WO2004098620A1 - Solution d'infusion de charbon actif, procede de preparation associe et son utilisation pour preparer un medicament de traitement du cancer - Google Patents

Solution d'infusion de charbon actif, procede de preparation associe et son utilisation pour preparer un medicament de traitement du cancer Download PDF

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WO2004098620A1
WO2004098620A1 PCT/CN2004/000045 CN2004000045W WO2004098620A1 WO 2004098620 A1 WO2004098620 A1 WO 2004098620A1 CN 2004000045 W CN2004000045 W CN 2004000045W WO 2004098620 A1 WO2004098620 A1 WO 2004098620A1
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Prior art keywords
activated carbon
particles
drug
activated
adsorption
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PCT/CN2004/000045
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English (en)
French (fr)
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WO2004098620A8 (fr
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Xiaochuan Chen
Pulin Wang
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Xiaochuan Chen
Pulin Wang
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Application filed by Xiaochuan Chen, Pulin Wang filed Critical Xiaochuan Chen
Priority to JP2006504190A priority Critical patent/JP2006525238A/ja
Priority to AU2004236381A priority patent/AU2004236381A1/en
Priority to EP04701884A priority patent/EP1652528A1/en
Priority to US10/507,570 priority patent/US20050123613A1/en
Priority to CA002524924A priority patent/CA2524924A1/en
Publication of WO2004098620A1 publication Critical patent/WO2004098620A1/zh
Publication of WO2004098620A8 publication Critical patent/WO2004098620A8/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/44—Elemental carbon, e.g. charcoal, carbon black
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock

Definitions

  • the present invention relates to an activated carbon infusion agent, a preparation method thereof, and an application thereof in preparing a medicine for treating cancer. More specifically, the present invention relates to an activated carbon preparation for intravenous infusion, a preparation method thereof, and an application thereof in preparing a medicine for treating cancer.
  • BACKGROUND ART Activated carbon has been used in the medical field for nearly 100 years.
  • Activated carbon is usually used in the purification steps of the preparation process of Chinese and western medicine injections, as described in the following comparative documents: CN1377689, CN1287838, CN1068958> CN 1062083, the activated carbon mentioned in these comparative documents is absorbed after absorbing impurities or residues in the pharmaceutical It is filtered out, and activated carbon is not included in the injection preparation.
  • activated carbon preparations can be used to treat various diseases, for example, oral activated carbon preparations can be used to treat gastric diseases: activated carbon preparations can be used to adsorb toxins into the stomach and intestines, such as sleeping pills poisoning, anti-drunk, etc .; Urine adsorbent; When skin infection is inflamed, externally apply activated carbon to abscess to absorb toxins and odors; EP620006 discloses oral activated carbon preparations for the treatment of diabetes; JP11029485 discloses oral activated carbon preparations for the treatment of obesity, and US4152412 discloses the use of 0.5 micron Activated carbon adsorbs immune vaccines, antigens and toxoids for animal use.
  • SU1465052 discloses that the activated carbon is mixed with an agent that prevents and treats animal tapeworms into an oil suspension. Enhance the therapeutic effect and extend the anti-insect effect to more than three months;
  • WO9108776 discloses the injection of inactive or slightly active carbon particles containing 1-6.8 ⁇ m in tumors, which can mark tumors before chemotherapy and surgery, and also Can be treated with laser or electromagnetic heating It absorbs energy and injects it near tumor tissues, allowing the drug to be slowly released to exert a therapeutic effect.
  • the carbon particles still play a slow-release role in tissues other than blood vessels and blood, which is an extension of the principle of external application.
  • activated carbon particles of the present invention This is directly related to the activated carbon particles of the present invention.
  • the inventors have proved through long-term research that activated carbon particles with a large specific surface area and a particle size mainly distributed in the 6 ⁇ m-2 nm are added to a traditional intravenous infusion liquid, and then input into human blood or into the abdominal cavity and chest cavity.
  • a variety of cancers, vascular atherosclerosis, coronary heart disease, cerebral thrombosis, infectious diseases, azotemia, acute organic and inorganic poisoning, etc. have extraordinary therapeutic effects.
  • the results of animal experiments also show that some tiny insoluble substances (rigid particles for short) such as agarose particles, dextran particles, cellulose particles, and even water-insoluble materials such as diatomite particles, zeolite particles, and bentonite particles, and their particles
  • the size within the range of 6 ⁇ m-2nm has inhibitory effect on tumors and drug loading effect, but its safety and treatment effect are obviously inferior to activated carbon.
  • SUMMARY OF THE INVENTION The object of the present invention is to provide an activated carbon infusion agent, which is an activated carbon preparation for intravenous infusion.
  • the activated carbon infusion agent of the present invention comprises a pure activated carbon microinjection for intravenous infusion, an activated activated carbon microinjection, an activated carbon injection with a catalyst adsorbed, and a drug-loaded activated carbon injection.
  • the drug-loaded activated carbon injection includes an anticancer drug injection and an adsorption anticoagulant.
  • cholesterol-lowering drug injections, adsorption antibiotic drug injections, and adsorption antiviral drug injections which are characterized by the use of raw material activated carbon that meets the following quality requirements: surface area 400-10000M 2 / g or higher, heavy metals containing Amount ⁇ 0. L-10ppm, other soluble metal ions O.
  • the activated carbon The particle size of the activated carbon particles contained in the infusion solution is 35Mm-2nm, the main particle size distribution range is 6wn-2nm, of which 3wn-2nm accounts for 99%, 6wn -3wn particles do not exceed 1%, and the maximum diameter of 35Mm -6Mm activated carbon particles does not exceed 2 X 10 4 / mg activated carbon fine powder.
  • the activated carbon microparticles have excellent compatibility with tissues after being transfused into the blood, have no toxic and side effects, have no adverse irritation, and have no immunogenicity, and are within the dosage range (i.e. effective treatment of a single blood transfusion)
  • the dosage is 0.1-5mg / kg body weight, input 1-7 times a week, the average total cumulative adult storage volume is less than 10g), within the range of formulation quality standards, no embolism of important organs will occur. Master the treatment amount and total storage amount, and you can enter it repeatedly and repeatedly. No poisoning and damage to important organs are found. It is confirmed by animal anatomy that the activated carbon particles are intravenously injected into the heart, liver, kidney, spleen, lung, Bone marrow and brain do not cause pathological damage.
  • the raw material activated carbon is pulverized into 120 mesh coarse particles by a mechanical method
  • the activated carbon coarse particles are adsorbed with an activator to activate the activated carbon, the concentration of the activator is 0.01-10%, and the activator is heated to 70-19 ° C in a high-pressure container, and the reaction time is 5-20 minutes to generate an oxidized form. Or reduced activated carbon; cooling and decompressing to remove residual gas, and then passing in 60-10CTC water vapor and ammonia gas under pressure to generate activated carbon containing carbon-hydroxyl, carbon-imino or carbon-hydrogen;
  • the activated carbon fine particles are impregnated with the adsorbed bio-directing agent, and then dried for a short period of time and quickly at a low temperature.
  • the activator is divided into an oxidizing agent and a reducing agent.
  • the oxidizing agent is selected from the group consisting of epoxy ethers, acid chlorides, acid anhydrides, and aldehydes.
  • the reducing agent is selected from LiAIH 4 and NaBH 4 .
  • the relevant drugs selected in step (3) include: 1 traditional anticancer drugs such as 5-FU, CTX, MTX, Ara-C / A, 6-MP, anticancer antibiotics, cis / carboplatin, and arsenic , Paclitaxel, etc. 2 Immune activation and regulation of cytokines such as IL-2, 4, 6, GM, G-CSF, ⁇ -IFN, TNF, FCF-B, VECF, 4-IBB / 4-IBBL, B7- 1 B7-2, toad protein, specific half antibodies, etc.
  • 1 traditional anticancer drugs such as 5-FU, CTX, MTX, Ara-C / A, 6-MP, anticancer antibiotics, cis / carboplatin, and arsenic , Paclitaxel, etc. 2 Immune activation and regulation of cytokines such as IL-2, 4, 6, GM, G-CSF, ⁇ -IFN, TNF, FCF-B, VECF, 4-IBB
  • Catalysts such as main metal organic compounds benzyl / butyl lithium, etc., transition metal copper ammonia agents, platinum, palladium agents, selenium, germanium compounds, etc., these combinations
  • the substance has dual functions of catalysis and tumor killing; 4 adsorption of biological enzymes such as oxidoreductases, aminotransferases, hydrolases, isomerases, etc.
  • the bio-directing agent includes iron porphyrin, or thymine, guanine, uracil, thymine, guanine and derivatives thereof, such as 5-fluorouracil, hydrogen deuterium thymus Pyrimidine, methotrexate, and tumor cell adhesion factors (such as VCAM-1) and tumor cell growth factors (such as VEGF).
  • iron porphyrin or thymine, guanine, uracil, thymine, guanine and derivatives thereof, such as 5-fluorouracil, hydrogen deuterium thymus Pyrimidine, methotrexate, and tumor cell adhesion factors (such as VCAM-1) and tumor cell growth factors (such as VEGF).
  • Selecting different drugs and bio-directors in steps (3) and (4) can prepare a variety of different drug-loaded activated carbon preparations, such as adsorption anti-cancer drug injections, adsorption anticoagulation, cholesterol-lowering drug injections, adsorption antibiotic drug injections, Adsorb antiviral injections.
  • the invention also provides the application of the activated carbon infusion agent in the preparation of a medicine for treating cancer, which is characterized in that the effective therapeutic dose for a single blood input is 0.1-5 mg / kg body weight, and 1 to 7 times per week, and the average cumulative total adult accumulation The amount is 10 g or less.
  • nano-micron activated carbon with a diameter in a small range of dogs has a very significant effect of alleviating cancer pain, inhibiting tumor growth, or killing tumor cells.
  • Injecting the activated carbon particles into the blood through the vein can be used to treat many Cancer, and can treat vascular atherosclerosis, coronary heart disease, cerebral thrombosis; the activated carbon particles also have immune-factor-like functions, such as lgG ⁇ A ⁇ M, DC small peptide molecules, and immunoglobulin superfamily molecules This kind of function can be used for the treatment of various refractory, microbial and viral infections.
  • the activated carbon particles have the function of promoting the repair of body tissues after being infused into the blood through the veins, have peculiar curative effects on chronic non-healing wounds, osteomyelitis, and other diseases, and can treat acute organic and inorganic poisoning.
  • the pure activated carbon micropowder particles having anti-cancer effects, they also have the functions of adsorption, immunomodulation, chemical catalysis, and drug carrier.
  • the pure activated carbon micropowder particles are further subjected to chemical activation treatment, drug loading treatment, and adsorption bio-director treatment. The action will be strengthened in the normal phase, so as to obtain an extraordinary therapeutic effect, which is the mechanism of the application of the activated carbon infusion agent of the present invention in the preparation of a drug for treating cancer. This will be explained in more detail below:
  • the activated carbon particles subjected to the activation treatment are further subjected to drug loading treatment and adsorption bio-director treatment:
  • the combination of activated carbon particles with bio-oriented material is an effective method to further improve the efficacy of activated carbon particle infusion.
  • the guiding material selection principle is: to take advantage of the characteristics of strong growth of cancer cells, select the cancer cell growth requirement intake than normal cell intake. Many materials are used as guiding materials, that is, cancer-prone materials are used as guiding materials.
  • Such materials must be non-immunogenic materials, such as selecting the base-pair materials (thymine, guanine, Uracil, thymine, guanine and its derivatives), cancer cell growth and metabolism intake hundreds of times more than normal cells (such as hematoporphyrin iron), or select tumor affinity substances, For example, tumor cell adhesion factors (such as VCAM-1) and tumor cell growth factors (such as VEGF) are used as guiding materials. These substances have the role of promoting tumor growth.
  • a very interesting phenomenon is that tumor cells like to capture such activated carbon particles, and swallow these activated carbon particles until they die or stop growing, while normal tissue cells almost ignore or rarely ask for such activated carbon particles.
  • Tumor affinity-oriented activated carbon particles are automatically concentrated around cancer cells, and the concentration of activated carbon particles in cancer tissues is hundreds of times or even tens of thousands times that of other normal tissues.
  • This creative guidance material is combined with activated carbon. It breaks through the principle of selecting bio-oriented materials, and solves the problem of the poor selectivity of tumor chemotherapeutics for a long time and the problem of resistance to guidance materials.
  • Viral affinity-viral interfering agent combination such as thymine bases for DNA viruses and uracil bases and interferons, IL-1, RNA viruses, etc.
  • This kind of bio-oriented activated carbon fine powder can absorb a variety of anti-cancer drugs with its huge specific surface area.
  • the drugs contained can choose different anti-cancer drugs
  • anti-cancer drugs such as chemotherapeutic drugs, radionuclides, immunomodulatory cytokines and palladium, platinum, copper, germanium, selenium, cobalt and other coordination catalytic metal substances, these drugs are directed to tumor cells, inside tumor microvessels and tumor cells
  • the drug can be concentrated to hundreds of times, or even tens of thousands of times of conventional treatment methods, which enhances the anti-tumor efficacy and reduces the toxic and side effects of chemotherapy drugs.
  • the dosage of chemotherapy and radiotherapy drugs mounted on activated carbon is generally 5-20% of the traditional treatment amount, which can achieve or exceed the effect of traditional treatment schemes, and minimize the damage of anti-cancer drugs to the normal cells and immune system of the body.
  • Rat toxicity test 12 rats, 135g ⁇ 10g, male and female, tail vein injection, observe the 28-day group dose mg / Kg number of animals (only) deaths (only) LDso confidence limit accumulation amount mg / Kg
  • A, B, and C correspond to the three groups of high, middle, and low in the acute poisoning experiment, but the number of injections is more than the acute poisoning experiment, and the observation days are also more.
  • Pathological anatomy results Two female and male animals were randomly sampled for pathological anatomy, and the results were as follows: Number of animals (only) Heart, liver, lung, spleen, kidney, brain, spinal cord, muscle, ribs, anterior ridge, intestinal lymph nodes
  • a male rat had small pieces of congestion on the lung surface, but no hemorrhagic pathological changes were seen in the lung entities, and the rest was normal:
  • the above animal experimental data is observational data during our research, and acute toxicology experiments were not strictly performed in accordance with the Pharmacopoeia or Chronic toxicology experiments are required to be performed.
  • the doses to rats are greater than the standard experimental requirements.
  • the feeding and observation time is longer than the standard requirements, and the number of rats is less than the standard requirements.
  • the main particle size distribution range is 6wn-2 nm Among them, 3Mm-2nm accounts for 99%, 6Mm-3Mm particles do not exceed 1%, and the maximum diameter of 35Wn-6mi activated carbon particles does not exceed 2x10 4 particles / mg activated carbon fine powder; the above activated carbon fine powder is used as a solute, and dimethyl sulfoxide (DMSO ) As a suspension solvent, 5000ml of 1% activated carbon suspension was prepared, and it was divided into 1ml or 2ml infusion injections under strong magnetic stirring.
  • DMSO dimethyl sulfoxide
  • hydroxylated activated carbon is prepared, 90 ° C water vapor is passed in for 2 hours, and then degassed under reduced pressure to generate hydroxylated activated carbon: If imidated activated carbon, 90'C'C pure ammonia vapor is passed in for 2 hours to generate Imidated activated carbon; if hydroxyl and amino activated carbon is prepared, pass through 90'C 10-40% ammonia-water vapor to generate activated carbon containing both hydroxyl and amino groups;
  • carbon-hydrogen activated carbon 100 g of activated carbon with a specific surface area of 6800 M 2 / g is taken, mechanically pulverized into a fine powder of 120 mesh, and LiALH 4 dissolved in ether is added to prepare 300 ml of a 1% solution, stirred and adsorbed for 2 hours, and centrifuged.
  • drugs can be selected for adsorption, for example, 6g of cisplatin, 0.4g of 5-FU, or 0.8g of cisplatin, 6-MP 0.8g dissolved in 100ml water, 10g added 120 mesh activated carbon or activated hydroxy-amino activated carbon, fully absorbed under stirring; high-speed centrifugation to take the precipitate, acetone dehydration, centrifugation to take the precipitate, and dry; then impregnate the precipitate with a 0.1% chitosan aqueous solution for 5 minutes, dehydrate with acetone, and dry; Use an air grinder to control the particle size to 35wn-2nm, and the main particle size distribution range is 6Mm-2nm, of which 3wn-2nm accounts for 99%, 6Mm-3 m The granules do not exceed 1%, the maximum diameter of 35Mm-6Mm activated carbon particles does not exceed 2x10 4 particles
  • the adsorption values determined by some drugs are as follows: Specific surface area 6800M 2 activated carbon / hydroxyl, amino carbon, and the measured value of its adsorption amount (active carbon adsorption value mg / hydroxyl, amino carbon adsorption value mg) is: uracil 33/51, thymidine 213 / 260, guanine 331/378, 5-chlorouracil 75/102, 5-fluorouracil 20/49, thymine 5/17, thymosin 90 (127, 6-MP220 / 304, cisplatin 995/1105, porphyrin Iron 283/311, CTX98 / 136, chloroform 10/4.
  • Adsorption anticoagulant and cholesterol-lowering drug injections For example, take 100mg of r-tPA or 80mg of cholesterol acetyltransferase or 220mg of niacin, and add 1g of hydroxy activated carbon particles with a particle size of 0.5pm or less by air pulverizer, and carry out a sufficient aqueous phase.
  • Adsorption high-speed centrifugation to take the precipitate, acetone dehydration, dry it, and then immerse it with 0.1% chitosan aqueous solution for 5 minutes, high-speed centrifugation to take the precipitate, dehydrate with acetone, dry, and divide into 10mg / bottle infusion injection for treatment Cardiac and cerebral embolism thrombolytic therapy and treatment of vascular sclerosis, hypertension, etc.
  • Adsorption of antibiotic drug injections For example, take 500mg of isoniazid or 200mg of rifampicin, and use an air grinder to pulverize 1 g of hydroxyl and amino activated carbon particles with a particle size of 0.7 ⁇ m or less, adsorb the water phase for 20 minutes, and centrifuge to obtain the precipitate by high speed Dehydrate and dry; then immerse in a 0.1% chitosan aqueous solution for 5 minutes, centrifuge the precipitate at high speed, dehydrate with acetone, dry, and divide into 20mg / bottle infusion injections for the treatment of refractory bone tuberculosis, miliary tuberculosis, etc. .
  • Adsorption of antiviral drug injection For example, take IFN-Y100mg and add it to an air grinder to pulverize 1g of hydroxy-amino activated carbon particles with a particle size of 0.3 M m or less for sufficient aqueous phase adsorption; take the precipitate by high-speed centrifugation, and perform acetone on the precipitate Dehydrate, dry at low temperature; immerse in serine, specific virus half-antibody director for 5 minutes, centrifuge the pellet at high speed, dehydrate with acetone, dry at low temperature, dispense into 10mg / bottle or 20mg / bottle infusion injection; It can also be used for the treatment of various intractable diseases of viral infections, such as EB virus Gumbali syndrome, viral brain, etc.

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Description

活性炭输液剂、 其制备方法及其在制备治疗癌症药中的应用
技术领域 本发明涉及活性炭输液剂、其制备方法及其在制备治疗癌症药中的应用。更确切地说， 本发明涉及供静脉输液用的活性炭制剂、 其制备方法及其在制备治疗癌症药物中的应用。 背景技术 在医学领域应用活性炭已有近百年历史。 通常将活性炭用于中、 西药针剂制备过程的 纯化步骤， 如下列对比文件所述： CN1377689、 CN1287838, CN1068958 > CN 1062083, 这些对比文件中提及的活性炭在吸收药剂中杂质或残留物后均被滤除， 在针剂制成品中并 不包含活性炭。 医学研究表明， 用活性炭制剂可治疗各种疾病， 例如， 口服活性炭制剂治 疗胃部疾病： 用活性炭制剂吸附进入肠胃的毒素如安眠药中毒、 防酒醉等； 运动员兴奋剂 检査时， 用活性炭作尿液吸附剂； 在皮肤感染发炎时， 用活性炭外敷于脓疮处吸附毒素和 臭味； EP620006公开了口服活性炭制剂治疗糖尿病； JP11029485公开了口服活性炭制 剂治疗肥胖症， US4152412公开了用 0.5微米的活性炭吸附供动物使用的免疫疫苗、抗原 和类毒素， 注射后免疫疫苗效果改善， 药剂被缓慢释放； SU1465052 公开了将活性炭与 预防、 治疗动物蛔虫的药剂混合成油混悬液形式皮下注射， 可以增强治疗效果并将抗虫药 效延长到三个月以上; WO9108776公开了在肿瘤内注射含有 1-6.8 μ m的非活性或略有活 性的炭微粒， 可在化疗和手术前标记肿瘤， 也可在激光或电磁波加热等治疗中吸收能量， 在肿瘤组织附近注射， 让药物缓慢释放以发挥治疗作用， 该炭微粒仍是在血管、 血液以外 的组织中起缓释作用， 是外用原理的延伸， 这与本发明将活性炭微粒直接输入血液， 在应 用途径及治疗机理方面有本质差别。 本发明人经长期研究证明， 将具有大比表面积， 粒径 主要分布在 6 μ m -2nm的活性炭微粒加入传统的静脉输液液体中，再输入人体血液中或输 入到腹腔、 胸腔中， 对多种癌症、 血管动脉粥样硬化、 冠心病、 脑血栓、 感染性疾病、 氮 质血症、急性有机和无机毒物中毒等均有超乎寻常的治疗效果。大量的动物试验结東表明， 该活性炭微粒输入血液后， 与组织相容性极好， 无毒副作用， 无不良刺激性， 无免疫原性， 且安全有效， 不会发生器官栓塞及产生病理性损害。
动物实验结果还表明， 一些微小不溶性物质 （简称刚性粒子） 如琼脂糖颗粒、 葡聚糖 颗粒、 纤维素类颗粒， 甚至于硅藻土颗粒、 沸石颗粒、 膨润土颗粒等非水溶性物质、 其粒 子大小在 6 u m-2nm范围以内对肿瘤都有抑制作用及载药作用， 只是其安全性及治疗效果 明显比活性炭差。 发明内容 本发明目的是提供一种活性炭输液剂， 它是供静脉输液用的活性炭制剂。
本发明另一个目的是提供该活性炭输液剂的制各方法， 该方法工艺独特， 操作简便。 本发明还有一个目的是提供该活性炭输液剂在制备治疗癌症药物中的应用。
本发明的活性炭输液剂， 包括供静脉输液用的纯活性炭微粒针剂、 活化活性炭微粒针 剂、 吸附有催化剂的活性炭针剂以及载药活性炭针剂， 该载药活性炭针剂包括吸附抗癌药 物针剂、 吸附抗凝和降胆固醇药物针剂、 吸附抗生素药物针剂、 吸附抗病毒药物针剂， 其 特征在于所用原料活性炭符合如下质量要求： 表面积 400-10000M2/g或更高， 重金属含 量≤0. l-10ppm,其它可溶性金属离子 O. l-10ppm,灰份 <2%,总孔容积 >0. 3- 6cm7g， 0. 15% 亚甲兰吸附值〉6-30，该活性炭输液剂中所含活性炭微粒粒径为 35Mm-2nm,主要粒度分布 范围为 6wn-2nm，其中 3wn-2nm占 99%， 6wn -3wn颗粒不超过 1 %，最大直径 35Mm -6Mm 活性炭微粒不超过 2 X 104个 /mg活性炭微粉。
经大量的动物试验证明， 该活性炭微粒输入血液后， 与组织相容性极好， 无毒副作用， 无不良刺激性， 无免疫原性， 在使用剂量范围以内 （即单次输入血液的有效治疗剂量为 0.1-5mg/kg体重， 每周输入 1-7次， 成人平均累计总储积量为 10g以下）， 在制剂质标准 范围以内， 不会发生重要器官的栓塞。 掌握好治疗量、 总储积量， 可以多次、 反复静脉输 入， 未发现有中毒及重要脏器损伤； 经动物解剖证实， 静脉输入这种活性炭微粒， 对心、 肝、 肾、 脾、 肺、 骨髓、 大脑不会产生病理性损害。
本发明活性炭输液剂的制备方法， 其特征在于该方法包括如下步骤：
( 1 ) 用机械方法将原料活性炭粉碎成 120目的粗颗粒；
(2) 使该活性炭粗颗粒吸附活化剂以使活性炭活化， 所述活化剂浓度为 0.01-10%， 在高压容器中加热到 70-19(TC， 反应时间为 5-20分钟， 生成氧化型或还原型活性炭； 冷 却减压， 排除残余气体， 再在压力下分别通入 60-10CTC水蒸气、 氨气， 生成含有炭-羟基、 炭-亚氨基或炭-氢的活性炭；
(3) 进行活性炭载药处理， 选择相关药物用经活化的活性炭或未经活化的纯洁性炭 进行液相饱和吸附， 然后低温干燥， 用空气粉碎机粉碎成所要粒径的活性炭微粒；
(4) 使该活性炭微粒浸渍吸附生物导向剂， 然后进行短时间、 快速低温干燥。
在步骤 （2) 中， 所述的活化剂分为氧化剂和还原剂， 氧化剂选自环氧醚类、 酰氯类、 酸酐类、 醛类氧化剂， 还原剂选自 LiAIH4、 NaBH4。
在步骤（3)中选择的相关药物包括：①传统的抗癌药物如 5-FU、CTX、MTX、Ara-C/A、 6-MP、 抗癌抗生素类、 顺 /卡铂、 砷剂类、 紫杉醇等； ②免疫激活、 调节类细胞因子类如 IL-2、 4、 6、 GM、 G-CSF、 γ-IFN, TNF、 FCF-B、 VECF、 4-IBB/4-IBBL、 B7-1 B7-2、 蟾毒蛋白、 特异性半抗体等； ③催化剂类如主金属有机化合物苄基 /丁基锂等， 过渡金属铜 氨剂、 铂、 钯剂、 硒、 锗化合物等， 这些结合物具有催化和杀肿瘤双重功能； ④吸附生物 酶类如氧化还原酶类、 转氨酶类、 水解酶类、 异构酶类等。
在步骤（4) 中， 所述的生物导向剂包括卟啉铁， 或胸腺嘧啶、 鸟嘧啶、 尿嘧啶、 胸腺 嘌呤、 鸟嘌呤及其衍生物一大类物质， 如 5-氟尿嘧啶、 氢氘胸腺嘧啶、 甲氨喋呤以及肿瘤 细胞粘附因子 （如 VCAM-1 )、 肿瘤细胞生长因子 （如 VEGF) 等。
在步骤 （3)和 （4) 中选择不同的药物和生物导向剂可制备各种不同的载药活性炭制 剂， 例如吸附抗癌药物针剂， 吸附抗凝、 降胆固醇药物针剂， 吸附抗生素药物针剂， 吸附 抗病毒药物针剂。
本发明还提供了该活性炭输液剂在制备治疗癌症药物中的应用， 其特征在于单次输入 血液的有效治疗剂量为 0.1-5mg/kg体重，每周输入 1-7次， 成人平均累计总储积量为 10g 以下。
经长期的研究表明，直径在一定犬小范围内的纳米-微米活性炭具有非常明显的缓解癌 症疼痛、 抑制肿瘤生长或杀死肿瘤细胞的作用， 将该活性炭微粒通过静脉输入血液可用于 治疗多种癌症， 并能治疗血管动脉粥样硬化、 冠心病、 脑血栓； 该活性炭微粒输入血液后 还具有类似免疫因子样的功能， 如 lgG\A\M、 DC小肽分子、 免疫球蛋白超家族分子样功 能， 可用于各种难治型、 微生物及病毒感染的治疗。 还发现该活性炭微粒通过静脉输入血 液后具有促进机体组织修复的功能， 对慢性不愈合性伤口、 骨髄炎等疾病有奇特疗效， 并 能治疗急性有机、 无机毒物中毒。 基于纯活性炭微粉颗粒本身具有抗癌作用外， 还具有吸附、 免疫调节、 化学催化、 药 物载体的作用， 对纯活性炭微粉颗粒进行进一步的化学活化处理、 载药处理以及吸附生物 导向剂处理， 上述作用将得到正相强化， 从而会得到超乎寻常的治疗效果， 这是本发明活 性炭输液剂在制备治疗癌症药物中应用的机理。 下面将作更详细说明：
1.对纯活性炭微粒进行进一步活化处理- 活性炭本身具有化学催化作用， 同时还可以用不同的化学基团修饰， 使活性炭结合多 种化学催化基团， 这些化学基团可以是含有羟基、 羧基、 氨基、 羰基、 芳环基的低分子有 机化合物； 与活性炭结合的化学活性催化基团可为酶类有机物， 或选择在常温常压下， 在 溶液中能起催化作用的主金属有机化合物、 过渡金属有机化合物或相应的无机化合物， 以 达到对氢、 氧、 烃、 肽、 脂的催化； 经化学活化处理的活性炭吸附值明显提高， 使其更有 针对性地发挥催化治疗作用或增加载药作用。
2.对经活化处理的活性炭微粒再进一步进行载药处理以及吸附生物导向 剂处理：
在活性炭微粒上结合生物导向材料， 这是进一步提高活性炭微粒输液剂疗效的有效方 法， 这种导向材料选择原则是： 利用癌细胞生长旺盛的特点， 选择癌细胞生长需求摄取量 比正常细胞摄取量多的物质作为导向材料， 即癌噬性强的物质为导向材料， 这类材料必需 是无免疫原性的物质， 例如选择构成 DNA或 RNA所必需的碱基对物质（胸腺嘧啶、 鸟嘧 啶、尿嘧啶、 胸腺嘌吟、 鸟嘌呤及其衍生物一大类物质）， 癌细胞生长代谢摄入量比正常细 胞多几百倍的物质 （如血卟啉铁）， 或选择肿瘤亲和物质， 例如肿瘤细胞粘附因子 （如 VCAM-1 ), 肿瘤细胞生长因子 （如 VEGF)等作为导向材料， 这些物质都具有促进'肿瘤生 长作用。 非常有趣的现象是肿瘤细胞非常喜欢俘获这样的活性炭微粒， 并大量吞噬这些活 性炭微粒直到死亡或停止生长， 而正常组织细胞几乎对这种活性炭微粒熟视无睹或者很少 问津， 这种具有癌噬性、 肿瘤亲和性导向的活性炭微粒自动浓集在癌细胞周围， 在癌组织 内部的活性炭微粒浓度是其它正常组织的几百倍、 甚至于达到上万倍， 这一创造性导向材 料与活性炭结合的应用， 突破生物导向材料选择原则， 并解决了长期以来肿瘤化疗药物选 择性不强的问题及对导向材料产生抵抗性的问题。
研究表明， 在新生血管非常丰富并且紊乱的肿瘤组织内， 这种带有癌噬性、 癌亲和性 物质的活性炭微粒或者纯活性炭微粒， 会在肿瘤组织微血管内或肿瘤新生微血管盲端内形 成极高浓度的堆积， 并被癌细胞大量吞噬； 癌组织内聚积了大量活性炭微粒， 这些活性炭 微粒进行着抗癌药物释放、 免疫调节、 化学催化、 及吸附物质动态平衡来干扰肿瘤生长， 完成综合杀瘤作用。
另一类抗病毒生物导向剂与载药组合选择原则为： 病毒亲和剂 -病毒干扰剂组合， 如 DNA病毒选用胸腺嘧啶碱基、 RNA病毒选用尿嘧啶碱基与干扰素、 IL-1、病毒转录酶抑制 剂、 聚合酶抑制剂类组合。 · 这种具有生物导向的活性炭微粉， 以其巨大的比表面积， 可以吸附多种抗癌药物， 药 物随着活性炭粉被导向并浓集于肿瘤细胞周围， 所载药物可以选择不同的抗癌药， 如化疗 药物类、 放射性核素类、 免疫调节细胞因子类以及钯、 铂、 铜、 锗、 硒、 钴等配位催化金 属类物质， 这些药物被导向肿瘤细胞， 在肿瘤微血管内部和肿瘤细胞间质中， 药物可以浓 集到常规治疗方法的几百倍， 甚至于上万倍， 增强了抗肿瘤疗效， 降低了化疗药物的毒副 作用。 挂载于活性炭上的化疗、 放疗药物剂量， 一般是传统治疗量的 5-20%, 就能够达到 或超过传统治疗方案的效果， 最大限度减少抗癌药物对机体正常细胞和免疫系统的损害。
本发明活性炭输液剂安全性动物实验如下： 1、 大鼠毒性实验： 大鼠 12只， 135g± 10g， 雌雄各半， 尾静脉注射法， 观察 28天 分组 剂量 mg/Kg 动物数量 （只） 死亡数 （只） LDso置信限 蓄积量 mg/Kg
A 0.2 2/W x 5 12 0 未找到 2
B 0.4 2/W x 5 12 0 4
C 1.6 2/W x 5 12 0 16
D 1.6 2 W x 16 12 0 25.6
E 30 6 0 30
因尾静脉连续注射困难， 最多只扎 2/W ； D相当于最大耐受量实验， E相当于权宜性 的限度实验，
A、 B、 C相当于动物急毒实验高中低三组，但注射次数比急毒实验多，观察天数也多。
2、 病理解剖结果： 随机抽样雌雄动物各 2只进行病理解剖， 结果如下 分组 动物数 （只） 心 肝 肺 脾 肾 脑 脊髓 肌肉 肋骨 髂前脊 肠淋巴结
未见异常病理现象
未见异常病理现象
未见异常病理现象
未见异常病理现象
4 一只雄鼠有肺表面小片状淤血， 但肺实体未见有出血性病理改变， 其余正常 说明： 以上动物实验资料是我们研究过程中的观察资料， 未严格按照药典进行急性毒 理实验或慢性毒理实验要求去作， 给大鼠投药剂量大于标准实验要求， 饲养观察时间也较 标准要求时间长一些， 而鼠的数量少于标准要求。
临床实验病例如下： ' 病例一：
男性， 57岁， 诊断为肺癌， 右锁骨上淋巴结活检： 腺癌， 多程化疗后因胸闷、 心悸、 气促、 不能平卧而入院.， 心脏 B超及肺部 CT显示： 大量心包积液， 心律 120次 /分， 每天 24 小时必须坐立， 抽心包积液因病人不能耐受而未成功。 经静脉注射本发明活性炭制剂 20mg, 24小时后， 胸闷、 心悸、 气促症状缓解， 可以平卧入睡， 心律 90次 /分。 48小时 复査心脏 B超， 心包积液完全消失。
病例二：
男性， 21岁， 诊断为肺泡细胞癌， 经化疗症状无缓解， 胸片显示， 双肺布满絮状阴影， 心电图呈急性肺心病改变， 需间断吸氧治疗。 由于患者对化疗药物产生抵抗， 症状日益加 重， 后胸片显示， 双侧气胸， 右侧压缩 50%, 左侧压缩 40%， 右侧胸腔抽气一次， 800ml 胸透胸腔仍有大量气体。经静脉注射本发明活性炭制剂 20mg加 DDP 20mg和 5-Fu 0.25g， 每隔三天一次， 共用四次， 用药后一周， 复査胸片， 气体完全吸收。
病例三：
女性， 42岁， 诊断为右鼻咽非何杰金淋巴瘤 T细胞型， 先后给于全身化疗， 鼻咽部放 疗， 右侧颈部 1x m大小淋巴结不消失。 经静脉注射本发明活性炭制剂 20mg， 二天后淋 巴结消失， 目前病情稳定， 未进行任何其他治疗。
病例四：
女性， 38岁， 诊断为乳腺癌， 全身骨转移， 吗啡止痛无效， 行走困难， 经静脉注射本 发明活性炭制剂 20mg， 7小时后疼痛明显缓解， 24小时后可以自由行走， 3个月后复查， 体重增加 2公斤， 并能从事一般性家务劳动。 病例五：
男性， 67岁， 先后患有血吸虫性肝硬化，慢性乙型肝炎，糖尿病 II型，酒精性肝硬化， 肺结核， 后因咳嗽咯血住院检查， 诊断为右上肺癌， 因患者年老多病， 不能进行手术， 化 疗、 放疗， 经静脉注射本发明活性炭制剂 20mg， 24 小时后， 咯血明显减少， 连续用药 10天， 症状消失， 3个月后复査胸片肿块影较前縮小， 边缘清晰， 病灶无明显变化， 未进 行任何治疗， 病情稳定。 具体实施方式 下面实施例仅为了进一步说明本发明， 而不是限制本发明。
实施例 1
制备纯活性炭微粒针剂. - 取比表面积为 6800M2的活性炭 500克， 机械粉碎成 120目的细粉， 然后输入空气粉 碎机进行粉碎， 控制粒径为 35Mm-2nm， 主要粒度分布范围为 6wn-2nm， 其中 3Mm-2nm 占 99%， 6Mm-3Mm颗粒不超过 1%， 最大直径 35Wn-6mi活性炭微粒不超过 2x104个 /mg 活性炭微粉； 用上述活性炭微粉作溶质， 用二甲基亚砜（DMSO) 作悬溶剂， 配制' 1%活 性炭混悬液 5000ml， 在强磁力搅拌下， 分装成每瓶 1ml或 2ml的输液针剂。
实施例 2
制备活化活性炭微粒针剂：
取比表面积为 6800M2/g的活性炭 100g, 机械粉碎成 120目的细粉， 加入 -10°C 1% 亚硫酰氯 /氯仿溶液 300ml, 搅拌吸附反应 2小时， 以 2万转高速离心， 取沉淀； 然后把沉 淀物容器放入压力容器内， 加热到 80°C， 5分钟后放气减压,生成氧化型活性炭； 然后再 向压力容器中分别通入活化剂， 以生成几种带有不同活性基的活化活性炭：
若制备羟基化活性炭，则通入 90°C水蒸汽 2小时，然后减压排气，生成羟基化活性炭： 若制备亚氨基化活性炭， 则通入 90'C 'C纯氨蒸汽 2小时， 生成亚氨基化活性炭； 若制备羟基、 氨基活性炭， 则通入 90'C 10-40%氨-水蒸汽， 生成同时含有羟基、 氨基 的活性炭；
若制备炭 -氢活性炭， 则取比表面积为 6800M2/g的活性炭 100克， 机械粉碎成 120 目的细粉， 加入乙醚溶解的 LiALH4， 配制成 1%的溶液 300ml， 搅拌吸附 2小时， 离心取 沉淀； 在压力容器内加热至 95'C 5分钟， 冷却减压， 制得结合有炭-氢和锂的活性 '炭； 将上述活化的活性炭， 输入空气粉碎机进行粉碎， 控制粒径为 35Mm-2nm, 主要粒度 分布范围为 6wn-2nm， 其中 3wn-2nm 占 99%， 6Mm-3Mm 颗粒不超过 1 %， 最大直径 35Wn-6Mm 活性炭微粒不超过 2x104个 /mg 活性炭微粉； 分别分装成每瓶含活化活性炭 10mg或 20mg输液针剂。
实施例 3
制备载药活性炭针剂：
①吸附抗癌药针剂： 在无药物拮抗情况， 可任意选取药物进行吸附， 例如， 顺铂 6g、 5-FU 0.4g , 或取顺铂 6g、 6-MP 0.8g溶于 100ml 水中， 加入 10g 120目活性炭或活化 的羟基-氨基活性炭， 搅拌下充分吸附； 高速离心取沉淀， 丙酮脱水， 离心取沉淀， 干燥； 然后用 0.1 %几丁聚糖水溶液浸渍沉淀 5分钟， 用丙酮脱水， 干燥； 用空气粉碎机粉碎， 控制粒径为 35wn-2nm，主要粒度分布范围为 6Mm-2nm,其中 3wn-2nm占 99%, 6Mm-3 m 颗粒不超过 1%, 最大直径 35Mm-6Mm活性炭微粒不超过 2x104个 /mg活性炭微粉； 将经 过粉碎暴露出新断面的载药活性炭微粒， 浸入 20%卟啉铁丙酮溶液 10分钟， 高速离心取 沉淀,.干燥； 分别分装成每瓶含相当活化活性炭 10mg或 20mg的输液针剂。
部分药物测定的吸附值如下： 比表面积 6800M2活性炭 /羟、 氨基炭， 其吸附量测定值 (活性炭吸附值 mg/羟、 氨基炭吸附值 mg) 为： 尿嘧啶 33/51、 胸嘌呤 213/260、 鸟嘌呤 331/378、 5-氯尿嘧啶 75/102、 5-氟尿嘧啶 20/49、 胸嘧啶 5/17、 胸腺肽 90(127、 6-MP220/304、 顺铂 995/1105、 卟啉铁 283/311、 CTX98/136、 氯仿 10/4。
② 吸附抗凝、降胆固醇药物针剂：例如，取 r-tPA 100mg或胆固醇乙酰转移酶 80mg 或烟酸 220mg， 加入经空气粉碎机粉碎成粒度为 0.5pm以下的羟基活性炭微粒 1g， 进行 充分水相吸附， 高速离心取沉淀， 丙酮脱水， 千燥 ·' 然后用 0.1 %几丁聚糖水溶液浸渍 5 分钟， 高速离心取沉淀， 用丙酮脱水， 干燥， 分装成 10mg/瓶输液针剂， 用于治疗心、 脑 栓塞溶栓治疗和治疗血管硬化、 高血压等。
③ 吸附抗生素药物针剂： 例如， 取异烟肼 500mg或利福平 200mg， 用空气粉碎机 粉碎成粒度为 0.7ym以下的羟基、 氨基活性炭微粒 1g， 水相吸附 20分钟， 高速离心取沉 淀， 丙酮脱水,干燥； 然后用 0.1%几丁聚糖水溶液浸渍 5分钟， 高速离心取沉淀， 用丙酮 脱水， 干燥， 分装成 20mg/瓶输液针剂， 用于治疗难治性骨结核、 粟粒性肺结核等。
④ 吸附抗病毒药物针剂： 例如， 取 IFN-Yl00mg， 加入空气粉碎机粉碎成粒度为 0.3Mm 以下的羟基-氨基活性炭微粒 1g， 进行充分水相吸附； 高速离心取沉淀， 对沉淀物 进行丙酮脱水， 低温千燥； 在丝胺酸、 特异型病毒半抗体导向剂中浸渍 5分钟， 高速离心 取沉淀， 丙酮脱水， 低温干燥， 分装成 10mg/瓶或 20mg/瓶的输液针剂； 用于治疗各种病 毒性感染的难治疗性疾病， 如 EB病毒性格林巴利氏综合症、 病毒脑等， 也可用于 Ήΐν的 治疗。

Claims

*g 利 要 求 书
1. 活性炭输液剂， 包括纯活性炭微粒针剂、 活化活性炭微粒针剂、 吸附有催化剂的活性炭 针剂以及载药活性炭针剂， 该载药活性炭针剂包括吸附抗癌药物针剂、 吸附抗凝和降胆 固醇药物针剂、 吸附抗生素药物针剂、 吸附抗病毒药物针剂， 其特征在于所用原料活性 炭表面积≥400-100001\/12/9 或更高， 重金属含量≤0.1-10ppm， 其它可溶性金属离子 ^ 0.1-10ppm， 灰份 <2%， 总孔容积 >0.3-6cm3/g， 0.15% 亚甲兰吸附值 >6-30， 该活性炭 输液剂中所含活性炭微粒粒径为 35μττ ·2 nm， 主要粒度分布范围为 6pm-2nm， 其中 3Mm-2nm占 99%， 6pm -3pm颗粒不超过 1%， 最大直径 35μηι -6μιη 活性炭微粒不超 过 2 Χ 104个 /mg活性炭微粉。
2. 权利要求 1所述的活性炭输液剂的制备方法， 其特征在于该方法包括以下步骤： ，
1) 用机械方法将原料活性炭粉碎成 120目的粗颗粒；
2) 使该活性炭粗颗粒吸附活化剂以使活性炭活化， 所述活化剂浓度为 0.01-10%， 在高 压容器中加热到 70-190'C， 反应时间为 5-20分钟， 生成氧化型或还原型活性炭； 冷 却减压， 排除残余气体， 再在压力下分别通入 60-100Ό水蒸气、 氨气， 生成含有炭- 羟基、 炭-亚氨基或炭-氢的活性炭；
3) 进行活性炭载药处理，选择相关药物用经活化的活性炭或未经活化的纯活性炭进行液 相饱和吸附， 然后低温干燥， 用空气粉碎机粉碎成所要粒径的活性炭微粒；
4) 使该活性炭微粒浸渍吸附生物导向剂， 然后进行短时间、 快速低温干燥。
3. 权利要求 2所述的活性炭输液剂的制备方法， 其特征在于步骤 （2) 中所述的活化剂分为 氧化剂和还原剂，氧化剂选自环氧醚类、酰氯类、酸酐类、醛类氧化剂,还原剂选自 LiAlH4、 NaBH4 o
4. 权利要求 2所述的活性炭输液剂的制备方法， 其特征在于步骤 （3) 中所述的选择相关药 物包括： ①传统的抗癌药物如 5-FU、 CTX、 MTX、 Ara-C\A、 6-MP、 抗癌抗生素类、 顺 / 卡铂、 砷剂类、 紫杉醇； ②免疫激活、 调节类细胞因子类如 IL-2、 4、 6、 GM、 G-CSF、 γ- 、 TNF、 FCF-B、 VECF、 4-IBB/4-IBBL B7-lB7-2、 蟾毒蛋白、 特异性半抗体; ③ 催化剂类如主金属有机化合物苄基 /丁基锂， 过渡金属铜氨剂、 铂、 钯剂、 硒、 锗化合物， 这些结合物具有催化和杀肿瘤双重功能； ④吸附生物酶类如氧化还原酶类、 转氨酶类、 水解酶类、 异构酶类。
5. 权利要求 2所述的活性炭输液剂的制备方法， 其特征在于步骤 （4) 中的生物导向剂包括 卟啉铁， 或胸腺嘧啶、 鸟嘧啶、 尿嘧啶、 胸腺嘌呤、 鸟嘌呤及其衍生物一大类物质， 如 5-氟尿嘧啶、 氢氘胸腺嘧啶、 甲氨喋呤以及肿瘤细胞粘附因子 （如 VCAM-1 ) 、 肿瘤细 胞生长因子 （如 VEGF) 类。
6. 权利要求 1 所述的活性炭输液剂在制备治疗癌症药物中的应用， 其特征在于单次输入血 液的有效治疗剂量为 0. l-5mg/kg体重， 每周输入 1-7次， 成人平均累计总储积查为 10g 以下。
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RU2362570C2 (ru) * 2004-06-02 2009-07-27 Куреха Корпорейшн Средство для устранения фактора циркуляторной дисфункции
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CN104379182B (zh) * 2012-03-29 2017-12-05 巴斯夫公司 非晶碳承载的包含镧系氧化物的纳米粒子及其制备方法
CN105832767B (zh) * 2016-04-12 2019-03-01 贵州泰柏妇科疾病研究中心 一种纳米活性炭与石墨烯在抗hpv病毒中的应用
CN105998063B (zh) * 2016-06-20 2019-04-26 贵州泰柏妇科疾病研究中心 一种纳米活性炭在抑制细菌中的应用
CN105920037B (zh) * 2016-06-20 2019-01-22 贵州泰柏妇科疾病研究中心 一种纳米活性炭溶胶在制备治疗疱疹病毒药物中的应用
TWI634891B (zh) * 2017-08-17 2018-09-11 逢甲大學 Medicine for treating or preventing colorectal cancer
KR101941871B1 (ko) * 2017-09-05 2019-01-24 서원대학교산학협력단 쌀도정 부산물과 한방생약의 발효 추출물을 포함하는 항혈전용 조성물
WO2020210376A1 (en) * 2019-04-09 2020-10-15 The Board Of Trustees Of The University Of Illinois Drug adsorbed highly porous activated carbon for enhanced drug delivery
CN114831934B (zh) * 2022-05-11 2023-05-26 回音必集团抚州制药有限公司 一种盐酸尼卡地平注射液的制备方法
CN115671315B (zh) * 2023-01-03 2023-04-28 北京弘堃医药科技有限公司 组织释药浓度可控的抗癌药物递送系统及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4152412A (en) * 1976-04-02 1979-05-01 Brewer John H Marking vaccine
WO1991008776A1 (fr) * 1989-12-11 1991-06-27 Assistance Publique Composition pour injection intratumorale, et utilisation pour le marquage prechimiotherapique et preoperatoire, en laserotherapie et en thermotherapie
RU2017492C1 (ru) * 1991-05-14 1994-08-15 Нестерова Ирина Вадимовна Способ лечения пищевой аллергии

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4152412A (en) * 1976-04-02 1979-05-01 Brewer John H Marking vaccine
WO1991008776A1 (fr) * 1989-12-11 1991-06-27 Assistance Publique Composition pour injection intratumorale, et utilisation pour le marquage prechimiotherapique et preoperatoire, en laserotherapie et en thermotherapie
RU2017492C1 (ru) * 1991-05-14 1994-08-15 Нестерова Ирина Вадимовна Способ лечения пищевой аллергии

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TA REN-ZHI ET AL.: "Development of the study on activated carbon particles as anticancer drug carrier into regional lymphnodes", JOURNAL OF SHENYANG PHARMACEUTICAL UNIVERSITY, vol. 19, no. 1, January 2002 (2002-01-01), pages 66 - 69, XP008102674 *

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