Preparation and in vivo evaluation of PEGylated spherulite formulations

Spherulites are multilamellar vesicles obtained by shearing a lamellar phase of lipids and surfactants. They consist of concentric bilayers of amphiphiles alternating with layers of aqueous medium in which hydrophilic drugs can be sequestered with high yield. To be useful for drug targeting applications, spherulites should be small and long circulating. The objectives of this work were threefold. First, the spherulite size was optimized to obtain a mean diameter of less than 300 nm. Second, the vesicle composition was adjusted to minimize in vitro leakage of internal content. Third, the spherulites were coated with 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-[methoxy poly(ethylene glycol)] (DSPE-PEG) to impart them with a long half-life. Then, the PEGylated spherulites (Phospholipon 90G/Solutol HS15/cholesterol/DSPE-PEG 2000 or 5000) were loaded with 1-β-d-arabinofuranosylcytosine (ara-C) and injected intravenously to rats. They were compared to uncoated spherulites and to an ara-C solution. The surface-modified vesicles exhibited long circulation times with areas under the blood concentration vs. time curve exceeding by 3.1- to 6.9-fold that of uncoated spherulites. Similarly, blood levels of ara-C encapsulated in PEGylated vesicles were higher than those of the controls, but they did not parallel the carrier pharmacokinetics. Two hours post-injection, most of the drug was cleared from the systemic circulation, reflecting rapid leakage of ara-C from the vesicles.