Evaluation of Olive Oil-Based Formulations Loaded with Baricitinib for Topical Treatment of Alopecia Areata

Abstract

Background: Alopecia areata is an autoimmune disorder that causes hair loss in clumps about the size and shape of a quarter. The estimated prevalence of the disorder is approximately 1 in 1000 people, with a lifetime risk of approximately 2 percent. One of the systemic therapies for alopecia areata consists of the use of glucocorticoids or immunosuppressants.

Methods: Baricitinib (BCT) is a Janus kinase (JAK) 1 and 2 selective inhibitor used as an immunosuppressant drug. In this study, three olive oil BCT formulations (Oil A, Oil B, and Oil C, which differ in their content in squalene, tocopherol, tyrosol, and hydroxytyrosol) have been developed for topical delivery. The formulations were physicochemically characterized and the in vitro drug release and ex vivo permeation through human skin tissues were assessed.

Results: The results showed nearly identical viscosity across all three formulations, exhibiting Newtonian behavior. The mathematical modeling used to describe the drug release profiles was the one-site binding hyperbola for all formulations. Oil-based formulations showed a slow BCT penetration into human skin. Skin integrity remained intact during the experiments, with no signs of irritation or alterations observed. In addition, all the formulations proved their efficacy in vivo.

Conclusions: Among the formulations, Oil A demonstrated the highest ability retention capacity (Q_r = 1875 ± 124.32 ng/cm²) in the skin, making it an excellent candidate for further investigation in the treatment of alopecia areata.

Introduction

Alopecia areata is a common non-scarring hair disorder, regularly presenting with patches of hair loss on the scalp. It can evolve into severe forms, such as alopecia totalis (loss of all scalp hair) and alopecia universalis (loss of all scalp and body hair) [1]. Many known and unknown factors govern the development of this dermatologic condition. Environmental factors, viral infections, trauma, and genetic predisposition are all believed to contribute to its pathogenesis [2]. Current treatments options, such as broad-acting corticosteroids, are effective in mild cases. However, more severe forms of alopecia areata remain challenging to manage clinically. Recent research has focused on targeting the reversible Janus-associated kinase (JAK) pathway as a potential therapeutic approach for alopecia [3].

In alopecia areata, hair loss occurs when the immune system fails to protect hair follicles, leading to the infiltration of natural killer group 2D (NKG2D) positive CD8+ T cells and CD4+ T cells [4]. These T cells release interferon-γ, which activates Janus kinase-1 and 2 (JAK1 and JAK2) in the epithelial cells of hair follicle. This activation triggers the secretion of interleukin-15, further stimulating JAK1 and JAK3 in the T cells. IL-15 promotes the survival, proliferation, and activation of cytotoxic CD8+ T cells, which are key players in the autoimmune attack on hair follicles in AA [5]. Ultimately, this leads to the damage of hair follicles and subsequent hair loss [2,6]. In small clinical studies, JAK inhibitors have demonstrated potential in the treatment of alopecia [7].

Baricitinib (BCT) (2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl) zetidine-3-yl) acetonitrile), with a molecular weight of 371.42 g/mol (C16H17N7O2S), is a small molecule able to inhibit the signaling pathway of JAK [8]. BCT is an oral medication that selectively inhibits JAK1 and JAK2 and is approved for the treatment of moderately to severely active rheumatoid arthritis in adults in over 70 countries [9]. Furthermore, in the European Union and Japan, it has been approved for treating moderate-to-severe atopic dermatitis in adults [10]. Moreover, BCT has shown anti-inflammatory properties in patients with autoimmune diseases [11,12]. It has been demonstrated that JAKs have a critical function in cytokine signaling. Consequently, inhibiting JAKs would lead to the blocking of specific cytokines and thereby reducing the inflammation [13]. Jabbari A et al. revealed a very successful clinical response to the treatment of alopecia areata with BCT [14]. BCT is rapidly absorbed after oral administration and reaches peak plasma concentrations at approximately 1 h. BCT oral bioavailability is 79% and it is moderately bound (about 50%) to plasma proteins, mainly albumin [15]. Olive oil is rich in fatty acids, such as its oleic, stearic, bioactive and antioxidant components. It has been used for hundreds of years to treat various pathologies such as inflammation, hypertension and gout and topical conditions such as wounds, sores, and infections on the mucosa or skin [15,16]. In cosmetics, it is used for its moisturizing properties to help strengthen the hair and increase its elasticity, helping prevent breakage or split ends [17,18]. Also, oleuropein present in olive oil impacts the hair-growth cycle in mice [18]. Due to its acidic components and permeability potential, olive oil might be a good carrier for treating topical conditions. Specifically, oils containing BCT seem to be a good approach to treating alopecia areata.

Lately, a few delivery systems have been investigated for topical baricitinib. Garrós et al. investigated liposomal formulations of baricitinib for ophthalmic use in Sjögren’s syndrome [19]. In another work, Mohammadi et al. developed a lipid-based solution of baricitinib (BCT-OS) for the topical treatment of psoriasis. The researchers formulated baricitinib in excipients like Transcutol® P, Labrafac® Lipophile WL 1349, and Lauroglycol® 90 [20]. Nene et al. examined a baricitinib-loaded nanoemulgel for atopic dermatitis, with promising results in reducing inflammation [21].

These studies demonstrated the potential of topical baricitinib. However, none of them explored olive oil-based formulations, not to mention that the researchers addressed different therapeutic targets. The novelty of our work lies in its unique approach of using olive oil-based formulations of baricitinib for the topical treatment of alopecia areata, addressing the specific limitations of the existing research. Therefore, the main purpose of this work was to study the effectiveness of three olive oil-based formulations in combination with BCT and Transcutol® P to stimulate hair growth as part of the treatment for alopecia areata. Olive oil with a higher content of squalene (Oil A), another containing hydroxytyrosol as major component (Oil B), and common extra virgin olive oil (Oil C) were used as part of the essayed formulations. The detailed physicochemical oil characterization, the in vitro release, the ex vivo permeation studies through skin tissues, and the histological evaluation of the effect of these oils were conducted as part of the more specific goals. In addition, we explored the antioxidant potential of the oils by DPPH analysis.

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Chemicals and reagents

Baricitinib (BCT) and Formic acid ammonium salt were bought at Sigma-Aldrich (Madrid, Spain). Transcutol^® P [Diethylene glycol monoethyl ether] was supplied by Gattefossé (Barcelona, Spain). DPPH (2,2-diphenyl-2-picrylhydrazyl hydrate) was acquired from (Sigma-Aldrich Chemie, Steinheim, Germany). Double distilled water was obtained from a Milli-Q^® purification system lab supply (Millipore Corporation, Burlington, MA, USA).

Beirampour, N.; Mallandrich, M.; Bustos-Salgado, P.; Domínguez-Villegas, V.; Garrós, N.; Mohammadi-Meyabadi, R.; Clares-Naveros, B.; Romero-Olid, M.N.; Pérez-Cano, F.J.; Girbal, M.; et al. Evaluation of Olive Oil-Based Formulations Loaded with Baricitinib for Topical Treatment of Alopecia Areata. Pharmaceutics 2025, 17, 475. https://doi.org/10.3390/pharmaceutics17040475

Read also our introduction article on Topical Excipients here: