Fingolimod Hydrochloride Gel for Dermatological Applications: Optimization of Formulation Strength and Effect of Colloidal Oatmeal (Aveeno®) as Penetration Enhancer

Abstract

Abstract. Fingolimod (FNGL) is an immune-modulatory agent prescribed for relapsing forms of multiple sclerosis. Because of its mechanism of action, FNGL is potentially a treatment for chronic, non-curable Tlymphocyte-driven inflammatory skin diseases (TLDISD) such as psoriasis and atopic dermatitis. Since severe side effects limit the systemic administration of FNGL, the objective of this study is to develop a hydroxypropyl cellulose (2%) FNGL gel for dermatological applications. First, the effect of FNGL strength (0.05%, 0.10%, 0.50%, and 1.00%) on skin permeability and retention was investigated. We carried out several permeation studies with vertical Franz diffusion cells and (i) cellulose or (ii) excised dorsal porcine ear skin (EDPES) as membrane. We also quantified FNGL in the stratum corneum and in dermis with the tape-stripping method. Permeability parameters as well as the amount retained in skin increased significantly (p<0.01) with strength; however, there was no statistically significant difference between the 0.50% and 1.00% gels for both cellulose and EDPES. Therefore, we selected the 0.50% gel to investigate the effect of colloidal oatmeal (0%, 1%, 3%, 6%, and 10%) on FNGL in vitro permeability and skin retention. Colloidal oatmeal has beneficial dermatological properties for TLDISD and may complement FNGL activity. Permeability increased significantly (p<0.001) with colloidal oatmeal at the 6% and 10% strength with an enhancement ratio of 3.5 and 2.4, respectively, whereas the amount retained in the skin decreased significantly (p<0.001) compared to the base gel. In conclusion, the 0.50% FNGL . HCL gel with 6% Aveeno® has very promising permeability characteristics for delivery of FNGL to the skin.

Fingolimod hydrochloride gel shows promising therapeutic effects in a mouse model of atopic dermatitis

“…This study investigates the hypothesis that FNGL, an immune modulator formulated as a topical gel, may reduce the clinical manifestations of AD, an immunological skin disease. Several gels were previously formulated and tested in vitro to find out the FNGL strength and concentration of the penetration enhancer (colloidal oatmeal) that exhibited the most promising skin permeability and retention characteristics . The gels selected for in vivo experiments consisted of 0.5% FNGL in a 2% Klucel ® hydroalcoholic gel base with or without addition of 6% colloidal oatmeal.…”

“…This suggests that Aveeno ® alone may have pH normalization properties. The pH of the gel formulations ranged from 5.02 to 5.73 …”

“…Klucel ® (2%) gel was prepared in batches of 20 g each according to a procedure previously described . Physical evaluation and stability of the gel formulations were also described in that article.…”

“…The availability of topical products of FNGL is a necessary step in the evaluation of FNGL as a therapeutic agent for AD or other immune‐mediated inflammatory skin disorders like acne vulgaris, psoriasis and systemic lupus erythematous. In a previous study, we developed a series of 2% hydroxypropyl cellulose gels containing various percentages of fingolimod (0.05%, 0.10%, 0.50% and 1.00%) and of colloidal oatmeal (0%, 1%, 3%, 6% and 10%) as a possible penetration enhancer. In vitro permeability and skin retention studies showed that the gel containing 0.50% FNGL had the most promising skin penetration properties over the other strengths and that the presence of colloidal oatmeal at the 6% level further enhanced FNGL penetration across porcine skin of 3.5‐fold compared to the base gel.…”

Sphingosine‐1‐phosphate modulators in inflammatory skin diseases – lining up for clinical translation

“…Importantly, the results from mouse models summarized above suggest that topical application of S1P receptor modulators is effective in the treatment of inflammatory skin diseases. In parallel, the development of topical formulations for S1P receptor modulators has significantly progressed . These developments make topical application of S1P receptor modulators possible.…”