TABLE 3.
Natural based nanoparticles used in ocular drug delivery.
| Type of carriers | Drug/Carrier | Method of Preparation | Size (nm) | Entrapment Efficiency (%) | Advantages and Considerations | Ref |
|---|---|---|---|---|---|---|
| Lipoid nanoparticles (LNs) | Curcumin loaded in NLC Coated with chitosan-N-acethyl cysteine (NAC) | Melt-emulsification method | 88.6 | 96.6 | Topical administration in rabbit eye. Controlled release of drug for 72 h. Enhanced the retention time and corneal permeation with no toxicity and irritation | Li et al. (2016) |
| Curcumin loaded in NLC | Hot melt emulsification/ultra-sonication method | 66.8 | 96 | Cur-NLC was stable for 3 months and could enhance the rabbit corneal permeability of Cur to 2.5 fold in comparison to Cur solution. So it is safe and effective formulation for anterior ocular drug delivery | Lakhani et al. (2018b) | |
| Quercetin loaded in Hybrid of NLC/hydrogel | Melt emulsification and ultra-sonication method | 71–76 | 96.8–97.6 | This PH and thermosensitive hydrogel system consists of CMCS and p407 that cross-linked by genipin (GP). Quercetin (QN) loaded into NLC/hydrogel to make QN-NLC-GEL-GP for ocular drug delivery that enhanced rabbit trans-corneal permeation and retention time thus improve the bioavailability of QN with no significant irritation. It could significantly increase the AUC of QN in comparison to the eye drop group (4.4 fold) | Yu et al. (2020) | |
| Quercetin in SLN | Melt emulsification method | 143 | 66.5 | Comparison of these two formulations, demonstrated that QT-SLN form shows better corneal permeability, more efficiency in protecting retina and corneal cells against stress oxidative, higher biocompatibility with corneal cells, and lower toxicity | Liu et al. (2015) | |
| Quercetin in Nanoemulsion (NE) | 138.3 | 74.2 | ||||
| Baicalin in NLC based hydrogel (CMCS and F127 poloxamer cross-linked by genipin) | Melt emulsification-ultra-sonication method | 99.6 | 89 | This PH and thermosensitive hydrogel administrated as eye drops on rabbit eyes with no significant irritation and indicated a prolonged release profile. The corneal penetration enhanced in comparison with BN eye drops (4.46-fold) | Yu et al. (2019) | |
| Baicalin loaded in SLN | emulsification/ultrasonication method | 91.4 | 62.4 | Topical administration on the rabbit eye indicated no irritation. This formulation followed a prolonged release profile that enhance the bioavailability, corneal permeability, and stability of BN. It can be used for cataract treatment | Liu et al. (2011) | |
| Baicalein Lipid NPs (coated with trimethyl chitosan (TMC)) | Thin film hydration method | 162.8 | 90.6 | To evaluate the trans-membrane permeability, the molecular dynamic stimulation was carried out. This topical formulation applied on rabbit eyes. The pre corneal retention time and ocular irritation indicated this formulation as a good carrier for ocular administration. The AUC of this formulation was increased 3.17 fold more than the control group and demonstrated sustained release profile. It used in the treatment and prevention of glaucoma and keratitis disorders | Li et al. (2020b) | |
| Tetrandrine in Cationic solid lipid NPs (TET-CNP) | Emulsion evaporation-solidification at low temperature | 15.2 | 94.1 | Topical administration on rabbit eyes indicated a prolonged drug release pattern with minimal toxicity in low concentration. Flow-cytometry results revealed more cellular uptake of TET-NP, so this formulation was more successful to apply in PCO. | Li et al. (2014) | |
| Tetrandrine in Anionic solid lipid NPs (TET-NP) | Emulsion evaporation-solidification at low temperature | 18.7 | 95.6 | Topical administration on rabbit eyes indicated a prolonged drug release pattern with minimal toxicity in low concentration. Flow-cytometry results revealed more cellular uptake of TET-NP, so this formulation was more successful to apply in PCO. | ||
| Tetrandrine in liquid crystalline nanoparticles (LCNPs) | Emulsion evaporation-solidification | 1700 | 95.4 | Topical administration of this formulation on rabbit eyes indicated more sustained release profile, corneal permeability, and enhanced bioavailability in comparison to the TET solution | Liu et al. (2016a) | |
| Genistein in NLC | Melt-emulsification technique followed by surface absorption of EDU RS 100 | 88.3 | 90.3 | Topically instilled GEN-NLC applied in the rabbit eyes, the corneal permeation increased 3.3-fold in comparison to the NLC solution. The Draize test exhibited no irritation in cornea tissue. No significant toxicity in ocular tissues was reported. The AUC of this formulation was 1.22-fold more than bare NLC formulation. It would be a promising candidate for PCO treatment | Zhang et al. (2014a) | |
| Genistein in NLC | Melt emulsification technique | 90.1 | 91.1 | In vitro study showed this formulation could enhance GEN permeation into human lens epithelial cells (HLECs). It was effective in inhibiting the growth of (HLECs). The drug release profile demonstrated controlled and sustained release pattern in 72 h this formulation has the potency to prevent PCO. | Zhang et al. (2013) | |
| Genistein in NLC modified with Chitosan hydrochlorides | Melt emulsification technique combined with ultra-sonication | 100–800 | 80.8–90.6 | By decreasing the size of NPs, the cellular uptake into epithelial cells of the human lens increased that results in a promising carrier for PCO treatment | Zhang et al. (2014b) | |
| Genistein loaded in NLC | Melt emulsification technique | 80.1 | 92.3 | In vitro drug release demonstrated sustained drug release for 72 h. It would be useful for PCO prevention after cataract surgery | Liu et al. (2016c) | |
| Lutein in Nanoemulsion | Sonication method | 10–12 | NA | Sustained drug release in the first 24 h and release pattern reached a plateau at 144 h which enhanced the solubility and permeability of Lutein to the ocular tissues | Lim et al. (2016) | |
| Mangiferin NLC | Ultrasonication method | 51.3 | 88.1 | Topically administration of formulation indicated sustained drug release for 3 months and enhanced MGN ocular bioavailability, corneal permeability, retention time, and stability. The Draize test demonstrated good ocular tolerability and no ocular irritation | Liu et al. (2012) | |
| EGCG in Lipid nanoparticles CTAB (cationic lipid as a surfactant) | Double emulsion technique | 90–300 | 98.9 | These formulations enhanced the stability, safety, bioavailability, and biodegradability of EGCG for ocular drug delivery and for the treatment of ophthalmic disorders such as AMD, DR, and glaucoma through their anti-inflammatory and anti-oxidative effects. They also indicated a prolonged release profile with improved corneal resistance time. EGCG-DDABLNs shows 3-fold higher transscleral permeability than EGCG-CTAB LNs | Fangueiro et al. (2014) | |
| EGCG in Lipid nanoparticles DDAB (cationic lipid as a surfactant) | Double emulsion technique | 130–380 | 96.8 | |||
| Micelle | Curcumin loaded in Nanomicelle with graft copolymer (PVCL-PVA-PEG) | Solvent evaporation/film hydration method | 50.1 | 99.3 | Topical administration in rabbit eye with no toxicity and irradiation. Enhanced the stability, corneal permeability, and anti-inflammatory effect of curcumin | Li et al. (2017) |
| Curcumin in Micelle, (in-situ gelling system based PEG-DSPE/solutol HS 15 mixed with gellan gum | Solvent evaporation method | 13.4 | 97.2 | More permeability through the cornea than free Cur. The biocompatible in-situ gelling form increased the retention time on the rabbit cornea with good tolerability and no irritation | Sai et al. (2020) | |
| Curcumin loaded in Micelle | Solvent evaporation method | 14–26 | 48–8 | This eye drop formulation indicated the high potency of cur-micelle in reducing VEGF expression in retinal cells (D407) and protection of them against oxidative stress. It shows sustained release profile for 1 month that is suitable for treatment of chronic retina diseases such as wet and dry AMD. | Alshamrani et al. (2019) | |
| Curcumin in Micelle (ion sensitive in-situ gel used P123/TPGS mixed with gellan gum) | Thin film dispersion method | 10.8 | 90.8 | Topical administration of this in-situ gel system, show sustained release pattern with high biocompatibility, corneal permeation, and no irritation that makes it suitable for ocular drug delivery | Duan et al. (2015) | |
| Genistein loaded in Flt1 peptide–HA conjugate micelles | Sonication and dialysis method | 172 | 40–50 | Synergistic effect of GEN and Flt1 peptide in the anti-angiogenesis effect results in a beneficial treatment of ocular neovascularization. This inhibitory effect on vascular permeability and corneal neovascularization was demonstrated in diabetic retinopathy and silver-nitrate cauterized corneas of SD rats respectively. This formulation was enabled to control drug release for 24 h | Kim et al. (2012) | |
| Genistein in Micelle (MPEG-b-PAE-modified with HA) | Diafiltration method | 84.5 | NA | Topically instilled eye drops into the rabbit eyes. It was able to increase the retention time of formulation on the cornea thus enhance corneal permeation that leads to enhance the bioavailability of GEN. The anti-angiogenesis effect of this formulation makes it suitable for DR, CNV, and AMD treatment | Li et al. (2018) | |
| Resveratrol in Micelle | Film dispersion method | 50.1 | 98.8 | Topical instillation on rabbit eyes used for corneal wound healing. SOL-RES indicated no cytotoxicity, improved corneal permeability and cell proliferation, high ocular tolerance, more chemical stability, and good storage ability for 12 weeks | Li et al. (2020a) | |
| Nanoparticles/Polymeric nanoparticles | Curcumin in B-cyclodextrin NPs modified with ethylene diamine (EDA) | Solvent evaporation method | 189–300 | NA | Topically drug delivery. Enhanced aqueous solubility and stability of Cur and improved corneal permeability | Liu et al. (2020) |
| Curcumin in Albumin NPs (Thermoresponse in-situ gelling system) (Cur-BSA-NPs-Gel) | Desolvation method | 221 | 85.4 | Topical administration for the treatment of DR with sustained release profile and enhanced the bioavailability of Cur with no obvious irritation on rabbit eyes | Lou et al. (2014) | |
| Curcumin loaded in Albumin based Nanosphere | Desolvation method | 203–354 | NA | Albumin based nanospheres indicated promising efficiency in increasing the solubility and bioavailability, anti-oxidant property of curcumin, and they followed the sustained release pattern to release drug | Kim et al. (2019) | |
| Quercetin loaded in Chitosan NPs modified with PEG (co-delivery with Resveratrol) | Ionic gelation Using TPP as a cross-linker | 308 | 81.3 | Eye drop instillation reduced the IOP in normotensive rabbits. This formulation show Sustained drug release profile with enhanced the corneal permeability, and bioavailability of RES. The loading and EE% decreased by increasing the PEG concentration. PEG was used to modify CSNPs to reduce IOP in the glaucoma treatment. This formulation showed more radical oxygen (ROs) scavenging effects and corneal permeation than singular RES and CUR dispersion | Natesan et al. (2017) | |
| Resveratrol in PEG NPs Modified with chitosan | Ionic gelation method | 129 | 91.8 | RES-PEG-CS NPs administrated to the conjunctival cul-de-sac, demonstrated sustained release profile with sufficient corneal permeability to target the intraocular tissues with no irritation. It was efficient to reduce IOP and glaucoma treatment | Pandian et al. (2016) | |
| Naringenin loaded in sulfobutylether-β-cyclodextrin/chitosan nanoparticles | Ionic gelation method | 446.4 | 67.1 | The Draize test indicated no irritation on the rabbit eye. This formulation indicated the sustained drug release profile, enhanced bioavailability of NG with enhancing the solubility of NG and the retention time of the formulation on the surface of the eye, and reduced the frequency of drug administration | Zhang et al. (2016) | |
| Pilocarpine in PLGA NPs | Double emulsion method | 82.7 | 57 | This eye drops formulation administrated to the rabbit model. The ocular resistance time and ocular bioavailability increased in comparison to the commercial eye drop which results in more miotic response. Indicated initial burst release during the first 2 h, which continued by sustained release profile for up to 24 h | Nair et al. (2012) | |
| Pilocarpine in PCL Nanocapsules (NCs) | Double emulsion-solvent evaporation (Pluronic F68 as a surfactant) | 235.4 | 89.2 | Two types of nanoparticles (NCs, NSs) applied to rabbit eyes. NCs indicated better therapeutic efficiency in reducing IOP and sustained drug release for 42 days and higher entrapment and loading efficiency | Lee et al. (2017b) | |
| Pilocarpine in PCL Nanospheres (NSs) | 227.7 | 30.1 | ||||
| Pilocarpine in Eudragit RL 100 | Solvent displacement | 121–291 | 41.6–72.9 | Pilocarpine nanosuspension developed to enhance the drug availability, decrease the frequency of administration and sustained drug release for 24 h this formulation was safe and stable for ocular drug administration | Khan et al. (2013) | |
| EGCG in Gelatin nanoparticles decorated with HA (GEH NPs) | Self-assembly method | 250 | 97 | Topically administrated formulation on rabbit eyes (twice daily) was efficient in DES treatment. It was no toxic for HCECs cells, reduced the inflammation effect, prolonged the retention time on ocular surface, without making any irritation on the surface of the rabbit eye | Huang et al. (2018) | |
| EGCG in Gelatin Nanoparticles coated with RGD-HA | Self-assembly method | 168.8 | 95 | These NPs applied to the cornea of neovascularization mouse model. It was effectively target the specific receptor and significantly reduced the corneal neovascularization and prevented angiogenesis in cornea | Chang et al. (2017) | |
| Kaempferol in Gelatin NPs | Desolvation method | 90 | 98 | GNPs illustrated anti-angiogenic effect and reduced blood vessel formation on rat eyes so it can be used topically for the treatment of corneal neovascularization. Hematoxylin and eosin (H&E) stain, and metalloproteinases (MMP)/(VEGF) quantification demonstrated the efficiency of GNP-KA in reducing the number of corneal blood vessels | Chuang et al. (2019) | |
| Catechin in PEG NPs | Solvent evaporation method | 5–200 | NA | PEG/catechin formulation could enhance water solubility of catechin to 100-fold and exhibited a high anti-inflammatory effect that is ideal for the treatment of DES. | Shim et al. (2019) | |
| Liposome | Thymoquinone and Latanoprost in Liposome | Thin film hydration method | 99.4–150 | 88–92 | (TQ) and (LAT) encapsulated in liposomal vesicles indicated the IOP lowering efficiency in glaucomatous rabbit eyes. Lip (LAT + TQ) and Lip (LAT) were the most effective formulations in lowering intraocular pressure for up to 48 h and enhancing sustained drug release without causing irritation on the eye surface. The drug loading efficiency for the liposomal form of TQ, LAT, and (TQ + LAT) reported 92%, 88%, and more that 88%, respectively. The particle size of these formulations increased by this order Lip (TQ) > Lip (LAT + TQ) > Lip (LAT) > Lip | Fahmy et al. (2018) |
| Baicalin in Liposome/Transferosome penetration enhancer vesicles (PEVs) | Thin film hydration | 667–1,341 | 41–99 | Eye drops instillation on rabbit eyes, used for the treatment of cataract. These formulations (liposome, penetration enhancer vesicles PEVs, and transfersomes) indicated more anti-oxidative properties and bioavailability than BN solution. They demonstrated high encapsulation efficiency to sustain ocular drug delivery of baicalin for 3 months with no toxic effects and high ocular tolerability | Ashraf et al. (2018) | |
| Combretastatin in Liposome | Thin film dispersion method | 109.2 | 74.3 | The uptake efficiently of this formulation evaluated by human umbilical vein endothelial cells (HUVECs). This formulation could be useful in the treatment of chronic ocular disorders such as choroidal neovascularization (CNV) and DR. | Ma et al. (2009) | |
| Lutein in Liposome | Thin film hydration method | 20-200 | NA | It was beneficial in protecting the rabbits’ retina from DNA damage and the harmful effects of cisplatin. It also enhanced the efficiency of Lutein | Ibrahim et al. (2019) | |
| Berberine in Liposome | Thin film hydration method | 103 | 89.6 | PAMAM G3.0-coated liposomes improved corneal permeation and adhesion in the human and corneal epithelium of the rabbit. Moreover, enhanced berberine bioavailability and protective effect in human RPE cells and rat retina after photooxidative retinal injury. No toxicity and side effects were observed on rabbit ocular tissues. So it would be a promising formulation for ocular drug delivery and treatment of AMD disorder | Lai et al. (2019) | |
| BBR and CHR loaded in Liposome coated PAMAM G3.0 | Thin film hydration method | 148 | 93.9 | |||
| Resveratrol in Nanogel (HCS and TPP as crosslinker) | Ionic gelation method | 140 | 59 | RES-HCS-NG used to controlled release of drugs. Efficient for treatment and prevention of ocular disease especially for AMD treatment | Buosi et al. (2020) | |
| Nanogel | Pilocarpine in Nanogel (polyvinyl pyrrolidone/polyacrylic acid) (PVP/PAAc) | Ionized radiation method | 80–120 | NA | This formulation enhanced the stability, bioavailability, ocular retention time of pilocarpine. It showed sustained release profile for 24 h and reduced the frequency of administration. The loading efficiency was 12–48% | Abd El-Rehim et al. (2013) |
| Curcumin entrapped in Nanogel in combination with cationic lipid nanoparticles (CNLC-GEL) | Film ultra-sonication technique | 158.1 | NA | The SOL-GEL transition temperature of Cur-CNLC-GEL was reported at 34°C. It follows the zero-ordered kinetics and increased 9.24 and 3.38 fold in AUC and Cmax of curcumin solution respectively. This formulation could enhance the bioavailability of Cur due to increase in corneal permeation and retention time | Liu et al. (2016b) | |
| Curcumin and latanoprost loaded in Chitosan- gelatin hydrogel | Emulsion-evaporation method | 161.1 | NA | Topical eye drops for glaucoma treatment. Sustained drug release for 7 days. Enhanced resistance time on rabbit eye and corneal permeation with minimal toxicity | Cheng et al. (2019) | |
| Niosomes | Curcumin in Proniosomal gel | Coacervation phase separation method | 212 | 96 | Curcumin loaded in proniosomal gel indicated high biocompatibility, safety, and anti-inflammatory effects. This formulation increased the ocular retention time and corneal permeability. It showed sustained release profile over 24 h | Aboali et al. (2020) |
| Nanofiber | EGCG in SFNF | Electrospinning method | 245 | NA | EGCG-SFNF with anti-VEGF properties and controlled release pattern for 6 days can be considered as a promising scaffold for corneal tissue engineering and delivery system | Forouzideh et al. (2020) |