Comprehensive Investigation of Hydroxypropyl Methylcellulose, Propylene Glycol, Polysorbate 80, and Hydroxypropyl-Beta-Cyclodextrin for use in General Toxicology Studies

This study was conducted to assess the safety and tolerability of the alternative formulation vehicles polysorbate 80 (PS80), propylene glycol (PG), and hydroxypropyl-beta-cyclodextrin (HPbCD) in general toxicology studies in the mouse, rat, dog, and monkey. Twenty (20) mg/kg of hydroxypropyl methylcellulose (MC, control), 10 mg/kg PS80, 1000 mg/kg PG, 500 mg/kg HPbCD, or 1000 mg/kg HPbCD were administered by oral gavage to mice, rats, dogs, and cynomolgus monkeys for approximately 90 days. The effects of these formulations on clinical observations, body weight and food consumption parameters, clinical pathology, and histopathology were evaluated across all species. The suitability of formulations containing up to 20 mg/kg MC,10mg/kgPS80,and1000mg/kgPGforuseinpreclinicalsafety studies was confirmed by a lack of effects on all parameters examined. However, formulations containing HPbCD produced elevated transaminase (aspartate and alanine aminotransferase) levels in rats and mice and fecal changes (loose and soft stool) in large animals. Although the etiology and toxicological significance of the transaminase elevations in rats and mice is uncertain, this finding could represent a significant liability for a preclinical formulation because of the critical importance of these biomarkers in the risk assessment of novel therapeutic agents. Based on these data,PS80andPGareconsideredtobepracticalalternativestoMC in preclinical toxicology studies. However, formulations containing HPbCD should be used with caution because of the elevations in rodent transaminase levels.