Improvement in postoperative pain control plays an important role in the quality of patient recovery and satisfaction. Single administration of a sustained-release local anesthetic may provide prolonged pain relief and minimize opioid use. Multilamellar vesicles formulated ropivacaine, TLC590 (Figure 1), is being developed to sustain the release of ropivacaine in situ to maintain the local concentration within the therapeutic window. The objective of the present study is to demonstrate its sustained-release profile and the prolonged analgesia by pharmacokinetic and pharmacodynamic studies after local injection in rats.
Materials and Methods
Twelve female Sprague-Dawley rats (randomly divided into two groups, six rats per group) were used in the pharmacokinetic study following the subcutaneous injections of TLC590 (19 mg of ropivacaine/kg) and ropivacaine solution (19 mg of ropivacaine/kg), respectively (Table 1). At designated time points (0.25, 1, 2, 4, 8, 24, 48 and 72 h post-injection), ropivacaine plasma concentrations were determined by a LC-MS/MS and the pharmacokinetic parameters were obtained with Phoenix WinNonlin.
A pharmacodynamic study employing the incisional pain model was performed in twenty male Sprague-Dawley rats (randomly divided into four groups, five rats per group) (Table 2). After intraplanar injection of TLC590 (1.9 mg of ropivacaine/rat), ropivacaine solution (1.9 mg of ropivacaine/rat), Exparel® (1.3 mg of bupivacaine/rat) or normal saline (as a control group) along a 1-cm incision line, the 50% paw withdrawal threshold (g) and percentage of maximum possible effects (%MPE) were measured using the von Frey test at preselected times post-injection.
Results and Discussion
Ropivacaine concentration in plasma versus time profiles of both groups following a single subcutaneous injection is illustrated in Figure 2. The half-life (t1/2) of ropivacaine after subcutaneous injection of TLC590 (26.1 h) was significantly prolonged (about 22-fold) compared with that of ropivacaine solution (1.19 h). While the maximum plasma concentration (Cmax) of ropivacaine after subcutaneous injection of TLC590 (142 ng/mL) was only around one-ninth (1/9) of that after subcutaneous administration of ropivacaine solution (1290 ng/mL), and the exposure of ropivacaine (AUC0-last and AUC0-∞) was similar between two groups (3410 vs. 3910 ng × h/mL for AUC0-last; 3940 vs. 3970 ng × h/mL for AUC0-∞) (Table 3).
The analgesic action attributed to the local anesthetic effect of the TLC590 after paw incision in rats is shown in Figure 3. The anesthetic effect of a single-dose of TLC590 was shown to have as quick an onset as ropivacaine solution but prolonged postoperative analgesia compared to ropivacaine solution. Furthermore, the analgesic effect of TLC590 lasted for 6 hours which was significantly longer than that of Exparel® (<5 hours).
TLC590 exhibited a sustained release profile in pharmacokinetic properties and pharmacodynamic effects after a single administration. These preclinical data indicate that a single administration of TLC590 is a promising candidate for improving postoperative pain management. The safety of TLC590 in different species is further disclosed in another ePoster (ID# 6921).