Sustained cysteamine delivery by nanobarrier contact lenses to replace 8xdaily drops with a daily disposable lens

Cystinosis is a metabolic disease caused by mutations in CTNS gene and characterized by loss of the cystine efflux pathway

in lysosomes resulting in accumulation of cystine crystals in many organs including kidneys and cornea. Cystinosis patients

begin showing ocular symptoms at the age of 16 months and without appropriate treatment, the entire peripheral stroma and

endothelium can be packed with crystals. By the age of 10-years, patients develop photophobia and eventually complications

such as corneal scars can occur resulting in irreversible damage to the eye. Cysteamine (β-mercaptoethylamine) treats the

disease by reacting with intra-lysosomal cystine to produce mixed disulfide cysteine-cysteamine dimers. The oral dose of

cysteamine achieves therapeutic effects in several organs but its concentration in cornea is inadequate and thus cysteamine eye drops (CYSTARAN® 0.44%, 8 times daily), are utilized for treating the ocular complications of cystinosis. The 8x

daily delivery of eye drops is difficult for patients and can lead to poor compliance. Additionally, the eye drops contain preservative benzalkonium chloride which can cause toxicity due to significant exposure from 8 drops daily. The

formulations also cause side effects including burning, redness, and blurred vision due to the acidic pH which is required to

maintain stability of cysteamine. Any exposure to oxygen leads to rapid oxidation of cysteamine to the inactive cystamine,

and thus eye drop bottles are shipped frozen. The oxidation, however, begins after the bottles are thawed and opened for

use, which reduces efficacy. Our goal is to develop contact lenses that can be worn continuously for 8-hours or longer if

vision correction is also needed, to deliver the same amount of drug to the cornea as eight drops a day therapy. Contact

lenses are ideal for treating cystinosis because a higher fraction of drug loaded in the lenses reaches cornea compared to

drops. Additionally, the lenses will be single use daily disposable and thus there will be no need for preservatives. We are

formulating our lenses at neutral pH which will eliminate the discomfort from low pH of the eye drop formulation. Sustained

delivery of cysteamine is challenging from contact lenses due to the low molecular weight. The drug diffuses rapidly in a few minutes from commercial contact lenses. We have addressed this limitation by developing a patented nanobarrier

technology which increases the release duration from a few minutes to about 2-8 hours for several drugs depending on the

loading of vitamin E nanobarriers in the lenses. Preliminary data shows 2-4 hours sustained release of cysteamine in vitro and in vivo with 20% vitamin E lenses, and efficacy in dissolving crystals in ex vivo cadaver eyes. The pharmacokinetic

studies in rabbits show that one lens can deliver sufficient drug to match the 7 drops, so about 15% increase in dose is

required. This proposal focuses on GMP manufacturing and one-year potency testing for lenses that are designed to release the drug in eight hours. Lenses will be developed in various corrective powers which will require changing drug

concentration in the packaging solution and vitamin E loading in lenses to achieve consistent release for all correction powers. In vivo studies will be conducted in rabbits with zero-power planar lens to demonstrate that the lenses provide

delivery comparable to the 8xdaily drop regimen. Success in this proposed research will be followed by a pre-IND meeting with the FDA, followed by Phase I clinical studies.