Cyclosporine A delivery to the eye: A comprehensive review of academic and industrial efforts

Abstract

Local ocular delivery of cyclosporine A (CsA) is the preferred method for CsA delivery as a treatment for ocular inflammatory diseases such as uveitis, corneal healing, vernal keratoconjunctivitis and dry eye disease. However, due to the large molecular weight and hydrophobic nature of CsA and the natural protective mechanisms of the eye, achieving therapeutic levels of CsA in ocular tissues can be difficult. This review gives a comprehensive overview of the current products available to clinicians as well as emerging drug delivery solutions that have been developed at both the academic and industry levels.

<p>A Review of Topical Cyclosporine A Formulations—A Disease-Modifying Agent for Keratoconjunctivitis Sicca</p>

“…12 Topical administration of CsA allows for lower systemic absorption, and thereby reduces the risk of systemic adverse events (AEs) such as nephrotoxicity, hypertension, anemia, and hyperesthesia. 13 Cyclosporine A is a calcineurin inhibitor and acts by blocking T cell infiltration, activation, and the subsequent release of inflammatory cytokines as illustrated in Figure 1. 12,14,15 In addition, CsA has an antiapoptotic and protective action on human conjunctival epithelial cells, unlike corticosteroids.…”

“…16 Although emulsions have the advantage of rapid ocular spreading upon application, lower bioavailability of lipophilic drugs from emulsions limits the amount of CsA available in an already challenging aqueous ocular environment. 13,16 Clinical results show that the time to onset of efficacy with CsA emulsions is 6 months on average. 21,22 Such long lead times to initial efficacy may interfere with patient adherence to treatment in KCS.…”

“…An ophthalmic emulsion of 0.05% CsA (Restasis ® ; Allergan, Inc., Irvine, CA, USA) ( Table 1) was the first topical CsA approved by the US Food and Drug Administration (FDA) in 2003 to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with KCS. 8,10,13 This conventional CsA 0.05% emulsion is a preservative-free anionic oil-in-water formulation comprising castor oil with polysorbate 80 and carbomer copolymer acting as an emulsifying and stabilizing agent, respectively. 13 In 2 multicenter and randomized Phase 3 trials, twice-daily administration of CsA 0.05% emulsion for 6 months significantly improved corneal staining and anesthetized Schirmer's tear test values from baseline compared with vehicle (P ≤0.05).…”

“…8,10,13 This conventional CsA 0.05% emulsion is a preservative-free anionic oil-in-water formulation comprising castor oil with polysorbate 80 and carbomer copolymer acting as an emulsifying and stabilizing agent, respectively. 13 In 2 multicenter and randomized Phase 3 trials, twice-daily administration of CsA 0.05% emulsion for 6 months significantly improved corneal staining and anesthetized Schirmer's tear test values from baseline compared with vehicle (P ≤0.05). 21 Conjunctival staining in temporal and nasal conjunctival zones improved significantly from baseline in both CsA 0.05% emulsion and vehicle groups; however, there was no significant difference between CsA 0.05% emulsion and vehicle treatment.…”

Drug Treatment of Corneal Neuropathies: Mini Review

“…But prevention of excessive inflammation is also a common treatment goal in many situations, such as in the highly prevalent dry eye syndrome [49]. The interesting cyclic 11 mer peptide cyclosporine A (CsA) (Figure 11) has a fairly long history [50] of use in suppressing ocular inflammation found in such conditions as dry eye syndrome, meibomian gland dysfunction, Sjogren syndrome, and recovery from LASIX surgery [51,52]. CsA is from the calcineurin family of immune suppressants.…”