title: Preformulation and pharmacokinetic studies on antalarmin: a novel stress inhibitor.
abstract: The preformulation, solubilization and pharmacokinetic evaluation of antalarmin, a stress inhibitor, have been conducted. Antalarmin has a poor water solubility of less than 1 microg/mL and is weakly basic with an experimentally determined pK(a) of 5.0. Multiple solubilization approaches including pH-control either alone or in combination with cosolvents, surfactants and complexing agents have been investigated. The applicability of lipid-based systems has also been explored. Four formulations, each with a targeted drug loading capacity of 100 mg/mL, show potential for oral administration. Three of these formulations are aqueous solutions (10% ethanol + 40% propylene glycol; 20% cremophor EL; 20% sulfobutylether-beta-cyclodextrin) each buffered at pH 1. The fourth formulation is a lipid-based formulation comprising of 20% oleic acid, 40% cremophor EL and 40% Labrasol. No precipitation was observed following dilution of the four formulations with water and enzyme free simulated gastric fluid. However, only the lipid-based formulation successfully resisted drug precipitation following dilution with enzyme free simulated intestinal fluid. Pharmacokinetic analysis conducted in rats revealed that the 20% cremophor EL solution formulation has a fivefold higher oral bioavailability compared to a suspension formulation. The lipid-based formulation resulted in over 12-fold higher bioavailability as compared to the suspension formulation, the highest amongst the formulations examined.
authors.affiliation: College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA. rsanghvi@pharmacy.arizona.edu
authors.forename: Ritesh
authors.initials: R
authors.lastname: Sanghvi
authors.forename: Erik
authors.initials: E
authors.lastname: Mogalian
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Machatha
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Narazaki
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Karlage
authors.forename: Parijat
authors.initials: P
authors.lastname: Jain
authors.forename: S Esmail
authors.initials: SE
authors.lastname: Tabibi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Glaze
authors.forename: Paul B
authors.initials: PB
authors.lastname: Myrdal
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Yalkowsky
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D008297:Male; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000502:physiology; D012995:Solubility; D013312:Stress, Physiological / Q000187:drug effects* / Q000502:physiology
chemical_list: D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin