| Abstract: |
Multicomponent Colloidal Drug Delivery Systems Abstract Liposomes and microemulsions are potential colloidal drug delivery systems for topical, ocular, parentral and oral administration. These systems are currently of interest to the pharmaceutical scientists because of their considerable potential to act as drug delivery vehicles by incorporating a wide range of drug molecules. They offer also the advantage of providing sustained and controlled release of drug for therapeutic use. Furthermore, they are able to improve solubilization, stabilization, bioavailability and decrease toxicity of administered drugs.The present thesis is divided into two parts:Part (I)Effect of some formulation parameters on encapsulation, release profile and biological activity of liposomes containing certain drugs.In this part liposomal vesicles of different structure and composition were prepared and the effect of different parameters such as type of phospholipid, additives, type of drug and pH on drug encapsulation and/or drug release from the liposomes were investigated. The effect of some of the above mentioned parameters on in vivo biological activity of drug was tested. Moreover, the structure of liposomal vesicles was confirmed by transmission electron microscope photomicrographs.The results of the study in this part could be summarized in the following:1- The electron photomicrographs of liposomal vesicles could confirm their multilamellar structure.2- The encapsulation efficiency of multilamellar liposomes (MLV) prepared from soya phosphatidylcholine (SPC) was higher than that of liposomes prepared from egg phosphatidylcholine (EPC). Moreover, incorporation of cholesterol in liposomal bilayer membranes enhanced the encapsulation efficiency of the resulting MLV giving maximum enhancement at phosphatidylcholine: cholesterol 1:1 molar ratio in case of EPC and at a ratio of 1: 0.5 in case of SPC. Additionally, the encapsulation capacity of the liposomes could be enhanced by incorporation of propolis. The percent drug encapsulated increased also by increasing the total lipid concentration, while drug concentration had insignificant effect. Relatively higher encapsulation efficiency could also be observed for more lipophylic drugs as well as at pH encouraging the formation of the unionized form of drug.3- Liposomes of the MLV type showed higher encapsulation efficiency than that of unilamellar type (ULV).4- The drug release has been shown to be influenced to a great extent by the composition of MLV and to less extent by the pH of the dispersion medium. The highest release rate was obtained from the solution form, while the lowest release rate was obtained from liposomes of hydrogenated soya phosphatidylcholine (HSPC): cholesterol 1:1 molar ratio. Also, the release rates decreased by either the addition of methyl cellulose (a viscosity imparting agent) or the incorporation of propolis.5- The in vivo performance of various formulations of atenolol was assessed on the basis of the influence of the drug on the intra-ocular pressure of rabbit’s eye. The results showed that the intra-ocular pressure reducing activity of atenolol using various liposomal forms was greater than that of solution form. EPC-MLV produced higher drug activity than EPC-ULV formula. Moreover, the activity of atenolol incorporated in different liposomal vesicles could be arranged in the following order: liposomes incorporating propolis (MLV-PEE)> liposomes containing methyl cellulose (MLV-MC)> Hydrogenated soya phosphatidylcholine MLV (HSPC-MLV)> EPC-MLV> SPC-MLV.6- Finally, it was clearly observed that for ophthalmic application, MLV-PEE, MLV-MC or HSPC-MLV seems to be a promising approach in modulating drug activity.Part (II)Formulation, in vitro and in vivo evaluation of microemulsion systems containing certain drugs.The objectives of this part were to evaluate microemulsion systems composed of different oils (oleic acid, ethyl oleate and triacetin), surfactant (tween 80), and cosurfactant (propylene glycol or n-butyl alcohol). Triangular phase diagrams were developed for these microemulsion systems using the water titration technique and phase diagrams were constructed at constant water percentage in order to elucidate the effect of microemulsion components on the area of microemulsion formation. The viscosity and conductivity of certain microemulsion formulations were followed as function of water dilution. Also, the effect of water content as well as surfactant/cosurfactant ratios of microemulsion systems on the solubility of model drugs (atenolol and ketoconazole) was tested. Furthermore, the influence of surfactant to cosurfactant ratio on the maximum water or oil contents to be incorporated into microemulsion was also studied. Beyond that, the selected systems underwent stability studies at room temperature over six month period.The in vitro release study for atenolol from microemulsion as drug delivery vehicle was conducted compared to either premicroemulsion concentrates or solution form. On the other hand, the in vitro antimicrobial activity of microemulsions as well as premicroemulsion formulations containing ketoconazole were tested using Candida albicans and Pseudomonas aeruginosa as fungal and bacterial models, respectively. Finally, the in vivo studies were carried out on the basis of the intraocular pressure lowering effect of atenolol using rabbit’s eye. For this purpose, premicroemulsion of ethyl oleate/tween 80/propylene glycol (Eo/T80/PG) as well as the two-fold water diluted samples (Eo/T80/PG-200%) were selected for the experiment and results were compared to that of the solution dosage form.The obtained results could be summarized in the following:1- The phase behavior was largely dependant upon the type of oil and the cosurfactant used. The clear isotropic area of oleic acid premicroemulsion was larger than that of ethyl oleate systems when propylene glycol was the cosurfactant. Triacetin gave the largest areas of microemulsion while oleic acid gave the smallest areas.2- The cosurfactant n-butyl alcohol was more efficient than propylene glycol in producing larger microemulsion areas of ethyl oleate oil.3- The amount of water that can be incorporated in a microemulsion system is directly proportional to surfactant/cosurfactant ratio and inversely proportional to the percentage amount of the oil phase present in the system.4- Preparation of microemulsions containing higher amounts of the oil phase required higher surfactant/cosurfactant ratios.5- The solubility of each of atenolol and ketoconazole could be substantially enhanced by using microemulsions as vehicles where different solubilization potentials were noted among systems comprising different compositions.6- Microemulsion systems displayed changes in their viscosity and conductivity upon water dilution.7- The in vitro release rate of atenolol from either premicroemulsion, microemulsion or solution form could be arranged in the following ascending way: premicroemulsion<microemulsion<solution form.8- Premicroemulsion and microemulsion systems have been shown to contribute to enhancement of both the in vitro antifungal and antibacterial effect of ketoconazole as well as the in vivo intraocular pressure lowering effect of atenolol.9- The results of this study led to formulation of microemulsion systems stable for six months at room temperature where no signs of turbidity or phase separation could be observed.
|
|
|