ABSTRACT
PURPOSE: The primary objective of this study was to compare uptake and distribution of the commercially available formulation of 0.2% olopatadine and the newly developed 0.77% olopatadine hydrochloride ophthalmic solution formulation with improved solubility following a single (30 µL), bilateral topical ocular dose in male New Zealand white rabbits. METHODS: Each animal received a single 30-µL topical ocular dose (0.2% olopatadine or 0.77% olopatadine hydrochloride ophthalmic solution) to the right (OD) eye followed by the left (OS) eye for a total dose of 60 µL. Olopatadine concentrations were measured in ocular tissues (cornea, bulbar, conjunctiva, choroid, iris-ciliary body, whole lens, retina), aqueous humor, and plasma at prespecified time points over 24 h using a qualified liquid chromatography coupled with mass spectrometry (LC-MS/MS) analytical method. RESULTS: Olopatadine was absorbed into the eye and reached maximal levels (Cmax) within 30 min (0.5 h) to 2 h (Tmax) in ocular tissues and plasma for both treatment groups, except for the lens in which the Tmax was 4 h in the 0.2% olopatadine group and 8 h in the 0.77% olopatadine hydrochloride group, respectively. Tissues associated with the site of dosing, that is, the conjunctiva and cornea, had the highest concentrations of olopatadine in both the 0.2% olopatadine (609 and 720 ng/g) and 0.77% olopatadine hydrochloride (3,000 and 2,230 ng/g) dose groups. The greatest differences between 0.2% olopatadine and 0.77% olopatadine hydrochloride were associated with the overall duration and level of ocular exposures. CONCLUSIONS: The newly developed 0.77% olopatadine hydrochloride ophthalmic solution formulation resulted in a higher and more prolonged olopatadine concentration in the target tissue, that is, conjunctiva compared to the commercial formulation of 0.2% olopatadine ophthalmic solution.
Subject(s)
Anti-Allergic Agents/administration & dosage , Anti-Allergic Agents/pharmacokinetics , Eye/metabolism , Olopatadine Hydrochloride/administration & dosage , Olopatadine Hydrochloride/pharmacokinetics , Animals , Aqueous Humor/metabolism , Chromatography, Liquid/methods , Conjunctiva/metabolism , Cornea/metabolism , Dose-Response Relationship, Drug , Male , Mass Spectrometry/methods , Ophthalmic Solutions/administration & dosage , Rabbits , Retina/metabolism , Tandem Mass Spectrometry/methodsABSTRACT
With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.
