Solid Lipid Nanoparticles as Carriers for the Synthetic Opioid LP2: Characterization and In Vitro Release

Angelo Spadaro,Miriam Lorenti,Ludovica Maria Santagati,Lorella Pasquinucci,Rita Turnaturi,Maria Grazia Sarpietro,Carmela Parenti,Lucia Montenegro

doi:10.3390/app112110250

Abstract

A synthetic dual-target mu opioid peptide receptor/delta opioid peptide receptor anti-nociceptive ligand, named LP2, has emerged as a promising candidate for the management of acute and/or persistent pain, but its lipophilicity limits further developments as a therapeutic agent. In this work, to allow designing aqueous formulations of LP2 for parenteral administration, solid lipid nanoparticles (SLNs) were investigated as LP2 nanocarriers. LP2-loaded SLNs were prepared by the phase-inversion temperature method, showing good technological properties (small mean particle, size, low polydispersity index, good stability). As LP2 was a diastereoisomeric mixture of 2R/2S-LP2, an HPLC method was developed to identify and quantify each diastereoisomer, and this method was used to assess LP2 in vitro release from SLNs. The developed method, based on reverse-phase chromatography using an isocratic mobile phase consisting of 50% methanol and 50% triethanolamine at 0.3% (pH = 3 with trifluoroacetic acid), allowed efficient separation of 2R- and 2S-LP2 peaks and reliable quantification with intra- and inter-day precision and accuracy within the acceptability limit, expressed as relative standard deviation set at ≤15%. The results of this study suggest that the incorporation of LP2 into SLNs could be a promising strategy to design suitable formulations for further pharmacological studies involving LP2.

Highlights

Unloaded solid lipid nanoparticles (SLNs), prepared by the PIT method, showed a small mean particle size, which was not affected by LP2 loading
LP2 was loaded into SLNs as a racemic mixture because especially useful in persistent pain treatment of SLNs samples was determined by the high‐performance previous studies highlighted that LP2, 2R-LP2, and 2S-LP2 exhibited a different profile liqui release was supposed to occur exclusively from the
LP2 was loaded into SLNs as a racemic mixture b previous studies highlighted that LP2, 2R‐LP2, and 2S‐LP2 exhibited a different pr modulating acute thermal nociception

Summary

Introduction

Solid lipid nanoparticles (SLNs) have been widely investigated as carriers for drug delivery by different administration routes [1,2,3,4,5]. A dual-target mu opioid peptide receptor (MOPr)/delta opioid receptor (DOPr) anti-nociceptive ligand, named LP2 [11], containing a benzomorphan nucleus (Figure 1), has been synthesized and investigated for its in vivo biological activities in animal models of acute and persistent pain [12]. Compounds with multitarget opioid activity are effective antinociceptive agents for pain management with a limited incidence of adverse effects, usually associated with clinically used opioid analgesics acting at a single target [16,17,18].

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