Nano-Based DDS for Glaucoma: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Kevin Yang Wu.

The eye is a complex and delicate organ that is protected by robust anatomical barriers. These barriers limit the penetration, bioavailability, and residence time of topically administered drugs. To address this challenge, researchers have developed polymeric nano-based drug delivery systems (DDS) that offer a promising solution. These DDS can penetrate ocular barriers, improving the bioavailability of administered drugs to targeted tissues and leading to better therapeutic outcomes. Biodegradable polymers are often used in these DDS to minimize adverse effects that can result from drugs that are not naturally decomposable, such as the risk of infection, tissue damage, or toxic byproducts.

This review article offers a comprehensive overview of the therapeutic potential of polymeric nano-based drug delivery systems (DDS) for ocular diseases. We summarize the current state of the field and highlight key findings from preclinical and clinical studies conducted between 2017 and 2022. Additionally, we cover the material science aspects of the biopolymers used in DDS and discuss recent advances in polymer science that have contributed to the evolution of ocular DDS. Specifically, we focus on the potential of these systems to manage patients with anterior segment diseases and glaucoma. To provide a well-rounded review, we also compare and contrast non-polymeric nano-based DDS for ocular diseases with polymeric nano-based DDS.

This article provides a comprehensive overview of the latest findings in the field, offering insights into the current state of the art and highlighting future directions for research in this area.

  • polymeric nanocarriers
  • biodegradable polymers
  • polymeric biomaterials
  • anteriorsegment diseases
  • glaucoma
  • ocular diseases
  • ocular drug-delivery

1. Nano-Based DDS for Glaucoma

Glaucoma is a leading cause of irreversible blindness worldwide, characterized byroup of eye diseases that damage the optic nerve, leading to progressive vision loss and damage to the optic nerve. Iblindness. It is the leading cause of irreversible blindness globally. To this day, intraocular pressure (IOP) management is currently tthe cornerstone of treatment. Nanocarriers have emerged as a promising approach for for glaucoma. With the aim of reducing intraocular pressure (IOP), there has been a recent surge in the use of nanocarriers to enhancinge ocular drug delivery, with the aim of reducing IOP. This is . This development is particularly significant as the long-term use of conventional IOP-lowering agents can ca, which are based on poorly penetrating molecules, can cause frequent ocular toxicity and intolerance due to their adverse effects on the corneal epithelium [1]. [45]

 

2. Nano-Based DDS Based on Regulating Intraocular Pressure (IOP)

Nano-Based DDS Based on Regulating Intraocular Pressure (IOP)

2.1. Preclinical Studies

Preclinical Studies

Nanoparticles can be modified with biodegradable polymers to enhance the bioavailability of drugs, which is particularly useful for drugs with low solubility, such as brinzolamide for glaucoma. Studies have formulated PLGA-modified (Polylactic-co-glycolic acid) nanoparticles for sustained release of brinzolamide, resulting in a significant reduction in IOP in animal models with minimal toxicity [15,46,47][2][3][4]. To improve entrapment efficiency and corneal permeation with topical delivery of brinzolamide, Song et al. (2020) coated PLGA nanoparticles with phosphatidylserine (PS) using a coaxial electrospray technique. However, systemic absorption was observed where there was an IOP reduction in the untreated eye as well [46][3]. Salama et al. (2017) used subconjunctival injection to enhance prolonged release of PLGA nanoparticles and provide targeted drug delivery, finding that efficacy depended on nanoparticle size. PLGA nanoparticles were also used to encapsulate SA-2, a nitric oxide (NO) donor and superoxide dismutase (SOD) activator [48][5]. A single-dose slow release of SA-2 significantly lowered IOP for up to 72 h, and increasing SOD enzyme activity provided cytoprotection in human trabecular meshwork (TM) cells.

Recent studies have explored the use of various polymers to form nanoparticles for ocular drug delivery. Cyclodextrin nanoparticles have been used to administer candesartan and irbesartan by LorenzoSoler et al. (2020), effectively lowering IOP comparable to timolol eye drops while preventing side effects observed with oral administration. Ultra-small chitosan nanoparticles were used to deliver nanobrimodine for open-angle glaucoma by Barwar et al. (2019), while galactomannan-based nanoparticles were used for the delivery of dorzolamide hydrochloride by Mittal et al. (2019), resulting in a prolonged IOP-lowering effect compared to conventional eye drops. Furthermore, Tan et al. (2021) delivered miRNA using polydopamine-polyethylenimine nanoparticles through intracameral injection, which showed comparable transfection efficacy with lower cytotoxicity and effectively lowered IOP in vivo.

Recent studies have modified Mesoporous Silica Nanoparticles (MSNs) to achieve biodegradation for clinical application, despite their poor degradability due to a pure silica framework. For instance, Fan et al. (2021) used biodegradable hollow mesoporous organosilica (HOS) nanocapsules to deliver NO in a stimulus-responsive manner, leading to improved penetration and bioavailability. However, prolonged use of NO-MSNs was previously found to increase IOP elevation following the initial decrease, likely caused by outflow tissue damage through protein nitration. To ameliorate these side effects, co-delivery of antioxidants such as MnTMPyP has been suggested. Meanwhile, alternative methods, such as developing biodegradable hollow polymeric nanocapsules, are currently under extensive research due to their high drug-loading capacity and ability to better control drug release.

Niosomes, a type of lipid-based vesicular system, are an effective drug delivery system (DDS) that can improve residence time and corneal permeation. Zafar et al. (2021) developed a chitosan-coated niosome that improved biodegradability and bioadhesion, enabling the delivery of carteolol (CT). Pilocarpine and latanoprost were also successfully delivered using niosomal gels to reduce IOP in rabbit models [57,58][6][7]. However, niosomes are known to have a limited shelf life and poor drug entrapment efficiency. To overcome these limitations, proniosomes (gel or granular) have been developed, which can rapidly convert to niosomes upon hydration, providing higher physical stability and minimizing niosomal dispersions [59,60][8][9].

Cubosomes have been investigated as a potential drug delivery system for ocular delivery due to their continuous lipid bilayer structure similar to the corneal epithelium. Teba et al. (2021) and Huang et al. (2017) used cubosomes to deliver acetazolamide and timolol maleate, respectively, resulting in improved bioavailability and IOP-lowering effects. Both studies used biodegradable polymers, such as P407 and GMO, to develop the cubosomes. This suggests that cubosomes may offer a promising DDS for ocular delivery with improved corneal permeation and residence time, as well as reduced ocular irritation.

Nanoemulsions have been used to carry both hydrophilic and hydrophobic materials and have been found to enhance drug absorption and prolong IOP-lowering effects of travoprost and brinzolamide. However, the high level of surfactants required for their synthesis can result in cytotoxicity, which is further compounded by the addition of preservatives. Therefore, long-term safety tests regarding toxicity are necessary for the use of this DDS.

Ocular inserts using nano-based carriers are being researched to improve treatment adherence and decrease administration frequency. Chitosan, a highly biodegradable polymer, has been modified to enhance its solubility in developing ocular inserts and films for topical delivery. Chondroitin sulfate and hydroxyethyl cellulose have been added to chitosan to develop modified chitosan inserts that can deliver 4-aminodiphenylamine and dorzolamide to lower IOP, while also exhibiting a neuroprotective effect towards the retinal ganglion cells. Sodium alginate-ethyl cellulose inserts have been reported to carry hydrophilic drugs, while a cyclodextrin multilayer film incorporating PBAE and graphene oxide enabled a time-controlled release of brimonidine, dependent on layer thickness in vitro. Li et al. (2020) presented an eco-friendly method of producing chitosan polymer dissolved in a water-based film, overcoming the solubility issue while retaining high cornea permeability.

Researchers have used nanomicelles to deliver both latanoprost and timolol using a drug-laden contact lens developed by Xu et al. (2019) [70][10]. They utilized biodegradable mPEG-PLA nanomicelles prepared through thin-film hydration to ensure the contact lens remained transparent and transmitted light. Although this approach provided a slow, sustained release of both drugs, ocular safety was confirmed, but it was reported that this system might impact the physical properties of the lens, making it rough after drug release. Another co-delivery system was developed by Samy et al. (2019), where they utilized PCL thin-film implants to deliver timolol and brimonidine [71][11]. Although this approach provided a controlled release of both drugs, systemic absorption and related side effects were not measured. These polymeric films were also used to deliver a novel hypotensive agent, DE-117, which resulted in a sustained IOP-lowering effect. However, due to the bulky size of the implant, there was a high risk of device migration and corneal endothelium damage [72][12].

Hydrogels have been extensively studied as a promising ocular delivery system, with properties of in situ sol-to-gel formation triggered by environmental factors like pH and temperature [73][13]. However, recent studies have developed hybrid systems embedding hydrogels with biodegradable nanoparticles to ensure sustained drug release. These have led to successful DDS, including sustained release of brimonidine tartrate [74][14], timolol maleate [75[15][16],76], and bimatoprost [77][17], as well as co-delivery of curcumin nanoparticles and latanoprost [78][18] from a thermosensitive in situ hydrogel. Chou et al. (2017) presented a DDS based on dual functions, delivering pilocarpine loaded with antioxidants GA through a biodegradable gelatin-based thermogel [79][19]. Modulating the degradation by controlling redox radical initiation reaction temperatures (20–50 ◦C) provides sustained release (ideal at 30 ◦C). This raises the possibility of modifying biodegradability to improve sustained drug release, with Luo et al. (2019) showing that an increase in the amination degree of gelatin in biodegradable thermogels enhances resistance to biodegradation [80][20], and in another study by the same group, increasing the deacetylation degree enhances resistance to biodegradation in chitosan-based thermogels [81][21].

Liposomes are highly biodegradable nanocarriers capable of carrying both hydrophilic and hydrophobic drugs. However, their low stability, low entrapment efficiency, and rapid release of hydrophilic drugs have been a common drawback. To address these issues, Hathout et al. (2018) developed gelatinized core liposomes for the sustained release of timolol maleate, which significantly improved entrapment efficiency and did not cause ocular irritation. TPGS-modified liposomes were also presented by Jin et al. (2018) as a carrier for brinzolamide, showing greater sustained release, maintained IOP reduction, and no significant side effects.

Liposomes, which are highly biodegradable nanocarriers, have the potential to carry both hydrophilic and hydrophobic drugs. Jin et al. (2018) modified liposomes with TPGS for brinzolamide, resulting in greater sustained release and maintained IOP reduction without significant side effects. However, their low stability, low entrapment efficiency, and rapid release of hydrophilic drugs are common drawbacks. To address these issues, Hathout et al. (2018) developed gelatinized core liposomes for the sustained release of the hydrophilic drug, timolol maleate. This method significantly increased entrapment efficiency and showed no signs of ocular irritation.

PAMAM (polyamidoamine) dendrimers have shown promise in sustaining the release of timolol with no observed cytotoxicity or ocular irritation in vitro. Further research involving in vivo models is necessary to optimize drug loading and investigate the effects of chronic application [85][22]. Lancina et al. (2017) utilized electrospun dendrimer-based nanofiber mats to deliver brimonidine tartrate (BT), which improved the effectiveness of IOP lowering over three weeks with daily dosing, but not with a single dosage.

Several DDS systems have been investigated for sustained ocular drug delivery. PAMAM dendrimers have been utilized to deliver timolol, showing no signs of cytotoxicity or ocular irritation in vitro, but further studies are needed to optimize drug loading and assess the effects of chronic use. Electrospun dendrimer-based nanofiber mats were used to deliver brimonidine tartrate, leading to improved efficacy of IOP lowering with daily dosing over 3 weeks. Self-assembly drug nanostructures (SADN) and phase transition microemulsions (PMEs) have also shown promise for sustained IOP lowering but require further investigation for cytotoxicity and systemic effects. Modified micelles delivering ligands targeting FLT-4/VEGFR3 receptors have shown receptor targeting and IOP lowering, but improvements in corneal permeability and sustained release are needed. Nanosuspensions have been used to deliver acetazolamide, demonstrating sustained drug release, improved solubility, and bioavailability, but the stability of nanosuspensions remains a limitation to be investigated. Finally, hyaluronic acid was used to stabilize the nanosuspension but was only able to maintain dispersion characteristics for up to 6 months.

Chae et al. (2020) proposed a drug-free, non-surgical method to reduce IOP using a hyaluronic acid hydrogel microneedle injection to expand the suprachoroidal space [91][23]. This method facilitates aqueous humor drainage through the uveoscleral outflow pathway and extends the lowering of IOP without the associated loss of endothelial cells seen in suprachoroidal MIGS such as Cypass and iStent Supra. The efficacy of this approach needs further mechanistic studies, and the prevention of fibrosis with multiple injection treatments needs to be addressed.

Recent studies have modified existing DDS, including microspheres [92,93][24][25], solid lipid nanoparticles (SLNs) [94][26], and chitosan nanoparticles, by embedding montmorillonite (Mt) in the biodegradable hybrid polymer. Mt is a biocompatible silicate with a negative surface charge that forms an ion complex with cationic drugs such as betaxolol hydrochloride (BH) and brimonidine, allowing for controlled and sustained drug release. These hybrid nanocarriers have been shown to cause a prolonged decrease in IOP.

Recent studies propose the use of electrospinning biodegradable polymers as an alternative to solid formulations for ocular delivery. While the latter provide prolonged ocular residence, they can interfere with vision and comfort. Andreadis et al. (2022) developed an in situ electrospun film gel for the delivery of timolol maleate, and Morais et al. (2021) created electrospun ocular implants for acetazolamide delivery. Both methods showed a significant sustained IOP-lowering effect and increased local delivery. However, further optimization of the implant sterilization methods is required to avoid adverse events and infection, without compromising efficacy.

 

2.2. Clinical Studies

Clinical Studies

Rubiao et al. (2021) conducted a Phase 2 controlled study to compare the efficacy and safety of a chitosan-based bimatoprost insert to conventional LumiganTM eyedrops in patients with POAG and ocular hypertension. The study enrolled 16 and 13 patients, respectively, with a small control group of 5 patients. The biodegradable nature of the insert eliminated the need for removal. The insert was well-tolerated with no significant side effects, changes in visual acuity, or central corneal thickness. IOP reduction was 30% by the third week, compared to 35% with eyedrops. Using inserts in 3-week intervals improved patient compliance and offers a better therapeutic regime. Rubiao et al. plans to conduct Phase 3 confirmatory studies.

In 2020, DurystaTM, an FDA-approved bimatoprost implant, was developed with poly-lactic acid and poly-lactic-co-glycolic polymers, similar to biodegradable sutures. This non-pulsatile, sustained release implant provides 10 µg bimatoprost and is currently being tested in multiple Phase 3 trials for long-term safety and efficacy in open-angle glaucoma or ocular hypertension patients. It is found to be non-inferior to timolol eye drops and reduces the treatment burden associated with glaucoma while improving adherence. Although there is a potential risk of adverse events, including corneal events, intraocular inflammation, or endophthalmitis, implant biodegradation was observed within 12 months while maintaining the IOP-lowering effect. The implant serves as a viable option for patients with glaucoma who are unreliable or have dementia, and those who are not suitable for incisional glaucoma surgery.

Brandt et al. (2017) investigated the sustained release of bimatoprost using an ocular ring in double-masked randomized Phase 2 clinical trials [104][27]. The safety and efficacy of the ocular ring were studied in 65 and 63 patients for 7 and 13 months, respectively. The ocular ring was found to be safe and well tolerated, but caused mucus discharge as a side effect. The study suggested that clinically significant IOP reduction can be achieved with applications at 6-month intervals. However, since the ocular ring is made of a silicone matrix over a polypropylene structure, further studies on its biodegradability are necessary to improve its biocompatibility.

Kouchak et al. (2017) conducted a randomized controlled trial on 20 patients with OAG and OH to compare the efficacy and safety of dorzolamide nanoliposomes (DRZ-nanoliposome) with a control group using dorzolamide eye drops (BiosoptTM) [105][28]. DRZ-nanoliposomes demonstrated greater reduction in IOP at days 14 and 28, with increased adhesion and corneal permeation attributed to the liposome delivery system. Reports of irritation and redness were similar between the groups, likely due to dorzolamide itself. This liposomal delivery system may provide extended release and higher intensity of the drug, potentially reducing the frequency of administration without compromising efficacy.

 

3. Nano-Based DDS for Neuroprotection

Nano-Based DDS for Neuroprotection

Conventional therapies for glaucoma focus on reducing IOP, but this is insufficient for addressing permanent damage to RGCs and the optic nerve, particularly in advanced diseases. Normotensive glaucoma and cases of controlled IOP can also lead to visual loss progression, highlighting the need for neuroprotective strategies. Nano-based biodegradable DDS may be a promising approach for delivering these drugs to the posterior segment of the eye, with increased drug permeation and long-lasting effects.

 

3.1. Preclinical Studies

Preclinical Studies

Brimonidine, a drug previously discussed for its ability to reduce IOP, also exhibits neuroprotective effects by regulating excitatory NMDA receptors in RGCs. Two studies investigated the delivery of brimonidine to the posterior eye for its neuroprotective effects in a glaucoma model. Lou et al. (2021) developed a dual-function PDA biodegradable nanoparticle loaded with brimonidine, where PDA aids in ROS scavenging and anti-inflammation effects, achieving sustained and increased permeation of brimonidine and promoting RGC survival. Rodrigo et al. (2020) proposed using a biodegradable LAPONITETM synthetic clay, capable of controlled release of drugs, which also achieved sustained and increased permeation of brimonidine, promoting RGC survival. However, the LAPONITE system had some adverse side effects in their in vivo model, including systemic absorption of brimonidine and CNS depressant effects leading to early deaths among rats.

To investigate the delivery of neurotrophic factors (NFs) for preventing retina damage in glaucoma models, studies have been conducted using nanoparticles. Yang et al. (2021) successfully delivered CTNF and oncostatin M (OSM) with nanoparticles, improving RGC survival and photoreceptor preservation. Similarly, Giannaccini et al. (2017) delivered NGF and BDNF using biodegradable magnetic nanoparticles, which prevented RGC loss with lower dosages of NFs. However, further studies are required to determine the optimal dosage using in vivo models that closely resemble human eye anatomy. Garcia-Caballero et al. (2017) delivered GDNF/Vitamin E through biodegradable PLGA microspheres, allowing for effective neuroprotection for up to 6 months. Additionally, multitherapy with dexamethasone, melatonin, and coenzymeQ10 reduced RGC loss and retinal stress in an in vivo model. Cubosomes were also used for targeted delivery of LM22A-4, a small NF mimetic, and were found to prevent RGC loss and improve functional outcomes through a gradual release.

Hydrogels have been utilized for sustained release and improved bioavailability of neuroprotective drugs. Chitosan thermogel, a biodegradable hydrogel, was used to deliver pilocarpine and RGFP966, an HDAC inhibitor, which protects RGCs and optic nerves from damage, in a study [122][29]. The thermogel had antioxidant effects, promoting myelin growth, and reducing RGC loss. Nguyen et al. (2019) co-delivered pilocarpine and ascorbic acid, an anti-inflammatory agent, through a PAMAM dendrimer thermogel [123][30], achieving sustained release of both agents for over 80 days, suppressing inflammation, and aiding in the regeneration of stromal collagen and retinal laminin.

Cannabinoids have potential as a neuroprotective treatment for glaucoma, but limited delivery to the posterior eye has hindered their effectiveness. Kabiri et al. (2018) used an HA-MC thermosensitive hydrogel loaded with CBGA nanoparticles to improve bioavailability, corneal permeation, and reduce ocular irritancy. Similarly, the derivative ∆9-Tetrahydrocannabinol-valine-hemisuccinate was delivered using SLNs, providing prolonged residence time and neuroprotective and IOP-lowering effects. However, further in vivo studies are necessary to evaluate the safety and cytotoxicity of these methods.

Nanoparticles have been used as drug delivery systems (DDS) for neuroprotective agents in various studies. For instance, biodegradable PEGylated nanoparticles were used to load memantine, an NMDA antagonist, which improved drug delivery and reduced RGC loss in an in vivo rodent model. Additionally, Gemini (PGL) Nanoparticles were used for a non-invasive gene delivery system by Narsineni et al. (2022), who delivered peptide-modified CAPgemini surfactants, a potential Aβ40 aggregation inhibitor. These surfactants showed a 10-fold improvement in Aβ40 aggregation inhibition, which is associated with RGC neurodegeneration. Further in vivo studies are required to evaluate the therapeutic efficacy of glaucoma neurodegeneration.

Li et al. (2020) utilized biodegradable PEG-based nanoparticles to co-deliver brinzolamide and miR-124, providing prevention to RGC damage and IOP-lowering effects through sustained release without ocular toxicity [131]. Zhao et al. (2017) employed a PEG-based nanoparticle system conjugated with cholera toxin B domain (CTB) to improve targeted delivery of DHEA, an FDA-approved S1R agonist, to RGCs, showing effective RGC protection [132][31]. However, entrapment improvement is required for a more efficient, sustained release of nanoparticles. Silva et al. (2022) used a chitosan and HA nanoparticle system to deliver Epoetin Beta, which has tissue-protective properties, showing sustained release for up to 21 days with no local or systemic adverse effects [133][32]. Further investigation is necessary to assess the therapeutic efficacy of these methods on glaucoma models.

Hsueh et al. (2021) proposed a microcrystal DDS that delivers sunitinib, an FDA-approved multi-kinase inhibitor that promotes RGC survival [134][33]. They achieved a sustained release of therapeutically relevant concentrations in a pig model and provided neuroprotection for at least 20 weeks in a rat optic nerve crush model.

 

3.2. Barriers to Clinical Translation

Barriers to Clinical Translation

Current neuroprotective trials for glaucoma are facing difficulties in replicating in vivo efficacy in humans due to the use of acute damage animal models, while human glaucoma is a chronic and prolonged disease. Moreover, current neuroprotective agents suffer from low bioavailability, chemical instability, and adverse effects. For example, brimonidine monotherapy has side effects like hyperemia, hypersensitivity, and ocular discomfort. Although stem cell therapy, NMDA antagonist-drugs, and neurotrophic factors show promise, they may cause undesired systemic absorption and low bioavailability to the posterior eye. To overcome these limitations, biodegradable nano-based DDS can improve bioavailability, targeted delivery, and sustained release, increasing patient adherence. However, many DDS approaches are still in vitro or preliminary in vivo stages, and animal models are needed to confirm these neuroprotective findings before clinical translation.

 

4. Nano-Based DDS after Laser and Surgical Treatment of Glaucoma

Nano-Based DDS after Laser and Surgical Treatment of Glaucoma

4.1. Preclinical Studies

Preclinical Studies

Nano-based DDS can also enhance anti-inflammatory and anti-fibrotic effects and provide sustained IOP-lowering after glaucoma filtration surgeries and SLT. In a recent study by Ghosn et al. (2022), the FDA-approved bimatoprost implant, DurystaTM, was tested in a beagle in vivo model to evaluate its effectiveness in reducing IOP post-selective laser trabeculoplasty (SLT) [136][34]. The results showed a sustained IOP lowering for up to 42 weeks after the implant was placed. However, the study had a small sample size, and translating these results to human patients with chronic glaucoma medication may pose challenges due to greater variability in IOP levels.

Andres-Guerrero et al. (2021) developed a collagen matrix implant loaded with bevacizumab and sodium hyaluronate to promote wound healing and reduce bleb failure post-conventional trabeculectomy [137][35]. The anti-VEGF properties of bevacizumab combined with mechanical support from sodium hyaluronate provided anti-scarring and improved tissue repair. However, there is a risk of collagen matrix-induced inflammation after degradation. While this system improved tissue repair in vitro, further improvement in DDS for controlled, sustained release may be required to achieve clinical significance.

Swann et al. (2019) formulated a PLGA film containing MMC and 5-FU, providing sustained anti-fibrotic treatment post-trabeculectomy. Vildanova et al. (2022) developed a biodegradable modified chitosan and HA hydrogel to improve sustained delivery of MMC and 5-FU, with in vitro studies reporting sustained release of both drugs, with MMC having a longer release compared to 5-FU. Qiao et al. (2017) used a chistosan-modified hydrogel to deliver heparin post-glaucoma surgery, maintaining filtration bleb and lowering IOP for a prolonged time. However, the cytotoxicity profiles for these studies, particularly the long-term effect on corneal limbal stem cells, need further investigation.

Chun et al. (2021) used a gelatin-based hydrogel to deliver siSPARC for reducing subconjunctival scarring post-trabeculectomy [140][36]. The hydrogel DDS was non-toxic, highly biocompatible, and effective in reducing scarring. Similarly, LbL (layer-by-layer) nanoparticles were used to deliver siSPARC by Seet et al. (2018) [141][37]. Although siSPARC showed no cellular toxicity, it is easily degradable, and a hydrogel may help improve its ocular delivery. Further optimization of the dosage to ensure sustained release is necessary for clinical applications.

 

4.2. Clinical Studies

Clinical Studies

In a recent clinical study, Johannesson et al. (2020) used dexamethasone nanoparticles (DexNP) to deliver MMC post-trabeculectomy in a randomized, single-masked clinical trial. DexNP proved non-inferior to conventional MMC MaxidexTM eye drops in a small sample of 20 patients. Despite limitations such as a small sample size and unmasked patients, this nanoparticle system offers a potentially safer alternative to MMC administration, which is associated with risks and complications.

 

[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196]

References

  1. Ridolfo R., Tavakoli S., Junnuthula V., Williams D.S., Urtti A., van Hest J.C.M. Exploring the Impact of Morphology on the Properties of Biodegradable Nanoparticles and Their Diffusion in Complex Biological Medium. Biomacromolecules. 2021;22:126–133. doi: 10.1021/acs.biomac.0c00726. - DOI - PMC - PubMedKwon, S.; Kim, S.H.; Khang, D.; Lee, J.Y. Potential Therapeutic Usage of Nanomedicine for Glaucoma Treatment. Int. J. Nanomed. 2020, 15, 5745–5765.
  2. Allyn M.M., Luo R.H., Hellwarth E.B., Swindle-Reilly K.E. Considerations for Polymers Used in Ocular Drug Delivery. Front. Med. 2021;8:787644. doi: 10.3389/fmed.2021.787644. - DOI - PMC - PubMedJiang, G.; Jia, H.; Qiu, J.; Mo, Z.; Wen, Y.; Zhang, Y.; Wen, Y.; Xie, Q.; Ban, J.; Lu, Z.; et al. PLGA Nanoparticle Platform for Trans-Ocular Barrier to Enhance Drug Delivery: A Comparative Study Based on the Application of Oligosaccharides in the Outer Membrane of Carriers. Int. J. Nanomed. 2020, 15, 9373–9387.
  3. Tsai C.-H., Wang P.-Y., Lin I.-C., Huang H., Liu G.-S., Tseng C.-L. Ocular Drug Delivery: Role of Degradable Polymeric Nanocarriers for Ophthalmic Application. Int. J. Mol. Sci. 2018;19:2830. doi: 10.3390/ijms19092830. - DOI - PMC - PubMedSong, J.; Zhang, Z. Brinzolamide Loaded Core-Shell Nanoparticles for Enhanced Coronial Penetration in the Treatment of Glaucoma. J. Appl. Biomater. Funct. Mater. 2020, 18, 228080002094271.
  4. Zhang X., Wei D., Xu Y., Zhu Q. Hyaluronic Acid in Ocular Drug Delivery. Carbohydr. Polym. 2021;264:118006. doi: 10.1016/j.carbpol.2021.118006. - DOI - PubMedIkuta, Y.; Aoyagi, S.; Tanaka, Y.; Sato, K.; Inada, S.; Koseki, Y.; Onodera, T.; Oikawa, H.; Kasai, H. Creation of Nano Eye-Drops and Effective Drug Delivery to the Interior of the Eye. Sci. Rep. 2017, 7, 44229.
  5. Orasugh J.T., Dutta S., Das D., Nath J., Pal C., Chattopadhyay D. Utilization of Cellulose Nanocrystals (CNC) Biopolymer Nanocomposites in Ophthalmic Drug Delivery System (ODDS) J. Nanotechnol. Res. 2019;1:75–87.Stankowska, D.L.; Millar, J.C.; Kodati, B.; Behera, S.; Chaphalkar, R.M.; Nguyen, T.; Nguyen, K.T.; Krishnamoorthy, R.R.; Ellis, D.Z.; Acharya, S. Nanoencapsulated Hybrid Compound SA-2 with Long-Lasting Intraocular Pressure-Lowering Activity in Rodent Eyes. Mol. Vis. 2021, 27, 37–49.
  6. Gupta B., Mishra V., Gharat S., Momin M., Omri A. Cellulosic Polymers for Enhancing Drug Bioavailability in Ocular Drug Delivery Systems. Pharmaceuticals. 2021;14:1201. doi: 10.3390/ph14111201. - DOI - PMC - PubMedJain, N.; Verma, A.; Jain, N. Formulation and Investigation of Pilocarpine Hydrochloride Niosomal Gels for the Treatment of Glaucoma: Intraocular Pressure Measurement in White Albino Rabbits. Drug Deliv. 2020, 27, 888–899.
  7. Tavakolian M., Jafari S.M., van de Ven T.G.M. A Review on Surface-Functionalized Cellulosic Nanostructures as Biocompatible Antibacterial Materials. Nano-Micro Lett. 2020;12:73. doi: 10.1007/s40820-020-0408-4. - DOI - PMC - PubMedFathalla, D.; Fouad, E.A.; Soliman, G.M. Latanoprost Niosomes as a Sustained Release Ocular Delivery System for the Management of Glaucoma. Drug Dev. Ind. Pharm. 2020, 46, 806–813.
  8. Junnuthula V., Sadeghi Boroujeni A., Cao S., Tavakoli S., Ridolfo R., Toropainen E., Ruponen M., van Hest J.C.M., Urtti A. Intravitreal Polymeric Nanocarriers with Long Ocular Retention and Targeted Delivery to the Retina and Optic Nerve Head Region. Pharmaceutics. 2021;13:445. doi: 10.3390/pharmaceutics13040445. - DOI - PMC - PubMedEmad Eldeeb, A.; Salah, S.; Ghorab, M. Proniosomal Gel-Derived Niosomes: An Approach to Sustain and Improve the Ocular Delivery of Brimonidine Tartrate; Formulation, in-Vitro Characterization, and in-Vivo Pharmacodynamic Study. Drug Deliv. 2019, 26, 509–521.
  9. Tundisi L.L., Mostaço G.B., Carricondo P.C., Petri D.F.S. Hydroxypropyl Methylcellulose: Physicochemical Properties and Ocular Drug Delivery Formulations. Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci. 2021;159:105736. doi: 10.1016/j.ejps.2021.105736. - DOI - PubMedFouda, N.H.; Abdelrehim, R.T.; Hegazy, D.A.; Habib, B.A. Sustained Ocular Delivery of Dorzolamide-HCl via Proniosomal Gel Formulation: In-Vitro Characterization, Statistical Optimization, and in-Vivo Pharmacodynamic Evaluation in Rabbits. Drug Deliv. 2018, 25, 1340–1349.
  10. Kumara B.N., Shambhu R., Prasad K.S. Why Chitosan Could Be Apt Candidate for Glaucoma Drug Delivery—An Overview. Int. J. Biol. Macromol. 2021;176:47–65. doi: 10.1016/j.ijbiomac.2021.02.057. - DOI - PubMedXu, J.; Ge, Y.; Bu, R.; Zhang, A.; Feng, S.; Wang, J.; Gou, J.; Yin, T.; He, H.; Zhang, Y.; et al. Co-Delivery of Latanoprost and Timolol from Micelles-Laden Contact Lenses for the Treatment of Glaucoma. J. Control Release 2019, 305, 18–28.
  11. Zamboulis A., Nanaki S., Michailidou G., Koumentakou I., Lazaridou M., Ainali N.M., Xanthopoulou E., Bikiaris D.N. Chitosan and Its Derivatives for Ocular Delivery Formulations: Recent Advances and Developments. Polymers. 2020;12:1519. doi: 10.3390/polym12071519. - DOI - PMC - PubMedSamy, K.E.; Cao, Y.; Kim, J.; Konichi da Silva, N.R.; Phone, A.; Bloomer, M.M.; Bhisitkul, R.B.; Desai, T.A. Co-Delivery of Timolol and Brimonidine with a Polymer Thin-Film Intraocular Device. J. Ocul. Pharmacol. Ther. 2019, 35, 124–131.
  12. Fabiano A., Beconcini D., Migone C., Piras A.M., Zambito Y. Quaternary Ammonium Chitosans: The Importance of the Positive Fixed Charge of the Drug Delivery Systems. Int. J. Mol. Sci. 2020;21:6617. doi: 10.3390/ijms21186617. - DOI - PMC - PubMedKim, J.; Kudisch, M.; da Silva, N.R.K.; Asada, H.; Aya-Shibuya, E.; Bloomer, M.M.; Mudumba, S.; Bhisitkul, R.B.; Desai, T.A. Long-Term Intraocular Pressure Reduction with Intracameral Polycaprolactone Glaucoma Devices That Deliver a Novel Anti-Glaucoma Agent. J. Control Release 2018, 269, 45–51.
  13. Kianersi S., Solouk A., Saber-Samandari S., Keshel S.H., Pasbakhsh P. Alginate Nanoparticles as Ocular Drug Delivery Carriers. J. Drug Deliv. Sci. Technol. 2021;66:102889. doi: 10.1016/j.jddst.2021.102889. - DOIZeng, Y.; Chen, J.; Li, Y.; Huang, J.; Huang, Z.; Huang, Y.; Pan, X.; Wu, C. Thermo-Sensitive Gel in Glaucoma Therapy for Enhanced Bioavailability: In Vitro Characterization, in Vivo Pharmacokinetics and Pharmacodynamics Study. Life Sci. 2018, 212, 80–86.
  14. Wong F.S.Y., Tsang K.K., Chu A.M.W., Chan B.P., Yao K.M., Lo A.C.Y. Injectable Cell-Encapsulating Composite Alginate-Collagen Platform with Inducible Termination Switch for Safer Ocular Drug Delivery. Biomaterials. 2019;201:53–67. doi: 10.1016/j.biomaterials.2019.01.032. - DOI - PubMedSharma, P.K.; Chauhan, M.K. Optimization and Characterization of Brimonidine Tartrate Nanoparticles-Loaded In Situ Gel for the Treatment of Glaucoma. Curr. Eye Res. 2021, 46, 1703–1716.
  15. Jiang G., Jia H., Qiu J., Mo Z., Wen Y., Zhang Y., Wen Y., Xie Q., Ban J., Lu Z., et al. PLGA Nanoparticle Platform for Trans-Ocular Barrier to Enhance Drug Delivery: A Comparative Study Based on the Application of Oligosaccharides in the Outer Membrane of Carriers. Int. J. Nanomed. 2020;15:9373–9387. doi: 10.2147/IJN.S272750. - DOI - PMC - PubMedIlka, R.; Mohseni, M.; Kianirad, M.; Naseripour, M.; Ashtari, K.; Mehravi, B. Nanogel-Based Natural Polymers as Smart Carriers for the Controlled Delivery of Timolol Maleate through the Cornea for Glaucoma. Int. J. Biol. Macromol. 2018, 109, 955–962.
  16. Swetledge S., Carter R., Stout R., Astete C.E., Jung J.P., Sabliov C.M. Stability and Ocular Biodistribution of Topically Administered PLGA Nanoparticles. Sci. Rep. 2021;11:12270. doi: 10.1038/s41598-021-90792-5. - DOI - PMC - PubMedEl-Feky, G.S.; Zayed, G.M.; Elshaier, Y.A.M.M.; Alsharif, F.M. Chitosan-Gelatin Hydrogel Crosslinked With Oxidized Sucrose for the Ocular Delivery of Timolol Maleate. J. Pharm. Sci. 2018, 107, 3098–3104.
  17. Zhang Y., Song W., Lu Y., Xu Y., Wang C., Yu D.-G., Kim I. Recent Advances in Poly(α-L-Glutamic Acid)-Based Nanomaterials for Drug Delivery. Biomolecules. 2022;12:636. doi: 10.3390/biom12050636. - DOI - PMC - PubMedYadav, M.; Guzman-Aranguez, A.; Perez de Lara, M.J.; Singh, M.; Singh, J.; Kaur, I.P. Bimatoprost Loaded Nanovesicular Long-Acting Sub-Conjunctival in-Situ Gelling Implant: In Vitro and in Vivo Evaluation. Mater. Sci. Eng. C 2019, 103, 109730.
  18. Wang Q., Zhang A., Zhu L., Yang X., Fang G., Tang B. Cyclodextrin-Based Ocular Drug Delivery Systems: A Comprehensive Review. Coord. Chem. Rev. 2023;476:214919. doi: 10.1016/j.ccr.2022.214919. - DOICheng, Y.-H.; Ko, Y.-C.; Chang, Y.-F.; Huang, S.-H.; Liu, C.J. Thermosensitive Chitosan-Gelatin-Based Hydrogel Containing Curcumin-Loaded Nanoparticles and Latanoprost as a Dual-Drug Delivery System for Glaucoma Treatment. Exp. Eye Res. 2019, 179, 179–187.
  19. Weng Y.-H., Ma X.-W., Che J., Li C., Liu J., Chen S.-Z., Wang Y.-Q., Gan Y.-L., Chen H., Hu Z.-B., et al. Nanomicelle-Assisted Targeted Ocular Delivery with Enhanced Antiinflammatory Efficacy In Vivo. Adv. Sci. Weinh. Baden-Wurtt. Ger. 2018;5:1700455. doi: 10.1002/advs.201700455. - DOI - PMC - PubMedChou, S.-F.; Luo, L.-J.; Lai, J.-Y. In Vivo Pharmacological Evaluations of Pilocarpine-Loaded Antioxidant-Functionalized Biodegradable Thermogels in Glaucomatous Rabbits. Sci. Rep. 2017, 7, 42344.
  20. Dai L., Li X., Yao M., Niu P., Yuan X., Li K., Chen M., Fu Z., Duan X., Liu H., et al. Programmable Prodrug Micelle with Size-Shrinkage and Charge-Reversal for Chemotherapy-Improved IDO Immunotherapy. Biomaterials. 2020;241:119901. doi: 10.1016/j.biomaterials.2020.119901. - DOI - PubMedLuo, L.-J.; Lai, J.-Y. Amination Degree of Gelatin Is Critical for Establishing Structure-Property-Function Relationships of Biodegradable Thermogels as Intracameral Drug Delivery Systems. Mater. Sci. Eng. C 2019, 98, 897–909.
  21. Hwang D., Ramsey J.D., Kabanov A.V. Polymeric Micelles for the Delivery of Poorly Soluble Drugs: From Nanoformulation to Clinical Approval. Adv. Drug Deliv. Rev. 2020;156:80–118. doi: 10.1016/j.addr.2020.09.009. - DOI - PMC - PubMedLuo, L.-J.; Huang, C.-C.; Chen, H.-C.; Lai, J.-Y.; Matsusaki, M. Effect of Deacetylation Degree on Controlled Pilocarpine Release from Injectable Chitosan-g-Poly(N-Isopropylacrylamide) Carriers. Carbohydr. Polym. 2018, 197, 375–384.
  22. Kuang G., Zhang Q., He S., Wu Y., Huang Y. Reduction-Responsive Disulfide Linkage Core-Cross-Linked Polymeric Micelles for Site-Specific Drug Delivery. Polym. Chem. 2020;11:7078–7086. doi: 10.1039/D0PY00987C. - DOILancina, M.G.; Wang, J.; Williamson, G.S.; Yang, H. DenTimol as A Dendrimeric Timolol Analogue for Glaucoma Therapy: Synthesis and Preliminary Efficacy and Safety Assessment. Mol. Pharm. 2018, 15, 2883–2889.
  23. Yu Y., Chen D., Li Y., Yang W., Tu J., Shen Y. Improving the Topical Ocular Pharmacokinetics of Lyophilized Cyclosporine A-Loaded Micelles: Formulation, in Vitro and in Vivo Studies. Drug Deliv. 2018;25:888–899. doi: 10.1080/10717544.2018.1458923. - DOI - PMC - PubMedChae, J.J.; Jung, J.H.; Zhu, W.; Gerberich, B.G.; Bahrani Fard, M.R.; Grossniklaus, H.E.; Ethier, C.R.; Prausnitz, M.R. Drug-Free, Nonsurgical Reduction of Intraocular Pressure for Four Months after Suprachoroidal Injection of Hyaluronic Acid Hydrogel. Adv. Sci. 2021, 8, 2001908.
  24. Xu X., Sun L., Zhou L., Cheng Y., Cao F. Functional Chitosan Oligosaccharide Nanomicelles for Topical Ocular Drug Delivery of Dexamethasone. Carbohydr. Polym. 2020;227:115356. doi: 10.1016/j.carbpol.2019.115356. - DOI - PubMedLiu, H.; Han, X.; Li, H.; Tao, Q.; Hu, J.; Liu, S.; Liu, H.; Zhou, J.; Li, W.; Yang, F.; et al. Wettability and Contact Angle Affect Precorneal Retention and Pharmacodynamic Behavior of Microspheres. Drug Deliv. 2021, 28, 2011–2023.
  25. Lai S., Wei Y., Wu Q., Zhou K., Liu T., Zhang Y., Jiang N., Xiao W., Chen J., Liu Q., et al. Liposomes for Effective Drug Delivery to the Ocular Posterior Chamber. J. Nanobiotechnol. 2019;17:64. doi: 10.1186/s12951-019-0498-7. - DOI - PMC - PubMedTian, S.; Li, J.; Tao, Q.; Zhao, Y.; Lv, Z.; Yang, F.; Duan, H.; Chen, Y.; Zhou, Q.; Hou, D. Controlled Drug Delivery for Glaucoma Therapy Using Montmorillonite/Eudragit Microspheres as an Ion-Exchange Carrier. Int. J. Nanomed. 2018, 13, 415–428.
  26. dos Santos G.A., Ferreira-Nunes R., Dalmolin L.F., dos Santos Ré A.C., Anjos J.L.V., Mendanha S.A., Aires C.P., Lopez R.F.V., Cunha-Filho M., Gelfuso G.M., et al. Besifloxacin Liposomes with Positively Charged Additives for an Improved Topical Ocular Delivery. Sci. Rep. 2020;10:19285. doi: 10.1038/s41598-020-76381-y. - DOI - PMC - PubMedLiu, S.; Han, X.; Liu, H.; Zhao, Y.; Li, H.; Rupenthal, I.D.; Lv, Z.; Chen, Y.; Yang, F.; Ping, Q.; et al. Incorporation of Ion Exchange Functionalized-Montmorillonite into Solid Lipid Nanoparticles with Low Irritation Enhances Drug Bioavailability for Glaucoma Treatment. Drug Deliv. 2020, 27, 652–661.
  27. Shafaa M.W., Elshazly A.H., Dakrory A.Z., Elsyed M.R. Interaction of Coenzyme Q10 with Liposomes and Its Impact on Suppression of Selenite—Induced Experimental Cataract. Adv. Pharm. Bull. 2018;8:1–9. doi: 10.15171/apb.2018.001. - DOI - PMC - PubMedBrandt, J.D.; DuBiner, H.B.; Benza, R.; Sall, K.N.; Walker, G.A.; Semba, C.P.; Budenz, D.; Day, D.; Flowers, B.; Lee, S.; et al. Long-Term Safety and Efficacy of a Sustained-Release Bimatoprost Ocular Ring. Ophthalmology 2017, 124, 1565–1566.
  28. Jin X., Zhu L., Xue B., Zhu X., Yan D. Supramolecular Nanoscale Drug-Delivery System with Ordered Structure. Natl. Sci. Rev. 2019;6:1128–1137. doi: 10.1093/nsr/nwz018. - DOI - PMC - PubMedKouchak, M.; Malekahmadi, M.; Bavarsad, N.; Saki Malehi, A.; Andishmand, L. Dorzolamide Nanoliposome as a Long Action Ophthalmic Delivery System in Open Angle Glaucoma and Ocular Hypertension Patients. Drug Dev. Ind. Pharm. 2018, 44, 1239–1242.
  29. Dave R.S., Goostrey T.C., Ziolkowska M., Czerny-Holownia S., Hoare T., Sheardown H. Ocular Drug Delivery to the Anterior Segment Using Nanocarriers: A Mucoadhesive/Mucopenetrative Perspective. J. Control Release Off. J. Control Release Soc. 2021;336:71–88. doi: 10.1016/j.jconrel.2021.06.011. - DOI - PubMedLuo, L.-J.; Nguyen, D.D.; Lai, J.-Y. Benzoic Acid Derivative-Modified Chitosan-g-Poly(N-Isopropylacrylamide): Methoxylation Effects and Pharmacological Treatments of Glaucoma-Related Neurodegeneration. J. Control Release 2020, 317, 246–258.
  30. Yang C., Yang J., Lu A., Gong J., Yang Y., Lin X., Li M., Xu H. Nanoparticles in Ocular Applications and Their Potential Toxicity. Front. Mol. Biosci. 2022;9:931759. doi: 10.3389/fmolb.2022.931759. - DOI - PMC - PubMedNguyen, D.D.; Luo, L.; Lai, J. Dendritic Effects of Injectable Biodegradable Thermogels on Pharmacotherapy of Inflammatory Glaucoma-Associated Degradation of Extracellular Matrix. Adv. Healthc. Mater. 2019, 8, 1900702.
  31. Tavares Luiz M., Delello Di Filippo L., Carolina Alves R., Sousa Araújo V.H., Lobato Duarte J., Maldonado Marchetti J., Chorilli M. The Use of TPGS in Drug Delivery Systems to Overcome Biological Barriers. Eur. Polym. J. 2021;142:110129. doi: 10.1016/j.eurpolymj.2020.110129. - DOIZhao, L.; Chen, G.; Li, J.; Fu, Y.; Mavlyutov, T.A.; Yao, A.; Nickells, R.W.; Gong, S.; Guo, L.-W. An Intraocular Drug Delivery System Using Targeted Nanocarriers Attenuates Retinal Ganglion Cell Degeneration. J. Control Release 2017, 247, 153–166.
  32. Ji T., Kohane D.S. Nanoscale Systems for Local Drug Delivery. Nano Today. 2019;28:100765. doi: 10.1016/j.nantod.2019.100765. - DOI - PMC - PubMedSilva, B.; Gonçalves, L.M.; Braz, B.S.; Delgado, E. Chitosan and Hyaluronic Acid Nanoparticles as Vehicles of Epoetin Beta for Subconjunctival Ocular Delivery. Mar. Drugs 2022, 20, 151.
  33. Di J., Gao X., Du Y., Zhang H., Gao J., Zheng A. Size, Shape, Charge and “Stealthy” Surface: Carrier Properties Affect the Drug Circulation Time in Vivo. Asian J. Pharm. Sci. 2021;16:444–458. doi: 10.1016/j.ajps.2020.07.005. - DOI - PMC - PubMedHsueh, H.T.; Kim, Y.-C.; Pitha, I.; Shin, M.D.; Berlinicke, C.A.; Chou, R.T.; Kimball, E.; Schaub, J.; Quillen, S.; Leo, K.T.; et al. Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells. Pharmaceutics 2021, 13, 647.
  34. Rebibo L., Tam C., Sun Y., Shoshani E., Badihi A., Nassar T., Benita S. Topical Tacrolimus Nanocapsules Eye Drops for Therapeutic Effect Enhancement in Both Anterior and Posterior Ocular Inflammation Models. J. Control Release Off. J. Control Release Soc. 2021;333:283–297. doi: 10.1016/j.jconrel.2021.03.035. - DOI - PMC - PubMedGhosn, C.; Rajagopalan, L.; Ugarte, S.; Mistry, S.; Orilla, W.; Goodkin, M.L.; Robinson, M.R.; Engles, M.; Dibas, M. Intraocular Pressure-Lowering Efficacy of a Sustained-Release Bimatoprost Implant in Dog Eyes Pretreated with Selective Laser Trabeculoplasty. J. Ocul. Pharmacol. Ther. 2022, 38, 311–318.
  35. Duan Y., Dhar A., Patel C., Khimani M., Neogi S., Sharma P., Siva Kumar N., Vekariya R.L. A Brief Review on Solid Lipid Nanoparticles: Part and Parcel of Contemporary Drug Delivery Systems. RSC Adv. 2020;10:26777–26791. doi: 10.1039/D0RA03491F. - DOI - PMC - PubMedAndrés-Guerrero, V.; Camacho-Bosca, I.; Salazar-Quiñones, L.; Ventura-Abreu, N.; Molero-Senosiain, M.; Hernández-Ruiz, S.; Bernal-Sancho, G.; Herrero-Vanrell, R.; García-Feijóo, J. The Effect of a Triple Combination of Bevacizumab, Sodium Hyaluronate and a Collagen Matrix Implant in a Trabeculectomy Animal Model. Pharmaceutics 2021, 13, 896.
  36. Lancina M.G., Yang H. Dendrimers for Ocular Drug Delivery. Can. J. Chem. 2017;95:897–902. doi: 10.1139/cjc-2017-0193. - DOI - PMC - PubMedChun, Y.Y.; Yap, Z.L.; Seet, L.F.; Chan, H.H.; Toh, L.Z.; Chu, S.W.L.; Lee, Y.S.; Wong, T.T.; Tan, T.T.Y. Positive-Charge Tuned Gelatin Hydrogel-SiSPARC Injectable for SiRNA Anti-Scarring Therapy in Post Glaucoma Filtration Surgery. Sci. Rep. 2021, 11, 1470.
  37. Wang J., Li B., Qiu L., Qiao X., Yang H. Dendrimer-Based Drug Delivery Systems: History, Challenges, and Latest Developments. J. Biol. Eng. 2022;16:18. doi: 10.1186/s13036-022-00298-5. - DOI - PMC - PubMedSeet, L.F.; Tan, Y.F.; Toh, L.Z.; Chu, S.W.; Lee, Y.S.; Venkatraman, S.S.; Wong, T.T. Targeted Therapy for the Post-Operative Conjunctiva: SPARC Silencing Reduces Collagen Deposition. Br. J. Ophthalmol. 2018, 102, 1460–1470.
  38. Lin D., Lei L., Shi S., Li X. Stimulus-Responsive Hydrogel for Ophthalmic Drug Delivery. Macromol. Biosci. 2019;19:e1900001. doi: 10.1002/mabi.201900001. - DOI - PubMed
  39. Lynch C.R., Kondiah P.P.D., Choonara Y.E., du Toit L.C., Ally N., Pillay V. Hydrogel Biomaterials for Application in Ocular Drug Delivery. Front. Bioeng. Biotechnol. 2020;8:228. doi: 10.3389/fbioe.2020.00228. - DOI - PMC - PubMed
  40. DHAHIR R.K., AL-NIMA A.M., AL-BAZZAZ F. Nanoemulsions as Ophthalmic Drug Delivery Systems. Turk. J. Pharm. Sci. 2021;18:652–664. doi: 10.4274/tjps.galenos.2020.59319. - DOI - PMC - PubMed
  41. Jacob S., Nair A.B., Shah J. Emerging Role of Nanosuspensions in Drug Delivery Systems. Biomater. Res. 2020;24:3. doi: 10.1186/s40824-020-0184-8. - DOI - PMC - PubMed
  42. Xie J., Luo Y., Liu Y., Ma Y., Yue P., Yang M. Novel Redispersible Nanosuspensions Stabilized by Co-Processed Nanocrystalline Cellulose-Sodium Carboxymethyl Starch for Enhancing Dissolution and Oral Bioavailability of Baicalin. Int. J. Nanomed. 2019;14:353–369. doi: 10.2147/IJN.S184374. - DOI - PMC - PubMed
  43. Gade S.S., Pentlavalli S., Mishra D., Vora L.K., Waite D., Alvarez-Lorenzo C.I., Herrero Vanrell M.R., Laverty G., Larraneta E., Donnelly R.F., et al. Injectable Depot Forming Thermoresponsive Hydrogel for Sustained Intrascleral Delivery of Sunitinib Using Hollow Microneedles. J. Ocul. Pharmacol. Ther. Off. J. Assoc. Ocul. Pharmacol. Ther. 2022;38:433–448. doi: 10.1089/jop.2022.0016. - DOI - PubMed
  44. Nettey H., Darko Y., Bamiro O.A., Addo R.T. Ocular Barriers. In: Addo R.T., editor. Ocular Drug Delivery: Advances, Challenges and Applications. Springer International Publishing; Cham, Switzerland: 2016. pp. 27–36.
  45. Kwon S., Kim S.H., Khang D., Lee J.Y. Potential Therapeutic Usage of Nanomedicine for Glaucoma Treatment. Int. J. Nanomed. 2020;15:5745–5765. doi: 10.2147/IJN.S254792. - DOI - PMC - PubMed
  46. Song J., Zhang Z. Brinzolamide Loaded Core-Shell Nanoparticles for Enhanced Coronial Penetration in the Treatment of Glaucoma. J. Appl. Biomater. Funct. Mater. 2020;18:228080002094271. doi: 10.1177/2280800020942712. - DOI - PubMed
  47. Ikuta Y., Aoyagi S., Tanaka Y., Sato K., Inada S., Koseki Y., Onodera T., Oikawa H., Kasai H. Creation of Nano Eye-Drops and Effective Drug Delivery to the Interior of the Eye. Sci. Rep. 2017;7:44229. doi: 10.1038/srep44229. - DOI - PMC - PubMed
  48. Stankowska D.L., Millar J.C., Kodati B., Behera S., Chaphalkar R.M., Nguyen T., Nguyen K.T., Krishnamoorthy R.R., Ellis D.Z., Acharya S. Nanoencapsulated Hybrid Compound SA-2 with Long-Lasting Intraocular Pressure-Lowering Activity in Rodent Eyes. Mol. Vis. 2021;27:37–49. - PMC - PubMed
  49. Lorenzo-Soler L., Olafsdottir O.B., Garhöfer G., Jansook P., Kristinsdottir I.M., Tan A., Loftsson T., Stefansson E. Angiotensin Receptor Blockers in Cyclodextrin Nanoparticle Eye Drops: Ocular Pharmacokinetics and Pharmacologic Effect on Intraocular Pressure. Acta Ophthalmol. 2021;99:376–382. doi: 10.1111/aos.14639. - DOI - PubMed
  50. Barwal I., Kumar R., Dada T., Yadav S.C. Effect of Ultra-Small Chitosan Nanoparticles Doped with Brimonidine on the Ultra-Structure of the Trabecular Meshwork of Glaucoma Patients. Microsc. Microanal. 2019;25:1352–1366. doi: 10.1017/S1431927619000448. - DOI - PubMed
  51. Mittal N., Kaur G. Leucaena Leucocephala (Lam.) Galactomannan Nanoparticles: Optimization and Characterization for Ocular Delivery in Glaucoma Treatment. Int. J. Biol. Macromol. 2019;139:1252–1262. doi: 10.1016/j.ijbiomac.2019.08.107. - DOI - PubMed
  52. Tan C., Jia F., Zhang P., Sun X., Qiao Y., Chen X., Wang Y., Chen J., Lei Y. A MiRNA Stabilizing Polydopamine Nano-Platform for Intraocular Delivery of MiR-21-5p in Glaucoma Therapy. J. Mater. Chem. B. 2021;9:3335–3345. doi: 10.1039/D0TB02881A. - DOI - PubMed
  53. Hu C., Sun J., Zhang Y., Chen J., Lei Y., Sun X., Deng Y. Local Delivery and Sustained-Release of Nitric Oxide Donor Loaded in Mesoporous Silica Particles for Efficient Treatment of Primary Open-Angle Glaucoma. Adv. Healthc. Mater. 2018;7:1801047. doi: 10.1002/adhm.201801047. - DOI - PubMed
  54. Hu C., Zhang Y., Song M., Deng Y., Sun X., Lei Y. Prolonged Use of Nitric Oxide Donor Sodium Nitroprusside Induces Ocular Hypertension in Mice. Exp. Eye Res. 2021;202:108280. doi: 10.1016/j.exer.2020.108280. - DOI - PubMed
  55. Song W., Zhang Y., Yu D.-G., Tran C.H., Wang M., Varyambath A., Kim J., Kim I. Efficient Synthesis of Folate-Conjugated Hollow Polymeric Capsules for Accurate Drug Delivery to Cancer Cells. Biomacromolecules. 2021;22:732–742. doi: 10.1021/acs.biomac.0c01520. - DOI - PubMed
  56. Zafar A., Alruwaili N.K., Imam S.S., Alsaidan O.A., Alharbi K.S., Yasir M., Elmowafy M., Ansari M.J., Salahuddin M., Alshehri S. Formulation of Carteolol Chitosomes for Ocular Delivery: Formulation Optimization, Ex-Vivo Permeation, and Ocular Toxicity Examination. Cutan. Ocul. Toxicol. 2021;40:338–349. doi: 10.1080/15569527.2021.1958225. - DOI - PubMed
  57. Jain N., Verma A., Jain N. Formulation and Investigation of Pilocarpine Hydrochloride Niosomal Gels for the Treatment of Glaucoma: Intraocular Pressure Measurement in White Albino Rabbits. Drug Deliv. 2020;27:888–899. doi: 10.1080/10717544.2020.1775726. - DOI - PMC - PubMed
  58. Fathalla D., Fouad E.A., Soliman G.M. Latanoprost Niosomes as a Sustained Release Ocular Delivery System for the Management of Glaucoma. Drug Dev. Ind. Pharm. 2020;46:806–813. doi: 10.1080/03639045.2020.1755305. - DOI - PubMed
  59. Emad Eldeeb A., Salah S., Ghorab M. Proniosomal Gel-Derived Niosomes: An Approach to Sustain and Improve the Ocular Delivery of Brimonidine Tartrate; Formulation, in-Vitro Characterization, and in-Vivo Pharmacodynamic Study. Drug Deliv. 2019;26:509–521. doi: 10.1080/10717544.2019.1609622. - DOI - PMC - PubMed
  60. Fouda N.H., Abdelrehim R.T., Hegazy D.A., Habib B.A. Sustained Ocular Delivery of Dorzolamide-HCl via Proniosomal Gel Formulation: In-Vitro Characterization, Statistical Optimization, and in-Vivo Pharmacodynamic Evaluation in Rabbits. Drug Deliv. 2018;25:1340–1349. doi: 10.1080/10717544.2018.1477861. - DOI - PMC - PubMed
  61. Teba H.E., Khalil I.A., El Sorogy H.M. Novel Cubosome Based System for Ocular Delivery of Acetazolamide. Drug Deliv. 2021;28:2177–2186. doi: 10.1080/10717544.2021.1989090. - DOI - PMC - PubMed
  62. Huang J., Peng T., Li Y., Zhan Z., Zeng Y., Huang Y., Pan X., Wu C.-Y., Wu C. Ocular Cubosome Drug Delivery System for Timolol Maleate: Preparation, Characterization, Cytotoxicity, Ex Vivo, and In Vivo Evaluation. AAPS PharmSciTech. 2017;18:2919–2926. doi: 10.1208/s12249-017-0763-8. - DOI - PubMed
  63. Ismail A., Nasr M., Sammour O. Nanoemulsion as a Feasible and Biocompatible Carrier for Ocular Delivery of Travoprost: Improved Pharmacokinetic/Pharmacodynamic Properties. Int. J. Pharm. 2020;583:119402. doi: 10.1016/j.ijpharm.2020.119402. - DOI - PubMed
  64. Mahboobian M.M., Seyfoddin A., Aboofazeli R., Foroutan S.M., Rupenthal I.D. Brinzolamide–Loaded Nanoemulsions: Ex Vivo Transcorneal Permeation, Cell Viability and Ocular Irritation Tests. Pharm. Dev. Technol. 2019;24:600–606. doi: 10.1080/10837450.2018.1547748. - DOI - PubMed
  65. Cesar A.L.A., Navarro L.C., Castilho R.O., Goulart G.A.C., Foureaux G., Ferreira A.J., Cronemberger S., Gomes Faraco A.A. New Antiglaucomatous Agent for the Treatment of Open Angle Glaucoma: Polymeric Inserts for Drug Release and in Vitro and in Vivo Study. J. Biomed. Mater. Res. A. 2021;109:336–345. doi: 10.1002/jbm.a.37026. - DOI - PubMed
  66. Franca J.R., Foureaux G., Fuscaldi L.L., Ribeiro T.G., Castilho R.O., Yoshida M.I., Cardoso V.N., Fernandes S.O.A., Cronemberger S., Nogueira J.C., et al. Chitosan/Hydroxyethyl Cellulose Inserts for Sustained-Release of Dorzolamide for Glaucoma Treatment: In Vitro and in Vivo Evaluation. Int. J. Pharm. 2019;570:118662. doi: 10.1016/j.ijpharm.2019.118662. - DOI - PubMed
  67. Li B., Wang J., Gui Q., Yang H. Drug-Loaded Chitosan Film Prepared via Facile Solution Casting and Air-Drying of Plain Water-Based Chitosan Solution for Ocular Drug Delivery. Bioact. Mater. 2020;5:577–583. doi: 10.1016/j.bioactmat.2020.04.013. - DOI - PMC - PubMed
  68. Nair R.V., Shefrin S., Suresh A., Anoop K.R., Nair S.C. Sustained Release Timolol Maleate Loaded Ocusert Based on Biopolymer Composite. Int. J. Biol. Macromol. 2018;110:308–317. doi: 10.1016/j.ijbiomac.2018.01.029. - DOI - PubMed
  69. Machado M., Silva G.A., Bitoque D.B., Ferreira J., Pinto L.A., Morgado J., Ferreira Q. Self-Assembled Multilayer Films for Time-Controlled Ocular Drug Delivery. ACS Appl. Bio Mater. 2019;2:4173–4180. doi: 10.1021/acsabm.9b00417. - DOI - PubMed
  70. Xu J., Ge Y., Bu R., Zhang A., Feng S., Wang J., Gou J., Yin T., He H., Zhang Y., et al. Co-Delivery of Latanoprost and Timolol from Micelles-Laden Contact Lenses for the Treatment of Glaucoma. J. Control Release. 2019;305:18–28. doi: 10.1016/j.jconrel.2019.05.025. - DOI - PubMed
  71. Samy K.E., Cao Y., Kim J., Konichi da Silva N.R., Phone A., Bloomer M.M., Bhisitkul R.B., Desai T.A. Co-Delivery of Timolol and Brimonidine with a Polymer Thin-Film Intraocular Device. J. Ocul. Pharmacol. Ther. 2019;35:124–131. doi: 10.1089/jop.2018.0096. - DOI - PMC - PubMed
  72. Kim J., Kudisch M., da Silva N.R.K., Asada H., Aya-Shibuya E., Bloomer M.M., Mudumba S., Bhisitkul R.B., Desai T.A. Long-Term Intraocular Pressure Reduction with Intracameral Polycaprolactone Glaucoma Devices That Deliver a Novel Anti-Glaucoma Agent. J. Control Release. 2018;269:45–51. doi: 10.1016/j.jconrel.2017.11.008. - DOI - PMC - PubMed
  73. Zeng Y., Chen J., Li Y., Huang J., Huang Z., Huang Y., Pan X., Wu C. Thermo-Sensitive Gel in Glaucoma Therapy for Enhanced Bioavailability: In Vitro Characterization, in Vivo Pharmacokinetics and Pharmacodynamics Study. Life Sci. 2018;212:80–86. doi: 10.1016/j.lfs.2018.09.050. - DOI - PubMed
  74. Sharma P.K., Chauhan M.K. Optimization and Characterization of Brimonidine Tartrate Nanoparticles-Loaded In Situ Gel for the Treatment of Glaucoma. Curr. Eye Res. 2021;46:1703–1716. doi: 10.1080/02713683.2021.1916037. - DOI - PubMed
  75. Ilka R., Mohseni M., Kianirad M., Naseripour M., Ashtari K., Mehravi B. Nanogel-Based Natural Polymers as Smart Carriers for the Controlled Delivery of Timolol Maleate through the Cornea for Glaucoma. Int. J. Biol. Macromol. 2018;109:955–962. doi: 10.1016/j.ijbiomac.2017.11.090. - DOI - PubMed
  76. El-Feky G.S., Zayed G.M., Elshaier Y.A.M.M., Alsharif F.M. Chitosan-Gelatin Hydrogel Crosslinked With Oxidized Sucrose for the Ocular Delivery of Timolol Maleate. J. Pharm. Sci. 2018;107:3098–3104. doi: 10.1016/j.xphs.2018.08.015. - DOI - PubMed
  77. Yadav M., Guzman-Aranguez A., Perez de Lara M.J., Singh M., Singh J., Kaur I.P. Bimatoprost Loaded Nanovesicular Long-Acting Sub-Conjunctival in-Situ Gelling Implant: In Vitro and in Vivo Evaluation. Mater. Sci. Eng. C. 2019;103:109730. doi: 10.1016/j.msec.2019.05.015. - DOI - PubMed
  78. Cheng Y.-H., Ko Y.-C., Chang Y.-F., Huang S.-H., Liu C.J. Thermosensitive Chitosan-Gelatin-Based Hydrogel Containing Curcumin-Loaded Nanoparticles and Latanoprost as a Dual-Drug Delivery System for Glaucoma Treatment. Exp. Eye Res. 2019;179:179–187. doi: 10.1016/j.exer.2018.11.017. - DOI - PubMed
  79. Chou S.-F., Luo L.-J., Lai J.-Y. In Vivo Pharmacological Evaluations of Pilocarpine-Loaded Antioxidant-Functionalized Biodegradable Thermogels in Glaucomatous Rabbits. Sci. Rep. 2017;7:42344. doi: 10.1038/srep42344. - DOI - PMC - PubMed
  80. Luo L.-J., Lai J.-Y. Amination Degree of Gelatin Is Critical for Establishing Structure-Property-Function Relationships of Biodegradable Thermogels as Intracameral Drug Delivery Systems. Mater. Sci. Eng. C. 2019;98:897–909. doi: 10.1016/j.msec.2019.01.051. - DOI - PubMed
  81. Luo L.-J., Huang C.-C., Chen H.-C., Lai J.-Y., Matsusaki M. Effect of Deacetylation Degree on Controlled Pilocarpine Release from Injectable Chitosan-g-Poly(N-Isopropylacrylamide) Carriers. Carbohydr. Polym. 2018;197:375–384. doi: 10.1016/j.carbpol.2018.06.020. - DOI - PubMed
  82. Jin Q., Li H., Jin Z., Huang L., Wang F., Zhou Y., Liu Y., Jiang C., Oswald J., Wu J., et al. TPGS Modified Nanoliposomes as an Effective Ocular Delivery System to Treat Glaucoma. Int. J. Pharm. 2018;553:21–28. doi: 10.1016/j.ijpharm.2018.10.033. - DOI - PubMed
  83. Fahmy H.M., Saad E.A.E.-M.S., Sabra N.M., El-Gohary A.A., Mohamed F.F., Gaber M.H. Treatment Merits of Latanoprost/Thymoquinone—Encapsulated Liposome for Glaucomatus Rabbits. Int. J. Pharm. 2018;548:597–608. doi: 10.1016/j.ijpharm.2018.07.012. - DOI - PubMed
  84. Hathout R.M., Gad H.A., Abdel-Hafez S.M., Nasser N., Khalil N., Ateyya T., Amr A., Yasser N., Nasr S., Metwally A.A. Gelatinized Core Liposomes: A New Trojan Horse for the Development of a Novel Timolol Maleate Glaucoma Medication. Int. J. Pharm. 2019;556:192–199. doi: 10.1016/j.ijpharm.2018.12.015. - DOI - PubMed
  85. Lancina M.G., Wang J., Williamson G.S., Yang H. DenTimol as A Dendrimeric Timolol Analogue for Glaucoma Therapy: Synthesis and Preliminary Efficacy and Safety Assessment. Mol. Pharm. 2018;15:2883–2889. doi: 10.1021/acs.molpharmaceut.8b00401. - DOI - PMC - PubMed
  86. Lancina M.G., Singh S., Kompella U.B., Husain S., Yang H. Fast Dissolving Dendrimer Nanofiber Mats as Alternative to Eye Drops for More Efficient Antiglaucoma Drug Delivery. ACS Biomater. Sci. Eng. 2017;3:1861–1868. doi: 10.1021/acsbiomaterials.7b00319. - DOI - PMC - PubMed
  87. Afify E.A.M.R., Elsayed I., Gad M.K., Mohamed M.I., Afify A.E.-M.M.R. Enhancement of Pharmacokinetic and Pharmacological Behavior of Ocular Dorzolamide after Factorial Optimization of Self-Assembled Nanostructures. PLoS ONE. 2018;13:e0191415. doi: 10.1371/journal.pone.0191415. - DOI - PMC - PubMed
  88. Gautam N., Kesavan K. Phase Transition Microemulsion of Brimonidine Tartrate for Glaucoma Therapy: Preparation, Characterization and Pharmacodynamic Study. Curr. Eye Res. 2021;46:1844–1852. doi: 10.1080/02713683.2021.1942071. - DOI - PubMed
  89. Vincent M.P., Stack T., Vahabikashi A., Li G., Perkumas K.M., Ren R., Gong H., Stamer W.D., Johnson M., Scott E.A. Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy. ACS Appl. Mater. Interfaces. 2021;13:32823–32836. doi: 10.1021/acsami.1c09294. - DOI - PMC - PubMed
  90. Donia M., Osman R., Awad G.A.S., Mortada N. Polypeptide and Glycosaminoglycan Polysaccharide as Stabilizing Polymers in Nanocrystals for a Safe Ocular Hypotensive Effect. Int. J. Biol. Macromol. 2020;162:1699–1710. doi: 10.1016/j.ijbiomac.2020.07.306. - DOI - PubMed
  91. Chae J.J., Jung J.H., Zhu W., Gerberich B.G., Bahrani Fard M.R., Grossniklaus H.E., Ethier C.R., Prausnitz M.R. Drug-Free, Nonsurgical Reduction of Intraocular Pressure for Four Months after Suprachoroidal Injection of Hyaluronic Acid Hydrogel. Adv. Sci. 2021;8:2001908. doi: 10.1002/advs.202001908. - DOI - PMC - PubMed
  92. Liu H., Han X., Li H., Tao Q., Hu J., Liu S., Liu H., Zhou J., Li W., Yang F., et al. Wettability and Contact Angle Affect Precorneal Retention and Pharmacodynamic Behavior of Microspheres. Drug Deliv. 2021;28:2011–2023. doi: 10.1080/10717544.2021.1981493. - DOI - PMC - PubMed
  93. Tian S., Li J., Tao Q., Zhao Y., Lv Z., Yang F., Duan H., Chen Y., Zhou Q., Hou D. Controlled Drug Delivery for Glaucoma Therapy Using Montmorillonite/Eudragit Microspheres as an Ion-Exchange Carrier. Int. J. Nanomed. 2018;13:415–428. doi: 10.2147/IJN.S146346. - DOI - PMC - PubMed
  94. Liu S., Han X., Liu H., Zhao Y., Li H., Rupenthal I.D., Lv Z., Chen Y., Yang F., Ping Q., et al. Incorporation of Ion Exchange Functionalized-Montmorillonite into Solid Lipid Nanoparticles with Low Irritation Enhances Drug Bioavailability for Glaucoma Treatment. Drug Deliv. 2020;27:652–661. doi: 10.1080/10717544.2020.1756984. - DOI - PMC - PubMed
  95. Li J., Tian S., Tao Q., Zhao Y., Gui R., Yang F., Zang L., Chen Y., Ping Q., Hou D. Montmorillonite/Chitosan Nanoparticles as a Novel Controlled-Release Topical Ophthalmic Delivery System for the Treatment of Glaucoma. Int. J. Nanomed. 2018;13:3975–3987. doi: 10.2147/IJN.S162306. - DOI - PMC - PubMed
  96. Andreadis I.I., Karavasili C., Thomas A., Komnenou A., Tzimtzimis M., Tzetzis D., Andreadis D., Bouropoulos N., Fatouros D.G. In Situ Gelling Electrospun Ocular Films Sustain the Intraocular Pressure-Lowering Effect of Timolol Maleate: In Vitro, Ex Vivo, and Pharmacodynamic Assessment. Mol. Pharm. 2022;19:274–286. doi: 10.1021/acs.molpharmaceut.1c00766. - DOI - PubMed
  97. Morais M., Coimbra P., Pina M.E. Comparative Analysis of Morphological and Release Profiles in Ocular Implants of Acetazolamide Prepared by Electrospinning. Pharmaceutics. 2021;13:260. doi: 10.3390/pharmaceutics13020260. - DOI - PMC - PubMed
  98. Rubião F., Araújo A.C.F., Sancio J.B., Nogueira B.S., Franca J.R., Nogueira J.C., Ferreira A.J., Faraco A.A.G., Foureaux G., Cronemberger S. Topical Bimatoprost Insert for Primary Open-Angle Glaucoma and Ocular Hypertension Treatment—A Phase II Controlled Study. Curr. Drug Deliv. 2021;18:1022–1026. doi: 10.2174/1567201818666210101112256. - DOI - PubMed
  99. Weinreb R.N., Bacharach J., Brubaker J.W., Medeiros F.A., Bejanian M., Bernstein P., Robinson M.R. Bimatoprost Implant Biodegradation in the Phase 3, Randomized, 20-Month ARTEMIS Studies. J. Ocul. Pharmacol. Ther. 2023;39:55–62. doi: 10.1089/jop.2022.0137. - DOI - PMC - PubMed
  100. Shirley M. Bimatoprost Implant: First Approval. Drugs Aging. 2020;37:457–462. doi: 10.1007/s40266-020-00769-8. - DOI - PMC - PubMed
  101. Medeiros F.A., Walters T.R., Kolko M., Coote M., Bejanian M., Goodkin M.L., Guo Q., Zhang J., Robinson M.R., Weinreb R.N., et al. Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1) Ophthalmology. 2020;127:1627–1641. doi: 10.1016/j.ophtha.2020.06.018. - DOI - PubMed
  102. Craven E.R., Walters T., Christie W.C., Day D.G., Lewis R.A., Goodkin M.L., Chen M., Wangsadipura V., Robinson M.R., Bejanian M., et al. 24-Month Phase I/II Clinical Trial of Bimatoprost Sustained-Release Implant (Bimatoprost SR) in Glaucoma Patients. Drugs. 2020;80:167–179. doi: 10.1007/s40265-019-01248-0. - DOI - PMC - PubMed
  103. Lewis R.A., Christie W.C., Day D.G., Craven E.R., Walters T., Bejanian M., Lee S.S., Goodkin M.L., Zhang J., Whitcup S.M., et al. Bimatoprost Sustained-Release Implants for Glaucoma Therapy: 6-Month Results From a Phase I/II Clinical Trial. Am. J. Ophthalmol. 2017;175:137–147. doi: 10.1016/j.ajo.2016.11.020. - DOI - PubMed
  104. Brandt J.D., DuBiner H.B., Benza R., Sall K.N., Walker G.A., Semba C.P., Budenz D., Day D., Flowers B., Lee S., et al. Long-Term Safety and Efficacy of a Sustained-Release Bimatoprost Ocular Ring. Ophthalmology. 2017;124:1565–1566. doi: 10.1016/j.ophtha.2017.04.022. - DOI - PubMed
  105. Kouchak M., Malekahmadi M., Bavarsad N., Saki Malehi A., Andishmand L. Dorzolamide Nanoliposome as a Long Action Ophthalmic Delivery System in Open Angle Glaucoma and Ocular Hypertension Patients. Drug Dev. Ind. Pharm. 2018;44:1239–1242. doi: 10.1080/03639045.2017.1386196. - DOI - PubMed
  106. Salama H.A., Ghorab M., Mahmoud A.A., Abdel Hady M. PLGA Nanoparticles as Subconjunctival Injection for Management of Glaucoma. AAPS PharmSciTech. 2017;18:2517–2528. doi: 10.1208/s12249-017-0710-8. - DOI - PubMed
  107. Fan W., Song M., Li L., Niu L., Chen Y., Han B., Sun X., Yang Z., Lei Y., Chen X. Endogenous Dual Stimuli-Activated NO Generation in the Conventional Outflow Pathway for Precision Glaucoma Therapy. Biomaterials. 2021;277:121074. doi: 10.1016/j.biomaterials.2021.121074. - DOI - PubMed
  108. Desai A.R., Maulvi F.A., Desai D.M., Shukla M.R., Ranch K.M., Vyas B.A., Shah S.A., Sandeman S., Shah D.O. Multiple Drug Delivery from the Drug-Implants-Laden Silicone Contact Lens: Addressing the Issue of Burst Drug Release. Mater. Sci. Eng. C. 2020;112:110885. doi: 10.1016/j.msec.2020.110885. - DOI - PubMed
  109. Desai A.R., Maulvi F.A., Pandya M.M., Ranch K.M., Vyas B.A., Shah S.A., Shah D.O. Co-Delivery of Timolol and Hyaluronic Acid from Semi-Circular Ring-Implanted Contact Lenses for the Treatment of Glaucoma: In Vitro and in Vivo Evaluation. Biomater. Sci. 2018;6:1580–1591. doi: 10.1039/C8BM00212F. - DOI - PubMed
  110. Seal J.R., Robinson M.R., Burke J., Bejanian M., Coote M., Attar M. Intracameral Sustained-Release Bimatoprost Implant Delivers Bimatoprost to Target Tissues with Reduced Drug Exposure to Off-Target Tissues. J. Ocul. Pharmacol. Ther. 2019;35:50–57. doi: 10.1089/jop.2018.0067. - DOI - PMC - PubMed
  111. Park C.G., Choi G., Kim M.H., Kim S.-N., Lee H., Lee N.K., Choy Y.B., Choy J.-H. Brimonidine–Montmorillonite Hybrid Formulation for Topical Drug Delivery to the Eye. J. Mater. Chem. B. 2020;8:7914–7920. doi: 10.1039/D0TB01213K. - DOI - PubMed
  112. Yellanki S.K., Anna B., Kishan M.R. Preparation and in Vivo Evaluation of Sodium Alginate—Poly (Vinyl Alcohol) Electrospun Nanofibers of Forskolin for Glaucoma Treatment. Pak. J. Pharm. Sci. 2019;32:669–674. - PubMed
  113. Naik S., Pandey A., Lewis S.A., Rao B.S.S., Mutalik S. Neuroprotection: A Versatile Approach to Combat Glaucoma. Eur. J. Pharmacol. 2020;881:173208. doi: 10.1016/j.ejphar.2020.173208. - DOI - PubMed
  114. Lou X., Hu Y., Zhang H., Liu J., Zhao Y. Polydopamine Nanoparticles Attenuate Retina Ganglion Cell Degeneration and Restore Visual Function after Optic Nerve Injury. J. Nanobiotechnol. 2021;19:436. doi: 10.1186/s12951-021-01199-3. - DOI - PMC - PubMed
  115. Yang J.-Y., Lu B., Feng Q., Alfaro J.S., Chen P.-H., Loscalzo J., Wei W.-B., Zhang Y.-Y., Lu S.-J., Wang S. Retinal Protection by Sustained Nanoparticle Delivery of Oncostatin M and Ciliary Neurotrophic Factor Into Rodent Models of Retinal Degeneration. Transl. Vis. Sci. Technol. 2021;10:6. doi: 10.1167/tvst.10.9.6. - DOI - PMC - PubMed
  116. Rodrigo M.J., Cardiel M.J., Fraile J.M., Mendez-Martinez S., Martinez-Rincon T., Subias M., Polo V., Ruberte J., Ramirez T., Vispe E., et al. Brimonidine-LAPONITE® Intravitreal Formulation Has an Ocular Hypotensive and Neuroprotective Effect throughout 6 Months of Follow-up in a Glaucoma Animal Model. Biomater. Sci. 2020;8:6246–6260. doi: 10.1039/D0BM01013H. - DOI - PubMed
  117. Giannaccini M., Usai A., Chiellini F., Guadagni V., Andreazzoli M., Ori M., Pasqualetti M., Dente L., Raffa V. Neurotrophin-Conjugated Nanoparticles Prevent Retina Damage Induced by Oxidative Stress. Cell Mol. Life Sci. 2018;75:1255–1267. doi: 10.1007/s00018-017-2691-x. - DOI - PMC - PubMed
  118. García-Caballero C., Prieto-Calvo E., Checa-Casalengua P., García-Martín E., Polo-Llorens V., García-Feijoo J., Molina-Martínez I.T., Bravo-Osuna I., Herrero-Vanrell R. Six Month Delivery of GDNF from PLGA/Vitamin E Biodegradable Microspheres after Intravitreal Injection in Rabbits. Eur. J. Pharm. Sci. 2017;103:19–26. doi: 10.1016/j.ejps.2017.02.037. - DOI - PubMed
  119. Arranz-Romera A., Davis B.M., Bravo-Osuna I., Esteban-Pérez S., Molina-Martínez I.T., Shamsher E., Ravindran N., Guo L., Cordeiro M.F., Herrero-Vanrell R. Simultaneous Co-Delivery of Neuroprotective Drugs from Multi-Loaded PLGA Microspheres for the Treatment of Glaucoma. J. Control Release. 2019;297:26–38. doi: 10.1016/j.jconrel.2019.01.012. - DOI - PubMed
  120. Brugnera M., Vicario-de-la-Torre M., Andrés-Guerrero V., Bravo-Osuna I., Molina-Martínez I.T., Herrero-Vanrell R. Validation of a Rapid and Easy-to-Apply Method to Simultaneously Quantify Co-Loaded Dexamethasone and Melatonin PLGA Microspheres by HPLC-UV: Encapsulation Efficiency and In Vitro Release. Pharmaceutics. 2022;14:288. doi: 10.3390/pharmaceutics14020288. - DOI - PMC - PubMed
  121. Ding Y., Chow S.H., Chen J., Brun A.P.L., Wu C.-M., Duff A.P., Wang Y., Song J., Wang J.-H., Wong V.H.Y., et al. Targeted Delivery of LM22A-4 by Cubosomes Protects Retinal Ganglion Cells in an Experimental Glaucoma Model. Acta Biomater. 2021;126:433–444. doi: 10.1016/j.actbio.2021.03.043. - DOI - PubMed
  122. Luo L.-J., Nguyen D.D., Lai J.-Y. Benzoic Acid Derivative-Modified Chitosan-g-Poly(N-Isopropylacrylamide): Methoxylation Effects and Pharmacological Treatments of Glaucoma-Related Neurodegeneration. J. Control Release. 2020;317:246–258. doi: 10.1016/j.jconrel.2019.11.038. - DOI - PubMed
  123. Nguyen D.D., Luo L., Lai J. Dendritic Effects of Injectable Biodegradable Thermogels on Pharmacotherapy of Inflammatory Glaucoma-Associated Degradation of Extracellular Matrix. Adv. Healthc. Mater. 2019;8:1900702. doi: 10.1002/adhm.201900702. - DOI - PubMed
  124. Kabiri M., Kamal S.H., Pawar S.V., Roy P.R., Derakhshandeh M., Kumar U., Hatzikiriakos S.G., Hossain S., Yadav V.G. A Stimulus-Responsive, in Situ-Forming, Nanoparticle-Laden Hydrogel for Ocular Drug Delivery. Drug Deliv. Transl. Res. 2018;8:484–495. doi: 10.1007/s13346-018-0504-x. - DOI - PMC - PubMed
  125. Taskar P.S., Patil A., Lakhani P., Ashour E., Gul W., ElSohly M.A., Murphy B., Majumdar S. Δ9-Tetrahydrocannabinol Derivative-Loaded Nanoformulation Lowers Intraocular Pressure in Normotensive Rabbits. Transl. Vis. Sci. Technol. 2019;8:15. doi: 10.1167/tvst.8.5.15. - DOI - PMC - PubMed
  126. El-Salamouni N.S., Farid R.M., El-Kamel A.H., El-Gamal S.S. Nanostructured Lipid Carriers for Intraocular Brimonidine Localisation: Development, in-Vitro and in-Vivo Evaluation. J. Microencapsul. 2018;35:102–113. doi: 10.1080/02652048.2018.1425753. - DOI - PubMed
  127. Sánchez-López E., Egea M.A., Davis B.M., Guo L., Espina M., Silva A.M., Calpena A.C., Souto E.M.B., Ravindran N., Ettcheto M., et al. Memantine-Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma. Small. 2018;14:1701808. doi: 10.1002/smll.201701808. - DOI - PubMed
  128. Narsineni L., Rao P.P.N., Pham A.T., Foldvari M. Peptide-Modified Gemini Surfactants as Delivery System Building Blocks with Dual Functionalities for Glaucoma Treatment: Gene Carriers and Amyloid-Beta (Aβ) Self-Aggregation Inhibitors. Mol. Pharm. 2022;19:2737–2753. doi: 10.1021/acs.molpharmaceut.2c00088. - DOI - PubMed
  129. Alqawlaq S., Sivak J.M., Huzil J.T., Ivanova M.V., Flanagan J.G., Beazely M.A., Foldvari M. Preclinical Development and Ocular Biodistribution of Gemini-DNA Nanoparticles after Intravitreal and Topical Administration: Towards Non-Invasive Glaucoma Gene Therapy. Nanomed. Nanotechnol. Biol. Med. 2014;10:1637–1647. doi: 10.1016/j.nano.2014.05.010. - DOI - PubMed
  130. Wang L., Mao X. Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications. Int. J. Mol. Sci. 2021;22:2360. doi: 10.3390/ijms22052360. - DOI - PMC - PubMed
  131. Li T., Wang Y., Chen J., Gao X., Pan S., Su Y., Zhou X. Co-Delivery of Brinzolamide and MiRNA-124 by Biodegradable Nanoparticles as a Strategy for Glaucoma Therapy. Drug Deliv. 2020;27:410–421. doi: 10.1080/10717544.2020.1731861. - DOI - PMC - PubMed
  132. Zhao L., Chen G., Li J., Fu Y., Mavlyutov T.A., Yao A., Nickells R.W., Gong S., Guo L.-W. An Intraocular Drug Delivery System Using Targeted Nanocarriers Attenuates Retinal Ganglion Cell Degeneration. J. Control Release. 2017;247:153–166. doi: 10.1016/j.jconrel.2016.12.038. - DOI - PMC - PubMed
  133. Silva B., Gonçalves L.M., Braz B.S., Delgado E. Chitosan and Hyaluronic Acid Nanoparticles as Vehicles of Epoetin Beta for Subconjunctival Ocular Delivery. Mar. Drugs. 2022;20:151. doi: 10.3390/md20020151. - DOI - PMC - PubMed
  134. Hsueh H.T., Kim Y.-C., Pitha I., Shin M.D., Berlinicke C.A., Chou R.T., Kimball E., Schaub J., Quillen S., Leo K.T., et al. Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells. Pharmaceutics. 2021;13:647. doi: 10.3390/pharmaceutics13050647. - DOI - PMC - PubMed
  135. Khatib T.Z., Martin K.R. Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine. Curr. Eye Res. 2020;45:327–338. doi: 10.1080/02713683.2019.1663385. - DOI - PubMed
  136. Ghosn C., Rajagopalan L., Ugarte S., Mistry S., Orilla W., Goodkin M.L., Robinson M.R., Engles M., Dibas M. Intraocular Pressure-Lowering Efficacy of a Sustained-Release Bimatoprost Implant in Dog Eyes Pretreated with Selective Laser Trabeculoplasty. J. Ocul. Pharmacol. Ther. 2022;38:311–318. doi: 10.1089/jop.2021.0104. - DOI - PMC - PubMed
  137. Andrés-Guerrero V., Camacho-Bosca I., Salazar-Quiñones L., Ventura-Abreu N., Molero-Senosiain M., Hernández-Ruiz S., Bernal-Sancho G., Herrero-Vanrell R., García-Feijóo J. The Effect of a Triple Combination of Bevacizumab, Sodium Hyaluronate and a Collagen Matrix Implant in a Trabeculectomy Animal Model. Pharmaceutics. 2021;13:896. doi: 10.3390/pharmaceutics13060896. - DOI - PMC - PubMed
  138. Vildanova R., Lobov A., Spirikhin L., Kolesov S. Hydrogels on the Base of Modified Chitosan and Hyaluronic Acid Mix as Polymer Matrices for Cytostatics Delivery. Gels. 2022;8:104. doi: 10.3390/gels8020104. - DOI - PMC - PubMed
  139. Qiao X., Peng X., Qiao J., Jiang Z., Han B., Yang C., Liu W. Evaluation of a Photocrosslinkable Hydroxyethyl Chitosan Hydrogel as a Potential Drug Release System for Glaucoma Surgery. J. Mater. Sci. Mater. Med. 2017;28:149. doi: 10.1007/s10856-017-5954-z. - DOI - PubMed
  140. Chun Y.Y., Yap Z.L., Seet L.F., Chan H.H., Toh L.Z., Chu S.W.L., Lee Y.S., Wong T.T., Tan T.T.Y. Positive-Charge Tuned Gelatin Hydrogel-SiSPARC Injectable for SiRNA Anti-Scarring Therapy in Post Glaucoma Filtration Surgery. Sci. Rep. 2021;11:1470. doi: 10.1038/s41598-020-80542-4. - DOI - PMC - PubMed
  141. Seet L.F., Tan Y.F., Toh L.Z., Chu S.W., Lee Y.S., Venkatraman S.S., Wong T.T. Targeted Therapy for the Post-Operative Conjunctiva: SPARC Silencing Reduces Collagen Deposition. Br. J. Ophthalmol. 2018;102:1460–1470. doi: 10.1136/bjophthalmol-2018-311937. - DOI - PMC - PubMed
  142. Jóhannesson G., Gottfredsdóttir M.S., Ásgrimsdóttir G.M., Loftsson T., Stefánsson E. Can Postoperative Dexamethasone Nanoparticle Eye Drops Replace Mitomycin C in Trabeculectomy? Acta Ophthalmol. 2020;98:607–612. doi: 10.1111/aos.14370. - DOI - PubMed
  143. Swann F.B., Singh S., Blake D., John V., Le C., Fullerton M., Margo C., Zhang Z., Muddasani N., Wall J., et al. Effect of 2 Novel Sustained-Release Drug Release Systems on Bleb Fibrosis: An In Vivo Trabeculectomy Study in a Rabbit Model. J. Glaucoma. 2019;28:512–518. doi: 10.1097/IJG.0000000000001215. - DOI - PubMed
  144. Goldberg D.F., Malhotra R.P., Schechter B.A., Justice A., Weiss S.L., Sheppard J.D. A Phase 3, Randomized, Double-Masked Study of OTX-101 Ophthalmic Solution 0.09% in the Treatment of Dry Eye Disease. Ophthalmology. 2019;126:1230–1237. doi: 10.1016/j.ophtha.2019.03.050. - DOI - PubMed
  145. Schopf L., Enlow E., Popov A., Bourassa J., Chen H. Ocular Pharmacokinetics of a Novel Loteprednol Etabonate 0.4% Ophthalmic Formulation. Ophthalmol. Ther. 2014;3:63–72. doi: 10.1007/s40123-014-0021-z. - DOI - PMC - PubMed
  146. Compositions and Methods for Ophthalmic and/or Other Applications—Patent US-10857096-B2—PubChem. [(accessed on 24 February 2023)]; Available online: https://pubchem.ncbi.nlm.nih.gov/patent/US-10857096-B2.
  147. Korenfeld M., Nichols K.K., Goldberg D., Evans D., Sall K., Foulks G., Coultas S., Brazzell K. Safety of KPI-121 Ophthalmic Suspension 0.25% in Patients With Dry Eye Disease: A Pooled Analysis of 4 Multicenter, Randomized, Vehicle-Controlled Studies. Cornea. 2021;40:564–570. doi: 10.1097/ICO.0000000000002452. - DOI - PubMed
  148. Gupta P.K., Venkateswaran N. The Role of KPI-121 0.25% in the Treatment of Dry Eye Disease: Penetrating the Mucus Barrier to Treat Periodic Flares. Ther. Adv. Ophthalmol. 2021;13:251584142110127. doi: 10.1177/25158414211012797. - DOI - PMC - PubMed
  149. Escobar-Chávez J.J., López-Cervantes M., Naik A., Kalia Y., Quintanar-Guerrero D., Ganem-Quintanar A. Applications of Thermo-Reversible Pluronic F-127 Gels in Pharmaceutical Formulations. J. Pharm. Pharm. Sci. 2006;9:339. - PubMed
  150. Mun J., won Mok J., Jeong S., Cho S., Joo C.-K., Hahn S.K. Drug-Eluting Contact Lens Containing Cyclosporine-Loaded Cholesterol-Hyaluronate Micelles for Dry Eye Syndrome. RSC Adv. 2019;9:16578–16585. doi: 10.1039/C9RA02858G. - DOI - PMC - PubMed
  151. Nagai N., Ishii M., Seiriki R., Ogata F., Otake H., Nakazawa Y., Okamoto N., Kanai K., Kawasaki N. Novel Sustained-Release Drug Delivery System for Dry Eye Therapy by Rebamipide Nanoparticles. Pharmaceutics. 2020;12:155. doi: 10.3390/pharmaceutics12020155. - DOI - PMC - PubMed
  152. Qiao H., Xu Z., Sun M., Fu S., Zhao F., Wang D., He Z., Zhai Y., Sun J. Rebamipide Liposome as an Effective Ocular Delivery System for the Management of Dry Eye Disease. J. Drug Deliv. Sci. Technol. 2022;75:103654. doi: 10.1016/j.jddst.2022.103654. - DOI
  153. Wang S., Wang M., Liu Y., Hu D., Gu L., Fei X., Zhang J. Effect of Rapamycin Microspheres in Sjögren Syndrome Dry Eye: Preparation and Outcomes. Ocul. Immunol. Inflamm. 2019;27:1357–1364. doi: 10.1080/09273948.2018.1527369. - DOI - PubMed
  154. Luo L.-J., Nguyen D.D., Lai J.-Y. Long-Acting Mucoadhesive Thermogels for Improving Topical Treatments of Dry Eye Disease. Mater. Sci. Eng. C Mater. Biol. Appl. 2020;115:111095. doi: 10.1016/j.msec.2020.111095. - DOI - PubMed
  155. Dünnhaupt S., Kammona O., Waldner C., Kiparissides C., Bernkop-Schnürch A. Nano-Carrier Systems: Strategies to Overcome the Mucus Gel Barrier. Eur. J. Pharm. Biopharm. 2015;96:447–453. doi: 10.1016/j.ejpb.2015.01.022. - DOI - PubMed
  156. Nepp J., Knoetzl W., Prinz A., Hoeller S., Prinz M. Management of Moderate-to-Severe Dry Eye Disease Using Chitosan-N-Acetylcysteine (Lacrimera®) Eye Drops: A Retrospective Case Series. Int. Ophthalmol. 2020;40:1547–1552. doi: 10.1007/s10792-020-01324-5. - DOI - PMC - PubMed
  157. Puri V., Sharma A., Kumar P., Singh I. Thiolation of Biopolymers for Developing Drug Delivery Systems with Enhanced Mechanical and Mucoadhesive Properties: A Review. Polymers. 2020;12:1803. doi: 10.3390/polym12081803. - DOI - PMC - PubMed
  158. Sheng Y., Sun X., Han J., Hong W., Feng J., Xie S., Li Y., Yan F., Li K., Tian B. N-Acetylcysteine Functionalized Chitosan Oligosaccharide-Palmitic Acid Conjugate Enhances Ophthalmic Delivery of Flurbiprofen and Its Mechanisms. Carbohydr. Polym. 2022;291:119552. doi: 10.1016/j.carbpol.2022.119552. - DOI - PubMed
  159. Bachu R.D., Chowdhury P., Al-Saedi Z.H.F., Karla P.K., Boddu S.H.S. Ocular Drug Delivery Barriers—Role of Nanocarriers in the Treatment of Anterior Segment Ocular Diseases. Pharmaceutics. 2018;10:28. doi: 10.3390/pharmaceutics10010028. - DOI - PMC - PubMed
  160. Bu J., Wu Y., Cai X., Jiang N., Jeyalatha M.V., Yu J., He X., He H., Guo Y., Zhang M., et al. Hyperlipidemia Induces Meibomian Gland Dysfunction. Ocul. Surf. 2019;17:777–786. doi: 10.1016/j.jtos.2019.06.002. - DOI - PubMed
  161. Seen S., Tong L. Dry Eye Disease and Oxidative Stress. Acta Ophthalmol. 2018;96:e412–e420. doi: 10.1111/aos.13526. - DOI - PubMed
  162. Choi S.W., Cha B.G., Kim J. Therapeutic Contact Lens for Scavenging Excessive Reactive Oxygen Species on the Ocular Surface. ACS Nano. 2020;14:2483–2496. doi: 10.1021/acsnano.9b10145. - DOI - PubMed
  163. Jo Y.J., Lee J.E., Lee J.S. Clinical Efficacy of 0.05% Cyclosporine Nano-Emulsion in the Treatment of Dry Eye Syndrome Associated with Meibomian Gland Dysfunction. Int. J. Ophthalmol. 2022;15:1924–1931. doi: 10.18240/ijo.2022.12.05. - DOI - PMC - PubMed
  164. Leonardi A., Doan S., Amrane M., Ismail D., Montero J., Németh J., Aragona P., Bremond-Gignac D., VEKTIS Study Group A Randomized, Controlled Trial of Cyclosporine A Cationic Emulsion in Pediatric Vernal Keratoconjunctivitis: The VEKTIS Study. Ophthalmology. 2019;126:671–681. doi: 10.1016/j.ophtha.2018.12.027. - DOI - PubMed
  165. Sun K., Hu K. Preparation and Characterization of Tacrolimus-Loaded SLNs in Situ Gel for Ocular Drug Delivery for the Treatment of Immune Conjunctivitis. Drug Des. Devel. Ther. 2021;15:141–150. doi: 10.2147/DDDT.S287721. - DOI - PMC - PubMed
  166. Mirzaeei S., Taghe S., Asare-Addo K., Nokhodchi A. Polyvinyl Alcohol/Chitosan Single-Layered and Polyvinyl Alcohol/Chitosan/Eudragit RL100 Multi-Layered Electrospun Nanofibers as an Ocular Matrix for the Controlled Release of Ofloxacin: An In Vitro and In Vivo Evaluation. AAPS PharmSciTech. 2021;22:170. doi: 10.1208/s12249-021-02051-5. - DOI - PMC - PubMed
  167. Deepthi S., Jose J. Novel Hydrogel-Based Ocular Drug Delivery System for the Treatment of Conjunctivitis. Int. Ophthalmol. 2019;39:1355–1366. doi: 10.1007/s10792-018-0955-6. - DOI - PubMed
  168. Aytekin E., Öztürk N., Vural İ., Polat H.K., Çakmak H.B., Çalış S., Pehlivan S.B. Design of Ocular Drug Delivery Platforms and in Vitro–in Vivo Evaluation of Riboflavin to the Cornea by Non-Interventional (Epi-on) Technique for Keratoconus Treatment. J. Control Release. 2020;324:238–249. doi: 10.1016/j.jconrel.2020.05.017. - DOI - PubMed
  169. Wo N., Zhai J. Combinatorial Therapeutic Drug Delivery of Riboflavin and Dexamethasone for the Treatment of Keratoconus Affected Corneas of Mice: Ex Vivo Permeation and Hemolytic Toxicity. Micro Nano Lett. 2021;16:492–499. doi: 10.1049/mna2.12079. - DOI
  170. Varela-Fernández R., García-Otero X., Díaz-Tomé V., Regueiro U., López-López M., González-Barcia M., Lema M.I., Otero-Espinar F.J. Design, Optimization, and Characterization of Lactoferrin-Loaded Chitosan/TPP and Chitosan/Sulfobutylether-β-Cyclodextrin Nanoparticles as a Pharmacological Alternative for Keratoconus Treatment. ACS Appl. Mater. Interfaces. 2021;13:3559–3575. doi: 10.1021/acsami.0c18926. - DOI - PubMed
  171. Chou T.Y., Hong B.Y. Ganciclovir Ophthalmic Gel 0.15% for the Treatment of Acute Herpetic Keratitis: Background, Effectiveness, Tolerability, Safety, and Future Applications. Ther. Clin. Risk Manag. 2014;10:665–681. doi: 10.2147/TCRM.S58242. - DOI - PMC - PubMed
  172. Colin J. Ganciclovir Ophthalmic Gel, 0.15%: A Valuable Tool for Treating Ocular Herpes. Clin. Ophthalmol. Auckl. NZ. 2007;1:441–453. - PMC - PubMed
  173. Yang X., Shah S.J., Wang Z., Agrahari V., Pal D., Mitra A.K. Nanoparticle-Based Topical Ophthalmic Formulation for Sustained Release of Stereoisomeric Dipeptide Prodrugs of Ganciclovir. Drug Deliv. 2016;23:2399–2409. doi: 10.3109/10717544.2014.996833. - DOI - PubMed
  174. Jain P., Jaiswal C.P., Mirza M.A., Anwer M.K., Iqbal Z. Preparation of Levofloxacin Loaded in Situ Gel for Sustained Ocular Delivery: In Vitro and Ex Vivo Evaluations. Drug Dev. Ind. Pharm. 2020;46:50–56. doi: 10.1080/03639045.2019.1698598. - DOI - PubMed
  175. Roy G., Galigama R.D., Thorat V.S., Mallela L.S., Roy S., Garg P., Venuganti V.V.K. Amphotericin B Containing Microneedle Ocular Patch for Effective Treatment of Fungal Keratitis. Int. J. Pharm. 2019;572:118808. doi: 10.1016/j.ijpharm.2019.118808. - DOI - PubMed
  176. Sebastián-Morelló M., Calatayud-Pascual M.A., Rodilla V., Balaguer-Fernández C., López-Castellano A. Ex Vivo Rabbit Cornea Diffusion Studies with a Soluble Insert of Moxifloxacin. Drug Deliv. Transl. Res. 2018;8:132–139. doi: 10.1007/s13346-017-0443-y. - DOI - PubMed
  177. Li J., Li Z., Liang Z., Han L., Feng H., He S., Zhang J. Fabrication of a Drug Delivery System That Enhances Antifungal Drug Corneal Penetration. Drug Deliv. 2018;25:938–949. doi: 10.1080/10717544.2018.1461278. - DOI - PMC - PubMed
  178. Titiyal J.S., Thangavel R., Kaur M., Venkatesh P., Velpandian T., Sinha R. Comparative Evaluation of Once-Daily and Twice-Daily Dosing of Topical Bromfenac 0.09%: Aqueous Pharmacokinetics and Clinical Efficacy Study. J. Cataract Refract. Surg. 2021;47:1115–1121. doi: 10.1097/j.jcrs.0000000000000589. - DOI - PubMed
  179. Neha K., Haider M.R., Pathak A., Yar M.S. Medicinal Prospects of Antioxidants: A Review. Eur. J. Med. Chem. 2019;178:687–704. doi: 10.1016/j.ejmech.2019.06.010. - DOI - PubMed
  180. Anbukkarasi M., Thomas P.A., Sheu J.-R., Geraldine P. In Vitro Antioxidant and Anticataractogenic Potential of Silver Nanoparticles Biosynthesized Using an Ethanolic Extract of Tabernaemontana Divaricata Leaves. Biomed. Pharmacother. Biomed. Pharmacother. 2017;91:467–475. doi: 10.1016/j.biopha.2017.04.079. - DOI - PubMed
  181. Chen H., Yang J., Sun L., Zhang H., Guo Y., Qu J., Jiang W., Chen W., Ji J., Yang Y.-W., et al. Synergistic Chemotherapy and Photodynamic Therapy of Endophthalmitis Mediated by Zeolitic Imidazolate Framework-Based Drug Delivery Systems. Small. 2019;15:e1903880. doi: 10.1002/smll.201903880. - DOI - PubMed
  182. Lee B., Lee M.J., Yun S.J., Kim K., Choi I.-H., Park S. Silver Nanoparticles Induce Reactive Oxygen Species-Mediated Cell Cycle Delay and Synergistic Cytotoxicity with 3-Bromopyruvate in Candida Albicans, but Not in Saccharomyces Cerevisiae. Int. J. Nanomed. 2019;14:4801–4816. doi: 10.2147/IJN.S205736. - DOI - PMC - PubMed
  183. Hanafy B.I. Ph.D. Thesis. Nottingham Trent University; Nottingham, UK: 2020. Formulation of Cerium Oxide Nanoparticles towards the Prevention and Treatment of Cataract.
  184. Zhu S., Gong L., Li Y., Xu H., Gu Z., Zhao Y. Safety Assessment of Nanomaterials to Eyes: An Important but Neglected Issue. Adv. Sci. 2019;6:1802289. doi: 10.1002/advs.201802289. - DOI - PMC - PubMed
  185. Liu Y., Dong Y., Pu X., Yin X. Fabrication of Anti-Oxidant Curcumin Loaded Ceria Nanoclusters for the Novel Delivery System to Prevention of Selenite-Induced Cataract Therapy in Alleviating Diabetic Cataract. Process Biochem. 2022;120:239–249. doi: 10.1016/j.procbio.2022.05.008. - DOI
  186. Li N., Zhao Z., Ma H., Liu Y., Nwafor E.-O., Zhu S., Jia L., Pang X., Han Z., Tian B., et al. Optimization and Characterization of Low-Molecular-Weight Chitosan-Coated Baicalin MPEG-PLGA Nanoparticles for the Treatment of Cataract. Mol. Pharm. 2022;19:3831–3845. doi: 10.1021/acs.molpharmaceut.2c00341. - DOI - PubMed
  187. Lan Q., Di D., Wang S., Zhao Q., Gao Y., Chang D., Jiang T. Chitosan-N-Acetylcysteine Modified HP-β-CD Inclusion Complex as a Potential Ocular Delivery System for Anti-Cataract Drug: Quercetin. J. Drug Deliv. Sci. Technol. 2020;55:101407. doi: 10.1016/j.jddst.2019.101407. - DOI
  188. Bodoki E., Vostinaru O., Samoila O., Dinte E., Bodoki A.E., Swetledge S., Astete C.E., Sabliov C.M. Topical Nanodelivery System of Lutein for the Prevention of Selenite-Induced Cataract. Nanomed. Nanotechnol. Biol. Med. 2019;15:188–197. doi: 10.1016/j.nano.2018.09.016. - DOI - PubMed
  189. Tauber J., Schechter B.A., Bacharach J., Toyos M.M., Smyth-Medina R., Weiss S.L., Luchs J.I. A Phase II/III, Randomized, Double-Masked, Vehicle-Controlled, Dose-Ranging Study of the Safety and Efficacy of OTX-101 in the Treatment of Dry Eye Disease. Clin. Ophthalmol. 2018;12:1921–1929. doi: 10.2147/OPTH.S175065. - DOI - PMC - PubMed
  190. Han Y., Jiang L., Shi H., Xu C., Liu M., Li Q., Zheng L., Chi H., Wang M., Liu Z., et al. Effectiveness of an Ocular Adhesive Polyhedral Oligomeric Silsesquioxane Hybrid Thermo-Responsive FK506 Hydrogel in a Murine Model of Dry Eye. Bioact. Mater. 2022;9:77–91. doi: 10.1016/j.bioactmat.2021.07.027. - DOI - PMC - PubMed
  191. Peng W., Chen R., Dai H., Zhu L., Li Y., Gao Z., Li X., Zhou S. Efficacy, Safety, and Tolerability of a Novel Cyclosporine, a Formulation for Dry Eye Disease: A Multicenter Phase II Clinical Study. Clin. Ther. 2021;43:613–628. doi: 10.1016/j.clinthera.2020.12.023. - DOI - PubMed
  192. Mahmoud D.B., Afifi S.A., El Sayed N.S. Crown Ether Nanovesicles (Crownsomes) Repositioned Phenytoin for Healing of Corneal Ulcers. Mol. Pharm. 2020;17:3952–3965. doi: 10.1021/acs.molpharmaceut.0c00742. - DOI - PubMed
  193. Terreni E., Burgalassi S., Chetoni P., Tampucci S., Zucchetti E., Fais R., Ghelardi E., Lupetti A., Monti D. Development and Characterization of a Novel Peptide-Loaded Antimicrobial Ocular Insert. Biomolecules. 2020;10:664. doi: 10.3390/biom10050664. - DOI - PMC - PubMed
  194. Eid H.M., Elkomy M.H., El Menshawe S.F., Salem H.F. Development, Optimization, and In Vitro/In Vivo Characterization of Enhanced Lipid Nanoparticles for Ocular Delivery of Ofloxacin: The Influence of Pegylation and Chitosan Coating. AAPS PharmSciTech. 2019;20:183. doi: 10.1208/s12249-019-1371-6. - DOI - PubMed
  195. Peng K., Vora L.K., Tekko I.A., Permana A.D., Domínguez-Robles J., Ramadon D., Chambers P., McCarthy H.O., Larrañeta E., Donnelly R.F. Dissolving Microneedle Patches Loaded with Amphotericin B Microparticles for Localised and Sustained Intradermal Delivery: Potential for Enhanced Treatment of Cutaneous Fungal Infections. J. Control Release. 2021;339:361–380. doi: 10.1016/j.jconrel.2021.10.001. - DOI - PubMed
  196. Khames A., Khaleel M.A., El-Badawy M.F., El-Nezhawy A.O.H. Natamycin Solid Lipid Nanoparticles-Sustained Ocular Delivery System of Higher Corneal Penetration against Deep Fungal Keratitis: Preparation and Optimization. Int. J. Nanomed. 2019;14:2515–2531. doi: 10.2147/IJN.S190502. - DOI - PMC - PubMed
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback