Custom fractional factorial designs to develop atorvastatin self-nanoemulsifying and nanosuspension delivery systems – enhancement of oral bioavailability

Abstract

Poor water solubility of a drug is a major challenge in drug delivery research and a main cause for limited bioavailability and pharmacokinetic parameters. This work aims to utilize custom fractional factorial design to assess the development of self-nanoemulsifying drug delivery systems (SNEDDS) and solid nanosuspensions (NS) in order to enhance the oral delivery of atorvastatin (ATR). According to the design, 14 experimental runs of ATR SNEDDS were formulated utilizing the highly ATR solubilizing SNEDDS components: oleic acid, Tween 80, and propylene glycol. In addition, 12 runs of NS were formulated by the antisolvent precipitation–ultrasonication method. Optimized formulations of SNEDDS and solid NS, deduced from the design, were characterized. Optimized SNEDDS formula exhibited mean globule size of 73.5 nm, zeta potential magnitude of −24.1 mV, and 13.5 μs/cm of electrical conductivity. Optimized solid NS formula exhibited mean particle size of 260.3 nm, 7.4 mV of zeta potential, and 93.2% of yield percentage. Transmission electron microscopy showed SNEDDS droplets formula as discrete spheres. The solid NS morphology showed flaky nanoparticles with irregular shapes using scanning electron microscopy. The release behavior of the optimized SNEDDS formula showed 56.78% of cumulative ATR release after 10 minutes. Solid NS formula showed lower rate of release in the first 30 minutes. Bioavailability estimation in Wistar albino rats revealed an augmentation in ATR bioavailability, relative to ATR suspension and the commercial tablets, from optimized ATR SNEDDS and NS formulations by 193.81% and 155.31%, respectively. The findings of this work showed that the optimized nanocarriers enhance the oral delivery and pharmacokinetic profile of ATR.

Dissolution Enhancement of Atorvastatin Calcium by Cocrystallization

“…8 In addition, its bioavailability is highly variable due to instability in acidic media. 9 Many approaches have been developed to improve the solubility of ATC, including: salt formation, solid dispersion technique using mannitol, PEG-4000, PEG-6000, and PVP-K30, 10 nanosuspension, 11 complexation with cyclodextrins, 12 self-emulsifying drug delivery system, 13,14 conjugation with chitosan, 15 and nanosuspension incorporated transdermal patch. 16…”

Self-nanoemulsifying Drug Delivery System of Cilnidipine

“…Smaller the droplet size, the larger is the surface area provided for drug absorption (Figure 3). 13 Droplet size = +49.52 + 6.04 A-60.80B -3.38AB + 3.28 A 2 -46.55 B 2 The droplet size of factorial batches was found to be between 20.41 to 174.86 nm. The linear effect of the amount of S mix (B) was found to be significant (p<0.05).…”

“…Type III formulations comprising mixture of hydrophilic surfactants and/or hydrophobic surfactants/ solvents are most effective for hydrophobic drugs such as lacidipine, 10 efavirenz, 11 docetaxol, 12 atorvastatin. 13 This type gives rise to self-emulsifying drug delivery systems which have greater acceptability as they have a plethora of advantages which include thermodynamically stable formulations with improved bioavailability and circumvention of first pass metabolism. 14 Self nanoemulsifying drug delivery systems (SNEDDS) are physically stable, isotropic mixtures of oil, surfactant and co-surfactant.…”