Haloperidol (Hal) is one of the widely used antipsychotic drugs. When orally administered, it suffers from low bioavailability due to hepatic first pass metabolism. This study aimed at developing Hal-loaded penetration enhancer-containing spanlastics (PECSs) to increase transdermal permeation of Hal with sustained release. PECSs were successfully prepared using ethanol injection method showing reasonable values of percentage entrapment efficiency, particle size, polydispersity index and zeta potential. The statistical analysis of the ex vivo permeation parameters led to the choice of F1L – made of Span^® 60 and Tween^® 80 at the weight ratio of 4:1 along with 1% w/v Labrasol^® – as the selected formula (SF). SF was formulated into a hydrogel by using 2.5% w/v of HPMC K4M. The hydrogel exhibited good in vitro characteristics. Also, it retained its physical and chemical stability for one month in the refrigerator. The radiolabeling of SF showed a maximum yield by mixing of 100 µl of diluted formula with 50 µl saline having 200 MBq of ^99mTc and containing 13.6 mg of reducing agent (NaBH₄) and volume completed to 300 µl by saline at pH 10 for 10 min as reaction time. The biodistribution study showed that the transdermal ^99mTc-SF hydrogel exhibited a more sustained release pattern and longer circulation duration with pulsatile behavior in the blood and higher brain levels than the oral ^99mTc-SF dispersion. So, transdermal hydrogel of SF may be considered a promising sustained release formula for Hal maintenance therapy with reduced dose size and less frequent administration than oral formula.

Voriconazole (VCZ) is a well-known broad spectrum triazole antifungal, mainly used orally and intravenously. The study aimed to formulate VCZ into ultradeformable elastosomes for the topical treatment of ocular fungal keratitis. Different formulae were prepared using a modified ethanol injection method, employing a 3³ Box-Behnken design. They were characterized by measuring their entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI) and zeta potential (ZP). The optimized formula was subjected to further in vitro investigations and in vivo evaluation studies. The prepared vesicles had satisfactory EE%, PS, PDI and ZP values. The numerical optimization process suggested an optimal elastosomal formula (OE) composed of phosphatidyl choline and brij S100 at the weight ratio of 3.62: 1, 0.25%w/v hyaluronic acid and 5% (percentage from phosphatidyl choline/brij mixture) polyvinyl alcohol. It had high EE (72.6%), acceptable PS and PDI (362.4 nm and 0.25, respectively) and highly negative ZP of −41.7 mV. OE exhibited higher elasticity than conventional liposomes, with acceptable stability for three months. Transmission electron microscopy demonstrated the spherical morphology of vesicles with an external transparent coat of Hyaluronic acid. OE was expected to cause no ocular irritation or blurring in vision as reflected by pH and refractive index measurements. The histopathological study revealed the safety of OE for ocular use. The fungal susceptibility testing using Candida albicans demonstrated the superiority of OE to VCZ suspension, with greater and more durable growth inhibition. Therefore, OE can be regarded as a promising formula, achieving both safety and efficacy.

This study introduces and statistically optimizes novel Tetra-Synergistic Bilosomes (TSB), an advanced nano-platform for topical delivery of voriconazole (VOR) in otomycosis therapy. The term “Tetra-Synergistic” reflects the incorporation of four complementary components: Cremophor® EL, sodium deoxycholate, Brij® 58, and Brij® S2, working in synergy to enhance therapeutic efficacy. TSB was fabricated using the thin-film hydration method and optimized through a 2 ³ D-optimal design. Three formulation factors were investigated: Cremophor® EL: VOR ratio, sodium deoxycholate: cholesterol ratio, and Brij® 58: Brij® S2 ratio, with the optimization goal of maximizing EE%, minimizing vesicular size, and maintaining ZP within the acceptable stability range. The model demonstrated excellent predictability, achieving a desirability value of 0.888. The optimized TSB exhibited high EE% (91.6%), a suitably small VS (217.9nm), and stable ZP (− 24.1mV). FTIR confirmed VOR entrapment, while TEM revealed nano-sized spherical vesicles. Moreover, TSB displayed a biphasic In-vitro release profile and remained stable for three months under refrigeration. Importantly, microbiological evaluation confirmed the superior antifungal performance of TSB. Compared with VOR suspension, TSB showed a larger inhibition zone, a lower minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC), and a faster fungicidal effect, eradicating fungal growth in 33% less time. Ex-vivo permeation studies revealed a 2.18-fold enhancement ratio, supported by confocal laser scanning microscopy confirming deeper tissue penetration. Histopathological analysis further validated the safety of topical application without any tissue damage. Collectively, these results establish TSB as a pioneering, microbiologically potent, and clinically promising nano-vesicular system for the effective management of otomycosis.

In the current study, voriconazole (VCZ) augmented glycerosomes were optimized for topical otomycosis management according to a 2³ factorial design, employing a thin film hydration method. By optimizing Glycerol volume, limonene: VCZ ratio and Span® 60: soybean phosphatidyl choline (PC) ratio, glycerosomes with maximum percentage entrapment efficiency (%EE) and zeta potential (ZP) and minimum vesicle size (VS) and polydispersity index (PDI) were to be obtained. An optimal augmented glycerosomal formula (OAG) that contained 10 mg VCZ, 150 mg PC, and 3 mL glycerol, comprising 2.5: and 0.92:1 ratios of the latter two independent variables, was proposed via numerical optimization. OAG exhibited high %EE and ZP values and acceptable low values for VS and PDI (84.3 ± 2.0 %, −38.8 ± 1.8 mV, 191.0 ± 1.1 nm, and 0.192 ± 0.01, respectively). Extensive in vitro testing of OAG revealed the entrapment of VCZ within OAG, biphasic in vitro release profile, stability for up to 3 months at 2–8 °C and spherical morphology of OAG with VS like that obtained via zetasizer. OAG demonstrated higher permeated amounts of VCZ and flux values than VCZ suspension, leading to an enhancement ratio of 2.56 in the ex vivo permeation study. The deeper penetration ability of OAG demonstrated by Confocal Laser Scanning Microscopy and its superior in vitro antifungal activity confirmed the validity of the ex vivo study. Also, the histopathological study confirmed the safety of OAG for topical use, suggesting that VCZ OAG was a promising topical antimycotic formula.