Chitosan Dextran Microparticles as the Potential Carrier for Colon Specific Delivery of 5- Fluorouracil

Introduction: Colorectal cancer is one of the most commonly diagnosed cancers in the world. The main and classic treatment of this cancer is 5-fluorouracil (5-Fu) that its cytotoxicity and low systemic absorption restricted its therapeutic efficacy. To overcome these problems, mucoadhesive and colonic microbially degradable formulations based on chitosan and dextran sulphate hydrogels could be effective. Methods and Results: 5-Fu loaded hydrogel microparticles were formed via polyelectrolyte complexation technique using chitosan and dextran sulphate solutions. It was optimized by a systematic multi-objective optimization approach in terms of the particle size and loading efficiency of the resulting microparticles. Under this condition, the molecular weight of chitosan and 5-Fu concentration are the two factors which significantly influence the particle size and loading efficiency, respectively. Then the optimized microparticles were prepared and were characterized based on particle size, zeta potential, drug loading and drug release behavior. Finally the cytotoxicity of optimized microparticles was assessed by MTT assay (SW742 cell line) compare to free drug solution. Therefore, spherical particles of 51.33±0.95 μm mean diameter and a narrow size distribution were obtained under optimal conditions. The zeta potential, loading efficiency and loading capacity of optimized microparticles were 18.1±0.87mv, 26.96±0.38 and 13.12±0.65%, respectively. The in vitro drug release profile was fitted on Higuchi model and the cytotoxicity MTT results indicated the higher cytotoxicity of studied formulation on cells compare to free drug. The hydrogel microparticles were further lyophilized to prepare the enteric coated tablets and all tests endorsed that the coating process was suited. Conclusions: The designed formulations have provided appropriate properties and offer a potential mean for colon specific delivery of 5-Fu via oral administration

Emergent Structure of Multi-Dislocation Ground States in Frustrated Assemblies

In this dissertation we study the emergent patterns of multi-dislocation ground states in two geometrically related classes of frustrated assemblies, twisted filament bundles and crystalline spherical cap. We discuss the fundamental role played by characteristic patterns of dislocations in restructuring the ordered phase of theses geometrically frustrated systems in the presence of external stresses. Our analysis on the formation of grain boundary scars leads to universal predictions for the features of defect patterns and their underlying energetic principles

Optimization and Characterization of a Parenteral In Situ Forming Gel Formulation of Tramadol to Use in Chronic Pains

Introduction: Targeted delivery systems such as smart polymers based on in situ forming gel can form controlled release formulations. These smart polymers based on in situ forming gel are thermosensitive and converse to gel in the site of injection and body temperature. Tramadol is an opiate-like analgesic that has tendency to μ-receptors of opioids. It inhibits the re-uptake of monoamines and serotonin in the central nervous system. In this research our goal is preparation, optimization and characterization of a parenteral in situ forming gel formulation of tramadol to use in chronic pains. Methods and Results:Optimization of formulation done by a D-optimal method. We found the effect of different factors such as; polymers’ concentrations, type and concentration of gelating agent on gelation time. The prepared in situ forming gel formulation in vitro were fully characterized. Morphologic study such as AFM and drug release in PBS environment with Franz cell were done. The release kinetics study was also performed. In optimum situation, the resulted concentration of chitosan, glycerophosphate, poloxamer F-127 and TPP are 1%, 14.5%, 20% and 0.5%. Gelation time and temperature were validated and the results show about 1.5 minutes and 37 ℃ respectively. The drug release profile of free drug showed the fastest release rate with about 100% at 8 h whereas the formulations with TPP and without TPP were about 94% and 38% at 28 h respectively. Conclusions: A parenteral in situ forming gel formulation was designed and in vitro evaluation showed that our gel formulation has a uniform texture and can release drug through its nanostructured pores, properly. So, it can be useful in chronic pains, according to its features and reduces the frequency of consumption.&nbsp

Cell organelle-shaped liposomes: A novel approach to present the stable intracellular drug delivery systems

Caveolae are lipid raft-enriched flask-shaped, expose in the plasma membrane of various cell types. It has become clear now that caveolae and their caveolin “marker proteins” are associated in a several cellular procedures including endocytosis, lipid homeostasis, signal transduction, and tumorigenesis. Caveolin has been shown to have high binding affinity for cholesterol and sphingolipids. Caveolin oligomers construct filamentous networks that are believed to stabilize the membrane. Liposomes are the well-known drug delivery systems with spherical shape that can be produced from natural non-toxic phospholipids and cholesterol. Liposomes have been used as a considerable tool in biology, biochemistry, medicine, and drug delivery. The utilization of liposomes as a drug-delivery system has become more attractive in carrying systemically administered drugs with narrow therapeutic windows. The similarity between plasma membrane and liposomes from several points of view gives hope that the incorporation of caveolin in the phospholipid bilayer structures of liposomes can result in tightening and therefore stabilizing and long circulation of these structures.</p

Preparation and Optimization of a Novel Disintegrating Golqand Pellets as a Traditional Persian Pharmacy Formulation: The Path to Be Embarked upon

Introduction: Multi-particulate dosage form of pellet is formed by agglomeration of fine powdered drugs and excipients, leading to free flowing spherical particles. The multi-step process of extrusion &amp; spheronization are mostly applied for preparation of uniformly-sized pellets. Golqand, a product of Traditional Persian Pharmacy containing Rosa damascena Mill petals is a heart and brain tonic, refresher, astringent, and a stomachic. It helps to improve appetite and relieves digestive diseases. Also, Golqand calms down nervous system. Based on traditional texts, it has been produced as a Jam-like preparation, imposing some difficulties in taking and dosing. In this study, we have prepared Golqand in pellet form, a novel solid dosage form and optimized this natural formulation. Methods and Results: In this study, a 20 runs D-optimal method was applied as an experimental design to establish the optimum conditions for Golqand pellet preparation by extruder spheronizer equipment. The preparation process of pellets was optimized by a systematic multi-objective-optimization approach in terms of D- values for the particle size distribution (i.e. D10, D50 &amp; D90) which are the intercepts for 10%, 50% and 90% of the cumulative mass obtained via sieving method. The Model F-value of 6.58 implied the models were significant.&nbsp; There is only a 0.34% chance that a "Model F-Value" this large could occur due to noise. The R2, adjusted R2, predicted R2, and adequate precision for D50 model were calculated 82%, 72%, 46%, and 10.06, respectively which means that there is a good correlation between parameters and model. Conclusions: In conclusion, presented models conducted us to prepare Golqand pellets with unimodal particle size distribution and pre-defined particle size. Applying pelletization method for Golqand preparation could resolve some critical challenges of natural formulations like taking similar doses

Synthesis and Characterization of Simvastatin-N-succinyl chitosan-citicoline Conjugated Form Intended for Improving Alzheimer’s Disease in Long Term Use of Simvastatin

Introduction: Simvastatin is a semisynthesis statin. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, a key enzyme of cholesterol synthesis, in AMPK (AMP-activated protein kinase) signaling pathway. Simvastatin is able to cross blood brain barrier more than the other statins, due to its lipophilic nature. There is controversy about the effect of simvastatin on Alzheimer’s disease (AD). For example, simvastatin can induce AD through insulin signaling pathway but can ameliorate AD via MAPK (Mitogen-Activated Protein Kinase) signaling pathway.&nbsp; In this study, we report the synthesis of a conjugated form of simvastatin with citicoline, to block negative effect of simvastatin on insulin signaling pathway and increase positive effect of simvastatin on MAPK signaling pathway and chitosan as a linker between these two drugs. &nbsp; Methods and Results: for simvastatin-n-succinyl chitosan-citicoline synthesis, chitosan reacted with succinic acid to form n-succinyl chitosan. Then simvastatin connected to n-succinyl chitosan via acetylation reaction. After 24 hours citicoline was added to reaction media. H-NMR and FT-IR were done to examine whether the conjugation reaction has been done or not. Characterization and morphology tests have been done on reaction result. H-NMRresults approved the synthesis of drug-polymer. FT-IR results showed both amide and ester peaks.&nbsp; Maximum absorptions (λmax) of all primary chemicals were seen in UV visible spectroscopy results of conjugated form.SEM result showed that the conjugated form has nanoparticulate structure in size range of 100-300 nanometers. X-RD result showed a peak under 25 theta. Another characterization test wasRBC hemolysis with six different concentrations, in which normal saline was negative control and Triton was positive control. Conclusions: Conjugation of lipophilic simvastatin with hydrophilic citicoline to improve AD can be done with helping of a polymer which is rich in carboxylic acid

A reversed-phase high performance liquid chromatography approach for analysis of 5-Fluorouracil

A reproducible, sensitive, accurate and selective high performance liquid chromatographic (HPLC) method with ultraviolet absorbance detection has been developed and validated to quantitate 5-Fluorouracil (5-FU), an antimetabolite chemotherapeutic agent used in treatment of colorectal cancer as a drug of choice. Chromatographic separations were performed on a C18 column (Eurosphar 100-5, 150 mm × 4.6 mm) as the reversed stationary phase, eluted with a mobile phase composed of deionized water and methanol (95:5) with the flow rate of 1.0 mL/min. The UV wavelength was set at 261nm. The method produced linear responses throughout 5-fluorouracil range of 25-500 ng/ml with a correlation coefficient of 0.998. A limit of quantitation (LOQ) was established at 25 ng/ml. The within-day and between-day precision and accuracy were both in acceptable ranges. The outcomes of these tests indicate a proper separation efficacy as well as accuracy and sensivity of method which is a potential tool in many pharmaceutical studies such as drug delivery of this anti-cancer agent. </p