WO2016062291A1 - 千忧解药物在用于制备治疗癌症的医药组合物中的用途 - Google Patents

千忧解药物在用于制备治疗癌症的医药组合物中的用途 Download PDF

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WO2016062291A1
WO2016062291A1 PCT/CN2015/092782 CN2015092782W WO2016062291A1 WO 2016062291 A1 WO2016062291 A1 WO 2016062291A1 CN 2015092782 W CN2015092782 W CN 2015092782W WO 2016062291 A1 WO2016062291 A1 WO 2016062291A1
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cancer
10min
use according
cells
treatment
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PCT/CN2015/092782
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English (en)
French (fr)
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陈丘泓
庄秀美
魏宗德
萧乃文
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朗齐生物医学股份有限公司
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Priority to AU2015335391A priority Critical patent/AU2015335391B2/en
Priority to EP15852557.6A priority patent/EP3210604B1/en
Priority to CN201580057095.3A priority patent/CN106999470A/zh
Priority to JP2017522418A priority patent/JP6539345B2/ja
Publication of WO2016062291A1 publication Critical patent/WO2016062291A1/zh
Priority to US15/492,859 priority patent/US10045962B2/en

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Definitions

  • the present invention is an application of a new indication for a Cosmetic drug, in particular, the use of the Nursing Drug for inhibiting various cancers.
  • Cancer has long been the leading cause of death worldwide, and the number of cancer patients has increased year by year. Therefore, treating cancer has become an important issue.
  • the treatment of cancer can be divided into surgical treatment, radiation therapy, chemotherapy and target treatment.
  • cancer drug treatment is intended to prevent cancer cells from replicating and dividing to block the spread and spread of tumors.
  • cancer drugs In the design of cancer drugs, they are also designed to target high-specific drug molecules or target antibodies. According to statistics, only about five out of every 10,000 new drugs can enter the first phase of clinical trials.
  • Duloxetine HCl duloxetine hydrochloride
  • SSNRI selective serotonin and norepinephrine reuptake inhibitor
  • Duloxetine had no significant affinity for dopaminergic, adrenergic, cholinergic or histaminergic receptors.
  • Duloxetine does not inhibit monoamine oxidase.
  • Duloxetine has been extensively metabolized, but its major metabolites have not been found to significantly have the pharmacological activity of duloxetine.
  • Chicai is a drug that has long been approved by the FDA and has a large amount of data on human research results.
  • Chit-Kitch has the potential to inhibit cancer cells.
  • the present invention aims at the development of new indications for the Chiayi drug, and achieves the goal of new use of the old drug.
  • the experimental design results show that the Chirosan drug has no or only minimal toxicity to normal cells, but whether Chihirosan has a selective effect between normal cells and tumor cells.
  • the present invention provides a use of a drug (Duloxetine HCl) drug for the preparation of a pharmaceutical composition for the treatment of cancer, wherein the pharmaceutical composition is selected from the group consisting of an effective dose of a solution to the problem and a pharmaceutically acceptable salt. composition.
  • a drug Duloxetine HCl
  • the pharmaceutical composition is selected from the group consisting of an effective dose of a solution to the problem and a pharmaceutically acceptable salt. composition.
  • the cancer is one or more selected from the group consisting of a chest-related cancer, an abdominal cavity-related cancer, an endocrine-related cancer, and a digestive tract-related cancer.
  • the cancer is one or more selected from the group consisting of an osteosarcoma-related cancer, a skin cancer-related cancer, and a blood cancer-related cancer.
  • chest cavity related cancer refers to lung cancer
  • the abdominal cavity-related cancer is selected from the group consisting of bladder cancer or/and cervical cancer.
  • the endocrine-related cancer is one or more selected from the group consisting of prostate cancer, breast cancer, and ovarian cancer.
  • the endocrine-related cancer is one or more selected from the group consisting of gastric cancer, liver cancer, colon cancer, pancreatic cancer, and tongue cancer.
  • the effective dose concentration of the Chiral Disinfectant is 20-500 mg/kg/day.
  • Fig. 1 shows the results of the application of the Chiari treatment of the present invention to inhibit cancer cell analysis.
  • Figure 3 shows the inhibitory effect of high-dose and low-dose Chicago drugs on tumor growth
  • Subculture of cell lines of different cancer types including cancerous lung cancer, gastric cancer, liver cancer, rectal cancer, skin cancer, cervical cancer, prostate cancer, bladder cancer, breast cancer, blood cancer, pancreatic cancer, ovarian cancer, tongue cancer Osteosarcoma, kidney cancer, and the control group also used normal cells of the kidney (HEK293 (Kidney)) and lung epithelial cells BEAS-2B (Lung Epithelial) for testing.
  • HEK293 Kidney
  • BEAS-2B Lung Epithelial
  • the cells corresponding to different species should be counted with the corresponding culture solution (Table 1), and the number of cells should be counted, and the number of cells should be 2 ⁇ 10 6 cells.
  • the culture medium to which the cell strain was cultured was added to a volume of 10 ml, and the culture was continued for 2-3 days. The cells were then counted and dispensed into 96-well plates where the number of cells per well was fixed at 3,000 and the volume was 100 ul.
  • the original culture solution in the 96-well plate was aspirated, and a commercially available drug having a concentration of 10 ⁇ m and a volume of 100 ul was added to each well. After 72 hours, 100 ul of diluted WST-1 reagent was added to each well, and the dilution ratio was the culture solution and The volume ratio of the WST-1 stock solution is 9:1, and finally the total volume of each well plate is 200ul, and then The 96-well plate was placed at 37 ° C for 30 to 90 minutes, and the absorbance was detected by OD450 using an elisa reader (enzyme-linked immunosorbent assay), and the survival rate of each cancer cell line was calculated.
  • the analysis of the effect of Chimo solution on the inhibition of peritoneal cancer-related cancer cells was mainly tested on two types of cells related to the abdominal cavity-related cancer.
  • the bladder cancer cell lines were TSGH and T24, respectively (Table 3), cervical cancer cell lines. They were HeLa cell line (Table 4), kidney cancer was 786-O cell line (Table 5), and the results of cancer cell inhibition experiments were performed 4 times each, and the average value was calculated. The results are shown below.
  • the prostate cancer cell lines were PC-3 and LNCap, respectively (Table 6), breast cancer cell lines.
  • Two cell lines, MCF7 and MDA-MB-231, respectively (Table 7), ovarian cancer cell lines were NIH-OVCAR-3 cell line and TOV-21G (Table 8), respectively. And calculate the average value, the results are listed as follows.
  • mice were tested for five kinds of gastrointestinal-related cancer cell lines.
  • the gastric cancer cell lines were AGS and MKN-45, respectively (Table 9), liver cancer cell lines. They were HepG2 and Hep3B, respectively (Table 10), the colorectal cancer cell lines were HCT116-wt and LoVo cell lines (Table 11), and the pancreatic cancer cell lines were AsPC and BxPC cell lines, respectively (Table 12).
  • the tongue cancer cell line was a SAS cell line (Table 13), and the results of the cancer cell inhibition experiments were performed 4 times each, and the average value was calculated, and the results are shown below.
  • the osteosarcoma cell line is U2OS cell line (Table 14)
  • the skin cancer cell line is A375 and BCC cell lines (Table 15), each doing 3 to 4
  • the secondary cancer cells inhibited the experimental results, and the average values were calculated, and the results are listed below.
  • the normal kidney cell line was HEK293 cell line (Table 16), and the normal lung epithelial cell line was BEAS-2B cell line (Table 17), each doing 4 times.
  • the cancer cells inhibited the experimental results and calculated their average values, and the results are listed below.
  • mice Female BALB/cAnN.Cg-Foxn1nu/CrlNarl mice were used as samples (purchased from National Laboratory Animal Center), weighing 21 ⁇ 1g, subcutaneously injected with hepatoma cells (HepG2), and the drugs were divided into three groups: Normal control group, low dose (100 mg/kg/day), high dose (200 mg/kg/day).
  • the tumor was formed over 100 mm 3 , the drug was administered by intraperitoneal injection every day; the tumor size was measured twice a week, and the tumor volume measurement formula was as follows: (L ⁇ W2); L represents the longest diameter of the tumor; W represents the shortest diameter of the tumor.
  • the high and low doses of Chishoujie can effectively slow down the tumor volume growth, and at the same time reduce the tumor volume, wherein the high dose of Chicai has a better effect.

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Abstract

本发明提供千忧解（盐酸度洛西汀）在制备治疗癌症的医药组合物中的用途。

Description

千忧解药物在用于制备治疗癌症的医药组合物中的用途 技术领域
本发明为千忧解药物的新适应症的应用，尤其该千忧解药物具有抑制多种癌症的用途。
背景技术
癌症长期高居全球死因之首，且罹患癌症人数更是逐年攀升，因此治疗癌症俨然成为重要的课题。癌症的治疗可区分为手术治疗、放射线治疗、化学治疗及标靶治疗。
一般来说，癌症药物治疗无论是化学治疗或标靶治疗，目的多是让癌细胞无法复制、分裂，来阻断肿瘤的蔓延扩张。
在癌症药物的设计上也是均朝向高专一性的药物分子开发或标靶型的抗体设计，根据统计，平均每一万个新药约只有五个能够进入第一期临床试验。
此外，除了药物本身是否能大量制造的难题外，还需克服药物安全性、病人筛选、试用剂量等问题，即便药物已经通过FDA的核准并上市，还是常遇到患者对于治疗药物的反应不佳。进一步，许多癌细胞相继产生抗药性，使药物的使用成效大幅降低，最终导致癌症治疗失败。由此可见药物开发具有一定的困难程度。
千忧解(Duloxetine HCl、盐酸度洛西汀)是一种为口服选择性血清素与正肾上腺素再吸收抑制剂(SSNRI)Duloxetine且于人体的抗忧郁作用机转未知，推测与其作用于中枢神经之血清素活性(serotonergic)与正肾上腺素活性 (noradrenergic)有关。臨床前试验显示duloxetine(度洛西汀)可有效阻断血清素与正肾上腺素的再吸收，而仅些微抑制多巴胺(dopamine)的再吸收。体外试验显示，Duloxetine对多巴胺性(dopaminergic)、肾上腺素性(adrenergic)、胆碱性(cholinergic)或组织胺性(histaminergic)接受器无显著亲合力。Duloxetine不抑制单胺氧化酶。Duloxetine经广泛代谢，但尚未发现其主要代谢物显著具有duloxetine的药理活性。千忧解是早已被FDA所认可的用药，具有大量人体研究成果资料。
由于临床应用上的差异，因此从来没有人认为千忧解具有抑制癌症细胞的可能性。
发明内容
为解决上述的问题，本发明针对千忧解药物进行新适应症的研发，而达到老药新用的目标。
经过实验设计结果显示千忧解药物对正常细胞没有或仅有微小的毒性，但至于千忧解在正常细胞与肿瘤细胞之间是否具有选择性的影响。
本发明提供一种千忧解(Duloxetine HCl)药物在用于制备治疗癌症的医药组合物中用途，其中所述医药组合物是选自由有效剂量的千忧解及药学上可接受的盐类所组成。
本发明一实施例中，其中所述癌症是选自由胸腔相关癌症、腹腔相关癌症、内分泌相关癌症、消化道相关癌症中的一种或多种。
本发明一实施例中，其中所述癌症是选自由骨肉瘤相关癌症、皮肤癌相关癌症、血癌相关癌症中的一种或多种。
本发明一实施例中，其中所述胸腔相关癌症是指肺癌。
本发明一实施例中，其中所述腹腔相关癌症是选自由膀胱癌或/和子宫颈癌。
本发明一实施例中，其中所述内分泌相关癌症是选自由前列腺癌、乳癌、卵巢癌中的一种或多种。
本发明一实施例中，其中所述内分泌相关癌症是选自由胃癌、肝癌、大肠癌、胰脏癌、舌癌中的一种或多种。
本发明一实施例中，其中所述千忧解药物的有效剂量浓度为20～500mg/kg/天。
附图说明
图1显示本发明千忧解用药应用于抑制癌细胞分析结果。
图2显示千忧解用药可对肿瘤体积的效果
图3显示高剂量及低剂量千忧解用药对肿瘤生长的抑制效果
具体实施方式
各种癌症细胞株建立
将不同癌症类型的细胞株进行继代培养，癌症细胞种类包含肺癌、胃癌、肝癌、直肠癌、皮肤癌、子宫颈癌、前列腺癌、膀胱癌、乳癌、血癌、胰腺癌、卵巢癌、舌癌、骨肉瘤、肾脏癌，并且对照组亦使用肾脏(HEK293(Kidney))、肺部上皮细胞BEAS-2B(Lung Epithelial)的正常细胞做测试。(表一)
先将各细胞于培养液培养后，由于各细胞的属性不同，因此针对不同种的细胞也要用相对应的培养液(表一)，计算细胞数目，回种2×106细胞数，然后加入培养该细胞株的培养液补至体积为10ml，继续培养2-3天。之后将细胞计数，并分装至96孔盘，其中每孔的细胞数目固定为3000颗，且体积为100ul。
表一、癌症测试细胞株及其培养所用的培养液
Figure PCTCN2015092782-appb-000001
细胞存活分析方法
将96孔盘中原有的培养液吸掉，每孔加入浓度10um、体积100ul的市售药物，放置72小时后，每孔再加入100ul已稀释的WST-1试剂，该稀释比例为培养液与WST-1原液的体积比为9：1，最后每个孔盘的总体积为200ul，然后将 96孔盘放置于37℃，30～90分钟，利用elisa reader(酶联免疫检测仪)于OD450侦测吸光值，并计算各癌症细胞株的存活率。
千忧解药对于各种癌细胞分析结果
千忧解对胸腔相关癌症细胞抑制效果的测试
本分析千忧解对胸腔相关癌症细胞抑制效果的测试，主要针对两种肺癌细胞进行测试，癌细胞株分别为A549和H1650两个细胞株，各做4次的癌细胞抑制实验结果，并且计算其平均值，结果表列如后。(表二)
表二、千忧解对肺癌相关癌症细胞抑制测试
  0524-10min 0526-10min 0529-10min 0531-10min 平均
A549 32.8 53.7 33.2 30.1 37.5
  1-10min 2-20min 3-20min 4-20min 平均
H1650 35.2 36.9 33.6 39.4 36.3
千忧解对腹腔相关癌症细胞抑制效果的测试
本分析千忧解对腹腔相关癌症细胞抑制效果的测试，主要针对两种腹腔相关癌症种类细胞进行测试，膀胱癌细胞株分别为TSGH和T24两个细胞株(表三)，子宫颈癌细胞株分别为HeLa细胞株(表四)，肾脏癌为786-O细胞株(表五)，各做4次的癌细胞抑制实验结果，并且计算其平均值，结果表列如后。
表三、千忧解对膀胱癌相关癌症细胞抑制测试
  0510-10min 0512-10min 0515-10min 0517-10min 平均
TSGH 36.1 59.0 61.2 40.5 49.2
  T24-1-30min T24-2-20min T24-3-20min T24-4-20min 平均
T24 81.7 90.6 71.4 97.2 85.2
表四、千忧解对子宫颈癌相关癌症细胞抑制测试
  0524-10min 0526-10min 0529-10min 0531-10min 平均
HeLa 27.7 29.9 25.4 52.1 33.8
C-334 34.3 52.4 33.7 42.4 40.7
表五、千忧解对肾脏癌相关癌症细胞抑制测试
  0524-10min 0526-10min 0529-10min 0531-10min 平均
786-O 60.4 89.7 49.0 70.1 67.3
千忧解对内分泌相关癌症细胞抑制效果的测试
本分析千忧解对腹腔相关癌症细胞抑制效果的测试，主要针对三种内分泌相关癌症种类细胞进行测试，前列腺癌细胞株分别为PC-3和LNCap两个细胞株(表六)，乳癌细胞株分别为MCF7和MDA-MB-231两个细胞株(表七)，卵巢癌细胞株分别为NIH-OVCAR-3细胞株和TOV-21G(表八)，各做4次的癌细胞抑制实验结果，并且计算其平均值，结果表列如后。
表六、千忧解对前列腺癌相关癌症细胞抑制测试
Figure PCTCN2015092782-appb-000002
表七、千忧解对乳癌相关癌症细胞抑制测试
Figure PCTCN2015092782-appb-000003
表八、千忧解对卵巢癌相关癌症细胞抑制测试
  7-3-30min 7-4-30min 7-7-30min -4-30min 平均
NIH-OVCAR-3 64.8 74.6 78.5 55.0 68.2
  7-3-30min 7-4-30min 7-7-30min -4-30min 平均
TOV-21G 30.9 41.9 34.7 31.9 34.9
千忧解对消化道相关癌症细胞抑制效果的测试
分析千忧解对消化道相关癌症细胞抑制效果的测试，主要针对五种消化道相关癌症种类细胞进行测试，胃癌细胞株分别为AGS和MKN-45两个细胞株(表九)，肝癌细胞株分别为HepG2和Hep3B两个细胞株(表十)，大肠癌细胞株分别为HCT116-wt和LoVo细胞株(表十一)，胰脏癌细胞株分别为AsPC和BxPC细胞株(表十二)，舌癌细胞株为SAS细胞株(表十三)，各做4次的癌细胞抑制实验结果，并且计算其平均值，结果表列如后。
表九、千忧解对胃癌相关癌症细胞抑制测试
  0510-10min 0512-10min 0515-10min 0517-10min 平均
AGS 25.0 15.9 37.3 15.8 23.5
  0510-10min 0512-10min 0515-10min 0517-10min 平均
MKN-45 59.5 75.3 46.0 57.9 59.7
表十、千忧解对肝癌相关癌症细胞抑制测试
  0524-20min 0526-20min 0529-20min 0531-20min 平均
HepG2 14.8 44.7 37.7 38.9 34.0
  0612-20min 0614-20min 0616-20min 0619-20min 平均
Hep3B 41.4 53.3 36.2 60.6 47.9
表十一、千忧解对大肠癌相关癌症细胞抑制测试
  0602-30min 0605-10min 0607-10min 0609-10min 平均
HCT116-wt 52.1 108.8 127.4 20.3 77.1
  0616-10min 0619-10min 0621-10min 0623-10min 平均
LoVo 44.8 63.4 49.9 31.0 47.3
表十二、千忧解对胰脏癌相关癌症细胞抑制测试
  1-7-3-30min 1-7-4-30min 1-7-7-30min 1-4-30min 平均
AsPC 75.7 78.0 26.0 61.7 60.3
  3-7-3-30min 3-7-4-30min 3-7-7-30min 3-4-30min 平均
BxPC 62.1 58.8 22.7 72.4 54.0
表十三、千忧解对舌癌相关癌症细胞抑制测试
  6-26-10min 6-28-10min 6-30-10min 7-3-10min 平均
SAS 45.7 88.9 96.2 98.9 82.4
千忧解对其他癌症细胞抑制效果的测试
分析千忧解对其他类型癌正进行测试，骨肉癌细胞株为U2OS细胞株(表十四)，皮肤癌细胞株分别为A375和BCC两个细胞株(表十五)，各做3～4次的癌细胞抑制实验结果，并且计算其平均值，结果表列如后。
表十四、千忧解对骨肉瘤相关癌症细胞抑制测试
  6-26-10min 6-28-10min 6-30-10min 7-3-10min 平均
U2OS 26.6 21.5 56.6 35.6 35.1
表十五、千忧解对皮肤癌相关癌症细胞抑制测试
Figure PCTCN2015092782-appb-000004
对照组实验设计
千忧解对正常细胞抑制效果的测试
分析千忧解对多种正常细胞进行测试，正常肾脏细胞株为HEK293细胞株(表十六)，正常肺部上皮细胞细胞株为BEAS-2B细胞株(表十七)，各做4次的癌细胞抑制实验结果，并且计算其平均值，结果表列如后。
表十六、千忧解对正常肾脏细胞抑制测试
  平均
HEK293 62.4
表十七、千忧解对正常肺部上皮细胞抑制测试
  0510-10min 0512-10min 0515-10min 0517-10min 平均
BEAS-2B 59.5 76.3 74.7 79.6 72.5
针对千忧解对各种癌症细胞抑制效果汇整于表十八中，清楚看出千忧解对于多项癌症有明显的抑制效果。经过发明人实验结果，千忧解药物对于不同的癌症细胞有明显的抑制效果。(图一)
表十八、千忧解对各种癌症细胞抑制效果的汇整
癌症细胞 抑制效果
肺癌 36.8743253
膀胱癌 67.2
子宫颈癌 36.76
前列腺癌 59.23
乳癌 48.57
卵巢癌 51.5
胃癌 41.6
肝癌 40.95
大肠癌 62.21
胰脏癌 57.2
舌癌 82.44
骨肉癌 35.09
皮肤癌 39.79
肾脏癌 67.3
肾脏 62.44
肺部上皮细胞 72.50
动物实验分析
本实验使用雌性BALB/cAnN.Cg-Foxn1nu/CrlNarl小鼠为样本(购自国家实验动物中心)，体重为21±1g，皮下注射肝癌细胞(HepG2)后随机分笼，测试药物分成三组:正常对照组、低剂量(100mg/kg/day)、高剂量(200mg/kg/day)。肿瘤形 成超过100mm3后，每天采取腹腔注射方式给予药物；每周测量肿瘤大小两次，肿瘤体积测量公式如下：(L×W2)；L代表肿瘤最长直径；W代表肿瘤最短直径。
Figure PCTCN2015092782-appb-000005
Figure PCTCN2015092782-appb-000006
依据第2图的结果，低剂量与高剂量的千忧解均对肿瘤具有良好的抑制效果，且于实验过程中各组小鼠的重量均未出现明显降低的现象，因此表示千忧解不论高低剂量在治疗过程均能使受测小鼠具有良好的健康状态而不死亡。
依据第3图的结果，高低剂量的千忧解平可有效减缓肿瘤体积增长，并可同时减少肿瘤体积，其中以高剂量的千忧解具有较佳的效果。
上列详细说明是针对本发明之一可行实施例的具体说明，惟该实施例并非用以限制本发明的专利范围，凡未脱离本发明技艺精神所为的等效实施或变更，均应包含于本发明的专利范围中。

Claims (8)

  1. 一种千忧解药物在用于制备治疗癌症的医药组合物中的用途，其特征是，所述医药组合物是选自由有效剂量的千忧解及药学上可接受的盐类所组成。
  2. 如权利要求1所述的用途，其特征是，所述癌症为胸腔相关癌症、腹腔相关癌症、内分泌相关癌症、消化道相关癌症中的一种或多种。
  3. 如权利要求1所述的用途，其特征是，所述癌症是选自骨肉瘤相关癌症、皮肤癌相关癌症、血癌相关癌症中的一种或多种。
  4. 如权利要求2所述的用途，其特征是，所述胸腔相关癌症是指肺癌。
  5. 如权利要求2所述的用途，其特征是，所述腹腔相关癌症是选自膀胱癌或/和子宫颈癌。
  6. 如权利要求2所述的用途，其特征是，所述内分泌相关癌症系选自由前列腺癌、乳癌、卵巢癌中的一种或多种。
  7. 如权利要求2所述的用途，其特征是，所述消化道相关癌症系选自由胃癌、肝癌、大肠癌、胰脏癌、舌癌中的一种或多种。
  8. 如权利要求1所述的用途，其特征是，所述有效剂量浓度为20～500mg/kg/天。
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PCT/CN2015/092780 WO2016062289A1 (zh) 2014-10-24 2015-10-23 帕罗西汀药物用于制备治疗癌症的医药组合物中的用途
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