Promising Ocular Drug Delivery System Research Articles

Novel nanomicelle butenafine formulation for ocular drug delivery against fungal keratitis: In Vitro and In Vivo study

Fungal keratitis (FK) is a serious infectious corneal disease that leads to blindness. Butenafine (BTF) is an allylamine drug with high antifungal activity, but its poor water solubility and low bioavailability limit its clinical application in ophthalmology. To increase its aqueous solubility and corneal permeability, butenafine was encapsulated in d-ɑ-tocopheryl polyethylene glycol succinate (TPGS) polymeric nanomicelles to improve the bioavailability of the drug for the treatment of FK. Butenafine was successfully fabricated into nanomicelles with a high EE of 96.34 ± 1.65 % and DL of 6.71 ± 0.099 %. The BTF-NM showed an average particle size of 13.12 ± 0.24 nm, a zeta potential of -0.56 ± 0.44 mV and a narrow PDI of 0.12 ± 0.02 with a nearly spherical shape. The characterization results of FTIR, XRD and DSC indicated that BTF was encapsulated in the TPGS nanomicelles. The BTF-NM formulation also showed high storage stability, and the in vitro drug release study showed typical biphasic-release characteristics. In addition, the BTF-NM formulation displayed good cellular tolerance and excellent ocular tolerance in rabbits. Significantly elevated in vitro antifungal activity was also observed in the BTF-NM formulation, and remarkable improvements regarding in vivo corneal permeation were observed compared with the BTF suspension formulation. Finally, the in vivo antifungal activity studies indicated that the BTF-NM formulation had a good therapeutic effect on FK and had similar efficacy to that of commercial natamycin suspension eye drops. These results suggest that the BTF-NM ophthalmic formulation could be a promising ocular drug delivery system for the treatment of FK.

Inhibition of Neovascularization and Inflammation in a Mouse Model of Corneal Alkali Burns Using Cationic Liposomal Tacrolimus.

Eye drops account for more than 90% of commercialized ophthalmic drugs. However, eye drops have certain shortcomings, such as short precorneal retention time and weak corneal penetration. The requirement of frequent instillation of eye drops also causes poor patient compliance, which may lead to further aggravation of the disease. We aimed to develop a cationic liposome formulation to increase the bioavailability of the therapeutic agent and solve the aforementioned problems. In the present study, we prepared cationic liposomal tacrolimus (FK506) with a surface potential of approximately +30 mV, which could bind to the negatively charged mucin layer of the ocular surface. Our results showed that the content of FK506 in the cornea was increased by 93.77, 120.30, 14.24, and 20.36 times at 5, 30, 60, and 90 min, respectively, in the FK506 liposome group (0.2 mg/ml) compared with the free drug group (0.2 mg/ml). Moreover, FITC-labeled FK506 liposomes significantly prolonged the ocular surface retention time to 50 min after a single dose. In addition, the results of the Cell Counting Kit-8 assay, live and dead cell assay, sodium fluorescein staining, and hematoxylin and eosin staining all indicated that FK506 liposomes had good biological compatibility in both human corneal epithelial cells and mouse eyeballs. Compared with the free drug at the same concentration, FK506 liposomes effectively inhibited vascular endothelial growth factor-induced green fluorescent protein-transduced human umbilical vein endothelial cell migration and tube formation in vitro. In a mouse corneal neovascularization model induced by alkali burns, FK506 liposomes (0.2 mg/ml) enhanced corneal epithelial recovery, inhibited corneal neovascularization, and reduced corneal inflammation, and its therapeutic effect was better than those of the commercial FK506 eye drops (1 mg/ml) and the free drug (0.2 mg/ml). Collectively, these results indicate that cationic FK506 liposomes could increase the efficacy of FK506 in the corneal neovascularization model. Therefore, cationic FK506 liposomes can be considered as a promising ocular drug delivery system.

Mucoadhesive phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer for topical ocular delivery of voriconazole: Synthesis, in vitro/vivo evaluation, and mechanism

Topical eye drops still face challenges of low-drug treatment effects and frequent dosing in ophthalmic applications due to the low preocular retention rate and low transcorneal permeability. Thus, we designed and synthesized a phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer (PBA-CS-VE) for use in mucoadhesive voriconazole (VRC)-loaded nanomicelles for fungal keratitis. In vitro mucin binding and ex vivo eyeball adhesion tests show that the copolymer has strong mucoadhesion. The transportation of coumarin-6 (C6) across a monolayer of HCE-T cells and 3D cell spheroids confirm the strong corneal penetration ability of PBA-CS-VE. The mechanism of promoting corneal penetration was studied in terms of intracellular calcium-ion concentration, cell membrane potential, cell membrane fluidity, and the tight junctions of cells. The pharmacokinetics in the aqueous humor were examined to evaluate the ability of nanomicelles in promoting corneal penetration and prolonging ocular retention. VRC-loaded PBA-CS-VE nanomicelles (PBA-CS-VE-VRC) yielded a very favorable therapeutic effect on a rabbit model of fungal keratitis in vivo as compared to the free drug. Overall, the results indicate that PBA-CS-VE nanomicelles are a mucoadhesive candidate with enhanced transcorneal permeability and prolonged preocular retention for efficient delivery of topical ocular drugs. Statement of significanceAlthough eye drops are widely used in ocular drug delivery, the disadvantages such as short retention time and weak corneal penetrating ability still seriously affect the therapeutic effect of the drug. Therefore, the mucoadhesive carrier seems to be an interesting strategy for ocular drug delivery. Herein, a novel phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer was designed and constructed as mucoadhesive nanomicelles loaded with voriconazole for fungal keratitis. These nanomicelles were able to improve the in vitro mucin binding and to prolong the residence time of the drug on the surface of the eyeball. Moreover, the nanomicelles exhibited an enhanced drug permeability in cell monolayer models and 3D cell culture models. This work provides a promising ocular drug delivery system.

Controllable release of pirfenidone by polyvinyl alcohol film embedded soft contact lenses in vitro and in vivo

To increase the amount of pirfenidone (PFD) loaded in polyvinyl alcohol (PVA) film embedded soft contact lens (SCL), and evaluate its function of sustaining delivery of drug in vitro and in vivo. Drug loading efficiency within PVA film and SCLs, drug release from SCLs in vitro, and the effects of parameters of SCLs and external environment on drug release in vitro were evaluated by ultraviolet–visible spectrophotometer at 312 nm. Safety of SCLs was evaluated in vitro by transformed human corneal epithelial cell. Safety in vivo was determined by optical coherence tomography and histology of anterior segment of rabbits. Drug release study in tear fluid and aqueous humor were measured by ultra-performance liquid chromatography. SCLs had smooth surface and were fit for experimental rabbits. Amount of PFD in PVA film and SCLs were 153.515 μg ± 12.508 and 127.438 μg ± 19.674, respectively, PFD in PVA film was significantly higher than SCLs (p=.006) and closed to 150 μg (targeting amount of PFD to be loaded). Thickness of SCLs, molecular weight of PVA, and amount of PVA used in SCLs affected drug release in vitro significantly. Thickness of PVA film and amount of drug in SCLs had no effect on drug release rate in vitro. SCLs were safe in vitro and in vivo, PFD released from SCLs could be detected around 12 hours in tears and aqueous humor, and the concentration of drug was higher than eye drop at all detected time points while amount of PFD in SCLs was lower than eye drop. Drug loaded PVA film embedded SCLs may be a promising ocular drug delivery system.

In vitro and in vivo evaluation of cubosomal nanoparticles as an ocular delivery system for fluconazole in treatment of keratomycosis.

The objective of the present study was to enhance ocular antifungal activity of fluconazole (FCZ) in treatment of keratomycosis through incorporation into cubosomal nanoparticles. FCZ-loaded cubosomal dispersions were prepared by emulsification method according to 23 full factorial design. Design-Expert® software was used to study the effects of different formulation factors on properties of FCZ-loaded cubosomal dispersions and select the optimal formulation. Eight FCZ-loaded cubosomal dispersions were prepared and were in vitro and in vivo evaluated. In vitro, the results revealed that the optimum formula exhibited a mean particle size of 48.17 ± 0.65 nm and entrapped 85.70 ± 2.56% of FCZ. The ex vivo permeation study confirmed a two-fold enhancement in FCZ permeation through rabbit cornea compared to aqueous FCZ solution. Furthermore, in vivo ocular tolerance and histopathological studies proved the efficacy and safety FCZ-loaded cubosomal dispersion in treatment of induced keratomycosis in rats compared to aqueous FCZ solution after topical ocular application. In conclusion, the obtained results indicated that cubosomes could be promising ocular drug delivery system for enhancing antifungal activity of FCZ in treatment of fungal keratitis in rats. Graphical abstract.

Chitosan-N-acetylcysteine modified HP-β-CD inclusion complex as a potential ocular delivery system for anti-cataract drug: Quercetin

The aim of this study was to develop a novel ocular drug delivery system based on the hydroxypropyl beta cyclodextrin (HP-β-CD) inclusion complex coated with the synthesized chitosan-N-acetyl-l-cysteine conjugate (CS-NAC) for the hydrophobic drug quercetin. The inclusion complex was prepared by the solvent evaporation method, and the concentration of HP-β-CD and CS-NAC was optimized by isolated corneal penetration test. The optimized concentration of HP-β-CD and CS-NAC was 20% (w/v) and 0.1% (w/v), respectively. The CS-NAC/quercetin-HP-β-CD had the effect on improving the ocular penetration with little ocular irritation and could increase the ocular distribution significantly. Meanwhile, Coumarin-6 (C6) labelled CS-NAC/C6-HP-β-CD possessed enhanced fluorescence and located deeper into the epithelium of cornea at the same time point compared with the uncoated one. It could also transport drug through the corneal epithelium by intracellular routes except for intercellular routes. Furthermore, it could delay the occurrence of cataract about 1 d when administrated with full-dosage quercetin. The HP-β-CD inclusion complex coated with CS-NAC is a safe and promising ocular drug delivery system for improving the bioavailability and corneal penetration of hydrophobic drug like quercetin.

Phenylboronic acid-tethered chondroitin sulfate-based mucoadhesive nanostructured lipid carriers for the treatment of dry eye syndrome

Dry eye syndrome is a common eye disease that affects many people worldwide. It is usually treated with eye drops, which has low bioavailability owing to rapid clearance from the ocular surface and leads to poor patient compliance and side effects. For the purpose of improving the therapeutic efficacy, nanostructured lipid carrier (NLC)-loaded dexamethasone (DEX) was prepared and functionalized with (3-aminomethylphenyl)boronic acid-conjugated chondroitin sulfate (APBA-ChS). As APBA has a boronic acid group, it can form a high-affinity complex with sialic acids present in the ocular mucin, which contributes to extension of corneal retention time and improvement of drug delivery. Compared with eye drops, Rhodamine B (RhB)-labeled APBA-ChS-NLC could significantly prolong the residence time on the corneal surface. Moreover, the DEX-APBA-ChS-NLC showed no irritation to the rabbit eye as indicated in irritation studies and histological images. The pharmacodynamics study indicated that DEX-APBA-ChS-NLC could relieve symptoms of dry eye disease in rabbits. These results demonstrated that the developed mucoadhesive drug carrier could improve the delivery of drugs and have promising potential to treat anterior eye diseases. Statement of SignificanceIn this research, (3-aminomethylphenyl)boronic acid-conjugated chondroitin sulfate (APBA-ChS)-based nanostructured lipid carriers (NLCs) including dexamethasone (DEX) were designed and constructed. APBA-ChS, which is present on the surface of DEX-NLC and contains the boronic acid group, can form complex with sialic acids in the ocular mucin, hence leading to prolonged precorneal retention. This affinity between boronic acid and sialic acids was used to develop a mucoadhesive drug delivery system. The developed mucoadhesive drug carrier demonstrated prolonged retention time and alleviation of dry eye syndrome. APBA-ChS-based NLC may be considered a promising ocular drug delivery system for treating anterior eye diseases.

Core-shell lipid-polymer nanoparticles as a promising ocular drug delivery system to treat glaucoma

Nowadays, tremendous researches have been focused on the core-shell lipid-polymer nanoparticles (LPNs) due to the advantages of both liposomes and polymer nanoparticles. In this work, LPNs were applied to encapsulate brinzolamide (Brz-LPNs) for achieving sustained drug release, improving drug corneal permeation and enhancing drug topical therapeutic effect. The structure of Brz-LPNs was composed of poly(lactic-co-glycolic) acid (PLGA) nanocore which encapsulated Brz (Brz-NPs) and lipid shell around the core. Brz-LPNs were prepared by a modified thin-film dispersion method. With the parameters optimization of Brz-LPNs, optimal Brz-LPNs showed an average particle size of 151.23 ± 1.64 nm with a high encapsulation efficiency (EE) of 86.7% ± 2.28%. The core-shell structure of Brz-LPNs were confirmed by transmission electronic microscopy (TEM). Fourier transformed infrared spectra (FTIR) analysis proved that Brz was successfully entrapped into Brz-LPNs. Brz-LPNs exhibited obvious sustained release of Brz, compared with AZOPT® and Brz-LPs. Furthermore, the corneal accumulative permeability of Brz-LPNs significantly increased compared to the commercial available formulation (AZOPT®) in vitro. Moreover, Brz-LPNs (1 mg/mL Brz) showed a more sustained and effective intraocular pressure (IOP) reduction than Brz-LPs (1 mg/mL) and AZOPT® (10 mg/mL Brz) in vivo. In conclusion, Brz-LPNs, as promising ocular drug delivery systems, are well worth developing in the future for glaucoma treatment.

A novel FK506 loaded nanomicelles consisting of amino-terminated poly(ethylene glycol)-block-poly(D,L)-lactic acid and hydroxypropyl methylcellulose for ocular drug delivery

FK506 (tacrolimus) is an effective immunosuppressant, but its poor water solubility and low bioavailability impose barriers to ocular drug delivery. The nanomicelles (NMs) formulations comprised of amino-terminated poly(ethylene glycol-block-poly(D,L)-lactic acid) (NH2-PEG-b-PLA) and hydroxypropyl methylcellulose (HPMC) were developed to increase the penetration of hydrophobic drugs in the eye and enhance the drug bioavailability for ocular disorder therapy. Spherical FK506/NH2-PEG-b-PLA/HPMC NMs with mean diameter of 101.4 ± 1.3 nm were prepared by solvent-evaporation-induced self-assembly in aqueous solution. The NMs that sufficiently solubilized FK506 were evaluated in terms of stability, drug loading, encapsulation efficiency, surface tension, cellular cytotoxicity and in vitro release, and the results revealed the NMs were suitable for intraocular drug delivery. Compared with the 0.05% FK506 suspension drops, the in vitro permeation amount of FK506 from NMs exhibited significant increase. Besides, the higher concentration and longer retention of FK506 in ocular tissue were also confirmed in vivo. Furthermore, the FK506/NH2-PEG-b-PLA/HPMC NMs obviously inhibited the allograft rejection after corneal transplantation in rats. In conclusion, FK506/NH2-PEG-b-PLA/HPMC NMs formulations as a promising ocular drug delivery system would be able to improve the bioavailability and efficacy of FK506 in anti-allograft rejection.

Ocular implant containing bevacizumab-loaded chitosan nanoparticles intended for choroidal neovascularization treatment.

Choroidal neovascularization (CNV) is among the leading causes of blindness worldwide. Bevacizumab has demonstrated promising effects on CNV treatment; however, frequent intravitreal injection is its major drawback. Current study aimed to address this issue by developing a sustained release formulation through nanoparticles of bevacizumab imbedded in an ocular implant. Bevacizumab-loaded chitosan nanoparticles were prepared by ionic gelation method and inserted in the matrix of hyaluronic acid and zinc sulfate. Despite the common approaches in using ultraviolet (UV)-spectrophotometry, microprotein-Bradford, and bicinchoninic acid (BCA), assay for protein assessment, our results revealed a remarkable UV-Vis absorption overlap of protein and chitosan during these analysis and thus enzyme-linked immunosorbent assay was employed for the antibody concentration assay. The size of optimized nanoparticles obtained through statistical analysis based on design of experiments was 78.5 ± 1.9 nm with polydispersity index of 0.13 ± 0.05 and the entrapment-efficiency and loading-efficiency were 67.6 ± 6.7 and 15.7 ± 5.7%, respectively. The scanning electron microscopy and confocal microscopy images revealed a homogenous distribution of nanoparticles in the implant matrix and the release test results indicated an appropriate extended release of bevacizumab from the carrier over two months. In conclusion, the prepared system provided a sustained release bevacizumab delivery formulation which can introduce a promising ocular drug delivery system intended for posterior segment disease. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2261-2271, 2018.

Hyaluronic-acid-modified lipid-polymer hybrid nanoparticles as an efficient ocular delivery platform for moxifloxacin hydrochloride

To improve the ocular bioavailability of the strongly hydrophilic moxifloxacin hydrochloride, hyaluronic-acid-modified lipid-polymer hybrid nanoparticles (HA-LCS-NPs) were designed and characterized. An in vivo precorneal retention study in rabbits showed that the mean residence time (MRT) and area under the curve (AUC0–6h) of HA-LCS-NPs were up to 6.74-fold and 4.29-fold higher than those of the commercial product. An in vitro corneal penetration study in rabbits demonstrated that the apparent permeability coefficient (Papp) of HA-LCS-NPs was increased by 3.29-fold compared to the commercial product, which might be observed because the surface-modified hyaluronic acid could expedite the cellular uptake of HA-LCS-NPs by receptor-mediated endocytosis. Moreover, in contrast with other formulations, the results of ex vivo fluorescence imaging showed that the fluorescence intensity was higher in the cornea and conjunctiva after administration of HA-LCS-NPs. Finally, an ocular irritation study indicated that HA-LCS-NPs displayed excellent ocular tolerance. In summary, the hyaluronic-acid-modified lipid-polymer hybrid nanoparticles with multifunctional properties might be a promising ocular drug delivery system for prolonged precorneal retention, better corneal permeability and enhanced ocular bioavailability.

Multifunctional properties of organic-inorganic hybrid nanocomposites based on chitosan derivatives and layered double hydroxides for ocular drug delivery

To improve the ocular bioavailability of the model drug of pirenoxine sodium (PRN), organic-inorganic hybrid nanocomposites including layered double hydroxides (LDH) and chitosan derivatives (chitosan-glutathione (CG), chitosan-glutathione-valine (CG-V) and chitosan-glutathione-valine-valine (CG-VV)) were designed and characterized. In vivo precorneal retention study on rabbits showed that mean residence time (MRT) and area under the curve (AUC0–6h) of CG-PRN-LDH nanocomposite eye drop was up to 2.1-fold and 6.3-fold higher than those of commercial product, respectively. In vitro corneal penetration on rabbits demonstrated that the cumulative permeation of CG-VV-PRN-LDH nanocomposite dispersion was increased by 5.2 folds compared to that of commercial product, which may be due to the active transport effect of the nanocomposites by peptide transporter-1 (PepT-1). In addition, the ex vivo fluorescence imaging showed that fluorescent intensity of crystalline lens in rabbits was increased after the administration of PRN-LDH, CG-PRN-LDH, CG-V-PRN-LDH and CG-VV-PRN-LDH (in increasing order) nanocomposite eye drop. Finally, in vivo distribution evaluation in ocular tissues of rabbits revealed that AUC0–8h and MRT in crystalline lens exhibited 14.7-fold and 2.2-fold increase in CG-VV-PRN-LDH nanocomposite eye drop group than those of commercial group, respectively. In summary, the organic-inorganic hybrid nanocomposites with multifunctional properties may be a promising ocular drug delivery system to achieve prolonged precorneal retention, better corneal permeability and enhanced ocular bioavailability. Statement of SignificanceDue to several structural and physiological intraocular barriers, drug delivery to the ocular mid-posterior segments still faces great challenges. In this manuscript, organic-inorganic hybrid nanocomposites based on chitosan derivatives and layered double hydroxides (LDH) were designed and constructed. Multifunctional properties of these hybrid nanocomposites were due to the possible active targeting to the peptide transporter-1 on the corneal epithelial cells, the bioadhesive ability and permeation enhancement of chitosan derivatives, and the electrostatic adsorption of LDH. Prolonged precorneal retention, better corneal permeability and enhanced ocular bioavailability of the model drug pirenoxine sodium were observed. Chitosan derivatives-LDH hybrid nanocomposites may be a promising ophthalmic drug system for the treatment of ocular diseases of mid-posterior segments.

Organic–inorganic hybrid nanocomposites based on chitosan derivatives and layered double hydroxides with intercalated phacolysin as ocular delivery system

This study was mainly aimed to evaluate the potential use of a novel ocular drug delivery system, organic–inorganic hybrid nanocomposites based on chitosan derivatives and layered double hydroxides (LDH). Organic polymers of chitosan–glutathione (CG) and pre-activated chitosan–glutathione (CG-2MNA) were successfully synthesized and characterized. LDH with intercalated phacolysin (PCL), including larger hexagonal LDH–PCL (Lh-LDH–PCL), larger spherical LDH–PCL (Ls-LDH–PCL), smaller hexagonal LDH–PCL (Sh-LDH–PCL), CG hybrid LDH–PCL (LDH–PCL-CG), and CG-2MNA hybrid LDH–PCL (LDH–PCL-CG-2MNA), were prepared. The nanocomposites with particle size of 107.2–274.9 nm were characterized by powder X-ray diffraction, Fourier transform infrared, transmission electron micrographs, etc. In vivo precorneal retention studies showed that the detectable time of all nanocomposites was prolonged from 2 to 6 h in comparison to PCL saline. Accordingly, the AUC0–6h values of Lh-LDH–PCL, Ls-LDH–PCL, Sh-LDH–PCL, LDH–PCL-CG, and LDH–PCL-CG-2MNA nanocomposites were increased by 2.27-, 2.08-, 3.08-, 4.67-, and 3.36-fold, respectively. The Draize test and hematoxylin and eosin staining demonstrated that modified LDH had no eye irritation after single and repeated administration. These results indicated that chitosan derivatives-LDH hybrid nanocomposite dispersion could be a promising ocular drug delivery system to improve precorneal retention time of drugs. Thiolated chitosan-LDH hybrid nanocomposite dispersion could be a promising ocular drug delivery system to improve precorneal retention time of drugs and may facilitate penetration of drugs into tissues of the eyes.

Fabrication and characterization of silk fibroin-coated liposomes for ocular drug delivery

The unique structure and protective mechanisms of the eye result in low bioavailability of ocular drugs. Using a mucoadhesive material is an efficient solution to improve ocular drug therapeutic efficacy. This study was designed to prepare a liposomal formulation coated by a novel adhesive excipient, silk fibroin (SF), for topical ocular drug delivery. The regenerated silk fibroins (SFs) with different dissolving time were coated onto the ibuprofen-loaded liposomes. The morphology, drug encapsulation efficiency, in vitro release and in vitro corneal permeation of SF-coated liposomes (SLs) were investigated in comparison with the conventional liposome. Cellular adhesion and cytotoxicity assay of SF and SLs were tested using human corneal epithelial cells (HCEC). SLs showed sustained drug release and in vitro corneal permeation of ibuprofen as compared to drug solution and conventional liposome. The cellular fluorescence appeared after 7min of exposure to SF, and the intensity increased sustainedly up to 12h with no detectable cytotoxicity. Higher fluorescence intensity of Nile red in SLs was observed in a short period of 15min showing a rapid uptake. These favorable properties make SF-coated liposome be a promising ocular drug delivery system.

Chitosan-based thermosensitive hydrogel as a promising ocular drug delivery system: Preparation, characterization, and in vivo evaluation

The purpose of this study was to evaluate the feasibility of in situ thermosensitive hydrogel based on chitosan in combination with disodium α-d-Glucose 1-phosphate (DGP) for ocular drug delivery system. Aqueous solution of chitosan/DGP underwent sol-gel transition as temperature increased which was flowing sol at room temperature and then turned into non-flowing hydrogel at physiological temperature. The properties of gels were characterized regarding gelation time, gelation temperature, and morphology. The sol-to-gel phase transition behaviors were affected by the concentrations of chitosan, DGP and the model drug levocetirizine dihydrochloride (LD). The developed hydrogel presented a characteristic of a rapid release at the initial period followed by a sustained release and remarkably enhanced the cornea penetration of LD. The results of ocular irritation demonstrated the excellent ocular tolerance of the hydrogel. The ocular residence time for the hydrogel was significantly prolonged compared with eye drops. The drug-loaded hydrogel produced more effective anti-allergic conjunctivitis effects compared with LD aqueous solution. These results showed that the chitosan/DGP thermosensitive hydrogel could be used as an ideal ocular drug delivery system in terms of the suitable sol-gel transition temperature, mild pH environment in the hydrogel as well as the organic solvent free.