A novel thermo-sensitive hydrogel-based on poly(N-isopropylacrylamide)/hyaluronic acid of ketoconazole for ophthalmic delivery

Figures & data

Figure 1. Photographs showing in situ gels before (room temperature) and after (33 °C) gelation.

Figure 2. Mean viscosity–temperature profiles of KCL PN-HA in situ gels. KCL (0.5%, w/v), PN-HA (1%, w/v), chlorhexidine acetate (0.01%, w/v), and glycerol (2%, w/v), (n = 3).

Table 1. The stability studies of the KCL in situ gel during the 3 months.

Date	Temperature (°C)	Appearance	pH	Gelling capacity	Drug content (%)	Osmotic pressure (osmol kg^−1)
0 day	4 ± 0.5	Milk white	6.43	+++	94.5	0.289
	25 ± 0.5	Milk white	6.42	+++	95.2	0.291
	40 ± 0.5	Milk white	6.37	+++	93.4	0.302
30 days	4 ± 0.5	Milk white	6.33	+++	92.6	0.297
	25 ± 0.5	Milk white	6.39	+++	93.2	0.304
	40 ± 0.5	Milk white	6.43	+++	92.5	0.299
60 days	4 ± 0.5	Milk white	6.35	+++	91.2	0.297
	25 ± 0.5	Milk white	6.32	+++	92.3	0.301
	40 ± 0.5	Milk white	6.33	+++	92.1	0.298
90 days	4 ± 0.5	Milk white	6.29	+++	89.9	0.302
	25 ± 0.5	Milk white	6.41	+++	91.1	0.299
	40 ± 0.5	Milk white	6.26	+++	88.7	0.302

Figure 3. In vitro release profiles of KCL in situ gels from three batches. Release experiments were carried out in distilled water as a dissolution medium at 33 ± 0.5 °C. Each point represents the mean value of three different mean ± SD. △: free drug; ▲: KCL in situ gels.

Table 2. Correlation coefficients for kinetic analysis of release data for KCL in situ gels.

	Correlation coefficient (r)
Formulation	Zero order	First order	Higuchi
KCL in situ gels	0.9726	0.9287	0.9993

Table 3. Score obtained from eye irritation assessment of KCL PN-HA in situ gels and commercial KCL eye drops in New Zealand white rabbits.

		Score obtained from assessment
Lesion	Score for each lesion	KCL PN-HA in situ gels	Commercial KCL eye drops
(A) Conjuctival edema (chemosis)
No swelling	0	0	1
Any swelling	1
Prominent swelling along with partial lid eversion	2
Swelling with half-closed lids	3
Swelling with totally closed lids	4
(B) Redness in conjunctiva
Absent	0	0	0
Abnormal conjunctival injections	1
More diffuse and deeper hyperemia, separate vessels cannot be seen easily	2
Diffuse and dense hyperemia	3
(C) Secretion
Absent	0	0	1
Any abnormal secretion	1
Secretion leading to wet eye lashes closer to lids	2
Secretion leading to wet lids and whole periorbital area	3
(D) Corneal opacity
Absent	0	0	1
Scattered or diffuse areas, detail of the iris discernible	1
Easy discernible, transparent areas, detail of the iris slightly darkened	2
Opalescent areas, no details of the iris discernible, size of the pupil barely discernible	3
Opaque cornea, iris not discernible	4
(E) Iris involvement
Absent	0	0	0
Pronounced deep folds, congestion, deep swelling circumcorneal injection, the iris still reacts to light	1
No response, hemorrhage, marked destruction	2
	Total score	0	3

Figure 4. Pathological observation of the corneal tissues in the established rabbits’ models. (×5000). A: normal; B: KCL PN-HA in situ gels; C: commercial KCL eye drops; D: negtive control.

Table 4. Effect of different KCL antifungal formulations on rabbits’ corneas (n = 12).

	Left eye		Right eye
Formulation	Cured	Not cured	Cured	Not cured
Placebo	0 (%)	24 (100%)	–	–
KCL PN-HA in situ gels	–	–	11 (91.7%)^a,^b	1 (8.3%)
Commercial KCL eye drops	–	–	8 (66.7%)^a	4 (33.3%)

^a p < .05, versus Placebo control group. ^bp < .05, KCL PN-HA in situ gels versus commercial KCL eye drops.