Formulation and Evaluation of Azithromycin-Loaded Niosomal Gel: Optimization, In Vitro Studies, Rheological Characterization, and Cytotoxicity Study.

Several novel, innovative approaches for improving transdermal delivery of BCS class III drugs have been proposed. Despite their great aqueous solubility, BCS class III drugs have the drawback of limited permeability. The objective of the current work was to screen the suitability of niosomes as a nanocarrier in permeation enhancement of azithromycin (AZM) transdermal delivery. Niosomes were prepared by an ether injection method using a nonionic surfactant (Span 60) and cholesterol at different concentrations. The ζ potential (ZP), polydispersity index (PDI), and particle size (PS) of AZM-loaded niosomes were evaluated. The size of the niosomes was found to vary between 288 and 394 nm. The results revealed that the niosomes prepared in a ratio of 2:1 (Span 60: cholesterol) had larger vesicle sizes, but all of them were characterized by narrow size distributions (PDI <0.95). Niosomal gel was successfully prepared using different polymers. The appearance, pH, viscosity, and ex vivo drug release of niosomal gel formulations were all examined. The flow curves showed that the niosomal gel displayed lower viscosity values than its corresponding conventional gels. Niosomal and conventional gels exhibited a domination of the elastic modulus (G') over the viscous modulus (G″) (G'>G″) in the investigated frequency range (0.1-100 rad/s), indicating stable gels with more solid-like properties. Ex vivo skin permeation studies for the niosomal gel show 90.83 ± 3.19% of drug release in 24 h as compared with the conventional gel showing significantly lower (P < 0.001) drug release in the same duration (1.25 ± 0.12%). Overall, these results indicate that niosomal gel could be an effective transdermal nanocarrier for enhancing the permeability of AZM, a BCS class III drug. In conclusion, this study suggests that transdermal formulations of AZM in the niosomal gel were successfully developed and could be used as an alternative route of administration.

Microemulsions as Lipid Nanosystems Loaded into Thermoresponsive In Situ Microgels for Local Ocular Delivery of Prednisolone.

This study aimed to develop and evaluate thermoresponsive in situ microgels for the local ocular delivery of prednisolone (PRD) (PRD microgels) to improve drug bioavailability and prolong ocular drug residence time. Lipid nanosystems of PRD microemulsions (PRD-MEs) were prepared and evaluated at a drug concentration of 0.25-0.75%. PRD microgels were prepared by incorporating PRD-MEs into 10 and 12% Pluronic® F127 (F127) or combinations of 12% F127 and 1-10% Kolliphor®P188 (F68). PRD microgels were characterized for physicochemical, rheological, and mucoadhesive properties, eye irritation, and stability. Results showed that PRD-MEs were clear, miscible, thermodynamically stable, and spherical with droplet size (16.4 ± 2.2 nm), polydispersity index (0.24 ± 0.01), and zeta potential (-21.03 ± 1.24 mV). The PRD microgels were clear with pH (5.37-5.81), surface tension (30.96-38.90 mN/m), size, and zeta potential of mixed polymeric micelles (20.1-23.9 nm and -1.34 to -10.25 mV, respectively), phase transition temperature (25.3-36 °C), and gelation time (1.44-2.47 min). The FTIR spectra revealed chemical compatibility between PRD and microgel components. PRD microgels showed pseudoplastic flow, viscoelastic and mucoadhesive properties, absence of eye irritation, and drug content (99.3 to 106.3%) with a sustained drug release for 16-24 h. Microgels were physicochemically and rheologically stable for three to six months. Therefore, PRD microgels possess potential vehicles for local ocular delivery.

Physiologically-based pharmacokinetic model for alectinib, ruxolitinib, and panobinostat in the presence of cancer, renal impairment, and hepatic impairment.

Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically-based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model-predicted plasma exposures in patients with different health conditions within average 2-fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non-small cell lung cancer, moderate HIP, and severe HIP at 1-, 1.5-, and 1.8-fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP.