Self-emulsifying drug delivery systems: A versatile approach to enhance the oral delivery of BCS class III drug via hydrophobic ion pairing

Biopharmaceutical classification systems (BCS) class III drugs belongs to a group of drugs with high solubility in gastrointestinal (GI) fluids and low membrane permeability result in significantly low bioavailability. Self-emulsifying drug delivery systems (SEDDS) considered a suitable candidate to enhance the bioavailability of poorly soluble drugs by improving their membrane permeability, however, incorporating hydrophilic drugs in to these carriers remained a great challenge. The aim of this study was to develop hydrophobic ion pairs (HIPs) of a model BCS class-III drug tobramycin (TOB) in order to incorporate into SEDDS and improve its bioavailability. HIPs of TOB were formulated using anionic surfactants sodium docusate (DOC) and sodium dodecanoate (DOD).

The efficiency of HIPs was estimated by measuring the concentration of formed complexes in water, zeta potential determination and log P value evaluation. Solubility studies of HIPs of TOB with DOC were accomplished to screen the suitable excipients for SEDDS development. Consequently, HIPs of TOB with DOC were loaded into SEDDS and assessed the log D_{SEDDS/release medium} and dissociation of these complexes at different intestinal pH over time. Moreover, cytotoxic potential of HIPs of TOB and HIPs loaded SEDDS formulations was evaluated. HIPs of TOB with DOC exhibited the maximum precipitation efficiency at a stoichiometric ratio of 1:5. Log P of HIPs of TOB improved up to 1500-fold compared to free TOB.

Zeta potential of TOB was shifted from positive to negative during hydrophobic ion pairing (HIP). HIPs of TOB with DOC was loaded at a concentration of 1% (w/v) into SEDDS formulations. Log D_{SEDDS/release medium} of loaded complexes in to oily droplets was above 2 and dissociated up to 20% at various pH within 4 h. Finding of this study suggested that improvement of the lipophilic character of BCS class-III drugs followed by incorporation into oily droplets can be deliberated as a promising tool to enhance the permeation across biological membranes.

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Materials

Tobramycin (TOB) was a gift sample from Welmark Pharmaceuticals (Hattar, Pakistan). Docusate sodium (DOC), sodium dodecanoate (DOD), Propylene glycol and acetonitril were obtained from Sigma-Aldrich (Darmstadt, Germany). Peceol (glycerol monooleate, HLB = 3), Cremophor RH (castor oil, hydrogenated, ethoxylated) and Maisine 35–1 (glycerol monolinoleate, HLB = 1) were a gift from Gattefossé (Lyon France).

Following excipients are mentioned in the study besides other: Capryol 90, Labrasol ALF, Peceol, Tween 20, Propylene Glycol

Asad M, Rasul A, Abbas G, Shah MA, Nazir I (2023) Self-emulsifying drug delivery systems: A versatile approach to enhance the oral delivery of BCS class III drug via hydrophobic ion pairing. PLoS ONE 18(6): e0286668. https://doi.org/10.1371/journal.pone.0286668