Topical 2% Ketamine - % Amitriptyline Gel: Which Poloxamer 407 Concentration Should Be Selected?

Introduction
A topical gel containing 2% w/V ketamine and 1% w/V amitriptyline is under development for the symptomatic treatment of neuropathic pain in patients with therapeutic failure. Poloxamer 407 (P407) was selected for its thermogelling properties: packaging in a tube in liquid form (after refrigeration), and application to the skin in gel form (at room temperature). The objective of this work was to determine an optimal P407 concentration to obtain a gelation temperature (Tgel) < 20°C and to study the factors likely to affect it.

Materials and Methods
Inter-batch variability and P407 concentration were evaluated on gels formulated without active ingredients (AIs), using 3 batches and 3 P407 concentrations (20%, 22.5%, and 25%) (n=1), and on gels containing AIs, using 2 batches and 2 P407 concentrations (22.5% and 25%) (n=3). The impact of the AIs was evaluated by comparing gels with and without AIs at 22.5% P407 (n=3). The influence of the dispersion process was evaluated by varying the duration and speed (V) of an Ultra-Turrax (UT) (1 min at V2 or 5 min at V3) or of a blade stirrer (1 min or 5 min), on gels formulated with 25% P407 without AIs (n=1). Tgel values were determined from viscosity measurements between 15 and 25°C obtained using an RM 200 CP 4000 PLUS Lamy Rheology rheometer with cone-and-plate geometry (angle: 1.98°, diameter: 20 mm).

Results
The mean Tgel values obtained from the 3 batches tested were 22.1 ± 0.8°C (CV=3.6%) at 20% P407, 20.0 ± 1.1°C (CV=5.5%) at 22.5% P407, and 17.0 ± 1.3°C (CV=7.6%) at 25% P407. The addition of the AIs changed the Tgel from 21.3 ± 0.5°C to 19.8 ± 0.4°C in a gel formulated with 22.5% P407. At 22.5% and 25% P407 with AIs, the Tgel obtained was below 20°C (19.8 ± 0.4°C and 16.9 ± 1.7°C, respectively). At 20%, the gel viscosity was insufficient, with a liquid texture upon extrusion from the tube. The Tgel values measured with dispersion of the gels using the UT were 18.7°C (1 min at V2) and 18.8°C (5 min at V3), and 18.5°C with the blade stirrer, regardless of the stirring duration, compared with 18.6°C without dispersion.

Discussion/Conclusion
Tgel depends on the P407 concentration and appears to decrease in the presence of the AIs. A P407 concentration between 22.5% and 25% would allow optimal topical application (Tgel < 20°C). However, inter-batch variability was observed (CV > 5%). This variability should be taken into account in order to achieve an optimal Tgel. Nevertheless, excessively high viscosity, related to a high concentration, may constitute a limitation for the preparation process. These trends remain to be confirmed with additional replicates and statistical tests. Scale-up and stability studies of the finished product will be determining steps in confirming the selected concentration.

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