[Show abstract][Hide abstract] ABSTRACT: N,N-Diethyl meta Toluamide (DEET) is an insect repellent agent that contrary to its benefits,
if is used in formulations with high skin permeation, will produce side effects of different
severity. This study attempted to achieve a semi-solid DEET containing formulation with
good appearance, sufficient spreadity, suitable viscosity for tube and jar filling, compatible pH
with skin, reasonable stability, longer release time, and the less skin permeation. To obtain
such a formulation, three types of DEET containing semi solids including gels (hydrophile),
creams (emulsion) and ointments (lipophile), and their characteristics were compared with each
other and with Off! Brand. Results showed that one of the prepared creams with the proper
viscosity, stability, appearance and spreadity, had the least drug release in six hours and less
skin permeation of DEET as compared with Off!. Hence the preparation was introduced as the
[Show abstract][Hide abstract] ABSTRACT: Polymeric delivery systems based on nanoparticles have emerged as a promising approach for peroral insulin delivery. The aim of the present study was to investigate the release of insulin nanoparticulate systems and ex vivo studies. The nanoparticles were prepared by the ion gelation method. Particle size distribution, zeta potential, and polydispersity index of the nanoparticles were determined. It was found that the nanoparticles carried positive charges and showed a size distribution in the range of 170–200 nm. The electrostatic interactions between the positively charged group of chitosan and negatively charged groups of Arabic gum play an important role in the association efficiency of insulin in nanoparticles.
In vitro insulin release studies showed an initial burst followed by a slow release of insulin. The mucoadhesion of the nanosystem was evaluated using excised rat jejunum. Ex vivo studies have shown a significant increase in absorption of insulin in the presence of chitosan nanoparticles in comparison with free insulin.
[Show abstract][Hide abstract] ABSTRACT: In the past decade, many strategies have been developed to enhance oral protein delivery. The aim of the current work was to develop a nanoparticulate system based on ionic gelation between chitosan and Arabic gum for loading of insulin. Various formulations were prepared using 2(3) factorial designs. The optimum association efficiency was obtained for formulations F2, F5, and F8. The release profile of insulin in phosphate buffer solutions (pH 6.5 and pH 7.2) is completely different than that in acidic medium (pH 1.2). Increased solubility of chitosan in acidic medium and better swelling of Arabic gum chains at pH >6.5 resulted in lower insulin release of nanoparticles at pH 6.5 in comparison with that of the other pH mediums. The values of the exponent n were 0.49 and 0.82 for formulations F8 and F5, respectively, indicating a non-Fickian transport. This suggests that release is possibly controlled by diffusion or relaxation of the polymer chains. FROM THE CLINICAL EDITOR: This paper summarizes the development of a nanoparticulate system based on ionic gelation between chitosan and gum Arabic for oral delivery of insulin. If preclinical studies in animal models will indicate reliable and quantifiable delivery of insulin, this method may pave the way to a novel and less invasive way of administering insulin to diabetes patients.
Nanomedicine: nanotechnology, biology, and medicine 06/2009; 6(1):58-63. DOI:10.1016/j.nano.2009.04.007 · 6.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this investigation was to design a novel Gas Empowered Drug Delivery (GEDD) system for CO(2) forced transport of peptide drugs together with mucoadhesive polymers to the surface of the small intestine. The GEDD effect of the core tablet was achieved using CO(2) gas to push insulin together with the mucoadhesive excipients poly(ethyleneoxide) (PEO) and the permeation enhancer trimethyl chitosan (TMC) to the surface of the small intestine. The in-vitro insulin release showed that almost 100% of the insulin was released from enterically coated tablets within 30 min at pH 6.8. The designed GEDD system was shown to increase the insulin transport by approximately 7 times in comparison with the free insulin across sheep's intestine ex-vivo. Three different peroral formulations were administered to male rabbits: F1 containing no TMC or PEO, F2 containing PEO but no TMC and F3 containing both PEO and TMC. The administrations of insulin using the formulation F1 resulted in a low FR value of 0.2%+/-0.1%, while the formulations F2 and F3 resulted in a much higher FR values of 0.6+/-0.2% and 1.1%+/-0.4%, respectively. Hence, the insulin permeation achieved by the GEDD system is primarily due to the enhancing effect of TMC and the mucoadhesive properties of PEO both of which synergistically increase the bioavailability of insulin.
[Show abstract][Hide abstract] ABSTRACT: TMC and DEMC, quaternized derivatives of chitosan, have been shown to have penetration enhancement properties and able to open the tight junctions of the intestinal epithelia at neutral and alkaline pH environments. The use of the nanoparticulate systems has the advantage of protecting the peptidic drugs from the harsh environment of the gastrointestinal tract. Hence, the aim of this study was to synthesize and characterize TMC and DEMC, both with quaternization degrees of 50+/-5%, which were then used to prepare insulin nanoparticles with two different methods: ionotropic gelation and the polyelectrolyte complexation (PEC) techniques. The obtained nanoparticles were then characterized for size, zeta potential, insulin loading and release as well as antibacterial activities. The results showed that nanoparticles prepared by the PEC method had higher insulin loading efficiency and zeta potential than those made by the ionotropic gelation method and may subsequently be used for further in vitro, ex vivo and in vivo studies. Moreover, the antibacterial studies suggest that the polymers in free form have higher antibacterial activity against Gram-positive bacteria than in the nanoparticulate form.
International Journal of Pharmaceutics 06/2008; 355(1-2):299-306. DOI:10.1016/j.ijpharm.2007.11.052 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to obtain detailed information on the mechanism of drug release from mixed-film of pectin-chitosan/Eudragit RS. Pellets (710-840 microm in diameter) containing 60% theophylline and 40% microcrystalline cellulose were prepared by extrusion-spheronization method. Eudragit L100-55 enteric coating capsules included film-coated pellets of theophylline in theoretical coating weight gains of 10, 15, and 20%, with pectin-chitosan complex contents of 5, 10, 15, and 20% for each level of weight gain were prepared and subjected to in vitro drug release. Drug release from this system showed a bimodal release profile characteristic with the drug release enhancement, being triggered (burst release) in the colonic medium. The reason for burst drug release may be due to the enzymatic degradation of pectin via pectinolytic enzymes in the simulated colonic medium. The mechanism of drug release from each formulation was evaluated in the terms of zero-order, first-order, Higuchi and Korsmeyer-Peppas models. It was observed that none of the enteric coating capsules showed any drug release in the simulated gastric medium (phase I). The analysis of release profiles showed that zero-order kinetics was found as the better fitting model for all formulations in the simulated small intestine (phase II) and it could be due to the pectin-chitosan swelling and subsequent formation of aqueous channels. In the colonic medium (phase III), due to degradation of pectin and its leaching from the mixed-film, there was a modification in drug release kinetics from swelling-controlled at phase II to anomalous at phase III. It also was found that both zero-order and Higuchi models contributed in colonic drug release from most of the formulations.
Drug Development and Industrial Pharmacy 05/2008; 34(4):390-402. DOI:10.1080/03639040701662453 · 2.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chitosan, a biodegradable and biocompatible polymer, has attracted great attention in the pharmaceutical and biomedical fields especially due to its properties to reversibly open the tight junctions of the epithelial tissues and to allow for paracellular transport of hydrophilic macromolecules. However, chitosan exhibits low solubility at pH values above 6 that may prevent its enhancing effects at the sites of intestinal absorption. Hence, a number of alkylated chitosan salts have been synthesized and characterized. These derivatives have been shown to have good solubility at neutral pH and act as effective permeation enhancers. In this study, two new derivatives of chitosan, C2—C6 trimethyl 6-amino-6-deoxy chitosan and C2—C6 triethyl 6-amino-6-deoxy chitosan were synthesized and characterized using 1H-NMR and FTIR spectra. Moreover, the zeta potential and the antibacterial properties of these polymers were compared to chitosan, trimethyl chitosan (TMC) and triethyl chitosan (TEC). Our results suggest that both C2—C6 trimethyl and triethyl 6-amino-6-deoxy chitosan, as highly water soluble polymers, have higher positive surface charge than chitosan, TMC, and TEC. Moreover, the new synthesized polymers show higher antibacterial activity against Gram-positive Staphylococcus aureus bacteria. Consequently, these polymers with substitution degrees of 50—60% may be good candidates for the enhancement of peptides in mucosal drug delivery.
Journal of Bioactive and Compatible Polymers 05/2008; 23(3):262-275. DOI:10.1177/0883911508091904 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study four quaternized derivatives of chitosan: trimethyl chitosan (TMC), dimethylethyl chitosan (DMEC), diethylmethyl chitosan (DEMC) and triethyl chitosan (TEC) with degree of substitution of approximately 50+/-5% were synthesized and their effect on the permeability of insulin across intestinal Caco-2 monolayers was studied and compared with chitosan both in free-soluble form and in nanoparticulate systems. Transepithelial electrical resistance (TEER) studies revealed that all four chitosan derivatives in free-soluble forms were able to decrease the TEER value in the following order TMC>DMEC>DEMC=TEC>chitosan, indicating their abilities to open the tight junctions. Recovery studies on the TEER showed that the effect of the polymers on Caco-2 cell monolayer is reversible and proves the viability of cells after incubation with all polymers. A similar rank order was also observed when measuring the zeta-potentials of the various polymers in solution form. Transport studies of insulin together with the soluble polymers across Caco-2 cell layers showed the following ranking: TMC>DMEC>DEMC>TEC>chitosan which is in agreement with the strength of the cationic charge of the polymer. In comparison to the free-soluble polymers, the nanoparticles prepared by ionic gelation of the chitosan and its quaternized derivatives had much lower effect on decreasing the TEER by opening of the tight junctions. This can be explained by the reduced available amount of positive charge at the surface of the nanoparticles. In accordance with these results, the insulin loaded nanoparticles showed much less permeation across the Caco-2 cell monolayer in comparison to the free-soluble polymers. Mass balance transport studies revealed that a substantial amount of the nanoparticles has been entrapped into the Caco-2 monolayer or attached to the cell surface. It can thus be stated that while free-soluble polymers can reversibly open the tight junctions and increase the permeation of insulin, the nanoparticles had basically only a low effect on the opening of the tight junction and the paracellular transport of insulin across the Caco-2 cell monolayer. These data convincingly show that nanoparticles consisting of chitosan and its quaternary ammonium derivatives loaded with insulin are less effective in facilitating paracellular transport across Caco-2 cell monolayers than the corresponding free polymers.
European Journal of Pharmaceutics and Biopharmaceutics 03/2008; 70(1):270-8. DOI:10.1016/j.ejpb.2008.03.004 · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: N, N-dimethyl N-ethyl chitosan (DMEC), a quanternized derivative of chitosan was synthesized based on a modified two-step method via a 22 factorial design to optimize the preparative conditions. The degree of deacetylation of the starting chitosan was determined by FTIR and NMR methods and was 95%. In the first step of the synthesis, mono-ethyl chitosan was prepared by introducing an ethyl group onto the amine group of chitosan via a Schiff base and in the next step methyl iodide was added to produce DMEC which was water soluble in a pH range of 4-8. The DMEC polymers with different degrees of quaternization were obtained and fully characterized using FTIR and 1H-NMR spectroscopic methods. Based on 1H-NMR calculations, the degree of quaternization was 52% by optimizing the two-step process.
Journal of Bioactive and Compatible Polymers 09/2006; 21(5):433-444. DOI:10.1177/0883911506068679 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the present study, a suitable enteric-coated capsule containing brilliant blue-chitosan beads was prepared and investigated by means of γ-scintigraphy for colon drug delivery. Chitosan brilliant blue gel beads were prepared by dropping drug-containing solution of chitosan into tripolyphosphate solution using ion complexation method. Moreover, effects of different variables were investigated using 23 factorial design experiments. It was shown that concentration of chitosan and tripolyphosphate, as well as, drug:polymer weight ratio had significant effects on drug entrapment and brilliant blue release from the beads. Moreover, decreasing drug solubility in the external phase has caused a significant increase in drug loading. Release data was studied kinetically and the drug release from chitosan beads was indicated to be a non-Fickian transport. It seemed that diffusion and/or relaxation of the polymer chains controlled the transport, γ-scintigraphy has shown that the gastric emptying of the enteric-coated capsule containing chitosan beads occurred at 37 ± 10 min under fasting condition. Small intestinal transit time in men was determined to be 228 ± 35 min; subsequently, the arrival time in the colon was 266 ± 41 min on average post-administration.
Journal of Drug Delivery Science and Technology 09/2005; 15(5):383-387. · 0.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chitosan exhibits favorable biological properties such as no toxicity, biocompatibility and biodegradability; therefore, it has attracted great attention in both pharmaceutical and biomedical fields. Chitosan exhibits poor solubility at pH values above 6 that prevents enhancing effects at the sites of absorption of drugs. In the present work, N-diethyl methyl chitosan (DEMC) was prepared and the enhancing effect of this polymer was investigated. Ex vivo studies have shown a significant increase in absorption of brilliant blue in the presence of diethyl methyl chitosan in comparison with chitosan. DEMC with positive charges is able to interact with tight junctions of colon epithelial cells and hence increases permeability of brilliant blue across the tight junctions. In vivo investigations have exhibited the absorption enhancer effects of DEMC on the colon absorption of insulin in normal and diabetic rats. The insulin absorption from the rat's colon was evaluated by its hypoglycemic effect. A significant decrease in blood glucose was observed, when mixture of insulin and DEMC was introduced in ascending colon of rats.
International Journal of Pharmaceutics 05/2005; 293(1-2):83-9. DOI:10.1016/j.ijpharm.2004.12.016 · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In previous studies, it was established that chitosan and its quaternized derivatives are potent enhancers of hydrophilic compounds absorption across intestinal epithelia. The aim of this study was to evaluate the application of a new quaternized chitosan, triethyl chitosan (TEC), in pharmaceutical approaches. TEC was synthesized by a one step process via a 2(2) factorial design to optimize the preparation conditions. In ex vivo experiments, everted rat colon sac was used to determine the effect of TEC on the penetration of hydrophilic compounds of different molecular masses (e.g., sodium fluorescein and brilliant blue) through colonic epithelia in comparison with chitosan at pH 7.4. These studies indicated a significant increase in absorption of sodium fluorescein and brilliant blue in the presence of TEC compared to chitosan. TEC bearing positive charge is able to interact with the tight junctions of colon epithelia and hence increase the permeation of sodium fluorescein and brilliant blue through the tight junctions. This investigation has shown that triethyl chitosan could be used as a penetration enhancer for poorly absorbable compounds in the colon drug delivery system.
[Show abstract][Hide abstract] ABSTRACT: Chitosan exhibits poor solubility above pH 6 which prevents absorption at treatment sites in the colon. pH titrations and infrared methods were used to determine the degree of deacetylation of the starting chitosan. In the present work, N,N-diethyl N-methyl chitosan (DEMC) was synthesized based on a modified two-step process via a 22 factorial design to optimize the preparative conditions. DEMC chloride was characterized using FTIR and 1H NMR spectroscopy. For pharmacological and pharmaceutical applications, DEMC needs to have specific degrees of quaternization. Based on the 1H NMR data, a high degree of quaternization was achieved by the two-step process. The N-diethyl methyl chitosan chlorides were completely soluble in water at room temperature. Sodium fluorescein and brilliant blue were used as model reagents for in vitro colonic absorption studies. These studies show a significant increase in the absorption of sodium fluorescein and brilliant blue in the presence of DEMC in comparison with normal chitosan. DEMC with positive charge is able to interact with tight junctions of colon epithelial cells and hence increased the permeability of sodium fluorescein and brilliant blue across the tight junctions. These investigations demonstrated that the DEMC derivative of chitosan could have a significant effect on colonic drug absorption.
Journal of Bioactive and Compatible Polymers 09/2004; 19(5):421-433. DOI:10.1177/0883911504046679 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chitosan with excellent biodegradable and biocompatible characteristics has received attention as an oral drug delivery vehicle. A quaternized chitosan (i.e., N-diethylmethyl chitosan, DEMC) was prepared based on a modified two-step process via a 22 factorial design to optimize the preparative conditions. DEMC was fully characterized using FTIR and 1H-NMR spectroscopies. As calculated using NMR-based data, high degree of quaternization was achieved through the optimized two-step process. The highly quaternized biopolymeric derivative was subjected to microbial experiments. The antimicrobial activities of chitosan and DEMC against Escherchia coli were compared by calculation of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Our data indicates that although the antimicrobial activity of DEMC is higher than that of chitosan in acetic acid medium, the both compounds are pH dependent and an increase in concentration of acetic acid results in a significant decrease in both MIC and MBC.
European Polymer Journal 07/2004; 40(7-40):1355-1361. DOI:10.1016/j.eurpolymj.2004.02.015 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In previous studies, it was established that chitosan and its quaternized derivatives are potent enhancers of hydrophilic compounds absorption across intestinal epithelia. The aim of this study was to evaluate the application of a new quaternized chitosan, triethyl chitosan (TEC), in pharmaceutical approaches. TEC was synthesized by a one step process via a 22 factorial design to optimize the preparation conditions. In ex vivo experiments, everted rat colon sac was used to determine the effect of TEC on the penetration of hydrophilic compounds of different molecular masses (e.g., sodium fluorescein and brilliant blue) through colonic epithelia in comparison with chitosan at pH 7.4. These studies indicated a significant increase in absorption of sodium fluorescein and brilliant blue in the presence of TEC compared to chitosan. TEC bearing positive charge is able to interact with the tight junctions of colon epithelia and hence increase the permeation of sodium fluorescein and brilliant blue through the tight junctions. This investigation has shown that triethyl chitosan could be used as a penetration enhancer for poorly absorbable compounds in the colon drug delivery system.
[Show abstract][Hide abstract] ABSTRACT: Chitosan exhibits poor solubility at pH values above 6 which prevents its enhancing effects at drugs absorption of sites. In the present work, N-triethylated chitosan (TEC) was prepared based on a modified one-step process via a 22 factorial design to optimize the preparative conditions. TEC polymer with different degree of quaternization for pharmacological and pharmaceutical experiments was achieved. Ethyl iodide and sodium hydroxide concentrations were chosen as independent variables. The degree of deacetylation of the starting chitosan was predetermined by pH-metric titration, infrared, and NMR methods. TEC chloride was fully characterized using FTIR and 1H-NMR spectroscopies. Based on NMR calculations, a high degree of quaternization was achieved through the optimized one-step process. These highly N-triethylated chitosan chlorides were soluble in water at room temperature.
Journal of Bioactive and Compatible Polymers 11/2003; 18(6):469-479. DOI:10.1177/0883911503040432 · 2.35 Impact Factor