A. A. Al-Angary

Effect of inclusion complexation with cyclodextrins on photostability of nifedipine in solid state.

Nifedipine is a highly photosensitive drug that requires restricted protection from light during manufacturing, storage and handling of its dosage forms. Inclusion complexation of nifedipine with cyclodextrins (CDs) could be advantageous in protecting the drug against the effect of light. In this study, solid inclusion complexes of nifedipine with beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and dimethyl-beta-cyclodextrin (DM-beta-CD) were prepared using the coprecipitation method. The obtained solid inclusion complexes have been confirmed by differential scanning calorimetry (DSC), X-ray diffraction and infrared spectroscopy (IR). The IR spectra indicated partial inclusion of nifedipine molecules into CD cavities through the dihydropyridine ring. Inclusion complexation was also associated with a dramatic enhancement of drug dissolution with magnitudes depended on the type of CD. The effect of exposure to fluorescent lamp and sunlight on the photodegradation of uncomplexed and complexed nifedipine was tested. Photodegradation of nifedipine was monitored using a high performance liquid chromatographic (HPLC) assay method. Inclusion complexation of nifedipine showed to retard drug photodegradation as indicated by degradation rate constant lowering with values depended on light source and type of complexing agent. This effect was the least with beta-CD compared with that of modified beta-CD. It was also interesting to notice that inclusion complexation of nifedipine offered much higher protection against the effect of fluorescent lamp than that of sunlight. The obtained results suggests that the design of solid dosage forms of nifedipine such as a fast dissolving nifedipine tablets is possible with the advantages of low required light protection.

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.

Oral administration of liposomes containing cyclosporine: a pharmacokinetic study

Abstract Liposomal formulation containing cyclosporine A (CSA) were prepared. The most stable liposomes with the composition of CSA, dipalmitoylphosphatidyl choline (DPPC) and cholesterol (Chol.) in molar ratio 1:0.2:1, respectively were administered orally to New Zealand rabbits. The pharmacokinetic of the administered CSA was compared with that of the commercially available oily oral formulation of CSA (Sandimmune) at dose of 15 mg/kg. Cyclosporine concentration in blood was monitored using a radioimmunoassay method (RIA). A change in the pharmacokinetic parameters of CSA due to liposomal encapsulation was observed. A peak concentration was reached in 50 min in case of liposomes compared with 225 min in case of Sandimmune. The rate of absorption ( C max /AUC 0–∞ ) was significantly faster following the liposome administration. A significant difference in the area under the concentration curve (AUC 0–∞ ) was found and this was attributed to the difference in the terminal half-lives ( t 1/2 β ) which were 8.88±1.94 and 19.3±8.48 h for liposomes and Sandimmune preparations, respectively. The mean residence time (MRT) and the mean absorption time (MAT) were dramatically decreased following the administration of liposomal formulation. Generally, there was less inter-individual variation in the values of rate of absorption, t 1/2 β and MRT when CSA liposomes were orally administered compared to the administration of Sandimmune. Thus, an oral liposomal formulation for CSA can be developed to offer the advantages of low variability and fast onset of action.

In vivo evaluation of arteether liposomes

Abstract Arteether is a potent antimalarial agent that is available as oily solution intended for intramuscular injection. Liposomal formulation composed of dipalmitoylphosphatidylcholine (DPPC), dibehynoyl-phosphatidylcholine (DBPC), cholesterol and arteether in the molar ratio of 1:1:2:1 was chosen for in vivo evaluation. This composition was found to give stable liposomes compared with other formulations and it gave 67.56% trapping efficiency and particle size of 3.21±0.76 μ m. The liposomes were administered orally and intravenously to New Zealand rabbits at a dose of 50 mg/kg. The pharmacokinetic parameters following drug administration were determined in each case. Pharmacokinetic parameters after oral administration of liposomes were compared with those of oral aqueous suspension of micronized arteether. High bioavailability of arteether was evident in case of oral liposomes where faster rate and better absorption of arteether were observed compared with aqueous suspension. Oral liposomes gave higher C max and shorter T max as well as a higher value for AUC. Almost complete arteether absorption was observed for oral liposomes where relative bioavailability was 97.91% compared with 31.83% for the oral suspension. Intersubject variations were found to be relatively high in oral liposomes. The obtained values for mean residence time (MRT) and mean absorption time (MAT) indicated that arteether remains longer in gastrointestinal tract (GIT) with longer time period for absorption in case of suspension compared with liposomal formulation. In addition, arteether was successfully administered intravenously in liposomal formulations and showed longer elimination half-life with respect to other artemisinin derivatives. Thus an optimum oral liposomal formulation for arteether can be developed for fast and complete absorption of the drug from GIT. Furthermore, liposomal formulation of arteether could allow for intravenous administration of the drug in high-risk malaria patients with long duration of effect.

Characterization, stability and in vivo targeting of liposomal formulations containing cyclosporin

Abstract Cyclosporin A (CSA) is a potent immunosuppressive drug that was recently encapsulated into different liposomal formulations. Optimization of CSA formulated liposomes preparation was the goal of this study. Liposomes composed of dipalmitylphosphatidylcholine (DPPC) containing CSA were prepared and characterized by differential scanning calorimetry (DSC). In vitro characterization of the formulated model liposomes including the entrapment efficiency and stability in the presence of mono- and divalent ions at different temperatures (5, 21, 37°C) and in the absence and presence of cholesterol (Chol) was carried out. Furthermore, in vivo targeting of CSA to mouse livers from liposomal preparations was investigated and compared with a non-liposomal formulation. A slight decrease in transition temperature (Tm) of the liposomes formed was noted with increase in CSA content. Entrapment of CSA in the liposomal vesicles was found to be dependent to some extent on the Chol level. The release rate of CSA from liposomes was enhanced in the presence of the divalent ions, Ca2+ and Mg2+ indicating low stability in the presence of these ions compared with Na+. The release rate was affected by storage temperature and depended on the existence of Chol. In the absence of Chol, the release rate decreased with increasing temperature. On the other hand, in the presence of Chol, the rate of release was directly proportional to the temperature. In vivo study showed that a higher CSA content which lasted for more than 11 days was achieved in mouse livers from liposomal compared with non-liposomal preparations.

Evaluation of liposomal formulations containing the antimalarial agent, arteether

Different liposomal formulations containing arteether have been prepared, using the phospholipids, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), egg phosphatidylcholine (EPC) or dibenhenoyl phosphatidylcholine (DBPC), alone or in mixtures. The effect of presence of arteether on the liposomal physico-chemical characteristics has been investigated. Arteether was found to change the thermotropic behavior of the liposomal phospholipids that contain a saturated acyl chain such as DMPC and DPPC. On the other hand, arteether did not significantly change the thermotropic behavior of EPC liposomes that contain unsaturated phospholipids. The type of the phospholipid as well as the incorporation of cholesterol in the liposomal bilayer was found to alter the trapping efficiency, liposomal particle size and drug release rate from the liposomes. The trapping of arteether in liposomal vesicles was increased by increasing the acyl chain length of the phospholipid and by addition of cholesterol. EPC liposomes exhibited relatively low trapping efficiency, due to high drug adsorption. Interestingly, liposomal particle size showed a decrease with the increase of acyl chain length in the presence of large molecules of arteether. Incorporation of cholesterol in the liposomal bilayer did not alter the liposomal particle size although it gave lower particle size and distribution. The release of arteether from the liposomal system was characterized by a fast phase for 2 days, followed by a slower phase. The fast phase was the highest with EPC liposomes, indicating the release of the adsorbed drug. Generally, the increase of the acyl chain length as well as the addition of cholesterol caused a decrease in the arteether release rate.

Bioavailability of sustained release indomethacin suppositories containing polycarbophil

The bioavailability of indomethacin from polyethylene glycol base, commercial suppositories Indocid∗, MSD and from polyethylene glycol base containing 5, 6 and 8% of polycarbophil, with the purpose of obtaining a controlled release suppositories, was determined in dogs. The results show that polycarbophil as a bioadhesive increased absorption and improved the bioavailability of indomethacin where the areas under the curves for the commercial suppositories and those containing 0, 5, 6 and 8% polycarbophil were 19.5, 14.9, 31.2, 21.4 and 21.2 μ h ml−1, respectively. The maximum plasma concentration (Cmax) and the time to reach Cmax (tmax) were 4.76, 2.98, 4.50, 2.36 and 1.29 μg/ml and 1, 1, 1, 1 and 12 h for the commercial suppositories and those containing 0, 5, 6 and 8% polycarbophil, respectively. The data indicate that as the polycarbophil concentration increased from 0 to 5% in the polyethylene glycol suppositories, the plasma levels and bioavailability improved significantly (p < 0.1, Students t-test), whereas on increasing from 5 to 6 and 8% the plasma levels and bioavailability decreased significantly (p < 0.05). At 8% polycarbophil concentration, sustained release suppositories were produced but a decrease in plasma levels was observed.

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.

High-performance liquid chromatographic analysis of indomethacin in serum.

A rapid high‐performance liquid chromatographic (HPLC) method for quantitative determination of indomethacin in serum is described. The assay was performed after single extraction of indomethacin and itraconazole (internal standard) from serum using diethyl ether and eluted from a 4 urn C‐18 reversed‐phase column at ambient temperature. The mobile phase consisted of ethanol:water:glacial acetic acid (65:34:1, v/v) pumped isocrati‐cally at a flow rate of l‐3ml/min. The effluent was monitored at 254 nm. Quantification was achieved by the measurement of the peak area ratio, and the absolute recoveries ranged from 94 to 97%. Within‐day coefficients of variation (CV) ranged from 2–72 to 5–70% and between‐day CV varied from 3–61 to 61%. Stability testing indicated that indomethacin is stable for at least 30 days in serum at – 20°C. The method was used to study indomethacin pharmacokinetics in rabbits.

Effect of food on bioavailability of bioadhesive-containing indomethacin tablets in dogs

Abstract The effect of food on the bioavailability of bioadhesive containing indomethacin tablets was evaluated on five male beagle dogs. Indomethacin was administered intravenously at a dose of 15 mg and orally in the fasting state and after food intake as a bioadhesive tablet at a dose of 25 mg. After dosing, serial blood samples were collected for a period of 6 h. Indomethacin plasma concentration was determined by a sensitive high-performance liquid Chromatographie assay. Food consumption dramatically reduced the area under the plasma concentration-time curve (AUC) and the maximum concentration (Cmax) by 86 and 76%, respectively. No significant differences were observed in the time to peak concentration (Tmax), mean residence time of the drug in the body (MRT), mean absorption time (MAT), elimination rate constant (Kel) and elimination half-life ( t 1 2 ) between the fasting and postprandial states. The mean gastrointestinal time (MGT) was found to be 0.81 h. The absolute bioavailability of the indomethacin bioadhesive tablets in the fasting state and after meal was 85.4 and 11.8%, respectively. Complexation of the bioadhesive material with the food contents is the most plausible explanation for the decrease in the extent of absorption of indomethacin.