Aim: The aim of the current work was to develop vardenafil hydrochloride (VRD)-loaded ethosome-derived invasomes as a possible transdermal system which could be used for patients suffering from pulmonary arterial hypertension. Methods: VRD-loaded ethosomes were developed at three concentrations of phosphatidylcholine (5, 10 and 15 mg/mL) and three percentages of ethanol (20%, 30% and 40%, v/v). The best achieved VRD-loaded ethosomes (ETH9) were optimized to invasomes via incorporation of terpenes (limonene, cineole and a 1:1 mixture) at three concentrations (0.5%, 1% and 2%, v/v). All systems were evaluated for vesicle size, zeta potential, drug entrapment efficiency (EE%), cumulative drug permeated percentages after 0.5hrs (Q_0.5h) and 12hrs (Q_12h) and steady-state flux (J_ss). The optimized system (ETH9-INV8) was further characterized for morphology, histopathology and confocal laser scanning microscopy (CLSM). Physiologically based pharmacokinetic (PBPK) modeling was employed to estimate VRD pharmacokinetic parameters from the optimized transdermal system and an oral aqueous drug dispersion, in adults and geriatrics. Results: The optimized invasomal system (ETH9-INV8) was characterized with spherical vesicles (159.9 nm) possessing negative zeta potential (− 20.3 mV), promising EE% (81.3%), low Q_0.5h (25.4%), high Q_12h (85.3%) and the largest steady-state flux (6.4 μg.cm^{− 2}h^{− 1}). Following a leave-on period of 12hrs in rats, it showed minor histopathologic changes. CLSM studies proved its ability to deeply permeate rat skin. Lower C_max values, delayed T_max estimates and greater AUC_0-24h folds in adults and geriatrics (≈ 2.18 and 1.69, respectively) were estimated following the transdermal application of ETH9-INV8 system. Conclusion: ETH9-INV8 is a promising transdermal system for VRD.

Aim: Agomelatine (AGM) is the first melatonergic antidepressant. It suffers from low oral bioavailability (< 5%) due to extensive hepatic metabolism. The current work aimed to develop an alternative AGM-loaded invasomes to enhance transdermal drug bioavailability. Methodology: AGM-loaded invasomes were developed using two drug: lipid ratios (1:10 or 1:7.5), four terpene types (limonene, cineole, fenchone or citral) and two terpene concentrations (0.75% or 1.5%, w/v). They were characterized for drug entrapment efficiency (EE%), particle size (PS), zeta potential (ZP) and drug released percentages after 0.5h (Q_0.5h) and 8h (Q_8h). The optimum invasomes (I1, I2 and I4) were evaluated for morphology, drug-crystallinity, and ex-vivo drug flux. The variables influencing sonophoresis of the best achieved invasomal gel system (I2) were optimized including, ultrasound frequency (low, LFU or high, HFU), mode (pulsed or continuous), application period (10 min or 15 min) and duty cycle (50% or 100%). AGM pharmacokinetics were evaluated in rabbits following transdermal application of I2-LFU-C4 system, relative to AGM oral dispersion. Results: The superiority of I2 invasomes [comprising AGM and phosphatidylcholine (1:10) and limonene (1.5% w/v)] was statistically revealed with respect to EE% (78.6%), PS (313 nm), ZP (− 64 mV), Q_0.5h (30.1%), Q_8h (92%), flux (10.79 μg/cm2/h) and enhancement ratio (4.83). The optimum sonophoresis conditions involved application of LFU in the continuous mode for 15 min at a 100% duty cycle (I2-LFU-C4 system). The latter system showed significantly higher C_max, and relative bioavailability (≈ 7.25 folds) and a similar T_max (0.5 h). Conclusion: I2-LFU-C4 is a promising transdermal system for AGM.

Aim: Norfloxacin (NFX) has low ocular bioavailability. The current work aimed to develop NFX-loaded nanoparticle (NP)-laden hydrogels to improve the ocular potential of NFX, minimize the need for frequent instillations and lower undesirable side effects. Methods: NFX-loaded NPs were developed via the double-emulsion/solvent evaporation technique, according to 2¹ .4¹ full factorial design, using two types of polylactic-co-glycolic acid (PLGA) polymer and four (drug: polymer) ratios. NPs were evaluated for particle size (PS), polydispersity index (PDI), zeta potential (ZP), drug entrapment efficiency percentage (EE%), drug percentage released after 30 min (Q_30min) and 12 hours (Q_12h), drug percentage permeated through goat corneas after 30 min (P_30min) and 12 hours (P_12h) and morphology. Two formulae were statistically selected and incorporated into hydroxypropyl methylcellulose (HPMC)-based hydrogels; G1 – G4. The latter systems were evaluated for appearance, clarity, pH, spreadability, rheology, drug percentages released, drug percentages permeated, antimicrobial activity against Pseudomonas aeruginosa, and histopathological changes. Results: The selected NPs (NP2 and NP6) were spherical in shape and possessed suitable PS (392.02 nm and 190.51 nm) and PDI (0.17 and 0.18), high magnitude of ZP (− 30.43 mV and − 33.62 mV), high EE% (79.24% and 91.72%), low Q_30min (10.96% and 16.65%) and P_30min (17.39% and 21.05%) and promising Q_12h (58.23% and 71.20%) and P_12h (53.31% and 65.01%), respectively. Clear, spreadable, tolerable, pseudoplastic, and thixotropic HPMC-based hydrogels were developed. They showed more prolonged drug release and drug permeation profiles. NP2- and NP6-laden hydrogels (G3 and G4 systems, respectively) had promising antibacterial activity, and reasonable histopathological safety. Conclusion: G3 and G4 are potential ocular delivery systems for NFX.

Aim: Etoricoxib is a selective inhibitor of COX-2 enzyme. It is proposed as a potent anti-inflammatory drug intended for the control of irritable bowel syndrome. The current work aimed at developing etoricoxib-loaded nanoparticles for colon- targeting. Materials and Methods: PLGA nanoparticles were developed via nano-spray drying technique. The D-optimal design was adopted for the investigation of the influence of i) DL-lactide-coglycolide (PLGA) concentration, ii) polyvinylpyrrolidone K30 (PVP K30) concentration and iii) lactide:glycolide ratio in the copolymer chain on the yield%, the encapsulation efficiency (EE%), particle size (PS) and percentage of drug release after 2h (P_2h), 4h (P_4h) and 12h (P_12h). To promote colon targeting of the systems, the best achieved system (M14) was either directly coated with poly(methacrylic acid-co-methyl methacrylate) [Eudragit^®-S100] or loaded into hard gelatin capsules and the capsules were coated with poly(methacrylic acid-co-methyl methacrylate) (E-M14C). The pharmacokinetic parameters of etoricoxib following oral administration of E-M14C in healthy volunteers were assessed relative to commercial etoricoxib tablets. Results: M14 system was prepared using PLGA (0.5% w/v) at a lactide:glycolide ratio of 100:0, in the presence of PVP K30 (2% w/v). M14 system was nano-spherical particles of 488 nm size possessing promising yield% (63.5%) and EE% (91.2%). The percentage drug released after 2, 4 and 12 hours were 43.41%, 47.34 and 64.96%, respectively. Following M14-loading into hard gelatin capsules and coating with poly(methacrylic acid-co-methyl methacrylate) [Eudragit-S100], the respective P_2h, P_4h and P_12h were 10.1%, 28.60% and 65.45%. Significant (p < 0.05) differences between the pharmacokinetic parameter of E-M14C in comparison with the commercial product were revealed with a delay in T_max (from 2.5h to 6h), a prolongation in MRT_0-∞ (from 24.4h to 34.7h) and an increase in the relative oral bioavailability (4.23 folds). Conclusion: E-M14C is a potential system for possible colon targeting of etoricoxib.