WO2024120371A1 - 肝动脉灌注治疗肝癌的方法 - Google Patents

肝动脉灌注治疗肝癌的方法 Download PDF

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WO2024120371A1
WO2024120371A1 PCT/CN2023/136366 CN2023136366W WO2024120371A1 WO 2024120371 A1 WO2024120371 A1 WO 2024120371A1 CN 2023136366 W CN2023136366 W CN 2023136366W WO 2024120371 A1 WO2024120371 A1 WO 2024120371A1
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fluorouracil
sodium
hepatic artery
drug combination
present
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French (fr)
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李文华
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上海汇伦医药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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 belongs to the field of medicine, and relates to a drug combination and a method for treating liver cancer by hepatic artery perfusion, and specifically relates to a drug combination of sodium leucovorin, fluorouracil and oxaliplatin and use of the drug combination in preparing a drug for treating liver cancer by hepatic artery perfusion.
  • Liver cancer (or hepatocellular carcinoma) is the fourth leading cause of cancer in the world. There are about 400,000 new patients in my country each year, of which more than half are in the middle and late stages. Due to limited treatment options, the overall survival (OS) is only 4.2-7.9 months.
  • Sorafenib molecular targeted therapy is the standard treatment for advanced liver cancer in current domestic and international guidelines, this targeted drug has poor effects on patients with hepatocellular carcinoma caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • FOLFOX treatment refers to three drugs including folic acid (FOLinic acid), fluorouracil (Fluorouracil) and oxaliplatin (OXaliplatin).
  • Folic acid is a synergist of fluorouracil;
  • fluorouracil is a homologue of uracil (a component of ribonucleic acid), and fluorouracil mainly interferes with DNA synthesis by blocking the conversion of deoxyribonucleic acid into thymidylic acid;
  • oxaliplatin is a third-generation platinum anticancer drug, its platinum atoms form cross-links with DNA chains, thereby blocking their replication and transcription.
  • FOLFOX was originally one of the most commonly used chemotherapy regimens for colorectal cancer. It has also been used in other tumors. In recent years, it has gradually gained attention in the treatment of hepatocellular carcinoma. However, the existing FOLFOX treatment regimen is not satisfactory in the treatment of liver cancer. Therefore, it is particularly important to find a suitable clinical treatment regimen that can improve the clinical efficacy of the existing treatment regimen.
  • the present invention has found a method that is superior to the existing liver cancer treatment method and can synergistically treat liver cancer or liver metastasis.
  • the present invention provides a drug combination or a combination product, wherein the drug combination or the combination product contains sodium leucovorin and fluorouracil.
  • the weight ratio of sodium folinate to fluorouracil is 1:5 to 15, calculated by weight ratio (mg/mg);
  • the weight ratio of sodium leucovorin to fluorouracil in the drug combination or combination product of the present invention is 1:8-12.
  • the weight ratio of sodium leucovorin to fluorouracil in the drug combination or combination product of the present invention is 1:9-12.
  • the drug combination or combination product of the present invention contains 200-300 mg/m 2 of sodium leucovorin.
  • the pharmaceutical combination or combination product of the present invention contains 200 mg/m 2 of sodium leucovorin.
  • the drug combination of the present invention or The combination product contains 250 mg/ m2 of sodium folinate.
  • the drug combination or combination product of the present invention contains 300 mg/m 2 of sodium folinate calculated per unit body surface area (mg/m 2 ).
  • the pharmaceutical combination or combination product of the present invention contains 2200-3000 mg/m 2 of fluorouracil calculated per unit body surface area (mg/m 2 ); preferably, contains 2400-2800 mg/m 2 of fluorouracil.
  • the pharmaceutical combination or combination product of the present invention contains 2400 mg/m 2 of fluorouracil.
  • the drug combination or combination product of the present invention contains 2600 mg/m 2 of fluorouracil calculated per unit body surface area (mg/m 2 ).
  • the pharmaceutical combination or combination product of the present invention contains 2800 mg/m 2 of fluorouracil.
  • the sodium leucovorin and fluorouracil in the drug combination or combination product of the present invention may be in the form of a pharmaceutical composition.
  • the drug combination When the drug combination is in the form of a pharmaceutical composition, it may also contain pharmaceutically acceptable excipients.
  • sodium leucovorin and fluorouracil may also be in the form of separate preparations.
  • sodium leucovorin and fluorouracil are administered via hepatic artery perfusion.
  • sodium folinate and fluorouracil are administered in the form of each independent preparation or pharmaceutical composition within no more than 72 hours, and the administration is repeated every three weeks; preferably, sodium folinate and fluorouracil are administered in the form of each independent preparation or pharmaceutical composition within no more than 48 hours; preferably, sodium folinate and fluorouracil are administered in the form of each independent preparation or pharmaceutical composition within no more than 44 hours; preferably, sodium folinate and fluorouracil are administered by hepatic artery infusion in the form of each independent preparation or pharmaceutical composition within no more than 48 hours.
  • sodium leucovorin and fluorouracil are administered simultaneously in the form of a pharmaceutical composition or in the form of separate preparations within no more than 72 hours, and the administration is repeated every three weeks.
  • the drug combination or combination product of the present invention further contains oxaliplatin, and the content of oxaliplatin is 85-130 mg/m 2 calculated based on body surface area.
  • the drug combination of the present invention contains 85 mg/m 2 .
  • the drug combination of the present invention contains 100 mg/m 2 .
  • the drug combination of the present invention contains 130 mg/m 2 .
  • the administration method of oxaliplatin is not particularly limited, and it can be administered intravenously or intraarterially, such as by intravenous injection, intravenous push injection, arterial drip, or arterial perfusion.
  • oxaliplatin is administered by arterial infusion.
  • oxaliplatin is administered by arterial infusion in the form of a separate preparation.
  • oxaliplatin is administered by intravenous or arterial infusion within no more than 12 hours; preferably, oxaliplatin is administered by intravenous or arterial infusion within no more than 8 hours; preferably, oxaliplatin is administered by intravenous or arterial infusion within no more than 12 hours.
  • oxaliplatin is administered by intravenous or arterial infusion within no more than 6 hours; preferably, oxaliplatin is administered by intravenous or arterial infusion within no more than 4 hours; preferably, oxaliplatin is administered by intravenous or arterial infusion within no more than 12 hours, and the administration is repeated every three weeks.
  • the drug combination contains sodium leucovorin, fluorouracil and oxaliplatin. Calculated per unit body surface area, it contains 250 mg/m 2 of sodium leucovorin, 2400-2800 mg/m 2 of fluorouracil and 85-130 mg/m 2 of oxaliplatin.
  • Another aspect of the present invention provides a use or method for treating a patient's disease, wherein the disease is liver cancer or liver metastasis requiring hepatic artery perfusion therapy.
  • the disease is liver cancer or liver metastasis requiring hepatic artery perfusion therapy.
  • sodium leucovorin and fluorouracil can be administered simultaneously or separately.
  • the present invention provides a use of the drug combination comprising sodium leucovorin and fluorouracil in preparing a drug for treating liver cancer or liver metastasis or a method for treating the drug.
  • the drug combination is used for preparing a drug for treating liver cancer or liver metastasis by hepatic artery perfusion.
  • sodium leucovorin and fluorouracil are in the form of independent preparations, which are pre-mixed and then administered simultaneously.
  • sodium leucovorin and fluorouracil are administered in the form of a pharmaceutical composition.
  • the patient disease treatment use or treatment method further contains oxaliplatin.
  • the oxaliplatin can be administered intravenously or intraarterially, such as by intravenous injection, intravenous push, arterial drip, or arterial perfusion.
  • sodium folinate and fluorouracil are premixed in the form of independent preparations and then administered simultaneously via hepatic artery infusion.
  • sodium leucovorin and fluorouracil are administered in the form of a pharmaceutical composition via hepatic artery infusion.
  • the weight ratio of sodium folinate to fluorouracil is 1:5-15; and calculated per unit body surface area, the sodium folinate is contained at 250 mg/ m2 .
  • the present invention further provides a drug kit, wherein the weight ratio of sodium leucovorin to fluorouracil in the drug combination of the present invention is 1:8-12, calculated by weight ratio (mg/mg).
  • the kit contains 250 mg/m 2 of sodium folinate, 2400-2800 mg/m 2 of fluorouracil, and 85-130 mg/m 2 of oxaliplatin, calculated per unit body surface area.
  • the present invention unexpectedly discovered that when sodium leucovorin and fluorouracil in the drug combination are simultaneously administered through hepatic artery infusion to treat liver cancer or liver metastasis, especially when sodium leucovorin and fluorouracil are premixed in the form of separate preparations and then administered simultaneously through hepatic artery infusion, the therapeutic effect can be further improved.
  • the sodium leucovorin of the present invention refers to (6S)-N-[4-[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl-L-glutamic acid.
  • the fluorouracil of the present invention refers to 5-fluoro-2,4(1H,3H)-pyrimidinedione, or 5FU for short.
  • the oxaliplatin of the present invention refers to (trans-1,2-cyclohexanediamine) oxalate platinum.
  • the sodium leucovorin and fluorouracil of the present invention are used in the form of independent preparations or pharmaceutical compositions, they can be in the form of preparations such as lyophilized powder for injection and injection solutions, and the preparations can further contain pharmaceutically acceptable excipients, which can include proppants, pH regulators, osmotic pressure regulators, etc.
  • the proppants are mannitol and glucose
  • the pH regulators are sodium hydroxide, disodium edetate, hydrochloric acid, etc.
  • the osmotic pressure regulators are sodium chloride, etc.
  • Non-limiting examples are that sodium leucovorin is presented in the form of a lyophilized powder, and the lyophilized powder can further contain excipients such as mannitol and sodium hydroxide; fluorouracil is presented in the form of an injection solution, and the injection solution can further contain excipients such as sodium chloride; oxaliplatin is presented in the form of an injection solution, and the injection solution can further contain excipients such as mannitol.
  • sodium leucovorin, fluorouracil and oxaliplatin are all known commercially available products.
  • drug combination or “combination product” described in the present invention refers to the combination or composition of the drugs prepared independently for the treatment of diseases.
  • Liver metastasis refers to cancer that metastasizes to the liver from tumors in other parts of the body outside the liver, such as colorectal cancer, gastric cancer, gallbladder cancer, lung cancer, esophageal cancer, breast cancer, etc.
  • the "separate administration” mentioned in the present invention refers to the sequential administration, staggered administration or continuous administration of drugs in the form of separate preparations.
  • spontaneous administration refers to simultaneous administration of drugs in the form of separate preparations, such as premixing before use and then administering simultaneously.
  • Body surface area can be calculated according to the conventional method based on the weight of the animal. For example, for an adult weighing 60 kg, the body surface area is about 1.6 m2 , and for an experimental rat weighing 0.2 kg, the body surface area is about 0.03 m2 .
  • the dosage for an adult is about 400 mg; for an experimental rat, the dosage is about 7.5 mg.
  • HAI hepatic artery infusion
  • ivgtt is intravenous drip
  • oxaliplatin was administered by arterial drip in G3, G5-G8 groups, and by intravenous drip in G4
  • leucovorin was administered first, followed by 5-FU;
  • test samples for each dosing group should be completed in an ultra-clean workbench.
  • CBRH-7919 rat hepatoma cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS). The cells were cultured in a humidified incubator at 37°C and 5% CO 2. CBRH-7919 cells in the exponential growth phase were collected and resuspended in PBS to a suitable concentration for subcutaneous tumor inoculation in nude mice.
  • FBS fetal bovine serum
  • the cultured rat liver cancer cells were injected subcutaneously into the back of nude mice. After the tumor was formed, it was removed and cut into 1*1*1mm tumor blocks. Then, the tumor blocks were inoculated into the left lobe of the liver of Wistar rats by intrahepatic tunnel implantation. On the day of surgery, hydrocortisone was injected intraperitoneally at 2mg/rat/d for 5 days. After the surgery, the biological behavior and survival of the tumor-bearing rats were closely observed. When the tumor grew to When the average volume was about 400 mm3, the rats were randomly divided into groups for administration according to tumor size and body weight.
  • the tumor volume reached about 400 mm 3 and was administered according to different administration methods and doses.
  • the hepatic artery perfusion administration group was anesthetized by intraperitoneal injection of chloral hydrate, and a 2.5-3 cm incision was made along the linea alba to expose the liver and tumor, and the long and short diameters of the tumor were measured with a vernier caliper.
  • the adhesions between the liver and the surrounding tissues were separated, the liver lobe was turned up, and the hepatic artery was found on the left side of the common bile duct above the portal vein.
  • the hepatic artery and gastroduodenal artery were gently peeled off with ophthalmic forceps, and the hepatic artery was punctured with a 1 ml insulin syringe (needle 29G) under a surgical microscope. After the puncture was successful, the drug was slowly injected. A total of 2 doses were administered, and the volume of the tumor was measured after each dose.
  • T RTV RTV of treatment group
  • C RTV RTV of model group
  • the entire process of drug administration, tumor measurement and body weight weighing is carried out in an ultra-clean workbench.
  • Macroscopic observation After the last administration, the abdominal cavity was opened to observe the liver tumor, and the tumor growth position was consistent with that before treatment, and it was single, round, and smooth. Macroscopic observation of tumor size showed that the tumor volume of rats in the model group increased significantly, and the tumor volume of rats in the other drug groups was significantly reduced after different drug treatments.
  • the volume size ranking after one and two administrations was G7 group ⁇ G6 group ⁇ G3 group ⁇ G8 group ⁇ G5 group ⁇ G4 group ⁇ G2 group ⁇ G1 group.
  • the tumor growth inhibition rate was calculated as follows: tumor inhibition rate, relative tumor proliferation rate was ranked as G7 group ⁇ G6 group ⁇ G3 group ⁇ G8 group ⁇ G5 group ⁇ G4 group ⁇ G2 group.
  • the comparison of tumor volume, rat body weight and relative tumor proliferation rate of each group before and after administration is shown in the table below.
  • the dose of oxaliplatin in the hepatic artery infusion group was 130mg/ m2 , 85mg/ m2 and 100mg/ m2
  • the dose of sodium folinate was 250mg/ m2 and 200mg/ m2
  • the dose of 5FU was 2800mg/ m2 and 2400mg/ m2
  • the tumor volume in the liver cancer rats was significantly smaller than that in the group administered with 5FU alone and the group administered with intravenous drip, which also shows that the hepatic artery infusion administration method has obvious anti-tumor efficacy.
  • the administration of drugs to liver cancer model rats by hepatic artery perfusion can effectively reduce the tumor volume of rats and has a good anti-tumor efficacy.

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Abstract

一种肝动脉灌注治疗肝癌的方法，该方法含有包括左亚叶酸钠、氟尿嘧啶、奥沙利铂的药物。通过将250mg/m 2左亚叶酸钠、氟尿嘧啶预混后同时经肝动脉灌注的方式，相对于现有治疗方法能显著提高治疗效果。

Description

肝动脉灌注治疗肝癌的方法 技术领域
本发明属于医药领域，涉及一种药物组合以及一种肝动脉灌注治疗肝癌的方法，具体涉及左亚叶酸钠、氟尿嘧啶、奥沙利铂的药物组合及其在制备肝动脉灌注治疗肝癌的药物中的用途。
背景技术
肝癌(或称为肝细胞癌)是全球第四大癌症病因，我国的新发患者每年约40万，其中属于中晚期的患者占了半数以上；并且由于治疗方案有限，总生存期(OS)仅为4.2-7.9个月。虽然索拉非尼(Sorafenib)分子靶向治疗是目前国内外指南对进展期肝癌的标准治疗方案，可是该靶向药物对乙型肝炎病毒(HBV)感染导致的肝细胞癌患者效果差，这使得在临床实践中，针对乙型肝炎为多数致病因素的我国患者，索拉非尼仍存在低有效率，并且生存期延长不明显的情形，因此寻找有效的治疗方案仍为一重大课题。
FOLFOX治疗是指包含叶酸(FOLinic acid)、氟尿嘧啶(Fluorouracil)和奥沙利铂(OXaliplatin)三种药物，其中叶酸是氟尿嘧啶的增效剂；氟尿嘧啶是尿嘧啶(核糖核酸的一个组分)的同类物，氟尿嘧啶主要通过阻断脱氧核糖尿苷酸转化为胸苷酸，而干扰DNA的合成；奥沙利铂是第三代铂类抗癌药，它的铂原子与DNA链形成交联，从而阻断其复制和转录。
FOLFOX原本是临床常用的结直肠癌化疗方案之一，在其他肿瘤中也有人施用，近年在治疗肝细胞癌上，也逐渐受到重视。然而现有的FOLFOX治疗方案在治疗肝癌的效果上却不尽如人意，因此寻找合适的能够提高现有治疗方案的临床疗效的临床治疗方案显得尤其重要。
发明内容
本发明发现一种优于现有肝癌治疗的方法，能够协同增效的治疗肝癌或肝转移癌。本发明在一方面提供一种用药物组合或组合产品，所述药物组合或组合产品中含有左亚叶酸钠和氟尿嘧啶
本发明所述的药物组合中，以重量比计算(mg/mg)，左亚叶酸钠和氟尿嘧啶的重量比为1:5～15；
在本发明的具体实施方式中，以重量比计算(mg/mg)，本发明所述的药物组合或组合产品中左亚叶酸钠和氟尿嘧啶的重量比为1:8～12。
在本发明的具体实施方式中，以重量比计算(mg/mg)，本发明所述的药物组合或组合产品中左亚叶酸钠和氟尿嘧啶的重量比为1:9～12。
本发明所述的药物组合中，以单位体表面积计算(mg/m2)，本发明所述的药物组合或组合产品中含有200～300mg/m2左亚叶酸钠。
在本发明的具体实施方式中，以单位体表面积计算(mg/m2)，本发明所述的药物组合或组合产品中含有200mg/m2左亚叶酸钠。
在本发明的具体实施方式中，以单位体表面积计算(mg/m2)，本发明所述的药物组合或 组合产品中含有250mg/m2左亚叶酸钠。
在本发明的具体实施方式中，以单位体表面积计算(mg/m2)，本发明所述的药物组合或组合产品中含有300mg/m2左亚叶酸钠
在本发明的具体实施方式中，以单位体表面积计算(mg/m2)，本发明所述的药物组合或组合产品中含有2200～3000mg/m2氟尿嘧啶；优选的，含有2400～2800mg/m2氟尿嘧啶。
在本发明的具体实施方式中，以单位体表面积计算(mg/m2)，本发明所述的药物组合或组合产品中含有2400mg/m2氟尿嘧啶。
在本发明的具体实施方式中，以单位体表面积计算(mg/m2)，本发明所述的药物组合或组合产品中含有2600mg/m2氟尿嘧啶
在本发明的具体实施方式中，以单位体表面积计算(mg/m2)，本发明所述的药物组合或组合产品中含有2800mg/m2氟尿嘧啶。
本发明所述的药物组合或组合产品中左亚叶酸钠和氟尿嘧啶可以为药物组合物的形式。当所述的药物组合为药物组合物的形式时，还包含药学上可接受的辅料。
本发明所述的药物组合或组合产品中左亚叶酸钠和氟尿嘧啶还可以为各自独立的制剂形式。
本发明所述的药物组合或组合产品中左亚叶酸钠、氟尿嘧啶通过肝动脉灌注给药。
在本发明具体的实施方式中，左亚叶酸钠、氟尿嘧啶以各自独立的制剂形式或药物组合物形式在不超过72小时内给药，每三周重复一次给药；优选的左亚叶酸钠、氟尿嘧啶以各自独立的制剂形式或药物组合物形式在不超过48小时内给药；优选的左亚叶酸钠、氟尿嘧啶以各自独立的制剂形式或药物组合物形式在不超过44小时内给药；优选的左亚叶酸钠、氟尿嘧啶以各自独立的制剂形式或药物组合物形式在不超过48小时内肝动脉灌注给药。
在本发明的具体实施方式中，左亚叶酸钠、氟尿嘧啶以药物组合物形式或以各自独立的制剂形式同时在不超过72小时内给药，每三周重复一次给药。
本发明所述的药物组合或组合产品中，还进一步含有奥沙利铂。以体表面积计算，含有奥沙利铂85～130mg/m2。
在本发明的具体实施方式或组合产品中，以单位体表面积计算(mg/m2)，本发明所述的药物组合中含有85mg/m2。
在本发明的具体实施方式或组合产品中，以单位体表面积计算(mg/m2)，本发明所述的药物组合中含有100mg/m2。
在本发明的具体实施方式或组合产品中，以单位体表面积计算(mg/m2)，本发明所述的药物组合中含有130mg/m2。
奥沙利铂的给药方式并无特别限定，可以静脉、动脉给药，如通过静脉注射、静脉推注、动脉滴注、动脉灌注的方式给药。
在本发明的具体实施方式中，奥沙利铂通过动脉滴注给药。
在本发明的具体实施方式中，奥沙利铂以独立的制剂形式动脉滴注给药。
在本发明具体的实施方式中，奥沙利铂经静脉或动脉滴注在不超过12小时内给药；优选的，奥沙利铂经静脉或动脉滴注在不超过8小时内给药；优选的，奥沙利铂经静脉或动脉滴 注在不超过6小时内给药；优选的，奥沙利铂经静脉或动脉滴注在不超过4小时内给药；优选的，奥沙利铂经静脉或动脉滴注在不超过12小时内给药，每三周重复一次给药。
在本发明的具体实施方式中，所述药物组合含有左亚叶酸钠、氟尿嘧啶、奥沙利铂，以单位体表面积计算，含有250mg/m2左亚叶酸钠；含有2400～2800mg/m2氟尿嘧啶，奥沙利铂85～130mg/m2。
本发明另一方面提供一种患者疾病治疗用途或治疗方法，所述疾病为患者需进行肝动脉灌注治疗的肝癌或肝转移癌。本发明所述药物组合中，左亚叶酸钠和氟尿嘧啶可以同时或分开给药。
本发明提供一种所述包含左亚叶酸钠和氟尿嘧啶的药物组合在制备治疗肝癌或肝转移癌的药物的用途或治疗方法。
在本发明的具体实施方式中，所述药物组合用于制备肝动脉灌注治疗肝癌或肝转移癌的药物的用途。
在本发明的具体实施方式中，左亚叶酸钠和氟尿嘧啶以独立的制剂形式，预先混合后同时给药。
在本发明的具体实施方式中，左亚叶酸钠和氟尿嘧啶以药物组合物的形式给药。
在本发明的具体实施方式中，所述患者疾病治疗用途或治疗方法还进一步含有奥沙利铂。所述奥沙利铂可以静脉、动脉给药，如通过静脉注射、静脉推注、动脉滴注、动脉灌注的方式给药。
在本发明的具体实施方式中，左亚叶酸钠与氟尿嘧啶以独立的制剂形式预混后同时经肝动脉灌注施用。
在本发明的具体实施方式中，左亚叶酸钠与氟尿嘧啶以药物组合物的形式经肝动脉灌注施用。
所述左亚叶酸钠与氟尿嘧啶重量比为1:5～15；且以单位体表面积计算，含有250mg/m2左亚叶酸钠。
本发明还进一步提供一种药物试剂盒，所述试剂盒中，以重量比计算(mg/mg)，本发明所述的药物组合中左亚叶酸钠和氟尿嘧啶的重量比为1:8～12。
在一些实施方式中，所述试剂盒以单位体表面积计算，含有250mg/m2左亚叶酸钠，2400～2800mg/m2氟尿嘧啶，85～130mg/m2奥沙利铂。
本发明出乎意料的发现，当所述药物组合中，左亚叶酸钠和氟尿嘧啶同时通过肝动脉灌注治疗肝癌或肝转移癌时，特别是左亚叶酸钠和氟尿嘧啶以各自独立的制剂形式预混后同时通过肝动脉灌注给药，能够进一步提高治疗效果。
具体实施方式
本发明左亚叶酸钠指(6S)-N-[4-[(2-氨基-5-甲酰基-1,4,5,6,7,8-六氢-4-氧代-6-蝶啶基)甲基]氨基]苯甲酰-L-谷氨酸。
本发明氟尿嘧啶指5-氟-2,4(1H,3H)-嘧啶二酮，或简称为5FU。
本发明奥沙利铂指(反-1,2-环己烷二胺)草酸铂。
本发明的左亚叶酸钠、氟尿嘧啶当以独立制剂形式，或药物组合物的形式使用时，可以是注射用冻干粉、注射液等制剂形式，所述制剂还可进一步包含药学上可接受的辅料，所述辅料可包括支撑剂、pH调节剂、渗透压调节剂等。所述支撑剂如甘露醇、葡萄糖，pH调节剂如氢氧化钠、依地酸二钠、盐酸等，渗透压调节剂如氯化钠等。非限制性的举例如左亚叶酸钠以冻干粉的制剂形式呈现，所述冻干粉可进一步含有甘露醇、氢氧化钠等辅料；氟尿嘧啶以注射液的制剂形式呈现，所述注射液可进一步含有氯化钠等辅料；奥沙利铂以注射液的制剂形式呈现，所述注射液可进一步含有甘露醇等辅料。
在本发明的具体实施例中，左亚叶酸钠、氟尿嘧啶、奥沙利铂均来自已知的市售产品。
本发明所述的“药物组合”或“组合产品”是指将所述各自独立制剂的药物联合或形成组合物用于疾病治疗。
“肝转移癌”是指肝以外其他部位肿瘤转移至肝脏的癌症，如结直肠癌、胃癌、胆囊癌、肺癌、食管癌、乳腺癌等转移至肝脏的癌症。
本发明所述的“分开给药”是指药物以各自独立的制剂形式先后给药、错时给药或连续给药。
所述的“同时给药”是指药物以各自独立的制剂形式同时给药，如在使用前预混后再同时给药。
“体表面积”可根据动物体重按照常规方法计算，例如对于体重60kg的成人，其体表面积约为1.6m2，对于体重0.2kg的实验大鼠，其体表面积约为0.03m2。本发明的药物当描述为以单位体表面积计算，例如含有250mg/m2左亚叶酸钠时，对与成人，其用药量约为400mg；对于实验大鼠，其用药量约为7.5mg。
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实施例
评价奥沙利铂、左亚叶酸钠和5FU经不同的剂量比例联合使用在大鼠肝癌模型中的抗肿瘤药效作用。
试验动物和模型：
肿瘤细胞信息：
试验设计：
每组的动物数及详细的给药途径、剂量和方案见下表。
表1.大鼠肝癌CBRH-7919皮下异种移植模型中给药剂量及给药方式
注：HAI为肝动脉灌注给药；ivgtt为静脉滴注给药；奥沙利铂在G3、G5-G8组均为动脉滴注给药，G4通过静脉滴注给药；G8组中先左亚叶酸钠，再5-FU给药；
各给药组供试品的配制应在超净工作台中完成。
细胞培养：
CBRH-7919大鼠肝癌细胞培养在含10％胎牛血清(FBS)的DMEM培养基中培养。细胞在37℃、5％CO2的环境中在加湿培养箱中培养。收集指数生长期的CBRH-7919细胞，PBS重悬至适合浓度用于裸鼠皮下肿瘤接种。
动物造模：
将培养好的大鼠肝癌细胞注射于裸小鼠背部皮下，成瘤后取出并切成1*1*1mm的瘤块，然后采用肝内隧道植入法将瘤块接种于wistar大鼠肝左叶。手术当天开始腹腔注射氢化可的松2mg/只/d*5d。手术后密切观察造模后荷瘤大鼠的生物学行为、生存情况等。待肿瘤生长至 平均体积约400mm3时根据肿瘤大小和大鼠体重随机分组给药。
分组：
在给药开始前，称量所有动物的体重，并用游标卡尺测量肿瘤体积。鉴于肿瘤体积会影响治疗的有效性，所以用随机分组设计的方法，根据大鼠的肿瘤体积对其分组，以保证不同组别间的肿瘤体积相近。每组测量结果的最终平均值将尽可能接近其他组的最终平均值。
给药：
大鼠接种种瘤后待肿瘤体积达到约400mm3后分别按照不同的给药方式和剂量进行给药。其中肝动脉灌注给药组给药时应用水合氯醛腹腔注射麻醉，沿腹白线做2.5-3cm切开，暴露肝脏及肿瘤，游标卡尺测定肿瘤长短径。分离肝脏与周围组织的粘连，将肝叶向上翻起，在胆总管的左侧，门静脉上方找到肝动脉，用眼科镊轻轻剥离出肝动脉及胃十二指肠动脉，手术显微镜下用1ml胰岛素注射器(针头29G)进行肝动脉穿刺，穿刺成功后缓慢注药。共计给药2次，分别测量每次给药后肿瘤的体积。
试验观察和数据收集：
大鼠接种肿瘤后，常规监测包括了肿瘤生长及治疗对动物正常行为的影响，具体内容有实验动物的活动性，摄食和饮水情况，体重增加或降低情况，眼睛、被毛及其它异常情况。试验过程中观察到的临床症状均记录在原始数据中。开始给药后，每周测量两次大鼠的体重和肿瘤的直径。肿瘤体积计算公式：肿瘤体积计算公式V(mm3)＝1/2×(a×b2)(其中a表示长径，b表示短径)。每次测量的相对肿瘤体积(RTV)计算公式为：RTV＝Vt/V0。其中V0为分组给药时体积，Vt为每一次测量时体积。抗肿瘤活性评价指标为相对肿瘤增值率T/C(％)，计算公式为：T/C(％)＝TRTV/CRTV*100％
TRTV：治疗组RTV；CRTV：模型组RTV；
给药、肿瘤测量及体重称量等全部过程都在超净工作台中进行。
统计分析：
采用统计软件对所得数据进行统计分析，计量资料用(平均值±SD)表示，比较采用GraphPad Prsim 8.3软件进行统计分析，以相对肿瘤增殖率≤40％且统计学P<0.05判定为药物有效。
试验结果：
肉眼观察：末次给药后开腹腔观察肝脏肿瘤，见肿瘤生长位置同治疗前一致，呈单发、类圆形，表面光滑。肉眼观察肿瘤大小，模型组大鼠的肿瘤体积明显增大，其余各给药组大鼠经不同的药物治疗后肿瘤体积明显缩小，给药一次、给药二次后体积大小排序均为G7组＜G6组＜G3组＜G8组＜G5组＜G4组＜G2组＜G1组。
经计算肿瘤生长抑制率如下，抑瘤率，相对肿瘤增殖率排序为G7组＜G6组＜G3组＜G8组＜G5组＜G4组＜G2组。给药前后各组肿瘤体积、大鼠体重及相对肿瘤增殖率比较详见下表。
表3.给药前后各组肿瘤体积对比表
表4.给药前后各组大鼠体重对比表
表5.给药后各组大鼠相对肿瘤增殖率对比表
试验结论：
在本次的大鼠肝癌抗肿瘤药效试验中，左亚叶酸钠以剂量250mg/m2、5FU以剂量2400～2800mg/m2采用肝动脉灌注的形式，联合奥沙利铂剂量85～130mg/m2，给药后可以显著降低肝癌大鼠体内的肿瘤体积，与模型组相比有极显著性差异(p＜0.001)。
当肝动脉灌注给药组中奥沙利铂的剂量为130mg/m2、85mg/m2和100mg/m2、左亚叶酸钠的剂量为250mg/m2和200mg/m2、5FU的剂量为2800mg/m2和2400mg/m2时，肝癌大鼠体内的肿瘤体积都明显小于单独给药5FU组和静脉滴注给药组，也说明了肝动脉灌注给药的方式具有明显的抗肿瘤药效作用。
此外，通过比较给药前后各组大鼠的体重，发现各肝动脉灌注给药组中大鼠体重略高于其它的组别，说明了肝动脉灌注给药后毒副作用降低。
综上，本次采用肝动脉灌注的形式对肝癌模型大鼠给药可以有效降低大鼠的肿瘤体积，具有良好的抗肿瘤药效作用。

Claims (12)

  1. 一种药物组合，所述药物组合含有左亚叶酸钠和氟尿嘧啶。
  2. 根据权利要求1所述药物组合在制备肝动脉灌注治疗肝癌或肝转移癌的药物的用途。
  3. 根据权利要求1所述的药物组合，其中左亚叶酸钠和氟尿嘧啶为各自独立的制剂形式，或为药物组合物的形式。
  4. 根据权利要求1-2任一所述的药物组合或或用途，所述左亚叶酸钠和氟尿嘧啶的重量比为1:5～15；优选1:8～12；更优选1:9～12。
  5. 根据权利要求1-2任一所述的药物组合或或用途，以单位体表面积计算，含有250mg/m2左亚叶酸钠；含有2400～2800mg/m2氟尿嘧啶。
  6. 根据权利要求1-2任一所述的药物组合或或用途，所述左亚叶酸钠和氟尿嘧啶以药物组合物的形式肝动脉灌注治疗肝癌或肝转移癌，或以各自独立的制剂形式错时、预混后同时肝动脉灌注治疗肝癌或肝转移癌。
  7. 根据权利要求1-2任一所述的药物组合或或用途，其还进一步含有奥沙利铂。
  8. 根据权利要求7所述的药物组合，以单位体表面积计算，含有奥沙利铂85～130mg/m2。
  9. 一种药物组合，所述药物组合含有左亚叶酸钠、氟尿嘧啶、奥沙利铂，以单位体表面积计算，含有250mg/m2左亚叶酸钠；含有2400～2800mg/m2氟尿嘧啶，奥沙利铂85～130mg/m2。
  10. 根据权利要求9所述的药物组合，其中左亚叶酸钠与氟尿嘧啶以各自独立的制剂形式预混后同时经肝动脉灌注施用；所述左亚叶酸钠与氟尿嘧啶重量比为1:5～15；且以单位体表面积计算，含有250mg/m2左亚叶酸钠。
  11. 包含权利要求9所述的药物组合在制备肝动脉灌注治疗肝癌或肝转移癌的药物的用途。
  12. 一种药物组合物，所述药物组合物含有如权利要求1所述的药物组合和药学上可接受的辅料；所述药物组合物中，所述左亚叶酸钠与氟尿嘧啶重量比为1:5～15；且以单位体表面积计算，含有250mg/m2左亚叶酸钠；所述左亚叶酸钠与氟尿嘧啶经肝动脉灌注施用。
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