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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 2.

Nanoparticles-based systems used for ophthalmic drug delivery.

Drug model Animal model In vivo studies In vivo results Ref
Natural materials
Chitosan Ganciclovir Rat Determination of drug concentration in aqueous humor by HPLC. AUC(0–∞) and Cmax values were found to be 4.69-fold and 2.7-fold higher, respectively, for NPs solution compared with aqueous solution. [63]
Diclofenac Rabbit Eye irritation test (Draize test). Determination of drug concentration in aqueous humor by HPLC. No sign of ocular irritation. AUC(0–720min) values were found to be 2.46-fold higher for NPs solution compared with commercial eye drops. Cmax was found to be similar for NPs solution and commercial eye drops. [64]
Cyclosporine A Sheep Determination of drug concentration in aqueous and vitreous humor by HPLC. After 2h, drug concentration was found to be 40.70±1.0 and 35.60±2.50 ng/mL in aqueous and vitreous humors, respectively. After 72h, drug concentration was found to be 41.70±0.90 and 36.70±0.30 ng/mL in aqueous and vitreous humors, respectively. [65]
Cyclosporine A Rabbit Determination of drug concentration in ocular tissues by liquid scintillation counting. Corneal and conjunctival drug levels were found 2- fold to 6-fold higher for NPs solution compared with standard aqueous solution. [66]
Indomethacin Rabbit Determination of drug concentration in aqueous humor by HPLC. AUC and Cmax values were found 17-fold and 13-fold higher, respectively, for NPs solution compared with standard solution. [67]
Celocoxib Rat Determination of drug concentration in ocular tissues by HPLC. AUC(0–24), AUC(0–∞) and Cmax values were found 4.8-fold to 27.7-fold higher for NPs solution compared with standard solution. [68]
Timolol Rabbit Precorneal retention by fluorescence imaging. Measurement of intraocular pressure. After 1.5h, higher precorneal retention for NPs solution compared with standard eye drops. Maximal IOP lowering effect was observed at 4h with a value of 10.5±0.51 mmHg for NPs solution. Maximal IOP lowering effect was observed at 3h with a value of 6.8±0.35 mmHg for standard eye drops. [69]
Carteolol Rabbit Precorneal retention by gamma scintigraphy. Measurement of intraocular pressure by a Schiotz tonometer. Standard solution showed a quick fall in radioactive counts on corneal surface with respect of time as compared to NPs suspension in 0.5h. Maximum IOP lowering effect was observed at 2h with a value of 18.04±0.697 mmHg for NPs solution. Maximum IOP lowering effect was observed at 1h with a value of 22.616±0.639 mmHg for NPs solution. [70]
Alginate-chitosan Azelastine Rat Determination of drug efficacy by counting of scratching instances, by analysis of conjunctival hyperemia, edema and by eosinophil count. Similar reduction in eye scratching behavior for NPs solution and Azelast®. Higher reduction of hyperemia and edema for NPs solution compared with Azelast®. Reduction of eosinophil count lasted 4h for Azelast® and 10h for NPs solution. [71]
5-Flourouracil Rabbit Determination of drug concentration in ocular tissues by HPLC. AUC(0–8) and Cmax values were found 17-fold and 13-fold higher, respectively, for NPs solution compared with standard solution. [72]
Albumin Pilocarpine Rabbit Measurement of intraocular pressure by a Schiotz tonometer. AUC values were found to be 3.19-fold and 1.67-fold higher for 1%-drug NPs solution compared with 1%-drug and 4%- drug standard solution, respectively. [73]
Albuminchitosan Tetracaine Rabbit Determination of blink response after cotton swab stimuli. No statistical difference of efficacy between NPs solution and standard solution. Duration of action was 4-fold higher for NPs solution compared with standard solution. [74]
Atropine Rabbit Measurement of mydriasis by video recording and analysis. AUC values were found to be at 10.67 for 0.66%-drug NPs solution and 10.02 for 1%- drug standard solution. Maximum effect (pupil-corneal ratio) was found to be at 0.630 for 0.66%-drug NPs solution and at 0.596 for 1%-drug standard solution. [75]
Gelatin Timolol Rabbit Eye irritation test (Draize test). Measurement of intraocular pressure by a plunger load tonometer. No sign of ocular irritation. AUC values were found to be 2.27-fold higher for NPs solutions compared with marketed eye drops. [76]
Moxifloxacin Rabbit Eye irritation test. Assessment of antimicrobial efficacy by observation of clinical parameters. No sign of ocular irritation. No difference in antimicrobial efficacy between NPs solution at a dose regime of twice a day and MOXIGRAM® at a dose regime of four times a day. NPs solution decreased secretion (discharge), redness and swelling faster when compared with MOXIGRAM®. [77]
HA-chitosan Dexamethasone Rabbit Eye irritation test (Draize test). Determination of
drug concentration in aqueous humor by HPLC.		 No sign of ocular irritation. AUC(0–∞) values were found to be 1.93-fold and 2.39-fold higher for chitosan NPs solution and chitosan-HA NPs solution, respectively, compared with standard solution. [78]
Dorzolamide or Timolol Rabbit Eye irritation test (Draize test). Measurement of intraocular pressure by a Schiotz tonometer. No sign of ocular irritation. IOP lowering effect peaked at 3h for marketed solution, at 4h and observed for up to 8h for chitosan NPs solution, and at 4h and observed for up to 12 h for chitosan-HA NPs solution. [79]
EC Acetazolamide Rabbit Measurement of intraocular pressure by a tonometer. Maximum IOP reduction was found 1.33-fold higher for NPs solution compared with standard solution. Mean time for IOP reducing effect was 6h for NPs solution and 5h for standard solution. [80]
Synthetic materials
Eudragit® Aceclofenac Rabbit Assessment of anti-inflammatory efficacy by observation of polymorphonuclear leucocyte (PMN) migration and lid closure. PMN count in tears were found to be 1.57-fold and 1.18-fold lower for NPs solution and standard aqueous solution, respectively, compared with control eyes. [81]
Aceclofenac Rabbit Assessment of anti-inflammatory efficacy by assessment of polymorphonuclear leucocyte (PMN) migration and lid closure. PMN count in tears at 3h were found to be 1.66-fold and 1.28-fold lower for NPs solution and standard aqueous solution, respectively, compared with control eyes. [82]
Diclofenac Rabbit Assessment of anti-inflammatory efficacy by assessment of polymorphonuclear leucocyte (PMN) migration and lid closure. Greater decrease of PMN count at all time points for NPs solution compared with standard aqueous solution. [83]
Ibuprofen Rabbit Eye irritation test (Draize test). Determination of drug concentration in ocular tissues by HPLC. No sign of ocular irritation. 2h after instillation, drug concentrations were 1.54±0.06 μg/mL for NPs solution and 0.93±0.08 μg/mL for standard solution. [84]
Betaxolol Rabbit Eye irritation test (Draize test). Determination of drug concentration in tear fluid by HPLC. Measurement of intraocular pressure by an indentation tonometer. NPs solution was found safer and less toxic than standard solution. Higher drug concentrations were found at all time points for NPs solution compared with standard solution. After 90 min, drug concentrations cannot be detected for standard solution, whereas drug concentrations were detected until 240 min for NPs solution. For standard solution, maximum IOP lowering effect was found at 30 min (5.04 mmHg) and the effect significantly declined after 60 min. For NPs solution, maximum IOP lowering effect was found at 120 min (4.89 mmHg). [85]
Acetozalamide Rabbit Measurement of intraocular pressure by a Riester tonometer. For standard solution, maximal IOP lowering effect was observed at 2h with a ΔIOP value of 2.98±0.11 mmHg. After 6h, no IOP lowering effect was observed. For NPs solution, maximal IOP lowering effect was observed at 8h with a ΔIOP value of 5.32±0.07 mmHg. [86]
Brimonidine Rabbit Eye irritation test (Draize test). Measurement of intraocular pressure by a Schiotz tonometer. No sign of ocular irritation. AUC(ΔIOP vs. t) values were found to be 3.55–6.98-fold higher for NPs solution, compared with IOBRIM®. [87]
Amphoterin B Rabbit Eye irritation test (Draize test). No sign of ocular irritation. [88]
Azelastine Rat Assessment of eye scratching, hyperemia, edema and eosinophils in the conjunctiva. No significant difference of eye scratching, hyperemia and edema between NPs solution and AZELAST®. Eosinophil counts were found lower at 6h and 10h for NPs solution compared with AZELAST®. [89]
Acetazolamide Rabbit Measurement of intraocular pressure by a tonometer. Maximum IOP reduction was found 1.51-fold higher for NPs solution compared with standard solution. [80]
PLADextran- PBA Cyclosporine A Mice Quantification of tear fluid production and fluorescein staining analysis after dry eye disease induction. Histopathology analysis. Similar tear fluid production and fluorescein staining were observed for NPs instilled once a week compared with the conventional treatment (RESTASIS®) instilled three times a day. No sign of ocular irritation. [90]
PLA-PMAPBA Cyclosporine A Rat Slit lamp and OCT imaging examination. No sign of ocular toxicity. [91]
PLGA Fluoromethalone Pig Eye irritation test (Draize test). Assessment of anti-inflammatory efficacy by scoring of clinical symptoms. Determination of drug concentration in ocular tissues by HPLC. No sign of ocular irritation. Ocular inflammation was found significantly lower for NPs solution compared with ISOPTOFLUCON®. [92]
Aceclofenac Rabbit Assessment of anti-inflammatory efficacy by observation of polymorphonuclear leucocyte (PMN) migration and lid closure. PMN counts were found significantly lower for MPs solution, compared with standard aqueous solution. [93]
PLGA-PEG Dorzolamide Rabbit Measurement of intraocular pressure by a tonometer. Similar efficacy on IOP lowering between one drop of NPs and 4 drops of TRUSOPT®. [94]
PCL Cyclosporine A Rabbit Determination of drug concentration in tear fluid by liquid scintillation counting. AUC values were significantly higher for NPs solution compared with oily control. [95]
Indomethacin Rabbit Determination of drug concentration in tear fluid by liquid scintillation counting. AUC(0–4h) and Cmax values were found to be 4-fold and 7-fold higher, respectively, for NPs solution compared with standard INDOCOLLYRE®. [96]
Combination of natural and synthetic materials
Chitosan- PLGA Forskalin Rabbit Eye irritation test (infra-red camera). Assessment of precorneal retention by gamma scintigraphy. Measurement of intraocular pressure by a Schiotz tonometer. No sign of ocular irritation. Precorneal retention was found significantly higher for NPs solution compared with standard solution. For standard solution, maximum IOP lowering effect was found at 1h (20.1±1.56 mmHg). For NPs solution, maximum IOP lowering effect was found at 8h (16.3±0.75 mmHg). [97]
Fluocinolone Rabbit Eye irritation test (Draize test). Determination of drug concentration in tear fluid by HPLC. No sign of ocular irritation. AUC(0–∞) and Cmax values were found to be 5.23-fold and 2.19-fold higher, respectively, for chitosan-PLGA NPs solution compared with PLGA NPs solution. [98]
Chitosan- PLA Amphotericin B Rabbit Eye irritation test (Draize test). Determination of drug concentration in tear fluid by HPLC. Assessment of corneal permeation by fluorescein staining. No sign of ocular irritation. AUC values were found 1.5-fold higher for NPs solution compared with standard solution. Higher permeation and retention effects were noted for NPs solution compared with fluorescein solution. [99]
Chitosan- PEG Resveratrol Rabbit Assessment of corneal permeation by fluorescein staining. Measurement of intraocular pressure by a tonometer. Increased fluorescent signal at the inner site of the cornea for chitosan-PEG NPs solution compared to chitosan NPs. Chitosan-PEG NPs solution reduced IOP by 4.3±0.5 mmHg up to 8h. [100]
Resveratrol and quercetin Rabbit Measurement of intraocular pressure by a tonometer. Chitosan-PEG NPs solution reduced IOP by 5.5±0.5 mmHg up to 8h. [101]
Chitosan-PEG-PCL Diclofenac Rabbit Eye irritation test (Draize test). Assessment of corneal permeation by Nile red staining. Determination of drug concentration in aqueous humor by HPLC. No sign of ocular irritation. AUC(0–24h) and Cmax values were found 2.3-fold and 2.11-fold higher, respectively, for NPs solution compared with commercial eye drops. [102]
Eduragit®-HA Gatifloxacin and prednisolone Rabbit Determination of drug concentration in aqueous humor by HPLC. AUC(0–24h) and Cmax values were found 1.77-fold and 1–76-fold higher, respectively, for NPs solution compared with commercial eye drops. [103]
Combination of polymers with lipidic vectors
Chitosan Methazolamide Rabbit Eye irritation test (Draize test). Measurement of intraocular pressure by a tonometer. No sign of ocular irritation. AUC(0–8h) values were 237.8 mmHg for chitosan lipid NPs, 175.2 mmHg for Azopt®, 81.2 mmHg for lipid NPs and 49.9 mmHg for standard solution. [104]
Dexamethasone Rabbit Eye irritation test (Draize test). Determination of drug concentration in aqueous humor by HPLC. AUC(0–24h) and Cmax values were found 5.38-fold and 2.37-fold higher, respectively, for NPs solution compared with commercial eye drops. [105]
Timolol Rabbit Eye irritation test. Assessment of precorneal retention by gamma scintigraphy. Determination of drug concentration in tear fluid by HPLC. Measurement of intraocular pressure by a tonometer. No sign of ocular irritation. Higher precorneal retention of chitosan-coated liposomes compared with standard eye drops and liposomes. AUC(0–∞) and Cmax values were found 1.72-fold and 2.67-fold higher, respectively, for chitosan-coated liposomes compared with uncoated liposomes. Maximum IOP was 19.67±1.11 mmHg for chitosan-coated liposomes and 23.80 ± 1.72 mmHg for standard eye drops. [106]
Amphotericin B Rabbit Eye irritation test (symptom scoring). Determination of drug concentration in tear fluid and aqueous humor by HPLC. No sign of ocular irritation. Chitosan-lipid carriers had a significantly greater percentage activity remaining in the pre-corneal area after 30 min (71.7%) as compared with lipid carriers (54.1%) and standard eye drops (40.8%). AUC(0–∞) and Cmax values were found 1.99-fold and 1.27-fold higher, respectively, for chitosan lipid carriers compared with lipid carriers. [107]
Amphotericin B Rabbit Eye irritation test (Draize test). Determination of drug concentration in tear fluid by mass spectrophotometry. No sign of ocular irritation. AUC(0–∞) values were found 2.05-fold higher, for chitosan/lecithin NPs compared with Fungizone®. [108]
Flurbiprofen Rabbit Eye irritation test (symptom scoring). Assessment of precorneal retention by gamma scintigraphy. No sign of ocular irritation. AUC(0–10min) values for chitosan-coated liposomes were found to be 2.84-fold and 1.53-fold higher in the cornea-conjunctiva region compared with standard eye drop and uncoated liposomes, respectively. [109]
Flurbiprofen Rabbit Eye irritation test (symptom scoring). Assessment of precorneal retention by gamma scintigraphy. No sign of ocular irritation. AUC(0–10min) values for chitosan-coated lipid carriers were found 4.66-fold and 1.70-fold higher in the cornea-conjunctiva region compared with standard eye drops and uncoated lipid carriers, respectively. [110]
Ofloxacin Rabbit Eye irritation test (Draize test). Assessment of precorneal retention by fluorescein staining. Determination of drug concentration in aqueous humor by HPLC. Assessment of anti-microbial efficacy by keratitis induction and symptoms scoring. Precorneal retention time was observed during 40–60 min for chitosan lipid carriers and for 20–40 min for lipid carriers. Maximum drug concentration was found at 1h for commercial eye drops and at 4h for chitosan lipid carrier. After keratitis induction, significantly lower conjunctival redness and corneal opacity was observed with chitosan lipid nanocarrier treatment compared with commercial solution. [111]
Natamycin Rabbit Eye irritation test (Draize test). Determination of drug concentration in tear fluid by mass spectrophotometry. No sign of ocular irritation. AUC(0–∞) values were found 1.47-fold higher, for chitosan/lecithin NPs compared with standard suspension. Clearance was significantly decreased (7.4-fold) for chitosan/lecithin NPs compared with standard suspension. [112]
Cyclosporin A Rabbit Determination of drug concentration in cornea, conjunctiva and sclera by HPLC. Higher drug absorptions in cornea, conjunctiva and sclera for chitosan-coated liposomes compared with liposomes. [113]
Ciprofloxacin Rabbit Assessment of anti-microbial efficacy by bacterial conjunctivitis induction and symptoms scoring. No significant difference of antimicrobial efficacy between chitosan-coated liposomes and Ciloxan®. [114]
Chitosan-HA Moxifloxacin Rabbit Eye irritation test (Draize test). Determination of drug concentration in tear fluid by HPLC. No sign of ocular irritation. AUC(0–∞) and Cmax values were found 6.74-fold and 3.17- fold higher, respectively for NPs solution compared with Vigamox®. [115]
HA Tacrolimus Rabbit Determination of drug concentration in aqueous humor by HPLC. The relative bioavailability of HA-coated niosomes was 2.3-fold and 1.2-fold for that of suspension and non-coated niosomes, respectively. [116]
Doxorubicin Rabbit Determination of drug concentration in aqueous humor. Assessment of drug permeation in cornea by laser scanning microscopy. AUC and Cmax values were found 1.68-fold and 1.36-fold higher, respectively, for NPs solution compared with standard solution. Higher drug permeation was noted for NPs solution compared with standard solution. [117]
PEG-PCL Diclofenac Rabbit Eye irritation test (Draize test). Determination of drug concentration in aqueous humor by HPLC. No sign of ocular irritation. AUC(0–24h) and Cmax values were found 2.02-fold and 3.03-fold higher, respectively, for NPs solution compared with standard solution. [118]
PEG-PLA Cyclosporin A Rabbit Determination of drug concentration in aqueous humor and cornea by HPLC. NPs solution exhibited 4.5-fold increase in retention effect on eyes compared with standard emulsions. [119]

Abbreviations: AUC= Area under the curve; Cmax = Maximal concentration; EC= Ethyl cellulose; HA= Hyaluronic acid; HPLC = High performance liquid chromatography; IOP= Intraocular pressure; MPs= Microparticles; NPs= Nanoparticles; PCL= Poly(epsilon-caprolactone); PEG= Polyethylene glycol; PLA= Polylactide; PBA = Phenylboronic; PMA = poly(methacrylic acid); PLGA= Poly(lactic-co-glycolic acid); PMN= Polymorphonuclear leucocyte ; ΔIOP= Intraocular pressure variation.