title: Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amorphous formulation approaches.
abstract: BMS-488043 is an HIV-attachment inhibitor that exhibited suboptimal oral bioavailability upon using conventional dosage forms prepared utilizing micronized crystalline drug substance. BMS-488043 is classified as a Biopharmaceutics Classification System (BCS) Class-II compound with a poor aqueous solubility of 0.04mg/mL and an acceptable permeability of 178nm/s in the Caco2 cell-line model. Two strategies were evaluated to potentially enhance the oral bioavailability of BMS-488043. The first strategy targeted particle size reduction through nanosizing the crystalline drug substance. The second strategy aimed at altering the drug's physical form by producing an amorphous drug. Both strategies provided an enhancement in oral bioavailability in dogs as compared to a conventional formulation containing the micronized crystalline drug substance. BMS-488043 oral bioavailability enhancement was approximately 5- and 9-folds for nanosizing and amorphous formulation approaches, respectively. The stability of the amorphous coprecipitated drug prepared at different compositions of BMS-488043/polyvinylpyrrolidone (PVP) was evaluated upon exposure to stressed stability conditions of temperature and humidity. The drastic effect of exposure to humidity on conversion of the amorphous drug to crystalline form was observed. Additionally, the dissolution behavior of coprecipitated drug was evaluated under discriminatory conditions of different pH values to optimize the BMS-488043/PVP composition and produce a stabilized, amorphous BMS-488043/PVP (40/60, w/w) spray-dried intermediate (SDI), which was formulated into an oral dosage form for further development and evaluation.
authors.affiliation: Biopharmaceutics R&D, Bristol-Myers Squibb, 1 Squibb Drive, P.O. Box 191, New Brunswick, NJ 08903-0191, USA. michael.fakes@bms.com
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fakes
authors.forename: Blisse J
authors.initials: BJ
authors.lastname: Vakkalagadda
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: Sridhar
authors.initials: S
authors.lastname: Desikan
authors.forename: Rajesh B
authors.initials: RB
authors.lastname: Gandhi
authors.forename: Chiajen
authors.initials: C
authors.lastname: Lai
authors.forename: Alice
authors.initials: A
authors.lastname: Hsieh
authors.forename: Miriam K
authors.initials: MK
authors.lastname: Franchini
authors.forename: Helen
authors.initials: H
authors.lastname: Toale
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brown
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004285:Dogs; D004339:Drug Compounding / Q000379:methods*; D016503:Drug Delivery Systems; D004355:Drug Stability; D005260:Female; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006813:Humidity; D007211:Indoles; D053758:Nanoparticles; D010316:Particle Size; D044367:Phase Transition; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011205:Povidone / Q000737:chemistry; D019289:Pyruvic Acid; D012995:Solubility; D013678:Technology, Pharmaceutical; D013696:Temperature
chemical_list: D023581:HIV Fusion Inhibitors; D007211:Indoles; D010879:Piperazines; D019289:Pyruvic Acid; D011205:Povidone; C509651:BMS-488043