Ocular Pharmacokinetics Profile of Different Indomethacin Topical Formulations

Purpose: This study evaluated the ocular pharmacokinetics of indomethacin following topical administration of two different formulations present in the market. Methods: Rabbits received a multiple topical instillation (30 μL) of indomethacin ophthalmic suspension containing hydroxypropylmethylcellulose (IND-HPMC; Indom™ Alfa-Intes) or indomethacin ophthalmic solution with hydroxypropyl-β-cyclodextrin (IND-CD; Indocollirio™ Bausch & Lomb). Aqueous humor, vitreous humor, and retina were collected from animals at fixed time intervals after dosing. Indomethacin ocular levels were measured by liquid chromatography mass spectrometry (LC-MS/MS), and the pharmacokinetic parameters—peak drug concentration (Cmax), time to peak value (Tmax), and area under the concentration–time curve between 0 and 240 min (AUC0–240)—were determined. All of the animals were treated according to the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research. Results: Peak concentrations of indomethacin in aqueous and vitreous were achieved within 30 min and 60 min after a single instillation of IND-HPMC and IND-CD, respectively. Retinal Tmax was 30 min and 120 min in the IND-HPMC-treated group and the IND-CD-treated group, respectively. Higher levels of indomethacin were found in retina after IND-HPMC administration compared to IND-CD (AUC0–240 272.9 ng/g per min vs. AUC0–240 73.5 ng/g/min, respectively; P<0.01). Also in the aqueous and vitreous, the drug levels were statistically higher (P<0.01) in the IND-HPMC group in comparison with the IND-CD group (AUC0–240 2039 ng/mL per min vs. AUC0–240 427.3 ng/mL per min, AUC0–240 53.8 ng/mL per min vs. AUC0–240 12.5 ng/mL per min, respectively). The highest drug levels in the ocular tissues were found following IND-HPMC administration compared with IND-CD (retina: Cmax 73.7±6.4 ng/g vs. 25.5±1.73 ng/g; aqueous: Cmax 952±6.8 ng/mL vs. 163±4.1 ng/mL; vitreous Cmax 31±3.5 ng/mL vs. 6.37±3.6 ng/mL). Conclusions: IND-HPMC treatment demonstrates a nonclinical ocular pharmacokinetic profile of indomethacin characterized by higher concentrations of drug in ocular tissues (4.7-, 4.3- and 3.7-fold higher in aqueous, vitreous, and retina, respectively) compared to the ND-CD-treated group. Taken together, these data seem to indicate that IND-HPMC formulation has good ocular distribution reaching relevant indomethacin levels in the back of the eye, and suggest that this formulation may be very useful for clinicians to manage retinal conditions.