Introduction: topical rapamycin has been established as an effective and safe therapy for facial angiofibromas in tuberous sclerosis. Different formulations have been tested for this skin disease, most using an ointment as a vehicle. Purpose: to improve the classical formulation of topical rapamycin and to determine the validity period of the proposed options based on chemical, physical and microbiological stability studies. Methods: four different 0.4% rapamycin formulations were prepared (ointment, emulsion, gel and liposomes). The stability studies for each formulation were: chemical (extraction with lipophilic solvents and high-performance liquid chromatography assay), physical (pH, uniformity, extensibility, absence of crystals, absence of phase separation and only for liposomal formulation was determined particle size, zeta potential and encapsulation efficiency) and microbiological (culture samples in blood-agar media) during 56 days. Results: only liposomes were chemically, physically and microbiologically stable after 8 weeks. Ointment, emulsion and gel formulations lost their chemical and physical stability before 56 days. Conclusions: this study describes a new four formulations to improve the previously treatment for facial angiofibromas in tuberous sclerosis. It also provides favorable stability data only for liposomes. However, more dermokinetic and clinical studies are needed to confirm that liposomes are most appropriate to ensure effectiveness, safety and high patient satisfaction.