfusion embolization for liver cancer, with a particle size of 30 ⁇ m.
  • -100 ⁇ m can be used for lung cancer, kidney cancer, tongue cancer, breast cancer, cervical cancer and other blood-rich tumors, can also be used for direct dispersion injection into other tumors; radioactive implantation therapy for tumors with a particle size of 100 ⁇ m or more Medical yttrium phosphate [ 90 Y 32 PO 4 ] carbon microspheres with a particle size of 100-150 nm are mainly used for the treatment of lymphoma and metastatic cancer, and medical yttrium phosphate [ 90 Y 32 PO 4 ] having a particle diameter of 10-100 nm Carbon microspheres have tumor-like properties and can be used for tumor targeted therapy.
  • the medical phosphonium phosphate [ 90 Y 32 PO 4 ] carbon microsphere for treating a medicament for a mammal having a medical condition, wherein the medical phosphonium phosphate [ 90 Y 32 PO 4 ] carbon microsphere is used Interventional catheters, syringes or implants in the body.
  • the yttrium phosphate [ 90 Y 32 PO 4 ] carbon microsphere of the present invention is formed by adsorbing a 90 Y-tartaric acid complex with carbon microspheres and then treating with a Na 3 32 PO 4 solution to form a 90 Y 32 PO 4 precipitate. After being purified by treatment, the prepared medical carbon microspheres have an adsorption rate of ⁇ -90 ( 90 Y) higher than 95%, and the adsorption efficiency of phosphorus-32 ( 32 P) nuclides is higher than 99%. The release rates of both ⁇ -90 ( 90 Y) and phosphorus-32 ( 32 P) are less than 0.01%, and the biocompatibility is good.
  • the medical yttrium phosphate [ 90 Y 32 PO 4 ] developed by the present invention is good.
  • the total activity of carbon microspheres is higher than that of radioactivity, and it continues to be effective for treating tumors, so it is more conducive to the treatment of various tumors.
  • the medical particle size of yttrium phosphate [ 90 Y 32 PO 4 ] carbon microspheres of the invention can be used for embolization of radiotherapy-containing tumors such as liver cancer, or for treatment of other tumors by dispersive injection of radiation, or for lymphatic cancer treatment and lymphatic metastasis
  • medical yttrium phosphate [ 90 Y 32 PO 4 ] carbon microspheres containing certain tumor-like functional groups can also be used for other tumor treatments.
  • the method is simple, the introduction of impurities is small, and the product purity is high.
  • ⁇ -90 ( 90 Y) and phosphorus-32 ( 32 P) are easily obtained from multiple sources.
  • the normal production of yttrium phosphate [ 90 Y 32 PO 4 ] carbon microspheres is not affected by the supply of raw materials, and can meet the production of perennial Supply requirements.
  • strontium phosphate [ 90 Y 32 PO 4 ] carbon microspheres is higher, and it can effectively treat tumors for a longer period of time, which is more conducive to effective treatment of tumors.
  • the medical yttrium phosphate [ 90 Y 32 PO 4 ] carbon microspheres have low production cost and are convenient for popularization and application.
  • the Mg 2+ ion and the Al 3+ ion are precipitated, and MgH 32 PO 4 and Al 32 PO 4 are converted into a radioactive Na 3 32 PO 4 , and the Na 3 32 PO 4 solution has a radiochemical purity of not less than 95%.
  • the concentration of the activity of the Na 3 32 PO 4 solution per ml is not less than 14.8 GBq (400 mCi) / mL, and is diluted to the desired concentration according to the use requirements.
  • the concentration of radioactivity of 90 YCl 3 solution is not less than 18.5 GBq (500 mCi) / mL (Y 3 + ion concentration is 40 mg / mL - 60 mg / mL), and then diluted to the required radioactive concentration according to the use requirements.
  • the yttrium phosphate [ 90 Y 32 PO 4 ] carbon microsphere prepared in this example has a adsorption rate of ⁇ -90 ( 90 Y) higher than 95%, and the adsorption rate of phosphorus-32 ( 32 P) is higher than 99%.
  • the release rates of both ⁇ -90 ( 90 Y) and phosphorus-32 ( 32 P) are less than 0.01%, and the biocompatibility is good, which can be used for tumor radiotherapy.

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Abstract

一种用于肿瘤治疗的医用磷酸钇碳微球及其制备方法。该医用磷酸钇[ 90Y 32PO 4]碳微球是用碳微球吸附 90YCl 3与酒石酸溶液反应生成的酒石酸钇-90( 90Y-酒石酸)络合物，再经Na 3 32PO 4溶液处理生成 90Y 32PO 4沉淀固化及净化处理制备而成的。

Description

医用磷酸钇碳微球及其制备方法 技术领域
本发明涉及一种肿瘤放射治疗药物及其制备方法，具体涉及一种医用磷酸钇[90Y32PO4]碳微球及其制备方法。
背景技术
恶性肿瘤是严重危害人类健康的疾病，外科手术疗法、化学疗法和放射疗法是目前治疗恶性肿瘤的主要方法。由于多数患者在确诊癌症时已进入中晚期，失去了手术治疗的机会，经过多次化疗后对化疗药物不再敏感，放射治疗成为某些癌症的关键治疗手段。例如肝癌，2015年中国肝癌发病例数估计值为46.61万例，死亡病例估计值为42.21万例，肝癌的发病例数和死亡病例数在所有癌症中排在第三位[Wanqing Chen,Jie He,et al.Cancer Statistics in China,2015.CA CANCER J CLIN 2016，66:115-132]。我国肝癌患者约70％在发现时已是晚期[吴孟超.我国肝切除技术发展的现状与展望.中华外科杂志，2010.48(3)：161-162]，且受各种因素影响，仅20％左右能手术切除[汤钊猷，杨秉辉.原发性肝癌的研究与进展.上海，上海医科大学出版社，1990,1-19]。因此非手术的介入治疗(Interventional Treatment)成为肝癌治疗的重要手段[Lencioni R,Crocetti L,De Simone P,et al.Loco-regional interventional treatment of hepatocellular carcinoma:techniques,outcomes,and future prospects.Transpl Int,2010,23(7):698-703]。但经肝动脉栓塞化疗术，因癌肿旁边产残留活癌细胞，成为复发或转移的根源[戴益民，仇灿荣，陈汉，等.肝动脉内灌注化疗栓塞剂后的病理形态研究.中华医学杂志.1991,71:366]研究表明[Lewandowski RJ,Kulik LM,Riaz A,et al.A comparative analysis of transarterial downstaging for hepatocellular carcinoma:chemoembolization versus radioembolization.American journal of transplantation:official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2009；9(8):1920-8]，经动脉栓塞放疗与经动脉栓塞化疗治疗肝癌相比，肿瘤反应率明显提高(61％vs.37％)，无事件生存率(17.7月vs.7.1月)。因此经动脉放射性栓塞微球治疗恶性肿瘤是一种很有效的方法。
钇-90(90Y)和磷-32(32P)是核医学最常用的的两个治疗核素，都可以制备成放射性玻璃微球用于肿瘤治疗，钇-90(90Y)玻璃微球的比放射性活度高，但钇-90(90Y)半衰期较短(64h)，而磷-32(32P)玻璃微球的比放射性活度较低，但磷-32(32P)半衰期较长(约14d)，用于治疗肿瘤各有优缺点。
发明内容
本发明的目的在于提供一种工艺简单、核素吸附率高、释放率低的同时具备钇-90 (90Y)和磷-32(32P)的医用磷酸钇[90Y32PO4]碳微球及其制备方法。
为了达到上述目的，本发明采用了以下技术方案：
本发明是利用碳微球为一种载体，吸附放射性的90YCl3溶液和酒石酸溶液生成的放射性络合物(90Y-酒石酸)，再与放射性磷酸钠(Na3 32PO4)溶液反应在碳微球内生成放射性磷酸钇(Y32PO4)沉淀，从而将钇-90(90Y)和磷-32(32P)两种核素固化，后经进一步净化处理制备成医用磷酸钇(90Y32PO4)碳微球。本发明制备的医用磷酸钇(90Y32PO4)碳微球对钇-90(90Y)核素的吸附率高于95％，对磷-32(32P)核素的吸附效率高于99％，而钇-90(90Y)和磷-32(32P)两种核素的释放率都低于0.01％，因总比放射性活度更高，对肿瘤有效治疗时间更长，更适用于肿瘤放射治疗。
本发明碳微球吸附是物理吸附，由于磷-32(32P)核素是以Na3 32PO4化合物形式存在，不能被碳微球直接吸附，但32PO4 3-离子(包括非放射性放射性PO4 3-离子)与放射性90Y3+离子(包括非放射性Y3+离子)反应能生成难溶的磷酸钇[90Y32PO4](包括非放射性YPO4)沉淀，因此应事先将放射性90Y3+离子(包括非放射性Y3+离子)吸附在碳微球内，再在碳微球内生成磷酸钇[90Y32PO4]沉淀，同时在碳微球内固化钇-90和磷-32两核素，但是由于钇-90(90Y)核素是以90YCl3化合物形式存在，钇-90(90Y)是正三价态阳离子(90Y3+)，在溶液酸度高时，被碳微球吸附直接物理吸附的量少(<30mgY/g微球)，在溶液pH值大于1时，90Y3+离子容易水解生成沉淀，因此为了提高碳微球吸附钇-90(90Y)核素的量，达到在碳微球内生成更多的磷酸钇[90Y32PO4]沉淀，必须采取适当措施防止90Y3+离子水解，并提高碳微球吸附钇-90(90Y)核素的吸附容量。具体方法是选择一种络合剂与90Y3+离子生成一种稳定络合物，防止90Y3+离子水解并使该络合物被碳微球牢固吸附，再用Na3 32PO4溶液与被碳微球吸附的90Y3+离子反应生成难溶的磷酸钇[90Y32PO4]沉淀把钇-90和磷-32两种核素同时固化在碳微球内，再经进一步纯化可制备成医用磷酸钇[90Y32PO4]碳微球。此碳微球对钇-90和磷-32两核素的释放率都低于0.01％，满足治疗肿瘤的要求。经过筛选试验，本发明发现络合剂酒石酸可与90Y3+络合生成90Y3+-酒石酸络合物被碳微球吸附，而32PO4 3+可与90Y3+反应生成磷酸钇[90Y32PO4]沉淀，同时将钇-90和磷-32两种放射性核素固化在碳微球内，因而可制备磷酸钇[90Y32PO4]碳微球。具体制备方法如下：
一种医用磷酸钇[90Y32PO4]碳微球，主要是由碳微球和沉淀固化在碳微球内的放射性核素钇-90和磷-32构成。
进一步的，所述的医用磷酸钇碳微球是由以下方法制得：利用碳微球吸附90YCl3溶液和酒石酸溶液生成的90Y-酒石酸络合物，再与放射性磷酸钠Na3 32PO4溶液反应生成磷酸钇 [90Y32PO4]沉淀固化，后经进一步净化处理制备而成。
一种医用磷酸钇[90Y32PO4]碳微球的制备方法包括以下步骤：
(1)吸附90Y-酒石酸络合物的碳微球的制备：将碳微球与90Y-酒石酸络合物溶液充分混合，在40-50℃恒温下震荡40-60分钟，经固液分离除去反应液后用纯化水反复清洗，洗去未被吸附的90Y-酒石酸络合物，即得吸附了90Y-酒石酸络合物的碳微球；
(2)医用磷酸钇[90Y32PO4]碳微球的制备：用含有32P大于7.4GBq(200mCi)的放射性Na3 32PO4溶液浸泡已吸附90Y-酒石酸络合物的碳微球，并在40℃-50℃恒温下震荡混合物20-30分钟，生成90Y32PO4沉淀，同时固化钇-90核素和磷-32核素，并经固液分离除去反应液后用纯化水反复清洗，得医用磷酸钇[90Y32PO4]碳微球。
所述放射性Na3 32PO4溶液的制备方法为：将磷酸氢镁或磷酸铝密封于石英玻璃管中置于热中子通量高于5×1013n/cm2.s的核反应堆辐照，经31P(n,r)32P生成放射性的MgH32PO4或放射性的Al32PO4，32P的核纯度不低于99.9％，比放射性活度大于148G Bq(4Ci)/gP，用盐酸溶解，并用NaOH溶液沉淀Mg2+离子和Al3+离子，将MgH32PO4或Al32PO4转化制备成放射性Na3 32PO4，Na3 32PO4溶液的放射化学纯度不低于95％，每毫升Na3 32PO4溶液放射性活度浓度不低于14.8GBq(400mCi)/mL，使用时再根据使用要求稀释成所需浓度。
所述90Y-酒石酸络合物的制备方法为：将90YCl3溶液与酒石酸溶液按1:2-2.5摩尔比混合生成90Y-酒石酸络合物，其溶液的pH值为1.0-2.0。
所述90YCl3溶液是将Y2O3密封于石英玻璃管中置于热中子通量高于5×1013n/cm2.s的核反应堆辐照，经89Y(n,r)90Y反应生成90Y2O3，比放射性活度大于370G Bq(10Ci)/gY，用盐酸溶解，其90YCl3溶液的Y3+离子浓度为40mg/mL-60mg/mL，溶液的pH值低于1.0，90YCl3溶液的核纯度90Y不低于99.9％，放化化学纯度不低于95％，每毫升的放射性活度浓度不低于18.5GBq(500mCi)/mL，使用时再根据使用要求稀释成所需放射性浓度。
所述酒石酸溶液是将酒石酸用纯化水溶解配制而成，其浓度为0.1g/mL。
所述医用磷酸钇[90Y32PO4]碳微球的制备方法还包括碳微球的纯化处理，具体为：将碳微球用醋酸乙酯、丙酮或乙醇浸泡去脂，用氢氧化钠溶液浸泡去碱溶杂质，用纯化水反复清洗至弱碱性，再用硝酸浸泡去酸溶杂质，用纯化水清洗至pH值为1-2后备用。
所述碳微球是指用富含碳有机材料制备的微球经高温碳化，再经脱脂、碱洗、酸洗等去掉各种杂质，制备成对人体无毒害、生物相容性好的球形微粒。
所述碳微球的直径为20-30μm。
所述碳微球的直径为30-100μm。
所述碳微球的直径为大于100μm。
所述碳微球的直径为10-100nm。
所述碳微球的直径为100-150nm。
所述医用磷酸钇碳微球中碳微球对32P核素的吸附率高于99％，对90Y核素的吸附率高于95％。
所述医用磷酸钇[90Y32PO4]碳微球中90Y核素和32P核素释放率均低于0.01％。
一种用作体内肿瘤放射治疗的制剂，由所述医用磷酸钇碳微球制备得到。用作体内肿瘤放射治疗的制剂中的钇-90(90Y)的放射性活度为1.85GBq-14.8GBq(50mCi-400mCi)，磷-32(32P)的放射性活度为1.85GBq-7.4GBq(50mCi-200mCi)，碳微球粒径大小根据用途而定：粒径为20-30μm的医用磷酸钇[90Y32PO4]碳微球主要用于动脉灌注栓塞放疗肝癌，粒径为30μm-100μm的可用于肺癌、肾癌、舌癌、乳腺癌、子宫颈癌等富含血管的肿瘤，也可用于直接分散注射到其它肿瘤内；粒径100μm以上的可用于肿瘤的放射性植入治疗；粒径为100-150nm的医用磷酸钇[90Y32PO4]碳微球主要用于淋巴癌及其转移癌的治疗，粒径为10-100nm的医用磷酸钇[90Y32PO4]碳微球具有趋肿瘤的性质，可用于肿瘤靶向治疗。
所述的医用磷酸钇[90Y32PO4]碳微球在治疗患有医学病症的哺乳动物的药物中的用途，其中所述的医用磷酸钇[90Y32PO4]碳微球是用介入导管、注射器或体内植入给予的。
本发明的有益效果在于：
1.本发明的磷酸钇[90Y32PO4]碳微球是通过用碳微球吸附90Y-酒石酸络合物，再用Na3 32PO4溶液处理生成90Y32PO4沉淀固化，后经净化处理制备而成的，所制备的医用碳微球对钇-90(90Y)的吸附率高于95％，对磷-32(32P)核素的吸附效率高于99％，而对于钇-90(90Y)和磷-32(32P)两核素的释放率都低于0.01％，并且生物相容性好，本发明研制的医用磷酸钇[90Y32PO4]碳微球的总比放射性活度更高，延续有效治疗肿瘤的更长，因此更有利于治疗各种肿瘤。本发明的不同粒径的医用磷酸钇[90Y32PO4]碳微球可用于栓塞放疗肝癌等含血管丰富的肿瘤，或通过分散注射放射治疗其它肿瘤，或可用于淋巴癌治疗和淋巴转移癌治疗，含有某些趋肿瘤官能团的医用磷酸钇[90Y32PO4]碳微球也可用于其它肿瘤治疗。
2.方法简便，引入杂质少，产品纯度高。
3.钇-90(90Y)和磷-32(32P)利用率高，产生放射性废物少，有利于环境保护。
4.钇-90(90Y)和磷-32(32P)释放率低，安全性好。
5.[90Y32PO4]碳微球的放射性活度可根据个体需要及时调整，可随时满足个体化的精准治疗要求。
6.钇-90(90Y)和磷-32(32P)容易从多渠道获得，磷酸钇[90Y32PO4]碳微球的正常生产不受原材料供货影响，能满足常年的生产供货要求。
7.磷酸钇[90Y32PO4]碳微球的比放射性活度更高，对肿瘤有效延续治疗时间更长，更有利于对肿瘤的有效治疗。
8.医用磷酸钇[90Y32PO4]碳微球的生产成本低，便于推广应用。
具体实施方式
实施例
(1)碳微球纯化处理：用乙酸乙酯、丙酮或乙醇等有机溶剂浸泡去脂；用稀氢氧化钠溶液(0.1-0.5mol/L)浸泡去碱溶杂质，再反复清洗至弱碱性(PH值为8-10)；再用稀硝酸(0.1mol/L-0.5mol/L)浸泡去酸溶杂质，清洗至pH值为1-2。
(2)将市售优级纯30g磷酸氢镁(MgHPO4)或磷酸铝(AlPO4)密封于石英玻璃管中置于热中子通量高于5×1013n/cm2.s的核反应堆辐照，经31P(n,r)32P生成放射性的磷酸氢镁(MgH32PO4)或放射性的磷酸铝(Al32PO4)，32P的核纯度不低于99.9％，比放射性活度大于148G Bq(4Ci)/gP，用HCl溶液[该处盐酸溶液用36-38％的HCl溶液与水按1:1(mL/mL)的比例稀释而成]溶解，并用NaOH溶液沉淀Mg2+离子和Al3+离子，将MgH32PO4和Al32PO4转化制备成放射性Na3 32PO4，Na3 32PO4溶液的放射化学纯度不低于95％。每毫升Na3 32PO4溶液放射性活度浓度不低于14.8GBq(400mCi)/mL，使用时再根据使用要求稀释成所需浓度。
(3)将市售优级纯25g Y2O3密封于石英玻璃管中置于热中子通量高于5×1013n/cm2.s的核反应堆辐照，经89Y(n,r)90Y反应生成90Y2O3，比放射性活度大于370GBq(10Ci)/gY，90Y的核纯度不低于99.9％，再用300mL的HCl溶液[该处盐酸溶液用36-38％的HCl溶液与水按1:1(mL/mL)的比例稀释而成]加微热溶解，冷却至室温后移至500mL容量瓶并用蒸馏水稀释至刻度，制备成90YCl3溶液，90YCl3溶液的放射化学纯度不低于95％。90YCl3溶液的放射性活度浓度不低于18.5GBq(500mCi)/mL(Y3+离子浓度为40mg/mL-60mg/mL)，使用时再根据使用要求稀释成所需放射性浓度。
(4)将分析纯酒石酸用纯化水溶解配成酒石酸溶液，其浓度为0.1g/mL，用于制备Y-酒石酸络合物。
(5)将上述步骤(3)所述制备的90YCl3溶液与步骤(4)制备的酒石酸溶液按1:2-2.5摩尔比混合生成90Y-酒石酸络合物，其溶液的pH值1.0-2.0。
(6)将1-3g碳微球与5-10mL90Y-酒石酸络合物溶液(Y含量大于100mg)充分混 合，在40-50℃恒温下震荡40-60分钟，经固液分离(离心或过滤)除去反应液后用纯化水5mL反复清洗，洗去未被吸附的90Y-酒石酸络合物，即得吸附了90Y-酒石酸络合物的碳微球，碳微球吸附钇(Y)含量大于95mg，可用于制备磷酸钇[90Y32PO4]碳微球。
(7)用步骤(2)制备的5-10mL含有32P大于7.4GBq(200mCi)(含总磷量50-60mg)的Na3 32PO4溶液浸泡按步骤(6)制备的1-3g已吸附90Y-酒石酸络合物后的碳微球，并在40℃-50℃恒温下震荡混合物20-30分钟，生成90Y32PO4沉淀，同时固化以-90(90Y)和磷-32(32P)两个核素，并经固液分离(离心或过滤)除去反应液后用纯化水5mL反复清洗，得医用磷酸钇[90Y32PO4]碳微球。
本实施例制备的磷酸钇[90Y32PO4]碳微球对钇-90(90Y)吸附率高于95％，对磷-32(32P)的吸附率高于99％，而对钇-90(90Y)和磷-32(32P)两核素的释放率都低于0.01％，生物相容性好，可用于肿瘤放射治疗。

Claims (20)

  1. 一种医用磷酸钇碳微球，其特征在于：该医用磷酸钇碳微球主要是由碳微球和沉淀固化在碳微球内的放射性核素钇-90和磷-32构成。
  2. 根据权利要求1所述的医用磷酸钇碳微球，其特征在于：所述的医用磷酸钇[90Y32PO4]碳微球是由以下方法制得：利用碳微球吸附90YCl3溶液和酒石酸溶液生成的90Y-酒石酸络合物，再与放射性磷酸钠Na3 32PO4溶液反应生成磷酸钇[90Y32PO4]沉淀固化，后经进一步净化处理制备而成。
  3. 一种医用磷酸钇碳微球的制备方法，其特征在于：该制备方法包括以下步骤：
    (1)吸附90Y-酒石酸络合物的碳微球的制备：将碳微球与90Y-酒石酸络合物溶液充分混合，在40-50℃恒温下震荡40-60分钟，经固液分离除去反应液后用纯化水反复清洗，洗去未被吸附的90Y-酒石酸络合物，即得吸附了90Y-酒石酸络合物的碳微球；
    (2)医用磷酸钇[90Y32PO4]碳微球的制备：用含有32P大于7.4GBq(200mCi)的放射性Na3 32PO4溶液浸泡已吸附90Y-酒石酸络合物的碳微球，并在40℃-50℃恒温下震荡混合物20-30分钟，生成90Y32PO4沉淀，同时固化钇-90核素和磷-32核素，并经固液分离除去反应液后用纯化水反复清洗，得医用磷酸钇[90Y32PO4]碳微球。
  4. 根据权利要求2或3所述的医用磷酸钇碳微球，其特征在于：所述放射性Na3 32PO4溶液的制备方法为：
    将磷酸氢镁或磷酸铝密封于石英玻璃管中置于热中子通量高于5×1013n/cm2.s的核反应堆辐照，经31P(n,r)32P生成放射性的MgH32PO4或放射性的Al32PO4，32P的核纯度不低于99.9％，比放射性活度大于148G Bq(4Ci)/gP，用盐酸溶解，并用NaOH溶液沉淀Mg2+离子和Al3+离子，将MgH32PO4或Al32PO4转化制备成放射性Na3 32PO4，Na3 32PO4溶液的放射化学纯度不低于95％，每毫升Na3 32PO4溶液放射性活度浓度不低于14.8GBq(400mCi)/mL，使用时再根据使用要求稀释成所需浓度。
  5. 根据权利要求2或3所述的医用磷酸钇碳微球，其特征在于：所述90Y-酒石酸络合物的制备方法为：将90YCl3溶液与酒石酸溶液按1:2-2.5摩尔比混合生成90Y-酒石酸络合物，其溶液的pH值为1.0-2.0。
  6. 根据权利要求5所述的医用磷酸钇碳微球，其特征在于：所述90YCl3溶液是将Y2O3密封于石英玻璃管中置于热中子通量高于5×1013n/cm2.s的核反应堆辐照，经89Y(n,r)90Y反应生成90Y2O3，比放射性活度大于370G Bq(10Ci)/gY，用盐酸溶解，其90YCl3溶液的Y3+离子浓度为40mg/mL-60mg/mL，溶液的pH值低于1.0，90YCl3溶液的核纯度90Y不低于99.9％，放射化学纯度不低于95％，每毫升的放射性活度浓度不低于18.5GBq(500mCi)/mL，使用时 再根据使用要求稀释成所需放射性浓度。
  7. 根据权利要求5所述的医用磷酸钇碳微球，其特征在于：所述酒石酸溶液是将酒石酸用纯化水溶解配制而成，其浓度为0.1g/mL。
  8. 根据权利要求1-7任意一项所述的医用磷酸钇碳微球，其特征在于：所述医用磷酸钇[90Y32PO4]碳微球的制备方法还包括碳微球的纯化处理，具体为：将碳微球用醋酸乙酯、丙酮或乙醇浸泡去脂，用氢氧化钠溶液浸泡去碱溶杂质，用纯化水反复清洗至弱碱性，再用硝酸浸泡去酸溶杂质，用纯化水清洗至pH值为1-2后备用。
  9. 根据权利要求1-7任意一项所述的医用磷酸钇碳微球，其特征在于：所述碳微球是指用富含碳有机材料制备的微球经高温碳化，再经脱脂、碱洗、酸洗等去掉各种杂质，制备成对人体无毒害、生物相容性好的球形微粒。
  10. 根据权利要求1-7任意一项所述的医用磷酸钇碳微球，其特征在于：其特征在于：所述碳微球的直径为20-30μm。
  11. 根据权利要求1-7任意一项所述的医用磷酸钇碳微球，其特征在于：其特征在于：所述碳微球的直径为30-100μm。
  12. 根据权利要求1-7任意一项所述的医用磷酸钇碳微球，其特征在于：其特征在于：所述碳微球的直径大于100μm。
  13. 根据权利要求1-7任意一项所述的医用磷酸钇碳微球，其特征在于：所述碳微球的直径为10-100nm。
  14. 根据权利要求1-7任意一项所述的医用磷酸钇碳微球，其特征在于：所述碳微球的直径为100-150nm。
  15. 根据权利要求1-7任意一项所述的医用磷酸钇碳微球，其特征在于：所述医用磷酸钇碳微球中碳微球对32P核素的吸附率高于99％，对90Y核素的吸附率高于95％。
  16. 根据权利要求1-7任意一项所述的医用磷酸钇碳微球，其特征在于：所述医用磷酸钇碳微球中90Y核素和32P核素释放率均低于0.01％。
  17. 一种用作体内肿瘤放射治疗的制剂，由权利要求1-7任意一项所述医用磷酸钇碳微球制备得到。
  18. 根据权利要求17所述的用作体内肿瘤放射治疗的制剂，其特征在于：用作体内肿瘤放射治疗的制剂中的钇-90的放射性活度为1.85GBq-14.8GBq(50mCi-400mCi)，磷-32的放射性活度为1.85GBq-7.4GBq(50mCi-200mCi)，碳微球粒径大小根据用途而定。
  19. 权利要求1-7任意一项所述的医用磷酸钇碳微球在治疗患有医学病症的哺乳动物的药物 中的用途。
  20. 权利要求19的用途，其中所述的医用磷酸钇碳微球是用介入导管、注射器或体内植入给予的。
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