Novel Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) for Oral Delivery of Cinnarizine: Design, Optimization, and In-Vitro Assessment

Abstract

Abstract. Due to its extreme lipophilicity, the oral delivery of cinnarizine (CN) encounters several problems such as poor aqueous solubility and pH-dependent dissolution, which result in low and erratic bioavailability. The current study aims to design self-nanoemulsifying drug delivery systems (SNEDDS) of CN that circumvent such obstacles. Equilibrium solubility of CN was determined in a range of anhydrous and diluted lipid-based formulations. Dynamic dispersion tests were carried out to investigate the efficiency of drug release and magnitude of precipitation that could occur upon aqueous dilution. Droplet sizes of selected formulations, upon (1:1,000) aqueous dilution, were presented. The optimal formulations were enrolled in subsequent dissolution studies. The results showed that increasing lipid chain length and surfactant lipophilicity raised the formulation solvent capacity, while adding co-solvents provoked a negative influence. The inclusion of mixed glycerides and/or hydrophilic surfactants improved the drug release efficiency. Generally, no significant precipitation was observed upon aqueous dilution of the formulations. Five formulations were optimal in terms of their superior self-emulsifying efficiency, drug solubility, dispersion characteristics, and lower droplet size. Furthermore, the optimal formulations showed superior dissolution profile compared to the marketed (Stugeron®) tablet. Most importantly, they could resist the intensive precipitation observed with the marketed tablet upon shifting from acidic to alkaline media. However, SNEDDS containing medium-chain mixed glycerides showed the highest drug release rate and provide great potential to enhance the oral CN delivery. Accordingly, the lipid portion seems to be the most vital component in designing CN self-nanoemulsifying systems.

Optimization of self-nanoemulsifying formulations for weakly basic lipophilic drugs: role of acidification and experimental design

“…This finding may appear inconsistent with the finding of a previous study (Shahba, Mohsin, Alanazi, 2012a) that showed higher CN solubility in long chain lipid formulations. However, thorough data review revealed that the previously compared formulations were uneven since the previous study (Shahba, Mohsin, Alanazi, 2012a) compared long chain free fatty acid with medium chain ester formulations. For a fair comparison, formulators should consider whether the evaluated fatty acid is in the free or ester form.…”

“…Equilibrium solubility studies CN solubility was previously screened in diverse formulation compositions (Shahba, Mohsin, Alanazi, 2012a). In the current study, we aimed to maximize CN solubility and to develop a formulation design framework for weakly basic lipophilic drugs.…”

“…One-way analysis of variance (ANOVA) followed by post hoc tests (LSD) were applied to compare solubility results (Atef, Belmonte, 2008;Shahba, Mohsin, Alanazi, 2012a). A value of p < 0.05 was considered significant.…”

“…After at least a three-day equilibration period, samples were withdrawn, centrifuged, and assayed using ultra-performance liquid chromatography (UPLC) (Abdel-Hamid et al, 2012;Shahba, Mohsin, Alanazi, 2012a).…”

“…It shows a pH-dependent solubility that is 0.29 mg/mL at pH 2, 0.017 mg/mL at pH 5, and 0.002 mg/mL at pH 6.5 (Gu et al, 2005;Raghuvanshi, Pathak, 2014). Therefore, it is vital to consider the influence of formulation acidity and pH variation during the design of CN-SNEF (Shahba, Mohsin, Alanazi, 2012a). In the current study, we aim to bridge the gaps regarding critical characterization issues, explore the role of formulation acidification, and utilize the experimental design for a time-effective and accurate optimization of SNEFs for weakly basic lipophilic drugs.…”