CN111617048A - 一种用于治疗非小细胞肺癌的厄洛替尼缓释制剂 - Google Patents
一种用于治疗非小细胞肺癌的厄洛替尼缓释制剂 Download PDFInfo
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Abstract
本发明涉及一种治疗非小细胞肺癌的厄洛替尼(盐酸厄洛替尼)制剂。它由下述百分含量的原辅料制备而成:厄洛替尼30%‑50%,缓释材料10%‑40%,填充剂30%‑50%,增溶剂1%‑10%,润滑剂1%‑4%。本发明还提供了该缓释片的制备方法:首先将厄洛替尼、缓释材料和填充剂放入高效湿法制粒机中混合均匀,然后将增溶剂加入纯化水配成溶液,将适量溶液加入锅内进行湿法制粒,颗粒干燥后加入适量润滑剂,混合均匀后压成片。与普通药物相比,降低了药物体内释放的“峰谷”效应,降低癌细胞出现耐药性的概率,减小药物血药浓度过高对患者产生的不良反应,使血药浓度持续平稳地维持在最佳治疗浓度上,提高了药物的生物利用度,增强疗效,增加了给药安全性。
Description
技术领域
本发明属于药物制剂领域,特别涉及厄洛替尼。
背景技术
本发明属于药物制剂,主要涉及一种治疗非小细胞肺癌的口服缓释制剂及其制备方法。
肺癌是发病率和死亡率增长最快、对人类健康和生命威胁最大的恶性肿瘤之一,其中非小细胞肺癌约占所有肺癌的80%,传统的治疗方案有手术、化疗、靶向药物治疗。手术疗法会对患者身体造成创伤,且不能切除所有癌细胞,术后易复发。化疗药物的选择性差,靶向效果差,往往会会杀死除了癌细胞之外的其他细胞,破坏人体自身的免疫系统,甚至造成基因突变、致癌的危险。
厄洛替尼单药用于非小细胞肺癌的推荐剂量为 150mg/日,超过每天150mg的推荐剂量时可能发生不能接受的严重不良反应(如腹泻、皮疹和肝脏转氨酶升高),表现出剂量限制性毒性,出现严重腹泻、皮疹的患者常需要减量。厄洛替尼上市制剂为速释制剂,每次给药期间,血药浓度波动大,导致“峰谷”现象。当血药浓度处于高峰时,超过最佳治疗量,易引起不良反应;当血药浓度处于低谷时,难以维持有效治疗浓度,而且会诱导癌细胞的药物耐受性。临床急需一种能够匀速持续释放厄洛替尼,保证疗效,同时又能减少不良反应。
发明内容
本发明的目的在于提供一种治疗非小细胞肺癌的缓释制剂,该缓释制剂为片剂,可以使药物的有效成分缓慢释放,血药浓度平稳。
根据本发明的一方面,提供了一种盐酸厄洛替尼的口服缓释制剂,含有盐酸厄洛替尼和亲水凝胶骨架材料。
根据本发明的一方面,提供了一种盐酸厄洛替尼的口服缓释制剂,其组成成分为:
盐酸厄洛替尼35.5%-52.5%
缓释材料15.0%-25.5%
填充剂45.0%-55.0%
增溶剂0.5%-5.0%
润滑剂1.0%-4.0%
薄膜包衣剂1.5%-4.5%。
根据本发明的一方面,提供了一种盐酸厄洛替尼的口服缓释制剂,其中盐酸厄洛替尼原料为晶型B。
根据本发明的一方面,提供了一种盐酸厄洛替尼的口服缓释制剂,其所用的缓释材料包括海藻酸钠、海藻酸钾、羟丙甲基纤维素、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素、聚乙烯比咯烷酮、丙烯酸树脂、纤维醋法酯中的一种或多种。
根据本发明的一方面,提供了一种盐酸厄洛替尼的口服缓释制剂,其所用的缓释材料为适当比例的羟丙甲基纤维素、聚乙烯比咯烷酮、纤维醋法酯。
根据本发明的一方面,提供了一种盐酸厄洛替尼的口服缓释制剂,所用的填充剂为乳糖、微晶纤维素。
根据本发明的一方面,提供了一种盐酸厄洛替尼的口服缓释制剂,所用的增溶剂为十二烷基硫酸钠。
根据本发明的一方面,提供了一种盐酸厄洛替尼的口服缓释制剂,所用的润滑剂为硬脂酸镁。
根据本发明的一方面,提供了一种盐酸厄洛替尼的口服缓释制剂的制备方法,包括以下步骤:
(1)将盐酸厄洛替尼、乳糖、微晶纤维素、十二烷基硫酸钠、缓释材料过80目筛,备用;
(2)将处方量的盐酸厄洛替尼、乳糖、微晶纤维素、十二烷基硫酸钠、缓释材料加入湿法制粒锅中,混合均匀;
(3)将适量纯化水加入湿法制粒锅中,继续搅拌,制软材;
(4)制湿颗粒,并用流化床干燥颗粒(含水量要求为1%~2%);
(5)24目筛整粒, 加入适量过80目筛的硬脂酸镁混合均匀;
(6)用10%欧巴代 II 包衣液包衣, 包衣增重 1 ~ 2%, 即得。
为了达到上述目的,本发明提供了一种用于治疗非小细胞肺癌的缓释制剂,该缓释剂为片剂,通过湿法制粒后压片、包衣制得。
其中,缓释材料可以延缓药物在体内的释放、吸收、分布、代谢和排泄过程,以达到延长药物作用的目的,其使得药物有效成分释放速度比较缓慢,药效平稳持久。所述的缓释材料选自海藻酸钠、海藻酸钾、羟丙甲基纤维素、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素、聚乙烯比咯烷酮、丙烯酸树脂、纤维醋法酯中的任意一种或一种以上。
其中,填充剂是指加入物料中改善性能或降低成本的物质 ;所述的填充剂选择磷酸氢钙、硫酸钙、碳酸钙、糊精、乳糖、淀粉、微晶纤维素、甘露醇、山梨醇中的任意一种或一种以上。
其中,增溶剂是指具有增溶能力的表面活性剂。增溶是指难溶性药物在表面活性剂的作用下,在溶剂中增加溶解度并形成溶液的过程。所述的增溶剂为十二烷基硫酸钠、泊洛沙姆、吐温80中的一种或多种。
其中,润滑剂可以增强粉体的流动性,上述是指硬脂酸镁、硬脂富马酸钠中的一种或两种。
其中,所述包衣材料选自欧巴代或聚乙烯比咯烷酮,但优选欧巴代,包衣溶剂选择纯化水。
附图说明
图1、为本发明实施例1平均累计溶出量图;
图2、为本发明实施例2平均累计溶出量图;
图3、为本发明实施例3平均累计溶出量图;
图4、为本发明实施例4平均累计溶出量图;
图5、为本发明实施例5平均累计溶出量图;
图6、为本发明实施例6平均累计溶出量图;
图7、为本发明实施例7平均累计溶出量图;
图8、为本发明实施例8平均累计溶出量图;
图9、为本发明实施例5制得的盐酸厄洛替尼缓释片药代动力学实验图。
具体实施方式
下面通过具体实施例进一步说明本发明的技术方案:
实施例1
处方(制成1000片):
盐酸厄洛替尼 150mg
乳糖 75 mg
微晶纤维素 75mg
十二烷基硫酸钠 3.75mg
羟丙甲纤维素 81.25mg
硬脂酸镁(内加) 1.87mg
硬脂酸镁(外加) 3.75mg
欧巴代 9.38mg
纯化水 适量
制备方法:
将处方量的盐酸厄洛替尼、乳糖、微晶纤维素、羟丙甲纤维素、硬脂酸镁分别粉碎并过80目筛,混合均匀,用处方量十二烷基硫酸钠的水溶液作粘合剂制软材,制粒,60℃流化床烘干,加入处方量的硬脂酸镁,混合均匀,压片,包衣,即得。
实施例2:
盐酸厄洛替尼 150mg
乳糖 75mg
微晶纤维素 75mg
十二烷基硫酸钠 3.75mg
海藻酸钠 81.25mg
硬脂酸镁(内加) 1.87mg
硬脂酸镁(外加) 3.75mg
欧巴代 9.38mg
纯化水 适量
制备方法:
将处方量的盐酸厄洛替尼、乳糖、微晶纤维素、海藻酸钠、硬脂酸镁分别粉碎并过80目筛,混合均匀,用处方量十二烷基硫酸钠的水溶液作粘合剂制软材,制粒,60℃烘干,加入处方量的硬脂酸镁,混合均匀,压片,包衣,即得。
实施例3:
盐酸厄洛替尼 150mg
乳糖 75mg
微晶纤维素 75mg
十二烷基硫酸钠 3.75mg
聚乙烯吡咯烷酮 81.25mg
硬脂酸镁(内加) 1.87mg
硬脂酸镁(外加) 3.75mg
欧巴代 9.38mg
纯化水 适量
制备方法:
将处方量的盐酸厄洛替尼、乳糖、微晶纤维素、聚乙烯吡咯烷酮、硬脂酸镁分别粉碎并过80目筛,混合均匀,用处方量十二烷基硫酸钠的水溶液作粘合剂制软材,制粒,60℃烘干,加入处方量的硬脂酸镁,混合均匀,压片,包衣,即得。
实施例4:
盐酸厄洛替尼 150mg
乳糖 75mg
微晶纤维素 75mg
十二烷基硫酸钠 3.75mg
羟丙甲纤维素 41.25mg、
海藻酸钠 40mg
硬脂酸镁(内加) 1.87mg
硬脂酸镁(外加) 3.75mg
欧巴代 9.38mg
纯化水 适量
制备方法:
将处方量的盐酸厄洛替尼、乳糖、微晶纤维素、羟丙甲纤维素、海藻酸钠、硬脂酸镁分别粉碎并过80目筛,混合均匀,用处方量十二烷基硫酸钠的水溶液作粘合剂制软材,制粒,60℃烘干,加入处方量的硬脂酸镁,混合均匀,压片,包衣,即得。
实施例5:
盐酸厄洛替尼 150mg
乳糖 75mg
微晶纤维素 75mg
十二烷基硫酸钠 3.75mg
羟丙甲纤维素 31.25mg
聚乙烯吡咯烷酮 30mg
纤维醋法酯 20mg
硬脂酸镁(内加) 1.87mg
硬脂酸镁(外加) 3.75mg
欧巴代 9.38mg
纯化水 适量
制备方法:
将处方量的盐酸厄洛替尼、乳糖、微晶纤维素、羟丙甲纤维素、聚乙烯吡咯烷酮、硬脂酸镁分别粉碎并过80目筛,混合均匀,用处方量十二烷基硫酸钠的水溶液作粘合剂制软材,制粒,60℃烘干,加入处方量的硬脂酸镁,混合均匀,压片,包衣,即得。
实施例6:
盐酸厄洛替尼 150mg
乳糖 75mg
微晶纤维素 75mg
十二烷基硫酸钠 3.75mg
海藻酸钠 41.25mg
聚乙烯吡咯烷酮 40mg
硬脂酸镁(内加) 1.87mg
硬脂酸镁(外加) 3.75mg
欧巴代 9.38mg
纯化水 适量
制备方法:
将处方量的盐酸厄洛替尼、乳糖、微晶纤维素、海藻酸钠、聚乙烯吡咯烷酮、硬脂酸镁分别粉碎并过80目筛,混合均匀,用处方量十二烷基硫酸钠的水溶液作粘合剂制软材,制粒,60℃烘干,加入处方量的硬脂酸镁,混合均匀,压片,包衣,即得。
实施例7:
盐酸厄洛替尼 150mg
乳糖 75mg
微晶纤维素 75mg
十二烷基硫酸钠 3.75mg
羟丙甲纤维素 36.25mg
聚乙烯吡咯烷酮 35mg
纤维醋法酯 10mg
硬脂酸镁(内加) 1.87mg
硬脂酸镁(外加) 3.75mg
欧巴代 9.38mg
纯化水 适量
制备方法:
将处方量的盐酸厄洛替尼、乳糖、微晶纤维素、羟丙甲纤维素、聚乙烯吡咯烷酮、硬脂酸镁分别粉碎并过80目筛,混合均匀,用处方量十二烷基硫酸钠的水溶液作粘合剂制软材,制粒,60℃烘干,加入处方量的硬脂酸镁,混合均匀,压片,包衣,即得。
实施例8:
盐酸厄洛替尼 150mg
乳糖 75mg
微晶纤维素 75mg
十二烷基硫酸钠 3.75mg
羟丙甲纤维素 26.25mg
聚乙烯吡咯烷酮 25mg
纤维醋法酯 30mg
硬脂酸镁(内加) 1.87mg
硬脂酸镁(外加) 3.75mg
欧巴代 9.38mg
纯化水 适量
制备方法:
将处方量的盐酸厄洛替尼、乳糖、微晶纤维素、羟丙甲纤维素、聚乙烯吡咯烷酮、硬脂酸镁分别粉碎并过80目筛,混合均匀,用处方量十二烷基硫酸钠的水溶液作粘合剂制软材,制粒,60℃烘干,加入处方量的硬脂酸镁,混合均匀,压片,包衣,即得。
盐酸厄洛替尼片的溶出度测定
色谱条件:用十八烷基硅烷键合硅胶为填充剂,以甲醇-pH3 .5磷酸盐缓冲液(25∶75,V/V)为流动相,流速1ml/min,柱温30℃,检测波长为342nm。
取本品,照溶出度测定法(中国药典2010年版附录X C第二法),以pH1 .0的盐酸溶
液(含1%十二烷基硫酸钠)1000ml为溶剂,转速为每分钟75转,依法操作,于1h、2h、3h、4h、6h、8h、10h、12h、14h、16h、18h、20h、22h、24h时,取溶液5ml,滤过,取续滤液作为供试品溶液;另取盐酸厄洛替尼对照品约10mg,精密称定,置100ml量瓶中,加流动相超声使溶解,用溶出液稀释至刻度,作为对照品溶液,再讲供试品倒入比色皿,测其吸光度,记录数据。实施例1~8平均累计溶出量图如图1~8。
表1 实施例1溶出度测定结果
时间/h | 第1片 | 第2片 | 第3片 | 第4片 | 第5片 | 第6片 | 平均值 | RSD/% |
2 | 3.05 | 4.36 | 3.95 | 4.76 | 4.18 | 4.92 | 4.20 | 15.93 |
4 | 9.63 | 11.92 | 10.12 | 12.03 | 10.7 | 12.55 | 11.16 | 10.53 |
6 | 16.81 | 18.21 | 17.15 | 18.88 | 17.99 | 18.85 | 17.98 | 4.77 |
8 | 26.28 | 28.56 | 26.78 | 29.75 | 29.04 | 29.98 | 28.40 | 5.43 |
10 | 38.84 | 41.59 | 36.61 | 41.17 | 40.22 | 42.31 | 40.12 | 5.23 |
12 | 49.52 | 52.2 | 50.95 | 52.37 | 51.94 | 54.01 | 51.83 | 2.90 |
14 | 70.78 | 71.29 | 71.66 | 74.57 | 73.32 | 75.79 | 72.90 | 2.74 |
16 | 84.68 | 86.39 | 84.52 | 86.74 | 86.02 | 87.32 | 85.95 | 1.31 |
18 | 91.3 | 92.26 | 92.15 | 93.27 | 92.63 | 94.12 | 92.62 | 1.05 |
20 | 96.14 | 97.99 | 97.48 | 97.63 | 96.85 | 97.67 | 97.29 | 0.70 |
22 | 96.98 | 98.1 | 97.51 | 98.19 | 97.98 | 98.33 | 97.85 | 0.52 |
24 | 97.05 | 98.24 | 97.96 | 98.42 | 98.1 | 98.54 | 98.05 | 0.54 |
表2 实施例2溶出度测定结果
时间/h | 第1片 | 第2片 | 第3片 | 第4片 | 第5片 | 第6片 | 平均值 | RSD/% |
2 | 2.97 | 4.93 | 3.18 | 5.07 | 3.06 | 5.26 | 4.08 | 27.25 |
4 | 6.69 | 8.57 | 7.32 | 9.99 | 6.96 | 9.56 | 8.18 | 17.09 |
6 | 9.08 | 10.54 | 9.52 | 10.79 | 9.25 | 11.03 | 10.04 | 8.47 |
8 | 14.22 | 15.13 | 14.47 | 15.58 | 13.88 | 15.54 | 14.80 | 4.83 |
10 | 20.61 | 21.95 | 21.19 | 22.69 | 20.26 | 23.53 | 21.71 | 5.80 |
12 | 28.68 | 29.78 | 29.46 | 28.71 | 28.06 | 29.44 | 29.02 | 2.22 |
14 | 35.37 | 36.25 | 35.71 | 35.66 | 35.14 | 36.33 | 35.74 | 1.32 |
16 | 45.02 | 46.27 | 45.19 | 45.59 | 45.66 | 46.11 | 45.64 | 1.08 |
18 | 55.66 | 56.31 | 55.36 | 56.77 | 56.11 | 56.65 | 56.14 | 0.98 |
20 | 59.97 | 60.89 | 59.82 | 60.49 | 60.73 | 60.94 | 60.47 | 0.79 |
22 | 62.97 | 63.63 | 62.86 | 63.79 | 62.76 | 63.56 | 63.26 | 0.71 |
24 | 64.61 | 65.17 | 64.59 | 65.24 | 64.46 | 64.98 | 64.84 | 0.51 |
表3 实施例3溶出度测定结果
时间/h | 第1片 | 第2片 | 第3片 | 第4片 | 第5片 | 第6片 | 平均值 | RSD/% |
2 | 10.96 | 11.63 | 8.55 | 10.68 | 12.46 | 12.29 | 10.97 | 12.90 |
4 | 21.61 | 22.92 | 18.84 | 21.03 | 23.54 | 23.21 | 21.61 | 8.09 |
6 | 36.28 | 38.48 | 32.53 | 35.31 | 37.52 | 36.97 | 36.28 | 5.77 |
8 | 56.96 | 60.41 | 52.67 | 55.46 | 58.91 | 59.04 | 56.96 | 4.95 |
10 | 74.13 | 78.97 | 71.14 | 72.05 | 79.89 | 80.05 | 74.13 | 5.36 |
12 | 91.47 | 93.15 | 89.88 | 92.16 | 94.27 | 94.46 | 91.47 | 1.90 |
14 | 95.01 | 96.78 | 91.56 | 95.78 | 97.95 | 97.98 | 95.01 | 2.51 |
16 | 98.34 | 99.25 | 95.62 | 99.15 | 100.51 | 99.34 | 98.34 | 1.68 |
18 | 98.98 | 99.62 | 97.08 | 99.52 | 100.89 | 99.75 | 98.98 | 1.27 |
20 | 99.51 | 100.05 | 97.94 | 100.42 | 99.17 | 99.54 | 99.51 | 0.86 |
22 | 99.54 | 100.11 | 98.26 | 100.35 | 99.56 | 99.81 | 99.54 | 0.73 |
24 | 99.36 | 99.88 | 100.15 | 100.14 | 99.88 | 99.81 | 99.36 | 0.29 |
表4 实施例4溶出度测定结果
时间/h | 第1片 | 第2片 | 第3片 | 第4片 | 第5片 | 第6片 | 平均值 | RSD/% |
2 | 3.28 | 4.59 | 2.03 | 5.76 | 5.55 | 3.64 | 4.14 | 34.58 |
4 | 5.86 | 7.48 | 3.56 | 8.82 | 8.4 | 6.58 | 6.78 | 28.38 |
6 | 11.77 | 12.85 | 10.24 | 13.74 | 13.46 | 12.25 | 12.39 | 10.34 |
8 | 20.89 | 22.75 | 19.53 | 23.59 | 23.17 | 21.55 | 21.91 | 7.05 |
10 | 30.66 | 34.98 | 29.93 | 33.06 | 32.84 | 31.97 | 32.24 | 5.63 |
12 | 41.25 | 42.69 | 40.96 | 42.17 | 43.44 | 41.91 | 42.07 | 2.18 |
14 | 58.72 | 60.23 | 59.58 | 60.25 | 59.46 | 59.56 | 59.63 | 0.95 |
16 | 69.28 | 70.13 | 69.69 | 70.35 | 70.52 | 70.63 | 70.10 | 0.74 |
18 | 77.69 | 78.12 | 77.84 | 78.48 | 78.59 | 78.36 | 78.18 | 0.46 |
20 | 80.67 | 81.18 | 80.45 | 81.25 | 80.67 | 80.92 | 80.86 | 0.39 |
22 | 83.27 | 84.71 | 83.91 | 84.25 | 84.69 | 84.24 | 84.18 | 0.64 |
24 | 85.35 | 85.87 | 85 | 85.42 | 85.91 | 86.12 | 85.61 | 0.49 |
表5 实施例5溶出度测定结果
时间/h | 第1片 | 第2片 | 第3片 | 第4片 | 第5片 | 第6片 | 平均值 | RSD/% |
2 | 5.07 | 4.38 | 5.28 | 5.66 | 6.39 | 5.45 | 5.07 | 12.37 |
4 | 9.79 | 8.61 | 10.21 | 10.27 | 11.63 | 10.55 | 9.79 | 9.69 |
6 | 17.94 | 15.89 | 18.34 | 18.55 | 19.44 | 18.18 | 17.94 | 6.53 |
8 | 26.11 | 24.09 | 26.7 | 27.01 | 28.24 | 26.26 | 26.11 | 5.16 |
10 | 36.2 | 35.37 | 37.03 | 37.46 | 38.68 | 36.14 | 36.2 | 3.18 |
12 | 45.12 | 43.46 | 45.98 | 46.57 | 48.21 | 45.82 | 45.12 | 3.43 |
14 | 56.05 | 54.98 | 57.23 | 57.96 | 59.98 | 56.93 | 56.05 | 2.99 |
16 | 65.51 | 64.16 | 66.36 | 67.79 | 69.22 | 66.54 | 65.51 | 2.64 |
18 | 74.08 | 71.94 | 75.04 | 76.68 | 77.29 | 75.25 | 74.08 | 2.55 |
20 | 83.81 | 81.39 | 84.91 | 85.78 | 86.19 | 85.15 | 83.81 | 2.06 |
22 | 93.87 | 93.13 | 95.12 | 96.11 | 96.71 | 95.39 | 93.87 | 1.42 |
24 | 99.46 | 98.98 | 99.72 | 99.85 | 101.59 | 100.56 | 100.03 | 0.92 |
表6 实施例6溶出度测定结果
时间/h | 第1片 | 第2片 | 第3片 | 第4片 | 第5片 | 第6片 | 平均值 | RSD/% |
2 | 4.15 | 3.66 | 5.09 | 4.47 | 5.58 | 4.77 | 4.62 | 14.78 |
4 | 5.74 | 6.79 | 10.07 | 9.35 | 10.53 | 9.95 | 8.74 | 22.66 |
6 | 10.51 | 11.74 | 12.33 | 12.57 | 13.59 | 13.62 | 12.39 | 9.51 |
8 | 16.92 | 17.81 | 18.58 | 17.89 | 19.52 | 19.66 | 18.40 | 5.79 |
10 | 25.38 | 26.51 | 27.87 | 26.84 | 28.58 | 28.29 | 27.25 | 4.48 |
12 | 33.98 | 34.43 | 36.59 | 35.88 | 37.08 | 36.74 | 35.78 | 3.61 |
14 | 45.42 | 45.48 | 46.55 | 46.39 | 46.47 | 47.05 | 46.23 | 1.39 |
16 | 55.11 | 55.46 | 55.28 | 55.97 | 56.02 | 56.49 | 55.72 | 0.94 |
18 | 65.36 | 65.28 | 65.34 | 66.49 | 66.75 | 66.69 | 65.99 | 1.10 |
20 | 72.57 | 72.7 | 72.85 | 73.13 | 73.42 | 72.99 | 72.94 | 0.42 |
22 | 77.21 | 77.08 | 77.56 | 78.45 | 77.83 | 77.37 | 77.58 | 0.64 |
24 | 82.44 | 82.85 | 82.46 | 82.57 | 83.78 | 82.21 | 82.72 | 0.68 |
表7 实施例7溶出度测定结果
时间/h | 第1片 | 第2片 | 第3片 | 第4片 | 第5片 | 第6片 | 平均值 | RSD/% |
2 | 5.57 | 5.58 | 6.28 | 5.76 | 7.39 | 5.48 | 6.01 | 12.23 |
4 | 10.64 | 10.66 | 12.06 | 11.02 | 14.28 | 10.46 | 11.52 | 12.76 |
6 | 20.93 | 19.97 | 21.77 | 20.69 | 23.21 | 19.57 | 21.02 | 6.27 |
8 | 34.13 | 33.45 | 34.89 | 33.9 | 34.05 | 31.75 | 33.70 | 3.15 |
10 | 50.4 | 49.58 | 51.75 | 50.04 | 50.72 | 46.71 | 49.87 | 3.43 |
12 | 68.46 | 68.81 | 67.03 | 67.56 | 68.51 | 61.94 | 67.05 | 3.87 |
14 | 83.17 | 83.51 | 81.25 | 82.25 | 84.13 | 74.92 | 81.54 | 4.16 |
16 | 100.46 | 100.88 | 98.06 | 100.31 | 101.66 | 93.15 | 99.09 | 3.18 |
18 | 100.35 | 100.03 | 98.45 | 99.89 | 100.31 | 94.48 | 98.92 | 2.31 |
20 | 99.98 | 100.53 | 98.64 | 99.67 | 100.88 | 95.06 | 99.13 | 2.16 |
22 | 100.12 | 100.46 | 99.47 | 100.02 | 100.05 | 95.09 | 99.20 | 2.06 |
24 | 100.25 | 100.06 | 99.85 | 99.68 | 100.23 | 94.96 | 99.17 | 2.09 |
表8 实施例8溶出度测定结果
时间/h | 第1片 | 第2片 | 第3片 | 第4片 | 第5片 | 第6片 | 平均值 | RSD/% |
2 | 8.86 | 6.05 | 7.69 | 7.56 | 8.42 | 8.63 | 7.87 | 13.09 |
4 | 16.72 | 14.15 | 15.01 | 14.74 | 16.42 | 16.78 | 15.64 | 7.29 |
6 | 29.19 | 25.97 | 26.27 | 25.8 | 28.73 | 29.36 | 27.55 | 6.19 |
8 | 43.68 | 40.25 | 41.4 | 40.77 | 43.09 | 44.04 | 42.21 | 3.80 |
10 | 57.57 | 53.21 | 54.71 | 53.89 | 56.9 | 58.14 | 55.74 | 3.71 |
12 | 72.18 | 66.54 | 68.35 | 67.34 | 71.71 | 72.68 | 69.80 | 3.86 |
14 | 86.29 | 79.86 | 81.62 | 80.75 | 85.18 | 86.35 | 83.34 | 3.52 |
16 | 97.77 | 92.7 | 94.63 | 93.68 | 94.55 | 97.84 | 95.20 | 2.25 |
18 | 98.34 | 97.98 | 100.02 | 99.02 | 99.93 | 99.41 | 99.12 | 0.84 |
20 | 99.12 | 98.56 | 99.8 | 99.87 | 100.05 | 99.69 | 99.52 | 0.57 |
22 | 99.65 | 99.89 | 100.2 | 99.55 | 100.26 | 100.03 | 99.93 | 0.29 |
24 | 99.68 | 100.02 | 99.94 | 99.76 | 100.09 | 99.89 | 99.90 | 0.16 |
由以上溶出曲线可以看出,处方-实施例5的体外溶出曲线在24h内释放速率平稳,溶出好,平台可达100%。
药代动力学实验
给大鼠服用以下两种不同药物,不同时间段来检测体内血药浓度水品。(1)上市销售的盐酸厄洛替尼片,比格犬3只;(2)本发明中实施例5工艺与处方所制得的盐酸厄洛替尼缓释片,比格犬3只。记录数据,计算平均值,结果见图9。
动物实验结果表明:
对照原研药在体内释放快速,服药后4h达到血药浓度峰值,后血药浓度逐步下降。缓释制剂较其而言,避免了药物血药浓度峰值,血药浓度能较长时间维持在稳定有效水平,因而降低了出现严重不良反应的几率,药物有效成分释放速度比较缓慢,药效平稳持久。需要指出的是,上述较佳实施例仅为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
Claims (9)
1.一种盐酸厄洛替尼的口服缓释制剂,其特征在于,含有盐酸厄洛替尼和亲水凝胶骨架材料。
2.根据权利要求1所述的盐酸厄洛替尼口服缓释制剂,其特征在于,所述盐酸厄洛替尼口服缓释制剂组成成分为:
盐酸厄洛替尼35.5%-52.5%
缓释材料15.0%-25.5%
填充剂45.0%-55.0%
增溶剂0.5%-5.0%
润滑剂1.0%-4.0%
薄膜包衣剂1.5%-4.5%。
3.根据权利要求2所述的盐酸厄洛替尼口服缓释制剂,其特征在于,所述盐酸厄洛替尼原料为晶型B。
4.根据权利要求2所述的盐酸厄洛替尼口服缓释制剂,其特征在于,所述盐酸厄洛替尼口服缓释制剂所用的缓释材料包括海藻酸钠、海藻酸钾、羟丙甲基纤维素、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素、聚乙烯比咯烷酮、丙烯酸树脂、纤维醋法酯中的一种或多种。
5.根据权利要求4所述的盐酸厄洛替尼口服缓释制剂,其特征在于,所述盐酸厄洛替尼口服缓释制剂所用的缓释材料为羟丙甲基纤维素、聚乙烯比咯烷酮、纤维醋法酯。
6.根据权利要求2所述的盐酸厄洛替尼口服缓释制剂,其特征在于,所述盐酸厄洛替尼口服缓释制剂所用的填充剂为乳糖、微晶纤维素。
7.根据权利要求2所述的盐酸厄洛替尼口服缓释制剂,其特征在于,所述盐酸厄洛替尼口服缓释制剂所用的增溶剂为十二烷基硫酸钠。
8.根据权利要求2所述的盐酸厄洛替尼口服缓释制剂,其特征在于,所述盐酸厄洛替尼口服缓释制剂所用的润滑剂为硬脂酸镁。
9.权利要求2所述的盐酸厄洛替尼口服缓释制剂的制备方法,其特征在于:包括以下步骤:
(1)将盐酸厄洛替尼、乳糖、微晶纤维素、十二烷基硫酸钠、缓释材料过80目筛,备用;
(2)将处方量的盐酸厄洛替尼、乳糖、微晶纤维素、十二烷基硫酸钠、缓释材料加入湿法制粒锅中,混合均匀;
(3)将适量纯化水加入湿法制粒锅中,继续搅拌,制软材;
(4)制湿颗粒,并用流化床干燥颗粒(含水量要求为1%~2%);
(5)24目筛整粒, 加入适量过80目筛的硬脂酸镁混合均匀;
(6)用10%欧巴代 II 包衣液包衣, 包衣增重 1 ~ 2%, 即得。
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