Discipline: Technology and Engineering
Subcategory: Biomedical Engineering
Session: 1
Room: Marriott Balcony B
Jorge Jimenez - University of Pittsburgh
Co-Author(s): Michael A. Washington, University of Pittsburgh, PA; Ken K. Nischal, Children's Hospital of Pittsburgh, PA; Morgan V. Fedorchak, University of Pittsburgh, PA.
Patients with Nephropathic Cystinosis experience intracellular accumulation of cystine throughout their body. Accumulated cystine leads to cystine crystal formation and damages tissues including the kidney, pancreas, thyroid and eyes. In the eye, cystine accumulates in all the ocular tissues but is most easily evident as crystal deposits in the cornea that lead to debilitating light sensitivity, corneal erosion, and foreign body sensation. Corneal cystine crystals are treated by hourly administration of topical cysteamine eyedrops (up to 12 drops/day). The eyedrop formulation requires a high concentration of cysteamine per drop to account for its instability (1-week shelf life) as it is easily oxidized to its inactive counterpart: cystamine. The strict dosing regimen and high concentration of drug per drop make this treatment inconvenient and painful for patients leading to almost universal non-compliance. When paired with the troublesome 1-week shelf life stability profile, current cysteamine eyedrops negatively impacts quality of life of Cystinosis patients dramatically. An ocular drug delivery system that provides cysteamine in a controlled and stable manner may help decrease the number of daily eyedrops, improve stability and prolong the effect of treatment. We have developed a thermoresponsive, gel-based eyedrop that contains cysteamine-loaded poly(lactic-co-glycolic acid) microparticles. We hypothesize that encapsulated cysteamine improves stability and when delivered topically by our gel drug delivery system – can provide cysteamine release in a controlled manner. This study describes the development of a spray-dried cysteamine microsphere formulation in vitro characterization for material properties, drug release, stability, and ocular sensitivity. Dynamic scanning calorimetry was performed to verify thermal properties of cysteamine microspheres in our gel system. Cysteamine drug release kinetics were quantified using reverse-phase high performance liquid chromatography. Stability profiles between our drug delivery system and standard cysteamine eyedrops were compared using proton magnetic nuclear resonance. Ocular sensitivity test based on organotypic irritation models (hen’s egg test on chorioallantoic and bovine corneal opacity and permeability test) were used to test and compare our formulation to cysteamine eyedrops. Results from our studies indicate sustained release of cysteamine or 24 hours in vitro, along with an improved stability profile of 7 weeks. The ocular irritation of our system was negligible and low when compared to standard cysteamine eyedrops, positive controls (sodium hydroxide), and negative controls (saline solution). These studies indicate the development of a stable formulation of cysteamine that delivers cysteamine for an extended time from a single drop. Future studies involve ocular biodistribution and pharmacokinetics in large size animals and corneal cystine reduction as efficacy in a disease rodent model.
Funder Acknowledgement(s): This study was supported by a grant from the Cystinosis Research Foundation awarded to Morgan V. Fedorchak, PhD, University of Pittsburgh, Pittsburgh, PA. I thank S.Wosu, S. Ambramotwitch, Y. Olaore of Pitt STRIVE (NSF-AGEP) for training support.
Faculty Advisor: Morgan V. Fedrochak, PhD, fedorchak@pitt.edu
Role: The research portions fulfilled by me (Jimenez) including the development and validation of high performance liquid chromatography methods, design of cysteamine microspheres, verification of thermal properties of gel and microspheres, and testing on organotypic models. Stability studies were carried out by Jimenez and M. Washington, with development of stability detection method by M. Washington.