Araícot Amparo, Torres-Molina Francisca, Saadeddin Anas, Cárcel-Trullols Jaime, Alvarez-Fuentes Josefa, Holgado Angeles, Fernández-Arévalo Mercedes, Peris José-Esteban
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Valencia, Valencia, Spain.
Arzneimittelforschung. 2008;58(12):647-52. doi: 10.1055/s-0031-1296566.
An in vivo preclinical study has been made of the oral absorption of morphine (CAS 57-27-2) from a new sustained release formulation (morphine-Eudragit L complex, MEC), which had shown good sustained release properties in in vitro dissolution studies. The absorption of morphine from capsules filled with morphine hydrochloride trihydrate (MHT) or MEC was compared in fasted and fed dogs. Mean plasma morphine concentrations obtained after administration of MHT and MEC to fasted dogs were similar, and no statistically significant differences were found in the pharmacokinetic parameters of morphine (Cmax, Tmax and area under the plasma morphine concentration versus time curve from time zero to the last time with a detectable concentration of morphine). When MHT and MEC were administered to fed animals, mean plasma morphine concentrations were again similar for both formulations, without statistically significant differences in the pharmacokinetic parameters of morphine. These results contrast with those obtained in vitro, and indicate the limited usefulness of in vitro assays for this kind of sustained release formulations in which pH and ionic strength are important factors for drug release from the polymeric structure. The plasma morphine concentrations obtained in fed dogs were generally lower than in fasted dogs, though they were detectable for a longer time, until 10 h after dosing, in contrast to up to 6 h in fasted dogs. It is postulated that the apparently prolonged absorption of morphine in fed dogs may be due to the enterohepatic recycling of the drug (excreted in bile as glucuronide, hydrolysed back to the parent compound in the intestine, and then reabsorbed) as a consequence of gallbladder emptying induced by food.
已对一种新型缓释制剂（吗啡 - 丙烯酸树脂L复合物，MEC）中吗啡（CAS 57 - 27 - 2）的口服吸收进行了体内临床前研究，该制剂在体外溶出度研究中显示出良好的缓释特性。在禁食和进食的犬中比较了从填充有三水合盐酸吗啡（MHT）或MEC的胶囊中吗啡的吸收情况。给禁食犬施用MHT和MEC后获得的平均血浆吗啡浓度相似，并且在吗啡的药代动力学参数（Cmax、Tmax以及从时间零到最后一次检测到吗啡浓度时血浆吗啡浓度与时间曲线下的面积）方面未发现统计学上的显著差异。当给进食动物施用MHT和MEC时，两种制剂的平均血浆吗啡浓度再次相似，吗啡的药代动力学参数无统计学显著差异。这些结果与体外获得的结果形成对比，表明对于这种pH和离子强度是药物从聚合物结构中释放的重要因素的缓释制剂，体外测定的实用性有限。进食犬中获得的血浆吗啡浓度通常低于禁食犬，尽管可检测的时间更长，给药后长达10小时，而禁食犬中长达6小时。据推测，进食犬中吗啡吸收明显延长可能是由于食物引起胆囊排空，导致药物肠肝循环（以葡萄糖醛酸苷形式随胆汁排泄，在肠道中水解回母体化合物，然后再吸收）。
