Chronic (180-day) and sub-chronic (90-Day) oral toxicity studies of a novel polyethyleneglycol (PEG)-carbohydrate-lipid conjugate in Wistar rats and beagle dogs

The toxicity of a new synthetic PEG-carbohydrate-lipid conjugate; 3,3-oleoyl-monomethoxy-polyethyleneglycol (n = 12 mean) ether-propanediamino-lactobionate or Oleoylpropane-diaminododecaethyleneglycolmonomethoxy ether-lactobionate ("DOPS-F02") has been evaluated in formal GLP (Good Laboratory Practice) chronic and sub-chronic toxicity studies. The oral toxicity study describes, for the first time, the unique safety features and characteristics of a PEG-saccharide-lipid conjugate. The oral toxicity studies of DOPS-F02 in male and female beagle dogs and Wistar rats documented no deaths or treatment-related signs at high doses. DOPS-F02 was individually administered (by gavage) to male and female Wistar rats at concentrations of 750, 1250, and 2500 mg/kg bodyweight for 180 consecutive days. For the sub-chronic study, juvenile beagle dogs were administered oral doses of DOPS-F02 at 600, 800 and 1000 mg/kg bodyweight, once daily for 90 consecutive days. All animals survived the duration of the studies, the No Observed Effect Level (NOEL) / No Observed Adverse Effect Level (NOAEL) were at the highest doses tested that did not produce any significant changes in clinical signs, hematological parameters, organ weights, ophthalmology evaluations, or histopathological findings. These studies establish that DOPS-F02 is non-toxic in rats and dogs following oral administration. The no-observed-adverse-effect level was determined at 2500 mg/kg for rats and 1000 mg/kg for dogs following oral administration. DOPS-F02 has been developed as a solubilizer with potential to improve formulation of poorly soluble drugs for oral administration. DOPS-F02 demonstrated a great potential for use as a safe solubilizer to improve the pharmacology profile and solubility of lipophilic drugs in aqueous systems by the absence of severe adverse events. Results from these studies are presented to support the future use of this new material in early clinical trials.