Physicochemical and biopharmaceutical approach to a topical formulation of dabrafenib for the local treatment of langerhansian histiocytosis

E. Fischer1, K. Tardivel1, M. Mazuel1, A. Louguet1, A. Dubromel3, C. Theillac4, S. Dalle4, N. Vantard5, C. Paillet2, C. Pivot2, B. Lapras1, C. Merienne1, S.Filali1, F. Pirot1
1 Hospices Civils de Lyon - Unité de Préparation et de Contrôle des Médicaments, plateforme FRIPHARM, Pharmacie à usage intérieur, Groupement Hospitalier Edouard Herriot
2 Hospices Civils de Lyon - Pharmacie à usage intérieur, Groupement Hospitalier Edouard Herriot
3 Hospices Civils de Lyon - Pharmacie et Stérilisations Centrales, Centre de Documentation et d’Information Pharmaceutiques
4 Hospices Civils de Lyon - Centre Hospitalier Lyon Sud, Service de dermatologie
5 Hospices Civils de Lyon - Centre Hospitalier Lyon Sud, Unité de Pharmacie Clinique Oncologique

A 38-year-old female patient presented with a very disabling localized form of Langerhansian histiocytosis (LH) in the vulvar genital area, with BRAF mutation. A systemic treatment with anti-BRAF, dabrafenib1, was not appropriated because of an unfavourable benefit-risk balance.

In this work, we report the development of a formulation of dabrafenib mesylate (MD) for mucosal administration and an evaluation of transmucosal absorption based on the physicochemical properties of MD.

Materials & methods
The chemicophysical properties of MD were log P = 4.57, molecular mass (MM) = 615.9 g/mol, aqueous solubility 3 µg/mL.
Only one commercial MD speciality reserved for hospital use was employed as raw material for the formulation of the topical preparation (0.01%). The product contained microcrystalline cellulose, magnesium stearate and colloidal anhydrous silica in one capsule. The content of the capsule (50 mg MD) was dispersed under agitation in either (i) a sterile commercial hydrogel (water, glycerine, chlorhexidine gluconate, lactone gluconate, hydroxyethyl cellulose, methylparaben, sodium hydroxide), or (ii) an oily excipient mixture (caprylic and dicaprylic ester, HLB 1), or a mixture (i) + (ii). Macro-microscopic observations of the formulations were reported after seven days storage at room temperature (15°C-20°C). Furthermore, an estimate of the transmucosal flux (J) of MD was evaluated from Fick’s law of diffusion such as J = Kp.C, with C the concentration of MD in the gel and Kp the permeability coefficient of MD determined as followed2 : log Kp = - 6.3 + 0.71 * log P - 0.0061 * MM.

Results and Discussion
The dispersion of the powder mixture (MD and excipients) in the hydrogel resulted in a homogeneous suspension suitable for topical administration for at least seven days. The use of a hydrogel facilitated the formulation spreading and its possible removal by washing. Considering an application surface of 20 cm2, J calculated ( 1 µg/h) was lower than the excretion rate of MD3 (5 mg/h), thus limiting the occurrence of systemic adverse effects.

In the absence of a commercially available speciality for topical treatment of LH by MD, a magistral formulation was developed taking into account the physicochemical properties of the MD and the biopharmaceutical aspects of the administration route.

1 Hazim AZ et al. Efficacy of BRAF-inhibitor therapy in BRAFV600E mutated adult langerhans cell histiocytosis. Oncologist. (2020) 25:1001–4.
2 Gary P. Moss, Darren R. Gullick, Simon C. Wilkinson. Predictive Methods in Percutaneous Absorption. Berlin : Springer-Verlag, 2015. 199
3 Puszkiel A et al. Clinical Pharmacokinetics and Pharmacodynamics of Dabrafenib. Clinical Pharmacokinetics. 2019;58:451-467

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