ReviewKeynoteModern approaches to the ocular delivery of cyclosporine A
Graphical abstract
Introduction
CsA is a metabolite of the fungi Tolypocladium inflatum and Beauveria nevus that was initially suggested for use as an antifungal agent. Its immunosuppressive activity soon became evident and, because of the reduced incidence of associated myelotoxicty, CsA eventually became the mainstay treatment after organ transplantation 1, 2. Systemic CsA is still used, although to a lesser extent, to treat several other autoimmune diseases, including those with eye involvement [3]. CsA is the preferred immunomodulatory agent for topical treatment of several immune-mediated ocular surface disorders [4], and its prevalence in the treatment of these ocular disorders is second only to corticosteroids, whose adverse effects are well documented [5]. CsA therapy has been approved for the treatment of keratoconjunctivitis sicca (KCS), more commonly known as dry eye syndrome (DES). It is also frequently used off-label to treat several other ophthalmic conditions, such as posterior blepharitis 6, 7, ocular rosacea 8, 9, vernal keratoconjunctivitis 10, 11, 12, 13, 14, atopic keratoconjunctivitis 15, 16, 17, acute corneal graft rejection [18], and conjunctival graft versus host disease 19, 20, 21.
DES is one of the most prevalent ocular surface disorders, and is usually characterized by increased evaporation or decreased production of tear fluid, resulting in damage to the interpalpebral ocular surface and moderate to severe discomfort [22]. Symptoms of DES have been reported in approximately one out of seven individuals above the age of 48, with its prevalence nearly doubling after 59 years of age 23, 24, 25. A recent study estimated that nearly 20% of hospitalized patients above the age of 50 had DES, with old age and illiteracy being major predictors of the disorder [26]. On the recommendation of the International Dry Eye Workshop in 2007, DES was classified as a multifactorial disease of the tears and ocular surface that can be triggered by a variety of underlying causes. However, recently, there has been increasing evidence that inflammation has a key role in the manifestation of DES. Ocular surface abnormalities, such as the appearance of inflammatory cell intermediates in the lacrimal gland and an increase in immune-related antigens and cytokines at the conjunctival epithelium, are commonly demonstrated by both autoimmune (Sjögren's syndrome) and non-autoimmune (non-Sjögren's syndrome)-mediated DES 27, 28, 29, 30, making treatment of the underlying cytokine–receptor-mediated inflammatory processes the primary ‘causative therapeutic approach’ 31, 32. A combination of symptomatic therapy, which includes modification of the ocular environment (by increasing humidity, occlusion of lacrimal canaliculi, or simulation of tears), and pathogenic treatments, including the use of antibacterial and anti-inflammatory agents (corticosteroids, antihistamines, tetracyclines, and CsA), is currently recommended for DES therapy [32].
CsA is the anti-inflammatory agent of choice for the treatment of DES, because it can be used long term without adverse effects commonly associated with other anti-inflammatory agents, such as steroids [5]. Furthermore, unlike corticosteroids, the activity of CsA results from specific and reversible action on T cells, making it safe for prolonged use. For example, corneal epitheliopathy and eyelid maceration associated with long-term CsA therapy were found to be reversible with complete cessation on discontinuation of the drug [33]. The immunomodulatory activity of CsA helps in reducing the inflammation associated with subconjunctival and lacrimal glands, resulting in increased goblet cell density and tear production 34, 35. CsA tends to bind with specific nuclear proteins that initiate the activation of T cells, thus preventing T cell production of inflammatory cytokines and disrupting the immune-mediated inflammatory response 31, 36. CsA is a hydrophobic molecule and, therefore, is difficult to formulate into conventional topical ocular delivery systems. Significant research has been performed over recent years to develop safe and effective ocular delivery systems for CsA. In this review, we highlight recent efforts to improve the ophthalmic delivery of CsA in terms of its bioavailability and ocular tolerability while reducing adverse effects.
Section snippets
Conventional CsA formulations
Systemic CsA is generally not considered for the treatment of ocular pathologies because of severe systemic adverse effects, such as nephrotoxicity and hypertension 2, 37, although significant concentrations of CsA have been reported in tears and lacrimal glands after oral administration [38]. Thus, the topical route is generally preferred because, as well as reducing systemic adverse effects, it also helps to achieve improved bioavailability and specific targeting to the ocular tissues 39, 40.
Recent approaches in CsA delivery
Over the past few years, several novel strategies have been suggested for delivering CsA to the ocular tissues, with topical, episcleral, subconjunctival, and intravitreal routes being investigated. Of these, topical administration remains the most preferred route for the treatment of DES, because it is non-invasive, painless, and convenient. For the purpose of this review, the key approaches to improving ocular drug delivery of CsA have been classified into three major areas of research: (i)
Concluding remarks
Ocular drug delivery is a challenging prospect because of the penetration barriers presented by the cornea and conjunctiva. Although topical application remains the preferred method for drug delivery to the front of the eye, excipients need to be selected carefully to avoid toxicity to the highly sensitive ocular mucosa. This becomes even more challenging when formulating hydrophobic drugs, such as CsA, because most nonaqueous solvents are not generally recognized as safe (GRAS). Moreover,
Conflict of interest
The authors are currently consulting for Novaliq GmbH.
Acknowledgement
The authors would like to thank Novaliq GmbH, Germany, for their financial support in form of a scholarship to P.A.
Priyanka Agarwal is currently pursuing a doctorate within the Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, University of Auckland, and is investigating novel cyclosporine A (CsA) formulations for topical administration. She completed her BPharm at the University of Mumbai, India, and subsequently obtained a Postgraduate Diploma in Health Sciences from the School of Pharmacy at the University of Auckland. Priyanka has extensive industrial research experience in formulation
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2022, European Journal of Pharmaceutical SciencesCitation Excerpt :Cyclodextrins (CDs) are three types of cyclic oligosaccharides (α, β, and γ) that have a hydrophobic cavity and hydrophilic outer surface. Usually, CDs are used to improve the solubility of hydrophobic drugs by forming water-soluble complexes (Agarwal and Rupenthal, 2016). This complex between drug and CD enhances drug solubility in the aqueous part of tear film and penetration to the mucin layer that provides sustained drug release and so, increases ocular drug bioavailability.
Priyanka Agarwal is currently pursuing a doctorate within the Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, University of Auckland, and is investigating novel cyclosporine A (CsA) formulations for topical administration. She completed her BPharm at the University of Mumbai, India, and subsequently obtained a Postgraduate Diploma in Health Sciences from the School of Pharmacy at the University of Auckland. Priyanka has extensive industrial research experience in formulation development and pharmacokinetics and worked as a Veterinary Formulation Development Scientist for several years. During her time in industry, she primarily worked on the development of new platforms for safe drug delivery to animals and she is currently one of the inventors on a series of patents filed in this field.
Ilva Rupenthal is a senior lecturer in the Department of Ophthalmology, New Zealand National Eye Center, University of Auckland, and the inaugural Director of the Buchanan Ocular Therapeutics Unit, which aims to translate ocular therapeutic-related scientific research into the clinical setting, whether pharmaceutical, cell, or technology based. Her current research, funded by a Sir Charles Hercus Health Research Fellowship from the New Zealand Health Research Council, focuses mainly on the development of stimuli-response devices, with projects investigating ocular implants responsive to light or a small electrical current. Moreover, Dr Rupenthal's group is developing tailored controlled delivery systems that specifically target the drug to the site of action with projects around dry eye, optic neuropathy, diabetic retinopathy, and age-related macular degeneration treatment.