High-Throughput Dissolution/Permeation Screening —A 96-Well Two-Compartment Microplate Approach
Early formulation screening can alleviate development of advanced oral drug formulations, such as amorphous solid dispersions (ASDs). Traditionally, dissolution is used to predict ASD performance. Here, a high-throughput approach is described that simultaneously screens drug dissolution and permeation employing a two-compartment 96-well plate. Freeze-drying from hydro-alcoholic solutions was used to prepare amorphous formulations. The screening approach was tested on amorphous and crystalline tadalafil formulations with and without Soluplus®. The workflow consisted of: 1) dispersion of the formulations; 2) incubation within the two-compartment plate, where a dialysis membrane separated donor (dispersed formulation) and acceptor; 3) sampling (donor and acceptor), where donor samples were centrifuged to remove non-dissolved material; and 4) quantification by UHPLC-UV. To identify optimal screening conditions, the following parameters were varied: dispersion medium (buffer / biomimetic media), acceptor medium (buffer / surfactant solutions), and incubation time (1, 3, and 6 h). Surfactants (acceptor) increased tadalafil permeation. Biomimetic medium (donor) enhanced dissolution, but not permeation, except for freeze-dried tadalafil, for which the permeated amount increased. The predictiveness was evaluated by comparing dissolution-/permeation-results with in vivo bioavailability. In general, both dissolution and permeation reflected bioavailability, whereof the latter was a better predictor. High-throughput dissolution/permeation is regarded promising for formulation screening.
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Drug Permeability Profiling Using the Novel Permeapad® 96-Well Plate
Purpose Here,firstexperienceswithaprototypetoolforhigh throughput (passive) permeability profiling, a 96-well plate comprising the Permeapad® membrane, are reported. The permeabilities of a set of drugs were determined and compared to published measures of oral absorption, such as human fraction absorbed (Fa) and in vitro permeability values obtained using other tools.
Methods The tool consists of a 96-well bottom and screen plate with the artificial, phospholipid-based barrier (Permeapad®) mounted between the plates’ lower and upper compartments. The permeability of 14 model compounds including high- and low-absorption drugs, cationic, anionic, zwitterionic and neutral molecules, was determined by quantifying the compounds’ transport over time, deriving the steady-state flux from the linear part of the cumulative curves and calculating the apparent permeability (Papp). The membrane structure was investigated in a high-resolution digital light microscope.
Results The Permeapad® 96-well plate was found suited to distinguish high and low absorption drugs and yielded a hyperbolic correlation to Fa. The Papp values obtained were congruent with those determined with in-house prepared Permeapad® in the Franz cell set-up. Furthermore, good to excellent correlations were seen with Caco-2 permeability (R2 = 0.70) and PAMPA permeability (R2 =0.89). Microscopic investigation of the Permeapad® barrier
revealed the formation of phospholipid vesicles and myelin figures in aqueous environment.
Conclusion The Permeapad® 96-well plate permeation setup is a promising new tool for rapid and reproducible passive permeability profiling.
Springer Science+Business Media, LLC, part of Springer Nature 2020
Self-emulsifying drug delivery systems: About the fate of hydrophobic ion pairs on a phospholipid bilayer
Purpose To investigate the fate of hydrophobic ion pairs (HIPs) and self-emulsifying drug delivery systems (SEDDS) containing HIPs on a phospholipid bilayer.
Methods HIPs of fluorescein (FL) were formed using the lipophilic cationic counter ion octadecylamine (OCT). HIPs were incorporated into SEDDS comprising 30% Capryol 90, 40% Cremophor RH, 20% Maisine 35-1 and 10% propylene glycol and evaluated regarding log DSEDDS/release medium and dissociation of these complexes at various pH values over time. Furthermore, in vitro permeation studies were carried out in order to evaluate the fate of HIPs and SEDDS containing HIPs on a phospholipid bilayer.
Results HIPs of FL with OCT showed the highest precipitation efficiency at a stoichiometric ratio of 1:1. HIPs (1% v/v) were incorporated into SEDDS pre-concentrate. Log DSEDDS/release medium of incorporated complexes was between 2.5 and 3.5. HIPs dissociated in aqueous media up to 20% at pH 6–7.4 within 4 h. In vitro permeation studies revealed 2.7-fold improved permeation of FL after complex formation and incorporation in SEDDS. Results suggest that SEDDS fuse with the phospholipid bilayer facilitating the permeation of incorporated HIPs.
Conclusion SEDDS enhance the stability of incorporated HIPs and improve their permeation across phospholipid bilayers.
In vitro digestion models to evaluate lipid based drug delivery systems; present status and current trends
During the past two decades, a range of in vitro models simulating the digestion processes occurring in the stomach and small intestine have been developed to characterize lipid based drug delivery systems (LbDDSs). This review describes the presently existing range of in vitro digestion models and their use in the field of oral drug delivery. The models are evaluated in terms of their suitability to assess LbDDSs, and their ability to produce in vitro - in vivo correlations (IVIVCs).
While the pH-stat lipolysis model is by far the most commonly utilized in vitro digestion model in relation to characterizing LbDDSs, a series of recent studies have shown a lack of IVIVCs limiting its future use. Presently, no single in vitro digestion model exists which is able to predict the in vivo performance of various LbDDSs. However, recent research has shown the potential of combined digestion-permeation models as well as species specific digestion models.