Tuberous sclerosis (TS) is a rare autosomal dominant disease with an incidence of 1 in 6000 to 1 in 10 000 individuals1 in which a series of mutations occur in tumor suppressor genes (TSC1 and TSC2). This leads to deregulation of the mTOR pathway and uncontrolled cell proliferation, resulting in multisystem formation of benign tumors called hamartomas.2 These tumors can have different severity and locations, one of the most common being the kidneys. In addition, they can be affected by slight traumas that can also cause uncontrolled bleeding.3

The most common skin manifestation of TS is facial angiofibromas (FA). They constitute a fundamental diagnostic criterion for the disease since they are present in up to 80% of patients. FA appear at an early age and tend to stabilize in number and size in adolescence, which sometimes represents an esthetic and psychological problem for these patients.4,5

Multiple treatments have been established for this skin condition. Physical treatments like radiofrequency, electrocoagulation, cryotherapy, dermabrasion, and laser therapy present certain problems because are invasive and painful and require anesthesia.6,7 The interest of mTOR inhibitors focuses pharmacological treatment on everolimus and sirolimus, and recent publications place topical rapamycin (sirolimus) as the most appropriate alternative. This molecule is a powerful mTOR inhibitor with immunosuppressive, antitumor, and antiangiogenic characteristics.8

We found multiple studies in the literature that ensure the effectiveness and safety of this pharmacological therapy, such as case series and several clinical trials, with a higher evidence level.9–13 However, significant variability was evident in the concentrations, dosages, and formulations tested in the literature.

In our hospital pharmacy service, we decided to optimize the conventional formulation commonly used by dermatologists in accordance with standard clinical practice: rapamycin 0.4% in vaseline. The result of galenic research and development was a more advanced and complex formula: a 0.4% liposomal formulation of rapamycin3,14 prepared in a biological safety cabinet. The exact composition of the liposomal formulation was rapamycin 0.4%, Transcutol® 3%, liposomal solution (Guinoxome®) 25%, cholesterol 0.1%, isopropyl myristate 10%, propylene glycol 10%, carbopol 2%, NaOH 10% q.s. pH 7.5, and water for injection q.s. 20 g. In the cosmetic and pharmaceutical fields, pre-prepared and commercially available lipid solutions are used, which can form liposomes upon incorporating an aqueous solution. Specifically, the Guinoxome® liposomal solution allows for easy and high-quality liposome formation. The remaining components of the formulation serve as humectants and stabilizers, with special attention given to transcutol. This solvent functions as an excellent absorption promoter, showing a higher solubility of rapamycin in this vehicle compared to liquid paraffin.15 The liposomes obtained were lighter, with better extensibility, and because of their characteristics, they are compatible with all skin types.16 In addition, previous studies have reported a greater release of the active ingredient in liposomal vesicles than in other formulations, like gels.17 This new liposomal formulation was validated based on its chemical, physical, and microbiological stability, with an encapsulation efficiency of 89% for rapamycin.18 The validity period was 3 months at 3–8 °C.19

According to standard clinical practice, topical liposomal rapamycin administration can improve the appearance of FA, demonstrating the drug's effectiveness and safety following formulation optimization.

This study aims to evaluate the effectiveness and safety of liposomal topical rapamycin for the treatment of FA in rare TS disease.

Eleven patients were screened. After exclusion of 8 ineligible patients, 11 patients were included (Fig. 1), of which 8 were women. The median age was 36 (11–64) years at screening. Most of the patients were of Caucasian ethnicity, which is predominant in Spain. Five patients additionally had hamarthromas in different locations, such as the kidneys or lungs. Three patients had prior treatment with topical rapamycin, while four underwent laser or surgical pre-treatment. However, these patients always met the inclusion/exclusion criteria. Two patients also presented atopic-prone skin as a dermatological condition (Table 1). Baseline FASI and IGA scores can be seen in Table 2.

Fig. 1.

Patient disposition.

AEs: adverse events.

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Eight patients completed 24 weeks of treatment, and 3 did not. Two due to drug-related AEs (patient 01 and patient 07) and one due to patient's refusal to treatment continuation (patient 08). Consequently, effectiveness and safety were evaluated in all patients except patient 08.

Evaluation of effectivenessObjective evaluation by investigator (OEI)

Eight of eleven (73%) patients obtained successful treatment according to FASI and IGA scores after 24 weeks of treatment (Table 2). All patients decreased or maintained their FASI and IGA scores after treatment. The final evaluation of effectiveness for patients 01 and 07 occurred at Vx (prior to week 24 of treatment). Table 2 displays the median values and IQR for the FASI score, including its subcategories (erythema, size, and extension), as well as the IGA score before and after treatment. The Fig. 2 corresponds to the box plots showing the distribution of FASI and IGA scores before and after treatment. The central line represents the median, the box spans the IQR, and outliers are depicted as individual data points.

Fig. 2.

Box plots of FASI, IGA, and DLQI scores before and after treatment, n=11.

FASI: facial angiofibroma severity index.

IGA: investigator's global assessment.

DLQI: dermatology life quality index.

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After 12 weeks of treatment, 6/11 patients (55%) achieved successful treatment according to the FASI score. In contrast, based on the IGA score, successful treatment was observed in 7 patients (64%) (Table 2).

The time to treatment success, measured in weeks of treatment according to the FASI score, was 12 weeks for 6 patients and 24 weeks for 2 patients. Likewise, according to the IGA score, treatment success occurred at 12 weeks for 7 patients and at 24 weeks for 1 patient (Table 2).

Subjective evaluation by investigator (SEI)

SIS of FA after treatment was minimal for 2/11 (18%) patients, good for another 2 patients and excellent for 6/11 (55%) patients (Table 2).

SIS of FA after 12 weeks of treatment was good for 8/11 (73%) patients (Table 2). Representative photographs of 2 patients are presented in Annex 4, with an excellent SIS after treatment.

Quality of life

Five of eleven (45%) patients improve their quality of life according to a decrease in score on DLQI questionnaire after treatment.

Median values and IQR for the DLQI questionnaire before and after treatment are shown in Table 2. Fig. 2 corresponds to the box plot showing the distribution of DLQI scores before and after treatment.

Four of eleven (36%) patients improve their quality of life according to a decrease in score on DLQI questionnaire after 12 weeks of treatment.

All patients who completed 24 weeks of treatment obtained successful treatment, according to FASI and IGA scores (8/11, 73%). Specifically, FASI score to measure effectiveness is a simple, reproducible, and validated tool for assessing the severity of FA and subsequent response to rapamycin treatment. As demonstrated, this scale provides a more objective assessment, evaluating erythema, size, and extension of FA.20 Statistical analysis demonstrated a significant difference (p<.05) between FASI score, erythema, FA size, and IGA score before and after treatment with rapamycin liposomal formulation. The non-parametric tests did not show significant differences regarding the extension of FA (Table 2).

Patients who completed 24 weeks of treatment considerably improved the appearance of their FA in subjective evaluation. Particularly, 6/11 (55%) patients obtained excellent improvement of their injuries. Regarding Annex 4, FA in both patients decreased in erythema, size, and extension, achieving considerable flattening of the lesions.

Patient satisfaction also represented a relevant aspect in our study, with an improvement in quality of life in 5/11 (45%) patients after treatment. Nevertheless, significant differences regarding the DLQI scores were not observed in the non-parametric tests (Table 2). FA appeared between 2 and 5 years of age and grow in number and size, stabilizing in adolescence.21 The visual impact of facial injuries implies a self-image issue4,5 especially in young patients, and sometimes dermatological treatment is not prioritized because there are other more serious complications associated with this rare disease. It has been observed that there is a greater angiogenic component at very early ages, while in elderly patients, fibromatous lesions tend to predominate. The exclusion criteria related to age are based on these observations and align with the criteria established by other similar clinical studies, including randomized clinical trials.

Overall, the new formulation was well tolerated, with mild adverse events reported that resolved upon completion of treatment. Two patients experienced moderate erythema, prompting early treatment discontinuation. Notably, both patients had a history of atopic-prone skin. Hematological and pharmacokinetic tests confirmed the lack of systemic absorption of rapamycin after topical administration, further enhancing the drug's safety profile.

Comparing our findings with existing studies proves difficult due to substantial variability in assessing effectiveness. Evaluation methods range from validated scales to subjective researcher opinions. Of the 5 randomized clinical trials found in the literature, only 2 studies evaluate effectiveness according to standardized objective scales.12,13 All patients treated with rapamycin showed significant improvement according to FASI and IGA scores compared to placebo. In our study, all patients who completed the 24-week treatment period achieved favorable effectiveness outcomes and the results align with previously published studies. Adverse reactions were consistent with literature and prior experiences, with no reported serious adverse events.

Greater long-term follow-up of liposomal rapamycin treatment would be appropriate to ensure effectiveness and safety. However, it should be noted that patients are not treated continuously, but rest during the summer months, to minimize or prevent the adverse events derived from rapamycin phototoxicity.

In any case, liposomes provide several advantages that allow a substantial improvement in the treatment of FA. This innovative formula exhibits superior organoleptic characteristics, appearance, and extensibility. Moreover, the sensation after application is more comfortable compared to vaseline.16,18 Additionally, it can be more easily removed with water and neutral soap than other formulations due to its lightweight nature, thus preventing the patient from irritating the facial skin during the washing process. All these benefits contribute to enhancing treatment compliance and patient satisfaction with topical therapy.

On the other hand, liposomes have been demonstrated to serve as carriers for molecules in chemotherapy and immunosuppressive treatments.22,23 Specifically, liposome-encapsulated rapamycin can reach the drug's site of action more quickly with a better release profile, providing an increased bioavailability of rapamycin and improving the penetration of the active substance.17 These results underscore the importance of focusing on the optimization of formulations and the incorporation of new drug delivery systems in magistral formulation within hospital pharmacy services. Our work is an example of this approach. Drug development in hospital pharmacy services is often the only pharmacological alternative available to treat the symptoms of rare diseases, when treatment options are limited or inadequate.

In these rare diseases, pharmacy services are key elements in the pharmacotherapeutic process. In collaboration with dermatologists, hospital pharmacists can conduct a clinical follow-up of patients, contributing to improve effectiveness and minimize adverse reactions.3 Pharmaceutical care demonstrates special relevance in the processes of formulation, dispensing, administration, and follow-up, promoting the correct supervision of these patients and greater integration of hospital pharmacists into the multidisciplinary team.

After galenic improvements and clinical evaluations, the rapamycin liposomal formulation proved to be effective and safe for the treatment of FA in rare TS disease. This innovative formulation was included as a magistral formula in the Pharmacy Service of the Doctor Peset University Hospital, now accessible for prescribing by dermatologists.

The limited number of participants in this observational study could impact the reliability and applicability of the study's results. The initial sample size was not calculated due to it being a rare disease, and patient recruitment proceeded through casual or incidental sampling, as cases occurred and were referred by dermatologists. The methodology used and the statistical tests applied have taken into consideration the sample size (n<30). However, it should be noted that TS is a rare disease that affects a minority of the population (fewer than 1 in 2000 people) and therefore recruiting patients is a more arduous and difficult task.

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  This observational study proves the effectiveness and safety of a new rapamycin liposomal formulation for the treatment of facial angiofibromas in rare tuberous sclerosis disease.

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  This innovative formula allows a substantial benefit for patients. Its organoleptic characteristics contribute to improve treatment compliance and patient satisfaction with topical rapamycin.

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  Liposome-encapsulated rapamycin can reach the drug's site of action more quickly with a better release profile, improving the penetration of the active substance.

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  This research provides new clinical data allowing support in therapeutic decisions for other authors, pharmacists, and dermatologists.

This study was evaluated and approved by the Clinical Research Ethics Committee of Doctor Peset University Hospital (Registration number: 16.102 on 6 May 2021, in Valencia, Spain).

All tests and procedures of the study were performed in accordance with the Declaration of Helsinki for medical research involving human subjects, including research on identifiable human material and data (Helsinki, 1964).

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Clara Cortell Fuster: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. María Amparo Martínez Gómez: Validation, Supervision, Investigation. Ana Cristina Cercós Lletí: Validation, Supervision, Methodology, Conceptualization. Mónica Climente Martí: Validation, Supervision, Resources, Methodology, Conceptualization. Tania Díaz Corpas: Validation, Supervision, Resources, Investigation. Almudena Mateu Puchades: Validation, Supervision, Resources, Methodology, Investigation, Conceptualization. Ángeles Revert Fernández: Validation, Supervision, Resources, Investigation.