الفهرس 
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Abstract
One of the alternatives to the oral route of drug administration, particularly for drugs that undergo first pass metabolism, is bioadhesive buccal delivery of drugs. Buccal drug delivery systems have the potential to deliver drugs to the systemic circulation via absorption through the mucosa at a preset and controlled rate. The main objectives in this work were; firstly, to design mucoadhesive buccal tablets containing labetalol hydrochloride, used for the treatment of hypertension, using different polymers. In addition, the bioavailability and the pharmacokinetic parameters of labetalol hydrochloride from selected formulations were also studied. Secondly, to formulate nanoemulsion-based mucoadhesive buccal films of atorvastatin calcium, used for treatment of hyperlipidemia. In vivo evaluation of the optimum formula was also studied. Methods : Part I focused on the development of mucoadhesive buccal tablets using various bioadhesive polymers, either alone or in blends of various ratios, such as carbopol 934 (CP 934), sodium alginate, and hydroxypropyl methylcellulose (HPMC). The prepared labetalol hydrochloride mucoadhesive buccal tablets were evaluated for their drug content uniformity, friability, hardness, swelling index, surface pH and in vitro bioadhesive strength and time. Also, in vitro and ex vivo release characteristics of the prepared tablets were evaluated and analyzed using variable kinetic orders and mathematical models. 2- The bioavailability and pharmacokinetic properties of the chosen optimum formulations of mucoadhesive buccal tablets of labetalol hydrochloride were studied on albino rabbits. The formulations were chosen based on the drug release properties that were acceptable. F1 and F6 were the formulations used for this study. For comparison, the control tablets (commercial Labipress tablets) were also tested. The pharmacokinetic parameters of labetalol hydrochloride (Cmax, Tmax, T1/2, AUC0-6 and AUC0-α) were calculated. The results were statistically analyzed using oneway analysis of variance (ANOVA) test. Part II dealt with the study of the preparation of nanoemulsion (NE) - based mucoadhesive buccal films of atorvastatin calcium by solvent casting technique using mucoadhesive polymer HPMC. Firstly, several evaluations were made for choosing the components of nanaoemulsions and their percentage then incorporated into film formulations with mucoadhesive properties. The prepared films were evaluated for their drug content, swelling index, surface pH, folding endurance, mucoadhesive properties and surface morphology. Also, ex vivo release characteristics of the prepared films were evaluated and analyzed using variable kinetic orders and mathematical models. All results were done in comparison to the control film (drug loaded without NE-base). The study of the effect of NE-based and the control films in lowering cholesterol level was performed using rabbits with diet induced hyperlipidemia. Histological examination of rabbit’s heart and liver was also studied. 3- Results : The obtained results in part I can be summarized as follow : 1. Differential scanning calorimetry and fourier transform infrared spectroscopy showed no chemical incompatibilities between labetalol hydrochloride and any of the polymer combinations. 2. The swelling profile of the prepared formulations was primarily determined by the HPMC ratio. More swelling was observed in formulations containing a larger amount of HPMC. The swelling properties of carbopol-containing formulations were higher than those of sodium alginate-containing formulations. 3. Due to carbopol-934’s strong mucoadhesive properties, formulations comprising it had stronger ex vivo mucoadhesive characteristics than those including sodium alginate. When compared to sodium alginate-containing formulations, carbopol-containing formulations had stronger bioadhesion forces and longer bioadhesive periods. 4. Sodium alginate-containing formulations had the highest in vitro drug release rates and ex vivo drug permeation rates when compared to carbopol-containing formulations. Increasing concentrations of HPMC resulted in decreased in vitro drug release rate in both carbopol-containing and sodium alginate-containing formulations. Both released the drug through non Fickian mechanism. 5. In comparison to oral dosing, the mucoadhesive buccal formulations (F1 and F6) showed improved systemic bioavailability of labetalol hydrochloride by 2.76 and 1.60 folds, respectively. This can be explained by the buccal mode of drug delivery avoiding first pass metabolism. 4- 6. A strong correlation was detected between in vitro drug release and ex vivo transmucosal permeation of labetalol hydrochloride with correlation coefficients of 0.97 for carbopol-934 formulation (F1) and 0.90 for sodium alginate formulation (F6). The obtained results in part II can be summarized as follow : 1. According to the results obtained from saturation solubility study, components of NEs, oil phase (oleic acid); surfactant (tween 20) and co-surfactant (ethanol) were chosen. 2. Different ratios of surfactant: co-surfactant mixtures (SCmix) were prepared. The turbid ratios were excluded from further evaluation. 3. Best ratios of SCmix (1:1, 1:2, 1:3, and 1:4) were used for plotting the pseudoternary phase diagram for determining the NE region. 4. from the NE region of each ternary diagram, percentage of the NEs components (10% oleic acid: 50% SCmix : 40% distilled water) were used for preparation of NEs (NE1, NE2, NE3 and NE4). 5. NEs were subjected to size analysis and NEs not present in the range of 20-200 nm were excluded (NE4). 6. NE1, NE2 and NE3 were used for preparation of the mucoadhesive buccal film formulations coded FL1, FL2, and FL3 respectively. 7. The film showed the best physical appearance (FL2) was subjected to further evaluation and compared with the control traditional film FL0 containing drug not in the NE form. 5- 8. Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy showed the solubility of drug in the film components and formation of inter and intramolecular hydrogen bonding. 9. Physicochemical and mucoadhesive properties of NE-based film were not significantly different from the control film as the same polymer was used. 10. The ex vivo release of drug from NE-based film was higher than the release of drug from the control film as the drug was in nano-size form which increased the solubility of drug and enhanced its release through the chicken pouch membrane. Both NE-based and control films released the drug through non fickian mechanism. 11. Rabbits treated with FL2 had considerably lower cholesterol and high-density lipoprotein (HDL) levels than group treated with the control film. Triglyceride levels, on the other hand, did not differ significantly between the two groups. 12. Histological examination of the heart and liver of sacrificed animals in the two groups revealed that animals receiving NE-based film had a better histological picture of hepatic lobules, hepatocytes, and cardiomyocytes than those in the control group, and these results were matched with blood analysis results. Conclusion : The produced mucoadhesive buccal tablets of labetalol hydrochloride, in part I, were successful in improving the systemic bioavailability of the drug in albino rabbits in comparison to the control commercial oral tablets. The formulated NE-based mucoadhesive buccal films, in part II, were successful in enhancing the lipid lowering effect of atorvastatin calcium in tested rabbits in comparison to the control film through improving its solubility and bioavailability.