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Ashish Thakur, Rajendra Kadam, Uday B. Kompella; Transscleral Retinal Delivery of Six Corticosteroids: Influence of Drug Physicochemical Properties. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3215.
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Therapeutic value of corticosteroid suspensions in treating diseases of the of back of the eye is well known. The objective of this study was to determine the influence of physicochemical properties of corticosteroids on their transscleral delivery to the back of the eye.
Solubility, lipophilicity (Log D at pH 7.4), particle size, bovine in vitro tissue:buffer partition coefficients for sclera and sclera-choroid-RPE (SCRPE), and in vitro SCRPE permeability were determined at pH 7.4 for triamcinolone, prednisolone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, and budesonide. Intraocular tissue distribution after posterior subconjunctival injection of 1 mg/ml suspension of each corticosteroid was assessed in vivo and ex vivo at 1 h post-dosing in Brown Norway rats.
Corticosteroid solubility, Log D, and particle size ranged from ~17-300 µg/ml, 0.7-2.98, and 0.84-4.33 µm, respectively. Corticosteroids partition coefficients ranged from 3.0-11.4 for sclera and 7.1-35.8 for CRPE, with the more lipophilic molecules partitioning more into both tissues. Tissue partitioning showed a positive correlation with drug lipophilicity (R2: 0.66-0.96). The cumulative % transport across sclera and SCRPE was in the range of 3.9-10.7% and 0.3-1.8%, respectively, and showed inverse correlation with drug lipophilicity (R2: 0.84-0.86) and tissue partitioning (R2: 0.89-0.92). Ex vivo and in vivo transscleral delivery from drug suspension indicated tissue distribution in the following order: CRPE ≥ sclera > retina > vitreous. Ex vivo and in vivo sclera, CRPE, retina, and vitreous tissue levels of all corticosteroids showed strong positive correlation with the drug solubility (R2: 0.91-1.0) but not lipophilicity (R2: 0.24-0.41) or tissue partitioning (R2: 0.24-0.90). Prednisolone with the highest solubility and smallest particle size was delivered more to all intraocular tissues. In vivo delivery was lower in all eye tissues assessed except cornea when compared to ex vivo delivery, with the in vivo : ex vivo ratios being the lowest in the vitreous humor (0.085-0.212).
Transscleral intraocular delivery from corticosteroid suspensions was primarily driven by drug solubility rather than lipophilicity.
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