CN116492323B - 一种苯乙烯酸类化合物的新用途 - Google Patents
一种苯乙烯酸类化合物的新用途 Download PDFInfo
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Abstract
本发明一种苯乙烯酸类化合物的新用途,提供了式I所示化合物在制备治疗皮肤癌的药物中的新用途。本发明苯乙烯酸类化合物可导致黑色素瘤内部出现坏死,减缓肿瘤增殖,发挥抗皮肤癌的作用。其与药学上可接受的辅料形成组合物制成可局部给药的制剂,可经皮肤或体腔吸收,减少药物的毒副作用,根据皮肤癌的位置,选用合适的含有该化合物的组合物剂型,能起到治疗或缓解疾病的目的,实现皮肤癌的靶向药物治疗。
Description
技术领域
本发明属于生物医药领域,具体涉及一种苯乙烯类化合物的新用途。
背景技术
皮肤癌即皮肤恶性肿瘤,包括鳞状细胞癌、基底细胞癌、恶性黑色素瘤、恶性淋巴瘤、特发性出血性肉瘤、汗腺癌、隆突性皮肤纤维肉瘤、血管肉瘤等。恶性黑色素瘤属于原发性皮肤癌,是一种高度恶性、容易出现肿瘤复发或转移的恶性肿瘤,主要好发于头颈、下肢和躯干皮肤、肢端、黏膜等部位,是最严重的皮肤癌类型之一,晚期黑色素瘤的有效率大约10%,中位生存期仅9个月左右,严重威胁患者生命。
多年来,研究人员为攻克恶性肿瘤治疗的难关,在抗肿瘤药物的研发过程中付出了诸多努力。血管生成抑制剂近年来在抗肿瘤治疗中获得了越来越多的关注。杂乱而无功能特性的血管生成是肿瘤生长的明显特征之一,肿瘤细胞通过新生的血管获得足够的氧气和营养,以满足其生长、增殖和转移的需要;通过血管生成抑制剂通过阻断肿瘤血管新生,或者使用具有血管靶向性的药物破坏肿瘤血管,可达到“饿死”肿瘤的治疗效果。例如,中国专利授权公告号CN101074189B公开了式A所示的苯乙烯酸类及其衍生物可用于制备血管靶向药物,具有抗肿瘤的潜力。
其具体公开了,(E)-3-(3’-羟基-4’-甲氧苯基)-2-(3”,4”,5”-三甲氧苯基)-2-丙烯酸甘氨酸盐、(E)-3-(3’-氨基-4’-甲氧苯基)-2-(3”,4”,5”-三甲氧苯基)-2-丙烯酸三乙醇胺盐、(E)-3-(3’,5’-二羟基苯基)-2-(3”,4”,5”-三甲氧苯基)-2-奎尼酸酯对肺癌细胞的抑制作用。
然而,不同肿瘤血管生成方式(包括出芽式血管生成、套入式血管生成、血管生成你太、马赛克血管等)不尽相同,血管生成过程中关键的生长因子也存在差别,该苯乙烯酸类化合物对不同肿瘤细胞的血管靶向和生成抑制作用尚未可知。尤其是对于黑色素瘤这种高度恶性肿瘤而言,血管生成方式非常复杂,单一的作用靶点往往效果不佳,给治疗带来了更大的难度。
此外,专利授权公告号CN105566100B公开了式A化合物中,R1、R4、R5为氢,R2为羟基,R3为甲氧基,R6为正丁基的化合物:(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐的制备方法,并公开了式A化合物中R1、R4、R5为氢,R2、R3为甲氧基的乙铵盐、正丙铵盐、正丁铵盐、正己铵盐和正庚铵盐在制备预防和/或治疗糖尿病眼病的药物中的应用。
然而,式A化合物,尤其是(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐抗黑色素瘤的用途目前尚未见报道。
发明内容
本发明的目的在于提供一种苯乙烯酸类化合物的新用途。
本发明提供了式I所示化合物在制备治疗皮肤癌的药物中的用途;
其中,M+为Na+、K+、Li+或有机铵离子。
进一步地,上述M+为有机铵离子CH3(CH2)nNH3 +,其中,n为0~5的任一整数。
更进一步地,上述n为3,M+为
进一步地,上述治疗皮肤癌的药物为治疗鳞状细胞癌、基底细胞癌、恶性黑色素瘤、恶性淋巴瘤、特发性出血性肉瘤、汗腺癌、隆突性皮肤纤维肉瘤或血管肉瘤的药物。
更进一步地,上述药物为治疗恶性黑色素瘤的药物。
进一步地,上述药物是以式I化合物为活性成分,加上药学上可接受的辅料制备而成的制剂。
更进一步地,上述制剂为局部用于皮肤或体腔的透皮给药制剂。
更进一步地,上述制剂为贴膏剂、贴剂、乳膏剂、软膏剂或凝胶剂。
更进一步地,上述制剂含有药物载体、粘合剂、增稠剂、保湿剂、填充剂、交联剂、稳定剂、透皮促进剂、pH调节剂、交联调节剂、消泡剂、遮光剂、溶剂中的至少一种。
更进一步地,上述药物载体包括高分子固体分散体、高分子包合物、高分子微粒、高分子微球、脂质体、微粉硅胶、乳糖、***胶、明胶、甘露醇、淀粉糊、三硅酸镁、滑石粉、玉米淀粉、角蛋白、胶体二氧化硅、马铃薯淀粉、尿素中的至少一种;
所述粘合剂包括:聚氨酯、聚苯乙烯、聚丙烯酸酯、乙烯-醋酸乙烯共聚物、虫胶、丁基橡胶、醋酸乙烯树脂、丙烯酸树脂、氯化橡胶、环氧树脂、聚乙烯醇、羧甲基纤维素、合成树脂、合成橡胶、天然橡胶、异戊二烯橡胶、苯乙烯-异戊二烯-苯乙烯嵌段共聚物、苯乙烯-丁二烯-苯乙烯嵌段共聚物、硅酮中的至少一种;
所述增稠剂包括淀粉类、藻蛋白酸钠、琼胶、***胶、槐豆胶、大豆胶、干酪素、瓜尔胶、海藻酸、海藻酸钠、海藻酸丙二醇酯、琼脂、***胶、西黄耆胶、果胶、壳聚糖、胍胶、黄原胶、明胶、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基淀粉、聚乙烯醇、聚乙烯吡咯烷酮、聚甲基丙烯酸乙烯酯、羧基乙烯基聚合物、卡波姆、聚丙烯酰胺、聚丙烯酸钠、聚环氧乙烯、聚胺树脂、环氧树脂、聚马来酸酐中的至少一种;
所述保湿剂包括甘油、丙二醇、丙三醇、聚乙二醇、山梨醇等中的至少一种;
所述填充剂包括高岭土、硅藻土、微粉硅胶、白陶土,二氧化钛、氧化锌中的至少一种;
所述交联剂包括金属螯合剂、三氯化铁、甘氨酸铝、高价金属氧化物中的至少一种;
所述pH调节剂包括三乙醇胺、乳酸、酒石酸、柠檬酸中的至少一种;
所述透皮促进剂包括亚砜类、吡咯烷酮类、氮酮类及类似物、脂肪酸及其酯、表面活性剂、醇类、多元醇类、萜类、胺类、酰胺类、环糊精类、氨基酸及其酯、大环化合物、有机溶剂类、磷脂类中的至少一种;
所述遮光剂包括二氧化钛、氧化铁中的至少一种;
所述溶剂包括乙醇、丙二醇、甘油、丁二醇与水的混合物中的至少一种。
实验结果表明,本发明苯乙烯酸类化合物可导致黑色素瘤内部出现坏死,减缓肿瘤增殖,发挥抗皮肤癌的作用。其与药学上可接受的辅料形成组合物制成可局部给药的制剂,可经皮肤或体腔吸收,减少药物的毒副作用,根据皮肤癌的位置,选用合适的含有该化合物的组合物剂型,能起到治疗或缓解疾病的目的,实现皮肤癌的靶向药物治疗。
显然,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。
附图说明
图1为对照组和使用本发明药物的实验组小鼠黑色素瘤组织的HE染色结果。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐可按照CN105566100B中公开的制备方法制备,结构为:
实施例1:含有(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐的药物组合物凝胶剂的制备
以(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐为主药,按以下配比和操作制备本发明所述的药物组合物凝胶剂。
主药及辅料名称用量
主药 50g
卡波姆934 25g
甘油 45g
氮酮 15g
对羟基苯甲酸乙酯 2g
蒸馏水 加至 1000g
制备方法
步骤:
(1)将卡波姆934与氮酮及500ml蒸馏水混合,搅拌使其溶解;
(2)将主药溶于75%乙醇溶液中,再加入对羟基苯甲酸乙酯和甘油,搅拌使其完全溶解;
(3)将步骤(2)加入步骤(1)中,搅拌使各组分混合均匀。
(4)三乙醇胺调节溶液的pH值在7.5,加水至总量1000g,继续搅拌待样品变成凝胶状;
实施例2:含有(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐的药物组合物凝胶剂的制备
以(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐为主药,按以下配比和操作制备本发明所述的药物组合物凝胶剂。
主药及辅料名称用量
主药 50g
卡波姆941 20g
丙二醇 50g
氮酮 15g
对羟基苯甲酸乙酯 2g
蒸馏水 加至1000g
制备方法
步骤:
(1)将卡波姆941与氮酮及600ml蒸馏水混合,搅拌使其溶解;
(2)将主药溶于75%乙醇溶液中,再加入对羟基苯甲酸乙酯和丙二醇,搅拌使其完全溶解;
(3)将步骤(2)加入步骤(1)中,搅拌使各组分混合均匀。
(4)三乙醇胺调节溶液的pH值在7.5,加水至总量1000g,继续搅拌待样品变成凝胶状;
实施例3:含有(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐的药物组合物软膏剂的制备
以(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐为主药,按以下配比和操作制备本发明所述的药物组合物软膏剂。
制备方法:将主药经粉碎过100目筛,将主药5g加入到50g PEG200中,在65℃的水浴中加热使主药溶解,然后将43g PEG4000、0.2g对羟基苯甲酸乙酯、1.8g氮酮加到上述溶液中,继续水浴加热直至全部溶解,搅拌混匀至冷凝,即得含有本化合物的软膏。
实施例4:含有(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐的药物组合物软膏剂的制备
以(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐为主药,按以下配比和操作制备本发明所述的药物组合物软膏剂。
制备方法:将主药经粉碎过100目筛,将主药5g加入到55g PEG400中,在70℃的水浴中加热使主药溶解,然后将38g PEG4000、0.2g对羟基苯甲酸乙酯、1.8g氮酮加到上述溶液中,继续水浴加热直至全部溶解,搅拌混匀至冷凝,即得含有本化合物的软膏。
实施例5:含有(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐的药物组合物贴膏剂的制备
以(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐为主药,按以下配比和操作制备本发明所述的药物组合物贴膏剂。
背衬层:无纺布
防粘层:聚乙烯膜
含药膏体层组份构成按重量计为如下:
制备方法:将主药进行粉碎过100目筛,按处方量称取主药、丙二醇、PEG-400、氮酮,加水,水浴加热使其溶解,再加入明胶使其溶解成胶液,再将聚乙烯吡咯烷酮、聚丙烯酸钠、微分硅胶和对羟基苯甲酸乙酯混合均匀,加入上述胶液中,搅拌混合均匀,得膏体,然后均匀涂布在无纺布上,干燥,盖上聚乙烯膜,剪切即得。
实施例6:含有(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐的药物组合物贴膏剂的制备
以(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐为主药,按以下配比和操作制备本发明所述的药物组合物贴膏剂。
背衬层:无纺布
防粘层:聚酯膜
含药膏体层组份构成按重量计为如下:
制备方法:将主药进行粉碎过100目筛,按处方量称取主药、丙二醇、PEG-400、氮酮,加水,水浴加热使其溶解,再加入明胶使其溶解成胶液,再将羧甲基纤维素钠、聚丙烯酸钠、氧化锌和对羟基苯甲酸乙酯混合均匀,加入上述胶液中,搅拌混合均匀,得膏体,然后均匀涂布在无纺布上,干燥,盖上聚酯膜,剪切即得。
以下通过实验例证明本发明的有益效果。
实验例1、体外透皮实验
采用改良Franz扩散池,将处理后的小鼠皮角质层皮肤固定于扩散池边缘四周,真皮面向接收室,角质层面向供给室,将自制制剂(实施例)贴敷在角质层面,接收池内放置一个磁性搅拌子,加入pH7.4的等渗磷酸盐缓冲液至刻度,将离体透皮装置置于恒温水浴中,温度保持在(37±0.5)℃,开启磁力搅拌器,于1.0、2.0、4.0、6.0、8.0、10.0、12.0、16.0和24.0h于侧管内取样2ml,同时补充等体积接收液。将样品用0.45μm微孔滤膜过滤,即得样品。用HPLC方法检测样品浓度。将实施例2~7制成的凝胶剂、软膏剂和巴布膏剂进行体外透皮吸收试验,离体透皮吸收试验结果符合零级动力学过程,24h累积透皮量均超过50%,试验结果见表1。
表1累计释放百分数与时间关系
可见,本发明实施例制备的透皮给药制剂均具有很好的透皮效果,能够经皮肤或体腔吸收,减少药物的毒副作用,可用于局部给药靶向治疗黑色素瘤。
实验例2、抑制黑色素瘤的动物实验研究
取商品源B16细胞株,采用含10%新生牛血清和青霉素(100U/ml)及链霉素(100μg/ml)的RPMI-1640培养液培养,0.25%胰蛋白酶消化对数生长期B16细胞,传代比例约为1:5,PBS洗涤细胞3次,以1000RPM离心5min。0.4%台盼蓝拒染法检测细胞存活率,存活率需大于90%,PBS调整细胞浓度为3×106/ml的B16细胞悬液。按每只鼠(BALB/C小鼠(SPF级),来源上海西普尔-必凯实验动物有限公司)皮内注射0.1ml的B16细胞悬液。接种后10~14天根据肿瘤大小重新分组,淘汰肿瘤过大和过小的动物,每组肿瘤平均体积基本一致。试验设以下2组,每组5只小鼠,1)空白对照,2)受试药物(实施例6)2mg/20g(受试药物给药剂量为2mg/20g体重)。
给药后不同时间点(2h、24h),处死小鼠解剖取肿瘤组织,用10%***固定,做病理切片,HE染色,拍照,观察肿瘤内部坏死情况,细胞增殖情况。
HE染色如图1所示,结果显示,受试药物(2mg/20g)透皮给药后2小时肿瘤组织内部开始出现坏死,24小时可以导致肿瘤内部大面积的坏死(浅色区域)。因此(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐可以引起黑色素瘤瘤内部增殖的减慢和肿瘤坏死,最终发挥抗肿瘤作用。
自接种第10天起每周2次用数显电子卡尺测量肿瘤长径a(mm),及相垂直的肿瘤短径b(mm),肿瘤体积计算公式为:TV=ab2/2,相对肿瘤体积计算公式为:RTV=Vt/Vo,Vo为分笼时(即d1)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。肿瘤抑制率%=(对照组平均RTV-给药组平均RTV)/对照组平均RTV×100%。受试药物对移植于小鼠背部的B16黑色素瘤细胞株肿瘤体积的影响及抑瘤率(单位:mm3),结果见表2。
表2
可以看出,本发明(E)-3-(3’-羟基-4’-甲氧基苯基)-2-(3”,4”,5”-三甲氧基苯基)-2-丙烯酸正丁铵盐可以显著降低黑色素瘤增殖,引起黑色素瘤坏死,显著降低黑色素瘤体积,具有非常优异的抑制黑色素瘤的作用。
综上,本发明提供了一种苯乙烯酸类化合物的新用途,它可导致黑色素瘤内部出现坏死,减缓肿瘤增殖,发挥抗皮肤癌的作用。其与药学上可接受的辅料形成组合物制成可局部给药的制剂,可经皮肤或体腔吸收,减少药物的毒副作用,根据皮肤癌的位置,选用合适的含有该化合物的组合物剂型,能起到治疗或缓解疾病的目的,实现皮肤癌的靶向药物治疗。
Claims (4)
1.式I所示化合物在制备治疗皮肤癌的药物中的用途;
其中,
M+为
所述皮肤癌为黑色素瘤;
所述药物是以式I化合物为活性成分,加上药学上可接受的辅料制备而成的制剂;所述制剂为局部用于皮肤或体腔的透皮给药制剂。
2.如权利要求1所述的用途,其特征在于,所述药物为治疗恶性黑色素瘤的药物。
3.如权利要求1所述的用途,其特征在于,所述制剂为贴剂、乳膏剂、软膏剂或凝胶剂。
4.如权利要求3所述的用途,其特征在于,所述制剂含有药物载体、粘合剂、增稠剂、保湿剂、填充剂、交联剂、稳定剂、透皮促进剂、pH调节剂、交联调节剂、消泡剂、遮光剂、溶剂中的至少一种;
所述药物载体包括高分子固体分散体、高分子包合物、高分子微粒、高分子微球、脂质体、微粉硅胶、乳糖、***胶、明胶、甘露醇、淀粉糊、三硅酸镁、滑石粉、玉米淀粉、角蛋白、胶体二氧化硅、马铃薯淀粉、尿素中的至少一种;
所述粘合剂为聚氨酯、聚苯乙烯、聚丙烯酸酯、乙烯-醋酸乙烯共聚物、虫胶、丁基橡胶、醋酸乙烯树脂、丙烯酸树脂、氯化橡胶、环氧树脂、聚乙烯醇、羧甲基纤维素、异戊二烯橡胶、苯乙烯-异戊二烯-苯乙烯嵌段共聚物、苯乙烯-丁二烯-苯乙烯嵌段共聚物、硅酮中的至少一种;
所述增稠剂为淀粉、藻蛋白酸钠、琼胶、槐豆胶、大豆胶、干酪素、海藻酸、海藻酸钠、海藻酸丙二醇酯、***胶、西黄耆胶、果胶、壳聚糖、胍胶、黄原胶、明胶、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基淀粉、聚乙烯醇、聚乙烯吡咯烷酮、聚甲基丙烯酸乙烯酯、羧基乙烯基聚合物、卡波姆、聚丙烯酰胺、聚丙烯酸钠、聚环氧乙烯、聚胺树脂、环氧树脂、聚马来酸酐中的至少一种;
所述保湿剂为甘油、丙二醇、聚乙二醇、山梨醇中的至少一种;
所述填充剂为硅藻土、微粉硅胶、白陶土、二氧化钛、氧化锌中的至少一种;
所述交联剂为金属螯合剂、三氯化铁、甘氨酸铝、高价金属氧化物中的至少一种;
所述pH调节剂为三乙醇胺、乳酸、酒石酸、柠檬酸中的至少一种;
所述透皮促进剂为亚砜、吡咯烷酮、氮酮、脂肪酸、表面活性剂、醇、萜、胺、酰胺、环糊精、氨基酸、大环化合物、磷脂中的至少一种;
所述遮光剂为二氧化钛、氧化铁中的至少一种;
所述溶剂为乙醇、丙二醇、甘油、丁二醇与水的混合物中的至少一种。
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