Abstract
Supersaturated lipid-based drug delivery systems have recently been investigated for oral administration for a variety of lipophilic drugs and have shown either equivalent or superior oral bioavailability compared to conventional non-supersaturated lipid-based drug delivery systems. The aim of the present work was to explore supersaturated versus non-supersaturated lipid-based systems at equivalent lipid doses, on in vivo bioavailability in rats and on in vitro permeation across a biomimetic PermeapadⓇ membrane to establish a potential in vivo - in vitro correlation. A secondary objective was to investigate the influence of lipid composition on in vitro and in vivo performance of lipid systems. Results obtained indicated that increasing the celecoxib load in the lipid-based formulations by thermally-induced supersaturation resulted in increased bioavailability for medium and long chain mono-/di-glycerides systems relative to their non-supersaturated (i.e. 85%) reference formulations, albeit only significant for the medium chain systems. Long chain systems displayed higher celecoxib bioavailability than equivalent medium chain systems, both at supersaturated and non-supersaturated drug loads. In vitro passive permeation of celecoxib was studied using both steady-state and dynamic conditions and correlated well with in vivo pharmacokinetic results with respect to compositional effects. In contrast, permeation studies indicated that flux and percentage permeated of supersaturated systems, either at steady-state or under dynamic conditions, decreased or were unchanged relative to non-supersaturated systems. This study has shown that by using two cell-free PermeapadⓇ permeation models coupled with rat-adapted gastro-intestinal conditions, bio-predictive in vitro tools can be developed to be reflective of in vivo scenarios. With further optimization, such models could be successfully used in pharmaceutical industry settings to rapidly screen various prototype formulations prior to animal studies.
Highlights
With numerous commercial successes, lipid-based drug delivery systems (LBDDS) have a proven track record to improve oral absorption of poorly water-soluble drugs (PWSDs) through a variety of mechanisms including increasing solubility, reducing food-induced exposure variability and improving overall intestinal uptake (Savla et al, 2017)
Results obtained indicated that increasing the celecoxib load in the lipid-based formulations by thermally-induced supersaturation resulted in increased bioavailability for medium and long chain mono-/di-glycerides systems relative to their non-supersaturated (i.e. 85%) reference formulations, albeit only significant for the medium chain systems
To-date the merits of LBDDS have been limited to a relatively small number of highly lipophilic drugs, and a key drawback is that the dose of drug that can be loaded in LBDDS is hindered by the drug solubility in lipids (Thomas et al, 2012; Michaelsen et al, 2016)
Summary
Lipid-based drug delivery systems (LBDDS) have a proven track record to improve oral absorption of poorly water-soluble drugs (PWSDs) through a variety of mechanisms including increasing solubility, reducing food-induced exposure variability and improving overall intestinal uptake (Savla et al, 2017). The need to administer high doses of PWSDs by the oral route, such as in pre-clinical safety and toxicological evaluation, has expanded the potential for use of supersaturated lipid-based drug delivery systems (sLBDDS) (Siqueira Jørgensen et al, 2018). Pharmacokinetic studies involving sLBDDS have indicated an improved in vivo performance relative to conventional non-supersaturated LBDDS or aqueous suspension for a range of either weakly basic or neutral drugs including halofantrine (Thomas et al, 2012; Michaelsen et al, 2016), simvastatin (Thomas et al, 2013), fenofibrate (Thomas et al, 2014) and R3040 (Siqueira Jørgensen et al, 2018) in different preclinical species (i.e. rat, dog and mini-pig). Given the compositional complexity of this specific LBDDS, involving three lipidic excipients plus a co-solvent, it would be preferable to consider less complex LBDDS that can be rapidly screened in an industrial drug development setting (Holm, 2019; Savla et al, 2017; Müllertz et al, 2010)
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