INTRODUCTION
Tuberous sclerosis (TS) is an autosomal dominant disease, characterised by the multisystem formation of benign non-invasive tumors, called hamartoma and distributed in tissues and organs such as: brain, kidneys, lungs, heart, eyes and skin (1). The most prevalent skin condition in TS are facial angiofibromas (FA), which occur due to an alteration of the mTOR (mammalian target of rapamycin) pathway. This facial injuries suppose an aesthetic and psychological problem (2,3) and multiple treatments have been established for this patients. Physical treatment like radiofrequency, electrocoagulation, cryotherapy, dermabrasion and laser therapy (4) are invasive and painful, and require anesthesia. The interest of mTOR inhibitors focuses pharmacological treatment on everolimus and sirolimus, and recent publications place topical rapamycin (sirolimus) as the most appropriate alternative (5).
We found multiple studies with topical rapamycin in the literature, including four randomized clinical trials (6-9) and all of them provide favorable data of effectiveness and safety. However, high variability between studies in terms of concentration, vehicle, posology, duration of treatment and effectiveness assessment forces to study several formulations to choose the most appropriate.
Several authors have studied different formulations other than the classic formulation (an ointment based on petrolatum) with the aim of achieving a better appearance and consistency of the formulation in order to improve patient compliance with treatment.
Bouguéon et al (10) studied the physico-chemical stability of a cream formulation with a commercialized excipient called Excipial hydrocrème®. Additionally, they used diethylene glycol monoethyl ether P (Transcutol®) as a vehicle and demonstrated that rapamycin was ten times more soluble in Transcutol®(fully soluble, 20.2 mg/ml) compared to liquid paraffin (<2 mg/ml). Guyader et al (11) conducted a physico-chemical and microbiological stability study on a gel-type formulation. Ghanbarzadeh et al formulated rapamycin integrated into a liposomal solution explaining the metodology in development of rapamycin liposomas and additionally studied their chemical stability using a validated high-performance liquid chromatography (HPLC) method (12,13).
Among all the concentrations and dosages reported in the literature, 0.4% concentration, three times per week, it is interesting to avoid exposure to the drug every day and thus minimize possible cutaneus adverse events without compromising effectiveness (14,15).
In addition, the current legal regulations in Spain on magistral formulas establishes that the validity period of non-typified magistral formulas corresponds to the full duration of the treatment (16). Secondly, the Guide to Good Practice of Preparation of Medications in Hospital Pharmacy Services in Spain establishes a validity period of 30 days for ointments and creams, which can be increased if demonstrated with stability studies (17).
The purpose of this study is to improve the classic formulation of topical rapamycin for FA in TS and determine the validity period of the proposed formulations based on chemical, physical and microbiological stability.