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Title

Investigation Of Physicochemical And Formulation Parameters For Transdermal Delivery Of Isoproterenol Hcl

Date of Award

1987

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Abstract

Effects of solubility, partition coefficient, pH and selected adjuvants (propylene glycol and Azone) on the percutaneous penetration of isoproterenol HCl in vitro have been investigated using human cadaver skin. Preliminary stability studies demonstrated that isoproterenol HCl was very stable (<1% decomposition) for 24 hours at 22(DEGREES) (+OR-) 0.5(DEGREES) in the pH range 1 to 7 in the following solvents: water, normal saline, propylene glycol and a series of propylene glycol-water mixtures (10,20,40 and 60% v/v). The rate of decomposition of the drug in aqueous solutions increased with pH beyond pH 8. In normal saline, the decomposition was significant when the temperature was raised to 37(DEGREES) (+OR-) 0.5(DEGREES). The solubility of isoproterenol HCl decreased and its skin/vehicle partition coefficient increased with increasing proportions of propylene glycol in the vehicle. Results of the physicochemical and percutaneous penetration studies revealed that 20% v/v propylene glycol in water should be the optimal vehicle for transdermal delivery of isoproterenol HCl. Optimal penetration enhancing effects of Azone('(REGTM)) were seen when incorporated at a concentration of 1% v/v in the 20% v/v propylene glycol-water vehicle and more dramatically when the skin was pretreated with pure Azone for 60 minutes prior to application of the drug formulation. The flux reached a maximum around pH 9 in agreement with the predicted favorable pH environment for neutral forms of isoproterenol HCl. Both neutral and charged forms of isoproterenol HCl were found to contribute to the total flux in agreement with the proposed model: J = (Kp (.) C)('ca) + (Kp (.) C)('an) + (Kp (.) C)('n). The calculated permeability coefficients for isoproterenol HCl were 0.2098 x 10('-3), 0.1570 x 10('-4) and -0.8665 x 10('-3) cm/h for neutral, cationic and anionic species, respectively. Azone enhanced the penetration of all forms of isoproterenol HCl, although the effect was more pronounced on the anionic species. This may be due to facilitation of penetration by formation of an ion-pair between isoproterenol HCl and Azone. The permeability coefficients for the neutral, cationic and anionic forms of isoproterenol HCl for penetration through Azone-pretreated skin were 0.8395 x 10('-3), 0.1701 x 10('-3) and 0.8091 x 10('-2) cm/h, respectively.

Pages

136

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