*3.10. Pharmacokinetics*

Ocular bioavailability is calculated as the amount of clarithromycin in the aqueous humor of rabbit eyes of first (CL10) and second groups (control) after single dose administration. The efficacy of topical antibiotics relies on the potential of the formulation to permeate across the corneal tissues and deliver an effective antimicrobial level in the target area. Various pharmacokinetic parameters including tmax, Cmax, and AUC were computed from the graph plotted between concentrations (ng/mL) in aqueous humor and time (h) by non-compartment model analysis. Data in Figure 13 signify that the drug aqueous humor level in CL10 and control were significantly different throughout the study period in the current experimental conditions. A certain amount of drug was detected in 0.5 h in both cases. The amount of clarithromycin permeated in control experiments could be related to the drug's lipophilic nature and high partition coefficient. At 1 h, the clarithromycin level increased (881.08 ± 80.96 ng/mL and 654.99 ± 39.53 ng/mL in CL10

and control, respectively), though it was statistically different (*p* < 0.0001). At 2 h, absorption of clarithromycin in CL10 was extended, and the drug level reached ~1000 ng/mL, while the clarithromycin level declined sharply in the control (~500 ng/mL). These data signify that ophthalmic drops were retained in the ocular cavity for a short time because of extensive pre-corneal drug loss through nasolacrimal discharge and tear turnover. Further, the tmax value for CL10 was 2 h, while it was 1 h in the control. On the other hand, CL10 showed a 150% increase in Cmax (~1066 ng/mL) and a 2.8-fold improvement in AUC (5736 ng h/mL) (*p* < 0.0001) as compared to the control solution (Cmax; 655 ng/mL and AUC; 2067 ng h/mL). Thus, it can be concluded from the available data that intraocular permeation of clarithromycin was significantly improved by the optimized SLNs. This observation is also in agreement with ex vivo permeation data, wherein the flux was considerably higher in CL10 (Figure 11). The ocular pharmacokinetics data observed with CL10 were also significantly higher than the values reported in the literature tested with same concentration of clarithromycin eye drops [58]. Therefore, ocular residence time of CL10 proved extended duration of action in comparison to control. The average drug concentration noticed in Figure 13 in the aqueous humor was more than the minimum effective concentration of clarithromycin in various bacterial endophthalmitis [59]. *Pharmaceutics* **2021**, *13*, x FOR PEER REVIEW 21 of 24

**Figure 13.** Ocular pharmacokinetics profile of clarithromycin after topical application of solid lipid nanoparticle (CL10) and control (solution) in rabbits. Data represented are mean ± SD (*n* = 6). **Figure 13.** Ocular pharmacokinetics profile of clarithromycin after topical application of solid lipid nanoparticle (CL10) and control (solution) in rabbits. Data represented are mean ± S.D. (*n* = 6).
