The Influence of Fed State Lipolysis Inhibition on the Intraluminal Behaviour and Absorption of Fenofibrate from a Lipid-Based Formulation

The bioavailability of lipophilic drugs may or may not be increased when administered with food due to increased solubilisation in fed state gastrointestinal (GI) fluids. The in vivo interplay between drug solubilisation, lipid phase digestion and drug absorption is complex and remains poorly understood. This study aimed to investigate the role of fed state GI lipolysis on the intraluminal behaviour and absorption of fenofibrate, formulated as the lipid-based formulation Fenogal. Therefore, a crossover study was performed in healthy volunteers using orlistat as lipase inhibitor. Fenofibrate concentrations were determined in the proximal jejunum and linked to simultaneously assessed systemic fenofibric acid concentrations. Inhibition of lipolysis by orlistat resulted in a faster onset of absorption in 4 out of 6 volunteers, reflected by a decrease in systemic Tmax between 20 and 140 min. In addition, the increase of undigested lipids present in the small intestine upon orlistat co-administration sustained drug solubilisation for a longer period, resulting in higher fenofibrate concentrations in the jejunum and improved absorption in 5 out of 6 volunteers (median AUC0–8h 8377 vs. 5832 μM.min). Sustaining drug solubilisation in the lipid phase may thus contribute to the absorption of lipophilic drugs. More research into the different mechanisms underlying lipophilic drug absorption from fed state media at different levels of digestion is warranted.

An oral lipidic native testosterone formulation that is absorbed independent of food

Context: There is no licensed oral Native Testosterone (NT) because of challenges in formulation. Licensed oral formulations of the ester, testosterone undecanoate (TU), require a meal for absorption and generate supraphysiological dihydrotestosterone (DHT) levels. Objective: To develop an oral NT formulation. Design and Methods: A lipid-based formulation of native testosterone filled into soft-gelatin capsules at 40mg per capsule was designed with 2 years stability at ambient temperature. Pharmacokinetic comparison studies of this oral lipidic NT formulation to oral TU were conducted in dogs and hypogonadal men. Results: In dogs, 40mg NT was well absorbed under fasted conditions whereas 40mg TU required a high fat meal: for NT the mean fed / fasted AUC ratio was 1.63 and for TU 7.05. In hypogonadal men fed and fasted NT had similar pharmacokinetics: Cmax mean 26.5 vs 30.4 nmol/l (769 vs 882 ng/dl), AUC0-10h 87 vs 88.6 h*nmol/l. NT (fed state) showed a testosterone AUC increase of 45% between 120mg and 200mg and NT 200mg gave a similar mean AUC0-10h to TU 80mg: 87 vs. 64.8 h*nmol/l. Serum TU levels were variable and on a molar basis were ~10-fold higher than serum testosterone levels after TU 80mg fed. The DHT:testosterone AUC0-10h ratio was more physiological for NT than TU being 0.19 vs 0.36. There were no emerging safety concerns with NT. Conclusion: This novel oral lipidic native testosterone formulation has potential advantages over oral TU of dosing independent of food and a lower risk of supraphysiological DHT levels.

Palm Oil in Lipid-Based Formulations and Drug Delivery Systems

Palm oil is natural oil packed with important compounds and fatty acids ready to be exploited in lipid-based formulations and drug delivery. Palm oil and palm kernel oil contain long-chain and medium-chain triglycerides, respectively, including phytonutrients such as tocotrienol, tocopherol and carotenes. The exploitation of these compounds in a lipid-based formulation would be able to address hydrophobicity, lipophilicity, poor bioavailability and low water-solubility of many current drugs. The utilisation of palm oil as part of the drug delivery system seemed to improve the bioavailability and solubility of the drug, stabilising emulsification of formulation between emulsifier and surfactant, promoting enhanced drug permeability and performance, as well as extending the shelf-life of the drug. Despite the complexity in designing lipid-based formulations, palm oil has proven to offer dynamic behaviour in providing versatility in drug design, form and delivery. However, the knowledge and application of palm oil and its fractions in lipid-based formulation are scarce and interspersed. Therefore, this study aims to focus on the research and outcomes of using palm oil in lipid-based formulations and drug delivery systems, due to the importance of establishing its capabilities and benefits.