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A novel proliposomal ropivacaine preparation: preclinical and human volunteer studies.
Abstract Number: O1-01
Abstract Type: Original Research
Slow-release liposomal formulations of local anesthetics prolong plasma redistribution and reduce peak plasma drug concentration. Clinical applicability of current liposomal preparations is limited by short liposomal shelf-life. We describe a novel proliposomal preparation of ropivaciane oil with a shelf-life of in excess of two years at room temperature, that produces multilamellar liposomal vesicles on exposure to aqueous media. Preliminary data demonstrated a maximal tolerable dose in mice at least 40 times greater than for plain ropivacaine. Here we present pharmacodynamic and pharmacokinetic data in human volunteers following subcutaneous administration.
Methods & Results:
In vitro: The formulation was assessed for nanoparticles using cryo-transmission electron microscopy (cryo-TEM). On exposure to plasma the study drug went from a particle-free homogenous oil to an emulsion containing multilamellar liposomal vesicles (Fig A-C).
Human PD: In a randomized / blinded study 15 volunteers received 2.5mL s.c. of proliposomal 4% ropivacaine, plain 0.5% ropivacaine and vehicle. Pinprick and experimental heat pain tolerance were assessed over 72 hrs. There was increased duration in pinprick anesthesia; proliposomal and plain ropvicaine were 28.8 (6.0) hours and 15.9 (3.5) hours respectively; mean difference 16.8 hours (95%CI 10.0 to 23.7; p=0.001). There was an increased duration in experimental heat pain analgesia; p=0.036.
Human PK: 9 volunteers received 2.5mL s.c. of either proliposomal 4% ropivacaine (n=6), plain 0.5% ropivacaine (n=3); plasma ropivacaine concentrations was assessed over 72 hours. There was only a 64% increase in peak plasma concentration in the proliposomal ropivacaine group (164 ± 43 ng/mL compared with 100 ± 41 ng/mL in the plain ropivacaine group) despite an eight-fold increase in ropivacaine dose in the proliposomal group. Peak plasma concentrations were well below the putative toxic plasma concentration for both groups. The terminal half life (13.8±3.6 hrs) and area under the curve (5090±1476 hng/mL) for proliposomal ropivacaine were greatly increased when compared to plain ropivacaine (5.9±2.3 hrs and 593±168 hng/mL respectively).
The PKPD effect of proliposomal ropivacaine is compatible with liposomal local anesthetics. The advantage of the proliposomal oil is its ease of preparation and its extended shelf-stability at room temperature.