(T1030-05-30) Toward a Physiologically Based Pharmacokinetic Model for Topical Ophthalmic Suspension

Purpose: Topical eye drops are the most common dosage form for the delivery of ophthalmic drugs, and poorly soluble drugs are often formulated as suspensions. Ocular bioavailability of topical suspensions depends on the retention and dissolution of drug particles in tear fluid, but the specificities remain poorly understood. The purpose of this work is to understand the key formulation parameters for ocular bioavailability and to generate data for a physiologically based pharmacokinetic (PBPK) model for topical ophthalmic suspensions.

Methods: Ocular pharmacokinetics of indomethacin were studied in vivo in New Zealand white rabbits after intracameral injection (dose 2 µg/eye). The animals were euthanised at designated time points up to four hours after intracameral injection, and aqueous humour (AH, n=4), cornea (n=2-4), and iris-ciliary body (ICB, n=4) were collected. Indomethacin levels in the tissues were quantified with LC/MS. The pharmacokinetics were analysed using compartmental modelling (AH) and non-compartmental analysis (cornea, ICB) (Phoenix WinNonlin®). Based on drug exposure in AH after intracameral injection, we calculated the absolute ocular bioavailability in AH (BA_AH) of six indomethacin suspensions after topical administration in rabbits using previously published data¹ We prepared six indomethacin suspensions similar to those in the aforementioned study¹ with small (~1.6 µm, IND01-03) or large (~3.7 µm, IND04-06) particles, and low (~1.8 mPa.s, IND01 and 04), medium (~5.9 mPa.s, IND02 and 05), or high viscosity (~16 mPa.s, IND03 and 06). The dissolution of the suspensions was studied in vitro in sink-conditions at 37°C in a Slide-A-Lyzer setup (cutoff 20 kDa, diameter 85 mm). In vitro dissolution rates were correlated with the calculated BA_AH of the similar suspensions. Furthermore, corneal and conjunctival permeability of indomethacin in solution was studied ex vivo in vertical Ussing chambers. Lucifer yellow was added to the chambers to monitor tissue integrity.

Results: Key parameters for the PBPK model under development are shown in Figure 1, including corneal and conjunctival permeability and intracameral pharmacokinetic parameters of indomethacin obtained from this study. Total intracameral clearance (CL_ic) equals the sum of AH outflow (CL_AH ~ 3 µL/min ² The concentration-time profile of indomethacin in AH after intracameral injection was fitted with a one-compartmental model. Drug exposure was greatest in cornea, followed by AH and ICB. Pharmacokinetic parameters are presented in Table 1. In Figure 2, dissolution half-lives of the six indomethacin suspensions are shown plotted against BA_AH after topical administration along with formulation characteristics. Small particles were dissolved more rapidly than large particles, and faster dissolution rate was associated with higher BA_AH across all viscosity levels. Although viscosity did not affect dissolution rate in vitro, BA_AH improved with increasing viscosity for both small and large particles.

Conclusion: Dissolution rate was dependent on particle size, but not on viscosity. Viscosity did, however, affect ocular bioavailability in vivo after topical administration. The effect of formulation viscosity on BA_AH is mainly due to extended retention time on the ocular surface. Faster dissolution rate correlated with higher BA_AH. This interplay of dissolution rate and viscosity determines ocular absorption from topical suspensions to a high degree; viscous medium is retained longer, giving more time for the particles to dissolve and the dissolved drug to penetrate the cornea. If the drug is dissolved too slowly, it does not have time to absorb before being washed away from the ocular surface. These data are invaluable for a complete quantitative understanding of the pharmacokinetics of topical ophthalmic suspensions. Currently, the demonstration of bioequivalence of topical suspensions is challenging and expensive. The eventual development of a PBPK model for topical suspensions will enable the in silico estimation of ocular bioavailability and bioequivalence, facilitating the development of generic topical suspensions.

References: 1. Toropainen, E. et al. Biopharmaceutics of Topical Ophthalmic Suspensions: Importance of Viscosity and Particle Size in Ocular Absorption of Indomethacin. Pharmaceutics 13, 452 (2021).
2. Reitsamer, H. A., Bogner, B., Tockner, B. & Kiel, J. W. Effects of Dorzolamide on Choroidal Blood Flow, Ciliary Blood Flow, and Aqueous Production in Rabbits. Invest. Ophthalmol. Vis. Sci. 50, 2301 (2009).
3. Heikkinen, E. M. et al. Distribution of Small Molecular Weight Drugs into the Porcine Lens: Studies on Imaging Mass Spectrometry, Partition Coefficients, and Implications in Ocular Pharmacokinetics. Mol. Pharmaceutics 16, 3968–3976 (2019).

Acknowledgements: Ashland and Barentz are acknowledged for providing us with free samples of HPMC K35M and HPMC E5, respectively.

Funding: This project was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award [75F40123C00072] totalling $477,341 with 100 percent funded by FDA/HHS. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement by, FDA/HHS, or the U.S. Government. We acknowledge NordForsk for the Nordic University Hub project #85352 (Nordic POP, Patient Oriented Products) for travel grants. Ethics approvals: Animal experiments were approved at University of Eastern Finland by the ethics committee (license number ESAVI/35788/2023, 14 Dec 2023-13 Dec 2026) and performed by authorized personnel. Conflict of Interest: The authors declare no conflict of interest.


Figure 1. Key ocular parameters of indomethacin in rabbits obtained from ex vivo permeability studies and in vivo administration of topical suspensions (125 µg/eye), and intracameral injection (2 µg/eye).
2 Reitsamer et al. 2009, 3 Heikkinen et al. 2019.


Table 1. Pharmacokinetic parameters after intracameral injection of indomethacin (2 µg/eye) in rabbits.


Figure 2. Dissolution half-life of indomethacin suspensions with small (~1.6 µm) or large (~3.7 µm) particles and low (~1.8 mPa.s), medium (~5.9 mPa.s), or high viscosity (~16 mPa.s) plotted against absolute ocular bioavailability in aqueous humour after topical administration.