Ibrahim M. El-Bagory

Controlled-release carbamazepine matrix granules and tablets comprising lipophilic and hydrophilic components

The objective of this study was to investigate the effect of lipophilic (Compritol® 888 ATO) and hydrophilic components (combination of HPMC and Avicel) on the release of carbamazepine from granules and corresponding tablet. Wet granulation followed by compression was employed for preparation of granules and tablets. The matrix swelling behavior was investigated. The dissolution profiles of each formulation were compared to those of Tegretol® CR tablets and the mean dissolution time (MDT), dissolution efficiency (DE%), and similarity factor (f2 factor) were calculated. It was found that increase in the concentration of HPMC results in reduction in the release rate from granules and achievement of zero-order is difficult from the granules. The amount of HPMC plays a dominant role for the drug release. The release mechanism of CBZ from matrix tablet formulations follows non-Fickian diffusion shifting to Case II by the increase of HPMC content, indicating significant contribution of erosion. Increasing in drug loading resulted in acceleration of the drug release and in anomalous controlled-release mechanism due to delayed hydration of the tablets. These results suggest that wet granulation followed by compression could be a suitable method to formulate sustained release CBZ tablets.

Controlled-release carbamazepine granules and tablets comprising lipophilic and hydrophilic matrix components.

The objective of this study was to investigate the effect of lipophilic (Compritol® 888 ATO) and hydrophilic components (combination of HPMC and Avicel) on the release of carbamazepine from granules and corresponding tablet. Wet granulation followed by compression was employed for preparation of granules and tablets. The matrix swelling behavior was investigated. The dissolution profiles of each formulation were compared to those of Tegretol® CR tablets and the mean dissolution time (MDT), dissolution efficiency (DE %) and similarity factor (f2 factor) were calculated. It was found that increase in the concentration of HPMC results in reduction in the release rate from granules and achievement of zero-order is difficult from the granules. The amount of HPMC plays a dominant role for the drug release. The release mechanism of CBZ from matrix tablet formulations follows non-Fickian diffusion shifting to case II by the increase of HPMC content, indicating significant contribution of erosion. Increasing in drug loading resulted in acceleration of the drug release and in anomalous controlled-release mechanism due to delayed hydration of the tablets. These results suggest that wet granulation followed by compression could be a suitable method to formulate sustained release CBZ tablets.

Formulation, Release Characteristics and Bioavailability Study of Oral Monolithic Matrix Tablets Containing Carbamazepine

This study examined the release of carbamazepine (CBZ) from hydrophobic (Compritol® 888 ATO) and hydrophilic-hydrophobic matrix combination (Compritol® 888 ATO-hydroxpropyl methylcellulose, HPMC). Hydrophobic matrix tablets were prepared by hot fusion technique, while hydrophilic-hydrophobic matrix tablets were prepared by wet granulation technique. The properties of the compressed matrix tablets were determined according to the US Pharmacopoeia. Both matrix formulations displayed a controlled-release profile when compared to the reference formulation (Tegretol® CR 200). The bioavailability of CBZ formulations and Tegretol® CR 200 were evaluated in beagle dogs. Carbamazepine presented a significant higher bioavailability from matrix tablets containing hydrophilic polymer (HPMC) than that obtained from Tegretol® CR200. The average inter-subject plasma concentration variability CV% was the least with tablet containing hydrophilic polymer (HPMC) and was the highest with Tegretol® CR 200 (33.8 and 54.1, respectively). Analysis of variance applied to log

Formulation and in vivo evaluation of diclofenac sodium sustained release matrix tablet: effect of compression force.

{\text{AUC}}_{0 - \alpha }

Formulation and in vitro evaluation of theophylline matrix tablets prepared by direct compression: Effect of polymer blends

and log C max showed statistical significant differences among the three formulations (P < 0.05). Plotting the fraction of CBZ released in vitro and fraction absorbed showed a statistically significant relationship (R2 = 0.935–0.975) for the three matrix tablets examined.

Effect of Gamma Irradiation on Pluronic Gels for Ocular Delivery of Ciprofloxacin: in Vitro Evaluation

The sensitivity of hydrocortisone to gamma radiation in aqueous and organic solvents was investigated to predict the feasibility of sterilizing the topical preparations by radiation. The drug showed a higher sensitivity to radiation in aqueous solutions than organic ones. Adding different types of surfactants like NaLS, CTAB or Cetomacrogol 1000 to aqueous solutions before irradiation resulted in a considerable protective effect, following the order NaLS > CTAB > Cetomacrogol1000. From the calculated G-values, it was evident that the sensitivity of organic solutions of the drug to radiation increased as the number of hydroxyl groups in the aliphatic alcohol increased. Also the position of hydroxyl groups in the aliphatic chain affected drug degradation rate. The sensitivity of drug to radiation in organic solvents was in the order: 1,3 propanediol > glycerol > propylene glycol > n-propanol. The high stability of the formulated creams to radiation was suggested to be due to the protective effect of the long-chain stearyl alcohol in the organic phase as well as the effect of NaLS in the aqueous phase. On the other hand, the stability of the drug in the formulated ointments was considerably affected by the propylene glycol content and slightly protected by cetyl alcohol.

EFFECTS OF SPHERE SIZE, POLYMER TO DRUG RATIO AND PLASTICIZER CONCENTRATION ON THE RELEASE OF THEOPHYLLINE FROM ETHYLCELLULOSE MICROSPHERES

Background: Micro-encapsulation is a process in which tiny particles or droplets are surrounded by a coating polymer to give micro capsules having many useful properties in drug pre-formulation. It can be used to control the release of a drug into the body, to obtain certain desired release pattern. Also may decrease toxic side effects for some drugs by preventing high initial concentrations in the blood.C is the number one cause of death in Canada, surpassing cardiovascular disease. Despite significant strides in understanding the mechanisms behind cancer, efficient and curative therapies are still missing. Chemotherapy is the treatment of choice in many cancers. However, it rarely cures cancer and mostly becomes ineffective by drug resistance. Moreover, emergence of intolerable toxicities by chemotherapeutic agents lowers the quality of life significantly, in cancer patients. Immunotherapy is the more recent and unconventional form therapy for cancer. Recent research has provided a strong case for the potential benefit of combined immuno and chemotherapy in the eradication of cancer. In both cases achieving high therapeutic efficacy requires targeted delivery -to cancer cells and its microenvironment in case of chemotherapy and to antigen presenting cells in case of cancer vaccines. The objective of our research is to design targeted vaccine and drug nano-delivery systems that can enhance the efficacy and reduce the toxicity of immunotherapy and chemotherapy in cancer. In this presentation, a brief update on the progress made by our research group in the design and development of engineered block-copolymer micelles as targeted nano-therapeutics that can enhance efficacy and reduce toxicity of chemotherapeuty in sensitive and resistant cancer phenotypes will be described. Development of nanoparticlulate delivery systems that can enhance immune responses against cancer leading to the rejection of established tumors in animal models by body’s defense mechanism will also be described.Saad Abdel-Rahman Sheta has completed his MD in Anesthesia & ICU from Alexandria University, Egypt (A Double Channel degree with St James’s hospital, Leads, UK) in 1989. He is Professor of Anesthesia, Faculty of Medicine, Alexandria University. Currently, he is affiliated to King Saud University, Riyadh, KSA, working as Professor, Head of Anesthesia Division, Oral-Maxillofacial Surgery Department. He has published more than 20 papers in reputable regional and international journals.P are short polymers of amino acids linked by peptide bonds. They are unstable in drastic conditions including strongly acidic or alkaline media and high temperature. Polymeric nanoparticles are most popular and more desirable in pharmaceutical field than other colloidal systems because of their stability in biological environment. Two biodegradable polymers of different properties were chosen for this study. Chitosan was chosen as a water soluble polymer while, poly(lacticco-glycolic) acid (PLGA) as an organic solvent soluble polymer. The polymeric nanoparticles were used as carriers for capreomycin. Capreomycin was chosen as a model therapeutic peptide. Double emulsion (w1/o/w2) solvent evaporation technique was used in the study. Many formulation factors for nanoparticles optimization were tested including: method of agitation, probe sonication intensity and time, high-shear homogenization speed, pH of dispersion media, in addition to concentration of polymer, drug polymer ratio, type and concentration of crosslinking agents (if needed) and concentration of polyvinyl alcohol (PVA). Controlling these factors allowed for optimizing polymeric nanoparticles as carrier for peptides with smallest possible particle sizes and highest possible entrapment efficiencies. The produced polymeric nanoparticles dispersion were lyophilized and allowed for drug release in phosphate buffer pH 7.4. Different slow release profiles were observed for chitosan and PLGA nanoparticles.Vascular and metabolic dysfunctions and mitochondrial failure are now believed to be contributors to Alzheimers disease (AD) pathogenesis. Vascular dysfunction includes reduced cerebral blood flow (CBF), blood-brain barrier (BBB) disturbances and cerebral amyloid angiopathy (CAA). Mitochondrial failure results in deregulation of Ca(2+) homeostasis and elevated reactive oxygen species (ROS) generation, both of which are linked to neurotoxicity. Increased levels of ROS stimulate proinflammatory gene transcription and release of cytokines, such as IL-1, IL-6, and TNF-α, and chemokines, thereby inducing neuroinflammation. Conversely, inflammatory reactions activate microglia and astrocytes to generate large amounts of ROS, so neuroinflammation could be perceived as a cause and a consequence of chronic oxidative stress. The interaction between oxidative stress and neuroinflammation leads to amyloid-β (Aβ) generation. The deposition of Aβ peptide in the brain generates a cascade of pathological events, including the formation of neurofibrillary tangles (NFTs), inflammatory reactions, increased oxidative stress and mitochondrial dysfunction, which are causative factors of cell death and dementia. The purpose of this paper is to provide current evidence on vascular dysfunction and mitochondrial failure, both in neurons and glia and in brain vascular wall cells in the context of potential application for treatment of AD and other neurodegenerations.M are tiny micron sized structures that can be used to disrupt the stratum corneum for increasing skin permeation of drugs. We have investigated the utility of microneedles (from DermarollerTM) in increasing in vitro skin permeation of prochlorperazine and betablockers. Microneedles when used either alone or in combination with iontophoresis, enhanced the transdermal flux of drugs investigated. The DermarollerTM induced microchannels were visualized using methylene blue staining and scanning electron microscopy. Transepidermal water loss was measured to confirm localized disruption of the stratum corneum. In vitro skin permeation studies were performed using vertical static Franz diffusion cells. Iontophoretic protocols involved application of direct current at a density of 0.1-0.5 mA/cm2 using Ag as an anode and Ag/AgCl as a cathode. The effect of drug concentration, number of passes of microneedles (0, 5, 10 and 20) on both iontophoretic and passive delivery was investigated. The effect of lipophilicity of drug on the microneedle mediated transdermal iontophoretic delivery was also investigated. The DermarollerTM was found to successfully breach the skin barrier and a linear relationship (r2 = 0.99) was observed between the number of passes of the DermarollerTM and the number of microchannels created. The transdermal flux increased following pretreatment with microneedle (used alone or in conjunction with iontophoresis). Depending on the physicochemical properties of the drug, there was about 8-80 fold increase in transdermal flux as compared to passive delivery. Lipophilicity of the molecule played a significant role on the electrically assisted transdermal delivery of drugs across the microporated skin.In the present study, Diclofenac Sodium (DS) matrix tablets were prepared by direct compression method under different compression forces (5, 10, 15 and 20 KN), using ethylcellulose as matrix forming material. The produced tablets were characterized on the foundation of satisfactory tablet properties such as hardness, friability, drug content, weight variations and in vitro drug release rate. Differential scanning calorimetry (DSC), Fourier Transform Infrared (FT-IR) spectroscopy and X-ray diffraction have been used to investigate any incompatibilities of the tablets ingredients. Additionally, in vivo bioavailability has been investigated on beagle dogs. Data obtained revealed that, upon increasing compression force the in vitro drug release was sustained and the T(max) value was four hours (for formulations compressed at 15 and 20 kN) compared to the conventional voltarine(®) 50 tablets (T(max) value of 2 hours).H aggressive and rapidly growing tumors have hypoxic (low oxygen) regions that can activate several signal transduction pathways to induce tumor angiogenesis and progression. Most of the mechanisms involved in hypoxia are due to the upregulation of hypoxia inducible factor 1α (HIF-1α). HIF-1α is a key regulator for the induction of several genes that are responsible for cellular adaption and survival at hypoxia. They are the potent inducer of angiogenic factors like vascular endothelial growth factor (VEGF) and erythropoietin and major stem cell marker like CD133 and multi drug resistance marker P-glycoprotein (Pgp). Hence there has been a growing interest to study the biological role of HIF-1α to overcome the associated poor prognosis. The present investigation describes the use of biologically active bovine milk glycoprotein lactoferrin (Lf) for targeting hypoxia. Lf has been proved to be a potent anti-cancer agent with several immuno-modulatory functions [1, 2]. Iron saturated bovineLf promisingly decreased the load of HIF-1α, anti-apoptotic proteins expressed in most cancers and VEGF as confirmed using flow cytometry and western blotting. Cancer cells were able to readily internalise Lf via Lf-receptors through receptor mediated endocytosis and decreased P-gp activity within the cells. This promising result led to the synthesis of bLf conjugates to improve cellular delivery of most widely used chemotherapeutic drug known as doxorubicin (Dox). The synthesized bLf-Dox conjugates were able to internalise into cells at both normoxic and hypoxic conditions. Interestingly, significant reduction (p ≤ 0.01) in P-gp expression was also noticed in cells treated with both bLf and bLf-Dox conjugates. Cells pre-treated with iron saturated bLf-Dox conjugate did not form spheroids when cultured until 72h. Caspase-3 expression was also found to be up-regulated with bLf-Dox conjugate treatments demonstrating the activation of apoptosis mediated cell death. The action of bLf-Dox conjugates on poly giant cancer cells (PGCC) which represents resistant form of tumor cells [3] were also studied using 400 μM CoCl2. bLf-Dox conjugates reduced the occurrence of PGCCs in the culture when compared to Dox alone treatments which showed increased number of PGCCs. Western blotting analysis proved the down-regulation of HIF-1α and CD133 in PGCCs treated with bLf-Dox conjugates. Generally, CD133 (+) cells are resistant to Dox alone treatments in solid tumors.