This thesis describes in-vitro and in-vivo evaluation of a transdermal atenolol formulation developed at Oregon State University, College of Pharmacy. The formulation was prepared from carbomer as a gel base with propylene glycol, glycerol, ethanol, polysorbate 80 and dimethyl-isosorbide (DMI) as mixture of penetration enhancing agents. The effect of the pH on the formulation stability was studied and it was found that pH of 7 can maintain a good stability of atenolol in the formulation. The permeation studies of the invitro phase of this thesis involved 3 different penetration barriers. Synthetic membranes with pore size of 0.45 u was used, followed by cloned human skin which were used to investigate the 6 proposed formulations. Then cloned human epidermis was used to test the three best formulations. Finally, freshly collected cat skin was used for further investigation of the atenolol permeation. Based on the permeation profiles for the different proposed formulations one optimized formulation was chosen which is Formulation (6) with 15% of DMI (Dimethyl isosorbide) and 15% of propylene glycol, 15% glycerol, 10% of ethanol and 5% of polysorbate 80. It was found that the concentration of atenolol 2 hours after application of formulation 6 to cat skin was 35.5 µg/ml. This correlates to 497 µg penetrating over 2 hours. The therapeutic concentration of atenolol is 260 ng/ml and by considering, atenolol has a volume of distribution of ~1000 ml in cat, therapeutic concentrations of atenolol was considered attainable using this optimized formula. The results of the percent cumulative drug release were examined in accordance to the kinetic models such as Zero-order, First-order, Higuchi equation, Korsmeyer–Peppas equation and Hixson–Crowell equation. In Zero order, R² was calculated for each formulation according to the different kinetic models the values of regression coefficient R² was 0.9012 for formulation 3, Formulation 5 R²= 0.9137 and Formulation 6 R²= 0.92. The graph of the data using Higuchi model was plotted. The cumulative percentage drug released versus square root of time for each formulation through cat skin was not linear and the value of regression coefficients of R²= 0.607 for formulation 3, and R²= 0.739 for formulation 5 and formulation 6 value of regression coefficient was R²= 0.701 were considerably less than the R2 values for the zero-order model. In Hixon-Crowell model, the value of regression coefficient was R²= 0.541 for formulation 3 and R²= 0.593 and R²= 0.653 for formulation 6. The zero-order release model provided the best explanation of drug diffusion through the membranes. The Korsmeyer-Peppas n value for the first phase was 0.8571 for the initial burst flux indicating a fickian diffusion process of a drug solution. The n value for the second flux phase was 0.2616. This indicates that dissolution of the drug from the drug particle occurs before diffusion through the cat skin. Erosion of the drug particle may also be involved in this process.
Three different atenolol formulations were developed to produce an effective formulation. The best formulations selected were tested to evaluate their ability to deliver the drug into the human skin in comparison to a simple aqueous atenolol solution containing the same amount of drug (1% w/v). All the atenolol formulations markedly (p < 0.001) improved the amount of drug that penetrated through the skin layers compared to the simple aqueous solution. A minimum of 700% increase atenolol penetration through cat skin in the case of Formulation 3, to 750% for Formulation 5 and up to a maximum of 900%, in the case of Formulation 6 was observed. Pharmacokinetic studies and pharmacodynamic studies were performed after a clinical trial on 8 cats and the results showed the feasibility of the optimized transdermal formulation. Six of seven cats had therapeutic atenolol serum concentrations after topical administration. The topical administration of atenolol produced therapeutic atenolol levels in cats about 81% of the time. The pharmacokinetic model predicted the serum concentrations using pharmacokinetic parameters from the literature and diffusion fluxes of the study. All cats reached therapeutic concentrations of atenolol for nearly the entire time. Four cats had a single data point where the serum concentration was not in the therapeutic range (4 data points out of 21 total data points). Atenolol stability in the designed formulation was studied up to 6 months. There was no significant change in the atenolol content in the formulation. The stability studies indicate minor loss in the atenolol concentration in the designed formulation both in room temperature and at 37.5 °C. The pH is a critical component of the formulation’s stability, and pharmacists should measure pH (target pH of 7) prior to dispensing this compounded medication.