Nanosizing of a poorly soluble drug: technique optimization, factorial analysis, and pharmacokinetic study in healthy human volunteers

Abstract

Context Diacerein (DCN) has low aqueous solubility (3.197 mg/L) and, consequently, low oral bioavailability (35%–56%). To increase both the solubility and dissolution rate of DCN while maintaining its crystalline nature, high pressure homogenization was used but with only a few homogenization cycles preceded by a simple bottom-up technique. Methods The nanosuspensions of DCN were prepared using a combined bottom-up/top-down technique. Different surfactants – polyvinyl alcohol, sodium deoxycholate, and sodium dodecyl sulfate – with different concentrations were used for the stabilization of the nanosuspensions. Full factorial experimental design was employed to investigate the influence of formulation variables on nanosuspension characteristics using Design-Expert ® Software. Particle size (PS), zeta potential, saturation solubility, in vitro dissolution, and drug crystallinity were studied. Moreover, the in vivo performance of the optimized formula was assessed by bioavailability determination in healthy human volunteers. Results The concentration of surfactant had a significant effect on both the PS and polydispersity index values. The 1% surfactant concentration showed the lowest PS and polydispersity index values compared with other concentrations. Both type and concentration of surfactant had significant effects on the zeta potential. Formula F8 (containing 1% sodium deoxycholate) and Formula F12 (containing 1% sodium dodecyl sulfate) had the highest desirability values (0.952 and 0.927, respectively). Hence, they were selected for further characterization. The saturated solubility and mean dissolution time, in the case of F8 and F12, were significantly higher than the coarse drug powder. Techniques utilized in the nanocrystals’ preparation had no effect on DCN crystalline state. The selected formula (F12) showed a higher bioavailability compared to the reference market product with relative bioavailability of 131.4%. Conclusion The saturation solubility, in vitro dissolution rate and relative bioavailability of DCN were significantly increased after nanocrystallization. Less time and power consumption were applied by the combination of bottom-up and top-down techniques.

Fabrication of novel elastosomes for boosting the transdermal delivery of diacerein: statistical optimization, ex-vivo permeation, in-vivo skin deposition and pharmacokinetic assessment compared to oral formulation

“…Figure 2(D) represents the thermograms of pure DCN, CH, Span 60, STC, Brij S2, physical mixture of DCN with elastosomal components and E1. The DSC scan of pure DCN depicted a single endothermic peak at 256.19 °C due to its crystalline nature (Elsayed et al., 2014 ). The thermogram of CH depicted sharp endothermic transition at 146.81 °C because of degradation (Rudra et al., 2010 ).…”

“…STC showed exothermic crystallization peak at 238.30 °C followed by endothermic one at 264.75 °C due to melting and hydration of the hydrophilic head in STC structure (Trivedi et al., 2015 ). With respect to the physical mixture of DCN with elastosomal components, the endothermic transition of DCN was shown with significant lower intensity compared to pure drug due to its dilution with the used excipients (Elsayed et al., 2014 ). Oppositely, complete absence of DCN peak was observed in thermogram of E1 confirming that DCN was entrapped in elastosomes with good interaction with their vesicular bilayer.…”

“…Hence, it manages the symptoms of osteoarthritis (OA), targets the underlying pathology, and arrests the disease progression (Medhi et al., 2007 ; Dhaneshwar et al., 2013 ). Being a BCS class II drug, DCN is slightly soluble in water (3.197 mg/L) with low oral bioavailability (35%–56%) (Elsayed et al., 2014 ). After DCN oral administration, the remaining unabsorbed drug induces laxative effect by stimulating prostaglandins (PGs) and acetylcholine release and consequently causes diarrhea (El-Laithy et al., 2015 ).…”

Implementing Central Composite Design for Developing Transdermal Diacerein-Loaded Niosomes: Ex vivo Permeation and In vivo Deposition

“…Gastrointestinal side effects like diarrhea was observed in patients with the incidence of 20% to 40% within the first 2 weeks of oral DCN administration which would lead to treatment discontinuation and prohibition of its use in some countries [22]. Furthermore, DCN is a BCS class II drug with poor water solubility (3.197 mg/L) and low oral bioavailability (35%-56%) [23]. Hence, DCN is considered as a good candidate for transdermal niosomal formulation for maintaining continuous DCN delivery across the skin into systemic circulation, avoiding its oral problems and consequently improving the patient compliance.…”

Enhancement of pharmacokinetic and pharmacological behavior of ocular dorzolamide after factorial optimization of self-assembled nanostructures

“…Patterns of X-ray diffraction were determined using MD-10 mini-diffractometer (MTI Corporation, CA, USA) operating at a voltage 25 kV and a current of 30 mA [ 18 ]. The test was performed for DH, PC and the optimized formulae.…”