CN1727340B - 一种替莫唑胺-8-羧酸酯及其组合物 - Google Patents
一种替莫唑胺-8-羧酸酯及其组合物 Download PDFInfo
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- CN1727340B CN1727340B CN 200410020215 CN200410020215A CN1727340B CN 1727340 B CN1727340 B CN 1727340B CN 200410020215 CN200410020215 CN 200410020215 CN 200410020215 A CN200410020215 A CN 200410020215A CN 1727340 B CN1727340 B CN 1727340B
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- Prior art keywords
- ester
- methyl
- imidazolo
- oxo
- temozolomide
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Abstract
本发明公开以替莫唑胺-8-羧酸正己酯为代表的一系列替莫唑胺-8-羧酸酯,抑制癌细胞活性和抑制小鼠体内癌块生长的活性,以及它们在制备抗癌制剂中的应用。本发明还公开了含有这种化合物的组合物,及其制备方法。
Description
技术领域
本发明涉及医药领域,具体涉及一种含有以替莫唑胺-8-羧酸正己酯为代表的一系列替莫唑胺-8-羧酸酯及其药物组合物,制备方法,以及在制备透皮吸收治疗皮肤癌制剂中的应用。
背景技术
替莫唑胺为一种烷化剂型抗癌药物,具有广谱抗肿瘤活性[L.H.Tsang,et al.CancerChemother Pharmacol.27(1991):342-346],尤其是对神经胶质瘤(脑癌)和黑色素瘤(皮肤癌)。替莫唑胺的胶囊剂已在欧美批准用于治疗恶性神经胶质瘤。WO 00/57867描述了一个周期给药方式。替莫唑胺的胶囊剂在我国也已批准临床。II期临床结果显示替莫唑胺对恶性黑色素瘤有效[N.M.Bleehen,et al.J.Clin.Oncol.13(1995):910-913]。近期的III期临床结果显示替莫唑胺治疗恶性黑色素瘤疗效与达卡巴嗪相同[M.R.Middleton,et al.J.Clin.Oncol.18(2000):158-166],同时显示服用替莫唑胺产生的副反应与达卡巴嗪副反应相似,如:白细胞减少、恶心、呕吐、脱发、红疹及便秘。此外口服替莫唑胺显示剂量限制的骨髓毒性[A.M.Heimberger,et al.Clin.Can.Res.6(2000):4148-′41′53].在以往剂型改变研究中证明替莫唑胺溶液腱鞘注射剂型可以降低副反应[J.H.Sampson,et al.Can.Res.5(1999):1183-11886]。因此替莫唑胺透皮制剂应该是用于治疗皮肤癌的理想剂型,尤其是在早期。已有研究证明托瑞米芬局部给药在肿瘤部位产生高的局部浓度,而系统药物浓度很低[L.Soe,et al.Cancer Chemother.Pharmacol.,39(1997):513-520],因此产生低的系统毒性。
皮肤给药通常受到皮肤屏障及药物理化性质的制约。我们研究证明(WO 00/57867)替莫唑胺不能通过人造皮肤(硅膜)、大鼠皮肤和人皮肤,不能直接制成透皮制剂。因此,替莫唑胺的应用范围受到一定的限制。
以往对替莫唑胺结构改造和衍生物的合成都集中在三位氮上的取代基的替换和八酰胺基氮上的取代基的改变。EP 0252682(1987)的通式结构中要求了替莫唑胺-8-羧酸甲,乙,丙,丁酯,但实例中没有一个替莫唑胺-8-羧酸酯,更没有它们抗癌活性的数据。
以上文献从没有公开替莫唑胺-8-羧酸酯抗皮肤癌的药理活性,如治疗黑色素瘤为目的的组合物研究,也没有替莫唑胺-8-羧酸酯抗杀瘤的探讨,尤其是皮肤癌从没有被揭示。
发明内容
本发明目的在于提供一种以替莫唑胺-8-羧酸正己酯为代表的一系列替莫唑胺-8-羧酸酯。
本发明的另一目的在于提供一种含有替莫唑胺-8-羧酸酯的药用组合物及其制备方法。
本发明的又一目的是提供了该组合物抑制肿瘤的药理作用及其在制备抑制肿瘤药物中的应用。
本发明所述的替莫唑胺-8-羧酸酯的结构如下同时所示:
其中X可以是0和S;
R可以是C3~C10的直链饱和烃基,可以是C3~C10的支链饱和烃基,可以是C3~C10的不饱和烯基,可以是C3~C10的不饱和炔基;
R可以是取代的上述直链的饱和烃,支链的饱和烃,不饱和烃,取代基可以是烃氧基,烃巯基,烃胺基,苯基,取代苯基。
上述化合物中的优选衍生物为替莫唑胺-8-羧酸正己酯。
其制备方法如下:
替莫唑胺与浓硫酸混合搅拌。将亚硝酸钠溶解在水中,然后在冰浴15℃以下滴加入反应混合物中,室温搅拌过夜。反应混合物中加入冰,冰浴冷却1小时,过滤收集产品固体替莫唑胺酸,真空干燥。
将无水DMF和无水THF注射进一个盛有替莫唑胺酸和Pybrop的烧瓶中,搅拌混合物使固体全部溶解。冰浴下,加入DMAP,然后注射入适量的无水烃醇或者烃巯醇,继续反应半小时,然后室温搅拌过夜。反应完成后,用布氏漏斗过滤悬浮液,母液蒸馏,剩余物中加入冰,然后用乙酸乙酯,萃取产品。合并乙酸乙酯相用无水硫酸镁干燥,旋蒸除乙酸乙酯,剩余物过硅胶柱纯化,蒸除溶剂后得到产物。
所得产物的结构经红外(IR)、1H-NMR、13C-NMR核磁和质谱(MS)确定,符合规定。
本发明的另一目的在于提供一种含有替莫唑胺-8-羧酸酯的药用组合物及其制备方法。
制剂(剂型)的选择是根据所要达到的效果,活性成分的性质以及患者的年龄、性别及患者病情病态进行设计。处方中除活性成分外一般还包括液体或固体稀释剂、湿润剂、防腐剂、矫味剂及着色剂等。
由于本发明人发现了替莫唑胺-8-羧酸酯良好的透皮吸收特点,所以其最适合制剂之一透皮吸收局部给药制剂。替莫唑胺-8-羧酸酯透皮吸收局部给药的系统设计基本有两种,分别为基质型和储库型。基质型又可分为单片基质(AM)及复合基质(PM)。储库型分为液体储库系统(LRS)及固体储库系统(SSR)两种,由多层粘合剂(MLA)或多层聚合物基质(MLM)的组成。基质型和储库型替莫唑胺-8-羧酸酯透皮吸收局部给药制剂基本包括:底片,聚合物基质,药物储库(即,药物溶液或悬浮液),控速膜,压力敏感粘合剂(PSAs),保护压力敏感粘合剂(PSAs)的释放层。具体分述如下:
固体储库型贴片:储库药物基质是由水相、油相和表面活性剂按不同比例配制形成的透明稳定的微乳及其制剂,分为固体型和液体型储库贴片。其中的固体型储库贴片,可以选择油酸或肉豆蔻酸异丙酯(IPM)作为油相,也可以选择月桂酸、蜂蜡、琼蜡醇、硬脂醇、液体石蜡、凡士林、无水羊毛脂、硬脂酸、棉子油、蓖麻油、亚麻酸等等。
本发明所说的替莫唑胺-8-羧酸酯优选为替莫唑胺-8-羧酸正己酯。
本发明替莫唑胺-8-羧酸正己酯固体储库型贴片的油相优选为肉豆蔻酸异丙酯(IPM)或油酸;水相优选为水;表面活性剂优选维生素E TPGS和柠檬酸。
液体储库型控释贴片由不可透过的底片或称“底片”、液体药物、控速膜、压力敏感粘合剂、释放层热合而成。
其中,本发明替莫唑胺-8-羧酸正己酯液储库型控释贴片所用的各部分结构如下:
底片,即不可透过的底片,一般是指那些具有渗透性或非渗透性的合成聚合物材料,如聚酯、聚乙烯、聚氯乙烯PVDC、聚亚安酯等,可以是天然的聚合物材料,如棉花、羊毛等。本发明中底片选自下列材料:聚氯乙烯、硝化甘油Nitroglycerin Transdermal、聚二甲基硅氧烷,即Nitrodisc、聚乙烯吡咯烷酮、聚乙烯醇,即Nitro-DurI、聚乙烯吡咯烷酮、聚乙烯氧化物复合物、聚乙二醇、聚乙二醇的各类衍生物例如聚乙二醇单甲醚或双甲醚,聚乙二醇琥伯酸酯及其琥伯酸聚乙二醇维生素E混合双酯(VETPGS)等;优选为聚乙烯、聚氯乙烯PVDC、聚亚氨酯或棉花。
控速膜优选为乙烯-醋酸乙烯共聚物膜或聚氨酯膜、乙二醇二乙酸酯膜等均质膜;压力敏感粘合剂一种独特的生物粘合剂,优选为聚硅氧烷压敏胶或聚丙烯酸酯压敏胶。
本发明的所述的储库型控释贴片可以按照如下步骤进行:
称取适量的替莫唑胺-8-羧酸正己酯,研成细粉;加水相,如水,和油相如油酸等,与表面活性剂,如Vitamin E TPGS等,混合均匀;加入粉碎的药物混合研磨制成微乳,加入控速膜,如乙烯-醋酸乙烯共聚物膜等,和压力敏感粘合剂适量,搅匀,水浴保温脱气,涂膜于聚乙烯底片上,烘干,切成贴片,即得。
单片粘附基质贴片:单片粘附基质型是药物分散在压敏胶中,压敏胶控制药物释放。此类释药系统的特点是剂型薄,工艺简单,易于工业化。其中本发明组合物的药物粘附基质辅料选自天然聚合物或合成聚合物,包括聚氯乙烯、聚丙烯酸酯、聚二甲基硅氧烷;亲水性的多聚物,包括聚乙烯吡咯烷酮、聚乙烯醇、凝胶制成的水凝胶,即Prostep、聚乙烯吡咯烷酮和聚乙烯氧化物复合物、聚乙二醇和聚乙二醇的各类衍生物,如聚乙二醇单甲醚或双甲醚,聚乙二醇琥伯酸酯及其琥伯酸聚乙二醇维生素E混合双酯(VETPGS);优选为聚丙烯酸酯。
除此之外,本发明药物组合物的另一主要适合制剂之一还包括口服的固体和液体制剂。
固体口服制剂包括片剂、丸剂、分散粉末、胶囊剂和颗粒剂。在这些种固体制剂中,一般替莫唑胺-8-羧酸酯与至少一种惰性稀释剂混合,包括:碳酸钙、淀粉、褐藻酸或乳糖等;此外,处方中还可包括其他辅料,如润滑剂,硬脂酸镁。
替莫唑胺-8-羧酸酯也可以制成口服液体制剂包括乳剂、溶液剂、悬浮液、糖浆。其中的惰性稀释剂常用含有表面活性剂的水性液体或液体石蜡。除了惰性稀释剂外,液体制剂还包括其他佐剂,例如湿润剂和悬浮剂,象聚乙烯吡咯烷酮、甜味剂、矫味剂、香料和防腐剂。
除上述给药途径外,替莫唑胺-8-羧酸酯的另一个主要适合制剂是栓剂,包括阴道和直肠给药的固体栓剂制剂。替莫唑胺-8-羧酸酯的栓剂制剂除包括常规的赋型剂之外还包括生物可降解的聚合物,如聚乳酸PLGA,聚酸酐和聚混合酸酐CPP∶SA,用以实现缓控释效果。
上述替莫唑胺-8-羧酸酯的剂量通常在0.1-200mg/kg体重/天,优选为1-20mg/kg体重/天之间。
下面通过替莫唑胺-8-羧酸酯体外抑瘤实验,说明本发明的有益效果。
替莫唑胺酸酯体外杀伤肿瘤细胞作用
氟尿嘧啶注射液(10ml:0.25g,上海旭东海普药业有限公司产品,批号:000612)选为阳性对照药同替莫唑胺正己酯和已知具有抗癌活性的替莫唑胺酸一起做杀伤癌细胞株的实验.癌细胞株包括HCT-8(人结肠癌细胞),A549(人肺癌细胞),MCF-7(人乳腺癌细胞),Bel7402(人肝癌细胞),BGC-823(人胃癌细胞),MV3(人黑色素瘤细胞).
实验结果表明(详见表1),替莫唑胺酸和替莫唑胺正己酯对所选用的细胞株的IC50多在10-30ug/ml之间,二者作用差别不明显。
表1.MTT法人癌细胞杀伤实验结果
细胞株 | IC50 | ||
氟尿嘧啶 | 替莫唑胺酸 | 替莫唑胺正己酯 | |
MV3MCF-7Bel-7402A549HCT-8BGC-823 | 0.4270.6290.4950.1260.6060.722 | 14.62514.91116.957>19.518.525>19.5 | 8.83519.99527.20326.63228.644>19.5 |
替莫唑胺酸正己酯局部涂抹药物对人黑色素瘤MV3裸小鼠异种移植瘤生长影响替莫唑胺酸正己酯溶解于二甲基亚砜(DMSO),制成50mg/ml溶液。BALB/c-nu裸小鼠接种人黑色素瘤MV3裸鼠异种移植瘤,待肿瘤体积生长至100-300mm3时将动物按肿瘤大小分层分组,每组8只小鼠。
将其中1组小鼠作为给药组,涂抹替莫唑胺酸正己酯溶液,另1组小鼠肿瘤自然生长作为对照。
每日2次(周六、周日为1次)在给药组小鼠肿瘤部位及周围约2×2cm2范围内涂抹药液,每次均在药液干燥后重复涂抹1-2遍。每只小鼠平均每日接受替莫唑胺酸正己酯剂量约20mg许。
每周2次测量动物肿瘤体积,动态观察、记录肿瘤生长情况并绘制肿瘤增长曲线图。待对照组肿瘤生长至一定体积,处死动物,剥瘤肿瘤,称瘤重,计算给药组肿瘤生长抑制率,用2组肿瘤相对体积计算相对肿瘤增殖(%T/C)。
结果我们可见,涂抹替莫唑胺正己酯对荷瘤小鼠生长显示明显抑制作用。替莫唑胺酸正己酯对人黑色素瘤MV3等肿瘤细胞具较强的杀伤作用,外用涂抹,每只鼠每日约20mg剂量对移植性肿瘤生长显示抑制作用,实验结束时肿瘤重量与肿瘤体积均与对照组显示明显统计学差别。详见图1两组实验小鼠实体照片和表2。
附表2替莫唑胺正己酯涂抹荷MV3裸小鼠肿瘤生长影响(约20mg/只/日)
组别 | 动物数 | 体重(g) | 肿瘤体积(mm3) | RTV | T/C(%) | 瘤重(g) | 抑制率(%) | |||
开始 | 结束 | 开始 | 结束 | 开始 | 结束 | |||||
阴性对照 | 8 | 8 | 23.7±1.50 | 25.0±0.535 | 105±79.9 | 2381±980.3 | 8.92±8.97 | 2.10±0.802 | ||
涂抹药物组 | 8 | 8 | 24.0±1.53 | 22.9±2.23 | 116±27 | 622±545.1* | 3.01±1.95 | 33.7 | 0.41±0.318 | 80.5 |
*P<0.05与阴性对照组比较,体重、瘤重、瘤体积以X±SD表示
附图说明
图1两组实验小鼠实体照片
图2适合替莫唑胺酸酯透皮吸收局部给药的基质型和储库型系统图解
具体实施方式
实施例1替莫唑胺酸的合成(EP0252682)
替莫唑胺(2.577mmol,0.5g)与4毫升浓硫酸混合搅拌。将亚硝酸钠(9.4mmol,0.65g)溶解在2.6毫升水中,然后在冰浴15℃以下滴加入反应混合物中,室温搅拌过夜。反应混合物中加入10克冰,冰浴冷却1小时,过滤收集产品固体替莫唑胺酸,真空干燥,得0.493克,收率98.6%。
实施例2替莫唑胺-8-羧酸酯的合成
将无水DMF(2毫升)和无水THF(3毫升)注射进一个盛有替莫唑胺酸(1mmol,0.195g)和Pybrop(1mmol,0.466g)的烧瓶中,搅拌混合物使固体全部溶解。冰浴下,加入DMAP(2mmol,0.244g),然后注射入适量的无水烃醇或者烃巯醇(2.2mmol),继续反应半小时,然后室温搅拌过夜。反应完成后,用布氏漏斗过滤悬浮液,母液蒸馏,剩余物中加入冰(10克),然后用乙酸乙酯(10mL×3)萃取产品。合并乙酸乙酯相用无水硫酸镁干燥,旋蒸除乙酸乙酯,剩余物过硅胶柱纯化,蒸除溶剂后得到产物。
所得产物的结构经红外(IR)、1H-NMR、13C-NMR核磁和质谱(MS)确定.典型产物的结构数据如下。
1.替莫唑胺-8-羧酸甲酯
1H NMR(d6-DMSO/ppm)δ8.86(s,1,H-6),3.90(s,3,CH 3-O),3.87(s,3,CH 3-N)13C NMR(d6-DMSO/ppm)δ161(COO),139(C-4),137(C-6),129(C-9),126(C-8),52.2(OCH2),36.4(NCH3)
vmax(KBr):3489,2961(C-H),1752(C=O),1727(C=O),1214(C-O),1062(C-O),828,556cm-1
MS:+ES:m/z=232[M+H]+,214[M+H-H2O]+
2.替莫唑胺-8-羧酸乙酯
1H NMR(CDCl3/ppm)δ8.45(s,1,H-6),4.52(q,2,J=7.1Hz,CH 2-O),4.04(s,3,CH 3-N),1.45(t,3,J=7.1Hz,CH2-CH 3)
13C NMR(d6-DMSO/ppm)δ161(COO),139(C-4),137(C-6),129(C-9),127(C-8),60.9(OCH2),36.4(NCH3),14.3(CH2 CH3)
vmax(KBr):3478,2991(C-H),1754(C=O),1700(C=O),1467(C-O),1258(C-O),1060(C-O),844,561cm-1
MS:+ES:m/z=246[M+H]+,228[M+H-H2O]+
3.替莫唑胺-8-羧酸丙酯
1H NMR(CDCl3/ppm)δ8.46(s,1,H-6),4.41(t,2,J=6.7Hz,CH 2-O),4.03(s,3,CH 3-N),1.83(sextet,2,J=7.1Hz,C-CH 2-C),1.03(t,3,J=7.4Hz,C-CH 3)
13C NMR(CDCl3/ppm)δ160(COO),138(C-4),136(C-6),130(C-9),128(C-8),67.1(OCH2),36.5(NCH3),21.7(CH2CH3),8.87(CH2 CH3)
vmax(KBr):3122,2960(C-H),1729(C=O),1700(C=O),1457(C-O),1200(C-O),1174(C-O),1052,942cm-1
MS:+ES:m/z=260[M+H]+,242[M+H-H2O]+
4.替莫唑胺-8-羧酸丁酯
1H NMR(CDCl3/ppm)δ8.45(s,1H-6),4.45(t,2,J=7.1Hz,CH 2-O),4.03(s,3,CH 3-N),1.79(quintet,2,J=7.4Hz,C-CH 2-C),1.46(sextet,2,J=7.3Hz,C-CH 2-CH3),0.95(t,3,J=7.3Hz,C-CH 3)
13C NMR(d6-DMSO/ppm)δ161(COO),139(C-4),137(C-6),129(C-9),127(C-8),64.5(OCH2),36.4(NCH3),30.3(OCH2 CH2),18.7(CH2CH3),13.6(CH2 CH3)
vmax(KBr):3156,2967(C-H),1746(C=O),1467(C-O),1261(C-O),1054(C-O),823,561cm-1
MS:+ES:m/z=274[M+H]+,256[M+H-H2O]+
5.替莫唑胺-8-羧酸戊酯
1H NMR(CDCl3/ppm)δ8.46(s,1,H-6),4.45(t,2,J=7.0Hz,CH 2-O),4.03(s,3,CH 3-N),1.79(quintet,2,J=7.1Hz,C-CH 2-C),1.29-1.40(m,4,C-(CH 2)2-CH3),0.96(t,3,J=6.9Hz,C-CH 3)
13CMR(d6-DMSO/ppm)δ161(COO),139(C-4),137(C-6),129(C-9),127(C-8),64.6(OCH2),36.4(NCH3),30.9(OCH2 CH2),28.2(O(CH2)2 CH2),22.8(CH2CH3),14.0(CH2 CH3)
vmax(KBr):3136,2967(C-H),1736(C=O),1459(C-O),1231(C-O),1154(C-O),923,761cm-1
MS:+ES:m/z=288[M+H]+,270[M+H-H2O]+
6.替莫唑胺-8-羧酸己酯
1H NMR(CDCl3/ppm)δ8.49(s,1,H-6),4.45(t,2,J=6.9Hz,CH 2-O),4.04(s,3,CH 3-N),1.79(quintet,2,J=7.1Hz,C-CH 2-C),1.29-1.40(m,6,C-(CH 2)3-CH3),0.87(t,3,J=6.9Hz,C-CH 3)
13CMR(d6-DMSO/ppm)δ161(COO),139(C-4),137(C-6),129(C-9),127(C-8),64.8(OCH2),36.4(NCH3),30.9(OCH2 CH2),28.2(O(CH2)2 CH2),25.1(CH2CH2CH3),22.1(CH2CH3),13.9(CH2 CH3)
vmax(KBr):3156,2967(C-H),1746(C=O),1467(C-O),1261(C-O),1054(C-O),823,561cm-1
MS:+ES:m/z=302[M+H]+,284[M+H-H2O]+
7.替莫唑胺-8-羧酸庚酯
1H NMR(CDCl3/ppm)δ8.39(s,1,H-6),4.38(s,2,CH 2-O),4.00(s,3,CH 3-N),1.75(s,2,C-CH 3-C),1.19(s,8,C-(CH 2)4-C),0.83(s,3,C-CH 3)
13C NMR(d6-DMSO/ppm)δ161(COO),139(C-4),137(C-6),129(C-9),127(C-8),64.8(OCH2),36.4(NCH3),31.1(OCH2 CH2),2×28.4(OCH2CH2(CH2)2),25.3(CH2CH2CH3),22.1(CH2CH3),13.8(CH2 CH3)
vmax(KBr):3146,2927(C-H),2858(C-H),1748(C=O),1718(C=O),1457(C-O),1245(C-O),828,566cm-1
MS:+ES:m/z=316[M+H]+,398[M+H-H2O]+
8.替莫唑胺-8-羧酸辛酯
1H NMR(CDCl3/ppm)δ8.36(s,1,H-6),4.36(s,2,CH 2-O),3.95(s,3,CH 3-N),1.74(s,2,C-CH 3-C),1.19(s,10,C-(CH 2)5-C),0.78(s,3,C-CH 3)
13C NMR(d6-DMSO/ppm)δ160(COO),139(C-4),137(C-6),129(C-9),127(C-8),64.8(OCH2),36.4(NCH3),31.2(OCH2 CH2),2×28.6(OCH2CH2(CH2)2),28.2(O(CH2)1 CH2),25.4(CH2CH2CH3),22.1(CH2CH3),13.9(CH2 CH3)
vmax(KBr):2925,2853,1758,1720,1467,1255,838,556cm-1
MS:+ES:m/z=330[M+H]+,312[M+H-H2O]+
实施例3替莫唑胺-8-羧酸正己酯固体储库系统的制备
称取3g的替莫唑胺-8-羧酸正己酯,研成细粉;取20g水、50g油酸,30gVitamin ETPGS和适量的柠檬酸,加入粉碎的药物混合研磨制成微乳,加入控速膜乙烯-醋酸乙烯共聚物膜,和压力敏感粘合剂聚硅氧烷压敏胶适量,搅匀,水浴保温脱气,涂膜于聚乙烯底片上,烘干,切成50个贴片,即得。
实施例4替莫唑胺-8-羧酸正己酯固体储库系统的制备
称取3g的替莫唑胺-8-羧酸正己酯,研成细粉;取20g水、50g油酸,30gVitamin ETPGS和适量的柠檬酸,加入粉碎的药物混合研磨制成微乳,加入控速膜聚氨酯膜,和压力敏感粘合剂聚丙烯酸酯压敏胶适量,搅匀,水浴保温脱气,涂膜于聚乙烯底片上,烘干,切成50个贴片,即得。
实施例5替莫唑胺-8-羧酸酯制剂的制备
将替莫唑胺-8-羧酸正己酯研成细粉,然后装入盛有5mg胶囊中,制成胶囊制剂。
实施例6替莫唑胺-8-羧酸酯制剂的制备
将替莫唑胺-8-羧酸正己酯研成细粉,然后装入盛有10mg胶囊中,制成胶囊制剂。
实施例7替莫唑胺-8-羧酸酯制剂的制备
将替莫唑胺-8-羧酸正己酯研成细粉,然后装入盛有25mg胶囊中,制成胶囊制剂。
实施例8替莫唑胺-8-羧酸酯制剂的制备
处方:替莫唑胺-8-羧酸正己酯 3g′
水 20g
油酸 50g
维生素ETPGS 30g
柠檬酸 适量
按处方量将上述物质混合制成微乳,加入控速膜乙烯-醋酸乙烯共聚物膜,和压力敏感粘合剂聚硅氧烷压敏胶适量,搅匀,水浴保温脱气,涂膜于聚乙烯底片上,烘干,切成50个贴片,即得。
实施例9替莫唑胺-8-羧酸酯制剂的制备
处方
替莫唑胺-8-羧酸正己酯 3g
聚丙烯酸酯 20g
柠檬酸三乙酯 30g
丙酮 50g
胶态二氧化硅 适量 适量
按处方量将上述物质混合,挥发溶剂后分别制成储库层和压敏胶层。
实施例10替莫唑胺-8-羧酸酯制剂的制备
处方:
替莫唑胺-8-羧酸正己酯 4.8%
聚丙烯酸酯 32.2%
柠檬酸三乙酯 3.0%
丙酮 60%
按处方量将上述物质混合,挥发溶剂后制成含药压敏胶层。
实施例11替莫唑胺-8-羧酸酯制剂的制备
替莫唑胺-8-羧酸正己酯 10mg
乳糖 65mg
预胶化淀粉 25mg
交联羧甲基纤维素钠 3mg
微粉硅胶 0.25mg
硬酯酸镁 0.30mg
将替莫唑胺-8-羧酸酯、乳糖、预胶化淀粉、交联羧甲基纤维素钠分别过65目筛备用。按处方量的替莫唑胺-8-羧酸正己酯,按等量递加法与其他辅料混合均匀,过65目筛3次;测休止角,小于30°;测含量,定装量;将该粉末装3号胶囊。
实施例12替莫唑胺-8-羧酸酯制剂的制备
将3g替莫唑胺-8-羧酸正己酯研成细粉,与15g水,50gVitamin E TPGS,35g肉豆蔻酸异丙酯(IPM)]和适量的苹果酸或延胡索酸,苯甲酸和异丙醇混合制成微乳,加入控速膜聚氨酯膜,和压力敏感粘合剂聚丙烯酸酯压敏胶适量,搅匀,水浴保温脱气,涂膜于聚乙烯底片上,烘干,切成50个贴片,即得。
实施例13替莫唑胺-8-羧酸酯制剂的制备
将3g替莫唑胺-8-羧酸正己酯研成细粉,与20g水,35g阿拉伯胶,45g肉豆蔻酸异丙酯(IPM)]和适量的乳酸,苯甲酸和异丙醇混合制成微乳。制成微乳分成本50份作为固体储库系统(SSR)用以上描绘的物质制成50个贴片。
实施例13替莫唑胺-8-羧酸酯制剂的制备
成分 储库层 压敏胶层
替莫唑胺-8-羧酸酯 4.0% 1.5%
硬脂酸 32.0% 34.0%
异丙醇 3.0% 4.5%
磷脂 60% 60%
柠檬酸和维生素E 适量 适量
按处方量将上述物质混合,分别制成储库层和压敏胶层。
Claims (1)
1.一种局部透皮贴剂,
其中的活性成分为替莫唑胺-8-羧酸正己酯,所述的局部透皮贴剂为固体储库型控释贴剂;
所述的固体储库型控释贴剂中的水相为水,油相为油酸,表面活性剂为维生素ETPGS和柠檬酸;
称取3g的替莫唑胺-8-羧酸正己酯,研成细粉;取20g水、50g油酸,30g维生素E TPGS和适量的柠檬酸,加入粉碎的药物混合研磨制成微乳,加入控速膜乙烯-醋酸乙烯共聚物膜,和压力敏感粘合剂聚硅氧烷压敏胶适量,搅匀,水浴保温脱气,涂膜于聚乙烯底片上,烘干,切成50个贴片,即得。
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DE2932305A1 (de) * | 1979-08-09 | 1981-02-26 | Basf Ag | Azolo- eckige klammer auf 5,1-d eckige klammer zu - eckige klammer auf 1,2,3,5 eckige klammer zu -tetrazin-4-one und verfahren zur herstellung dieser verbindungen |
GB2125402A (en) * | 1982-08-17 | 1984-03-07 | May & Baker Ltd | New tetrazine derivatives |
EP0252682A2 (en) * | 1986-07-02 | 1988-01-13 | May & Baker Limited | Tetrazines |
CN1485327A (zh) * | 2002-09-29 | 2004-03-31 | 天津天士力集团有限公司 | 替莫唑胺-8-羧酸脂和-8-酰胺衍生物,它们的合成方法以及它们在制备抗癌制剂中的应用 |
CN1752088A (zh) * | 2004-09-22 | 2006-03-29 | 天津市金士力药物研究开发有限公司 | 含有替莫唑胺酯的药用组合物 |
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DE2932305A1 (de) * | 1979-08-09 | 1981-02-26 | Basf Ag | Azolo- eckige klammer auf 5,1-d eckige klammer zu - eckige klammer auf 1,2,3,5 eckige klammer zu -tetrazin-4-one und verfahren zur herstellung dieser verbindungen |
GB2125402A (en) * | 1982-08-17 | 1984-03-07 | May & Baker Ltd | New tetrazine derivatives |
EP0252682A2 (en) * | 1986-07-02 | 1988-01-13 | May & Baker Limited | Tetrazines |
CN1485327A (zh) * | 2002-09-29 | 2004-03-31 | 天津天士力集团有限公司 | 替莫唑胺-8-羧酸脂和-8-酰胺衍生物,它们的合成方法以及它们在制备抗癌制剂中的应用 |
CN1752088A (zh) * | 2004-09-22 | 2006-03-29 | 天津市金士力药物研究开发有限公司 | 含有替莫唑胺酯的药用组合物 |
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