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. Author manuscript; available in PMC: 2021 May 10.
Published in final edited form as: J Control Release. 2020 Feb 3;321:1–22. doi: 10.1016/j.jconrel.2020.01.057

Table 3.

Drug delivery systems combining nanoparticles and in situ forming gels.

NP types In situ gels Drug model In vivo model In vivo study In vivo results Ref
Chitosan Alginate-HPMC Levofloxacin Rabbit Precorneal retention by gamma scintigraphy. NPs-gel retained for longer duration at corneal surface and negligible radioactivity was observed in other organs compared with aqueous solution. [131]
Chitosan and alginate Poloxamer Brimonidine Mice Measurement of intraocular pressure by Tonolab tonometer. For chitosan NPs, AUCtotal values were found 4.14-fold and 5.09-fold higher for in situ gel and NPs-gel, respectively, compared with ALPHAGAN P®. For alginate NPs, AUCtotal values were found 3.72-fold and 4.66-fold higher for in situ gel and NPs-gel, respectively, compared with ALPHAGAN P®. [132]
Chitosan-HA Chitosan 5-fluorouracil Rabbit Determination of drug concentration in aqueous humor by HPLC. AUC(0–8h) was found 3.5-fold higher for in situ gel compared to standard eye drops. In situ gel achieved a Cmax of approximatively 0.65 μg/mL followed by a slow decline. NPs-gel had a plateau (0.25–0.3 μg/mL) in the time interval of 0.5–7 hours. [133]
PLGA Chitosan Levofloxacin Rabbit Drug retention on corneal surface by gamma scintigraphy Marketed formulation reached into the systemic circulation via nasolacrimal drainage in 5h. Faster decline in radioactivity counts on the corneal surface for marketed formulation, compared with in situ gel, NPs and NPs-gel. [134]
Albumin Poloxamer Curcumin Rabbit Eye irritation test (Draize test). Determination of drug concentration in aqueous humor by HPLC. No sign of ocular irritation. Cmax was found to be 5.6-fold higher and AUC(0– 25h) 4.4-fold higher for NPs-gel compared to standard eye drop. [135]
Poloxamer Poloxamer Dexamethasone Rabbit Eye irritation test (Draize test). Determination of drug concentration in aqueous humor by HPLC. No sign of ocular irritation. AUC(0–12h) was found 2.8-fold and 2.86-fold higher for in situ gel and NPs-gel, respectively, compared with TOBRADEX®. Cmax was found to be 1.56-fold and 1.91-fold higher for in situ gel and NPs-gel, respectively, compared with TOBRADEX®. [136]
Eudragit® Poloxamer-HPMC Keratolac Rabbit Eye irritation test (Draize test and winking method). Determination of drug concentration in aqueous humor by HPLC. No sign of ocular irritation and no abnormal winking compared with simulated tear fluid. AUC(0–8h) was found to be 2.03-fold and 2.51-fold higher for NPs and NPs-gel, respectively, compared with ACULAR®. Cmax was found to be 1.41-fold and 1.20-fold higher for NPs and NPs-gel, respectively, compared with ACULAR®. [137]
PLGA Carbomer Pranoprofen Rabbit Eye irritation test (Draize test). Anti-inflammatory efficacy assessment by inflammation symptom scoring. No sign of ocular irritation. Better anti-inflammatory effica cy for NPs-gel compared to OFTALAR®. [138]
PLGA-Eudragit ® or PCL-Eudragit ® Carbomer Vancomycin Rabbit Eye irritation test (Draize test). Determination of drug concentration in external ocular tissues by the disc diffusion. No sign of ocular irritation. AUC(0.25–24h) was found 2.14-fold and 2.33-fold higher for PLGA-Eudragit NPs-gel and PCL-Eudragit NPs-gel, respectively, compared with in situ gel. Cmax was found 8.73-fold and 10.06-fold higher for PLGA-Eudragit NPs-gel and PCL-Eudragit NPs-gel, respectively, compared with in situ gel. [139]
pNIPAAm pNIPAAm Epinephrine Rabbit Measurement of intraocular pressure by ophthalmic tonometer. In situ gel decreased IOP for at least 32h with a minimum of 6.1 mmHg at 6h. Standard eye drop decreased IOP for 6h with a minimum of 4.7 mmHg. [23]
Liposomes HA Fluconazole Rabbit Eye irritation test (Draize test). Determination of drug concentration in aqueous humor by HPLC. No sign of ocular irritation. Drug concentration was found above MIC (minimum inhibitory concentration, 8 μg/mL) for 24h for NPs-gel and for 6h for standard drug solution. [140]
Liposomes Gellan gum Timolol Rabbit Eye irritation test for a single and multiple dosing. Measurement of intraocular pressure by invagination tonometer. No sign of ocular irritation. Liposomes-gel decreased IOP from 30–300 min and a minimum of 11.96±0.74 mm/Hg was observed at 1h. Standard eye drops decreased IOP from 30–180min, with a minimum of 13.61 mm/Hg at 2h. [141]

Abbreviations: AUC= Area Under the Curve; Cmax= Maximal concentration; HA= Hyaluronic acid; HPLC= High performance liquid chromatography; HPMC= Hydroxypropyl methyl cellulose; IOP= Intraocular pressure; NPs= Nanoparticles; PCL= Poly(epsilon-caprolactone); PLGA= Poly(lactic-co-glycolic acid); pNIPAAm = Poly(N-isopropylacrylamide)