Mohamed A. Al-Meshal

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.

Determination of Ketoconazole in Plasma and Dosage Forms by High-Performance Liquid Chromatography and a Microbiological Method

Abstract A simple and rapid high-performance liquid chromatographic (HPLC) method for the determination of ketoconazole in plasma and in tablets was developed. the method employs benzafibrate as internal standard and is sufficiently rapid and sensitive for use in pharmacokinetic studies. Separation of the drug from plasma was achieved by extraction with acetonitrile followed by a reversed phase chromatography on a μ Bondapak column using the isocratic mobile phase of methanol-water-glacial acetic acid (67.5:32:0.5). With this eluting solvent ketoconazole and the internal standard. were well separated from the components of plasma. A linear relationship was obtained between the ratio of the area under the peak of drug to that of the internal standard versus the concentration of the drug. Data comparing the microbiological assay with the HPLC procedure, which was developed, are shown. In the microbiological assay, Candida albicans, was the test organism, using the agar diffusion technique. Both methods were...

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.

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.

The effect of colestipol and cholestyramine on the systemic clearance of intravenous ibuprofen in rabbits

Abstract— The effect of oral administration of the non‐absorbable anion‐exchange resins cholestyramine and colestipol on the systemic clearance and other pharmacokinetic parameters of intravenously administered ibuprofen (25 mg kg−1) was studied in rabbits. Single doses of colestipol hydrochloride (0·4 g kg−1) or cholestyramine (0·17 g kg−1) were given 30 min before ibuprofen administration. In cholestyramine‐treated rabbits a significant reduction in ibuprofen plasma concentration was observed compared with both control (water only) and colestipol‐treated rabbits. Cholestyramine treatment resulted in a significant decrease in the terminal elimination half‐life and the mean residence time. Furthermore, a 31% increase in the systemic clearance and 23% decrease in the area under the plasma concentration‐time curve were also observed in cholestyramine‐treated rabbits. Colestipol treatment did not change these parameters. The volume of distribution parameters (Vdss and Vdarea) did not change following either treatment. The changes in the pharmacokinetic parameters are compatible with an acceleration of ibuprofen elimination induced by oral administration of cholestyramine and not by colestipol. This effect is thought to be due to augmentation of net biliary excretion through enteric binding.

ACCELERATED CLEARANCE OF INTRAVENOUS INDOMETHACIN BY ORAL ACTIVATED CHARCOAL IN RABBITS

The effect of oral activated charcoal on the systemic clearance and other pharmacokinetic parameters of intravenously administered indomethacin (2 mg /kg) was studied in rabbits. Following a single oral dose of activated charcoal (10 g), a significant reduction in indomethacin serum concentrations was observed. Charcoal treatment resulted m a significant decrease in the terminal elimination half-life (1.26 ± 0.14 and 0.82 ± 0.03 h for the control and treated groups, respectively) and the mean residence time (1.29 ± 0.14 and 0.79 ± 0.03 h for the control and treated groups, respectively). Further, a 68% increase in the systemic clearance (1.92 ± 0.19 and 3.23 ± 0.15 ml/min per kg for the control and treated rabbits, respectively) and 41% decrease in the area under the serum concentration-time curve (17.56 ± 1.82 and 10.34 ± 0.48 μg h/ml in the control and treated groups, respectively) were also noted. Charcoal administration did not significantly alter the volume of distribution (Vc, Vss and Varea). Regarding the microconstants of the two-compartment phannacokinetic model which adequately described indomethacin kinetic in the control and treated rabbits, charcoal administration produced a significant increase in the rate of transfer of indomethacin from the tissue compartment to the central compartment (K21) and out of the central compartment (K10). The results indicate that administration of oral activated charcoal accelerates the systemic elimination of indomethacin. This is presumably mediated by interruption of the enterohepatic circulation of indomethacin by activated charcoal.