Miranda Margarida, Veloso Cláudia, Brown Marc, C Pais Alberto A C, Cardoso Catarina, Vitorino Carla
Faculty of Pharmacy, University of Coimbra, Portugal; Coimbra Chemistry Center, Department of Chemistry, University of Coimbra, Portugal.
MedPharm Ltd, Surrey Research Centre, Guildford, Surrey, UK.
Int J Pharm. 2022 May 25;620:121705. doi: 10.1016/j.ijpharm.2022.121705. Epub 2022 Mar 28.
Documenting topical bioequivalence can be an extremely complex process, which is intrinsically dependent on the formulation technological features. According to EMA guideline, for simple formulations, BE may be demonstrated by documenting the qualitative (Q1), quantitative (Q2), microstructure (Q3) and performance (Q4) equivalence. Nevertheless, when addressing complex semisolids, equivalence regarding local availability should also be demonstrated. The purpose of this study is to pursue this strategy using two opposite scenarios: a simple dimetindene maleate 1 mg/g gel formulation and a diclofenac diethylammonium 23.2 mg/g emulgel, representing a complex formulation. For both formulations, Q1/Q2 test (TP) and reference products (RP) were used. Rheology, in vitro release (IVRT) and in vitro permeation methods (IVPT) were developed and validated for both products. For the dimetindene formulation, equivalence pertaining to Q4 was established. However, high variability was observed for some rheology endpoints, especially for the different RP batches. Therefore, equivalence could not be established for Q3 as per EMA requirements. Can some rheology endpoints be waived? Can we establish reasonable criteria that are overall feasible for generic manufacturers and at the same time safe for the patient? An attempt was made to propose a wider acceptance range based on the inter-batch variability of the RP. For that, the rationale presented in the EMA guideline on bioequivalence for highly variable products was used. For the diclofenac formulation, Q3 equivalence was likewise not established. Q4 equivalence was only found for some batch combinations and when applying a wider acceptance criterion (75-133%). Furthermore, IVPT equivalence also failed to be demonstrated. Nevertheless, since the TP displays an equivalent pharmacokinetic profile compared to the RP, the observed Q3, Q4 and local availability differences are not expected to be clinically significant. This study draws attention to an effective search to determine the most appropriate strategy for assessing topical bioequivalence on a case-by-case basis.
记录局部生物等效性可能是一个极其复杂的过程，这本质上取决于制剂的技术特性。根据欧洲药品管理局（EMA）的指南，对于简单制剂，可通过记录定性（Q1）、定量（Q2）、微观结构（Q3）和性能（Q4）等效性来证明生物等效性。然而，在处理复杂的半固体制剂时，还应证明局部可用性方面的等效性。本研究的目的是通过两种相反的情况来推行这一策略：一种简单的1mg/g马来酸氯苯那敏凝胶制剂和一种23.2mg/g双氯芬酸二乙胺乳胶剂，后者代表一种复杂制剂。对于这两种制剂，均使用了受试产品（TP）和参比产品（RP）。针对这两种产品开发并验证了流变学、体外释放（IVRT）和体外渗透方法（IVPT）。对于马来酸氯苯那敏制剂，确立了与Q4相关的等效性。然而，在一些流变学终点观察到了高变异性，尤其是不同的RP批次。因此，根据EMA的要求，无法确立Q3的等效性。能否省略一些流变学终点？我们能否制定出对仿制药制造商总体可行且同时对患者安全的合理标准？尝试根据RP的批次间变异性提出一个更宽的接受范围。为此，采用了EMA关于高变异产品生物等效性指南中阐述的基本原理。对于双氯芬酸制剂，同样未确立Q3的等效性。仅在某些批次组合且应用更宽的接受标准（75 - 133%）时发现了Q4的等效性。此外，也未能证明IVPT的等效性。然而，由于TP与RP相比显示出等效的药代动力学特征，观察到的Q3、Q4和局部可用性差异预计在临床上无显著意义。本研究提请注意进行有效探索，以便逐案确定评估局部生物等效性的最合适策略。
