Biodegradable Calcium Phosphate Nanoparticles as a New Vehicle for Delivery of a Potential Ocular Hypotensive Agent

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Abstract
The purpose of this study was to determine the efficacy of a newly prepared formulation containing biodegradable calcium phosphate nanoparticles (CAP) and 7-hydroxy-2-dipropyl-aminotetralin (7-OH-DPAT) in pigmented and non-pigmented rabbits using the surrogate end points of intraocular pressure (IOP) and aqueous flow rate. IOP (mmHg) was measured by utilizing a manometrically calibrated Mentor pneumatonometer. Rates of aqueous humor flow were measured with a Fluorotron Master by estimating the dilution rate of fluorescein. In non-pigmented rabbits, the ocular hypotension induced by topical administration of 7-OH-DPAT (75 microg) with CAP (115 microg) was more pronounced and sustained than that of 7-OH-DPAT without CAP. Furthermore, IOP-lowering effects of topically administered 7-OH-DPAT (125 microg) alone were markedly diminished in pigmented rabbits compared to non-pigmented rabbits. However, topical application of 7-OH-DPAT formulated with CAP produced significant dose-related (37.5, 75, 125 microg) reductions of IOP accompanied by suppression of aqueous humor flow rates in pigmented rabbits. It is postulated that 7-OH-DPAT in vehicle without CAP binds to pigments in the anterior segment of the pigmented rabbit's eyes, and this binding limits the 7-OH-DPAT's action. Pretreatment with raclopride, a dopamine D2/D3 receptor antagonist, reduced the ocular hypotensive effect induced by 7-OH-DPAT in vehicle containing CAP thereby supporting the role for dopamine D2/D3 receptors in modulating IOP. It is concluded that CAP, as a delivery system, enhances activity by 7-OH-DPAT in pigmented rabbit eyes suggesting that CAP is potentially useful for achieving controlled and targeted drug delivery for treatment of ocular diseases.