(M1430-01-05) A Systematic Approach to Developing Lipid-Based Drug Delivery Systems (LBDDS) with Fenobrate as Model Drug

Purpose: With a growing number of new chemical entities (NCEs) having poor aqueous solubility, a systematic approach is needed to streamline the overall formulation development process. To this effect, LBDDS are commonly used because they offer several advantages. These include improved wetting properties, higher drug solubility and delivery of the API in solubilized form, reduced food effect, and enhanced absorption that result in overall improvement of the bioavailability for these poorly soluble compounds. In this study a systematic approach was used to design LBDDS for a model drug fenofibrate. This involved general screening for solubility, miscibility, dispersion, and dissolution in the presence of lipolytic enzymes. Following these steps, a series of formulations were developed by strategically combining lipid-based excipients (surfactant, co-surfactant, and oil/co-solvent). The effect of changing formulation composition, including fatty acid chain length and excipient HLB’s were taken into consideration in the interpretation of the results.

Methods: Formulation Preparation: Formulations were prepared by mixing API and single or multiple excipient blends. Mixtures were stirred at room temperature until all the API solubilized completely. With combination formulations, the drug load was fixed at 80mg/g. With single excipient formulations, drug load was maintained at 75% saturation solubility. Dispersion test: For dispersibility testing, 2g of each formulation was added to 400ml of DI-H₂O at 37 °C and stirred at 100 rpm using USP apparatus II (Paddles). Aliquots were taken at the 30- and 60- minute marks and centrifuged (21000xg and 37 °C) for 30-minutes prior to formulation assay using Ultra High Performance (UPLC). In vitro Lipolysis: Formulations were tested in digestion media at 37 °C. During the first 10 minutes, the formulation was allowed to disperse.  This was followed by 60 minutes of digestion using porcine pancreatic enzyme. Aliquots were taken at select time points and centrifuged (21000xg and 37 °C) for 30 minutes, followed by assay using UPLC. Stability Study: Select formulations were placed on stability at 25 °C/ 60% RH and 40 °C/ 75 % RH conditions. Samples were taken at 1-month and 3-month mark and tested for API content (UPLC), acid value, and peroxide value.

Results: Following screening for fenofibrate solubility in a range of lipid-based excipients,  various formulations. These were strategic combinations, consisting of medium chain fatty acid esters (Labrasol® ALF, Capryol® 90), long chain fatty acid esters (Labrafil® M1944 CS and Plurol® Oleique CC), and/or oils/co-solvent (Labrafac™ lipophile 1349 WL/Transcutol® HP) at select ratios to achieve improved dissolution profiles during invitro lipolysis. Overall, formulations consisting of multi-component self-emulsifying drug delivery systems (SEDDS) performed significantly better during in vitro lipolysis testing (See Figures 1-3) than single excipient formulations. Long chain fatty acid ester-based formulations were able to maintain a higher amount of fenofibrate in the aqueous phase than the medium chain fatty acid ester-based formulations (Figure 1 and Figure 2). Lastly, the introduction of a co-solvent (Transcutol®) further enhanced the in vitro lipolysis performance for fenofibrate significantly (Figure 3). The formulations that performed well during in vitro lipolysis, were placed on stability. No significant loss in fenofibrate content was observed at long term and accelerated conditions over the course of three months.

Conclusion: Following a systematic approach made the overall process of developing LBDDS for bioavailability enhancement more streamlined. Optimized combinations worked better than single excipient systems showing a synergistic effect for fenofibrate. Formulations with combinations of long chain and medium chain fatty acid esters were able to solubilize higher amount of fenofibrate during in vitro lipolysis compared to medium chain fatty acid esters on their own. At the same time medium chain fatty acid esters like Labrasol® ALF were needed to attain the desired drug load of 80mg/g. Lastly, no loss or degradation of fenofibrate was observed for up to three months at long term and accelerated storage conditions.

Figure 1: In vitro lipolysis profile of single excipient formulations with fenofibrate at 75% saturation solubility



Figure 2: In vitro lipolysis profile of Labrafil® M1944 CS based formulation with 80 mg/g fenofibrate loading



Figure 3: In vitro lipolysis profile of Transcutol® based SEDDS formulation with 80 mg/g fenofibrate loading