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