Date Published: June 2, 2020
Publisher: Springer International Publishing
Author(s): Dorota Danielak, Bartłomiej Milanowski, Krzysztof Wentowski, Maria Nogowska, Michał Kątny, Piotr Rogowski, Łukasz Konwicki, Ewa Puk, Jarosław Pieczuro, Marek Bawiec, Grzegorz Garbacz, Janina Lulek.
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.
The global pharmaceutical market requires high-quality generic drugs. Solely in the USA, approximately 90% of prescribed drugs are generic; at the same time, they account for less than a quarter of total expenses on prescription drugs (1). In 2018, savings from generic drug prescription amounted to 292.6 billion dollars in the USA alone (2). Pharmaceutical companies are required to prove bioequivalence of the manufactured generic drug with a brand name product unless the regulatory agency approves biowaiver. This process is time- and cost-consuming. Therefore, the sponsor of the study should make all the efforts to develop a formulation that will ensure the success of the pharmacokinetic bioequivalence trial. Drug pharmacokinetics differs both within and between subjects due to physiological conditions such as sex, age, or genetic polymorphisms of enzymes involved in the metabolism of xenobiotics. Therefore, variability of drug dissolution should be as low as possible. Also, drug release from generic formulation should resemble the brand name product as closely as possible under fasted and fed conditions, if applicable. It is even more critical in modified (MR) and extended-release (ER) formulations. As the ER forms are designed to release the active ingredient over prolonged time, they are prone to food effects (3). Koziolek et al. (3) distinguished three categories of food effects relevant for MR and ER dosage forms: (i) drug-related factors including partition coefficient, stability in different pH values, or absorption rate; (ii) formulation-related factors comprising dose, size, excipients, and drug release profiles; and (iii) physiology-related factors including gastrointestinal motility, specific pH profile, gastric emptying, or food composition and caloric content. Novel test methods allow the in vitro evaluation of drug dissolution profiles under physiologically relevant conditions. They allow the use of media simulating the composition of fluids in human gastrointestinal tract, such as simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) (4). Additionally, devices such as Dissolution Stress Test (5) or a Fed Stomach Model (6) can effectively simulate shear stresses generated by peristaltics during gastrointestinal passage. As shown in the SmartPill® studies, these contractions generate pressure up to 500 mbar, especially in the antro-pyloric region during gastric emptying (7).
In the present study, we demonstrate how the use of biorelevant methods, i.e., the biorelevant stress test device, supported the development of a generic ER trazodone formulation. The test protocols were utilized to predict the drug delivery behavior of the tested formulations. In this context, the performed study served as a proof-of-concept for the predictive power of the StressTest device. As a result, the developed formulation fulfilled the bioequivalence criteria under fed conditions.
In summary, the present study shows that a preclinical development of ER formulations may be aided by advanced dissolution studies that take into account not only the composition of luminal fluids and respective residence times but also timing and fortitude of the physiological mechanical stress that occurs during the gastrointestinal passage.