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Abstract：
Development of generic extended-release (ER) formulations is challenging. Especially under fed conditions, the risk of failure in bioequivalence trials is high because of long gastric residence times and susceptibility to food effects. We describe the development of a generic trazodone ER formulation that was aided with a biorelevant dissolution evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both in USP and EMA compliant conditions and in the StressTest device that simulated both physicochemical and mechanical conditions of the gastrointestinal passage. The final formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines. Initially developed formulations dissolved trazodone similarly to the originator under standard conditions (f2 factor above 50), but their dissolution kinetics differed significantly in the biorelevant tests. The formulation was optimized by the addition of low-viscosity hypromellose and mannitol. The final formulation was approved for the bioequivalence trial. Calculated Cmax were 1.92 ± 0.77 and 1.92 ± 0.63 [μg/mL], AUC0-t were 27.46 ± 8.39 and 29.96 ± 9.09 [μg∙h/mL], and AUC0-∞ were 28.22 ± 8.91 and 30.82 ± 9.41 [μg∙h/mL] for the originator and test formulations, respectively. The 90% confidence intervals of all primary pharmacokinetic parameters fell within the 80-125% range. In summary, biorelevant dissolution tests supported successful development of a generic trazodone ER formulation pharmaceutically equivalent with the originator under fed conditions. Employment of biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER formulations.
摘要：
通用延长释放(ER)制剂的开发具有挑战性。尤其是在饲料条件下，生物等效性试验失败的风险很高，因为胃停留时间长和对食物的影响。我们描述了在生物相关溶出评估的帮助下开发的通用曲唑酮ER制剂。在符合USP和EMA的条件下以及在模拟胃肠通道的物理化学和机械条件的StressTest设备中溶解盐酸曲唑酮300-mg整体基质片剂。最后的配方对发起人进行了测试，TritticoXR300毫克，在44名健康志愿者的随机交叉生物等效性试验中，与EMA准则一致。最初开发的制剂在标准条件下(f2因子高于50)与鼻祖相似地溶解曲唑酮,但是在生物相关测试中，它们的溶解动力学存在显着差异。通过添加低粘度羟丙甲纤维素和甘露醇来优化配方。最终制剂被批准用于生物等效性试验。计算的Cmax为1.92±0.77和1.92±0.63[μg/mL]，AUC0-t分别为27.46±8.39和29.96±9.09[μg·h/mL]，和AUC0-∞分别为28.22±8.91和30.82±9.41[μg·h/mL]，分别。所有主要药代动力学参数的90％置信区间在80-125％范围内。总之,生物相关的溶出测试支持在喂食条件下与鼻祖在药学上等效的通用曲唑酮ER制剂的成功开发。采用生物相关溶出试验可降低ER制剂生物等效性试验失败的风险。
