Gamal M. Mahrous

Preparation and evaluation of sustained release cross-linked chitosan microspheres containing phenobarbitone

Chitosan microspheres containing phenobarbitone were successfully prepared by glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in light liquid paraffin containing sorbitan mono-oleate as a stabilizing agent. Uniform and spherical microspheres, with a loading efficiency up to 57.2%, could be prepared depending on the preparation conditions. The main parameters affecting the preparation and the performance of the prepared microspheres were the molecular weight and concentration of chitosan as well as the concentration of the used stabilizing agent. The incorporation of citric acid into the microspheres was found to increase the formation of a water-soluble gel when the microspheres come in contact with the dissolution medium increasing the rate of drug release. The particle size was shifted towards smaller diameters with increased concentration of sorbitan mono-oleate, up to 4.0% v/v, by use of a lower concentration of chitosan (1.0% w/v) and chitosan with low molecular weight. Rapid initial drug release (20-30% of the incorporated drug) was exhibited in all the prepared microspheres followed by slow release of the remaining amount of the drug. The release rate of the drug from the microspheres prepared from high molecular weight chitosan was slow in comparison with that prepared from medium and low molecular weight chitosan. High concentrations of sorbitan mono-oleate increased the rate of drug release.

The use of spray-drying to enhance celecoxib solubility

The present research investigates the enhancement of the dissolution rate of celecoxib by using spray-drying to prepare a solid dispersion with various polymers, namely Kollicoat IR® (Kollicoat), polyvinyl alcohol (PVA) 22000, or polyethylene glycol 6000 (PEG). The investigated drug-to-polymer mass ratios were 1:1, 1:2, and 1:4 by weight. Hydroalcoholic or methylene chloride solvent systems were used. The obtained yields ranged from 65% to 78%, whereas the entrapment efficiencies were between 68% and 82%. The results revealed an increase in the dissolution rate of the prepared particles up to 200% within 20 min. The prepared particles were investigated using differential scanning calorimetry, scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The increased dissolution rate was attributed to hydrogen bond formation between celecoxib and each polymer together with the reduced size of the formed particles offering a greater overall surface area. It was concluded that spray-drying may be considered a successful one-step technique to improve the dissolution rate of celecoxib when using Kollicoat, PVA, or PEG as the carrier polymer.

Mucoadhesive Polymeric Hydrogels for Nasal Delivery of Acyclovir

The study evaluated different mucoadhesive polymeric hydrogels for nasal delivery of acyclovir. Gels containing poly-N-vinyl-2-pyrrolidone (PVP) were prepared with crosslinking achieved by irradiation with a radiation dose of 15 kGy being as efficient as 20 kGy. Gels containing chitosan and carbopol were also evaluated. The mucoadhesive properties of gels were measured by a modification of a classical tensile experiment, employing a tensile tester and using freshly excised sheep nasal mucosa. Considering the mucoadhesive force, chitosan gel and gel prepared with 3% PVP in presence of polyethylene glycol (PEG) 600 were the most efficient. The in vitro drug release depended on the gel composition. Higher release rates were obtained from PVP gels compared to chitosan or carbopol gels. The release rate of drug from PVP gels was increased further in presence of PEG or glycerol. Histopathological investigations proved that the PVP was a safe hydrogel to be used for mucosal delivery. The PEG in gel formulations caused less damages to the nasal mucosal compared to formulation containing glycerol.

Sensitive High-Performance Liquid Chromatographic Determination of Mebeverine in Plasma Using Fluorescence Detection

Abstract A sensitive high-performance liquid chromatographic (HPLC) method for mebeverine (MB) determination in plasma is described. Sample preparation involves extraction of MB and Ibuprofen (internal standard) from 0.5 ml plasma. The analysis is carried out on reversed-phase chromatographic system using U-Bondapack C18 column with a mobile phase consisting of water: acetonitrile:acetic acid (59:40:1) mixture. The effluent was monitored using a fluoremetric detection at excitation and emission wave lengths 270 and 362 nm, respectively. The method gave accurate, precise and reproducible results with high sensitivity. The within-day coefficients of variation ranged from 2.5 to 6.1% and between-days from 7.5 to 13.5% at four different concentrations. Injection-volumes containing as small amount of MB as 0.5 ng in plasma was detected. This method was applied to a bioavailability study with a single 10 mg/kg oral dose in two rabbits.

Effects of Kollicoat IR and hydroxypropyl-beta-cyclodextrin on the dissolution rate of omeprazole from its microparticles and enteric-coated capsules.

Omeprazole microparticles were prepared by different drying techniques using Kollicoat IR® and hydroxypropyl-β-cyclodextrin hydrophilic polymers. Physico-chemical properties were investigated using differential scanning calorimetry and powder X-ray diffractometry. Dissolution rate was determined and compared to the physical mixtures and the morphology was studied using a scanning electron microscope. Omeprazole transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the characteristic of the crystalline peaks. Omeprazole dissolution rate was enhanced significantly from its spray- and freeze-dried microparticles as compared to the corresponding physical mixtures and drug alone (P < 0.05). F3 and F5 formula possessed superior release rate over other formulations. In acidic medium, the release of drug from enteric-coated capsules was not detectable, while it is completely released within 40 min after changing dissolution medium to phosphate buffer (pH 7.4). The transformation of OME from crystalline to amorphous state by using either Kollicoat IR® or hydroxylpropyl-β-cyclodextrin is considered a promising way to improvement of drug dissolution.

Effect of sucralafate and antacids on the bioavailability of sulpride in humans

The effect of two anti-ulcer drugs, sucralafate and an antacid, containing aluminum and magnesium hydroxide on the bioavailability of another anti-ulcer drug, sulpride, was studied. Using a latin-square design, six healthy male volunteers participated in the trials. Concomitant administration of the antacid or sucralafate with sulpride significantly (ANOVA, P < 0.01) reduced its extent of bioavailability, as measured by total urinary excretion in 48 h. A therapeutic dose of sucralafate decreased the oral bioavailability from 31 ± 8.4% to 18.6 ± 4.4%, a 40% reduction. A therapeutic dose of the antacid decreased the oral bioavailability from 31 ± 8.4 to 20.9 ± 4.5%, a 32% reduction. There was no change in the rate of urinary excretion and hence no change in biological half-life of sulpride. When the antacid or sucralafate were given 2 h before sulpride, the extent of bioavailability reduction was about 25%. The interaction between sulpride and the other two anti-ulcer drugs is thought to be due to binding or complexation resulting in interference with the gastrointestinal absorption of sulpride. This interaction is expected to be clinically significant and it is recommended that if these drugs are used concurrently, sulpride should be given 2 h before and not with or after the antacid or sucralafate.

Preparation and Evaluation of Sustained release Indomethacin Nonpareil Seeds

AbstractA controlled release oral drug delivery system of Indomethacin was developed using nonpareil seeds as a matrix system. These seeds were coated with different concentrations of drug release controlling materials viz Eudragit RL100 and Eudragit RS100, and bees wax. The particle size of the seeds and the concentration as well as the type of the drug release controlling Eudragits has a pronounced effect on the release rate profile of Indomethacin. All types of formulations showed release rate pattern which can be described by both first-order and diffusion controlled mechanism.

Indomethacin sustained release pellets prepared by extrusion-spheronization

Gastrointestinal side effects may interrupt essential therapy with indomethacin, a non-steroidal anti-inflammatory drug. Formulation of this drug into sustained release multiparticulate form may reduce some of these side effects by avoiding contact of drug crystals with gastrointestinal mucosa at high concentrations, as may happen with immediate release dosage forms. Indomethacin (IM) sustained release pellets containing 5 or 10 % w/w of the drug were prepared using an extrusion-spheronization technique. Different concentrations of hydrophilic polymers, polyethylene glycol 4000 (PEG 4000), hydroxypropyl methylcellulose E5 LV premium (HPMC) and polyvinyl pyrrolidone (PVP K30), were mixed at different concentrations (5,10 and 20 %) with Avicel PH 101 to prepare the sustained release formulae. Moreover, a mixer torque rheometer was used to quantitatively determine the suitable moisture content in the pastes before the extrusion process. The resulting pellets were characterized for content, particle size, shape and dissolution profile. The studies on the effect of the polymers used on Avicel rheological properties revealed that the magnitude of torque for the system was decreasing as the polymer concentration increased. The in vitro release of IM from the prepared Avicel pellets was found to be dependent upon the type and concentration of the added polymer. The rank order of IM release in the presence of the investigated polymers was as follows: PEG > HPMC > PVP. Furthermore, the magnitude of IM release rate from the pellet formulations was found to be dependent on the magnitude of the peak torque of the pellet forming paste, which in turn depends on the type and concentration of the added polymer. Increasing IM loading from 5 to 10 % has led to an increase in dissolution rates. At least two of the prepared pellet formulations showed dissolution profiles similar to the commercial product Bonidon 75 SR capsules. In conclusion, the formulation of IM sustained release pellets successfully controlled the drug release which might be beneficial in lowering the risk of side effects and improving patient convenience as an advantage of the pellets as a drug delivery system.

A SENSITIVE HIGH‐PERFORMANCE LIQUID CHROMATOGRAPHIC ANALYSIS OF PROPRANOLOL IN SERUM

A rapid and sensitive high‐performance liquid chromatographic (HPLC) assay was developed for quantitative determination of propranolol in serum. The assay is performed after single extraction of propranolol and indenolol [internal standard (IS)] from alkalinized serum into ether and eluted from C‐18 U Bondapak column with a mobile phase composed of methanol: 0·01 M phosphate buffer pH 3·4 (40:60%, v/v). The column eluant was monitored on a fluorescence detector. Measurement was achieved by taking the peak height ratio of propranolol and comparing it to that of the IS. The detection limit for propranolol in serum is 2·5 ng/ml. Intraday coefficients of variation (CV) ranged from 2·84 to 4·0% and interday (CVs) from 5·8 to 8·4% at three different concentrations. The relative and absolute recoveries varied from 93·8 to 102·3%. Preliminary stability tests showed that propranolol is stable for at least 3 weeks in serum after freezing. The method is applied for the determination of the pharmacokinetic parameters of propranolol after intravenous administration (1 mg/kg) to rabbits.

Effects of fenugreek, garden cress, and black seed on theophylline pharmacokinetics in beagle dogs

Abstract Context: Herb–drug interactions are a serious problem especially for drugs with a narrow therapeutic index, taking into consideration that herbal medicines are commonly used in various parts of the world. Objective: The present study investigates the effect of fenugreek, garden cress, and black seed on the pharmacokinetics of theophylline in beagle dogs. Materials and methods: Beagle dogs received theophylline (200 mg) orally and blood samples were withdrawn at different time intervals (0.33, 0.66, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24, and 30 h). After a suitable washout period, each herb was given orally at doses of 25, 7.5, and 2.5 g, twice daily for 7 d. On the eighth day, theophylline was re-administrated orally and blood samples were collected. Plasma concentrations of theophylline were determined using HPLC and pharmacokinetic parameters were calculated using a non-compartmental analysis. Results: Treatment with fenugreek (25 g, orally) lead to a decrease in Cmax and AUC0–t of theophylline of about 28% (p < 0.05) and 22% (p < 0.05), respectively, with no significant changes in T1/2λ compared with the baseline values. Garden cress caused a decrease in Cmax to a lesser extent and delayed Tmax of theophylline (2.10 ± 0.24 h versus 3.40 ± 0.74 h), while AUC0–∞ increased by 37.44%. No significant effect was observed for the black seed treatment on theophylline disposition as measured by Cmax, Tmax, AUC0–∞, and CL/F. Discussion and conclusion: The concurrent use of fenugreek or garden cress alters theophylline pharmacokinetic behavior in an animal model. This could represent a modulation in cytochrome P450 activity, which is responsible for theophylline metabolism in beagle dogs. Further confirmation of these results in humans will warrant changes in theophylline dosing before the co-administration of such herbs.