Stability study of alternative formulation to sirolimus 0.1% cream in a context of raw material breakage

Introduction
A formulation of Sirolimus cream (SRL) 0.1% is indicated for the treatment of angiofibromas caused by tuberous sclerosis of Bourneville. Unavailability of the main excipient (ME: Excipial^® Hydrocrème) associated with increasing requests of healthcare establishments, led us to seek an alternative to still provide SRL. A substitute excipient, a hydrophilic emulsion (SE: Codexial® Obase), was proposed to replace EP.

Objectives
Check the stability of SRL following the change of excipient for this alternative formulation.

Methods
The alternative formulation was made according to Bougueon et al. by replacing ME with SE, then packaged in 30g aluminum tubes and stored in a 30°C /65% RH climatic chamber (Memmert).
To ensure conformity of the preparation, the laboratory control department carried out various tests:
* SRL determination by HPLC was used (Waters) for each sample (triplicate) with UV spectrometry detection method of the analyte (λ = 278 nm), associate with degradation products detection thanks to diode-array UV detector (210 nm to 400nm).
* pH was measured with a specific electrode (Mettler Toledo - Inlab Visquous).
* Viscosity was assayed (triplicate) using a Brookfield viscometer.
All these tests were carried out at D0, D7, D14, D21 and will be carried out at D30. One tube was used per test day.

Results
No degradation was observed during stability study period. The concentration of SRL was always > 95% in comparison to initial assay D0.
The pH observed with SE is higher than formulation with ME (6.6 vs. 6.0), but stable (variation < 2%) and within the range accepted by the laboratory marketing SE. Viscosity with SE is also higher than formulation with ME (72,000 mPa/s vs. 45,000 mPa/s), and likewise no significantly variation was observed during study period (variation <10%).

Discussion-Conclusion
Controls carried out on this alternative formulation concluded that it was stable over the study period. Our establishment will therefore be able to offer this alternative formulation, 0.1% sirolimus cream Codexial® Obase, with 30 days of stability. It would be interesting to complete this study with an anti-microbial preservation test.

Référence
Bouguéon G, Lagarce F, Martin L, Pailhoriès H, Bastiat G, Vrignaud S. Formulation and characterization of a 0.1% rapamycin cream for the treatment of Tuberous Sclerosis Complex-related angiofibromas. Int. J. Pharm. (2016)

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