A Paradigm Shift in Ocular Drug Delivery to Posterior Segment: Review on Current Drug Delivery Approaches

Objectives: Owing to the increasing number of patients suffering from posterior eye disorders, efficient medicine delivery to the posterior segment is now in great demand in the clinical services. With unmet medical requirements, the posterior eye segment is an important therapeutic target. So, physicians should be informed of new indications and current strategies of drug delivery when new technologies enter the market. Summary: The most common causes of vision impairment in developed nations are abnormalities of the posterior eye tissues. Poor drug distribution to lesions in patient's eyes is a key barrier to ocular disease therapy. The existence of barriers, such as the corneal barrier, aqueous barrier, and inner and outer blood-retinal barriers, severely limits medication accessibility in these locations. Because of its anatomical peculiarities, the posterior portion is particularly difficult to access for medications. The use of several new strategies for drug delivery is therefore a viable option for enhanced therapy of ocular disorders since recent advances in ocular drug delivery systems research have brought fresh insights into drug development. Conclusion: This article provides an overview of several aspects of ocular medication Review Article Koduru et al.; JPRI, 33(40A): 106-119, 2021; Article no.JPRI.72133 107 administration to the posterior region, with a focus on nano carrier-based approaches, suprachoroidal drug delivery system and ophthalmic devices, including the structure of the eye, its barriers, delivery routes, and the present status of drugs/devices.


INTRODUCTION
Pharmaceutical scientists are faced with one of the most appealing and hard endeavours: ophthalmic medication delivery. The eye is a multi-compartmental, tiny organ. Its anatomy, physiology, and biochemistry made it highly impervious to xenobiotics [1].
Of the total ocular diseases, 55% are posterior segment diseases, while these diseases may lead to permanent vision loss if left untreated. The number of diseases affecting the posterior eye segment is expanding at an alarming rate [2]. In industrialized countries, posterior segment ocular disorders are the most common cause of vision impairment. These diseases include, for example, age-related macular degeneration and diabetic retinopathy [3].
Over the last few decades, significant progress has been made in research, particularly in the development of advanced drug delivery systems aimed at delivering ocular therapeutics to target sites in an optimized and controlled manner, either by increasing penetration across mucosa or by extending the contact time of the carrier with the ocular surface. Emerging new controlled drug delivery systems such as dendrimers, microemulsions, mucoadhesive polymers, hydrogels, iontophoretic drug delivery, laser therapy along with sclera plugs, non-viral gene therapy, stem cells technology, and s-RNA based approaches are also developed. Advancement in material sciences and formulations has provided new exciting possibilities to deliver drugs to the posterior segment of the eye as well [1]. This review will give an update on recent case reports and updates on the recent progress and trends in ocular drug delivery systems.

The Anatomy and Physiology
The human eye is a globular structural organ that is around 24 mm in diameter. It generates a 3D mobile image that is frequently colored in natural light. The retina's cone cells and rod cells aid in light detection and visual perception. Colors can be distinguished and depth perception can be discerned. It is divided into two sections: the anterior and posterior regions [4]. The eyeball is made up of three translucent layers: the outer coat, the tunica media, and the intima. The sclera is a tough tissue that runs from the back of the eye to the front, producing the cornea, which is transparent. The uveal coat in the middle is primarily made up of cribriform tissue that is densely vascularized and pigmented, and it is separated into three sections: the iris in front, the choroid in the back, and the ciliary body in between. The visual receptor is hidden behind the retina, which is a highly specialized neuronal membrane. In front of the ciliary body, it atrophies [5].
The cornea, which is roughly 0.5 mm thick and 11.5 mm in diameter, is connected to the larger posterior part, which includes the retina, vitreous humor, choroid, and the outermost white shell known as the sclera, by a distinct curve. With a diameter of around 24 mm, the posterior component makes up the remaining five-sixths [6]. The limbus is a connective tissue that connects the sclera and cornea. The iris is the pigmented framework around the eye center and the darkly colored pupil. The iris dilator and muscles in the sphincter govern the size of the pupil, which controls the amount of light that enters the eyes [1].

Ocular Pharmacokinetics: Barriers in Drug Delivery
Drugs can be administered locally or systemically to reach the ocular tissues. Drugs can't get to their targets because of tissue barriers (Fig. 1). The ocular surface is protected by corneal and conjunctival epithelial barriers. The bloodaqueous barrier, which is made up of uveal capillary endothelia and ciliary epithelia, prevents chemicals from entering the anterior chamber from the systemic circulation, whereas the bloodretina barrier prevents drug diffusion from the systemic blood into the retina and vice versa. The outer and inner blood-retina barriers, created by the retinal pigment epithelium (RPE) and the tight retinal capillary walls, respectively, make up the barrier [3]. The physicochemical features of the medication, its removal from fluid, corneal barriers, and non absorption are the key obstacles and deciding variables in ocular drug delivery. The route and rate of penetration in the cornea are further affected by lipophilicity, solubility, molecule size and shape, charge, and degree of ionization. The penetration of ionizable drugs, such as weak acid and weak bases, is influenced by the chemical balance between ionized and unionized drugs.
Tight junctions act as a selective barrier for tiny molecules, preventing macromolecules from diffusing through the paracellular pathway. The rate-limiting barrier for ocular absorption of most lipophilic medicines is the hydrophilic corneal stroma. Topically administered ocular medications that are not absorbed by the corneal pathway may be absorbed by non routes, resulting in drug loss at the targeted spot [1].
Tears consist of proteins and mucins that attach to drug molecules, lowering the effective concentration of medication in contact with the cornea. This has a detrimental impact bioavailability. The physicochemical features of the medication, its removal from the lacrimal fluid, corneal barriers, and non-corneal absorption are the key obstacles and deciding variables in ocular drug delivery. The route and rate of penetration in the cornea are further affected by lipophilicity, solubility, molecule size e, charge, and degree of ionization. The penetration of ionizable drugs, such as weak acid and weak bases, is influenced by the chemical balance between ionized and unionized drugs.
Tight junctions act as a selective barrier for tiny macromolecules from diffusing through the paracellular pathway. The limiting barrier for ocular absorption of most lipophilic medicines is the hydrophilic corneal stroma.
Topically administered ocular medications that are not absorbed by the corneal pathway may be absorbed by non-corneal routes, resulting in drug loss at the targeted spot Tears consist of proteins and mucins that attach to drug molecules, lowering the effective concentration of medication in contact with the cornea. This has a detrimental impact on drug The blood-aqueous and blood-retina barriers are the two primary barriers in the intraocular environment. These two components prevent molecules from penetrating the eye chamber, resulting in ineffective intraocular tissue treatment [6].
The blood-ocular barrier (BOB) has purposes: it keeps infections out of the eye, regulates tissue/fluid composition, and creates aqueous-humor. The blood-aqueous barrier is formed by tight junctions at the level of the iris vascular epithelium and non-pigmented ciliary epithelium, while the blood-retinal barrier is formed by tight junctions at the retinal pigment epithelium (RPE) and vascular endothelium levels [7] The BOB not only prevents germs from entering the eye but also prevents from entering. Surgery, uveitis, diabetes, and ocular infection, as well as specific therapies like photocoagulation and cryopexy, can all compromise this barrier. When the BOB fails, medicines can more readily enter and exit the eye; Starling forces (forces that govern fluid balance) can change, producing macular edema; and serum can leak into the eye, causing cellular proliferation and aqueous hyposecretion [8].
(1) Trans-corneal permeation from the lachrymal fluid into the anterior chamber, (2) noncorneal permeation across conjunctiva and sclera into anterior uvea, (3) distribution of drug from the bloodstream through the blood barrier into the anterior chamber, (4) drug elimination from the anterior chamber by aqueous humor passage into the trabecular meshwork and canal of Schlemm, (5) elimination of the drug from aqueous humor into the systemic circulation across the blood-aqueous barrier, (6) distribution of drug from blood into posterior eye across the blood barrier, (7) intravitreal drug administration, (8) elimination of drug from vitreous through the posterior route across the blood-retina barrier, and (9) drug from vitreous through anterior route to the posterior chamber.
; Article no.JPRI.72133 retina barriers are the two primary barriers in the intraocular environment. These two components prevent molecules from penetrating the eye chamber, resulting in ineffective intraocular tissue ocular barrier (BOB) has three major purposes: it keeps infections out of the eye, regulates tissue/fluid composition, and creates aqueous barrier is formed by tight junctions at the level of the iris pigmented ciliary retinal barrier is formed by tight junctions at the retinal pigment epithelium (RPE) and vascular endothelium The BOB not only prevents germs from entering the eye but also prevents medications from entering. Surgery, uveitis, diabetes, and ocular infection, as well as specific therapies like photocoagulation and cryopexy, can all compromise this barrier. When the BOB fails, medicines can more readily enter and exit the forces (forces that govern fluid balance) can change, producing macular edema; and serum can leak into the eye, causing cellular proliferation and aqueous hyposecretion corneal permeation from the lachrymal fluid into the anterior chamber, noncorneal permeation across conjunctiva and sclera into anterior uvea, (3) distribution of drug from the bloodstream through the blood-aqueous barrier into the anterior chamber, (4) drug elimination from the anterior chamber by the trabecular meshwork and canal of Schlemm, (5) elimination of the drug from aqueous humor into the systemic aqueous barrier, (6) distribution of drug from blood into posterior eye across the blood-retina treal drug administration, (8) elimination of drug from vitreous through the posterior route across the retina barrier, and (9) drug from vitreous through anterior route to the

Strategies for Delivering Drugs to the Posterior Segment
There are three techniques of delivering medications to the eye from a conceptual standpoint: 1. Distribute vast amounts of medicines throughout the body Drugs are usually given systemically in doses that are theoretically large enough to reach therapeutic levels in the eye. In reality, however, the BOB limits the number of medications that reach the posterior segment, necessitating systemic administration of extremely large dosages to obtain even borderline therapeutic retinal drug levels. The systemic toxicity related to the relatively high systemic medication levels required to overcome the BOB is typically a limiting issue in this strategy.

Introduce modifications to the BOB
Modifying the permeability of the BOB to allow better drug penetrance and access to specific medications and substances [e.g., histamines, bradykinin agonists, and vascular endothelial growth factor (VEGF)] that can enhance vascular permeability is the second route to drug administration. This method is rarely employed.

Drugs are delivered locally to the eye
The third technique entails delivering medications to the target tissues on a local level. There is evidence that local medication delivery to the posterior segment is the most successful technique for treating posterior segment disorders, and this is the strategy that is most usually employed in clinical practice [8].

CURRENT STATUS
Ocular drug delivery devices designed to maintain drug release are now available on the market or in clinical studies. The majority of them are used to treat long-term disorders of the eye's posterior portion. Macular degeneration, viral infections (such as CMV infections), glaucoma, ocular inflammations, dry eye syndrome, and retinal degenerations are all key indications for ocular drug delivery systems. The goal is to create a system that has increased ocular medication absorption and activity duration while posing a low risk of ocular problems.

Implants
Implants are effective drug delivery systems for chronic ocular diseases. Implants once adjusted, in the eye, prolonged the drug residence time to an appropriate time. They are commonly used for the treatment of ocular disorders such as cytomegalovirus (CMV) retinitis which is an ocular infection occurs in AIDS patient and one of the leading to blindness. Earlier, nonbiodegradable polymers were used but they needed surgical procedures for insertion and removal but now the trend has been changed to biodegradable ones. Biodegradable polymers such as PLA are safe and effective to deliver drugs in the vitreous cavity and show no toxic signs when inserted [7].
The implants have the advantages of (1) bypassing the blood-ocular barriers to delivering constant therapeutic levels of drug directly to the site of action, (2) avoiding the side effects associated with frequent systemic and intravitreal injections, and (3) requiring a smaller amount of drug during treatment [9]. The implants are always implanted intravitreally, in the pars plana of the eye (posterior to the lens and anterior to the retina), for intraocular delivery, which necessitates minimal surgery, some of the FDA approved implants are mentioned in Table 2 [3].

Microspheres
The medicament will be encapsulated in microparticles (1-1000 mm) or nanoparticles (1-1000 nm) using this carrier technology. Polymers that are biodegradable and biocompatible, such as polylactide and PLGA, which have both been approved by the FDA, are employed. These methods are primarily implanted through intravitreal injection, which is a less invasive method than surgery. They provide drugs for weeks or even months at a time, reducing the number of injections required [2]. Intravitreal injections of particle systems have the potential to produce vitreal clouding. Microparticles, on the other hand, tend to settle to the bottom of the vitreal cavity, but nanoparticles are more likely to induce clouding in the vitreous. It has been documented how erodible, non-erodible, and lipid microspheres can be used for ocular administration. In the polymer matrix, the drug is uniformly spread (monolithic system). As a result, the drug-loaded microparticles are suspended in a liquid carrier medium, which may also include the drug [10].
Sridhar Duvvuri et al., (2007) observed an ideal in vitro release of encapsulated ganciclovir was obtained by physically mixing microspheres prepared from different polymer blends before its dispersion in the thermo-gelling polymer. The formulation maintained mean vitreal concentrations of ganciclovir at approximately 0.8 micron/mL for 14 days, whereas direct injections could maintain drug levels above 0.8 microns/mL for 54 h only [11].  It is a corticosteroid intravitreal implant indicated for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.

Lipid nanoparticles
Three types of lipid nanoparticles, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and hybrid lipid nanoparticles are often used in the studies. The former two nanoparticle systems typically form a solid lipid core and have the capability of loading both lipophilic drugs and hydrophilic drugs into the lipid matrix. SLN is strictly made up of more than one solid lipids, whose melting point is above 40°C. SLN shows the advantages of controlled release dating from the early 1990s [14], reduced toxicity for cells, high compatibility, and in vivo tolerability [15]. NLC containing liquid lipids and solid lipids in their components appear with the advantages of higher drug-loading capacity, better stability during storage, and improved release properties compared to SLN. Nevertheless, hybrid lipid nanoparticles modified by multifunctional polymers [16], combine the merits of polymeric nanoparticles and lipid-based systems, which simultaneously improve pharmacokinetics and biodistribution of the loaded drug.
study is about Triamcinolone acetonide (TA) which is a corticosteroid drug currently administered by intravitreal injection for a broad spectrum of inflammatory, edematous, and angiogenic ocular diseases. To increase the drug's bioavailability by ocular instillation, TA was encapsulated in nanostructured lipid carriers (NLC), previously optimized by their group using a factorial design approach [19].

Nanoparticles
Polymeric nanoparticles of colloidal nanosized systems (1 nm<d<1000nm) are ideally appropriate for ocular medication administration to the required locations due to the variety of polymers in their compositions [20]. Because of their structural differences, polymeric nanoparticles are divided into nanospheres and nano-capsules. Nanospheres have a polymeric matrix with three drug-loading options: (1) encapsulating medicines in the spheres, (2) absorbing drugs on the surface, and (3) dispersing medications throughout the polymeric network. In contrast, the drug-loading forms of core-shell nano-capsules are restricted to dissolve drugs in the core or absorb medications on the shell [21]. The polymers utilized in the nanoparticles are natural materials or modified ones, such as natural materials chitosan, dextran sulfate, hyaluronic acid, and synthetic polymers poly (lactic acid) (PLA), poly(lactic-co-glycolicacid) (PLGA), poly(ε-caprolactone). The polymeric nanoparticles can enhance the precornea retention period and are biocompatible and biodegradable for ocular application. Furthermore, to employ polymers in ocular medication administration, it is critical to assess their potential toxicity [22].

Wai-Leung Langston Suen et al., (2013) presented
folate-decorated polymeric nanoparticles as carriers for poorly soluble therapeutic compounds to be delivered intracellularly and for a long time to RPE cells. Internalization of these nanoparticles into ARPE-19 (human RPE cell line) via receptor-mediated endocytosis resulted in considerably greater cellular absorption than particles without folate treatment. Triamcinolone acetonide (TA) was successfully encapsulated (>97%) within the folate-decorated nanoparticles and slowly released over 4 weeks at pH 5.5 and 8 weeks at pH 7.4 [23].

Liposomes
Liposomes are self-assembled vesicles and form when lipid materials are dispersed in an aqueous medium. The nanosized liposomes are made up of phospholipid bilayers with aqueous units that can transport both hydrophilic and hydrophobic medicinal molecules to the target locations [22]. The biocompatible phospholipids used to formulate liposomes mainly include phosphatidylserine (PS), soya phosphatidylcholine, phosphatidylcholine (PC), and phosphatidylethanolamine, which are similar to the lipid on the cell membrane and could enhance pre-corneal permeation [26].
The very next generation liposome, which has been engineered with mucoadhesive and penetration-enhancing polymers, may not only entrap drug molecules but also target specific locations on the cornea by adhering to the surface [27].
Hirofumi et al., (2012) prepared diclofenacloaded multilamellar liposomes that are modified by polyvinyl alcohol (PVA 205) and polyvinyl alcohol derivatives (PVA-R) through the calcium acetate gradient method for the first time [28].

Nano micelles
Nano micelles are colloidal drug delivery devices that may entrap therapeutic chemicals at their core and self-assemble in a solution. They are formed up of amphiphilic surfactants or block copolymers and range in size from 10 to 200 nm. When the concentration of polymers in a solution exceeds a certain concentration known as the critical micellar concentration (CMC), nano micelles form instantly. Because of hydrophobic interactions, nano micelles can encapsulate hydrophobic medicines in the hydrophobic core of the micelles. While the hydrophilic corona interacts with the external aqueous fluid, a somewhat lipophilic drug's solubility is increased. This colloidal dosage form may be used to make clear aqueous solutions that may be used as eye drops. Surfactant nano micelles and polymeric nano micelles are two types of nano micelles

Iontophoresis
Many medicines, including fluorescein, hormones, antibiotics, antivirals, and macromolecules, have been demonstrated to promote transscleral permeability using iontophoresis. It is a non-invasive approach that uses a tiny electric current to increase the penetration of an ionized medication into the tissue [5]. With negligible side effects, transscleral iontophoresis delivers large concentrations of the administered medicine to the choroid and retina. Epithelial edema, a reduction in endothelial cells, inflammatory infiltration, and burns are all side effects of iontophoresis, the severity of which varies depending on the place of application, current density, and duration. Iontophoresis has been proven to harm the choroid and destroy retinal layers at greater current densities [7]. isoleucine, Ile and lysine, Lys) using whole porcine eyes globes in vitro. When compared to passive diffusion, transscleral iontophoresis (3 mA/cm2 for 10 min) boosted the overall drug distribution of the TA-AA prodrugs by 14-30 times. The study added to the growing body of data that transscleral iontophoresis has the potential to treat posterior segment inflammatory disorders non-invasively [34].

CURRENT STRATEGIES
IVT injections and implants, as well as systemic intravenous injections, are now the most common methods of delivering medications to the posterior portion of the eye. Elevated VEGF, depleted antioxidants, and inflammation are reported to be key culprits in most posterior segment disorders such as DR, RVO, DME, AMD, CNV, CMV retinitis, and so on.

Intravitreal Injections of Anti-VEGF Agents
The earliest mention of VEGF in ophthalmology is from 1940 when a group of scientists claimed that a diffusible factor was responsible for proper vasculature development. In proliferative diabetic retinopathy, an imbalance in the particular factor resulted in neovascularization (DR). VEGF was discovered to be a possible mediator of choroidal and intraocular neovascularization in individuals with age-related macular degeneration in the late 1990s (AMD).
In numerous animal models, proof of concept studies showed that VEGF blockade inhibited neovascularization, indicating that VEGF blockade might be a possible new method to overcome retinal illnesses involving neovascularization [8].

Suprachoroidal Drug Delivery Through Hollow Microneedles
The delivery of treatments in the suprachoroidal region has shown promise in terms of delivering therapeutic drugs at a higher concentration to the target tissue (retina and choroid). Anatomical investigations indicating the diffusion of therapeutic substances following drug application at the suprachoroidal space support this theory.

Ophthalmic Devices
Due to its efficacy in restoring normal visual acuity, ocular implants and medication delivery systems have attracted a lot of attention in recent years [9]. These devices can be nonbiodegradable, biodegradable, or stimuliresponsive systems that are implanted into the eye for drug delivery or to repair a defect. Drug delivery systems have become more important in recent years as a result of their capacity to administer medicine or drug in a regulated and sustained way for both the anterior and posterior segments of the eye [39]. The following ophthalmic equipment which are given in Table 3 are extremely important in the diagnosis, treatment, and monitoring of posterior segment illnesses [40].

Nano-formulations
Nanotechnology has infiltrated every facet of medicine, and ocular therapies cannot be left behind. Liposomes, microspheres, dendrimers, and other nano-formulations have been used to treat illnesses of the posterior portion of the eye It offers 6 months duration of sustained efficacy, improved administration due to smaller needle size, and possibly a better safety profile due to lower peak drug levels.

CONCLUSION
Intricate structure and physiology of the eye, recommends local treatment for eye illness. Disorders associated with the anterior segment of the eye are usually treated with topical formulations such as eye drops, ointments, ocular inserts, etc. Whereas, chronic disorders affecting the posterior segment need specific treatment other than topical formulations, as they are ineffective in this case, thus enabling the need for a new DDS.
In this review article, we investigated new DDS with several strategies that showed potential enhancement in the treatment of posterior segment disorders. Nanotechnology-based formulations with improved penetration and retention for efficient long-term drug release have been reported. Ophthalmic devices offer convenience and sustained efficacy in restoring normal visual acuity. Intravitreal injections of Anti-VEGF Agents showed VEGF blockade to overcome retinal illnesses involving neovascularization whereas Suprachoroidal Drug Delivery through hollow microneedles boost posterior drug targeting inside SCS and showed promising delivery of therapeutic drugs at a higher concentration into the retina and choroid demonstrating safe delivery with no adverse effects.
Longer-acting medication administration and good long-term illness control are now possible thanks to technological advancements. Greater target specificity, potentially real-time monitoring of active drug levels, and reciprocal dosage changes will be possible with future devices.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.

ACKNOWLEDGEMENT
I'm very thankful to Faculty at Department of Pharmaceutics and Pharmaceutical Regulatory Affairs, Shri Vishnu College of Pharmacy (Autonomous), Bhimavaram-534202. I would also like to thank the Management for providing the necessary facilities to carry out this work.