Block Marco, Sieger Peter, Truenkle Cornelius, Saal Christoph, Simon Roman, Truebenbach Ines
Department of Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß 88397, Germany.
Department of Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß 88397, Germany.
Eur J Pharm Sci. 2024 May 1;196:106733. doi: 10.1016/j.ejps.2024.106733. Epub 2024 Feb 24.
Microencapsulation of active pharmaceutical ingredients (APIs) for preparation of long acting injectable (LAI) formulations is an auspicious technique to enable preclinical characterization of a broad variety of APIs, ideally independent of their physicochemical and pharmacokinetic (PK) characteristics. During early API discovery, tunable LAI formulations may enable pharmacological proof-of-concept for the given variety of candidates by tailoring the level of plasma exposure over the duration of various timespans. Although numerous reports on small scale preparation methods for LAIs utilizing copolymers of lactic and glycolic acid (PLGA) and polymers of lactic acid (PLA) highlight their potential, application in formulation screening and use in preclinical in vivo studies is yet very limited. Transfer from downscale formulation preparation to in vivo experiments is hampered in early preclinical API screening by the large number of API candidates with simultaneously very limited available amount in the lower sub-gram scale, lack of formulation stability and deficient tunability of sustained release. We hereby present a novel comprehensive platform tool for tailored extended-release formulations, aiming to support a variety of preclinical in vivo experiments with ranging required plasma exposure levels and timespans. A novel small-scale spray drying process was successfully implemented by using an air brush based instrument for preparation of PLGA and PLA based formulations. Using Design of Experiments (DoE), required API amount of 250 mg was demonstrated to suffice for identification of dominant polymer characteristics with largest impact on sustained release capability for an individual API. BI-3231, a hydrophilic and weakly acidic small compound with good water solubility and permeability, but low metabolic stability, was used as an exemplary model for one of the many candidates during API discovery. Furthermore, an in vitro to in vivo correlation (IVIVC) of API release rate was established in mice, which enabled the prediction of in vivo plasma concentration plateaus after single subcutaneous injection, using only in vitro dissolution profiles of screened formulations. By tailoring LAI formulations and their doses for acute and sub-chronic preclinical experiments, we exemplary demonstrate the practical use for BI-3231. Pharmacological proof-of-concept could be enabled whilst circumventing the need of multiple administration as result of extensive hepatic metabolism and simultaneously superseding numerous in vivo experiments for formulation tailoring.
用于制备长效注射剂（LAI）制剂的活性药物成分（API）微囊化是一种很有前景的技术，可用于对多种API进行临床前表征，理想情况下不受其物理化学和药代动力学（PK）特性的影响。在API早期发现阶段，可调节的LAI制剂可以通过在不同时间段内调整血浆暴露水平，为给定的各种候选药物提供药理学概念验证。尽管有许多关于利用乳酸和乙醇酸共聚物（PLGA）和乳酸聚合物（PLA）制备LAI的小规模制备方法的报道突出了它们的潜力，但在制剂筛选中的应用以及在临床前体内研究中的使用仍然非常有限。在临床前API早期筛选中，从小规模制剂制备向体内实验的转化受到阻碍，原因包括大量API候选药物同时可获得量非常有限，处于较低的亚克规模，缺乏制剂稳定性以及缓释的可调性不足。我们在此提出一种用于定制缓释制剂的新型综合平台工具，旨在支持各种临床前体内实验，这些实验具有不同的所需血浆暴露水平和时间段。通过使用基于气刷的仪器成功实施了一种新型小规模喷雾干燥工艺，用于制备基于PLGA和PLA的制剂。使用实验设计（DoE），证明250mg的所需API量足以确定对单个API的缓释能力影响最大的主要聚合物特性。BI-3231是一种亲水性弱酸性小化合物，具有良好的水溶性和渗透性，但代谢稳定性低，被用作API发现过程中众多候选药物之一的示例性模型。此外，在小鼠中建立了API释放速率的体外到体内相关性（IVIVC），这使得仅使用筛选制剂的体外溶出曲线就能预测单次皮下注射后的体内血浆浓度平台。通过为急性和亚慢性临床前实验定制LAI制剂及其剂量，我们示例性地展示了BI-3231的实际用途。可以实现药理学概念验证，同时避免由于广泛的肝脏代谢而需要多次给药，并且同时取代大量用于制剂定制的体内实验。
