盐酸拉贝洛尔时控缓释微丸的研制(1)
[摘要] 目的 研究制备盐酸拉贝洛尔时控缓释微丸。 方法 采用挤出滚圆法制备载药丸芯，通过流化床包衣法分别覆上交联羧甲基纤维素钠作为溶胀层、乙基纤维素和羟丙甲纤维素作为控释层制备时控缓释微丸，通过单因素考察筛选溶胀层、控释层的处方组成对体外释药性能的影响。 结果 以微晶纤维素、羧甲基淀粉钠和乳糖为添加剂可制得性能良好的高载药微丸。随着溶胀层厚度的增加，药物释放时滞变短，速率显著增加；随着控释层包衣厚度的增加，时滞延长，释药减慢；控释层中羟丙甲纤维素用量增加，时滞缩短；控释层中增塑剂用量增加，时滞延长。 结论 所得包衣微丸具有良好的释药性能，有广阔的应用前景。
[关键词] 盐酸拉贝洛尔；时控缓释微丸；溶胀层；控释层
[中图分类号] R943 [文献标识码] A [文章编号] 1673-7210(2016)07(a)-0026-05
[Abstract] Objective To develop a novel time-controlled pellets for labetalol hydrochloride with sustained-release behavior. Methods The labetalol-loaded pellets cores were prepared by extrusion-spheronization， then were coated with croscarmellose sodium as swelling layer， followed by the mixture of ethyl cellulose and hydroxypropyl methyl cellulose as controlled release layer via the fluid bed coating equipment. The effects of swelling layer and controlled release membrane on the profile of drug release in vitro were investigated by single factor test. Results The high labetalol-loaded pellet cores made of microcellulose， sodium carboxymethyl starch and lactose showed satisfactory characters. With the thickness of the swelling layer increasing， the lag time of drug release was prolonged and the release rate increased. With the increase of HPMC ratio in the controlled release layer， the lag time increased. The lag time was also prolonged with the addition of plasticizer. Conlusion The obtained pellets display good drug release behavior， which suggests a great potential in clinic application.
[Key words] Labetalol hydrochloride； Sustained-release pellets of time-controlled； Swelling layer； Controlled-release layer
盐酸拉贝洛尔(labetalol hydrochloride)是兼具α、β受体阻断作用的抗高血压药物，临床用于治疗各种类型的高血压[1-4]。高血压的发生具有明显的时辰节律性，市售盐酸拉贝洛尔制剂多为注射液、片剂和胶囊等普通制剂，需一日多次给药且不能满足夜间治疗的要求[5-6]。本研究针对其发作的时间特殊性，制备具有3 h时滞的时控缓释微丸，使其达到晚间睡前服药，发病高峰期维持治疗疗效的血药浓度。微丸是多单元释药体系，可以避免个别单元因制造缺陷或不寻常的胃刺激引起的药物解体失效的弊端，具有更好的重现性[7-9]。本研究采用挤出滚圆法制备载药丸芯，以高溶胀性能的交联羧甲基纤维素钠CC-Na作溶胀层，以羟丙甲纤维素(HPMC)和乙基纤维素(EC)混合物为控释层，通过单因素考察筛选溶胀层、控释层的处方组成，并对其体外释药性能和释药机制进行初步考察。
1 仪器与试剂
Mini DPL 0.2多功能制粒/包衣机(重庆精工制药机械有限责任公司)；Mini-250低温挤出滚圆机(深圳信宜特科技有限公司)；ZRS-8G型智能溶出仪(天大天发科技有限责任公司)；FA2004B型电子天平(上海佑科仪器仪表有限公司)；Helios λ紫外可见分光光度计(美国热电公司)；FT-2000型脆碎度仪(天津大学精密仪器厂)。
盐酸拉贝洛尔(南京爱里凯德化工有限公司)；微晶纤维素(MCC)、羧甲基淀粉钠(CMS-Na)、交联羧甲基纤维素钠(CC-Na)、羟丙基甲基纤维素(HPMC)、柠檬酸三乙酯(TEC)、蓖麻油均由安徽山河药用辅料股份有限公司惠赠；乙基纤维素(EC)(卡乐康公司)，其他试剂皆为分析纯。
2 方法与结果
2.1 载药丸芯的制备
采用挤出滚圆法制备载药丸芯，称取处方用量的盐酸拉贝洛尔、MCC、CMS-Na和乳糖，混合均匀后，加适量纯化水制软材，经挤出滚圆机制成载药微丸[10]。挤出速率为25 r/min，滚圆转速为1200 r/min，滚圆时间为4 min，40℃烘干过夜，过筛，取18～24目微丸，备用。 (高捷 朱淼 沃联群 王文喜)
[关键词] 盐酸拉贝洛尔；时控缓释微丸；溶胀层；控释层
[中图分类号] R943 [文献标识码] A [文章编号] 1673-7210(2016)07(a)-0026-05
[Abstract] Objective To develop a novel time-controlled pellets for labetalol hydrochloride with sustained-release behavior. Methods The labetalol-loaded pellets cores were prepared by extrusion-spheronization， then were coated with croscarmellose sodium as swelling layer， followed by the mixture of ethyl cellulose and hydroxypropyl methyl cellulose as controlled release layer via the fluid bed coating equipment. The effects of swelling layer and controlled release membrane on the profile of drug release in vitro were investigated by single factor test. Results The high labetalol-loaded pellet cores made of microcellulose， sodium carboxymethyl starch and lactose showed satisfactory characters. With the thickness of the swelling layer increasing， the lag time of drug release was prolonged and the release rate increased. With the increase of HPMC ratio in the controlled release layer， the lag time increased. The lag time was also prolonged with the addition of plasticizer. Conlusion The obtained pellets display good drug release behavior， which suggests a great potential in clinic application.
[Key words] Labetalol hydrochloride； Sustained-release pellets of time-controlled； Swelling layer； Controlled-release layer
盐酸拉贝洛尔(labetalol hydrochloride)是兼具α、β受体阻断作用的抗高血压药物，临床用于治疗各种类型的高血压[1-4]。高血压的发生具有明显的时辰节律性，市售盐酸拉贝洛尔制剂多为注射液、片剂和胶囊等普通制剂，需一日多次给药且不能满足夜间治疗的要求[5-6]。本研究针对其发作的时间特殊性，制备具有3 h时滞的时控缓释微丸，使其达到晚间睡前服药，发病高峰期维持治疗疗效的血药浓度。微丸是多单元释药体系，可以避免个别单元因制造缺陷或不寻常的胃刺激引起的药物解体失效的弊端，具有更好的重现性[7-9]。本研究采用挤出滚圆法制备载药丸芯，以高溶胀性能的交联羧甲基纤维素钠CC-Na作溶胀层，以羟丙甲纤维素(HPMC)和乙基纤维素(EC)混合物为控释层，通过单因素考察筛选溶胀层、控释层的处方组成，并对其体外释药性能和释药机制进行初步考察。
1 仪器与试剂
Mini DPL 0.2多功能制粒/包衣机(重庆精工制药机械有限责任公司)；Mini-250低温挤出滚圆机(深圳信宜特科技有限公司)；ZRS-8G型智能溶出仪(天大天发科技有限责任公司)；FA2004B型电子天平(上海佑科仪器仪表有限公司)；Helios λ紫外可见分光光度计(美国热电公司)；FT-2000型脆碎度仪(天津大学精密仪器厂)。
盐酸拉贝洛尔(南京爱里凯德化工有限公司)；微晶纤维素(MCC)、羧甲基淀粉钠(CMS-Na)、交联羧甲基纤维素钠(CC-Na)、羟丙基甲基纤维素(HPMC)、柠檬酸三乙酯(TEC)、蓖麻油均由安徽山河药用辅料股份有限公司惠赠；乙基纤维素(EC)(卡乐康公司)，其他试剂皆为分析纯。
2 方法与结果
2.1 载药丸芯的制备
采用挤出滚圆法制备载药丸芯，称取处方用量的盐酸拉贝洛尔、MCC、CMS-Na和乳糖，混合均匀后，加适量纯化水制软材，经挤出滚圆机制成载药微丸[10]。挤出速率为25 r/min，滚圆转速为1200 r/min，滚圆时间为4 min，40℃烘干过夜，过筛，取18～24目微丸，备用。 (高捷 朱淼 沃联群 王文喜)