Development of loteprednol etabonate-loaded cationic nanoemulsified in-situ ophthalmic gel for sustained delivery and enhanced ocular bioavailability

Figures & data

Table 1. Ranges of the factors investigated using 3² factorial experimental design.

	Coded value		Actual value
Batch no	X1	X2	X1 (Oil)	X2 (Smix)
F1	−1	−1	5	25
F2	0	−1	10	25
F3	1	−1	15	25
F4	−1	0	5	32.5
F5	0	0	10	32.5
F6	1	0	15	32.5
F7	−1	1	5	40
F8	0	1	10	40
F9	1	1	15	40
Variables and their levels in 3^2 factorial design
		Levels
Independent variables		Low (−1)	Middle (0)	High (+1)
X1 = Amount of Oil (% w/w)		5	10	15
X2 = Amount of Smix (% w/w)		25	32.5	40
Dependent variables		Goal
Y1 = Mean globule size (nm)		Minimize (Less than 100 nm)
Y2 = Polydispersity index		Minimize (Less than 1.0)

Figure 1. Comparative solubility profiles of LE in various (A) oils, (B) surfactants and (C) cosurfactants.

Figure 2. Pseudoternary phase diagrams composed of Capryol 80: Tween 80: Transcutol P dispersed with water at 37 °C. S_mix ratio = 1:1 (A), 2:1 (B), 3:1 (C) and 4:1 (D).

Table 2. Results of physicochemical properties of prepared LE-loaded nanoemulsions and statistical analysis of measured responses.

Batch No.	Mean Globule Size (nm)	PDI	Zeta Potential (mV)	Refractive index (cps)	% Transmittance	pH	Osmolarity (mOsmol/L)	Drug Content
F1	26.54 ± 1.2	0.95	−6.22 ± 5.3	1.366 ± 0.04	99.45 ± 0.13	5.52 ± 0.24	223.18	99.24 ± 0.25
F2	40.98 ± 1.5	0.75	−7.02 ± 2.4	1.397 ± 0.02	98.45 ± 0.34	5.60 ± 0.47	232.54	98.50 ± 0.20
F3	53.45 ± 0.8	0.56	−8.15 ± 1.5	1.415 ± 0.02	97.19 ± 0.21	5.44 ± 0.36	250.13	97.15 ± 0.48
F4	21.34 ± 0.6	1.1	−10.95 ± 2.1	1.370 ± 0.06	98.90 ± 0.23	5.58 ± 0.52	245.75	96.90 ± 0.35
F5	36.87 ± 1.4	0.78	−13.92 ± 1.2	1.399 ± 0.01	97.95 ± 0.35	5.65 ± 0.64	260.23	99.24 ± 0.42
F6	50.53 ± 1.5	0.6	−16.28 ± 3.8	1.422 ± 0.04	97.40 ± 0.15	6.49 ± 0.31	258.45	98.00 ± 0.22
F7	15.32 ± 1.3	1.3	−17.54 ± 2.4	1.376 ± 0.03	98.10 ± 0.65	5.78 ± 0.41	238.15	99.15 ± 0.48
F8	28.45 ± 2.1	0.89	−18.20 ± 2.5	1.404 ± 0.03	97.35 ± 0.20	5.56 ± 0.37	257.79	98.90 ± 0.14
F9	45.87 ± 1.2	0.62	−20.27 ± 3.5	1.430 ± 0.02	96.22 ± 0.48	6.42 ± 0.53	249.28	97.12 ± 0.47
Fitting model	Factors	Coefficient	p-value	ANOVA
Mean globule size	Intercept	35.48		F = 412.05R^2= 0.9928Model p-value < 0.0001p-value of lack-of-fit = 0.4350PRESS = 24.54
	X1	14.44	<0.0001
	X2	−5.22	<0.0001
	X1X2	0.91	0.2281
	X1^2	0.07	0.9354
	X2^2	−1.15	0.2716
PDI	Intercept	0.84		F = 105.33R^2= 0.9844Model p-value < 0.0001p-value of lack-of-fit = 0.6521PRESS = 0.030
	X1	−0.26	<0.0001
	X2	0.092	0.0022
	X1X2	−0.073	0.0138
	X1^2	0.05	0.0895
	X2^2	0.01	0.4169

Figure 3. Response surface plot (A) for mean globule size and (B) PDI and (C) Contour plot for overall desirability (D).

Figure 4. (A) Rheological profile of NE-ISG5 before and after gelation, (B) comparison of ex-vivo transcorneal permeation, (C) comparison of Aqueous humor concentration–time profiles of NE-ISG2 and the marketed formulation in rabbits (mean ± SD, n = 5).