Omaima N. El-Gazayerly

Fluconazole mucoadhesive buccal films: in vitro/in vivo performance.

Fluconazole mucoadhesive buccal films were prepared using film forming polymers namely; hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), chitosan, Eudragit and sodium alginate (SALG) either alone or in combination with bioadhesive polymers. The bioadhesive polymers studied were sodium carboxymethyl cellulose (SCMC), Carbopol 974P, and polycarbophil (AA-A). The prepared films were characterized by means of film thickness, surface pH, swelling capacity, in vitro adhesion, in vivo residence time, in vitro drug release and in vivo drug release to determine the amount of drug release from selected film formulae using microbiological assay and HPLC. Optimum release behavior, convenient bioadhesion, acceptable elasticity were exhibited by film containing 2% HPMC and 1% SCMC (fresh or stored for 6 months). Determination of the amount of drug released in saliva after application of the selected fluconazole films confirmed the ability of the film to deliver the drug over a period of approximately 300 minutes and to reduce side effects and possibility of drug interaction encountered during systemic therapy of fluconazole, which would be beneficial in the case of oral candidiasis.

Characterization and evaluation of tenoxicam coprecipitates.

Tenoxicam is a nonsteroidal anti-inflammatory drug belonging to the oxicam group. The drug is slightly soluble in water. In a trial to increase its dissolution, different commonly used excipients were selected to prepare coprecipitates with tenoxicam. The coprecipitates were prepared using the solvent evaporation method, and the ratio used was 1:3 drug to additive. The prepared coprecipitates were subjected to a dissolution study, and they were characterized using infrared (IR) and differential scanning calorimetry (DSC) techniques. Dissolution profiles of most of the prepared coprecipitates demonstrated higher dissolution than pure tenoxicam. The characteristic peaks of tenoxicam in the IR spectrum disappeared in the spectra of all the prepared coprecipitates except those prepared with sodium chloride, for which the IR spectrum was identical to that of the pure drug. The characteristic peaks of tenoxicam disappeared in the DSC thermograms of the coprecipitates under study, indicating a change in structure from pure tenoxicam. Characterization of the coprecipitates by IR and DSC techniques revealed structural changes in the prepared coprecipitates from the plain drug, which may account for increased dissolution rates.

Effect of formulation design and freeze-drying on properties of fluconazole multilamellar liposomes.

Fluconazole-entrapped multilamellar liposomes were prepared using the thin-film hydration method. The effects of cholesterol molar ratio, charge-inducing agents, and α-tocopherol acetate on encapsulation efficiency values and in vitro drug release of multilamellar liposomes were studied. Freeze-dried liposomal products were prepared with or without cryoprotectants. Results showed that incorporation of stearylamine resulted in an increased entrapment of fluconazole, whereas incorporation of dicetyl phosphate decreased the drug entrapment efficiency. The incorporation of α-tocopherol acetate into fluconazole multilamellar liposomes resulted in the increase of entrapment efficiency of fluconazole liposomes. In vitro release studies revealed that incorporation of cholesterol into multilamellar liposomal formulations decreased drug permeability from formulations. Positively charged fluconazole multilamellar liposomes gave rise to a slow release rate compared to neutral liposomes whereas negatively charged fluconazole liposomes showed a rapid release rate. Physical stability studies showed that lyophilized cake of liposomes without cryoprotectants was compact and difficult to reconstitute compared to fluffy easily reconstituted cakes upon using cryoprotectants. Fluconazole retained in freeze-dried liposomes without cryoprotectants was 63.452% compared to 91.877% using three grams of trehalose as a cryoprotectant per gram lipid in positively charged multilamellar liposomes. Physical stability studies showed superior potentials of the lyophilized product after reconstitution in comparison with those of a solution product.

Chitosan lactate wafer as a platform for the buccal delivery of tizanidine HCl: in vitro and in vivo performance.

Tizanidine HCl is a skeletal muscle relaxant that suffers from extensive hepatic metabolism resulting in 34-40% oral bioavailability. It also suffers from short half-life (2.1-4.2h) that necessitates frequent administration thus reducing patient compliance. In addition, tizanidine HCl is water soluble, so it is a challenging candidate for controlled drug delivery. In our study, tizanidine was encapsulated in chitosan lactate beads cross-linked with sodium tripolyphosphate. The beads were further incorporated into chitosan lactate wafer to be easily applied to buccal mucosa, aiming to bypass the hepatic metabolism. A central composite face-centered design was applied to statistically optimize the formulation variables; tripolyphosphate concentration, chitosan lactate concentration and polymer/drug ratio. The optimized formula suggested by the software composed of; 3.03% tripolyphosphate, 4.92% chitosan lactate and 2.13 polymer/drug ratio. It provided encapsulation efficiency of 56.5% and controlled tizanidine release over 8h. It is also characterized by being mucoadhesive and nonirritant. Pharmacokinetic parameters of tizanidine from the optimized formula were compared to those of the immediate release tablet, Sirdalud(®), as reference in human volunteers using a randomized crossover design. Significant increase was observed for Tmax and AUC(0-∞). The increase in relative bioavailability of TIZ from the optimized formula was 2.27 fold.

Release of Pentoxifylline from Xanthan Gum Matrix Tablets

Abstract Pentoxifylline-controlled release tablets were prepared using xanthan gum. The effects of polymer concentration, rotation speed, ionic strength, and pH of the dissolution medium on the release of the water-soluble pentoxifylline were studied. The release rate decreased with increasing polymer concentration in the tablet, which was reflected in the increase in the mean dissolution time. A higher rotation speed and increased ionic strength of the dissolution medium resulted in a higher rate of drug release of xanthan-based tablets. A higher release rate of pentoxifylline was also observed using acidic dissolution medium.

REVERSED PHASE LIQUID CHROMATOGRAPHIC DETERMINATION OF VINPOCETINE IN HUMAN PLASMA AND ITS PHARMACOKINETIC APPLICATION

ABSTRACT A simple, rapid specific and reliable high performance liquid chromatographic assay of vinpocetine in human plasma has been developed. Reversed phase chromatography was conducted using a mobile phase of methanol : water (80 : 20 v/v), containing 0.1% triethylamine, pH 7, adjusted with glacial acetic acid. The flow rate was 2 mL/min, UV detection at 274 nm. The drug after extraction from plasma was chromatographed using a C18 reversed–phase column. The average recoveries of vinpocetine from spiked plasma in the concentration range from (0.01–0.1) µg/mL was 91.83% and the coefficient of variation was 3.03%. Regression analysis for the calibration plot for plasma standards obtained on three different days for the drug concentrations between (0.01–0.1) µg/mL indicated excellent linearity (r>0.999) and the coefficient of variation of the slopes of the three lines was <2%. Analysis of variance of the data showed no detectable difference in the slopes of the three standard plots (F = 3.2, P>0.01). The high correlation coefficients and the similarities in the slopes are good indication of the excellent reproducibility and linearity of the proposed method. The proposed method was applied to study the bioequivalence of a commercial product of vinpocetine using as reference standard the innovator drug product. The study was conducted on using two tablets (2 × 5 mg) of each of the commercial product and the reference standard in a two way open randomized crossover design involving twenty four volunteers. The criteria used to assess bioequivalence of the products were AUC (0–∞), C max, t max, t 1/2 and K. The obtained values for these parameters were 519.8 ± 8.2 ng h/mL, 64.3 ± 1.6 ng/mL, 1.5 h, 2.09 ± 0.27 h and 0.34 ± 0.04 h−1 for product A whereas, for product B they were, 514.6 ± 10.7 ng h/mL, 63.5 ± 1.3 ng/mL, 1.5 h, 2.2 ± 0.35 h and 0.32 ± 0.04 h−1 respectively.

Rapidly absorbed orodispersible tablet containing molecularly dispersed felodipine for management of hypertensive crisis: Development, optimization and in vitro/in vivo studies

A liquisolid orodispersible tablet of felodipine, a BCS Class II drug, was developed to improve drug dissolution and absorption through the buccal mucosa for management of hypertensive crisis. A 24 full-factorial design was applied to optimize felodipine liquisolid systems (FLSs) having acceptable flow properties and possessing enhanced drug dissolution rates. Four formulation variables; The liquid type, X1 (PG or PEG), drug concentration, X2 (10% and 20%), type of coat, X3 (Aerosil® and Aeroperl®) and excipients ratio, X4 (10 and 20) were included in the design. The systems were assessed for dissolution and flow properties. Following optimization, the formulation components (X1, X2, X3 and X4) were PEG, 10%, Aerosil® and 20, respectively. The optimized FLS was compressed into felodipine liquisolid orodispersible tablet using Prosolv® as carrier material (FLODT-2). The in vitro and in vivo disintegration times of FLODT-2 were 9 and 7 s, respectively. The in vivo pharmacokinetic study using human volunteers showed a significant increase in dissolution and absorption rates of the formulation of FLODT-2 compared to soft gelatin capsules filled with felodipine solution in PEG under the same conditions. Our results proposed that the optimized FLODT formulation could be promising to manage hypertensive crisis.

Novel Chewable Sustained‐Release Tablet Containing Verapamil Hydrochloride

The aim of this research is to produce a compactable self‐sealing chewable tablet of verapamil hydrochloride. Tablets were prepared by compressing beads coated with multiple layers including drug, hydroxypropyl methylcellulose, polyethylene oxide, ethylcellulose, lactose, and sodium starch glycolate. Dissolution studies were carried out according to the USP XXII paddle method for 14 h. A new tablet formulation was evaluated in three different forms: 1) whole tablet, 2) crushed tablet using a commercial tablet crusher, and 3) tablet chewed in the mouth and then expelled into dissolution fluid. Sustained release from the new formulation was maintained and was similar in all three different treatments, and similar to drug release from intact commercially available Isoptin SR®, but crushing or chewing destroyed the sustained release property of Isoptin SR® (as expected). This new formulation can be administered either by swallowing the whole tablet or by first crushing or chewing the tablet. Controlled release properties of this new formulation do not change by chewing or crushing the tablet first. Such a tablet could be valuable for all patients including those who have difficulty swallowing, such as pediatrics and geriatrics.

Novel non-ionic surfactant proniosomes for transdermal delivery of lacidipine: optimization using 23 factorial design and in vivo evaluation in rabbits

Abstract Context: Proniosomes offer a versatile vesicle drug delivery concept with potential for delivery of drugs via transdermal route. Objectives: To develop proniosomal gel using cremophor RH 40 as non-ionic surfactant containing the antihypertensive drug lacidipine for transdermal delivery so as to avoid its extensive first pass metabolism and to improve its permeation through the skin. Materials and methods: Proniosomes containing 1% lacidipine were prepared by the coacervation phase separation method, characterized, and optimized using a 23 full factorial design to define the optimum conditions to produce proniosomes with high entrapment efficiency, minimal vesicle size, and high-percentage release efficiency. The amount of cholesterol (X1), the amount of soya lecithin (X2), and the amount of cremophor RH 40 (X3) were selected as three independent variables. Results and discussion: The system F4 was found to fulfill the maximum requisite of an optimum system because it had minimum vesicle size, maximum EE, maximum release efficiency, and maximum desirability. The optimized system (F4) was then converted to proniosomal gel using carbopol 940 (1% w/w). In vitro permeation through excised rabbit skin study revealed higher flux (6.48 ± 0.45) for lacidipine from the optimized proniosomal gel when compared with the corresponding emulgel (3.04 ± 0.13) mg/cm2/h. The optimized formulation was evaluated for its bioavailability compared with commercial product. Statistical analysis revealed significant increase in AUC (0 − α) 464.17 ± 113.15 ng h/ml compared with 209.02 ± 47.35 ng h/ml for commercial tablet. Skin irritancy and histopathological investigation of rat skin revealed its safety. Conclusions: Cremophor RH 40 proniosomal gel could be considered as very promising nanocarriers for transdermal delivery of lacidipine.

Ultrahigh antibacterial efficacy of meropenem-loaded chitosan nanoparticles in a septic animal model

Antimicrobial resistance is one of the most significant health challenges worldwide. Meropenem is a broad spectrum beta-lactam antibiotic that possesses high activity against Gram-positive and Gram-negative bacteria. However, it has a short plasma half-life, and thus requiring frequent administration of high doses. For the first time, meropenem-loaded chitosan nanoparticles were prepared and evaluated as a potential tool to overcome antimicrobial resistance and to improve pharmacokinetics of the drug. Spherical nanosized particles were prepared and demonstrated ultrahigh encapsulation efficiency of meropenem (i.e. 76.3%). The nanoparticles could be stored in a freeze-dried powdered form while maintaining their physicochemical characteristics. In vitro, higher antibacterial activities of the drug-loaded nanoparticles were observed against methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, as compared to the free drug. The nanoparticles were then tested in a septic rat model of Klebsiella pneumoniae and showed exceptional improvement of survival and bacterial clearance, as compared to the animals treated with the free drug. Hence, meropenem-loaded chitosan nanoparticles might have great potential for overcoming antimicrobial resistance.