Agomelatine-based in situ gels for brain targeting via the nasal route: statistical optimization, in vitro, and in vivo evaluation

Agomelatine (AGM) is an antidepressant drug with a low absolute bioavailability due to the hepatic first pass metabolism. AGM-loaded solid lipid nanoparticles were formulated in the form of an in situ gel to prolong the intranasal retention time and subsequently to increase the absorbed amount of AGM. The optimized in situ gel formula had a sol–gel transition temperature of 31 °C ± 1.40, mucociliary transport time of 27 min ±1.41%, released after 1 and 8 h of 46.3% ± 0.85 and 70.90% ± 1.48. The pharmacokinetic study of the optimized in situ gel revealed a significant increase in the peak plasma concentration, area under plasma concentration versus time curve and absolute bioavailability compared to that of the oral suspension of Valdoxan® with the values of 247 ± 64.40 ng/mL, 6677.41 ± 1996 ng.min/mL, and 37.89%, respectively. It also gave drug targeting efficiency index of 141.42 which revealed more successful brain targeting by the intranasal route compared to the intravenous route and it had direct transport percent index of 29.29 which indicated a significant contribution of the direct nose to brain pathway in the brain drug delivery

Engineering of a novel optimized platform for sublingual delivery with novel characterization tools: in vitro evaluation and in vivo pharmacokinetics study in human

The aim of this work was to develop a novel and more efficient platform for sublingual drug delivery using mosapride citrate (MSP) as a model drug. The engineering of this delivery system had two stages, the first stage was tuning of MSP physicochemical properties by complexation with pure phosphatidylcholine or phosphatidylinositol enriched soybean lecithin to form MSP-phospholipid complex (MSP-PLCP). Changes in physicochemical properties were assessed and the optimum MSP-PLCP formula was then used for formulation into a flushing resistant platform using two mucoadhesive polymers; sodium alginates and sodium carboxymethylcellulose at different concentrations. Design of experiment approach was used to characterize and optimize the formulated flushing resistant platform. The optimized formulation was then used in a comparative pharmacokinetics study with the market formulation in human volunteers. Results showed a marked change in MSP physicochemical properties of MSP-PLCP compared to MSP. Addition of mucoadhesive polymers to flushing resistant platform at an optimum concentration balanced between desired mucoadhesive properties and a reasonable drug release rate. The optimized formulation showed significantly a superior bioavailability in humans when compared to the market sublingual product. Finally, the novel developed sublingual flushing resistant platform offers a very promising and efficient tool to extend the use of sublingual route and widen its applications

Engineering of a novel optimized platform for sublingual delivery with novel characterization tools: <i>in vitro</i> evaluation and <i>in vivo</i> pharmacokinetics study in human

<p>The aim of this work was to develop a novel and more efficient platform for sublingual drug delivery using mosapride citrate (MSP) as a model drug. The engineering of this delivery system had two stages, the first stage was tuning of MSP physicochemical properties by complexation with pure phosphatidylcholine or phosphatidylinositol enriched soybean lecithin to form MSP-phospholipid complex (MSP-PLCP). Changes in physicochemical properties were assessed and the optimum MSP-PLCP formula was then used for formulation into a flushing resistant platform using two mucoadhesive polymers; sodium alginates and sodium carboxymethylcellulose at different concentrations. Design of experiment approach was used to characterize and optimize the formulated flushing resistant platform. The optimized formulation was then used in a comparative pharmacokinetics study with the market formulation in human volunteers. Results showed a marked change in MSP physicochemical properties of MSP-PLCP compared to MSP. Addition of mucoadhesive polymers to flushing resistant platform at an optimum concentration balanced between desired mucoadhesive properties and a reasonable drug release rate. The optimized formulation showed significantly a superior bioavailability in humans when compared to the market sublingual product. Finally, the novel developed sublingual flushing resistant platform offers a very promising and efficient tool to extend the use of sublingual route and widen its applications.</p

An Improvement of Model Predictive for Aircraft Longitudinal Flight Control Based on Intelligent Technique

This paper introduces a new intelligent tuning for the model predictive control (MPC) based on an effective intelligent algorithm named the bat-inspired algorithm (BIA) for the aircraft longitudinal flight. The tuning of MPC horizon parameters represents the main challenge to adjust the system performance. So, the BIA algorithm is intended to overcome the tuning issue of MPC parameters due to conventional methods, such as trial and error or designer experience. The BIA is adopted to explore the best parameters of MPC based on the minimization of various time domain objective functions. The suggested aircraft model takes into account the aircraft dynamics and constraints. The nonlinear dynamics of aircraft, gust disturbance, parameters uncertainty and environment variations are considered the main issues against the control of aircraft to provide a good flight performance. The nonlinear autoregressive moving average (NARMA-L2) controller and proportional integral (PI) controller are suggested for aircraft control in order to evaluate the effectiveness of the proposed MPC based on BIA. The proposed MPC based on BIA and suggested controllers are evaluated against various criteria and functions to prove the effectiveness of MPC based on BIA. The results confirm that the accomplishment of the suggested BIA-based MPC is outstanding to the NARMA-L2 and traditional PI controllers according to the cross-correlation criteria, integral time absolute error (ITAE), system overshoot, response settling time, and system robustness

Ultrahigh verapamil-loaded controlled release polymeric beads using superamphiphobic substrate: D-optimal statistical design, in vitro and in vivo performance

Controlled-release multiparticulate systems of hydrophilic drugs usually suffer from poor encapsulation and rapid-release rate. In the present study, ultra-high loaded controlled release polymeric beads containing verapamil hydrochloride (VP) as hydrophilic model drug were efficiently prepared using superamphiphobic substrates aiming to improve patient compliance by reducing dosing frequency. Superamphiphobic substrates were fabricated using clean aluminum sheets etched with ammonia solution and were treated with 1.5% (w/v) perfluorodecyltriethoxysilane (PFDTS) alcoholic solution. The effect of the main polymer type (lactide/glycolide (PLGA) 5004A, PLGA 5010, and polycaprolactone (PCL)), copolymer (Eudragit RS100) content together with the effect of drug load on encapsulation efficiency (EE%) and in vitro drug release was statistically studied and optimized via D-optimal statistical design. In vivo pharmacokinetic study was carried out to compare the optimized system relative to the market product (Isoptin®). Results revealed that superamphiphobic substrates were successfully prepared showing a rough micro-sized hierarchical structured surface upon observing with scanning electron microscope and were confirmed by high contact angles of 151.60 ± 2.42 and 142.80°±05.23° for water and olive oil, respectively. The fabricated VP-loaded beads showed extremely high encapsulation efficiency exceeding 92.31% w/w. All the prepared systems exhibited a controlled release behavior with Q12 h ranging between 5.46 and 95.90%w/w. The optimized VP-loaded system composed of 150 mg (1.5% w/v) PCL without Eudragit RS100 together with 160 mg VP showed 2.7-folds mean residence time compared to the market product allowing once daily administration instead of three times per day

An Improvement of Model Predictive for Aircraft Longitudinal Flight Control Based on Intelligent Technique

This paper introduces a new intelligent tuning for the model predictive control (MPC) based on an effective intelligent algorithm named the bat-inspired algorithm (BIA) for the aircraft longitudinal flight. The tuning of MPC horizon parameters represents the main challenge to adjust the system performance. So, the BIA algorithm is intended to overcome the tuning issue of MPC parameters due to conventional methods, such as trial and error or designer experience. The BIA is adopted to explore the best parameters of MPC based on the minimization of various time domain objective functions. The suggested aircraft model takes into account the aircraft dynamics and constraints. The nonlinear dynamics of aircraft, gust disturbance, parameters uncertainty and environment variations are considered the main issues against the control of aircraft to provide a good flight performance. The nonlinear autoregressive moving average (NARMA-L2) controller and proportional integral (PI) controller are suggested for aircraft control in order to evaluate the effectiveness of the proposed MPC based on BIA. The proposed MPC based on BIA and suggested controllers are evaluated against various criteria and functions to prove the effectiveness of MPC based on BIA. The results confirm that the accomplishment of the suggested BIA-based MPC is outstanding to the NARMA-L2 and traditional PI controllers according to the cross-correlation criteria, integral time absolute error (ITAE), system overshoot, response settling time, and system robustness

Second-Generation Phenylthiazole Antibiotics with Enhanced Pharmacokinetic Properties

A series of second-generation analogues for 2-(1-(2-(4-butyl­phenyl)-4-methyl­thiazol-5-yl)­ethylidene)­amino­guanidine (<b>1</b>) have been synthesized and tested against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). The compounds were designed with the objective of improving pharmacokinetic properties. This main aim has been accomplished by replacing the rapidly hydrolyzable Schiff-base moiety of first-generation members with a cyclic, unhydrolyzable pyrimidine ring. The hydrazide-containing analogue <b>17</b> was identified as the most potent analogue constructed thus far. The corresponding amine <b>8</b> was 8 times less active. Finally, incorporating the nitrogenous side chain within an aromatic system completely abolished the antibacterial character. Replacement of the <i>n</i>-butyl group with cyclic bioisosteres revealed cyclohexenyl analogue <b>29</b>, which showed significant improvement in <i>in vitro</i> anti-MRSA potency. Increasing or decreasing the ring size deteriorated the antibacterial activity. Compound <b>17</b> demonstrated a superior <i>in vitro</i> and <i>in vivo</i> pharmacokinetic profile, providing compelling evidence that this particular analogue is a good drug candidate worthy of further analysis