Enhanced bioavailability and efficacy in antimalarial treatment through QbD approach enteric encased inclusion delivery

<b>Aim:</b> In this study, we aimed to prepare enteric encapsulated spheroids containing inclusion complex using quality by design approach. <b>Methods:</b> A Box–Behnken design was employed to determine effects of variables on selected responses. Risk assessment was conducted using Ishikawa fishbone diagram. A model with a <i>p</i>-value was less than 0.5 for being a significant error of model was determined based on significance ‘lack of fit’ value. Spheroids were formulated using the extrusion spheronization technique and were characterized using analytical techniques. <b>Results:</b><i>In vitro</i> release was performed in both acidic (pH 1.2) and simulated intestinal (pH 6.8) conditions. Permeability studies demonstrated tenfold enhancement compared with arteether. <i>In vivo</i> studies further validated increase of 51.8% oral bioavailability. <i>Ex vivo</i> studies revealed 3.4-fold enhancement in antimalarial activity compared with arteether. <b>Conclusion:</b> These findings highlight effectiveness of inclusion complexation technique as a viable approach to enhance solubility and bioavailability for drugs with low aqueous solubility. The enteric encapsulated spheroids of ART-cyclodextrin (CD) inclusion complex were prepared by extrusion spheronization using quality-by-design approach. A Box–Behnken design was consequently employed for investigation of impact on the response on selected variables. The preparation of spheroids was confirmed by x-ray diffraction, solubility studies, scanning electron microscopy, differential scanning calorimetry and flow properties. <i>In vitro</i> release studies confirmed that around 80% drug was released in 4.5 h which validated that the drug was released in intestine, the preferred absorption site. Flow property characterization confirmed free flowing nature of prepared spheroids. The permeability of ART containing formulations was investigated using the Franz diffusion cell technique. The concentration of ART-CD spheroids to pure ART in the pig’s intestine was compared. A nearly 7.1-fold, 6.8-fold, sevenfold, 4.6-fold increase in permeability compared with ART in its pure form was observed with SLNs, NLCs, SMEDDS, ART-CD inclusion complex respectively. For establishing plasma drug concentration-time profile of pure drug suspension, spheroids in enteric coated capsule shells were administered orally in rabbits. The pharmacokinetic parameters of the prepared formulations revealed that the absolute bioavailabilities of the formulations ART-CD spheroids (51.8%) were comparable with marketed formulation i.e. i.m. injection (43.73%). In order to compare the antimalarial efficacy of ART and ART-CD complx, IC₅₀ values against <i>P. falciparum</i> stain Pf3. The IC₅₀ value of ART and ART-CD complex were estimated to be 0.76 ng/ml and 0.733 ng/ ml in dimethylsulfoxide as solvent. The IC₅₀ value of ART-CD complex was almost equivalent to ART reflecting the acceptability of antimalarial activity of ART-CD complex drug. Therefore, it is concluded that present study have explored the feasibility to prepare oral formulation of ART with acceptable bioavailability. With benefits including higher acceptance, particularly among adolescents and female patients, enhanced compliance, lesser production cost and many dose-related difficulties, the suggested formulation may offer a new vista in the treatment of malaria. Application of various prevalent industrial approaches involving total quality management based on intergrative strategies like critically analysis, quality risk management, analytical method validation, formulation-by-design and ultimately quality by design in present study also provide a comprehensive solution to develop oral formulation of arteether with desired bioavailability at industrial scale.