Background: Fungal keratitis (FK) is a serious pathogenic condition usually associated with significant ocular morbidity. Natamycin (NAT) is the first-line and only medication approved by the Food and Drug Administration for the treatment of FK. However, NAT suffers from poor corneal penetration, which limits its efficacy for treating deep keratitis. Purpose: The objective of this work was to prepare NAT solid lipid nanoparticles (NAT-SLNs) to achieve sustained drug release and increased corneal penetration. Methods: NAT-SLNs were prepared using the emulsification-ultrasonication technique. Box-Behnken experimental design was applied to optimize the effects of independent processing variables (lipid concentration [X 1 ], surfactant concentration [X 2 ], and sonication frequency [X 3 ]) on particle size (R 1), zeta potential (ZP; R 2), and drug entrapment efficiency (EE%) (R 3) as responses. Drug release profile, ex vivo corneal permeation, antifungal susceptibility, and cytotoxicity of the optimized formula were evaluated. Results: The optimized formula had a mean particle size of 42 r.nm (radius in nanometers), ZP of 26 mV, and EE% reached ~85%. NAT-SLNs showed an extended drug release profile of 10 hours, with enhanced corneal permeation in which the apparent permeability coefficient (P app) and steady-state flux (J ss) reached 11.59×10-2 cm h-1 and 3.94 mol h-1 , respectively, in comparison with 7.28×10-2 cm h-1 and 2.48 mol h-1 for the unformulated drug, respectively. Antifungal activity was significantly improved, as indicated by increases in the inhibition zone of 8 and 6 mm against Aspergillus fumigatus ATCC 1022 and a Candida albicans clinical isolate, respectively, and minimum inhibitory concentration values that were decreased 2.5-times against both of these pathogenic strains. NAT-SLNs were found to be non-irritating to corneal tissue. NAT-SLNs had a prolonged drug release rate , that improved corneal penetration, and increased antifungal activity without cytotoxic effects on corneal tissues. Conclusion: Thus, NAT-SLNs represent a promising ocular delivery system for treatment of deep corneal keratitis.

To cite this article: Ahmed Khames (2017) Investigation of the effect of solubility increase at the main absorption site on bioavailability of BCS class II drug (risperidone) using liquisolid technique, Drug Delivery, 24:1, 328-338, DOI: 10.1080/10717544.2016 Department of Pharmaceutics and Pharmacy Technology, Taif University, Taif, Saudi Arabia Abstract BCS class II drugs usually suffer inadequate bioavailability as dissolution step is the absorption rate limiting step. In this work, the effect of solubility increase at the main absorption site for these drugs was investigated using risperidone as a drug model. Liquisolid technique was applied to prepare risperidone per-oral tablets of high dissolution rate at intestinal pH (6.8) using versatile nonionic surfactants of high solubilizing ability [Transcutol HP, Labrasol and Labrasol/Labrafil (1:1) mixture] as liquid vehicles at different drug concentrations (10-30%) and fixed (R). The prepared liquisolid tablets were fully evaluated and the dissolution rate at pH 6.8 was investigated. The formulae that showed significantly different release rate were selected and subjected to mathematical modeling using DE 25 , MDT and similarity factor (f2). Depending on mathematical modeling results, formula of higher dissolution rate was subjected to solid state characterization using differential scanning calorimetric (DSC), infrared spectroscopy (IR) and X-ray diffraction (XRD). Finally, the drug bioavailability was studied in comparison to conventional tablets in rabbits. Results showed that liquisolid tablet prepared using Labrasol/ Labrafil (1:1) mixture as liquid vehicle containing 10% risperidone is a compatible formula with law drug crystallinity and higher dissolution rate (100% in 25 min). The drug bioavailability was significantly increased in comparison to the conventional tablets (1441.711 mg h/mL and 137.518 mg/mL in comparison to 321.011 mg h/mL and 38.673 mg/mL for AUC and Cp max , respectively). This led to the conclusion that liquisolid technique was efficiently improved drug solubility and solubility increase of BCS class II drugs at their main absorption site significantly increases their bioavailability.

Because Eplerenone (EPL) is a Biopharmaceutical Classification System (BCS) class-II drug and is prone to extensive liver degradation, it suffers from poor bioavailability after oral administration. This work aimed to prepare liquisolids loaded with EPL-nanoemulsions (EPL-NEs) that have a higher drug release rate and improved bioavailability by the oral route. Based on solubility studies, mixtures of Triacetin (oil) and Kolliphor EL/PEG 400 surfactant/co-surfactant (Smix) in different ratios were used to prepare EPL-NE systems, which were characterized and optimized for droplet size, zeta potential, polydispersity index (PDI), and drug content. Systems were then loaded onto liquisolid formulations and fully evaluated. A liquisolid formulation with better drug release and tableting properties was selected and compared to EPL-NEs and conventional EPL oral tablets in solid-state characterization studies and bioavailability studies in rabbits. Only five NEs prepared at 1:3, 1:2, and 3:1 Smix met the specified optimization criteria. The drug release rate from liquisolids was significantly increased (90% within 45 minutes). EPL-NE also showed significantly improved drug release but with a sustained pattern for four hours. Liquisolid bioavailability reached 2.1 and 1.2 relative to conventional tablets and EPL-NE. This suggests that the EPL-NE liquisolid is a promising oral delivery system with a higher drug release rate, enhanced absorption, decreased liver degradation, and improved bioavailability.