WO2019228524A1 - 用于治疗肾癌的药物组合物及其应用 - Google Patents

用于治疗肾癌的药物组合物及其应用 Download PDF

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WO2019228524A1
WO2019228524A1 PCT/CN2019/089637 CN2019089637W WO2019228524A1 WO 2019228524 A1 WO2019228524 A1 WO 2019228524A1 CN 2019089637 W CN2019089637 W CN 2019089637W WO 2019228524 A1 WO2019228524 A1 WO 2019228524A1
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acid
pharmaceutical composition
chlorogenic acid
coumaric
composition
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French (fr)
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张洁
陈晓光
黄望
张雅
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四川九章生物科技有限公司
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Priority to US15/734,105 priority Critical patent/US20210330626A1/en
Publication of WO2019228524A1 publication Critical patent/WO2019228524A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of biomedicine, and particularly relates to a pharmaceutical composition and use thereof in preparing a drug for treating renal cancer.
  • Renal cell carcinoma referred to as kidney cancer
  • kidney cancer is one of the most common tumors of the urinary system, with an incidence of 2% of adult malignancies.
  • the incidence of renal cell carcinoma ranks second in urinary tumors, second only to bladder cancer.
  • Epidemiological survey results show that there were 63,000 new cases and 14,000 deaths from kidney cancer in the United States in 2016, which is the 9th most common cancer.
  • renal cancer patients With the continuous advancement of diagnostic technology, renal cancer patients have been treated earlier, and the overall 5-year survival rate of renal cancer has reached 74%, but only 12% have advanced metastases. Therefore, it is of great clinical significance to explore and find effective drugs for treating renal cancer to improve the survival rate of renal cancer patients.
  • Radiotherapy for the treatment of renal cancer, surgical treatment is the first choice for localized renal cancer. Radical nephrectomy or nephron-sparing surgery can be selected according to the stage and classification of the patient's tumor.
  • renal cancer is generally resistant to chemotherapeutic drugs, and there is no ideal breakthrough in chemotherapy.
  • Chemotherapy based on drugs such as gemcitabine and 5-fluorouracil has improved the efficacy to some extent, but it has a significant effect on progressive survival and overall survival. No significant change in period.
  • kidney cancer is not sensitive to radiation, so it is traditionally considered to be ineffective, but as a palliative treatment for advanced unresectable kidney cancer, it can achieve the purpose of reducing local pain and all other symptoms such as hematuria to improve the quality of life of patients.
  • preoperative radiotherapy can reduce the tumor volume, reduce tumor cell spread during the operation, and reduce local water, which is helpful for intraoperative separation.
  • Chlorogenic acid is widely present in various medicinal plants, such as honeysuckle. At present, the chemical structure of it has been clear. Some people have conducted medicinal research on it, and reported that chlorogenic acid can be used to treat tumors and other diseases. Patent CN201110373137 discloses that chlorogenic acid has a certain therapeutic effect on renal cancer, which directly targets the molecular mechanism that causes canceration, is more selective and effective than traditional chemotherapy, and has no antagonistic effect in combination with paclitaxel drugs.
  • the structural formula of the chlorogenic acid is as follows:
  • Coumaryl quinic acid is similar to chlorogenic acid and is widely present in higher plants. In the biosynthetic pathway, it is generally believed that coumaryl CoA and caffeoyl CoA are respectively catalyzed to combine with quinic acid to form coumaryl quinine. Nitric acid and chlorogenic acid. At present, there is no report on the study of the activity of coumarylquinic acid in the prior art.
  • a first aspect of the present invention is to provide a pharmaceutical composition for treating renal cancer, which includes chlorogenic acid (Colorarylquinic acid) and coumarylquinic acid (Coumarylquinic acid).
  • the mass ratio of chlorogenic acid to coumarylquinic acid is 100: 0.01-10; further, the mass ratio of chlorogenic acid to coumarylquinic acid is 100: 0.01 -1.
  • the pharmaceutical composition includes chlorogenic acid, coumaric quinic acid, and a targeted drug, and the mass ratio of the three is 100: 0.01-1: 0.1-1.
  • the targeted drug is selected from one of sorafenib, sunitinib, and pazopanib.
  • the second aspect of the present invention provides a pharmaceutical preparation, which is prepared by using the above pharmaceutical composition as an active ingredient and adding a pharmaceutically acceptable excipient.
  • the pharmaceutical formulation is an oral formulation or an injection formulation.
  • the excipient is selected from the group consisting of starch, ⁇ -cyclodextrin, dextrin, carbomer, microcrystalline cellulose, hydroxypropylmethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl Sodium cellulose, polyethylene glycol (PEG), sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, mannitol, sodium lauryl sulfate, croscarmellose sodium, lactose , Glucose, vitamins, glutathione, folic acid, polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone, magnesium stearate, talc, micronized silica gel, aspartame, sweet orange flavor, sodium bisulfite, One or more of sodium bicarbonate, sodium carbonate, and enteric coating powder.
  • PEG polyethylene glycol
  • PVP polyvinylpyrrolidone
  • PVP polyvinyl
  • a third aspect of the present invention provides the use of the pharmaceutical composition in preparing a medicament for treating renal cancer.
  • the administration time and the number of administrations of the pharmaceutical composition of the present invention need to be determined according to the specific diagnosis result of the condition, which is within the technical scope grasped by those skilled in the art.
  • the effective dose of all drugs to humans can be converted by the effective dose of the drug to mice, which is easy for those skilled in the art to realize. of.
  • the present invention finds that although chlorogenic acid and coumaric quinic acid are relatively similar in structure, the inhibitory effects of the two on renal cancer cell lines are quite different, and chlorogenic acid has a significant inhibitory effect on renal cancer cells, and Coumarylquinic acid has only a very weak inhibitory effect. Surprisingly, there was a significant synergy in the treatment of kidney cancer when the two were combined. Furthermore, the present invention also found that when chlorogenic acid and coumaric quinic acid are combined with first-line targeted drugs for treating renal cancer, the synergistic effect is the best. In order to facilitate the clinical application of the pharmaceutical composition, the present invention also provides related preparations of the pharmaceutical composition.
  • the synergistic effect refers to a biological effect after the combination of components, and the activity of the composition is significantly higher than that of a single component when compared to the content required to produce a given biological effect based on the use of a single component alone.
  • the mass ratio of chlorogenic acid to coumarylquinic acid is 100: 0.01-10; further, the mass ratio of chlorogenic acid to coumarylquinic acid is 100: 0.01 -1.
  • the mass ratio of the chlorogenic acid to coumaric quinic acid may be 100: 0.01, 100: 0.1, 100: 0.2, 100: 0.5, 100: 1, 100: 2, 100: 5, 100 : 10.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • Example 1 Formulation of the oral preparation of the pharmaceutical composition of the present invention
  • Preparation method Aseptically weigh the chlorogenic acid and coumaryl quinic acid according to the prescription, mix them evenly, and sterilize them into powders.
  • Preparation method Weigh out chlorogenic acid, coumaryl quinic acid, filler, binder, granulate, granulate, and divide into granules according to the prescription.
  • Preparation method Weigh out chlorogenic acid, coumaric quinic acid, filler, binder, granulate, whole granule, add lubricant, and tablet according to the prescription to obtain tablets.
  • the filler is one or more of mannitol, lactose, starch, microcrystalline cellulose, and dextrin; the binder is sodium carboxymethyl cellulose, PVP; the lubricant is magnesium stearate, talc, Micronized silica gel.
  • Preparation method (1) Weigh out chlorogenic acid and coumarylquinic acid aseptically according to the prescription, mix them evenly, and sterilize the powder into injections.
  • Preparation method (2) Weigh out chlorogenic acid and coumarylquinic acid according to the prescription, dissolve them in water for injection, filter and sterilize, freeze-dry to obtain lyophilized powder injection.
  • Preparation method Weigh out chlorogenic acid, coumaric quinic acid, stent, and antioxidant according to the prescription, dissolve it in water for injection, filter and sterilize, freeze-dry to obtain lyophilized powder injection.
  • the stent is mannitol, lactose, glucose; the antioxidants are sodium bisulfite, vitamins, glutathione, and folic acid.
  • Test drug 1 chlorogenic acid
  • Test drug 2 Coumaryl quinic acid
  • Test drug 3 chlorogenic acid and coumaric quinic acid composition (100: 0.01)
  • Test drug 4 Composition of chlorogenic acid and coumaric quinic acid (100: 0.1)
  • Test drug 5 Composition of chlorogenic acid and coumaric quinic acid (100: 1)
  • Test drug 6 Composition of chlorogenic acid and coumaric quinic acid (100: 5)
  • Test drug 7 Composition of chlorogenic acid and coumaric quinic acid (100: 10)
  • Human kidney cancer cell line A498 and mouse kidney cancer cell line RuCa were passaged just before use. Cells with good growth status and in the logarithmic phase were used for backup.
  • Medium and reagents medium RPML1640 (Gibco), calf serum (Lanzhou Minhai), penicillin (North China Pharmaceutical Co., Ltd.), streptomycin sulfate (North China Pharmaceutical Co., Ltd.), WST-1 (Roche Corporation, USA) ).
  • Carbon dioxide cell incubator (SANYO, Japan), IX70 inverted phase contrast fluorescence microscope (Olympus, Japan), biosafety cabinet (US NUAIRE), ⁇ -Quant microplate analyzer (BioTek), culture vessel: 96-well culture plate, culture bottle (BD company).
  • WST-1 Cell Proliferation Reagent (Roche 11644807001) reagents are refrigerated as required.
  • the cells were adhered the following day after the inoculation, and the drugs were added in the following groups, and the cells were allowed to stand for 48 hours.
  • the wells of the normal control group of tumor cells were set, and no drug treatment was performed, and only an equal amount (100 ⁇ l) of complete medium was added, and the experiment was performed simultaneously with the test drug group.
  • Composition of chlorogenic acid and coumaric quinic acid (100: 0.01) 1.058 55.03% Composition of chlorogenic acid and coumaric quinic acid (100: 0.1) 0.900 61.78% Composition of chlorogenic acid and coumaric quinic acid (100: 1) 1.270 46.03% Composition of chlorogenic acid and coumaric quinic acid (100: 5) 1.587 32.57% Composition of chlorogenic acid and coumaric quinic acid (100: 10) 1.857 21.09% Negative control group 2.354 ⁇ -
  • chlorogenic acid monomer compound test drug had a certain effect on cell growth; coumaric quinic acid had almost no effect on cell growth; and
  • the test drug group of chlorogenic acid and coumaric quinic acid composition has a significant inhibitory effect on the growth of human kidney cancer cell line A498, and in the ratio of the two monomers 100: 0.01 to 100: 10, each composition All can inhibit the growth of human kidney cancer cell line A498.
  • the composition's inhibitory effect on human kidney cancer cell line A498 increases first and then decreases, of which In the ratio of 100: 0.01 to 100: 1, the two monomer compounds have a synergistic effect, and the ratio of 100: 0.1 is the best.
  • the cell morphology was observed under an inverted microscope.
  • the chlorogenic acid monomer compound test drug had a certain effect on cell growth, and some cells became round, shed, and suspended; Coumarin The acylquinic acid has almost no effect on cell growth, and the cells adhere to the wall, showing irregular growth, while the test drug group of the chlorogenic acid and coumaric quinic acid composition has a significant inhibitory effect on the growth of RuCa in rat kidney cancer cell lines.
  • the chlorogenic acid monomer compound test drug had a certain effect on cell growth; coumaric quinic acid had almost no effect on cell growth; and
  • the test drug group of the chlorogenic acid and coumaric quinic acid composition has a significant inhibitory effect on the growth of RuCa in rat kidney cancer cell lines, and in the ratio of two monomers of 100: 0.01 to 100: 10, each composition All can inhibit the growth of RuCa in rat kidney cancer cell lines.
  • the composition's inhibitory effect on RuCa in rat kidney cancer cell lines increases first and then decreases. In the ratio of 100: 0.01 to 100: 1, the two monomer compounds have a synergistic effect, and the ratio of 100: 0.1 is the best.
  • the chlorogenic acid monomer compound has a certain effect on cell growth; coumaryl quinic acid has almost no effect on cell growth, and the composition ratio of chlorogenic acid and coumaryl quinic acid is 100: 0.01 to
  • the test drug group at a ratio of 100: 10 has an inhibitory effect on the growth of human kidney cancer cell line A498 and mouse kidney cancer cell line RuCa.
  • the composition The inhibitory effect on RuCa of human kidney cancer cell line A498 and mouse kidney cancer cell line first increased and then decreased, and the two monomers had a synergistic effect in the range of 100: 0.01 to 100: 1. , And the best ratio of 100: 0.1.
  • A, B, and C refer to the doses of the three components in the pharmaceutical composition
  • Ae, Be, and Ce refer to the doses of the individual components required to use a single compound alone to achieve the tumor suppressing efficiency of the pharmaceutical composition.
  • composition 1 Composition 2
  • Composition 3 Composition 4 CI 0.369 0.230 0.212 0.484
  • chlorogenic acid and coumaric quinic acid produced a significant synergy, and when sorafenib was added to the pharmaceutical composition, the synergy between the three was further enhanced.
  • chlorogenic acid, coumarylquinic acid, and sorafenib produced significant synergistic effects on the mouse kidney cancer cell line RuCa.
  • chlorogenic acid and coumaric quinic acid have a synergistic effect with sunitinib or pazopanib.
  • chlorogenic acid and coumaryl quinic acid Acid and sunitinib produced a significant synergy, but the synergy index with pazopanib was only about 1, indicating that it was only an additive effect.
  • the above results indicate that the chlorogenic acid and coumaric quinic acid composition can produce significant synergistic effects with first-line treatment of renal cancer, and have broad clinical application prospects.
  • Test drug 1 chlorogenic acid
  • Test drug 2 Coumaryl quinic acid
  • Test drug 3 chlorogenic acid and coumaric quinic acid composition (100: 0.01)
  • Test drug 4 Composition of chlorogenic acid and coumaric quinic acid (100: 0.1)
  • Test drug 5 Composition of chlorogenic acid and coumaric quinic acid (100: 1)
  • Test drug 6 Composition of chlorogenic acid and coumaric quinic acid (100: 5)
  • Test drug 7 Composition of chlorogenic acid, coumaric quinic acid, and sorafenib (100: 0.1: 0.5)
  • Murine kidney cancer cell line RuCa was established by inoculating subcutaneously into the axillary of mice. The cell inoculation amount was 1 ⁇ 10 7. After transplantation, the transplanted tumor was used in mice for 3 passages.
  • mice 80 BABL / C-nu mice, half male and half male, weighing 18 to 22 g;
  • mice of the above specifications were taken and inoculated subcutaneously in the right armpit of the mice with 0.1 ml of cell suspension.
  • test drug group 1 the test drug group 2
  • test drug group 3 the test drug group 4
  • test drug group 4 There were 5 test drugs, 6 test drugs, 7 test drugs, and negative group.
  • the test drug group was injected intraperitoneally (ip) at 30 mg / kg / time once a day for 15 consecutive times; the negative group was injected intraperitoneally with the same dose of normal saline once a day and weighed before administration.
  • mice were sacrificed by cervical dissection and weighed, and the tumor was stripped to calculate the tumor suppression rate.
  • Tumor inhibition rate% [1- (average tumor weight in the administration group / average tumor weight in the negative group)] ⁇ 100%.
  • the experimental results show that compared with the blank control group, the chlorogenic acid monomer compound has a certain inhibitory effect on RuCa in transplanted tumors of mice; coumaric quinic acid has no obvious tumor suppressive effect;
  • the test drug group of the Nary acid composition has a significant inhibitory effect on RuCa in transplanted tumors of mice.
  • the ratio of chlorogenic acid to coumaric quinic acid composition is 100: 0.01 to 100: 5.
  • the test drug group is transplanted to mice.
  • the growth of RuCa in tumors has an inhibitory effect.
  • the inhibitory effect of the composition on mouse transplanted tumors of RuCa increases first and then decreases. Now, they all have synergistic effects, and the ratio of 100: 0.1 is the best.
  • the composition of chlorogenic acid, coumaric quinic acid and sorafenib exhibited the best synergistic effect.
  • the present invention investigates other quinic acid derivatives, and observes whether quinic acid derivatives and chlorogenic acid have a significant synergistic effect on the renal cancer cell line Ruca.
  • Composition of chlorogenic acid and ferulylquinic acid (100: 1) 39.22% Composition of chlorogenic acid and ferulylquinic acid (100: 10) 33.61% Composition of chlorogenic acid and cinnamoquinic acid (100: 0.1) 36.27% Composition of chlorogenic acid and cinnamoquinic acid (100: 1) 37.53% Composition of chlorogenic acid and cinnamoquinic acid (100: 10) 39.14% Negative control group ——
  • composition consisting of chlorogenic acid and ferulylquinic acid or cinnamic quinic acid did not observe a significant synergistic effect in inhibiting the proliferation of renal cancer cell lines, which indicated that chlorogenic acid and coumaric quinic acid
  • the synergistic effect of acids is highly specific.

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Abstract

本发明公开了一种药物组合物及其在制备治疗肾癌药物中的用途，属于生物医药领域。该药物组合物含有绿原酸和香豆酰奎尼酸，绿原酸与香豆酰奎尼酸联合使用，在一定比例内可以发挥协同增效作用，有效抑制人肾癌细胞株A479、鼠肾癌细胞株RuCa和小鼠移植瘤RuCa的生长，为临床治疗肾癌提供了一种新的选择，具有良好的市场应用前景。

Description

用于治疗肾癌的药物组合物及其应用 技术领域
本发明属于生物医药领域，具体涉及一种药物组合物及其在制备治疗肾癌药物中的用途。
背景技术
肾细胞癌简称肾癌，是泌尿系统最常见的肿瘤之一，发病率占成人恶性肿瘤的2％。在中国，肾细胞癌的发病率位居泌尿系肿瘤的第2位，仅次于膀胱癌。流行病学调查结果显示，2016年美国有63000例新发病例及14000例肾癌死亡病例，是第9位最常见的癌症。随着诊断技术的不断进步，肾癌患者得到了较早期的治疗，肾癌总体的5年生存率达到74％，但晚期转移者仅为12％。因此，探索寻找治疗肾癌的有效药物对提高肾癌患者的生存率具有重要的临床意义。
对于肾癌治疗来说，手术治疗是局限性肾癌首选的治疗方法，根据患者肿瘤的分期、分级情况不同可选择根治性肾切除术或保留肾单位手术。而对于放化疗来说，肾癌对化疗药物普遍耐药，化疗没有理想突破，以吉西他滨、5-氟尿嘧啶等药物为基础的化疗在某种程度上提高了疗效，但对于进展生存期、总生存期无明显改变。另外，肾癌对放射不敏感，因此传统上认为疗效不佳，但作为晚期不能切除肾癌的姑息治疗，能达到减轻局部疼痛，缓解血尿等其他一些症状的目的，以改善患者生活质量。对于生长速度快、毒性症状严重但能够手术切除的肿瘤，术前放疗可以使肿瘤体积缩小，减少术中瘤细胞扩散，并且局部水中减轻，有助于术中分离。
目前，肾癌的一线治疗推荐有索拉非尼、舒尼替尼、帕唑帕尼、贝伐珠单抗和干扰素等，二线治疗包括卡博替尼、纳武单抗、阿昔替尼、依维莫司等。2015年《新英格兰医学杂志》(N Engl J Med)发表的研究证明，卡博替尼在进展期肾细胞癌患者中治疗效果明显优于依维莫司，同年N Engl J Med又有发表研究证明纳武单抗优于依维莫司。但上述治疗药物普遍存在腹泻、皮疹、乏力、高血压以及炎症等副反应，并且随着给药时间的延长，生存后期存在较强的耐药性。
绿原酸广泛存在于各种药用植物，如金银花中，目前对它的化学结构研究已经清楚，已有人对其进行药用研究，报道了绿原酸可以应用于治疗肿瘤等疾病。专利CN201110373137公开了绿原酸对于肾癌具有一定的治疗作用，其直接针对引起癌变分子机制，比传统化疗更有选择性和疗效，并且与紫杉醇类药物联用没有拮抗作用。所述绿原酸的结构式如下：
Figure PCTCN2019089637-appb-000001
香豆酰奎尼酸与绿原酸类似，广泛存在于高等植物中，在生物合成路径中，一般认为香豆酰CoA和咖啡酰CoA分别经催化与奎尼酸化合，最终形成香豆酰奎尼酸和绿原酸。目前现有技术没有关于香豆酰奎尼酸活性研究的报道，
Figure PCTCN2019089637-appb-000002
发明内容
本发明的第一方面是提供一种用于治疗肾癌的药物组合物，其包括绿原酸(Chlorogenic acid)和香豆酰奎尼酸(Coumarylquinic acid)。
在一些实施方案中，所述绿原酸与香豆酰奎尼酸的质量比为100：0.01-10；进一步地，所述绿原酸与香豆酰奎尼酸的质量比为100：0.01-1。
在另一些实施方案中，所述药物组合物其包括绿原酸、香豆酰奎尼酸和靶向药物，三者的质量比为100：0.01-1：0.1-1。
在具体的实施方案中，所述靶向药物选自索拉非尼、舒尼替尼和帕唑帕尼中的一种。
本发明的第二方面提供了一种药物制剂，其是以上述药物组合物为有效成分，加入药学上可接受的辅料制备而成。
在一些实施方案中，所述药物制剂为口服制剂或注射制剂。
在进一步的实施方案中，所述辅料选自淀粉、β-环糊精、糊精、卡波姆、微晶纤维素、羟丙基甲基纤维素、低取代羟丙基纤维素、羧甲基纤维素钠、聚乙二醇(PEG)、羧甲基纤维素钠、甲基纤维素、乙基纤维素、甘露醇、十二烷基硫酸钠、交联羧甲基纤维素钠、乳糖、葡萄糖、维生素、谷胱甘肽、叶酸、聚乙烯吡咯烷酮(PVP)、交联聚乙烯吡咯烷酮、硬脂酸镁、滑石粉、微粉硅胶、阿斯巴甜、甜橙香精、亚硫酸氢钠、碳酸氢钠、碳酸钠、肠溶包衣粉中的一种或多种。
本发明的第三方面提供了所述药物组合物在制备治疗肾癌药物中的用途。
在上述医药用途中，对于本发明药物组合物的给药时间和给药次数需要根据病情的具体诊断结果而定，这在本领域技术人员掌握的技术范围之内。例如，将对小鼠或大鼠的治疗方案应用于人身上，所有药物对人的有效剂量可以通过该药物对小鼠的有效剂量进行换算，这对于本领域的普通技术人员来说是容易实现的。
本发明发现虽然绿原酸和香豆酰奎尼酸在结构上较为相似，但是两者对于肾癌细胞株的抑制作用却有着较大差别，绿原酸对肾癌细胞具有明显的抑制作用，而香豆酰奎尼酸仅具有极微弱的抑制作用。出人意料的是，当两者合用时在治疗肾癌方面产生了明显的协同作用。进一步地，本发明还发现当绿原酸和香豆酰奎尼酸与治疗肾癌一线靶向药物合用时，协同效果最佳。为了方便药物组合物的临床应用，本发明还提供了药物组合物的相关制剂。
具体实施方式
根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
在本发明中，所述协同作用是指组分组合后的生物学效应，与基于单独使用单个组分时期望产生给定的生物效应所要求的含量相比，组合物的活性明显高于单个组分的叠加效应。通俗来讲，即组合物产生了1+1>2的生物学效应。
在一些实施方案中，所述绿原酸与香豆酰奎尼酸的质量比为100：0.01-10；进一步地，所述绿原酸与香豆酰奎尼酸的质量比为100：0.01-1。具体地讲，所述绿原酸与香豆酰奎尼酸的质量比可以为100：0.01，100：0.1，100：0.2，100：0.5，100：1，100：2，100：5，100：10。
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1本发明药物组合物口服制剂处方
1、处方一
绿原酸1000g、香豆酰奎尼酸10g。
制备方法：按处方无菌称取绿原酸和香豆酰奎尼酸，混合均匀后，无菌分装成散剂。
2、处方二
绿原酸1000g、香豆酰奎尼酸5g、填充剂500g、粘合剂5g。
制备方法：按照处方称取绿原酸、香豆酰奎尼酸、填充剂、粘合剂，制粒，整粒、分装成颗粒剂。
3、处方三
绿原酸1000g、香豆酰奎尼酸1g、填充剂500g、粘合剂5g、润滑剂3g。
制备方法：按照处方称取绿原酸、香豆酰奎尼酸、填充剂、粘合剂，制粒，整粒，加润滑剂，压片，得片剂。
上述填充剂为甘露醇、乳糖、淀粉、微晶纤维素、糊精当中的一种或几种；粘合剂为羧甲基纤维素钠、PVP；润滑剂为硬脂酸镁、滑石粉、微粉硅胶。
实施例2本发明药物组合物注射制剂处方
1、处方一
绿原酸1000g、香豆酰奎尼酸1g。
制备方法(1)：按处方无菌称取绿原酸和香豆酰奎尼酸，混合均匀后，无菌分装成粉针剂。
制备方法(2)：按照处方称取绿原酸和香豆酰奎尼酸，溶解于注射用水，过滤除菌，冷冻干燥，得冻干粉针剂。
2、处方二
绿原酸1000g、香豆酰奎尼酸1g、支架剂2667g、抗氧化剂67g。
制备方法：按照处方称取绿原酸、香豆酰奎尼酸、支架剂、抗氧化剂，溶解于注射用水，过滤除菌，冷冻干燥，得冻干粉针剂。
上述支架剂为甘露醇、乳糖、葡萄糖；抗氧化剂为亚硫酸氢钠、维生素、谷胱甘肽、叶酸。
以下用实验例的方式说明本发明的有益效果：
实验例1药物组合物及其单体化合物体外治疗肾癌实验
1.材料
1.1受试药物
受试药物1：绿原酸
受试药物2：香豆酰奎尼酸
受试药物3：绿原酸与香豆酰奎尼酸组合物(100:0.01)
受试药物4：绿原酸与香豆酰奎尼酸组合物(100:0.1)
受试药物5：绿原酸与香豆酰奎尼酸组合物(100:1)
受试药物6：绿原酸与香豆酰奎尼酸组合物(100:5)
受试药物7：绿原酸与香豆酰奎尼酸组合物(100:10)
1.2细胞株
人肾癌细胞株A498、小鼠肾癌细胞株RuCa，临用前传代，取生长状态良好，处于对数期生长的细胞备用。
1.3主要试剂
培养基及试剂：培养基RPML1640(Gibco公司)，小牛血清(兰州民海)，青霉素(华北制药股份有限公司)、硫酸链霉素(华北制药股份有限公司)，WST-1(美国Roche公司)。
1.4主要仪器
二氧化碳细胞培养箱(日本SANYO)，IX70倒置相差荧光显微镜(日本Olympus)，生物安全柜(美国NUAIRE)，μ-Quant微孔板测定仪(BioTek公司)，培养器皿：96孔培养板，培养瓶(BD公司)。
2.试验方法
2.1培养液配制
RPML1640细胞培养基溶解于超纯水(1000ml)中，搅拌溶解，加2.2g NaHCO 3和10ml HEPES搅拌溶解，再加青霉素适量(终浓度为100U/ml)和链霉素适量(终浓度为100μg/ml)，充分混合后，用0.22μm滤膜无菌过滤，分装，于-20℃冻存，此为基础培养基。临用前37℃水浴解冻，加10％的小牛血清，调整培养液pH为7.2～7.4，此为完全培养基。
2.2细胞增殖检测试剂
Cell Proliferation Reagent(WST-1)(Roche 11644807001)试剂按要求冷藏。
3.细胞复苏及接种
3.1细胞复苏
将冻存细胞株从-152℃超低温冰柜中取出，40℃水浴解冻，离心并用基础培养基洗涤后用完全培养基悬浮细胞，转移到细胞培养瓶内，静置于5％CO 2细胞培养箱中37℃培养，每2～3天换液。细胞生长铺满细胞瓶后用0.25％胰蛋白酶消化传代培养至实验所需细胞数量。
3.2细胞接种
取对数生长期细胞，0.25％胰蛋白酶消化，用基础培养基洗涤离心(1000rpm 5min两次)，用完全培养基悬浮细胞并调整细胞浓度为6×10 4/ml，接种细胞于96孔板内，每孔50μl(细胞数量6×10 3/孔)，每个药物浓度接种3个复孔，并设阴性对照组(肾癌细胞+完全培养基)和空白对照组(完全培养基)，每组3个复孔。
3.3加药
接种后次日细胞贴壁后按以下分组加药，静置培养48小时。
(1)受试药物组
用完全培养基将各受试药物组储存溶液配制成60μg/ml的溶液，备用；取50μl上述各受试药物组的完全培养基到已接种细胞的96孔板中，使各组终浓度为30μg/ml，每个浓度3复孔。
(2)正常对照组
设肿瘤细胞正常对照组孔，不加药物处理，只加等量(100μl)完全培养基，与受试药物组同步实验。
(3)空白对照组
每孔不接种细胞，只加等量(100μl)完全培养基，设3个复孔作为空白对照。
3.4测定
加药后细胞培养48小时，在倒置显微镜下观察细胞形态，随后在上述受试药物组、阴性对照组和空白对照组孔内加入10μl WST-1溶液，置37℃细胞培养箱继续孵育4小时后，在μ-Quant微孔板测定仪上测定不同药物组、阴性对照组和空白对照组440nm波长处的吸收值。
3.5数据处理：
计算GI(生长抑制率)＝(1-OD 药物组/OD 对照组)×100％
4试验结果
4.1各实验组对人肾癌细胞A498的体外抑瘤作用
4.1.1细胞形态观察结果
各实验组处理48小时后，在倒置显微镜下观察细胞形态，与阴性对照组比较，绿原酸单体化合物受试药物对细胞生长有一定的影响，部分细胞变圆、脱落、悬浮；香豆酰奎尼酸对细胞生长几乎没影响，细胞贴壁，呈不规则生长，而绿原酸与香豆酰奎尼酸组合物受试药物组对人肾癌细胞株A498生长抑制作用显著，在两种单体配比为100:0.01至100:1的比例中，有大量细胞变圆、脱落、悬浮，100:5至100:10的比例中，部分细胞变圆、脱落、悬浮；说明两种单体配比为100:0.01至100:10比例中，均可抑制人肾癌细胞株OS-RC-2的生长，随着组合物中香豆酰奎尼酸占有比例的升高，组合物对人肾癌细胞株OS-RC-2抑制作用先升高后呈下降趋势，并以100:0.01至100:1区间配比最好。
4.1.2各实验组对人肾癌细胞株A498的抑制率
各实验组对人肾癌细胞株A498的抑制率见表1、图1。
表1各实验组对人肾癌细胞株A498的抑制率
分组 OD值(平均值) 抑制率(％)
绿原酸 1.494 36.51％
香豆酰奎尼酸 2.280 3.13％
绿原酸与香豆酰奎尼酸组合物(100:0.01) 1.058 55.03％
绿原酸与香豆酰奎尼酸组合物(100:0.1) 0.900 61.78％
绿原酸与香豆酰奎尼酸组合物(100:1) 1.270 46.03％
绿原酸与香豆酰奎尼酸组合物(100:5) 1.587 32.57％
绿原酸与香豆酰奎尼酸组合物(100:10) 1.857 21.09％
阴性对照组 2.354 ―—
各实验组作用于人肾癌细胞株A498之后，与阴性对照相比，绿原酸单体化合物受试药物对细胞生长有一定的影响；香豆酰奎尼酸对细胞生长几乎没影响；而绿原酸与香豆酰奎尼酸组合物受试药物组对人肾癌细胞株A498生长抑制作用显著，且在两种单体配比为100:0.01至100:10比例中，各组合物均能抑制人肾癌细胞株A498的生长，随着组合物中香豆酰奎尼酸占有比例的升高，组合物对人肾癌细胞株A498抑制作用先升高后呈下降趋势，其中在100:0.01至100:1比例中,两种单体化合物具有协同增效的效果，并以100:0.1的配比效果最好。
4.4绿原酸对鼠肾癌细胞株RuCa的体外抑瘤作用
4.4.1细胞形态观察结果
各实验组处理48小时后，在倒置显微镜下观察细胞形态，与阴性对照组比较，绿原酸单体化合物受试药物对细胞生长有一定的影响，部分细胞变圆、脱落、悬浮；香豆酰奎尼酸对细胞生长几乎没影响，细胞贴壁，呈不规则生长，而绿原酸与香豆酰奎尼酸组合物受试药物组对鼠肾癌细胞株RuCa生长抑制作用显著，在两种单体配比为100:0.01至100:1的比例中，有大量细胞变圆、脱落、悬浮，100:5至100:10的比例中，部分细胞变圆、脱落、悬浮；说明两种单体配比为100:0.01至100:10比例中，均可抑制鼠肾癌细胞株RuCa的生长，随着组合物中香豆酰奎尼酸占有比例的升高，组合物对鼠肾癌细胞株RuCa抑制作用先升高后呈下降趋势，并以100:0.01至100:1区间配比最好。
4.4.2各实验组对鼠肾癌细胞株RuCa的抑制率和剂量效应曲线
各实验组对鼠肾癌细胞株RuCa的抑制率见表2、图2。
表2各实验组对小鼠肾癌细胞株RuCa的抑制率
分组 OD值(平均值) 抑制率(％)
绿原酸 1.248 38.45％
香豆酰奎尼酸 1.909 5.85％
绿原酸与香豆酰奎尼酸组合物(100:0.01) 0.855 57.85％
绿原酸与香豆酰奎尼酸组合物(100:0.1) 0.690 65.95％
绿原酸与香豆酰奎尼酸组合物(100:1) 1.005 50.42％
绿原酸与香豆酰奎尼酸组合物(100:5) 1.349 33.47％
绿原酸与香豆酰奎尼酸组合物(100:10) 1.458 28.08％
阴性对照组 2.028 ——
各实验组作用于鼠肾癌细胞株RuCa之后，与阴性对照相比，绿原酸单体化合物受试药物对细胞生长有一定的影响；香豆酰奎尼酸对细胞生长几乎没影响；而绿原酸与香豆酰奎尼酸组合物受试药物组对鼠肾癌细胞株RuCa生长抑制作用显著，且在两种单体配比为100:0.01至100:10比例中，各组合物均能抑制鼠肾癌细胞株RuCa的生长，随着组合物中香豆酰奎尼酸占有比例的升高，组合物对鼠肾癌细胞株RuCa抑制作用先升高后呈下降趋势，其中在100:0.01至100:1比例中,两种单体化合物具有协同增效的效果，并以100:0.1的配比效果最好。
5.结论
绿原酸单体化合物受试药物对细胞生长有一定的影响；香豆酰奎尼酸对细胞生长几乎没影响，而绿原酸与香豆酰奎尼酸组合物配比为100:0.01至100:10比例中受试药物组对人肾癌细胞株A498和小鼠肾癌细胞株RuCa的生长均有抑制作用，随着组合物中香豆酰奎尼酸占有比例的升高，组合物对人肾癌细胞株A498和小鼠肾癌细胞株RuCa抑制作用先升高后呈下降趋势，且在两种单体在100:0.01至100:1配比区间，都具有协同增效的效果，并以100:0.1的配比效果最好。
实验例2药物组合物及其单体化合物体外治疗肾癌实验
根据实验例1的结果，进一步考察了绿原酸和香豆酰奎尼酸(100:0.1)与肾癌一线治疗药物的联用效果，试验与检测方法同实验例1，仅给药方案存在不同，具体给药方案及结果如下：
表3各实验组对人肾癌细胞株A498的抑制率
Figure PCTCN2019089637-appb-000003
Figure PCTCN2019089637-appb-000004
为了客观评价三种化合物组合的协同效果，根据非专利文献Chou T C.Theoretical basis,experimental design,and computerized simulation of synergism and antagonism in drug combination studies.[J].Pharmacological Reviews,2006,58(3):621-681.提出的标准确立特定组分是否具有协同、相加或拮抗作用，计算药物组合物的协同作用指数(Combination Index，CI)：
A/Ae+B/Be+C/Ce＝CI
A、B和C是指药物组合物中三种组分的剂量，Ae、Be、和Ce是指单独采用单一化合物达到药物组合物的抑癌效率所需的单个组分的剂量，当CI值小于1时，说明组分具有协同作用，CI值越小协同作用越强，CI值等于1或大于1时说明组分具有等效或拮抗作用。
具体地我们采用Biosoft公司的Calcusyn软件进行CI计算，具体结果如下：
表4各组合物的协同作用指数(CI)
  组合物1 组合物2 组合物3 组合物4
CI 0.369 0.230 0.212 0.484
从上表可以看出，绿原酸和香豆酰奎尼酸产生了明显的协同作用，而当在药物组合物中添加索拉非尼后，三者之间的协同作用进一步增强。另外，我们在小鼠肾癌细胞株RuCa上也观察到了绿原酸、香豆酰奎尼酸和索拉非尼对该细胞株产生了明显的协同作用。在此基础上，我们对绿原酸和香豆酰奎尼酸与舒尼替尼或帕唑帕尼是否具有协同作用进行了考察，在细胞株A498和RuCa上，绿原酸和香豆酰奎尼酸与舒尼替尼产生了明显的协同作用，但与帕唑帕尼的协同作用指数仅在1左右，说明仅是相加作用。上述结果表明，绿原 酸和香豆酰奎尼酸组合物与肾癌一线治疗可以产生明显的协同作用，具有广泛的临床应用前景。
实验例3组合物及其单体化合物治疗肾癌的动物试验
1试验材料
1.1受试药物
受试药物1：绿原酸
受试药物2：香豆酰奎尼酸
受试药物3：绿原酸与香豆酰奎尼酸组合物(100:0.01)
受试药物4：绿原酸与香豆酰奎尼酸组合物(100:0.1)
受试药物5：绿原酸与香豆酰奎尼酸组合物(100:1)
受试药物6：绿原酸与香豆酰奎尼酸组合物(100:5)
受试药物7：绿原酸、香豆酰奎尼酸和索拉非尼组合物(100:0.1:0.5)
1.2受试细胞株
鼠肾癌细胞株RuCa接种于小鼠腋窝皮下而建立。细胞接种量为1×10 7，接种形成移植瘤后再在小鼠体内传3代后使用。
1.3受试动物
BABL/C-nu小鼠，80只，雌雄各半，体重18～22g；
2试验方法
2.1给药途径
腹腔注射(ip)
2.3给药方法
取生长旺盛期的瘤组织剪切成1.5mm 3左右，在无菌条件下匀浆后制备成1×10 7/ml细胞悬液。取上述规格小鼠80只，以0.1ml细胞悬液接种于小鼠右侧腋窝皮下。于接种后的第二日，称重，并按体重随机分8组，每组10只，分别为受试药物1组、受试药物2组、受试药物3组、受试药物4组、受试药物5组、受试药物6组、受试药物7组、阴性组。受试药物组腹腔注射(ip)给药，30mg/kg/次，每日一次，连续给药15次；阴性组腹腔注射同等剂量生理盐水，每日一次，给药前称体重。
2.4抗肿瘤作用评价
在给药结束后停止实验，脱颈椎处死小鼠并称重，剥取肿瘤，计算抑瘤率。
抑瘤率％＝[1-(给药组平均瘤重/阴性组平均瘤重)]×100％。
3实验结果
各实验组对小鼠移植瘤RuCa的抑制作用见表3、图3。
表5各实验组对小鼠移植瘤RuCa的抑制作用(
Figure PCTCN2019089637-appb-000005
n＝10)
Figure PCTCN2019089637-appb-000006
经Oneway-ANOVA检验，与阴性组比较*p＜0.01。
4结论
实验结果表明，与空白对照组相比，绿原酸单体化合物对小鼠移植瘤RuCa具有一定的抑制作用；香豆酰奎尼酸抑瘤效果不明显；而绿原酸与香豆酰奎尼酸组合物受试药物组对小鼠移植瘤RuCa抑制作用显著，绿原酸与香豆酰奎尼酸组合物配比为100:0.01至100:5比例中受试药物组对小鼠移植瘤RuCa的生长均有抑制作用，随着组合物中香豆酰奎尼酸占有比例的升高，组合物对小鼠移植瘤RuCa抑制作用先升高后呈下降趋势，且在两种单体在，都具有协同增效的效果，并以100:0.1的配比效果最好。进一步地，绿原酸、香豆酰奎尼酸和索拉非尼组合物体现出了最佳的协同增效效果。
对比例1药物组合物的体外筛选
按照实验例1的方法，本发明对其他奎尼酸衍生物进行了考察，观察奎尼酸衍生物与绿原酸在肾癌细胞株Ruca上是否存在明显的协同增效效果。
具体结果如下：
表6各实验组对小鼠肾癌细胞株RuCa的抑制率
分组 抑制率(％)
绿原酸 37.29％
阿魏酰奎尼酸 10.42％
肉桂酰奎尼酸 13.94％
绿原酸与阿魏酰奎尼酸组合物(100:0.1) 38.57％
绿原酸与阿魏酰奎尼酸组合物(100:1) 39.22％
绿原酸与阿魏酰奎尼酸组合物(100:10) 33.61％
绿原酸与肉桂酰奎尼酸组合物(100:0.1) 36.27％
绿原酸与肉桂酰奎尼酸组合物(100:1) 37.53％
绿原酸与肉桂酰奎尼酸组合物(100:10) 39.14％
阴性对照组 ——
结果表明绿原酸与阿魏酰奎尼酸或肉桂酰奎尼酸组成的组合物，在抑制肾癌细胞株增殖方面没有观察到明显的协同增效作用，这说明绿原酸与香豆酰奎尼酸的协同作用具有较强的特异性。

Claims (10)

  1. 一种药物组合物，其包括绿原酸和香豆酰奎尼酸。
  2. 根据权利要求1所述的药物组合物，其特征在于：所述绿原酸与香豆酰奎尼酸的质量比为100：0.01～10。
  3. 根据权利要求2所述的药物组合物，其特征在于：所述绿原酸与香豆酰奎尼酸的质量比为100：0.01～1。
  4. 根据权利要求1所述的药物组合物，其特征在于：所述药物组合物其包括绿原酸、香豆酰奎尼酸和靶向药物。
  5. 根据权利要求4所述的药物组合物，其特征在于：所述靶向药物选自索拉非尼、舒尼替尼和帕唑帕尼中的一种。
  6. 根据权利要求4所述的药物组合物，其特征在于：绿原酸、香豆酰奎尼酸和靶向药物的质量比为100：0.01-1：0.1-1。
  7. 一种药物制剂，其特征在于：其是以权利要求1-6任一项所述药物组合物为有效成分，加入药学上可接受的辅料制备而成的。
  8. 根据权利要求7所述的药物制剂，其特征在于：所述制剂为口服制剂或注射制剂。
  9. 根据权利要求7所述的药物制剂，其特征在于：所述辅料选自淀粉、β-环糊精、糊精、卡波姆、微晶纤维素、羟丙基甲基纤维素、低取代羟丙基纤维素、羧甲基纤维素钠、聚乙二醇(PEG)、羧甲基纤维素钠、甲基纤维素、乙基纤维素、甘露醇、十二烷基硫酸钠、交联羧甲基纤维素钠、乳糖、葡萄糖、维生素、谷胱甘肽、叶酸、聚乙烯吡咯烷酮(PVP)、交联聚乙烯吡咯烷酮、硬脂酸镁、滑石粉、微粉硅胶、阿斯巴甜、甜橙香精、亚硫酸氢钠、碳酸氢钠、碳酸钠、肠溶包衣粉中的一种或多种。
  10. 权利要求1-6任一项所述药物组合物在制备治疗肾癌药物中的用途。
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