Hydrogel eye drops as a non-invasive drug carrier for topical enhanced Adalimumab permeation and highly efficient uveitis treatment

Highlights

• The hydrogel eye drops slowly release drug and prolong the ocular drug retention.

• A novel hydrogel provides a non-invasive way to boost ocular drug bioavailability.

• The adalimumab-loaded LCGH performs excellent therapeutic efficacy for uveitis.

Abstract

Uveitis is one of the most popular blind-causing eye diseases worldwide. Adalimumab (ADA) is used for the uveitis treatment through systemic or intravitreal injection at the expense of systemic side effects and increased medical risks. Although eye drops, a non-invasive topical treatment, could be a potential strategy to reduce side effects, it remains challenging to apply due to limited bioavailability mainly linked to poor retention time and permeation capacity for eye biological barriers. Here, we reported hydrogel eye drops composed of low-deacetylated chitosan and β-glycerophosphate as an ADA carrier and tested its toxicity, tolerability, intraocular permeability, and efficacy of non-invasive treatment for uveitis. It’s found the ADA-loaded hydrogel eye drops were more efficient than free ADA both in permeation rate and clinical efficacy for uveitis, Overall, this study provides a friendly non-invasive strategy to improve drug permeation rate and uveitis treatment efficacy, which may be valuable to clinically ophthalmic medication.

Introduction

As a group of eye diseases, non-infectious uveitis accounts for an estimated 83 % in pediatric uveitis (Tsirouki et al., 2018). It can lead to vision loss and blindness. Diagnosis and treatment of non-infectious uveitis are complicated and challenging, especially in pediatric populations. In clinical practice glucocorticoids are the mainstay of therapy. However, this treatment is not suitable for long term use in chronic or recurrent disease and especially in pediatric population or in patients with underlying conditions like hyperglycemia and other. Steroids are also associated with long-term side effects systemically and topically, such as glaucoma and cataract (Sheppard, Comstock, & Cavet, 2016). Adalimumab (ADA) treatment provides a promising strategy for these patients to significantly reduce the risk of flare-ups or visual acuity diminution for non-infectious uveitis (LaMattina & Goldstein, 2017). ADA, a fully human anti-TNF-α monoclonal antibody, has been used in the treatment of many conditions, such as rheumatoid arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis (Lambert et al., 2007; Schmeling et al., 2014; Weinblatt et al., 2003). Moreover, the addition of ADA can reduce the need for steroid use which may cause cataract, intraocular hypertension and glaucoma (Ku, Lin, & Tsai, 2018). However, systemic treatment of ADA can result in immunosuppression with subsequent increased risk of infection and risk of tumor occurrence (Burmester, Panaccione, Gordon, McIlraith, & Lacerda, 2013; Llorenc et al., 2019). Thus, developing a broadly applicable technology to enhance the efficiency of ADA for uveitis treatment and reduce side effects remains a significant unmet clinical need.

Eye drops are a noninvasive treatment, applied locally to the ocular surface. However, the eye as a complex and delicate organ, has some biological barriers (e.g. corneal epithelium and blood-retinal barrier) and the lacrimal turnover to protect it from external aggressions. These barriers can limit both retention and permeation of eye drops (Ramsay et al., 2018; Urtti, 2006). The ocular retention time of eye drops has been reported to be no more than 15 s, and less than 5% of drug can penetrate the barriers and play roles (Seyfoddin, Shaw, & Al-Kassas, 2010). The efficacy of drug administered via eye drops is lower than that via other more invasive methods such as injection (e.g. subconjunctival, subtenon or intravitreal injection). More invasive methods are associated with many risks such as endophthalmitis, vitreous hemorrhage, and retinal detachment (Falavarjani & Nguyen, 2013; Smith, Smith, & Mohney, 2014).

Up to now, many forms of drug carriers, such as hydrogels, micelles, nanoparticles and microneedles, have been developed to enhance the effect of eye drop treatment by prolonging retention time or improving corneal permeability of drugs (Huang et al., 2018; Seyfoddin et al., 2010; Shi et al., 2019; Than et al., 2018). Recently, chitosan-based hydrogel has been widely developed in various oculopathy therapy due to excellent biodegradability, biocompatibility, hydrophilic muco-adhesiveness, easiness to load and ability to release drug in a controllable way (Bruinsmann et al., 2019; Chen et al., 2012; Chenite et al., 2000; Tsai et al., 2016). In addition, the positively-charged amino groups of chitosan make it available to be absorbed on the negatively-charged mucin layer of the tear film, which further can enhance retention time and permeation rate of loaded drugs (Almeida, Amaral, Lobao, Silva, & Loboa, 2014). Besides, after chitosan treatment in vitro, Claudin 4 (CLDN 4) was endocytosed and degraded which opened the tight junctions between cells temporarily, which is the major component of the epithelium barrier (Gaudana, Ananthula, Parenky, & Mitra, 2010; Hsu et al., 2012). However, few reports regarding the delivery of ADA in ocular tissue have been published, especially using eye drops.

We developed chitosan-based hydrogel eye drops as a carrier for non-invasive uveitis treatment, which were prepared by mixing chitosan and β-glycerophosphate (β-GP) (Filion & Buschmann, 2013). In the first part of our study, diclofenac sodium (DIC) was chosen as a model drug to form the hydrogel eye drops to evaluate its sustain released ability and biocompatibility. In the second part, ADA was encapsulated into the hydrogel to treat uveitis. Compared to free drug treatment, hydrogel eye drops exhibited sustained ADA release behavior, enhanced permeation rate and improved treatment efficacy of drug loading in in vitro and in vivo. This study provides a description of a non-invasive strategy to improve ADA permeation rate and potentially uveitis treatment efficacy with topical treatment, and may be of interest as it could help to enhance the clinical efficacy of a broad range of drugs for eye disease.