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Solubilization of a Tripeptide HIV Protease Inhibitor Using a Combination of Ionization and Complexation with Chemically Modified Cyclodextrins by Mark D. Johnson; Barbara L. Hoesterey; Bradley D. Anderson is a Chemistry article available to read on EtoBox.

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Kynostatin (KNI-272), an experimental HIV protease inhibitor, is currently undergoing preclinical testing for the treatment of AIDS. This transition state mimetic tripeptide exhibits extremely low aqueous solubility (4 micrograms/mL) making target concentrations (5-50 mg/mL) for parenteral solution formulations difficult to achieve. The presence of an ionizable (5-isoquinolinyloxy)acetyl moiety makes solubilization via pH adjustment possible, but a solubility > 5 mg/mL requires an adjustment in pH below 2.0, which would be physiologically unacceptable. This study examines and compares two approaches for solubilizing kynostatin: (1) inclusion complex formation at chemically distinct hydrophobic binding sites using (2-hydroxypropyl)-beta-cyclodextrin (HPCD) and a sulfobutyl ether derivative of beta-cyclodextrin (beta-CD-SBE) and (2) a combined strategy utilizing ionization of the isoquinoline moiety coupled with inclusion complex formation at the remaining binding site(s). Macroscopic binding constants determined from solubility profiles as a function of pH and HPCD concentration have been compared with the microscopic binding constant for formation of the isoquinoline-HPCD inclusion

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Author

Mark D. Johnson; Barbara L. Hoesterey; Bradley D. Anderson

Publisher

John Wiley and Sons; Elsevier ; Elsevier Inc.; Elsevier BV (ISSN 0022-3549)

Published

1994

Language

EN

Field

Chemistry (Physical Sciences)