Celecoxib (CXB) is a Biopharmaceutical Classification System (BCS) Class II molecule with high permeability that is practically insoluble in water. Because of the poor water solubility, there is a wide range of absorption and limited bioavailability following oral administration. These unfavorable properties can be improved using dry co-milling technology, which is an industrial applicable technology. The purpose of this study was to develop and optimize CXB nanoformulations prepared by dry co-milling technology, with a quality by design approach to maintain enhanced solubility, dissolution rate, and oral bioavailability. The resulting co-milled CXB composition using povidone (PVP), mannitol (MAN) and sodium lauryl sulfate (SLS) showed the maximum solubility and dissolution rate in physiologically relevant media. Potential risk factors were determined with an Ishikawa diagram, important risk factors were selected with Plackett-Burman experimental design, and CXB compositions were optimized with Central Composite design (CCD) and Bayesian optimization (BO). Physical characterization, intrinsic dissolution rate, solubility, and stability experiments were used to evaluate the optimized co-milled CXB compositions. Dissolution and permeability studies were carried out for the resulting CXB nanoformulation. Oral pharmacokinetic studies of the CXB nanoformulation and reference product were performed in rats. The results of in vitro and in vivo studies show that the CXB nanoformulations have enhanced solubility (over 4.8-fold (8.6 ± 1.06 µg/mL vs. 1.8 ± 0.33 µg/mL) in water when compared with celecoxib pure powder), and dissolution rate (at least 85% of celecoxib is dissolved in 20 min), and improved oral pharmacokinetic profile (the relative bioavailability was 145.2%, compared to that of Celebrex^®, and faster t_max 3.80 ± 2.28 h vs. 6.00 ± 3.67 h, indicating a more rapid absorption rate).

Diabetes is characterized by chronic hyperglycemia. Although metformin hydrochloride (MHCl)- and glyburide (GLB)-containing conventional tablets are available in the market and used to treat diabetes, orally disintegrating tablets (ODTs) containing the combination of these drugs are not commercially available. Therefore, the aim of this study was to prepare ODTs containing MHCl and GLB by direct-compression (DC-ODTs) and freeze-drying (FD-ODTs) methods. Physical properties of the powder mixture of DC-ODT formulation were determined (Angle of repose: 37.18 ± 1.27°; compressibility index: 20.31 ± 1.06%; Hausner ratio:1.25 ± 0.03). Its moisture content was 0.3 ± 0.09%. The hardness values and the disintegration times for DC-ODTs and FD-ODTs were 221.60 ± 40.82 N and 66.54 ± 2.68 N, and 80 s and 30 s, respectively. Friability values were 0.24% for DC-ODTs and 0.38% for FD-ODTs. In uniformity-of-mass for single-dose-preparations test, the average weight was 684.38 ± 1.97mg for DC-ODTs and 342.93 ± 2.4mg for FD-ODTs, with less than 5% deviation for all 20 tablets. Water-absorption ratio for DC-ODTs was 1.30 ± 0.05. More than 90% of MHCl and GLB were dissolved within 5 min in both DC-ODTs and FD-ODTs. Although Caco-2 permeability of MHCl was influenced by the ODTs, GLB permeability was not. These results indicated that MHCl- and GLB-containing ODTs may be used as promising formulations for the treatment of diabetes.

The aim of this study was to improve the aerodynamic behavior and redispersibility of a lyophilized dry powder inhaler (DPI) formulation containing nanoparticles. Paclitaxel (PTX)-human serum albumin (HSA) nanoparticles were used as a model, and DPIs containing the nanoparticles were produced by lyophilization using different carriers and carrier ratios. A central composite design was employed to optimize the formulation. L-leucine and mannitol were chosen as independent variables, and mass median aerodynamic diameter (MMAD), emitted fraction, fine particle fraction (FPF), nanoparticle size, polydispersity index (PDI), zeta potential were selected as dependent variables. The water content of DPIs was less than 5% for all DPIs. The cytotoxicity of the DPIs, determined using A549 cells, was due to PTX alone. Particle sizes of 204.3 ± 1.65 nm and 94.3–1353.0 nm were obtained before and after lyophilization, respectively. The developed method resulted in a reduction in the MMAD from 8.148 µm to 5.274 µm, an increase in the FPF from 17.63% to 33.60%, and an increase in the emitted fraction from 77.68% to 97.03%. The physico-chemical characteristics of the optimized formulation were also assessed. In conclusion, this study demonstrates that lyophilization can be used to produce nanoparticle-containing DPI formulations with improved redispersibility and aerodynamic properties. Graphical Abstract

Introduction: Glyburide is a drug for the treatment of diabetes mellitus and has a potential effect on Alzheimer's disease. It is also a BCS Class II drug with low solubility and low permeability. Developing a nanosuspension formulation and increasing the solubility and dissolution rate of glyburide is required to overcome this challenge. Methods: Thus, the goal of this work was to create glyburide nanosuspensions by ball milling and homogenizing glyburide to increase its solubility and rate of dissolution. To achieve this, the nanosuspension formulation was optimized using a central composite design. Zeta potential, particle size distribution and solubility were selected by way of dependent variables, and ball milling time, homogenization cycles, and Pluronic F-127/glyburide ratio were chosen as independent variables. Glyburide nanosuspensions were obtained with a particle size of 244.6 ± 2.685 nm. In vitro release and solubility studies were conducted following optimization. Results: The saturation solubility of glyburide was nearly doubled as a result of the nanocrystal formation. X-ray diffraction (XRD), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and fourier-transform infrared spectroscopy (FT-IR) were used to assess the nanosuspension. SEM images confirmed that the nanocrystal formation process was successful. Glyburide and the excipients have no incompatibilities, their physical states have not changed, and the preparation method has not affected the stability of glyburide, according to DCS, XRD, and FT-IR analyses. Conclusion: These studies indicated that a combination of ball milling and homogenization techniques significantly enhanced the solubility of glyburide and its release from the formulation. Consequently, this approach can be applied to formulations characterized by low absorption and limited bioavailability.