Impact of manufacturing process on the stability of an anesthetic topical gel

Introduction
The combination of three active substances (APIs), lidocaine (LDO), epinephrine (EPI) and tetracaine (TRA) in solution, is used to treat skin wounds in children. A new gel formulation was developed to ensure easy and safe administration. Metabisulfite (MBS) was used as a preservative. Preliminary studies revealed the rapid appearance of a critical impurity linked to EPI, epinephrine sulfonic acid (ESUL). As EPI is sensitive to its environment, an analysis of the critical parameters of the preparation process was carried out. The aim of this study was to assess the impact of the manufacturing process on ESUL formation. The combination of three key factors was studied: protection from light, order of addition of constituents and preparation time.

Materials and methods
Gels containing LDO (4%), EPI (0.05%) and TRA (0.5%) were prepared according to two protocols. The first protocol (P1) involved dissolving MBS in the solution containing the 3 PAs and an alginate solution, filtered before adding calcium for gel formation. This protocol required 3 days of preparation. In the second protocol (P2), amber vials were used, MBS was added with calcium and the protocol duration was 2 days. Three batches were prepared separately per protocol (n = 3). Samples stored at 5°C for 3 months were analyzed by reverse-phase liquid chromatography coupled with a UV detector (RPLC-UV) to determine the levels (in area normalization, AN%) of EPI and ESUL. Rheological properties of the gel, pH and EPI and ESUL contents were checked at different times.

Results
The gels obtained by the two protocols showed similar viscosities (14.0 ± 1.4 Pa.s and 13.0 ± 0.6 Pa.s for P1 and P2) over the 3-month study period. The pH values were 4.6 ± 0.0 and 4.1 ± 0.1 respectively for P1 and P2. EPI contents for P1 and P2 were 96.3 ± 2.2% and 102.9 ± 1.1% respectively. For ESUL, at T0, P1 showed an average content of 0.5 ± 0.0% versus 0.2 ± 0.0% with P2. At 3 months, P1 and P2 showed a mean content of 2.5 ± 0.0% and 0.8 ± 0.2% respectively. This change in protocol reduced the level of impurities present at the end of preparation, keeping it below 1.0% after 3 months of cold storage.

Discussion/Conclusion
The preparation protocol is an important factor in the development of a new formulation. Protecting from light, changing the order of incorporation of constituents and reducing preparation time reduced significantly the critical impurity content. Optimization of this protocol will enable us to envisage a longer shelf-life for the hospital preparation of this new topical gel.