Formulation and characterization of a 0.1% rapamycin cream for the treatment of Tuberous Sclerosis Complex-related angiofibromas

Bouguéon, Guillaume; Lagarce, Frédéric; Martin, Ludovic; Pailhoriès, Hélène; Bastiat, Guillaume; Vrignaud, Sandy

doi:10.1016/j.ijpharm.2016.05.064

Cited by 17 publications

(11 citation statements)

References 11 publications

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“…Among the different types of topical preparations based on rapamycin, a single cream containing 0.1% rapamycin solubilised in Transcutol and mixed with a marketed cream (Excipial) was studied for its stability. 10 However, stability has only been achieved over 85 days while our gel is stable at 4°C for a shelf life of at least 1 year. Moreover, our results were obtained using a highly selective and validated RP-HPLC method, allowing good separation of isomers and degradation products, including secorapamycin, an open ring isomer with extremely low immunosuppressive activity.…”

Section: Discussionmentioning

confidence: 93%

“…11 In addition, it has been shown that this method indicates stability with a very good extraction coefficient (more than 90% for both formulas in hydro-alcoholic gel compared with 64.2%±1.2% in Excipial). 10 The choice to develop a 0.1% rapamycin hydrogel was based on the literature. As shown by several studies, the efficacy and tolerance of the different preparations used are more or less good, depending on the concentration of rapamycin, the type of raw material (API standard powders, ground tablets or oral solutions of rapamycin), the vehicle used for the topical route and the age of the patients.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Bouguéon et al proposed a cream with 0.1% rapamycin solubilised with 5% Transcutol to avoid any bleeding problem and this oily sensation, with stability data. 10 Consequently, this work aimed to develop and characterise a hydro-alcoholic gel containing rapamycin solubilised and surfactant-free to improve the bioavailability of the active molecule, obtain a good appearance and allow skin tolerance. Finally, a long-term stability study at 4°C was performed to determine its shelf life.…”

Section: Introductionmentioning

confidence: 99%

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Long-term stability of 0.1% rapamycin hydrophilic gel in the treatment of facial angiofibromas

et al. 2018

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Objectives In recent years, various formulations containing rapamycin, mainly petrolatum-based, have been tested on facial angiofibromas in tuberous sclerosis. They are often poorly tolerated due to irritation and bleeding. In addition, their effectiveness was insufficient in young adults. The objective of this study was to develop and characterise a hydro-alcoholic gel containing solubilised rapamycin. The stability of the product stored at 4°C was evaluated over 1 year. Methods Two different 0.1% rapamycin gels were formulated with or without α-tocopherol and urea. Different methods were used to characterise the gels: HPLC, gas chromatography, pH, visual observation and optical microscopy. A physico-chemical and microbiological stability study was also conducted for 1 year at 4°C. results Gels were physically and microbiologically stable after 1 year at 4°C: organoleptic characteristics and pH unchanged, no significant decrease in rapamycin was observed, tocopherol droplet size was constant and rheological behaviour was not altered. Conclusions This study describes a new gel formulation to improve skin penetration using various excipients to promote skin tolerance. This study provides, for the first time, detailed stability data for a hydro-alcoholic rapamycin gel.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-term stability of 0.1% rapamycin hydrophilic gel in the treatment of facial angiofibromas

et al. 2018

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“…Dexeryl ® is composed mainly of water, glycerin (15%, w/w) and 10% of lipophilic phase (8% petroleum jelly and 2% paraffin oil, w/w). For F3, API was previously solubilized in 5% (w/w) of Transcutol ® P (Diethylene glycol monoethyl ether, from Gattefossé) and mixed in Excipial ® hydrocream (Galderma) (F3) [30]. Excipial ® hydrocream is composed of 35.5% lipid phase and contains the following excipients: water, paraffin oil, isopropyl myristate, cetearyl alcohol, glyceryl stearate, pentylene glycol, and polysorbate 20.…”

Section: Rapamycin Formulations Testedmentioning

confidence: 99%

Comparison of the In Vitro and Ex Vivo Permeation of Existing Topical Formulations Used in the Treatment of Facial Angiofibroma and Characterization of the Variations Observed

Guyader

Vieillard

et al. 2020

Pharmaceutics

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Rapamycin has been used topically to treat facial angiofibromas associated with tuberous sclerosis for more than a decade. In the absence of a commercial form, a large number of formulations have been clinically tested. However, given the great heterogeneity of these studies, particularly with regard to the response criteria, it was difficult to know the impact and thus to compare the relevance of the formulations used. The objective of this work was therefore to evaluate the link between the diffusion of rapamycin and the physico-chemical characteristics of these different formulations on Strat-M® membranes as well as on human skin using Franz cells. Our results underline the importance of the type of vehicle used (hydrogel > cream > lipophilic ointment), the soluble state of rapamycin and its concentration close to saturation to ensure maximum thermodynamic activity. Thus, this is the first time that a comparative study of the different rapamycin formulations identified in the literature for the management of facial angiofibromas has been carried out using a pharmaceutical and biopharmaceutical approach. It highlights the important parameters to be considered in the development and optimization of topical rapamycin formulations with regard to cutaneous absorption for clinical efficacy.

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“…The formulation of topical sirolimus was developed by the pharmacy team of CHU Angers. Its stability and conservation have been tested and published [23]. Sirolimus cream will be prepared by first solubilizing rapamycin in Transcutol®.…”

Section: Interventionmentioning

confidence: 99%

Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial

Leducq

Caille

Barbarot³

et al. 2019

Trials

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BackgroundCutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults.MethodsThis French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm2.DiscussionFor patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment.Trial registrationClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018–001359-11.

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Formulation and characterization of a 0.1% rapamycin cream for the treatment of Tuberous Sclerosis Complex-related angiofibromas

Cited by 17 publications

References 11 publications

Long-term stability of 0.1% rapamycin hydrophilic gel in the treatment of facial angiofibromas

Long-term stability of 0.1% rapamycin hydrophilic gel in the treatment of facial angiofibromas

Comparison of the In Vitro and Ex Vivo Permeation of Existing Topical Formulations Used in the Treatment of Facial Angiofibroma and Characterization of the Variations Observed

Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial

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