title: Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by supersaturatable formulations.
abstract: Supersaturatable cosolvent (S-cosolvent) and supersaturatable self-emulsifying drug delivery systems (S-SEDDS) are designed to incorporate water soluble cellulosic polymers such as hydroxypropyl methylcellulose (HPMC), which may inhibit or retard drug precipitation in vivo. A poorly soluble drug, PNU-91325, was used as a model drug in this study to illustrate this formulation approach. The comparative in vitro studies indicated that the presence of a small amount HPMC in the formulation was critical to achieve a stabilized supersaturated state of PNU-91325 upon mixing with water. An in vivo study was conducted in dogs for assessment of the oral bioavailability of four formulations of PNU-91325. A five-fold higher bioavailability (approximately 60%) was observed from a S-cosolvent formulation containing propylene glycol (PG)+20 mg/g HPMC as compared to that (approximately 12%) of a neat polyethylene glycol (PEG) 400 formulation. The low bioavailability of the PEG 400 formulation is attributed to the uncontrolled precipitation of PNU-91325 upon dosing, a commonly observed phenomenon with the cosolvent approach. A S-SEDDS formulation composed of 30% w/w Cremophor (surfactant), 9% PEG 400, 5% DMA, 18% Pluronic L44, 20% HPMC, and other minor components showed an oral bioavailability of approximately 76%, comparable to that of a neat tween formulation (bioavailability: approximately 68%). The significant improvement of the oral bioavailability of the supersaturatable S-cosolvent and S-SEDDS formulations is attributed to a high free drug concentration in vivo as a result of the generation and stabilization of the supersaturated state due to the incorporation of polymeric precipitation inhibitor.
authors.affiliation: Worldwide Pharmaceutical Sciences, Pfizer Inc., Kalamazoo, Michigan 49007, USA. ping.gao@pfizer.com
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Michael E
authors.initials: ME
authors.lastname: Guyton
authors.forename: Tiehua
authors.initials: T
authors.lastname: Huang
authors.forename: Juliane M
authors.initials: JM
authors.lastname: Bauer
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Stefanski
authors.forename: Qun
authors.initials: Q
authors.lastname: Lu
mesh_terms: D000277:Adjuvants, Pharmaceutic; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D016503:Drug Delivery Systems; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065347:Hypromellose Derivatives; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008747:Methylcellulose / Q000031:analogs & derivatives; D014677:Pharmaceutical Vehicles; D011725:Pyridines / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry*; D012995:Solubility
chemical_list: D000277:Adjuvants, Pharmaceutic; D007004:Hypoglycemic Agents; D007328:Insulin; C488474:PNU91325; D014677:Pharmaceutical Vehicles; D011725:Pyridines; D065347:Hypromellose Derivatives; D008747:Methylcellulose