Pharmacokinetics and Anti-Diabetic Studies of Gliclazide Nanosuspension.

Gliclazide (GCZ), an antidiabetic medication, has poor solubility and limited oral bioavailability due to substantial first-pass metabolism. Thus, the purpose of the current study was to optimize and formulate a GCZ nanosuspension (NS) employing the antisolvent precipitation technique. A three-factor, three-level Box-Behnken design (BBD) was used to examine the impact of the primary formulation factors (drug concentration, stabilizer, and surfactant %) on particle size. The optimized NS contains 29.6 mg/mL drug, 0.739% lecithin, and 0.216% sodium dodecyl sulfate (SDS). Under scanning microscopy, the topography of NS revealed spherical particles. Furthermore, NS had a much better saturation solubility than the pure material, which resulted in a rapid dissolving rate, which was attributed to the amorphous structure and smaller particle size of the NS particles. Studies on intestinal permeability using the in vitro noneverted intestinal sac gut method (duodenum, jejunum, and ileum) and single-pass intestinal permeability (SPIP) techniques showed that the effective permeability was also increased by more than 3 fold. In the pharmacokinetic study, the Cmax and AUC0-t values of NS were approximately 3.35- and 1.9-fold higher than those of the raw medication and marketed formulation (MF). When compared to plain drug and commercial formulations, the antidiabetic efficacy of NS demonstrated that it had a significant impact on lowering glucose levels.

QbD aided development of ibrutinib-loaded nanostructured lipid carriers aimed for lymphatic targeting: evaluation using chylomicron flow blocking approach.

Ibrutinib (IBR) is the choice of drug for the treatment of chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). IBR has low oral bioavailability of 2.9% owing to its high first pass metabolism. Present study was aimed to develop the nanostructured lipid carriers (NLC) using glyceryl monostearate (GMS) as solid lipid and Capryol™ PGMC as liquid lipid. Plackett-Burman design (PBD) was applied to screen the significant factors; furthermore, these significant factors were subjected to optimisation using Central Composite design (CCD). The size, poly dispersity index (PDI) and entrapment efficiency (E.E.) of the developed NLC were 106.4 ± 8.66 nm, 0.272 ± 0.005 and 70.54 ± 5.52% respectively. Morphological evaluation using transmission electron microscope (TEM) and field emission scanning electron microscope (FESEM) revealed spherical particles. Furthermore, differential scanning calorimetry (DSC) indicates the formation of molecular dispersion of drug in the melted lipid matrix while Powder X-Ray Diffraction (PXRD) studies reveal the absence of crystalline drug peaks in the formulation diffractogram. In-vivo pharmacokinetics of NLC displayed an increase in Cmax (2.89-fold), AUC0-t (5.32-fold) and mean residence time (MRT) (1.82-fold) compared with free drug. Furthermore, lymphatic uptake was evaluated by chylomicron flow blocking approach using cycloheximide (CXI). The pharmacokinetic parameters Cmax, AUC0-t and MRT of NLC without CXI were 2.75, 3.57 and 1.30 folds higher compared with NLC with CXI. The difference in PK parameters without CXI indicates significant lymphatic uptake of the formulation. Hence, NLC can be a promising approach to enhance the oral bioavailability of drugs with high first-pass metabolism. Graphical abstract.

Effect of Baghdadite Substitution on the Physicochemical Properties of Brushite Cements.

Brushite cements have been clinically used for irregular bone defect filling applications, and various strategies have been previously reported to modify and improve their physicochemical properties such as strength and injectability. However, strategies to address other limitations of brushite cements such as low radiopacity or acidity without negatively impacting mechanical strength have not yet been reported. In this study, we report the effect of substituting the beta-tricalcium phosphate reactant in brushite cement with baghdadite (Ca3ZrSi2O9), a bioactive zirconium-doped calcium silicate ceramic, at various concentrations (0, 5, 10, 20, 30, 50, and 100 wt%) on the properties of the final brushite cement product. X-ray diffraction profiles indicate the dissolution of baghdadite during the cement reaction, without affecting the crystal structure of the precipitated brushite. EDX analysis shows that calcium is homogeneously distributed within the cement matrix, while zirconium and silicon form cluster-like aggregates with sizes ranging from few microns to more than 50 µm. X-ray images and µ-CT analysis indicate enhanced radiopacity with increased incorporation of baghdadite into brushite cement, with nearly a doubling of the aluminium equivalent thickness at 50 wt% baghdadite substitution. At the same time, compressive strength of brushite cement increased from 12.9 ± 3.1 MPa to 21.1 ± 4.1 MPa with 10 wt% baghdadite substitution. Culture medium conditioned with powdered brushite cement approached closer to physiological pH values when the cement is incorporated with increasing amounts of baghdadite (pH = 6.47 for pure brushite, pH = 7.02 for brushite with 20 wt% baghdadite substitution). Baghdadite substitution also influenced the ionic content in the culture medium, and subsequently affected the proliferative activity of primary human osteoblasts in vitro. This study indicates that baghdadite is a beneficial additive to enhance the radiopacity, mechanical performance and cytocompatibility of brushite cements.