Differential scanning calorimetry approach to investigate the transfer of the multitarget opioid analgesic LP1 to biomembrane model

• The interaction of the multitarget opioid analgesic LP1 freebase with MLV is studied.
• The data are compared with those obtained with LP1 oxalate.
• LP1, freebase and oxalate, is incorporated in the phospholipid bilayers of MLV.
• The release of LP1 from a lipophilic carrier to a biomembrane model is studied.
• LP1 freebase is released by liposomes reducing potential side effects of oxalate.

An emerging approach in pain management is the use of multitarget opioid ligands, owing an improved analgesic effect coupled to a reduced incidence of side effects. With a mu opioid receptor agonist/delta opioid receptor antagonist profile, the benzomorphan-based compound LP1 belongs to multitarget ligands class. Previous in vivo investigations showed that LP1 – subcutaneously administered as oxalate salt – was an antinociceptive agent as potent as morphine with a low tolerance-inducing capability. Because the renal toxicity of oxalate is known, an alternative approach allowing the administration of LP1 freebase could be more biocompatible. In this study the interaction of LP1 freebase and LP1 oxalate salt with multilamellar vesicles, as membrane model, was evaluated using differential scanning calorimetry technique. Despite the good membrane interaction showed by LP1 freebase, it was not capable to diffuse in the aqueous medium and to be uptaken by multilamellar vesicles. On the other hand, LP1 freebase possessed a good transfer profile by a liposomal carrier to a biomembrane model. Considering our findings and the need of safe formulations, studies for the development of a suitable carrier for a systemic administration of LP1 freebase are in progress.

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