Rheumatoid arthritis (RA) is a chronic and heterogeneous autoimmune disorder characterized by pain and inflammation of joints. More than 17.6 million people across the world had RA in 2020, indicating a sharp increase by 14.1% in cases since 1990 [1]. There are various treatments approved for the RA, which includes biologics and synthetic disease modifying anti-rheumatic drugs (DMARDs), corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and sometimes analgesics as well to relieve pain and inflammation. Leflunomide, a synthetic and conventional DMARD, is a dihydroorotate dehydrogenase (DHODH) inhibitor causing alterations in immune responses and is a widely prescribed for the management of RA. Due to various challenges such as severe adverse effects like hepatotoxicity, gastrointestinal (GIT) disturbances, other factors such as varying clinical responses, encounter in LEF delivery to RA patients, it is underutilized [2]. The safety and efficacy issues of LEF can be resolved through innovative and novel drug delivery systems which can lead to as a safe, affordable, and easily available treatment.

Currently, LEF is available as 10, 20, 100 mg tablets under the brand name ARAVA® [3]. A variety of challenges are faced during oral delivery of tablets mainly includes its side effects [2]. LEF have high albumin binding in blood plasma showing a high protein binding inside the body. The conversion of LEF to its active metabolite, teriflunomide in vivo and its deposition due to low blood circulation time in vital organs like liver causes toxicity in the body. Due to high drug plasma concentration after stoppage of dosage administration, a washout period for almost 2 weeks for complete removal of drug from the body is generally required. The complete removal of teriflunomide can take up to 2 years without accelerated elimination. The active metabolite, teriflunomide is removed through direct biliary elimination of untransformed drug along with renal excretion of metabolites. The removal of teriflunomide (metabolite of leflunomide) can be increased by administration of activated charcoal or cholestyramine. After this accelerated elimination, almost 23.1% was found more excreted through feces [4]. This longer retention of active metabolite in the body is the reason for teratogenicity of LEF, that’s why it is contraindicated in pregnant females [5]. The current dosage form of LEF also counters a non-specific target producing off-target effects and high plasma protein binding. Therefore, the potential strategies are still to be explored for elimination of drug accumulation even after termination of drug administration and also for decreasing the high drug protein binding.

Additionally, a number of side effects such as hepatotoxicity, GIT disturbances, bone marrow suppression, weight loss and diabetes, hematological effects, skin rashes, ulcerative colitis, and others [2,6]. These side effects should be monitored using suitable assessment methodologies to get rid of safety issues that occur with LEF delivery. Patient counselling regarding proper administration and use of drug is still an important challenge which must be considered. Different clinical responses in different patient population are an issue which is a major concern. Since LEF has a very good oral bioavailability but still it is underutilized due to safety concerns, however, when other DMARDs are not effective, LEF is prescribed in such cases. Prolonged retention and slow onset of action is also a major reason for restricted use of LEF.

Several drug delivery approaches are underway to check their potential in minimizing the current underutilization of LEF due to delivery via conventional oral route which causes safety issues along with cost implications. Novel strategies such as use of nano-cargoes for LEF delivery, stimuli-responsive drug release, lipid-based drug delivery, photothermal and photodynamic therapy, and other types of drug delivery platforms have garnered attention in recent years [2]. The surface alteration/functionalization of nano-cargoes is another emerging strategy which can result in improved penetration for transdermal and topical delivery, controlled drug release, and tailored drug delivery. Additionally, topical and transdermal route are also explored to unravel their potential in safer delivery of LEF [7]. Hybrid and multifunctional systems are other carriers which have shown desired outcomes during last years in recent investigations. Hydrogel and injectable depot systems have also been instrumental in delivering the LEF to the inflamed sites with reduced side effect and increased efficacy [7–9]. Stimuli responsive delivery of LEF could also be gamechanger if its drug release can be controlled with certain internal or external stimulus to reduce dose and minimize side effects [10]. A rational drug combination of LEF with other DMARDs and drugs must be carried in a controlled-dosage regimens that can allow low dose with safer and more effective delivery [11]. The proper and personalized adjustment of titration period for maintenance and loading dose of LEF might also reveal a strategic adaptability in fluctuation of clinical responses that currently occur in patients [12]. Furthermore, a patient centered approach such as regular counselling and guidance before and after treatment must be followed, especially for females on LEF dosing and planning to conceive [13]. Since it is well established that LEF is prescribed when other DMARDs doesn’t respond in the patient for RA, hence, such dose adherence tools and methodologies should be designed to ensure easy persistence of patients on LEF [2,13]. The personalized therapy could be another innovative remedy for designing the particular dose and time period of LEF therapy according to the state and symptoms of the RA patients [14]. Detailed research on innovative and novel solutions to find potential options for safer and efficacious delivery of LEF is required for RA patients.

Numerous studies have been conducted to check the potential of various alternate drug delivery methods which can be instrumental in minimizing LEF underutilization. Shareef and coworkers developed LEF loaded transferosomes based hydrogel for the treatment of RA. In vitro evaluation of formulation depicted excellent hemocompatibility, high permeability, and sustained release behavior. In vivo studies in RA induced model demonstrated increased pharmacodynamic activity when assessed via quantification of attenuated behavioral responses, superior oxidative safety, and radiographic diagnosis [7]. Krishnan and coworkers formulated the LEF loaded nano-lipidic carrier for lymphatic targeting via chylomicron formation to reduce systemic side effects and increase bioavailability. In vivo test in Sprague-Dawley rats confirmed the antiarthritic potential of nano-lipidic carriers of LEF for almost 30 days with a significant reduction in inflammation when compared to standard drug. Intraduodenal administration of formulation showed the intestinal uptake of 40.34 μg/ml for LEF loaded nano-lipidic carriers as compared to 10.04 μg/ml of LEF drug solution. Histopathological studies confirmed the development of healthy cartilage in RA-induced rats [15]. Nanaki and colleagues designed chitosan nanoparticles (CS-NPs) for LEF delivery for preparation of aliphatic polyester-based skin patches. CS-NPs were incorporated into poly (l-lactic acid) (PLLA) or poly (lactic-co-glycolic acid) (PLGA) to prepare thin film skin patches for LEF delivery. A remarkable increase in LEF release rate was observed in CS-NPs after their incorporation in polymeric skin patches for drug delivery [16]. Zewail and her coworkers formulated nanostructured lipid carriers (NLCs) for LEF delivery coated with chondroitin sulphate (CHS) or chitosan (CS) to increase the therapeutic outcomes in RA. In vivo studies in RA induced rats improved inflammation of joints and showed marked reduction in liver toxicity after oral administration of LEF loaded CS/CHS coated NLCs suspension as compared to standard LEF drug solution. While highest plasma drug concentration and lowest tumor necrosis factor-alpha (TNF- α) were observed in CHC-NLCs. A synergistic effect is seen during joint healing with enhanced LEF concentration at inflamed joints [17]. Abbas and coworkers developed LEF-loaded emulsomes (EMLs) for intra-articular delivery in RA. EMLs were loaded with supramagnetic nanoparticles (SPIONs) to increase joint targeting. The drug release was achieved using the application of external magnetic field as a stimulus to SPIONs for enhanced localization of drug in joints [18]. A number of investigations are being conducted to find remedial alternatives for LEF delivery in RA to overcome its underutilization in RA, but clinical milestones to a significant status for greater efficacy and safety are yet to be established.

The future progress of LEF for treatment of RA lies in the development of patient-centered innovative and novel drug delivery strategies which can address problems in current dosage form. The integration of smart technologies such as stimuli-triggered drug release with novel approaches like nano-cargoes for LEF delivery could be exemplary in near future to unravel potential newer options for RA treatment with reduced side effects and raised efficacy. Nanocarriers such as nanoparticles, lipid-based formulation, etc. could resolve the issues of side effects associated with LEF, especially hepatotoxicity by opening new avenues for safer LEF in RA patients. Other unexplored routes of administration for LEF such as topical or transdermal should be researched using suitable robust RA induced animal models. Additionally, the newer drug combinations either LEF with some other DMARD for dual-drug delivery or multi-drug therapies should be investigated that can be helpful in unlocking newer solutions for RA treatment. The clinical translation of all developed technologies and strategies is yet another challenge in successful repositioning of LEF for safer and effective delivery.

Since LEF faces serious side effects and efficacy issues in current dosage form, finding the novel innovative formulation strategies for safe delivery of LEF can emerge as an optional therapy for RA over other DMARDs. The LEF delivery through topical or transdermal routes could also be a remedy to problems encountered in currently approved oral dosage form. Overall, it can be said that innovative and smart formulation strategies for safe and effective delivery of LEF through alternative routes of administration can reveal newer potential options.

Authors are thankful to NIPER-A library for providing necessary support in drafting this manuscript.

Authors declare no conflicts of interest.