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Daniel Lee Smoot, Rami F Elhayek, Zachary Lattrell, Mike McGrath, Timothy Jarrett, Courtney Rosales, Peter K Jarrett, Amar Sawhney; Sustained Delivery of Cyclosporine from an Intracanalicular Depot in a Canine Model. Invest. Ophthalmol. Vis. Sci. 2016;57(12):423.
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© ARVO (1962-2015); The Authors (2016-present)
To develop a hydrogel intracanalicular depot sustaining the delivery of cyclosporine A (CsA) for dry eye.
Micronized CsA was suspended in a multi-arm PEG solution and injected into small bore tubing prior to cross-linking. The immunosuppressant in hydrogel matrix was subsequently dried and cut into cylindrical depots (Fig 2). CsA depots (OTX-CP) were inserted into the inferior canaliculus of beagles then removed at predetermined time points for imaging and drug content analysis. Tear fluid samples were collected weekly then analyzed by LC/MS. Tear levels from OTX-CP were compared to those of beagles treated with a single Restasis drop (0.05%) and sampled at 1, 2, 4, 6 and 12 hrs. (Fig 1).
CsA concentration in tear fluid was determined to be about 100x IC50 required for T-cell activation inhibition. Single drop Restasis instillation yielded tear fluid concentrations of 8 and 0.2 µg/mL at 1 and 12 hours respectively. Tear fluid concentrations of CsA released from OTX-CP were sustained in the range of 1.0 - 1.8 µg/mL through 10 weeks. Data reported in Fig 1 indicates that the CsA tear fluid sustained level from OTX-CP remains above the therapeutic threshold represented by the 12 hrs time point for Restasis (prescribed BID). Pictures of OTX-CP pre and post hydration are shown in Fig 2. It should be noted that OTX-CP explanted/analyzed at 6 weeks showed 52% of drug released trending the releasing profile towards the 3 months target.
Topical immunosuppressants such as Restasis are commonly used to treat dry eye. Many therapies require multiple daily administrations for a prolonged period making a single dose therapy a more convenient option that may help ensure patient compliance and deliver improved treatment. OTX-CP has the advantage of delivering therapeutic levels of CsA while reducing overall drug dose relative to Restasis drops (0.05% BID). Sustained delivery of CsA in a dosage form that also provides punctal occlusion may deliver a combined benefit for the treatment of dry eye while reducing the potential burning sensation associated with the Cmax from eye drops. The ability to deliver CsA from a single resorbable intracanalicular depot, offers a versatile technology capable of delivering immunosuppressant therapy without the need of daily eye drops.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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