Corneal and conjunctival drug permeability: Systematic comparison and pharmacokinetic impact in the eye

Abstract

On the surface of the eye, both the cornea and conjunctiva are restricting ocular absorption of topically applied drugs, but barrier contributions of these two membranes have not been systemically compared. Herein, we studied permeability of 32 small molecular drug compounds across an isolated porcine cornea and built a quantitative structure-property relationship (QSPR) model for the permeability. Corneal drug permeability (data obtained for 25 drug molecules) showed a 52-fold range in permeability (0.09-4.70 × 10 cm/s) and the most important molecular descriptors in predicting the permeability were hydrogen bond donor, polar surface area and halogen ratio. Corneal permeability values were compared to their conjunctival drug permeability values. Ocular drug bioavailability and systemic absorption via conjunctiva were predicted for this drug set with pharmacokinetic calculations. Drug bioavailability in the aqueous humour was simulated to be <5% and trans-conjunctival systemic absorption was 34-79% of the dose. Loss of drug across the conjunctiva to the blood circulation restricts significantly ocular drug bioavailability and, therefore, ocular absorption does not increase proportionally with the increasing corneal drug permeability.

Drug Delivery to the Posterior Segment of the Eye: Biopharmaceutic and Pharmacokinetic Considerations

“…This retentive effect is more pronounced in case of lipophilic drugs, resulting in a drug sustained action [112] but decreases its pharmacological activity [5]. Overall, the drug bioavailability in the aqueous humor through this route has been determined to be less than 5% of the applied dose [113].…”

“…It also must be taken into account that between 34% and 79% of the administered dose on the ocular surface is primarily removed by this way into the systemic circulation due to the high degree of conjunctival vascularization and its large surface area (16-18 cm 2 ) [113]. Therefore, for a drug to penetrate must have a molecular weight no greater than 70 kDa [116].…”

<p>Comparative Assessment of Distribution Characteristics and Ocular Pharmacokinetics of Norvancomycin Between Continuous Topical Ocular Instillation and Hourly Administration of Eye Drop</p>

“…In addition, the trans-conjunctival route is one of the pathways that leads to systemic drug absorption. [26][27][28] In our study, the NVCM concentrations in the ocular tissue and blood plasma in rabbits were measured by the established HPLC-PDA method. HPLC determination showed a good linear correlation and was validated via extraction recovery, intra-and inter-day methodological recovery, and stability of NVCM in serum.…”

“…Trans-conjunctival routes play an important role in drop absorption, mainly because NVCM is hydrophilic and the corneal epithelium favours lipophilic drugs. 28,29 However, continuous NVCM delivery can narrow the difference between these two routes. For systemic absorption, the levels in plasma were higher in the CTOIDD group.…”

Gelatin Nanoparticles-HPMC Hybrid System for Effective Ocular Topical Administration of Antihypertensive Agents

“…Eye drops can be straightforwardly instilled on the ocular surface in a comfortable way for patients. However low ocular bioavailability, typically lower than 5%, is generally achieved for classical eye drops formulations [6,7]. This is due to the presence of ocular protective barriers and precorneal tear clearance that reduce the drug residence time on the ocular surface.…”