FORMULATION AND OPTIMIZATION OF SOLID SELF-NANOEMULSIFYING SYSTEM USING POROUS CARRIERS FOR ORAL DELIVERY OF CINNARIZINE

Objective: The present study aims to utilize the nanotechnology technique to formulate the Cinnarizine (CNZ) in the form of solid self-nano emulsifying system to enhance the dissolution and hence the bioavailability.Methods: Screening study for solubility of CNZ in different vehicles was carried out. The selected system was optimized for saturated solubility, globule size, zeta potential, polydispersity index (PDI) and self-emulsification time. The solidified nanoemulsion was prepared using; Aeroperl 300, Aerosil 200, hydrophilic nanosilica and Neusilin US2 as porous carrier materials. The compressed CNZ tablets were evaluated regarding their physicochemical characteristics, in-vitro release, and bioavailability study.Results: Self nano-emulsifying system composed of Labrafil (oil), tween 80 (surfactant), and transcutol (cosurfactant) was successfully developed with a droplet size range of 11.37-92.58 nm. The in-vitro release results revealed that the developed formulation improved the release of CNZ and enhanced the bioavailability in the rabbits (190%) more than the commercial product (Stugeron® tablets).Conclusion: Solid self-nano-emulsifying system of CNZ was successfully developed by different ratios of Labrafil (oil), tween 80 (surfactant), transcutol (cosurfactant) and solidified by the adsorption on hydrophilic nano silica and the optimized formula could be expected to increase and improve the bioavailability of CNZ.Â

Standalone closed-form formula for the throughput rate of asynchronous normally distributed serial flow lines

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Flexible flow lines use flexible entities to generate multiple product variants using the same serial routing. Evaluative analytical models for the throughput rate of asynchronous serial flow lines were mainly developed for the Markovian case where processing times, arrival rates, failure rates and setup times follow deterministic, exponential or phase-type distributions. Models for non-Markovian processes are non-standalone and were obtained by extending the exponential case. This limits the suitability of existing models for real-world human-dependent flow lines, which are typically represented by a normal distribution. We exploit data mining and simulation modelling to derive a standalone closed-form formula for the throughput rate of normally distributed asynchronous human-dependent serial flow lines. Our formula gave steady results that are more accurate than those obtained with existing models across a wide range of discrete data sets

DESIGN AND EVALUATION OF DOMPERIDONE SUBLINGUAL TABLETS

Objective: The aim of this work was to enhance the bioavailability of poorly soluble, anti-emetic drug; domperidone (DMP) having a poor oral bioavailability (13-17%) due to extensive first pass metabolism. The goal of this study was achieved through solubilization of DMP using solid dispersion technology followed by incorporation of solid dispersions into sublingual tablets to bypass pre-systemic metabolism.Methods: Solid dispersions of DMP with Pluronic F-68 were prepared in different weight ratios by fusion method and they were evaluated for their in vitro dissolution rate to select the best ratio for final formulation. Then, solid dispersions were formulated into sublingual tablets in combination with various soluble excipients. Sublingual tablets were prepared by direct compression technique and evaluated for their physical properties, in vitro dissolution rate and kinetics of drug release. The best formulae were selected for in vivo studies in rabbits in comparison with marketed oral tablets; Motinorm®.Results: Solid dispersions of DMP with Pluronic F-68 in a weight ratio of 1:7 (w/w) showed the highest dissolution rate and were selected for sublingual tablets formulation. Sublingual tablets formulae S16 (containing Fructose and 10% w/w Ac-Di-Sol) and S20 (containing Fructose and 10% w/w Explotab) showed the best results and were selected for in vivo studies in rabbits. The selected formulae showed marked enhancement of DMP bioavailability compared with the commercial oral tablets; Motinorm®, with relative bioavailability values of 432.49±10.13% and 409.32±11.59 % for S16 and S20, respectively.Conclusion: The results confirmed that sublingual tablets were an effective tool for DMP delivery with marked enhancement of bioavailability.Keywords: Domperidone, Solubility, Solid dispersions, Sublingual tablets, First-pass metabolism, Bioavailabilit

Process Control Parameters Evaluation Using Discrete Event Simulation for Business Process Optimization

The quest for manufacturing process improvement and higher levels of customer satisfaction mandates that organizations must be equipped with advanced tools and techniques in order to respond towards ever changing internal and external customer demands by maintaining the optimal process performance, lower cost and higher profit levels. A manufacturing process can be defined as a collection of activities designed to produce a specific output for a particular customer or market. To achieve internal and external objectives, significant process parameters must be identified and evaluated to optimize the process performance. This even becomes more important to deal with fierce competition and ever changing customer demands. This paper illustrates an integrated approach using design of experiments techniques and discrete event simulation (Simul8) to understand and optimize the system dynamic based on operational control parameter evaluation and their boundary conditions. Further, the proposed model is validated using a real world manufacturing process case study to optimize the manufacturing process performance. Discrete event simulation tool is used to mimic the real world scenario, which provides a flexible and powerful way to comprehensively understand the manufacturing process variations and allows controlled 'What-If´ analysis based on design of experiments approach. Finally, this paper discusses the potential applications of the proposed methodology in the cable industry in order to optimize the cable manufacturing process by regulating the operational control parameters such as dealing with various product configurations with different equipment settings, different product flows and work in process (WIP) space limitations

Protection of hippocampal CA1 neurons against ischemia/Reperfusion injury by exercise preconditioning via modulation of Bax/Bcl-2 ratio and prevention of Caspase-3 Activation

Introduction: Ischemia leads to loss of neurons by apoptosis in specific brain regions, especially in the hippocampus. The purpose of this study was investigating the effects of exercise preconditioning on expression of Bax, Bcl-2, and caspase-3 proteins in hippocampal CA1 neurons after induction of cerebral ischemia. Methods: Male rats weighing 260-300 g were randomly allocated into three groups (sham, exercise, and ischemia). The rats in exercise group were trained to run on atreadmill 5 days a week for 4 weeks. Ischemia was induced by the occlusion of both common carotid arteries (CCAs) for 20 min. Levels of expression of Bax, Bcl-2, and caspase-3 proteins in CA1 area of hippocampus were determined by immunohistochemical staining . Results: The number of active caspase-3-positive neurons in CA1 area were significantly increased in ischemia group, compared to sham-operated group (P<0.001), and exercise preconditioning significantly reduced the ischemia/reperfusion-induced caspase-3 activation, compared to the ischemia group (P<0.05). Also, results indicated a significant increase in Bax/Bcl-2 ratio in ischemia group, compared to sham-operated group (P<0.001). Discussion: This study indicated that exercise has a neuroprotective effects against cerebral ischemia when used as preconditioning stimuli

Improvement of heart failure by human amniotic mesenchymal stromal cell transplantation in rats

Background: Recently, stem cells have been considered for the treatment of heart diseases, but no marked improvement has been recorded. This is the first study to examine the functional and histological effects of the transplantation of human amniotic mesenchymal stromal cells (hAMSCs) in rats with heart failure (HF). Methods: This study was conducted in the years 2014 and 2015. 35 male Wistar rats were randomly assigned into 5 equal experimental groups (7 rats each) as 1-Control 2-Heart Failure (HF) 3-Sham 4-Culture media 5-Stem Cell Transplantation (SCT). Heart failure was induced using 170 mg/kg/d of isoproterenol subcutaneously injection in 4 consecutive days. The failure confirmed by the rat cardiac echocardiography on day 28. In SCT group, 3�106 cells in 150 μl of culture media were transplanted to the myocardium. At the end, echocardiographic and hemodynamic parameters together with histological evaluation were done. Results: Echocardiography results showed that cardiac ejection fraction in HF group increased from 58/73 � 9 to 81/25 � 6/05 in SCT group (p value &lt; 0.001). Fraction shortening in HF group was increased from 27/53 � 8/58 into 45/55 � 6/91 in SCT group (p value &lt; 0.001). Furthermore, hAMSCs therapy significantly improved mean diastolic blood pressure, mean arterial pressure, left ventricular systolic pressure, rate pressure product, and left ventricular end-diastolic pressure compared to those in the HF group, with the values reaching the normal levels in the control group. A marked reduction in fibrosis tissue was also found in the SCT group (p value &lt; 0.001) compared with the animals in the HF group. Conclusion: The transplantation of hAMSCs in rats with heart failure not only decreased the level of fibrosis but also conferred significant improvement in heart performance in terms of echocardiographic and hemodynamic parameters. � 2016, Tehran Heart Center. All rights reserved

Causality Verification and Enforcement for Microelectronic Package Macromodels

The design and analysis phase of passive structures of high speed microelectronic systems require suitable macromodels that capture the relevant electromagnetic properties that affect the signal and power quality. These models are constructed either from direct measurements or electromagnetic simulations using macromodeling techniques such as Vector Fitting, for example. The raw data that are used for extraction of such models have the form of discrete port frequency responses and they may be contaminated by errors due to a noise, inadequate calibration techniques in case of direct measurements or approximation and discretization errors in case of numerical simulations. Besides, these data are typically available over a finite frequency range as discrete sets with a limited number of samples. All this may affect the performance of the macromodeling algorithm. Often the underlying cause of such behavior is the lack of causality in given data. The thesis conducts a study of system causality, starting from an overview of macromodeling of microelectronics packages, signal and power distribution networks and simultaneous switching noise. Various system causality definitions, conditions and requirements are presented. Different available methods for causality verification in time and frequency domains are discussed. Motivated by the limitations and drawbacks associated with conventional methods of causality verification and enforcement, namely, that the frequency responses are available on a finite bandwidth in a discrete form, the thesis presents two new methods that check and enforce causality in the frequency domain. The methods are based on Kramers-Kr""onig relations, also called dispersion relations. Both of methods construct periodic continuations of the given frequency responses, so that the resulting function is periodic on a wider domain. The first method uses periodic polynomial continuation with the subsequent use of Fast Fourier Transform to compute discrete Hilbert Transform and characterize causality. The second approach approximates frequency responses by a Fourier series using SVD-based method. Causality is imposed directly and exactly on Fourier coefficients. The two methods are successfully tested on several analytic and simulated examples that represent interconnect macromodeling systems to show excellent performance of the proposed techniques. Artificial causality violations were imposed to demonstrate that both methods are able to detect them successfully.Thesis (Ph.D., Electrical and Computer Engineering)--University of Idaho, May 201