Determination of Key Parameters for a Mechanism-Based Model to Predict Doxorubicin Release from Actively Loaded Liposomes

Mechanistic model and analysis of doxorubicin release from liposomal formulations

“…The combination of these factors is believed to result in the prolonged circulation of DXR in vivo. [30] Many of these factors, along with others, including DXR self-association, binding to the lipid membrane, [20] and the binding and transport of DXR to the dialysis membrane are expected to govern Figure 2. Structure of the cationic species of DXR that predominates in aqueous solution at low to neutral pH.…”

“…the range relevant to release studies), its transport is governed by the concentration gradient of the neutral, monomeric form of the drug (i.e., the permeable species [20]) between the aqueous intra-and extra-vesicular compartments (denoted as and , respectively). The release rate constant, k m , is dependent on the permeability coefficient for the neutral form of DXR as reported previously [20] while the constant a, the ratio of the aqueous volume of the intravesicular compartment,…”

“…The control factors of lipid content and reservoir pH were selected based on previous studies which identified DXR binding to lipid bilayers and pH-sensitive uptake of DXR into liposomal formulations. [20] Ammonia concentration in the reservoir solution was selected as the third control factor based on previous studies that showed increasing the ammonia concentration in solution accelerated liposomal release of DXR (DXR has virtually no release in the absence of ammonia) [29] and another weakly basic drug. [17] DXR release rates were measured using dynamic dialysis in a manner similar to previous studies with other liposomal formulations.…”

“…[20] A Waters Alliance 2695 Separations Module coupled to a Waters Scanning Fluorescence Detector (M474) (Waters, Milford, MA) was employed with excitation and emission wavelengths at 475 and 580 nm, respectively. A Waters Symmetry C18 column (5 µm, 3.9 × 150 mm) and guard column (3.9 × 20 mm) were used with a mobile phase composition of 55% methanol and 45% of an aqueous solution of 0.1% ammonium formate at pH 3.0 (adjusted with formic acid).…”

“…[11,12,18,[25][26][27] In the present study, liposomal formulations resembling DOXIL  serve as model drug delivery systems to explore a mechanism-based modeling approach to predict drug release under various conditions. The approach relies on previously determined physicochemical properties of DXR and liposomes having the same composition as those used in DOXIL  formulations [20] along with new data for the dialysis membrane binding and transport of DXR across dialysis membranes. Since DXR may undergo various degradation reactions during the time course for release from DOXIL ® (which can take many days to complete), ammonia was added to the reservoir to rapidly raise the intravesicular pH and accelerate release such that testing could be completed prior to substantial drug degradation.…”