WO2018121669A1 - 一种用于治疗癌症的药物组合物及其应用 - Google Patents

一种用于治疗癌症的药物组合物及其应用 Download PDF

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WO2018121669A1
WO2018121669A1 PCT/CN2017/119360 CN2017119360W WO2018121669A1 WO 2018121669 A1 WO2018121669 A1 WO 2018121669A1 CN 2017119360 W CN2017119360 W CN 2017119360W WO 2018121669 A1 WO2018121669 A1 WO 2018121669A1
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capecitabine
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treating cancer
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pharmaceutical composition
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陈晓华
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陈晓华
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Priority to JP2019536209A priority Critical patent/JP6845332B2/ja
Priority to ES17888483T priority patent/ES2842376T3/es
Priority to EP17888483.9A priority patent/EP3563856B1/en
Priority to US16/474,516 priority patent/US20200022965A1/en
Priority to KR1020197021557A priority patent/KR20190099500A/ko
Publication of WO2018121669A1 publication Critical patent/WO2018121669A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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  • the invention relates to a pharmaceutical composition, a kit and a application thereof for treating cancer, and belongs to the technical field of medicine.
  • 5-fluorouracil is one of the earliest anti-metabolic drugs widely used in the treatment of malignant tumors and is a thymidine synthetase inhibitor.
  • the anti-tumor effect of 5-fluorouracil is exact, but its half-life in vivo is short.
  • Clinical use generally requires continuous intravenous infusion, and its toxicity and adverse reactions are high, thus limiting its clinical application.
  • prodrugs of 5-fluorouracil and combinations with other drugs to increase their efficacy and reduce their side effects.
  • the chemical name is 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine nucleoside, a new anti-tumor drug developed by Swiss Roche, which was approved by the FDA in the United States in 1998.
  • the trade name is XELODA (Xeloda); currently China has approved the import of this product.
  • Capecitabine is clinically used for the treatment of advanced metastatic breast cancer, colorectal cancer, and other solid tumors. It has good anti-tumor effects and few adverse reactions.
  • Capecitabine is a highly potent and selective intratumoral activated oral fluorouracil carbamate antitumor drug that is converted to fluorouracil (FU) by three enzymes in the liver and tumor. It is completely passed through the gastrointestinal wall after oral administration, first catalyzed by the liver carboxylesterase to 5'-deoxy-5-fluorocytidine (5'-DFCR), and then through the cytosine deaminase in liver and tumor cells. Catalytic conversion to 5'-deoxy-fluorouracil (5'-DFUR), and finally catalyzed conversion to fluorouracil (FU) by thymidine phosphorylase (TP) to exert cytotoxic effects.
  • TP thymidine phosphorylase
  • capecitabine and tegafur are both prodrugs of 5-fluorouracil, the high selectivity and specificity of capecitabine for tumors is significantly better than that of tegafur.
  • Capecitabine has enhanced antitumor activity. The toxic side effects are greatly reduced, so it is widely used in clinical practice.
  • capecitabine The structure of capecitabine is as follows:
  • capecitabine Compared with tegafur, capecitabine is significantly different in both molecular structure and in vivo metabolism. Due to the large side effects and limited effects, tegafur has rarely been used clinically alone. Because of its excellent targeting, capecitabine has become the first choice for clinically anti-metabolic drugs for the treatment of tumors.
  • the pairs of fluorouracil (5-FU), tegafur (FT-207), and capecitabine are shown in Table 1.
  • TS-1 manufactured by Taiho Pharmaceutical Co., Ltd., contains a three-component antitumor agent which is an active ingredient of tegafur, gimaste and oxazine acid or a salt thereof.
  • FT-207 tegafur
  • ORTC orotate ribose transferase
  • DPD hepatic dihydropyrimidine dehydrogenase
  • DPD is the major rate-limiting enzyme for 5-FU degradation, and its maintenance of plasma 5-FU levels depends on DPD activity.
  • CDHP is a reversible inhibitor of DPD, and its effect of inhibiting DPD activity is 180 times that of uracil, thereby effectively inhibiting the degradation of 5-FU.
  • the main role of potassium oxonate is to inhibit the activity of ORTC in the small intestine.
  • ORTC In the metabolism of tegafur, about 10% of 5-FU enters the intestinal tissue, and phosphorylation is produced under the catalysis of orotate ribosyltransferase. This process is considered to be the main cause of intestinal toxic side effects. the reason.
  • the role of OXO is to effectively inhibit ORTC, thereby inhibiting the phosphorylation of 5-FU in the intestine.
  • Another significant feature of OXO is that after oral administration into the body, most of it is distributed on the surface of small intestinal mucosal cells, and only a small part of it enters the blood circulation, tumor tissue and other normal tissues.
  • 5-FU must be activated by metabolic conversion to pseudouridine nucleotides and pseudo-deoxyuridine nucleotides that interfere with DNA synthesis and RNA function due to 5-FU and its natural counterpart Uracil differs only in the 5-position fluorine substitution, which is easily activated in cancer patients. However, its structural similarity to uracil also causes it to be inactivated by rapid and extensive conversion to degradation products without anti-tumor activity. Dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting step for 5-FU degradation (inactivation). Studies have shown that inhibition of DPD can prolong the half-life of 5-FU in plasma.
  • DPD Dihydropyrimidine dehydrogenase
  • DPD inhibitors have been investigated, including inhibitors that irreversibly inactivate DPD, and inhibitors that reversibly inhibit DPD.
  • 5-ethynyl uracil also known as eniluracil
  • eniluracil is an irreversible inactivator of DPD that reduces or eliminates the metabolic inactivation of 5-FU, so in the presence of very low amounts of eniluracil, DPD is destroyed and can no longer inactivate 5-FU.
  • the patent CN101068549 proposes to combine anti-tumor with a DPD inhibitor (enuracil) + 5-FU prodrug (capecitabine).
  • One of the objects of the present invention is to provide a pharmaceutical composition for treating cancer.
  • it is a pharmaceutical composition capable of enhancing the antitumor effect of capecitabine and reducing side effects.
  • Another object of the present invention is to provide a pharmaceutical kit for clinical use which can enhance the antitumor effect of capecitabine and reduce side effects.
  • a third object of the present invention is to provide a method of treating mammalian susceptible 5-fluorouracil.
  • the present inventors conducted extensive research, and combined with the mechanism and effect of TS-1, studied a drug combination for enhancing the antitumor effect of capecitabine. It was found that when the ineffective dose of capecitabine alone was used in combination with an effective amount of anti-tumor synergistic effect of Gimmost and an effective amount of potassium oxonate to reduce side effects, the card could be significantly increased on the basis of reducing side effects.
  • the anti-tumor effect of piracetabine was used in combination with an effective amount of anti-tumor synergistic effect of Gimmost and an effective amount of potassium oxonate to reduce side effects.
  • the three components of the present invention are all known compounds, all of which can be prepared by a conventional method.
  • Gimaster includes its pharmaceutically acceptable salts.
  • the chloride ion of Gimaster can be replaced by a halogen ion such as fluorine, bromine and iodine atoms, and preferably 2,4-dihydroxy-5-chloropyridine, 2,4-dihydroxy-5-cyanopyridine or the like.
  • Potassium oxonate includes its pharmaceutically acceptable salts, including acid addition salts and salts of basic compounds.
  • Useful acids capable of forming acid addition salts are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, Methanesulfonic acid, benzoic acid and similar organic acids.
  • useful basic compounds capable of forming a salt of a pharmaceutically acceptable basic compound are sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogencarbonate and the like.
  • the key technical feature of the present invention is that it is found that Gimmost and potassium oxonate combined with capecitabine enhance the anti-tumor effect and reduce side effects, and the molar ratio between the above components is not the present invention.
  • Important technical features, all of which are known compounds, have a specific range of effective values in mammals, and therefore, the invention is not limited to the above range of molar ratios, including all doses that can be safely used in mammals. range.
  • the anti-tumor synergistic composition of the present invention is obtained by formulating a compound of Gimmost and potassium oxonate or a single preparation or two corresponding separate preparations.
  • the single formulation or two separate formulations may be administered simultaneously or separately with capecitabine formulated in an optional dosage form.
  • the invention also provides a pharmaceutical kit for treating cancer, which is used for enhancing the anti-tumor effect of capecitabine and reducing the side effects of capecitabine after the drug combination, and the kit 1 includes the component (I) and the group.
  • component (I) is an effective amount of anti-tumor synergistic effect of Gimmost
  • component (II) is an effective amount of potassium oxonate to reduce side effects.
  • component (I) and component (II) are contained in separate containers.
  • the two components can be separately combined with a pharmaceutically acceptable carrier to provide the formulation in an optional unit dosage form which is then administered.
  • component (I) and component (II) are contained in the same container.
  • the two components can be admixed with a pharmaceutically acceptable carrier to provide a single formulation in an optional unit dosage form followed by administration.
  • the above kit may be administered at any time when capecitabine is administered, that is, it may be administered prior to capecitabine administration, or concurrently with capecitabine, or after capecitabine administration.
  • the invention also provides a pharmaceutical kit for treating cancer, and the kit 2 comprises three components, namely component (I), component (II) and component (III), and component (I) is resistant.
  • the three components are each contained in a different container.
  • the three components are known compounds which can be admixed with a pharmaceutically acceptable carrier to provide in an optional unit dosage form and then administered Single preparation.
  • component (I) is contained in a separate container, and component (II) and component (III) are contained in the same container.
  • Component (II) and component (III) can be admixed with a pharmaceutically acceptable carrier to provide a single formulation in an optional unit dosage form which is then administered.
  • component (II) and component (III) are contained in separate containers, and component (I) is contained in a different container containing component (II) and component (III).
  • Component (I) and component (II) may be admixed with a pharmaceutically acceptable carrier to provide a single formulation in an optional unit dosage form followed by administration.
  • Component (I) and component (III) may be admixed with a pharmaceutically acceptable carrier to provide a single formulation in an optional unit dosage form followed by administration.
  • the above two components of the kit may be administered simultaneously, or may be administered in any combination of the three components in any order, regardless of the order.
  • the present invention provides a cancer drug for treating a mammalian susceptible 5-fluorouracil disease by administering an antitumor effective amount of capecitabine to a mammal, an antitumor effect synergistically effective amount of Gimmost, and reducing side effects An effective amount of potassium oxonate.
  • the dose of capecitabine is 0.05-800 mg/kg
  • the dose of Gimmost is 0.05-400 mg/kg
  • the dose of potassium oxonate is 0.05-800 mg/kg.
  • Example 1 is a histogram of tumor weight after two weeks of administration in the solvent group, the capecitabine group, the capecitabine + gemester group in Example 1;
  • Figure 2 is a histogram of tumor volume after two weeks of administration in the solvent group, the capecitabine group, the capecitabine + gemester group in Example 1;
  • Figure 3 is a sectional view of the tumor volume after two weeks of administration in the solvent group, the capecitabine group, the capecitabine + gemester group in Example 1;
  • Figure 4 is a graph showing the survival rate of the solvent group, the capecitabine group, the capecitabine + gemester group, the capecitabine + eniluracil group in Example 1;
  • Figure 5 is a graph showing the tumor volume of the solvent group, the capecitabine group, the capecitabine + gemester group, the capecitabine + enuridine group in Example 1;
  • 6 is a graph showing the survival rate of the solvent group, the 5-FU+Gimoster group, the capecitabine+Gimoster group in Example 1;
  • Figure 7 is a sectional view of the tumor volume of the solvent group, the capecitabine + gemester group, the capecitabine + gemester + potassium oxonate group in Example 1;
  • Figure 8 is a weight-loss diagram of the solvent group, the capecitabine + gemester group, the capecitabine + gemester + potassium oxonate group in Example 1;
  • Figure 9 is a graph showing the survival rate of the solvent group, the capecitabine + gemester + potassium oxonate group, the tegafur + gemester + oxonate group in Example 1.
  • Figure 10 is a line drawing of the body weight of the solvent group, capecitabine + gemester + potassium oxonate group, tegafur + gemester + oxonate group in Example 1.
  • Nude mice were implanted with colon cancer cell HCT116, and the tumors were grown to 200-300 mm 3 , randomly divided into groups of 8 and administered for 2 weeks.
  • the dosage regimen is as follows:
  • Card capecitabine
  • Kyrgyzstan Gimaster
  • oxygen potassium oxonate
  • en uridine: tegafur
  • solvent 0.5% CCNNa.
  • Gimester has a synergistic effect on capecitabine.
  • the dose of capecitabine group could not reduce the volume and weight of the tumor within 2 weeks, which was not statistically significant compared with the solvent group, and Gimester+ Compared with the capecitabine group, the capecitabine group significantly reduced the volume and weight of the tumor, which was statistically significant compared with the solvent group.
  • the efficacy of the capecitabine + gemester group and the capecitabine + eniluracil group is comparable, but the survival rate graph of Figure 4 shows that the cape His side + eniluracil group had more side effects than the capecitabine + gemester group.
  • Potassium oxonate can reduce the side effects of capecitabine combined with Gimmost.
  • the capecitabine + gemester + potassium oxonate group was similar to the capecitabine + gemester group, but from the weight line chart of Figure 8. Seen, the capecitabine + gemester + potassium oxonate group had no change in body weight compared with the control group, while the capecitabine + gemester group had more weight loss than the control group. Therefore, the capecitabine + gemester + potassium oxonate group was significantly able to reduce side effects relative to the capecitabine + gemester group.
  • capecitabine + Gimester + potassium oxonate combination is better than TS-1
  • Nude mice were implanted with colon cancer cell HCT116, and the tumors were grown to 100-200 mm 3 , randomized into groups of 8 rats for 19 days.
  • the dosing schedule is as follows:
  • the three groups of different molar ratio compositions reduced the volume and weight of the tumor at the time of administration for 19 days, wherein the 2, 3 groups of the kaki oxygen were statistically significant relative to the solvent group.

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Abstract

一种用于治疗癌症的药物组合物和试剂盒，用于增强卡培他滨的抗肿瘤效果且降低副作用，该药物组合物包含有抗肿瘤有效量的卡培他滨、抗肿瘤增效效应有效量的吉莫斯特以及降低副作用有效量的氧嗪酸钾，用于治疗对5-氟尿嘧啶敏感的哺乳动物的肿瘤。

Description

一种用于治疗癌症的药物组合物及其应用 技术领域
本发明涉及一种治疗癌症的药物组合物、试剂盒及其应用，属于药物技术领域。
背景技术
恶性肿瘤已经成为影响人类健康的主要疾病之一，目前恶性肿瘤的治疗很大程度上仍以化疗为主，但是化疗药物已经从传统的细胞毒性药物逐渐转变为具有靶向性且对肿瘤细胞具有高选择性的靶向小分子药物。5-氟尿嘧啶(5-FU)是最早广泛应用于治疗恶性肿瘤的抗代谢类药物之一，是胸腺嘧啶合成酶抑制剂。5-氟尿嘧啶抗肿瘤作用疗效确切，但是其在体内半衰期短，临床使用一般需要静脉持续灌注给药，毒性和不良反应较高，因而限制了其在临床上的应用。为了克服上述缺陷，科研工作者开发了5-氟尿嘧啶的前药以及与其他药物的组合从而增加其疗效并降低其副作用。
1、替加氟
化学名称：1-(四氢-2-呋喃基)-5-氟-2,4(1H,3H)-嘧啶二酮，属于嘧啶类抗癌药之一，它是5-氟尿嘧啶(5-FU)的前体药物，对多数实体瘤有抑制作用。其在体内能干扰阻断DNA、RNA及蛋白质的生物合成，从而产生其抗癌作用。但由于存在比较严重的骨髓抑制，肠胃道反应和肝肾损伤等副作用，故在临床上已很少单独使用，常常需要和其他药物配合使用来减小其严重的副作用。
替加氟的结构式如下：
Figure PCTCN2017119360-appb-000001
2、卡培他滨
化学名为5’-脱氧-5-氟-N-[(戊氧基)羰基]-胞嘧啶核苷，是由瑞士罗氏公司研制的新型抗肿瘤药物，于1998年被FDA批准在美国上市，商品名为XELODA(希罗达)；目前我国已批准进口该产品。卡培他滨临床用于晚期转移性乳腺癌，结、直肠癌以及其他实体瘤的治疗，具有良好的抗肿瘤作用和极少的不良反应。
卡培他滨(capecitabine)是一种极具潜力的选择性肿瘤内激活的口服氟尿嘧啶氨基甲酸酯类抗肿瘤药物，它通过肝脏和肿瘤内的3种酶转化为氟尿嘧啶(FU)。其口服后完整地通过胃肠壁，首先经肝脏羧酸酯酶催化代谢为5'-脱氧-5-氟胞苷(5'-DFCR)，然后经肝脏和肿瘤细胞中的胞苷脱氨酶催化转化为5'-脱氧-氟尿嘧啶(5'-DFUR)，最后经胸苷磷酸化酶(TP)催化转化为氟尿嘧啶(FU)而发挥细胞毒作用。卡培他滨和替加氟虽然都是5-氟尿嘧啶的前药，但卡培他滨对肿瘤的高度选择性和特异性明显优于替加氟，卡培他滨在抗肿瘤活性增强的同时毒副作用大大减少，因此在临床上应用广泛。
卡培他滨结构式如下:
Figure PCTCN2017119360-appb-000002
相对于替加氟，卡培他滨无论在分子结构还是在体内代谢方式上均显著不同。由于副作用大且效果存在局限，替加氟在临床上已经很少单独使用。而卡培他滨由于其优异的靶向性，较低的副作用已成为临床上治疗肿瘤的抗代谢类药物的首选。氟尿嘧啶(5-FU)、替加氟(FT-207)、卡培他滨三者的对比如表1所示。
Figure PCTCN2017119360-appb-000003
表1
3、TS-1：
商标：TS-1，Taiho Pharmaceutical Co.，Ltd.制造，含有作为活性成分的替加氟、吉莫斯特和氧嗪酸或其盐的三组分抗肿瘤剂。
吉莫斯特(CDHP)和氧嗪酸钾(OXO)分别单独使用没有明显的抗癌 活性，他们与替加氟联合使用是为了提高疗效和降低毒性。
CDHP的作用是为了提高替加氟(FT-207)的抗癌疗效，当FT-207口服进入体内后，先在肝脏P450活化酶的催化下转变成5-FU，之后除10％左右进入肠道并在乳清酸核糖转移酶(ORTC)催化下产生磷酸化外，其余90％左右的5-FU是在肝脏二氢嘧啶脱氢酶(DPD)的催化下，循5-FU的代谢途径转变成三磷酸氟尿苷(FUTP)和一磷酸去氧氟尿苷(FdUMP)两个活性产物发挥抗癌作用。因此，DPD是5-FU降解的主要限速酶，其血浆5-FU水平的保持取决于DPD活性。CDHP是DPD的可逆性抑制剂，其抑制DPD活性的效果是尿嘧啶的180倍，因而能够有效抑制5-FU的降解。
氧嗪酸钾的主要作用是抑制小肠组织ORTC的活性。在替加氟的代谢过程中，有10％左右的5-FU进入肠道组织，在乳清酸核糖转移酶的催化下，产生磷酸化，这一过程被认为是产生肠道毒副作用的主要原因。OXO的作用特点是能有效的抑制ORTC，进而抑制肠道中5-FU的磷酸化。OXO的另外一个显著的特点是口服进入体内后，绝大部分分布于小肠粘膜细胞表面，只有极少部分进入血液循环、肿瘤组织及其他正常组织。
因为吉莫斯特的增效作用，此抗肿瘤剂的抗肿瘤效果增大，吉莫斯特对5-FU的降解抑制效果是尿嘧啶的180倍。而且，当替加氟和吉莫斯特结合使用时，氧嗪酸及其盐尤其抑制可能伴随着抗肿瘤效果增强的肠胃中毒性的增加，从而降低副作用。
4、DPD抑制剂+5-FU前药组合
5-FU必须通过代谢转化成伪尿苷核苷酸和伪脱氧尿苷核苷酸而被激活，所述伪核苷酸能干扰DNA合成和RNA功能，由于5-FU与它的天然对应物尿嘧啶的不同仅在于5位的氟取代，它在癌症患者体内易被激活。但是，它与尿嘧啶的结构相似性也导致它被快速和广泛的转化成没有抗肿瘤活性的降解产物而失活。二氢嘧啶脱氢酶(DPD)是 5-FU降解(失活)的第1个和限速的步骤。研究表明，抑制DPD能延长5-FU在血浆中的半衰期。现已研究了若干种DPD抑制剂，包括不可逆地使DPD失活的抑制剂，以及可逆地抑制DPD的抑制剂。5-乙炔基尿嘧啶，又被称作恩尿嘧啶，它是DPD的不可逆的灭活剂，能减少或消除5-FU的代谢失活，因此在存在极低量恩尿嘧啶的情况下，DPD被破坏，并且不再能够使5-FU失活。鉴于此，专利CN101068549中提出将DPD抑制剂(恩尿嘧啶)+5-FU前药(卡培他滨)联用抗肿瘤。
发明内容
本发明的目的之一是提供一种用于治疗癌症的药物组合物。特别是一种能够增强卡培他滨的抗肿瘤效果，并且降低副作用的药物组合物。
本发明的目的之二是提供一种临床使用的，能够增强卡培他滨的抗肿瘤效果，降低副作用的药物试剂盒。
本发明的目的之三是提供一种哺乳动物易感5-氟尿嘧啶的治疗方法。
根据上述的现状，本发明人进行了广泛的研究，结合TS-1的作用机理及效果，研究了增强卡培他滨的抗肿瘤作用的药物组合。结果发现，当单独治疗无效剂量的卡培他滨在组合使用抗肿瘤增效效应有效量的吉莫斯特以及降低副作用有效量的氧嗪酸钾时，可以在降低副作用的基础上显著增加卡培他滨的抗肿瘤效果。
本发明提供一种治疗癌症的药物组合物，组合物中卡培他滨：吉莫斯特：氧嗪酸钾＝1:0.1-3:0.5-4，其中三者的比值为摩尔比。
作为优选，组合物中卡培他滨：吉莫斯特：氧嗪酸钾＝1:0.4:1，其中三者的比值为摩尔比。
本发明的三个组分都是已知的化合物，均可以通过常规方法制备。
吉莫斯特包括其在药学上可接受的盐。其中吉莫斯特的氯离子可用卤素离子代替，例如：氟、溴和碘原子等，优选2,4-二羟基-5-氯 吡啶、2,4-二羟基-5-氰基吡啶等。
氧嗪酸钾包括其在药学上可接受的盐，包括酸加成盐和碱性化合物的盐。能够形成酸加成盐的有用的酸是盐酸、硫酸、磷酸、氢溴酸等无机酸，草酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、丙二酸酸、甲磺酸、苯甲酸和类似的有机酸。能够形成药学上可接受的碱性化合物的盐的有用的碱性化合物的实例为氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠、碳酸氢钾等。
需要特别说明的是，本发明的重点技术特征在于发现吉莫斯特与氧嗪酸钾联合卡培他滨增强抗肿瘤效果，降低副作用，而上述各个组分之间的摩尔比不是本发明的重要技术特征，三者都是已知化合物，在哺乳动物上用量均有具体的有效数值范围，因此，本发明不局限于上述的摩尔比范围值，包括能够在哺乳动物上安全使用的所有剂量范围。
本发明的抗肿瘤增效作用的组合物是通过配制吉莫斯特和氧嗪酸钾的化合物或其成单一制剂或成两个相应单独的制剂获得。在单一制剂或两个单独的制剂可以独立地或与一个可选的剂型配制的卡培他滨同时给药。
本发明还提供一种治疗癌症的药物试剂盒一，用于增强卡培他滨的抗肿瘤效果并降低药物联用后卡培他滨的副作用，试剂盒一中包括组分(Ⅰ)以及组分(Ⅱ)，组分(Ⅰ)为抗肿瘤增效效应有效量的吉莫斯特，组分(Ⅱ)为降低副作用有效量的氧嗪酸钾。
优选地，组分(Ⅰ)以及组分(Ⅱ)被容纳在分开的容器中。两种组分可以分别与药学上可接受的载体混合，以提供在一个可选的单位剂量形式，然后施用的制剂。
优选地，组分(Ⅰ)以及组分(Ⅱ)被容纳在同一容器中。两种组分可以与药学上可接受的载体相互混合，以提供在一个可选的单位剂量形式，然后施用的单一制剂。
上述试剂盒可以在卡培他滨施用时的任何时间给药，也就是说可以在卡培他滨施用前施用，或者与卡培他滨同时施用，或者在卡培他滨施用后再施用。
本发明还提供一种治疗癌症的药物试剂盒二，试剂盒二包括三个组份，分别为组分(Ⅰ)、组分(Ⅱ)及组分(Ⅲ)，组分(Ⅰ)为抗肿瘤有效量的卡培他滨，组分(Ⅱ)为抗肿瘤增效效应有效量的吉莫斯特，组分(Ⅲ)为降低副作用有效量的氧嗪酸钾。
优选地，三个组份分别容纳在不同的容器中。三种组分(卡培他滨、吉莫斯特以及氧嗪酸钾)都是已知化合物，可以与药学上可接受的载体相互混合，以提供在一个可选的单位剂量形式，然后施用的单一制剂。
优选地，组分(Ⅰ)容纳在单独的容器中，组分(Ⅱ)及组分(Ⅲ)容纳在同一容器中。组分(Ⅱ)及组分(Ⅲ)可以与药学上可接受的载体相互混合，以提供在一个可选的单位剂量形式，然后施用的单一制剂。
优选地，组分(Ⅱ)及组分(Ⅲ)容纳在不同的容器中，组分(Ⅰ)包含在含有组分(Ⅱ)及组分(Ⅲ)的不同容器中。组分(Ⅰ)和组分(Ⅱ)可以与药学上可接受的载体相互混合，以提供在一个可选的单位剂量形式，然后施用的单一制剂。组分(Ⅰ)和组分(Ⅲ)可以与药学上可接受的载体相互混合，以提供在一个可选的单位剂量形式，然后施用的单一制剂。
上述试剂盒二、三种组分可以同时施用，也可以三种组分顺序任意组合施用，不分先后顺序。
本发明提供了用于治疗哺乳动物易感5-氟尿嘧啶疾病的癌症药物，通过向哺乳动物施用抗肿瘤有效量的卡培他滨，抗肿瘤效果增效有效量的吉莫斯特，和降低副作用有效量的氧嗪酸钾。
上述应用中卡培他滨的剂量为0.05-800mg/kg，吉莫斯特的剂量 为0.05-400mg/kg，氧嗪酸钾的剂量为0.05-800mg/kg。
附图说明
图1是实施例1中溶剂组、卡培他滨组、卡培他滨+吉莫斯特组给药两周后的瘤体重柱状图；
图2是实施例1中溶剂组、卡培他滨组、卡培他滨+吉莫斯特组给药两周后的瘤体积柱状图；
图3是实施例1中溶剂组、卡培他滨组、卡培他滨+吉莫斯特组给药两周后的瘤体积折线图；
图4是实施例1中溶剂组、卡培他滨组、卡培他滨+吉莫斯特组、卡培他滨+恩尿嘧啶组的存活率图；
图5是实施例1中溶剂组、卡培他滨组、卡培他滨+吉莫斯特组、卡培他滨+恩尿嘧啶组的瘤体积折线图；
图6是实施例1中溶剂组、5-FU+吉莫斯特组、卡培他滨+吉莫斯特组的生存率图；
图7是实施例1中溶剂组、卡培他滨+吉莫斯特组、卡培他滨+吉莫斯特+氧嗪酸钾组的瘤体积折线图；
图8是实施例1中溶剂组、卡培他滨+吉莫斯特组、卡培他滨+吉莫斯特+氧嗪酸钾组的体重折线图；
图9是实施例1中溶剂组、卡培他滨+吉莫斯特+氧嗪酸钾组、替加氟+吉莫斯特+氧嗪酸组的存活率图；
图10是实施例1中溶剂组、卡培他滨+吉莫斯特+氧嗪酸钾组、替加氟+吉莫斯特+氧嗪酸组的体重折线图。
具体实施方式
下面结合附图对本发明作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。
实施例1：
实验方案:
裸鼠植入结肠癌细胞HCT116，待瘤体长到200-300mm 3，随机分组，每组8只，给药2周，给药方案如下表2：
Figure PCTCN2017119360-appb-000004
表2
注释：卡：卡培他滨；吉：吉莫斯特；氧：氧嗪酸钾；恩：恩尿嘧啶替：替加氟；溶剂：0.5％CMCNa。
实验数据：
1、目的：吉莫斯特对卡培他滨有协同增效的作用。
从图1、图2、图3中可以看到，该剂量的卡培他滨组在2周时间内无法缩小瘤的体积和重量，相对于溶剂组无统计学意义，而吉莫斯特+卡培他滨组对比卡培他滨组，明显缩小了瘤的体积和重量，相对于溶剂组具有统计学意义。
2、目的：吉莫斯特与卡培他滨联用增效作用比恩尿嘧啶与卡培他滨联用的效果更优。
从图5的瘤体积折线图中可以看到，卡培他滨+吉莫斯特组和卡培他滨+恩尿嘧啶组的疗效相当，但是从图4的存活率图可看出卡培他滨+恩尿嘧啶组比卡培他滨+吉莫斯特组毒副作用大。
3、目的：5-FU+DPD抑制剂作用差于5-FU前药+DPD抑制剂DPD抑制剂选用吉莫斯特，从图6的生存率图看出，5-FU+吉莫 斯特组比卡培他滨+吉莫斯特组毒副作用大。
4、目的：氧嗪酸钾能降低卡培他滨与吉莫斯特联用后的副作用。
从图7的瘤体积中可以看到，卡培他滨+吉莫斯特+氧嗪酸钾组与卡培他滨+吉莫斯特组的疗效相似，但是从图8的体重折线图上看，卡培他滨+吉莫斯特+氧嗪酸钾组与对照组相比，体重基本无变化，而卡培他滨+吉莫斯特组与对照组相比，体重减少比较多，因此，卡培他滨+吉莫斯特+氧嗪酸钾组相对于卡培他滨+吉莫斯特组明显能够减少副作用。
5、目的：卡培他滨+吉莫斯特+氧嗪酸钾组合优于TS-1
从图9的存活率来看，随着时间的推移，TS-1的生存率明显不如卡培他滨+吉莫斯特+氧嗪酸钾组。从图10的体重图来看，很明显，卡培他滨+吉莫斯特+氧嗪酸钾组的体重与对照组无明显区别，而TS-1组的体重下降明显，因此，卡培他滨+吉莫斯特+氧嗪酸钾组相对于TS-1组，副作用更小。
实施例2：
实验方案：
裸鼠植入结肠癌细胞HCT116，待瘤体长到100-200mm 3，随机分组，每组8只，给药19天，给药方案如下表3：
Figure PCTCN2017119360-appb-000005
表3
注释：溶剂对照组：0.5％CMCNa卡吉氧：卡培他滨+吉莫斯特+氧嗪酸钾
d1：开始给药第一天d19：给药结束时间
*p<0.05**p<0.01，vs溶剂对照组。
实验数据：
从表3中可以看到，三组不同摩尔比的组合物在19天的给药时间均缩小瘤的体积和重量，其中卡吉氧2、3组相对于溶剂组有统计学意义。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变形，这些改进和变形也应视为本发明的保护范围。

Claims (9)

  1. 一种治疗癌症的药物组合物，用于增强卡培他滨的抗肿瘤效果且降低副作用，其特征在于：所述药物组合物包含有抗肿瘤有效量的卡培他滨、抗肿瘤增效效应有效量的吉莫斯特以及降低副作用有效量的氧嗪酸钾。
  2. 如权利要求1所述的一种治疗癌症的药物组合物，其特征在于：所述组合物中卡培他滨：吉莫斯特：氧嗪酸钾＝1:0.1-3:0.5-4，其中三者的比值为摩尔比。
  3. 如权利要求1所述的一种治疗癌症的药物组合物，其特征在于：所述组合物中卡培他滨：吉莫斯特：氧嗪酸钾＝1:0.4:1，其中三者的比值为摩尔比。
  4. 如权利要求1所述的一种治疗癌症的药物组合物，其特征在于：所述吉莫斯特包括其在药学上可接受的盐。
  5. 如权利要求1所述的一种治疗癌症的药物组合物，其特征在于：所述氧嗪酸钾包括其在药学上可接受的盐，包括酸加成盐和碱性化合物的盐。
  6. 一种治疗癌症的药物试剂盒，其特征在于：所述试剂盒包括三个组份，分别为组分(Ⅰ)、组分(Ⅱ)及组分(Ⅲ)，组分(Ⅰ)为抗肿瘤有效量的卡培他滨，组分(Ⅱ)为抗肿瘤增效效应有效量的吉莫斯特，组分(Ⅲ)为降低副作用有效量的氧嗪酸钾。
  7. 如权利要求6所述的一种治疗癌症的药物试剂盒，其特征在于：所述吉莫斯特包括其在药学上可接受的盐。
  8. 如权利要求6所述的一种治疗癌症的药物试剂盒，其特征在 于：所述氧嗪酸钾包括其在药学上可接受的盐，包括酸加成盐和碱性化合物的盐。
  9. 如权利要求1-8中的任意一项药物组合物或者试剂盒在用于制备治疗哺乳动物易感5-氟尿嘧啶药物中的用途。
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