Mohsen A. Bayomi

Preparation of casein–chitosan microspheres containing diltiazem hydrochloride by an aqueous coacervation technique

Sustained release casein-chitosan microspheres containing diltiazem hydrochloride (DTZ) were prepared with colloidal coacervation technique in a completely aqueous environment. The interaction between chitosan solution in dilute acetic acid (5% v/v) and casein solution in 0.5 M sodium hydroxide was the basis for the microspheres formation. Formaldehyde was used for the surface hardening of the droplets by cross-linking and thus fixing the shape and surface morphology of the formed microspheres. The entrapment efficiencies of the microspheres were variables (14.5-53.7%) depending on the preparation conditions. The prepared microspheres exhibited an angle of repose values between 31.9-42.0 degrees indicating good free flowing nature, whereas DTZ powder as such was non-flowable. The dissolution profiles of DTZ from casein-chitosan microspheres showed retarded release pattern of the drug into distilled water. Casein and chitosan concentrations, initial drug concentration and stirring time were found to be the main parameters that affect the properties and the performance of the prepared microspheres. The retarded release of DTZ was increased by increasing casein concentration, and stirring time. On the other hand, increasing chitosan concentration and using high initial drug loading showed a fast drug release.

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.

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.

Excipient-Excipient Interaction in the Design of Sustained-Release Theophylline Tablets: In Vitro and In Vivo Evaluation

Sustained-release (SR) theophylline (TPH) tablets were prepared by applying the moisture-activated dry granulation method. The interaction between the excipients sodium alginate (SAL) and calcium gluconate (CG) was the base for the formation of a cross-linked matrix that may regulate TPH release from the formulated tablets. The prepared granules showed good physical characteristics concerning the flow properties and compressibility, with the angles of repose in the range 29–31, and the compressibility indices ranged between 15% and 25%. The granules had low friability values (3.0%–4.2%), depending on SAL:CG ratios. The corresponding tablets showed good physical properties, with a lower rate of drug release compared with the commercial TPH tablets (Quibron®). The release of TPH from the prepared tablets was not markedly affected by either the concentration of added dry binder (carbopol 934) or the tablet hardness, indicating that the rate-determining step in drug release was the diffusion through the produced calcium alginate matrix. Tablets formulated with equal ratios of CG and SAL that showed good physical properties and slow TPH release were chosen for bioavailability studies in beagle dogs, and results were compared with those for Quibron. The in vivo data showed a comparable plasma concentration profile for both tablet formulations, with prolonged appearance of drug in the plasma in detectable amounts for up to 24 h. The formulated tablets showed 104.65% bioavailability relative to that of the commercial tablets. The rate and extent of absorption of TPH showed no significant differences from that of the commercial tablets. Moreover, no significant differences were found in the pharmacokinetic parameters related to the rate and extent of TPH absorption from the prepared and commercial tablets.

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.

Design of liposomal colloidal systems for ocular delivery of ciprofloxacin

Ophthalmic drug bioavailability is limited due to protective mechanisms of the eye which require the design of a system to enhance ocular delivery. In this study several liposomal formulations containing ciprofloxacin (CPX) have been formulated using reverse phase evaporation technique with final dispersion of pH 7.4. Different types of phospholipids including Phosphatidylcholine, Dipalmitoylphosphatidylcholine and Dimyristoyl-sn-glycero-3-phosphocholine were utilized. The effect of formulation factors such as type of phospholipid, cholesterol content, incorporation of positively charging inducing agents and ultrasonication on the properties of the liposomal vesicles was studied. Bioavailability of selected liposomal formulations in rabbit eye aqueous humor has been investigated and compared with that of commercially available CPX eye drops (Ciprocin®). Pharmacokinetic parameters including Cmax, Tmax, elimination rate constant, t1/2, MRT and AUC0-∞, were determined. The investigated formulations showed more than three folds of improvement in CPX ocular bioavailability compared with the commercial product.

Aqueous Preparation and Evaluation of Albumin‐Chitosan Microspheres Containing Indomethacin

Controlled‐release egg albumin‐chitosan microspheres containing indomethacin as a model drug were successfully prepared by coacervation method. The proposed method can offer a simple method for microsphere preparation in an aqueous system with the elimination of the use of organic solvents that are usually needed in conventional techniques of microencapsulation. The interaction between negatively charged egg albumin molecules in phosphate buffer, pH 7.2, or sodium hydroxide solution and positively charged chitosan molecules dissolved in diluted acetic acid to form an insoluble precipitate was the principle for the formation of the microspheres. The effects of many process variables, such as amount of formaldehyde as a cross‐linking agent, stirring time, final pH of encapsulation medium, initial drug loading, and albumin concentration or albumin‐to‐chitosan weight ratio, on the properties of the prepared microspheres were investigated. Incorporation efficiencies of the microspheres to the drug were high in most cases and ranged between 63.3 ± 3.6% and 92.39 ± 3.2%, while particle sizes were 435.2 ± 12.6 up to 693.9 ± 34.6 µm for the different tested batches. On the other hand, the values of angles of repose and compressibility indices were in the range of 23.5 ± 0.4 to 32.0 ± 0.7 degrees and 11.1 ± 0.7% to 23.6 ± 0.7% respectively, which indicate overall good free flowing nature of the microspheres of all batches. The maximum required amount of the cross‐linking agent was determined to avoid excessive unnecessary chemicals. It was also noticed that excessive time of stirring and excessive initial drug loading are not recommended as it may lead to microspheres of low properties. The pH of the encapsulation media (pH 3.77 up to pH 4.91) significantly affected the properties of the microspheres. As the pH of the encapsulation media was increased, the incorporation efficiency, particle size, and flowability decreased, along with increase of drug release rate, which could be related to incomplete cross linking of the microspheres matrix. It was also observed that high concentration of albumin solution and accordingly the increase of albumin‐to‐chitosan weight ratio were accompanied with increases in incorporation efficiency and particle size with improved microsphere flowability and slow indomethacin release. Thus, the proposed microspheres showed the ability to control the release of indomethacin, and their properties were highly affected by many process variables that could be controlled to obtain an optimized system.

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.