| The diffusion characteristics of selective phosphodiesterase-5 inhibitor (PDE5) Tadalafil was studied to determine its in vitro permeation behavior from a number of different formulations across cellulose membrane and human cadaver skin using Franz diffusion cells. The goal of the study was to develop a 7-day gel for a reservoir patch for a 5 mg dose of Tadalafil to treat both erectile dysfunction and benign prostetic hyperplasia. A number of different studies were conducted in order to develop a successful formulation: i) Analytical method development ii) Solubility studies iii) Selection of gelling agent and iv) in vitro release studies through cellulose membrane and v) in vitro permeation studies through human cadaver skin using various penetration enhancers and different concentration of penetration enhancers to optimize the formulation.;The concentration of the permeant in the vehicle system, as a function of its saturation solubility in that system, characterizes the thermodynamic activity of the permeant in the donor vehicle (1). Thermodynamic activity of the permeant in the donor vehicle is the driving force for diffusion across the skin (1). Increasing the concentration of the drug in the vehicle system close to its saturation point increases the thermodynamic activity of the drug and the escaping tendency of the drug from the vehicle (1).;Solubility studies were conducted in single solvents and tertiary vehicle systems to find the medium with maximum solubility for Tadalafil. The drug was found to be freely soluble in DMSO, soluble in NMP (4.528%), and sparingly soluble in PEG 400 (1.725%). Tadalafil is slightly soluble in ethanol and PG, and practically insoluble in water. Different ratios of DMSO, NMP and PEG 400 were evaluated for the maximum solubility of Tadalafil. An optimum tertiary system of DMSO/NMP/PEG400 in the ratio of 44.44/44.44/11.12% was selected as an ideal vehicle system for transdermal delivery of Tadalafil, solubilizing up to 6.7% of the drug (w/v). PEG400 was included in developing a 7-day transdermal gel for Tadalafil, because it can be used to slow the release rate of the active agent from the formulation, while still delivering the amount of drug required to reach the desired flux (4).;In vitro diffusion studies were conducted using cellulose membrane to determine the optimal concentration and viscosity of the formulation. Tadalafil gels were first formulated with three polymeric agents, including Klucel MF, Methocel K4 and Carbopol 971 P, with 3% gelling agent and 2% drug concentration to determine which polymer results in best drug release through cellulose membrane. From these experiments, Klucel MF was selected as the optimal gelling agent and drug release was further studied from a series of formulations containing three different Klucel concentrations (1%, 2% and 3%), as well as three different drug concentrations (2%, 2.6%, and 3%). The optimal formulation selected to be studied on human cadaver skin contained 3% drug and 2% Klucel MF. A number of different chemical penetration enhancers were included in the formulation to enhance the percutaneous absorption of the drug through human cadaver skin. The permeation of Tadalafil increased significantly in the presence of penetration enhancers, such as palmitic acid, from a flux value of 9.34 ug/cm2 /hr when diffused alone to a flux value of approximately 30 ug/cm 2/hr when diffused in the presence of 5% palmitic acid. The effect of different concentrations of palmitic acid (2.5%, 5%, and 7.5%) on Tadalafil permeation through human cadaver skin was also evaluated, resulting in concentration-dependent permeation from 2.5% and 5% palmitic acid formulations, but reaching saturation point at 5% with no significant difference in flux values for 5% and 7.5% enhancer formulation. The study demonstrated that the optimal transdennal formulation for a 7-day Tadalafil gel would contain 5% palmitic acid with a flux of 30 ug/cm2/hr and a lag-time of approximately 2 hrs. |
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