(W1130-03-16) Development of Novel Local Anesthetics-Clay Composite Formulations to Improve Stability and Reduce Onset Time

Purpose: This study is to develop a novel formulation to enhance the stabilty of the local anesthetics with ester group linkages, such as Tetracaine. Local anesthetics (LAs) can be divided into two types according to their structural characteristics. One type contains ester group linkages (e.g., Tetracaine) and the other contains amide group linkages (e.g., Lidocaine)^[1]. The ester bond is prone to hydrolysis, resulting in poor stability of Tetracaine. Pliaglis cream is the most potent commercially available local anesthetics containing 7% Lidocaine and 7% Tetracaine. Due to Tetracaine’s instability, Pliaglis cream must be stored at low temperatures (2-8℃) to achieve 2 yrs shelf-life stability. During the formulation development process, we initially faced challenges with physical stability, as evidenced by phase separation observed after 3 months of storage at room temperature. After the formulation modifications, we successfully created a novel LAs-clay composite formulation. This innovative formulation aims not only to enhance shelf-life stability and anesthetic effectiveness but also to improve physical stability at room temperature.

Methods: A homogeneous formulation was achieved by first mixing Lidocaine and  Tetracaine and a polar solvent with a mechanical mixer to dissolve both drugs , then adding the cellulose polymer (with stir), and clay (with intense stir) sequentially. We further assessed the formulation’s performance through accelerated stability tests, in vitro skin permeation studies, and an animal efficacy model.

Results: Accelerated stability test: This novel LA-clay composite formulation maintained approximately 98.6% of its original concentration after 3 months. The main generation rate of Tetracaine degradation product BABA in LA-clay composite formulation was significantly lower when stored at 40℃ (0.14%) comparing to Pliaglis cream stored at 25℃ (1.53%). In addition, this LA-clay composite formulation has no phase separation stored at 40℃ after 3 months. In vitro skin permeation study: This novel LA-clay composite formulation comparing to Pliaglis cream has increased permeation flux (Lidocaine/1.7 times; Tetracaine/1.1 times) and higher skin retention (Lidocaine/2.0 times; Tetracaine/1.6 times). In vivo efficacy evaluation: This study was conducted on Wistar Rats, this formulation has shown the higher pain threshold (1.3 times) and shorter onset time of the anesthetic effect compared to Pliaglis cream.

Conclusion: In summary, our local anesthetics-clay composite formulation has shown remarkable advancements. Firstly, it exhibited significantly improved physical and chemical stability, as evidenced by the results obtained from a 3-month, 40℃/75%RH study. Additionally, this formulation has demonstrated superior retention of both drugs in the skin compared to Pliaglis cream. Finally, it has achieved enhanced efficacy with a shorter onset time.

References: [1] Local anesthetics review of pharmacological considerations. Anesthesia progress. 2012; 59: 90-102


Permeation of Lidocaine and Tetracaine


Lidocaine and Tetracaine amount / skin weight


Threshold increased after 10 mins of drug removal