AuthorUgwu, Sydney Onye.
Committee ChairBlanchard, James
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractThe overall objective of this dissertation was to develop formulations suitable for the delivery of α-melanotropic peptides. A HPLC assay with UV detection was developed to evaluate the performance of melanotan-II (MT-II) in vitro and in vivo. The method was validated to establish linearity, precision and accuracy and also was successfully applied to a pharmacokinetic study in rats. Correlation of the plasma MT-II concentrations determined using HPLC and frog skin bioassay methods indicated the existence of a significant linear correlation. Next, the stability of MT-II in aqueous buffered solution was studied in order to facilitate the formulation of stable dosage forms. Results indicated that the degradation of MT-II followed apparent first-order kinetics. MT-II was most stable at approximately pH 5.0. Shelf-life at 25 °C and activation energy were 27 hr and 7.5 kcal/mole, respectively. The degradation rate was directly proportional to phosphate concentration and temperature, but independent of the ionic strength. In another phase of the study, a novel method was developed for the determination of acid dissociation constants of peptides. The method involved potentiometric titrations, following which data were analyzed using the Gran plot and the Best program. The method was also capable of accurately determining the contamination of the peptide sample with weak acids, strong acids, or water. The method was validated using boric acid and a peptide molecule. Finally, bioavailability (F) of Melanotan-I (MT-I) and Melanotan-II (MT-II) solutions, administered intra-jejunally to rats were 1.6 and 5.0%, respectively. The administration of MT-I with dimethyl-β-cyclodextrin (DMCD), a permeation enhancer, did not significantly increase the absorption of MT-I. However, after intrajejunal administration of MT-I in the presence of DMCD and Aprotinin (APRO), a protease inhibitor, the F was significantly increased by 4-fold. This result showed that enzymatic degradation appeared to be a significant barrier to the intestinal absorption of MT-I.
Degree ProgramPharmaceutical Sciences