Comparative Preclinical Study of Lidocaine and Mepivacaine in Resilient Hyaluronic Acid Fillers

Abstract

Background: Hyaluronic acid-based filler injections are now well-established aesthetic procedures for the correction of skin tissue defects and volume loss. Filler injections are becoming increasingly popular, with a growing number of injections performed each year. Although classified as a minimally invasive procedure, the introduction of a needle or a canula may remain painful for the patient. A major improvement was achieved with the incorporation of local anesthetics into the formulation for pain relief.

Methods: In this study, two well-known anesthetics, lidocaine and mepivacaine, were systematically compared to assess their influence on filler mechanical and biological features. The impact of each anesthetic was monitored in terms of gel rheological properties, stability, durability, and degradation. The release profiles of each anesthetic were also recorded. Finally, the pharmacokinetics of each anesthetic in rats were assessed.

Results: For all the rheological and biological experiments performed, lidocaine and mepivacaine influences were comparable. The addition of either anesthetic into a soft-tissue filler showed no significant modifications of the stability, durability, and degradability of the gel, with similar release profiles and pharmacokinetics at an equivalent concentration.

Conclusions: Substituting lidocaine with mepivacaine does not impact the properties of the gels, and thus both can be equally incorporated as anesthetics in soft-tissue fillers.

Keywords: anesthetics; hyaluronic acid; lidocaine; mepivacaine; pharmacokinetics; release; soft-tissue fillers.

Figure 1

Shelf-life stability of PNT-1 and PNT-4 in the presence of lidocaine and mepivacaine over 3 years. The difference of phase angle between mepivacaine and lidocaine groups was monitored. At each timepoint, 3 syringes were evaluated for each group. Results are expressed as means ± SD. No significant variations were observed when comparing the products with either anesthetic, since the difference remained centered around 0. In each case, both groups maintained their rheological properties within their specifications over 3 years of storage, which makes these fillers deliver their optimal clinical outcomes within the use-by date.

Figure 2

Release profiles of lidocaine and mepivacaine from PNT-1 and PNT-4. For each time point, and for each formulation, 3 gels were evaluated. Results are expressed as means ± SD. Complete release is almost reached after 6 h in the conditions of the test. Lidocaine and mepivacaine release profiles showed very similar trends and were considered equivalent, since no significance was observed between the different formulations at each time point. The significance was evaluated with a Fisher test F2.

Figure 3

Enzymatic degradation test of PNT-1 and PNT-4 in presence of lidocaine or mepivacaine. (A) Fast degradation test with a high enzyme dose. The test highlighted the rapidness of degradation (5 min) of PNT-1 and PNT-4 with no influence of the anesthetic, which is mandatory for these kinds of medical devices in case of adverse events. (B) Persistence test with multiple low enzyme doses. This test showed similar behaviors of the gels either with lidocaine or mepivacaine, suggesting a similar clinical duration for each formulation either with lidocaine or mepivacaine. Each test was performed on 3 different HA gels for each formulation (n = 3). No significance was noticed between lidocaine and mepivacaine formulations.

Figure 4

Pharmacokinetics curves of lidocaine and mepivacaine in rat plasma from PNT-4. PNT-4 gels were injected intradermally into rats. After a quick release of anesthetic in the plasma in the first hour, a rapid decrease of the plasma concentrations of both anesthetics was observed for 6 h. Lidocaine appeared in the plasma first and reached a higher maximum concentration compared to mepivacaine, while the mepivacaine plasma concentration was sustained for a longer duration compared to lidocaine. However, no statistical differences were observed between formulations at any timepoint. Three repeated measurements (n = 3) were carried out for each condition. Results are expressed as means ± SD.