Microparticle formulations alter the toxicity of fenofibrate to the zebrafish Danio rerio embryo.

A wide variety of active pharmaceutical ingredients are released into the environment and pose a threat to aquatic organisms. Drug products using micro- and nanoparticle technology can lower these emissions into the environment by their increased bioavailability to the human patients. However, due to this enhanced efficacy, micro- and nanoscale drug delivery systems can potentially display an even higher toxicity, and thus also pose a risk to non-target organisms. Fenofibrate is a lipid-regulating agent and exhibits species-related hazards in fish. The ecotoxic effects of a fenofibrate formulation embedded into a hydroxypropyl methylcellulose microparticle matrix, as well as those of the excipients used in the formulation process, were evaluated. To compare the effects of fenofibrate without a formulation, fenofibrate was dispersed in diluted ISO water alone or dissolved in the solvent DMF and then added to diluted ISO water. The effects of these various treatments were assessed using the fish embryo toxicity test, acridine orange staining and gene expression analysis assessed by quantitative RT polymerase chain reaction. Exposure concentrations were assessed by chemical analysis. The effect threshold concentrations of fenofibrate microparticle precipitates were higher compared to the formulation. Fenofibrate dispersed in 20%-ISO-water displayed the lowest toxicity. For the fenofibrate formulation as well as for fenofibrate added as a DMF solution, greater ecotoxic effects were observed in the zebrafish embryos. The chemical analysis of the solutions revealed that more fenofibrate was present in the samples with the fenofibrate formulation as well as fenofibrate added as a DMF solution compared to fenofibrate dispersed in diluted ISO water. This could explain the higher ecotoxicity. The toxic effects on the zebrafish embryo thus suggested that the formulation as well as the solvent increased the bioavailability of fenofibrate.

Predicting the environmental emissions arising from conventional and nanotechnology-related pharmaceutical drug products.

Today, environmental pollution with pharmaceutical drugs and their metabolites poses a major threat to the aquatic ecosystems. Active substances such as fenofibrate, are processed to pharmaceutical drug formulations before they are degraded by the human body and released into the wastewater. Compared to the conventional product Lipidil® 200, the pharmaceutical product Lipidil 145 One® and Ecocaps take advantage of nanotechnology to improve uptake and bioavailability of the drug in humans. In the present approach, a combination of in vitro drug release studies and physiologically-based biopharmaceutics modeling was applied to calculate the emission of three formulations of fenofibrate (Lipidil® 200, Lipidil 145 One®, Ecocaps) into the environment. Special attention was paid to the metabolized and non-metabolized fractions and their individual toxicity, as well as to the emission of nanomaterials. The fish embryo toxicity test revealed a lower aquatic toxicity for the metabolite fenofibric acid and therefore an improved toxicity profile. When using the microparticle formulation Lipidil® 200, an amount of 126 mg of non-metabolized fenofibrate was emitted to the environment. Less than 0.05% of the particles were in the lower nanosize range. For the nanotechnology-related product Lipidil 145 One®, the total drug emission was reduced by 27.5% with a nanomaterial fraction of approximately 0.5%. In comparison, the formulation prototype Ecocaps reduced the emission of fenofibrate by 42.5% without any nanomaterials entering the environment. In a streamlined life cycle assessment, the lowered dose in combination with a lowered drug-to-metabolite ratio observed for Ecocaps led to a reduction of the full life cycle impacts of fenofibrate with a reduction of 18% reduction in the global warming potential, 61% in ecotoxicity, and 15% in human toxicity. The integrated environmental assessment framework highlights the outstanding potential of advanced modeling technologies to determine environmental impacts of pharmaceuticals during early drug development using preclinical in vitro data.

Evaluation of potential environmental toxicity of polymeric nanomaterials and surfactants.

Nanomaterials have gained huge importance in various fields including nanomedicine. Nanoformulations of drugs and nanocarriers are used to increase pharmaceutical potency. However, it was seen that polymeric nanomaterials can cause negative effects. Thus, it is essential to identify nanomaterials with the least adverse effects on aquatic organisms. To determine the toxicity of polymeric nanomaterials, we investigated the effects of poly(lactic-co-glycolid) acid (PLGA), Eudragit® E 100 and hydroxylpropyl methylcellulose phthalate (HPMCP) on zebrafish embryos using the fish embryo toxicity test (FET). Furthermore, we studied Cremophor® RH40, Cremophor® A25, Pluronic® F127 and Pluronic® F68 applied in the generation of nanoformulations to identify the surfactant with minimal toxic impact. The order of ecotoxicty was HPMCP < PLGA < Eudragit® E100 and Pluronic® F68 < Pluronic® F127 < Cremophor® RH40 < Cremophor® A25. In summary, HPMCP and Pluronic® F68 displayed the least toxic impact, thus suggesting adequate environmental compatibility for the generation of nanomedicines.