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Cataract Surgery | Nov/Dec 2011

Chitosan-N-Acetylcysteine Eye Drops

Prolonged resident time on the ocular surface was shown in preclinical studies, and no safety problems were seen in early clinical results.

As patients age, dry eye syndrome (DES) becomes one of the main reasons for consulting an ophthalmologist. Data from epidemiologic studies indicate that approximately 14% of the population 48 years of age and older have some level of DES.1 Treatment encompasses a variety of approaches, but today topically administered lubricants remain the mainstay of therapy. The ideal topical lubricant varies among patients; however, most available lubricants do not stay on the ocular surface for more than 10 or 15 minutes.

IMPROVED MUCOADHESION

One of the most important prerequisites for successful topical lubrication is a long residence time on the ocular surface, which can limit the need for frequent instillations and lead to better patient compliance. A promising approach is chitosan-N-acetylcysteine eye drops (Croma Pharma GmbH, Leobendorf, Austria). This biopolymer formulation consists of chitosan, a polycationic polysaccharide derived from alkaline deacetylation of chitin, which has high biocompatibility and low toxicity,2,3 and N-acetylcysteine, a derivative of the amino acid L-cysteine, which is a reducing agent with antioxidant activity. The N-acetylcysteine is covalently bound to the polymeric backbone of chitosan.

Most important, the chitosan has been chemically modified by immobilization of sulhydryl-bearing ligands on the polymeric backbone, a technique that is usually referred to as thiomer technology. This introduction of thiol groups leads to significantly improved mucoadhesive properties compared with corresponding unmodified polymers.

Chemically speaking, the formation of disulfide bonds between thiol groups of the thiomer and cysteine-rich subdomains of glycoproteins of the mucous gel layer are responsible for the improvement in mucoadhesion. These bonds lead to adhesion of the modified chitosan to the ocular surface and, in turn, to a long residence time on the ocular surface.

PRECLINICAL, CLINICAL STUDIES

Chitosan-N-acetylcysteine eye drops have been tested in preclinical and clinical studies to determine ocular residency time in vivo. In a preclinical study, radioactively labeled chitosan- N-acetylcysteine eye drops were applied to rabbit eyes. This experimental setting showed that even a single drop remained on the ocular surface 22 hours after application. 4,5 In two preclinical proof-of-principle studies, the effect of topically applied chitosan-N-acetylcysteine eye drops was investigated in dry eye mouse models. Evaluation of dry eye biomarkers such as IL-1, IL-10, IL-alpha, and TNFbeta suggested that chitosan-N-acetylcysteine eye drops may have some protective ocular surface properties, indicated by decreased ocular surface mRNA expression.6,7

Preceding first use in humans, preclinical data demonstrated good safety and tolerability of chitosan-N-acetylcysteine. Mild cytotoxicity was observed at high concentrations, most likely caused by the high viscosity of the test product. Acute oral toxicity at a dose of 1,000 mg/kg was tested in a rat model, with no observed toxic effects and no mortality.

Two phase 1 clinical studies were performed. In the first cohort, a single administration of chitosan-N-acetylcysteine was tested in three increasing concentrations (0.1%, 0.05%, and 0.025%). Each concentration was administered in six patients, for a total of 18 administrations. Investigators concluded that the overall tolerability of chitosan- N-acetylcysteine was excellent. In the second cohort, safety was tested after two-times-daily instillation in a group of 12 healthy patients. Again, the study revealed an excellent safety profile.

CONCLUSION

Results of preclinical and clinical studies of chitosan-Nacetlycysteine eye drops indicate excellent tolerability and prolonged resident time on the ocular surface. This indicates that chitosan-N-acetlycysteine eye drops have the potential to be a promising new approach to treat symptoms of DES.

Gerhard Garhöfer, MD, is an Assistant Professor in the Department of Clinical Pharmacology, Medical University of Vienna, Austria. Dr. Garhöfer states that he is a paid consultant to Croma Pharma. He may be reached at tel: +43 1 40400 2981; email: gerhard.garhoefer@meduniwien.ac.at.

Leopold Schmetterer, PhD, is a Professor in the Department of Clinical Pharmacology, Medical University of Vienna, Austria. Dr. Schmetterer states that he is a paid consultant to Croma Pharma. He may be reached at email: geopold.schmetterer@meduniwien.ac.at.

  1. Moss SE,Klein R,Klein BEK.Prevalence of and risk factors for dry eye syndrome.Arch Ophthalmol. 2000;118:1264-1268.
  2. Felt O,Furrer P,Mayer JM,Plazonnet B,Buri P,Gurny R.Topical use of chitosan in ophthalmology:tolerance assessment and evaluation of precorneal retention.Int J Pharm.1999;180:185-193.
  3. Illum L.Chitosan and its use as a pharmaceutical excipient.Pharm Res.1998;15:1326-1331.
  4. Dangl D,Hornof M,Hoffer M,Kuntner C,Wanek T,Kvaternik H. In vivo evaluation of ocular residence time of 124I-labelled thiolated chitosan in rabbits using microPET technology.Invest Ophthalmol Vis Sci.2009;50:E-Abstract 3689.
  5. Kuntner C,Wanek T,Hoffer M,Dangl D,Hornof M,Kvaternik H,Langer O.Radiosynthesis and assessment of ocular pharmacokinetics of 124I-labeled chitosan in rabbits using small-animal positron emission tomography. Mol Imaging Biol.2011;13(2):222-226.
  6. Hongyok T,Chae JJ,Joo Shin Y,Na D,Li L,Chuck RS.Effect of chitosan-N-acetylcysteine conjugate in a mouse model of botulinum toxin B-induced dry eye.Arch Ophthalmol.2009;127(4):525-532.
  7. Hornof M,Hoffer M,Clausen A.Thiolated chitosan for the treatment of dry eye - Evaluation in mice using the controlled-environment chamber model.Invest Ophthalmol Vis Sci.2009;50:E-Abstract 3663

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