Tofacitinib Loaded Squalenyl Nanoparticles for Targeted Follicular Delivery in Inflammatory Skin Diseases.

Rebekka Christmann,Wolfgang Bäumer,Marcus Koch,Jenny Wilzopolski,Claus-Michael Lehr,Brigitta Loretz,Thomas Vogt,Sangeun Lee,Duy-Khiet Ho,Ulrich F Schaefer

doi:10.3390/pharmaceutics12121131

Abstract

Tofacitinib (TFB), a Janus kinase inhibitor, has shown excellent success off-label in treating various dermatological diseases, especially alopecia areata (AA). However, TFB’s safe and targeted delivery into hair follicles (HFs) is highly desirable due to its systemic adverse effects. Nanoparticles (NPs) can enhance targeted follicular drug delivery and minimize interfollicular permeation and thereby reduce systemic drug exposure. In this study, we report a facile method to assemble the stable and uniform 240 nm TFB loaded squalenyl derivative (SqD) nanoparticles (TFB SqD NPs) in aqueous solution, which allowed an excellent loading capacity (LC) of 20%. The SqD NPs showed an enhanced TFB delivery into HFs compared to the aqueous formulations of plain drug in an ex vivo pig ear model. Furthermore, the therapeutic efficacy of the TFB SqD NPs was studied in a mouse model of allergic dermatitis by ear swelling reduction and compared to TFB dissolved in a non-aqueous mixture of acetone and DMSO (7:1 v/v). Whereas such formulation would not be acceptable for use in the clinic, the TFB SqD NPs dispersed in water illustrated a better reduction in inflammatory effects than plain TFB’s aqueous formulation, implying both encouraging good in vivo efficacy and safety. These findings support the potential of TFB SqD NPs for developing a long-term topical therapy of AA.

Highlights

Alopecia areata (AA) is one of the major non-scarring hair loss disorders with a lifetime incidence of 2% [1,2,3]
We investigated the performance of TFB squalenyl derivative (SqD) NPs compared to formulations of the plain drug and vehicle controls in some established ex vivo and in vivo models
We evaluated the hair follicles (HFs) targeted transport and therapeutic efficacy of TFB SqD NPs in comparison to plain drug solutions in an ex vivo pig ear model and an allergic dermatitis mouse model, respectively

Summary

Introduction

Alopecia areata (AA) is one of the major non-scarring hair loss disorders with a lifetime incidence of 2% [1,2,3]. Long-term systemic treatment with TFB can cause a broad and severe spectrum of adverse effects due to the wide bioactive range of such JAKs [14]. In 2019, TFB received an FDA-boxed warning due to an “increased risk of blood clots and death with higher dose” [16]. Those facts emphasize the necessity of generating a safer treatment profile for TFB, especially in non-life-threatening diseases like AA [5,17]

Objectives

Methods

Findings

Conclusion