Assessing the Solubility of Baricitinib and Drug Uptake in Different Tissues Using Absorption and Fluorescence Spectroscopies

The low water solubility of baricitinib (BCT) limits the development of new formulations for the topical delivery of the drug. The aims of this study were to assess the solubility of BCT in different solvents, including Transcutol, a biocompatible permeation enhancer that is miscible in water, to evaluate the drug uptake in human skin and porcine tissues (sclera, cornea, oral, sublingual, and vaginal), and to subsequently extract the drug from the tissues so as to determine the drug recovery using in vitro techniques. Analytical methods were developed and validated for the quantification of BCT in Transcutol using absorption and fluorescence spectroscopies, which are complementary to each other and permit the detection of the drug across a broad range of concentrations. Results show that Transcutol permits an increased drug solubility, and that BCT is able to penetrate the tissues studied. The solutions of BCT in Transcutol were stable for at least one week. Hence, Transcutol may be a suitable solvent for further development of topical formulations.

Introduction

Topical delivery is a noninvasive route and an alternative to oral administration. The topical route involves the skin and the nasal, buccal, sublingual, ophthalmic, rectal, and vaginal mucosae. Some patients struggle with oral administration, while in contrast the topical route is easy to administer, which may improve the patients’ compliance; some medications administered orally cause digestive side-effects, but the topical route may avoid this inconvenience. Additionally, drug abuse through the topical dosage form is lower than under oral administration. Topical delivery seeks the permeation of drugs through the skin or mucosae [1]. However, drugs face some barriers in penetrating into the tissues, these can include the presence of mucus on the mucosae, low water content, or the existence of the stratum corneum, which is the outermost skin layer and has the main barrier function [2].

Baricitinib (BCT), named 2-[1-ethylsulfonyl-3-[4-(7 H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile according to IUPAC (Figure 1), is an oral selective and reversible Janus-associated kinase (JAK) inhibitor, which modulates the signaling pathway. It has a known anti-inflammatory profile in patients with autoimmune diseases. The BCT mechanism of action consists of inhibiting the signal transduction of IL-6, IL-12, IL-20, IL-22, IL-23, and IFN-γ [3,4,5,6]. BCT was approved by the European Medicines Agency (EMA) for the treatment of moderately to severely active rheumatoid arthritis (RA) in adults and for the management of specific cases of atopic dermatitis [7]. Recently, the US Food and Drug Administration (FDA) approved BCT for emergency use in the treatment of COVID-19 due to its capability of modulating the immunopathology associated with SARS-CoV-2 infection, as well as for the treatment of alopecia areata in adults [8,9].

The therapeutic effectiveness and safety of BCT have been investigated, showing sufficient effectiveness and tolerability in clinical trials [10,11]. It is typically administered orally, after which 80% oral bioavailability has been reported in healthy human subjects, but it decreased by 11–18% in the presence of high-fat meals [8]. BCT has a relatively low molecular weight (371.42 Da), and, although BCT is very poorly soluble in water (0.357 mg/mL to 0.46 mg/mL at 25 °C) [3,12], it is bound to plasma and serum proteins; thus, its oral administration implies systemic distribution. After intravenous administration, its volume of distribution is high (76 L), confirming that distribution to the tissues is significant, which is also in line with its low water solubility.

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Materials

The BCT bulk powder ingredient was supplied by Henrikang Biotech Co., Ltd. (Xi’an, China). Transcutol, Labrafac, Isostearyl Isostearate, Labrasol, Lauroglycol 90, Labrafil M 1944 CS, Plurol oleique, and Capryol 90 were acquired from Gattefossé (Saint-Priest, France). Dimethyl sulfoxide (DMSO), Tween-80, and oleic acid were provided by Panreac Química SA (Barcelona, Spain); limonene, α-pinene, nonane, 1-decanol 99%, octanoic acid, lauryl sulfate, sebacic acid, castor oil, and phosphate-buffered solution pH 7.4 were purchased from Sigma Aldrich (St. Louis, MO, USA); Surfadone LP 100, N-ethyl pyrrolidone (NEP), and N-methyl pyrrolidone were obtained from ISP (West Yorkshire, UK). Perhydro Squalene was acquired from Fagron Iberica (Terrassa, Spain), liquid paraffin was supplied by Roig Farma, (Terrassa, Spain), and distilled water and purified water were obtained using a Station 9000 purification unit.

Mohammadi-Meyabadi, R.; Beirampour, N.; Garrós, N.; Alvarado, H.L.; Limón, D.; Silva-Abreu, M.; Calpena, A.C.; Mallandrich, M. Assessing the Solubility of Baricitinib and Drug Uptake in Different Tissues Using Absorption and Fluorescence Spectroscopies. Pharmaceutics 2022, 14, 2714. https://doi.org/10.3390/pharmaceutics14122714