Ahmed Mahmoud Abdelhaleem Ali

Hydrocortisone nanosuspensions for ophthalmic delivery: A comparative study between microfluidic nanoprecipitation and wet milling

Recently, drug nanosuspensions have shown a potential for ophthalmic delivery. In this study, a hydrocortisone (HC) nanosuspension (NS) was developed using microfluidic nanoprecipitation as a recent, simple and cost-effective bottom-up technique of drug nanonization. For comparison, a second HC NS was prepared by top-down wet milling procedures. The produced nanosuspensions were characterized for particle size, shape and zeta potential. HC nanosuspensions of approximately 300nm particle size were produced by adjusting experimental conditions of the two processing techniques. Results of X-ray diffraction and differential scanning calorimetry revealed that HC maintained the crystalline structure upon milling, while predominant amorphous particles were generated after precipitation. Ocular bioavailability of HC nanosuspensions was assessed in albino rabbits using HC solution as a control. A sustained drug action was maintained up to 9h for the nanosuspensions compared to 5h for the drug solution. The precipitated and milled NS achieved comparable AUC(0-9h) values of 28.06±4.08 and 30.95±2.2, respectively, that were significantly (P<0.05) higher than that of HC solution (15.86±2.7). After 2 months storage at room temperature, the milled HC NS showed good stability with no discernable changes in particle size, whereas the particle size of the precipitated HC NS increased to 440nm.

Prevalence of avian respiratory viruses in broiler flocks in Egypt

Abstract In this study, respiratory viral pathogens were screened using real-time RT-PCR in 86 broiler chicken flocks suffering from respiratory diseases problems in 4 Egyptian governorates between January 2012 and February 2014. The mortality rates in the investigated flocks ranged from 1 to 47%. Results showed that mixed infection represented 66.3% of the examined flocks. Mixed infectious bronchitis (IBV) and avian influenza (AI)-H9N2 viruses were the most common infection (41.7%). Lack of AI-H9N2 vaccination and high rates of mixed infections in which AI-H9N2 is involved indicate an early AI-H9N2 infection with a potential immunosuppressive effect that predisposes for other viral infections. High pathogenic AI-H5N1 and virulent Newcastle disease virus (vNDV) infections were also detected (26.7% and 8.1%, respectively). Interestingly, co-infection of AI-H9N2 with either AIV-H5N1 or vNDV rarely resulted in high mortality. Partial cell-mediated immunity against similar internal AI genes, as well as virus interference between AI and vNDV, could be an explanation for this. Highly prevalent IBV and AI-H9N2 were isolated and were molecularly characterized based on S1 gene hypervariable region 3 (HVR3) and hemagglutinin gene (HA) sequences, respectively. IBV strains were related to the variant group of IBV with multiple mutations in HVR3. Though AI-H9N2 viruses showed low rate of evolution in comparison to recent strains, few amino acid substitutions indicative of antibody selection pressure were observed in the HA gene. In conclusion, mixed viral infections, especially with IBV and AI-H9N2 viruses, are the predominant etiology of respiratory disease problems in broiler chickens in Egypt. Further investigations of the role of AI, IBV, and ND viruses’ co-infections and interference in terms of altering the severity of clinical signs and lesions and/or generating novel reassortants within each virus are needed.

Modelling of in-vitro and in-vivo performance of aerosol emitted from different vibrating mesh nebulisers in non-invasive ventilation circuit

&NA; Substituting nebulisers by another in non‐invasive ventilation circuit (NIV) involves many process variables which must be adjusted to ensure patient optimum therapy. However, there is a doubt when nebulisers use the same technology. Data mining technology based on artificial neural networks and genetic algorithms were used here to model in‐vitro inhalation process and predict bioavailability from inhaled doses delivered by three different vibrating mesh nebulisers (VMNs) in NIV. Modelling of data indicated that in‐vitro performance of VMNs was dependent mainly on fine particle fraction, mass median aerodynamic diameter (MMAD), total emitted dose (TED) and to lesser extent on nebuliser type. Ex‐vivo model indicated that amount of salbutamol collected on facemask filter was directly affected by TED. In‐vivo model showed that amount of salbutamol deposited into the lung (0.5 hQ) and amount absorbed systemically (24 hQ) were dependent directly on MMAD and TED. Female patients showed higher 24 hQ values than males. Nebuliser type affected TED, 0.5 hQ but not 24 hQ values. Results indicate suitability of VMNs in achieving appropriate in‐vitro inhalation performance model. The results also, indicate that the three VMNs are comparable and can be interchanged with no fear of any additional toxicity. Graphical abstract Figure. No caption available.

In vitro/in vivo evaluation of an optimized fast dissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylic acids.

Abstract Improvement of water solubility, dissolution rate, oral bioavailability, and reduction of first pass metabolism of OL (OL), were the aims of this research. Co-amorphization of OL carboxylic acid dispersions at various molar ratios was carried out using rapid solvent evaporation. Characterization of the dispersions was performed using differential scanning calorimetry (DSC), Fourier transform infrared spectrometry (FTIR), X-ray diffractometry (XRD), and scanning electron microscopy (SEM). Dispersions with highest equilibrium solubility were formulated as fast dissolving oral films. Modeling and optimization of film formation were undertaken using artificial neural networks (ANNs). The results indicated co-amorphization of OL-ascorbic acid through H-bonding. The co-amorphous dispersions at 1:2 molar ratio showed more than 600-fold increase in solubility of OL. The model optimized fast dissolving film prepared from the dispersion was physically and chemically stable, demonstrated short disintegration time (8.5 s), fast dissolution (97% in 10 min) and optimum tensile strength (4.9 N/cm2). The results of in vivo data indicated high bioavailability (144 ng h/mL) and maximum plasma concentration (14.2 ng/mL) compared with the marketed references. Therefore, the optimized co-amorphous OL-ascorbic acid fast dissolving film could be a valuable solution for enhancing the physicochemical and pharmacokinetic properties of OL.

Clozapine-carboxylic acid plasticized co-amorphous dispersions: Preparation, characterization and solution stability evaluation.

Abstract This study addressed the possibility of forming of co-amorphous systems between clozapine (CZ) and various carboxylic acid plasticizers (CAPs). The aim was to improve the solubility and oral bioavailability of clozapine. Co-amorphous dispersions were prepared using modified solvent evaporation methodology at drug/plasticizer stoichiometric ratios of 1:1, 1:1.5 and 1:2. Solid state characterization was performed using differential scanning calorimetry, X-ray diffraction and infra red spectroscopy. Highly soluble homogeneous co-amorphous dispersions were formed between clozapine and CAPs via hydrogen bonding. The co-amorphous dispersions formed with tartaric acid (1:2) showed the highest dissolution percentage (> 95 % in 20 minutes) compared to pure crystalline CZ (56 %). Highly stable solutions were obtained from co-amorphous CZ-citric and CZ-tartaric acid at 1:1.5 molar ratio. The prepared dispersions suggest the possibility of peroral or sublingual administration of highly soluble clozapine at a reduced dose with the great chance to bypass the first pass metabolism.

Optimization of propranolol HCl release kinetics from press coated sustained release tablets

Press-coated sustained release tablets offer a valuable, cheap and easy manufacture alternative to the highly expensive, multi-step manufacture and filling of coated beads. In this study, propranolol HCl press-coated tablets were prepared using hydroxylpropylmethylcellulose (HPMC) as tablet coating material together with carbopol 971P and compressol as release modifiers. The prepared formulations were optimized for zero-order release using artificial neural network program (INForm, Intelligensys Ltd, North Yorkshire, UK). Typical zero-order release kinetics with extended release profile for more than 12 h was obtained. The most important variables considered by the program in optimizing formulations were type and proportion of polymer mixture in the coat layer and distribution ratio of drug between core and coat. The key elements found were; incorporation of 31–38 % of the drug in the coat, fixing the amount of polymer in coat to be not less than 50 % of coat layer. Optimum zero-order release kinetics (linear regression r2 = 0.997 and Peppas model n value > 0.80) were obtained when 2.5–10 % carbopol and 25–42.5% compressol were incorporated into the 50 % HPMC coat layer.

Experimental co-infection of infectious bronchitis and low pathogenic avian influenza H9N2 viruses in commercial broiler chickens

Abstract In this study, commercial broilers were experimentally infected with single (classical IBV, variant IBV or AIV-H9N2) or mixed AIV-H9N2 with classical, variant or vaccine strains of IBV. Birds were monitored for clinical and pathological outcomes and virus shedding for 10days post infection (DPI). Clinical signs were limited to the respiratory tract in all challenged groups and varied from mild to moderate mouth breathing to severe respiratory signs with snorting sound and extended head. Mortalities were only recorded in mixed AIV-H9N2/variant IBV challenge group. AIV-H9N2 challenge caused tracheal petechial hemorrhage that progressed to tracheal congestion and caseation. In mixed AIV-H9N2/IBV vaccine challenge, severe tracheitis with bronchial cast formation was observed. In mixed AIV-H9N2/variant IBV challenge severe congestion of the tracheal mucosa and excessive exudates with a tendency to form tubular casts were observed. Kidney ureate deposition was only observed in variant IBV challenge group. Histopathologically, tracheal congestion, severe degeneration, and deciliation were noticed in all groups of mixed infection. Interestingly, hemorrhage and atrophy were observed in thymus gland of birds challenged with single AIV-H9N2 or mixed AIV-H9N2/IBV. There was no difference in the tracheal shedding level of variant IBV between single and mixed infected groups while classical IBV shedding increased in mixed infection group. Interestingly, the AIV-H9N2 showed constantly high shedding titers till 7DPI with variant or vaccine IBV co-infection. In conclusion, co-infection of IBV and AIV-H9N2 induced severe clinical outcome and high mortality. Also, IBV co-infection increased the shedding of AIV-H9N2 in experimentally infected birds.

Development of a nanogel formulation for transdermal delivery of tenoxicam: a pharmacokinetic–pharmacodynamic modeling approach for quantitative prediction of skin absorption

Abstract This study investigates potentials of solid lipid nanoparticles (SLN)-based gel for transdermal delivery of tenoxicam (TNX) and describes a pharmacokinetic–pharmacodynamic (PK–PD) modeling approach for predicting concentration–time profile in skin. A 23 factorial design was adopted to study the effect of formulation factors on SLN properties and determine the optimal formulation. SLN-gel tolerability was investigated using rabbit skin irritation test. Its anti-inflammatory activity was assessed by carrageenan-induced rat paw edema test. A published Hill model for in vitro inhibition of COX-2 enzyme was fitted to edema inhibition data. Concentration in skin was represented as a linear spline function and coefficients were estimated using non-linear regression. Uncertainty in predicted concentrations was assessed using Monte Carlo simulations. The optimized SLN was spherical vesicles (58.1 ± 3.1 nm) with adequate entrapment efficiency (69.6 ± 2.6%). The SLN-gel formulation was well-tolerated. It increased TNX activity and skin level by 40 ± 13.5, and 227 ± 116%, respectively. Average Cmax and AUC0–24 predicted by the model were 2- and 3.6-folds higher than the corresponding values computed using in vitro permeability data. SLN-gel is a safe and efficient carrier for TNX across skin in the treatment of inflammatory disorders. PK–PD modeling is a promising approach for indirect quantitation of skin deposition from PD activity data.

Influence of pellet aggregate populations on the variability of pellet filling into hard shell capsules: a comparison of experiment and computer simulation.

Variations in pellet filling into hard shell capsules and other cavities are attributed to many factors including fluctuations in pellet size, shape polydispersity, presence of aggregates and electrostatic charge. The influence of pellet aggregation has not previously been investigated, and therefore modelling of the filling behaviour of pellet populations with different levels of twin, triplet and tetrahedral aggregates was evaluated in this study. Pellet/aggregate mixtures were also filled experimentally alongside simulation. The experimental and simulation results for fill weight variability showed that predictions of the trends and values of the percentage coefficient of weight variation (% CV) for mixtures containing twin aggregates up to a level of 20% (w/w) could be achieved. The filling behaviour for triplet and tetrahedral aggregates could not however be simulated effectively due to pellet segregation.

Modeling and optimization of nebulizers' performance in non-invasive ventilation using different fill volumes: Comparative study between vibrating mesh and jet nebulizers

BACKGROUNDS Substituting nebulisers by another, especially in non-invasive ventilation (NIV), involves many process-variables, e.g. nebulizer-type and fill-volume of respirable-dose, which might affect patient optimum-therapy. The aim of the present work was to use neural-networks and genetic-algorithms to develop performance-models for two different nebulizers. METHODS In-vitro, ex-vivo and in-vivo models were developed using input-variables including nebulizer-type [jet nebulizer (JN) and vibrating mesh nebulizer (VMN)] fill-volumes of respirable dose placed in the nebulization chamber with an output-variable e.g. average amount reaching NIV patient. Produced models were tested and validated to ensure effective predictivity and validity in further optimization of nebulization process. RESULTS Data-mining produced models showed excellent training, testing and validation correlation-coefficients. VMN showed high nebulization efficacy than JN. JN was affected more by increasing the fill-volume. The optimization process and contour-lines obtained for in-vivo model showed increase in pulmonary-bioavailability and systemic-absorption with VMN and 2 mL fill-volumes. CONCLUSIONS Modeling of aerosol-delivery by JN and VMN using different fill-volumes in NIV circuit was successful in demonstrating the effect of different variable on dose-delivery to NIV patient. Artificial neural networks model showed that VMN increased pulmonary-bioavailability and systemic-absorption compared to JN. VMN was less affected by fill-volume change compared to JN which should be diluted to increase delivery.