Preparation, Characterization, and Stability of Liposome-Based Formulations of Mitoxantrone

Abstract

The preparation, characterization, and stability of lyophilized liposome-based formulation of mitoxantrone was investigated. Mitoxantrone was entrapped inside small, unilamellar liposomes composed of dioleoylphosphocholine (DOPC), cholesterol, and cardiolipin. The mean vesicle size and drug entrapment efficiency of the liposomes were ~ 150 nm and ~ 99%, respectively. Less than 1% of drug was lost and mean vesicle size remained unchanged after sterile filtration. The pre-lyophilized (pre-lyo) formulations were characterized by a differential scanning calorimetric (DSC) method. Results showed that the glass transition temperatures (Tg′) increased as the molar ratios of sucrose:lipid and trehalose:lipid in the formulations were increased. The maximum Tg′ of the pre-lyo formulations containing 10:1 sucrose:lipid and trehalose:lipid molar ratios were − 37°C and − 41°C, respectively. After reconstitution of the lyophilized cake of the sucrose-containing formulation, the mean vesicle size was comparable to pre-lyo liposome size. In vitro release studies showed that less than 2% of mitoxantrone was released after an extensive dialysis against phosphate buffered saline (PBS) at 37°C, indicating that the mitoxantrone was highly associated and retained inside the liposomes. Short-term stability studies of the sucrose-containing formulations revealed that the reconstituted and eight-fold diluted formulations were stable for up to 8 hours at room temperature. Long-term stability studies of lyophilized liposomal mitoxantrone showed that the lyophilized formulation was stable for up to 13 months after storage at refrigerated condition.

Key Words:

• Mitoxantrone stability
• Liposomes
• Injectable formulation
• Lyophilization