Fabian Jung (1,2), Manuela Thurn (1,2), Katharina Krollik (2), Fiona G. Gao (2), Indra Hering (3), Elke Eilbrecht (3), Marc Weiler (4), Nazende Günday-Türeli (4), Emre Türeli (4), Michael J. Parnham (1), Matthias G. Wacker (5)
(1) Fraunhofer Institute for Molecular Biology and Applied Ecology, Branch for Translational Medicine and Pharmacology, Germany, (2) Institute of Pharmaceutical Technology, Goethe University, Germany, (3) Fraunhofer Institute for Molecular Biology and Applied Ecology, Branch for Applied Ecology, Germany, (4) MJR Pharmjet GmbH, Germany, (5) Department of Pharmacy, National University of Singapore, Singapore
Introduction: A rising number of active pharmaceutical ingredients (API) possess physicochemical properties unfavorable for oral absorption [1]. While traditional approaches tried to overcome this issue by applying increased doses, a growing number of enhanced formulations such as nanoparticle have been entered the market recently [1,2]. On the other side, the growing number of nanoformulations in the pharmaceutical market has raised concerns about contamination of the aquatic ecosystems [3].
Objectives: Aim of the current work was the evaluation of possible benefits and risks of API nanosizing for patients and environment with regard to pharmacokinetic, ecotoxicology and particle size specific properties.
Methods: The different aspects in the risk assessment were studied on the model compound fenofibrate in the commercial available formulations Lipidil® 200 Lipidil 145 One® as well as a new developed semi-liquid formulation (Ecocaps). A PBPK model was developed to predict the human pharmacokinetic as well as the emitted amount and particle size of fenofibrate and its metabolite, fenofibric acid, to the environment. The current approach combined therefore in vitro studies of release properties, ecotoxicology in zebra fish embryos and particle transformation during a simulated gastrointestinal (GI) transit. For the dissolution experiments, an absorption-related biorelevant medium was developed which enable a final dissolution plateau similar to the fraction absorbed found in vivo. The different formulations were then tested in these medium until the dissolution process was completed and the resulting release profiles were fitted and converted to differential equations. The toxicity of fenofibrate and fenofibric acid was investigated in a fish embryo toxicity test (FET) and lethal concentration (LC50) values were calculated. Finally the transformation of nanoparticle during the transit through the GI tract was measured with nanoparticle tracking analysis (NTA) using biorelevant media for stomach (FaSSGF), intestine (FaSSIF-V2) and colon (FaSSCOF).
Results: Particle measurements revealed a broad and asymmetric size distribution in the micrometer range for the product Lipidl® 200. The Lipidil 145 One® tablet, on the other side, exhibited a Gaussian size distribution in the nanometer range while the new Ecocaps formulation was ranked in between. Dissolution experiments under biosimilar conditions revealed superior release properties for the nanoformulation as well as the Ecocaps compared to the microproduct Lipidil® 200. These results were successfully transformed to pharmacokinetic simulations of the different formulations, demonstrated by absolute average fold errors (AAFE) of 1.5 (Lipidil® 200) and 1.4 (Lipidil 146 One®). Furthermore, the ratios of cmax and AUC of the commercial products were found to be within the range of 0.8 and 1.25, which is applied by regulatory authorities to assess bioequivalence [3]. The FET assay showed an increased toxicity for fenofibrate (LC50 29.58) compared to fenofibric acid (LC50 53.32). The particle tracking analysis of the nanoparticle displayed stability in the gastric and intestinal compartment, but a remarkably aggregation in the colonic compartment resulting in a 57.0% lower particle concentration.
Conclusions: In conclusion, the combination of biorelevant release testing with PBPK modelling enabled a detailed environmental exposure analysis of fenofibrate. Within the limits of this simulation, the fractions of fenofibrate and fenofibric acid but also the content of nanoparticles after digestion was predicted. It could be shown that nanosizing enabled a higher bioavailability of fenofibrate without a significant risk of environmental emission of nanoparticles and additionally, a lower ecotoxicological exposure due to the higher detoxification of the API in humans.
References:
[1] Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.; Yu, L. X.; Amidon, G. L., A Provisional Biopharmaceutical Classification of the Top 200 Oral Drug Products in the United States, Great Britain, Spain, and Japan. Molecular Pharmaceutics 2006, 3, (6), 631-643.
[2] Sauron, R.; Wilkins, M.; Jessent, V.; Dubois, A.; Maillot, C.; Weil, A., Absence of a food effect with a 145 mg nanoparticle fenofibrate tablet formulation. International journal of clinical pharmacology and therapeutics 2006, 44, (2), 64-70.
[3] aus der Beek, T.; Weber, F. A.; Bergmann, A.; Hickmann, S.; Ebert, I.; Hein, A.; Kuster, A., Pharmaceuticals in the environment–Global occurrences and perspectives. Environmental toxicology and chemistry 2016, 35, (4), 823-35.
Reference: PAGE 28 (2019) Abstr 8858 [www.page-meeting.org/?abstract=8858]
Poster: Methodology - Other topics