•Drug-catalyzed lipid degradation is a concern that is unique to irinotecan liposomes.•Intraliposomal salt form and extraliposomal pH impact storage stability.•Liposomes containing doxorubicin and ...vinorelbine, two drugs that are not in the camptothecin class, do not show this hydrolytic phospholipid degradation.•Liposomal irinotecan contains an insoluble amorphous stoichiometric salt of irinotecan with the liposome-loading aid sucrose octasulfate.•Exhausting the membrane-traversing cation gradient during loading of the drug into the liposomes was possible owing to the stoichiometric nature of irinotecan sucrose octasulfate and was instrumental in preventing phospholipid degradation.
Therapeutics at or close to the nanoscale, such as liposomal irinotecan, offer significant promise for the treatment of solid tumors. Their potential advantage over the unencapsulated or free form of the drug is due in part to their altered biodistribution. For slow and sustained release, significant optimization of formulation is needed to achieve the required level of stability and allow long-term storage of the drug product. Gradient-based liposomal formulation of camptothecins such as irinotecan poses unique challenges owing to the camptothecin- and acid-catalyzed hydrolysis of phospholipid esters in the inner monolayer of the liposomal membrane. We demonstrated that a narrow set of conditions related to the external pH, temperature, intraliposomal concentration, identity of the drug-trapping agent, physical form of the drug inside the liposomes, and final drug load have a marked impact on the stability of the liposome phospholipid membrane. The physical form of the drug inside the liposome was shown to be an insoluble gel with an irinotecan-to-sulfate ratio approximating 1:1, reducing the potential for irinotecan-catalyzed phospholipid hydrolysis in the internal phospholipid monolayer. As a result of this work, a stable and active liposome formulation has been developed that maintains phospholipid chemical stability following long-term storage at 2-8°C.
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