Soluble Angiotensin-Converting Enzyme 2 Protein Improves Survival and Lowers Viral Titers in Lethal Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection with the Delta Variant.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme 2 (ACE2) as its main receptor for cell entry. We bioengineered a soluble ACE2 protein termed ACE2 618-DDC-ABD that has increased binding to SARS-CoV-2 and prolonged duration of action. Here, we investigated the protective effect of this protein when administered intranasally to k18-hACE2 mice infected with the aggressive SARS-CoV-2 Delta variant. k18-hACE2 mice were infected with the SARS-CoV-2 Delta variant by inoculation of a lethal dose (2 × 104 PFU). ACE2 618-DDC-ABD (10 mg/kg) or PBS was administered intranasally six hours prior and 24 and 48 h post-viral inoculation. All animals in the PBS control group succumbed to the disease on day seven post-infection (0% survival), whereas, in contrast, there was only one casualty in the group that received ACE2 618-DDC-ABD (90% survival). Mice in the ACE2 618-DDC-ABD group had minimal disease as assessed using a clinical score and stable weight, and both brain and lung viral titers were markedly reduced. These findings demonstrate the efficacy of a bioengineered soluble ACE2 decoy with an extended duration of action in protecting against the aggressive Delta SARS-CoV-2 variant. Together with previous work, these findings underline the universal protective potential against current and future emerging SARS-CoV-2 variants.

Design, optimization, and in-vivo hypoglycaemic effect of nanosized glibenclamide for inhalation delivery.

The aim of this research was the development and optimization of nanoniosomes for delivery of glibenclamide (Gbn) as hypoglycaemic agent to the lung in an inhaler dosage form. Fifteen formulae of niosomal dispersions were prepared according to Box-Behnken design. The effect of drug amount, Cholesterol molar ratio, and Hydrophilic lipophilic balance (HLB) values of the surfactant on the mean vesicle size, Zeta potential (ZP), polydispersity index (PDI), entrapment efficiency, and in-vitro released of Gbn were investigated. A quality control check was performed on an inhaler filled with the optimum nanoniosomal formula. The in-vivo hypoglycaemic effect of nanoniosomal inhalation was also evaluated. The vesicle size observed of the optimized formula was 172 ± 4.6 nm, PDI was 0.304 ± 0.06 and ZP was -49.9 ± 1.5 mv with 69 ± 9.3% in-vitro drug release after 2 h. The Cholesterol molar ratio and the HLB value showed a statistically significant effect on dependent variables. In-vivo results proved that nanoniosomes were efficiently delivered from the inhalation canister showing a mass median aerodynamic diameter of 1.4 micron. The inhaled nanoniosomal dispersion loaded with Gbn showed a decrease in blood glucose level of hyperglycaemic rats by 51.42 ± 5.2%± after 180 min which was nearly two folds compared to oral Gbn. Gibenclamide nanoniosomes inhaler could be suggested as a novel effective dosage form for the treatment of Diabetes mellitus.

Glibenclamide nanosuspension inhaler: development, in vitro and in vivo assessment.

Objective: The development of nanosuspension for targeted delivery of glibenclamide as hypoglycemic agent to the lung in an inhaler dosage form.Method: Glibenclamide nanosuspension formulations were prepared using Box-Behnken design to investigate the effect of independent factors on the dependent variables, Fourier-transform Infrared spectroscopy, Differential Scanning Calorimetry, evaluation of glibenclamide nanosuspension inhaler and in vivo hypoglycemic efficacy were performed to determine glibenclamide nanosuspension inhaler effect.Results: The results revealed that the mean particle sizes of the prepared nanosuspension ranged from 0.216 to 0.856 µm, zeta potential from +9 to +16 mV, the solubility ranged from 43% to 75%, the mass median aerodynamic diameter was 2.34 µm and the glucose level in rat was significantly reduced by about 60%.Conclusion: These results confirmed that glibenclamide nanosuspension inhaler enhance hypoglycemic effectiveness and reduce adverse effect of glibenclamide, opening up new dosage form in Diabetes mellitus treatment.