Abstract
Recent studies have highlighted the benefit of repurposing oral erlotinib (ERL) treatment in some rare skin diseases such as Olmsted syndrome. The use of a topical ERL skin treatment instead of the currently available ERL tablets may be appealing to treat skin disorders while reducing adverse systemic effects and exposure. A method to prepare 0.2% ERL cream, without resorting to a pure active pharmaceutical ingredient, was developed and the formulation was optimized to improve ERL stability over time. Erlotinib extraction from tablets was incomplete with Transcutol, whereas dimethyl sulfoxide (DMSO) allowed 100% erlotinib recovery. During preliminary studies, ERL was shown to be sensitive to oxidation and acidic pH in solution and when added to selected creams (i.e., Excipial, Nourivan Antiox, Pentravan, and Versatile). The results also showed that use of DMSO (5% v/w), neutral pH, as well as a topical agent containing antioxidant substances (Nourivan Antiox) were key factors to maintain the initial erlotinib concentration. The proposed ERL cream formulation at neutral pH contains a homogeneous amount of ERL and is stable for at least 42 days at room temperature in Nourivan cream with antioxidant properties.
Highlights
Erlotinib (ERL) is a very lipophilic drug and potent epidermal growth factor receptor (EGFR) inhibitor (IC50 ~ 2 nM) currently marketed as tablets (Tarceva®) for the treatment of EGFR mutation-positive non-small-cell lung cancer [1,2]
Based on its mechanism of action, the repurposing of this tyrosine kinase inhibitor drug has been studied in the treatment of local skin disorders such as palmoplantar keratoderma in selected patients with Olmsted syndrome [3], cutaneous squamous cell carcinoma [4], and psoriasis [5]
The use of topical ERL instead of or in addition to the oral ERL tablets may be especially interesting in the control of local skin diseases, as the oral drug is known to induce side effects such as folliculitis, diarrhea, paronychia, fatigue, and hair changes [10]
Summary
Erlotinib (ERL) is a very lipophilic drug (clog P ~ 3.2) and potent epidermal growth factor receptor (EGFR) inhibitor (IC50 ~ 2 nM) currently marketed as tablets (Tarceva®) for the treatment of EGFR mutation-positive non-small-cell lung cancer [1,2]. Based on its mechanism of action, the repurposing of this tyrosine kinase inhibitor drug has been studied in the treatment of local skin disorders such as palmoplantar keratoderma in selected patients with Olmsted syndrome [3], cutaneous squamous cell carcinoma [4], and psoriasis [5]. The use of topical ERL instead of or in addition to the oral ERL tablets may be especially interesting in the control of local skin diseases, as the oral drug is known to induce side effects such as folliculitis, diarrhea, paronychia, fatigue, and hair changes [10]. This study was conducted to design a stable ERL skin cream To make this formulation more feasible without access to ERL marketed pharmaceutical pure powder, the available form of pharmaceutical grade erlotinib (e.g., tablets), commonly used excipients, and reproducible preparation conditions were chosen. The stability of the optimized formulation was assessed by following the content of erlotinib by using a validated stabilityindicating chromatographic method
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