Clozapine-Encapsulated Binary Mixed Micelles in Thermosensitive Sol–Gels for Intranasal Administration

(1) Background: Clozapine is the most effective antipsychotic. It is, however, associated with many adverse drug reactions. Nose-to-brain (N2B) delivery offers a promising approach. This study aims to develop clozapine-encapsulated thermosensitive sol–gels for N2B delivery. (2) Methods: Poloxamer 407 and hydroxypropyl methylcellulose were mixed and hydrated with water. Glycerin and carbopol solutions were added to the mixture and stirred overnight at 2–8 °C. Clozapine 0.1% w/w was stirred with polysorbate 20 (PS20) or polysorbate 80 (PS80) at RT (25 °C) before being added to the polymer solution. The final formulation was made to 10 g with water, stirred overnight at 2–8 °C and then adjusted to pH 5.5. (3) Results: Formulations F3 (3% PS20) and F4 (3% PS80) were selected for further evaluation, as their gelation temperatures were near 28 °C. The hydrodynamic particle diameter of clozapine was 18.7 ± 0.2 nm in F3 and 20.0 ± 0.4 nm in F4. The results show a crystallinity change in clozapine to amorphous. Drug release studies showed a 59.1 ± 3.0% (F3) and 53.1 ± 2.7% (F4) clozapine release after 72 h. Clozapine permeated after 8 h was 20.8 ± 3.0% (F3) and 17.8 ± 3.1% (F4). The drug deposition was higher with F4 (144.8 ± 1.4 µg/g) than F3 (110.7 ± 2.7 µg/g). Both sol–gels showed no phase separation after 3 months. (4) Conclusions: Binary PS80-P407 mixed micelles were more thermodynamically stable and rigid due to the higher synergism of both surfactants. However, binary mixed PS20-P407 micelles showed better drug permeation across the nasal mucosa tissue and may be a preferable carrier system for the intranasal administration of clozapine.

Comparison Between Interaction of Hydrophobic-anionic and Hydrophobic-cationic Mixed Micellar System with Drug Ciprofloxacin

The interaction studies of drug ciprofloxacin with two mixed micellar systems are reported. The mixed micelles comprise a nonionic hydrophobic surfactant, pluronic L-81, an anionic surfactant, Ammonium dodecyl sulfate (ADS); and a cationic surfactant, Cetylpyridinium bromide (CPB). The various combinations chosen were L-81-ADS and L-81-CPB. The properties of both the mixed micelles were compared. Spectrophotometric, conductometric, co-solvent effect, and Infrared studies were used for the investigations. The studies were carried out in a wide range of mixed micellar concentrations in the post micellar region of the individual surfactants. The solubilization of drug CPX in the L-81-ADS was higher than that in L-81-CPB mixed micelle, as evidenced by UV studies. Ethanol and ethylene glycol were found to be effective co-solvents for both the mixed micellar systems. The conductivity studies of CPX with ADS and CPB surfactants, displayed a higher value of conductance for CPX and ADS, from 0.37µs-1 to 0.74µs-1 compared to CPX and CPB. The drug-mixed micelle displayed a higher molecular weight complex formation as seen from the IR spectra.

Scrutinizing the Feasibility of Nonionic Surfactants to Form Isotropic Bicelles of Curcumin: a Potential Antiviral Candidate Against COVID-19

Investigating bicelles as an oral drug delivery system and exploiting their structural benefits can pave the way to formulate hydrophobic drugs and potentiate their activity. Herein, the ability of non-ionic surfactants (labrasol®, tween 80, cremophore EL and pluronic F127) to form curcumin loaded bicelles with phosphatidylcholine, utilizing a simple method, was investigated. Molecular docking was used to understand the mechanism of bicelles formation. The % transmittance and TEM exhibited bicelles formation with labrasol® and tween 80, while cremophor EL and pluronic F127 tended to form mixed micelles. The surfactant-based nanostructures significantly improved curcumin dissolution (99.2 ± 2.6% within 10 min in case of tween 80-based bicelles) compared to liposomes and curcumin suspension in non-sink conditions. The prepared formulations improved curcumin ex vivo permeation over liposomes and drug suspension. Further, the therapeutic antiviral activity of the formulated curcumin against SARS-CoV-2 was potentiated over drug suspension. Although both Labrasol® and tween 80 bicelles could form bicelles and enhance the oral delivery of curcumin when compared to liposomes and drug suspension, the mixed micelles formulations depicted superiority than bicelles formulations. Our findings provide promising formulations that can be utilized for further preclinical and clinical studies of curcumin as an antiviral therapy for COVID-19 patients.

Detailed Calorimetric Analysis of Mixed Micelle Formation from Aqueous Binary Surfactants for Design of Nanoscale Drug Carriers

While numerous papers have been published according to the binary surfactant mixtures, only a few articles provide deeper information on the composition dependence of the micellization, and even less work attempts to apply the enhanced feature of the mixed micelles. The most important parameter of the self-assembled surfactants is the critical micelle concentration (cmc), which quantifies the tendency to associate, and provides the Gibbs energy of micellization. Several techniques are known for determining the cmc, but the isothermal titration calorimetry (ITC) can be used to measure both cmc and enthalpy change (ΔmicH) accompanying micelle formation. Outcomes of our calorimetric investigations were evaluated using a self-developed routine for handling ITC data and the thermodynamic parameters of mixed micelle formation were obtained from the nonlinear modelling of temperature- and composition- dependent enthalpograms. In the investigated temperature and micelle mole fractions interval, we observed some intervals where the cmc is lower than the ideal mixing model predicted value. These equimolar binary surfactant mixtures showed higher solubilization ability for poorly water-soluble model drugs than their individual compounds. Thus, the rapid and fairly accurate calorimetric analysis of mixed micelles can lead to the successful design of a nanoscale drug carrier.

Internalization and Transport of PEGylated Lipid-Based Mixed Micelles across Caco-2 Cells Mediated by Scavenger Receptor B1

The aim of this study was to get insight into the internalization and transport of PEGylat-ed mixed micelles loaded by vitamin K, as mediated by Scavenger Receptor B1 (SR-B1) that is abundantly expressed by intestinal epithelium cells as well as by differentiated Caco-2 cells. Inhibition of SR-B1 reduced endocytosis and transport of vitamin-K-loaded 0%, 30% and 50% PEGylated mixed micelles and decreased colocalization of the micelles with SR-B1. Confocal fluorescence microscopy, fluorescence-activated cell sorting (FACS) analysis, and surface plasmon resonance (SPR) were used to study the interaction between the mixed micelles of different compositions (varying vitamin K loading and PEG content) and SR-B1. Interaction of PEGylated micelles was independent of the vitamin K content, indicating that the PEG shell prevented vitamin K exposure at the surface of the micelles and binding with the receptor and that the PEG took over the micelles’ ability to bind to the receptor. Molecular docking calculations corroborated the dual binding of both vita-min K and PEG with the binding domain of SR-B1. In conclusion, the improved colloidal stability of PEGylated mixed micelles did not compromise their cellular uptake and transport due to the affinity of PEG for SR-B1. SR-B1 is able to interact with PEGylated nanoparticles and mediates their subsequent internalization and transport.