Cellulosic Polymers for Enhancing Drug Bioavailability in Ocular


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pharmaceuticals

Review
Cellulosic Polymers for Enhancing Drug Bioavailability in Ocular Drug Delivery Systems
Bharti Gupta 1, Varsha Mishra 1 , Sankalp Gharat 1, Munira Momin 1,2 and Abdelwahab Omri 3,*

1 Department of Pharmaceutics, SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle, Mumbai 400056, India; [email protected] (B.G.); [email protected] (V.M.); [email protected] (S.G.); [email protected] (M.M.)
2 Director(I/C), SVKM’s Shri C. B. Patel Research Centre for Chemistry and Biological Science, Vile Parle (West), Mumbai 400056, India
3 The Novel Drug and Vaccine Delivery System Facility, Department of Chemistry and Biochemistry, Laurentian University, Sandbury, ON P3E 2C6, Canada
* Correspondence: [email protected]

Citation: 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. https://doi.org/ 10.3390/ph14111201

Abstract: One of the major impediments to drug development is low aqueous solubility and thus poor bioavailability, which leads to insufficient clinical utility. Around 70–80% of drugs in the discovery pipeline are suffering from poor aqueous solubility and poor bioavailability, which is a major challenge when one has to develop an ocular drug delivery system. The outer lipid layer, pre-corneal, dynamic, and static ocular barriers limit drug availability to the targeted ocular tissues. Biopharmaceutical Classification System (BCS) class II drugs with adequate permeability and limited or no aqueous solubility have been extensively studied for various polymer-based solubility enhancement approaches. The hydrophilic nature of cellulosic polymers and their tunable properties make them the polymers of choice in various solubility-enhancement techniques. This review focuses on various cellulose derivatives, specifically, their role, current status and novel modified cellulosic polymers for enhancing the bioavailability of BCS class II drugs in ocular drug delivery systems.
Keywords: ocular drug delivery system; hydroxypropyl methylcellulose; carboxymethyl cellulose; ethylcellulose; methylcellulose; hydroxyethyl cellulose; solubility; sustained release; bioavailability

Academic Editor: Silviya Petrova Zustiak
Received: 30 September 2021 Accepted: 16 November 2021 Published: 22 November 2021
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

1. Introduction
The major challenges to developing ocular drug delivery systems are the presence of protective barriers, the complex anatomy, and pathophysiological functions of eye [1]. The lower absorption of drugs from conventional dosage forms such as eye drops is mainly due to rapid clearance of the drug with excessive lacrimal drainage and various ocular barriers [1]. A topically administered drug has less than 5% bioavailability in the anterior region and less than 1% bioavailability in the posterior region. Hence, a high dose of the drug is required to show the therapeutic effect, which in turn may cause toxicity. Frequent dosing also leads to low patient compliance [2,3]. The ocular system is a complex sensory organ with a size of 24 mm and a weight of 7.5 g, which is considered 0.05% of the human body [4,5]. The ocular system is classified into two regions: the anterior region, which includes the cornea, aqueous humor, conjunctiva, iris, ciliary body, and lens; and the posterior region, which includes the vitreous humor, retina, choroid, and the optic nerve [5].
To understand the fate of a drug in the eye it is important to understand the anatomy of the eye. The ocular system is made up of three layers: outer, middle, and inner. The outer region includes the cornea and sclera. The cornea is a physical barrier whereas the sclera holds the shape of the eye (Figure 1). The cornea has a vascular structure and contains sensory nerves that give the cornea transparency [6]. The negative charge on a cornea favors permeation of hydrophilic cationic drugs as compared to anionic drugs.

Pharmaceuticals 2021, 14, 1201. https://doi.org/10.3390/ph14111201

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The permeability challenges from the cornea is also due to the five layers that are present in the cornea, i.e., epithelial layer, bowman’s membrane, stroma, descemet’s membrane, and endothelium. The epithelial layer is a multilayer of stratified squamous epithelial cells that are connected by a tight junction and limit the hydrophilic drug penetration [4]. The stroma is charged and highly organized hydrophilic collagen, which further limits hydrophobic drug penetration [4]. The middle layer of the ocular system includes the iris, ciliary body, and choroid. The iris maintains pupil size and controls the quantity of light that enters the pupil. The ciliary body produces aqueous humor—a clear, slightly alkaline ocular fluid that supplies nutrients to the retina [6]. Three mechanisms are involved in the formation of aqueous humor: diffusion, ultrafiltration, and active secretion. Active secretion is the major contributor to aqueous humor formation. Around 70–90% of the aqueous humor leaves through the conventional path (aqueous humor passes through the trabecular meshwork, across the inner wall of Schlemm’s canal, into its lumen, and into draining collector channels, aqueous veins, and episcleral veins), whereas 10–30% leaves through the non-conventional pathway, which includes the ciliary muscle and supraciliary and suprachoroidal spaces [7]. Another important part of the eye is the conjunctiva, which is a thin, highly vascularized and semi-transparent connective tissue that covers the surface of the eyeball. It secretes mucous under the eyelids and extends to the corneal limbus. The conjunctiva plays an important role in maintaining the motion of the eyeball and eyelid due to its elastic nature [8]. The conjunctiva and sclera facilitate the absorption of large and hydrophilic drug molecules, whereas the nasolacrimal drainage absorption is facilitated by the pharynx, nasal mucosa, and GI tract [9]. The inner chamber of the eye is a vitreous chamber that is present behind the lens and filled by a gel-like material known as vitreous humor [3]. The lacrimal system contains the tear production system and the drainage system, which is an uninterrupted system that originates from the lacrimal puncta and proceeds from the lacrimal canaliculi to the lacrimal sac [10]. Another important anatomy includes the intraocular pressure of the eye, which is due to the presence of barriers such as the blood–aqueous and blood–retinal barriers, which may restrict the entry of the drugs into the intraocular chamber, resulting in loss of therapeutic efficacy of the drug [11]. To overcome these anatomical barriers, cellulosic derivatives offer their potential applications Pharmaceuticals 2021, 14, x FOR PEER dRuEVeIEtoWtheir properties such as sustained release, improve residence time, and contr3oollfe4d4 tunable drug release. Apart from these properties, cellulosic polymers are also used as tear substitutes due to their hydrophilic nature and water-retention capability.

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2. Challenges in Ocular Drug Delivery System The presence of protective barriers in the ocular system restricts the entry of drug
molecules into it. The cornea (epithelial part) and conjunctiva (bulbar part) are major bar‐ riers on the outer surface of the ocular system (Figure 2) [2]. The nonionizable lipophilic

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hydrolytic enzymes are esterases, which are located in the epithelium and stromal‐endothe‐ lium of the cornea. Carbonic anhydrase is found in the iris‐ciliary body of pigmen3 toef d42rab‐
bits, and aminopeptidases M and A and dipeptidyl peptidase IV are found in the cornea of
pig, rat, and humans. Cholinesterases are found in the retina and retinal pigmented epithe‐ lium of rTathsi.sTrehveiemwofnoocu‐asecsylonglcyhcaelrleonlgliepsainsetheendzyevmeleofpomuenndt oinf vthareionuosno‐cpuilgamr dernutgeddeclilviearryy ep‐ ithelsiuysmtemofsm, aincedpthlaeyrsoalemofajcoerllruolloeseinainndcrtehaesirindgerthiveaitnivteras‐ioncaudladrrepsrseisnsgutrheebsyotluhbeimliteytaanbdolism of enbdiooagveaniloabuislit2y‐aisrsaucehoidf oBnCySlcglalyssceIIrodlru[g1s6.]. Apart from this, ocular barriers are generally
class2i.fiCedhaallsenstgaetsicinanOdcudlyanr aDmruicg.DTehleivsetraytiScybsatermrier is also known as an anatomical barrier, which inTchluedpersestehnececoorfnperao,tescctlievrea,bcaorrniejursncintivthae, aoncudlarrestiynsate. mThreesdtryicntsamthieceonrtrpyhoyfsdioruloggical barrimerosleicnuclleusdienstocoitn.juTnhceticvoarlnbelao(oedpiftlhoewli,acl hpoarrot)idaanldbcloonojdunflcotwiva, ly(bmulpbhaartpicarctl)eaarraenmcea,joerfflux transbparorriteerrsso,nntahseoolauctreirmsuarlfdacreaionfathgee,oacnuldartesyasrtteumrn(Foivgeurre[22]).[T2]h. eThcoernnoenaiol neipziatbhleeliliaplobpahrirliicer al‐ lowsdtrhuegspaarsesadgisetroibfulitpedopmhoilriec imn othleccuolrensebalurtehginond,ewrshtehreapsaisosnaigzaebolef lhipyodprohpilihcildicrudgrsuggest and
thosdeiwstritibhumteodleincutlhaer asqizueeolaursgherumthoarn[15]0. AT°h.eAbnaorrtiheersr fboaurnriderinfotrheocaunltaeridoruagnddeploivsteerryioirs the aqueroeguisonhsuomfothr,ewbhodicyhlrimedituacbessotrhpetitorna,nws hciocrhnienaltudrinffuafsfieocnts[t1h2e].bioavailability of many
drugs [12].

Figure 2. Anatomy of the ocular barriers. Figure 2. Anatomy of the ocular barriers.
The corneal and noncorneal routes are the two main pathways for intraocular ab-
sPoropsttieornio. rThbeacrorirenresalsruocuhteaasbstohrebsscslmeraall apnrdovlipdoephilgichmeropleecrumleesavbiailitthye tfroarnshcyedllurolaprhilic
drugrosuthteanantdhepcreovrnenetasbthuet reensttrryicotfs hthyedreonpthryiliocfdmruagcsrothmroulegchutlhese. pTahreacreeltliunlarlirmouitse.thTehentry of lanrognecrodrnrueaglsr(o>u7t5e iknDclau)d. eWs itthhe acgoninjugn, ctthiveaB–srculecrha’.s mTheemcborrnaneael broeucotemfaecsiltihtaicteks, twhehiacbh- de‐ creassoersptthioentorfanhyspdroorpt hoiflicddruruggsacwroitshshtihgheemr memolbecrualnaer wanedighdtrsaoifn5s0t0h0e–1l0ip,0o0p0 hDiali,cwdhreuregassinto the bthloeocdorcniercaualnadtioscnl.erTahaelleopwitphaeslisaalgleaoyfedr rius galmsoolaecmulaejsorwbitahrrmieorletchualtairswcoeingnhet cletessdtbhyantight junc5ti0o0nDs,aw[5h,9i,c1h3]l.imThietsintflhuexpaenndeetrfflautixontraonfsphoyrdterrospphrielsiecndt rinugthse. cSotrrnoema,ac,ownjhuincchtivisa,croemtinpao, sed
and blood–ocular barrier region affect the transport of drug molecules. Modification of
of hitghhesleytorarngsapnoirzteedrs hisyodnreompheitlhiocdcofollraignecrne,alsiimngitbsiothaveaeilnatbriylitoy.fEhfyflduxrotprahnosbpoicrtderrsusgusch[4a]s. The effluPx-gtrpaannsdpomruteltrisdrpurge-sreesnitstoannttphreobteliono(dM–RrePt)itnraanl sbpaorrrtiethrse ddreucgreoausteotfhtehebcioelalvaanidladbeiclirteyasoef the admtihneiisrtebrioeadvdairluabgisl.itTy.hTehpeeMrmRePaetfiflonuxotfrdanruspgotrhterrosutgrahntshpeorbtltohoedo–ragqanuiecoaunsiobnasrrainedr dtheepirends on thcoenojusgmaotetsicouptreosf sthuerecealln[d14n].aItnuflruexotfrathnespdorutegrsmtroanlescpuolrets[d1r2u].gs and the nutrients across
the biological membrane. LAT1, LAT2, ASCT1, ASCT2, and B (0,+) are the amino acid-
3. Robuasteeds ionfflOuxcturalanrspDorrtuegrsD, wehlievreearsyPSEyPsTt1emand PEPT2 are peptide-based influx transporters
that play a major role in the influx of drugs in the corneal region [14].
TheDreruagreditfhfurseieonrobuyttehse ocofronceuallarorudtersuhgavdeevliavreioryus: toocpuliacrabl,alroricearsl,, sauncdh assytsetaermtuicrn[o1v7e]r.,The ideanl arsooulatecroimf aadl dmraininisatgrea,tcioornnoeaflderpuitghseliisudme,tierridmiainl beldoobdyflthowe ,retrgaiboencuolfart,haenedyuevteoo-bseclterreaal ted. Topiocuatlfltorwea. tWmheenretauss, uthaellbyarwrioerrskfsoerftfheectdiivffeulsyioonnththroeucgohnnjuonn-cctoivrnae,aclorronueteas, aarnetceorniojurncchtiavma,ber, and sicrliesr[a1,8m].uAcussmtuorsntotvoepr,icreatlinfoalrmpigumlaetniotnepsidthoelniuomt e(nRtPeEr )t,haendpocshtoerriioocrapreilglairoisn,[9lo].cMaleitnabjeoc-tion
or sylistteesmobicsetrrveeadtminetnhet iesyeofatreenbreecaquusiereodf t.he ocular metabolism or the hepatic or extrahepatic
metabolism [15]. Ocular non-P450 oxidative and reductive enzymes are aldehyde oxidases,

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which are highly present in the ciliary body followed by the RPE, choroid, and iris. Xanthine oxidoreductase and xanthine oxidase are involved in the anterior regions’ microbial protection, whereas keto-reductase is found higher in the corneal epithelium. Ocular hydrolytic enzymes are esterases, which are located in the epithelium and stromal-endothelium of the cornea. Carbonic anhydrase is found in the iris-ciliary body of pigmented rabbits, and aminopeptidases M and A and dipeptidyl peptidase IV are found in the cornea of pig, rat, and humans. Cholinesterases are found in the retina and retinal pigmented epithelium of rats. The mono-acyl glycerol lipase enzyme found in the non-pigmented ciliary epithelium of mice plays a major role in increasing the intra-ocular pressure by the metabolism of endogenous 2-arachidonyl glycerol [16]. Apart from this, ocular barriers are generally classified as static and dynamic. The static barrier is also known as an anatomical barrier, which includes the cornea, sclera, conjunctiva, and retina. The dynamic or physiological barriers includes conjunctival blood flow, choroidal blood flow, lymphatic clearance, efflux transporters, nasolacrimal drainage, and tear turnover [2]. The corneal epithelial barrier allows the passage of lipophilic molecules but hinders the passage of hydrophilic drugs and those with molecular size larger than 10 A◦. Another barrier for ocular drug delivery is the aqueous humor, which reduces the trans corneal diffusion [12].
Posterior barriers such as the sclera provide higher permeability for hydrophilic drugs than the cornea but restricts the entry of macromolecules. The retina limits the entry of larger drugs (>75 kDa). With aging, the Bruch’s membrane becomes thick, which decreases the transport of drug across the membrane and drains the lipophilic drugs into the blood circulation. The epithelial layer is also a major barrier that is connected by tight junctions, which limits the penetration of hydrophilic drugs. Stroma, which is composed of highly organized hydrophilic collagen, limits the entry of hydrophobic drugs [4]. The efflux transporters present on the blood–retinal barriers decrease the bioavailability of the administered drugs. The permeation of drug through the blood–aqueous barrier depends on the osmotic pressure and nature of the drug molecule [12].
3. Routes of Ocular Drug Delivery System
There are three routes of ocular drug delivery: topical, local, and systemic [17]. The ideal route of administration of drugs is determined by the region of the eye to be treated. Topical treatment usually works effectively on the conjunctiva, cornea, anterior chamber, and iris [18]. As most topical formulations do not enter the posterior region, local injection or systemic treatment is often required.
3.1. Topical Route
The topical route is preferred for management of anterior segment diseases, due to their low cost, ease of administration, and patient compliance [19,20]. However, this route is not able to deliver the drug to the posterior segment due to the anatomical and physiological barriers of the eye. This route is applied for the administration of eye drops, ointments, and gels that are used for anterior segment diseases. However, the topical route has several disadvantages, such as less contact time, low permeability, and faster elimination of the drug [21]. The high tear turnover, nasolacrimal drainage, and tear dilution results in loss of 90% of the topically administered drug [22].
3.2. Local Route
Periocular routes include delivery of the drugs through the sub-conjunctival and retro-bulbar regions. Through this route, the drug is delivered to the external surface of the sclera, thereby decreasing the risk of endophthalmitis and retinal damage, which is observed in the intravitreal route [23]. In the subconjunctival route, the formulation is injected in the area below the conjunctival membrane, the drug bypasses the conjunctivalcornea barrier and directly enters the sclera. The sclera has low resistance to penetration of drugs and has less or negligible protease activity as compared to the cornea. In the retro bulbar route the formulation is injected into the eyelid and orbital fascia for deposition

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of the drug behind the globe in the retrobulbar space [17]. However, this route is not much preferred as it may damage the orbital structure of the optic nerve [24,25]. The sub-retinal route is used to deliver the drug directly to the outer retina for management of the retinal degenerations, which originate in the photoreceptors and RPE [26,27]. It is a highly invasive method and causes ocular damage such as lesions in RPE, sub or pre-retinal fibrosis, hemorrhage, and retinal detachment [25]. Intravitreal route is the main route that delivers large molecules to the posterior region of the eye [28]. It can deliver formulations of up to 20 to 100 µL; however, reapplication of a local anesthetic is required. Intravitreal injection creates complications, such as retinal detachment, endophthalmitis, intraocular hemorrhage, and uveitis cataract [29]. Furthermore, the intra-cameral route is used for direct delivery of the drug to the anterior chamber; however, general anesthesia is required before injection. This route may cause damage to intraocular structures such as the iris, lens, and corneal endothelium [25,30].
3.3. Systemic Route
The systemic route is used to treat the diseases of the posterior segment, which are difficult to treat by the topical route [31]. However, the systemic route has some drawbacks, such as the need for a high dose and frequent dosing due to drug dilution in the blood, blood ocular barriers, and low cardiac output to the eye. In the systemic route, the drug undergoes metabolism by the liver and clearance by the kidney, which causes less of the drug to reach the vitreous humor. [14].
4. Conventional Ocular Drug Delivery System
There are various conventional ocular drug delivery systems on the market, such as eye drops, ointments, emulsion, suspension, and polymeric gels [32,33]. The eye drops makes almost 70% of the prescribed dosage form for eye treatment due to its advantages such as patient compliance, drug efficacy, cost-efficacy, non-invasive, safe, and ease of bulk manufacturing of the formulation [34,35] Only 20% of the total inserted eye drop dose is retained in the precorneal region because of the blinking effect loss and excessive lachrymal fluid secretion. [35]. The bioavailability of the drug from eye drops is limited due to dilution and loss of the drug due to tear drainage and the eye pocket size, which has a low liquid holding capability [36]. The loss of the drug due to the abovementioned reasons leads to multiple administration, leading to patient non-compliance [37,38]. One of the strategies to improve the residence time of the solution is to increase the viscosity of eye drops, thereby improving the bioavailability of the drug. Polymers such as hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), and poly alcohols have been extensively explored for improved residence time and bioavailability of the drug given in the form of eye drops. Further, the permeation enhancers such as cyclodextrins improve the uptake of the drug and the solubility of the hydrophobic drug. However, it is important that the selection of additives for modification in the drug delivery system is done very carefully as the eye is a highly sensitivity organ [32,35].
Other conventional formulations used for ocular delivery are emulsions and suspensions [39]. Patel et al. in their study showed that emulsions can increase the solubility and bioavailability of ocular drugs [35]. The oil in water (o/w) type of emulsion is generally preferred because of its better tolerance and low ocular irritation [40]. Liang et al. proved that an emulsion enhanced the corneal permeation, precorneal residence time, sustained drug release, and bioavailability of the drug in male albino rabbits [41]. However, the conventional emulsions have several disadvantages, such as being less stable and prone to instabilities such as coalescence, flocculation, and creaming, and also destabilization by the tear fluid [32]. Suspensions are advantageous over eye drops (solutions) as they increase the contact time of the drug and duration of action because of the dispersed insoluble drug that cannot be washed away by the dilution of the tear [42]. Conventional suspensions do not have a uniform size distribution, which increases the duration of action. Smaller drug

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particles in the suspension absorb quickly while the larger particles retain and dissolve slowly in the precorneal section [42]. Despite these advantages, suspensions have several disadvantages, such as the need to shake before use and variation in the dose, which may reduce the drug accuracy [32]. To overcome these problems, ointments are used. Because of their viscous nature, they do not get washed away by the tear fluids, unlike the liquid preparations [43]. As the viscosity of the ointments is high, it causes blurring of vision [37,44]. Polymeric gels are made up of mucoadhesive polymers to increase the contact time of the formulation. Mucoadhesive polymers are generally used to enhance the efficacy of the formulation as these polymers adhere to the biological tissues and increase the contact time and bioavailability [45,46]. Polymeric gels are of two types: in situ gelling systems and preformed gels [46]. In situ gels are preferred over preformed gels as these formulations act smartly by changing the viscosity in the site of application [47].
Presence of barriers and defense mechanisms, such as a high tear turnover rate, dilutes the efficacy of the conventional systems. Therefore, conventional formulations requires a high concentration of drugs, which may cause local cellular damage and other systemic adverse effects that decrease the efficacy of the treatment [9].
5. Novel Ocular Drug Delivery
Apart from advantages, conventional formulations suffer from some disadvantages such as a short retention time, leading to rapid tear clearance and nasolacrimal drainage, resulting in low ocular solubility and bioavailability (that is, <5%) [48,49]. This disadvantage leads to the development of novel ocular drug delivery systems such as nanoparticles, nano-micelles, liposomes, contact lenses, inserts, implants, and microneedles [48].
5.1. Nanoparticles
A nanoparticle is defined as any particle that has a diameter range of 1 to 100 nm [50] and is made of natural and synthetic lipids, polymers, phospholipids, or metals. Nanoparticles are of two types, such as a nano-capsule and nanosphere [51]. The drug is encapsulated into a polymeric capsule in the nano-capsule whereas the drug is uniformly dispersed throughout the polymeric matrix in the nanosphere. One of the approaches of the nanoparticle is solid lipid nanoparticles [52] as it has certain advantages, such as enhancing corneal absorption and corneal bioavailability for both types of drugs—hydrophilic and hydrophobic; providing autoclave sterilization of the formulation; and does not have toxicity, as the lipids used are physiological at the time of preparation. SLN also has a sustained-release activity; for example, tobramycin SLN shows a six-hour sustained release compared to tobramycin eye drops of the same dose [32]. Yan et al. prepared a nanoparticle for ocular delivery for the treatment of ocular wound healing by the use of cellulose nanofibrils and poly lactic acid [53].
5.2. Nanomicelles
Nanomicelles are the commonly used carrier to deliver the drug to the clear aqueous solution. It is made of surfactants or polymers that are amphiphilic in nature, and have the property to self-assemble themselves in the micelle form [54]. Micelles are of three types: regular, reverse, and unimolecular. Regular micelles self-assemble in an aqueous medium whereas reverse micelles self-assemble in a non-aqueous medium, and both are copolymers [55]. Unimolecular micelles are block copolymers that have a hydrophilic and hydrophobic site in them. The advantage of nanomicelles are their easy preparation method, improve drug solubility, increase penetration into tissue, low toxicity, and targeted delivery [32]. Mehra et al. developed copolymer-based nanomicelles for delivery of Everolimus for the treatment of uveitis by using a grafted polymer of polyvinyl caprolactam–polyvinyl alcohol–polyethylene glycol (PVCL-PVA-PEG) [56].

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5.3. Liposomes
The drug is encapsulated in the liposome and is delivered as an eye drop [57]. Natarajan et al. prepared a latanoprost-loaded egg phosphatidylcholine liposome. A liposome is stable for 6 months when stored at 4 ◦C and it is stable for 1 month when stored at 25 ◦C. The 60% latanoprost release was slow and sustained for two weeks in vitro; a more sustained IOP-lowering property is seen in liposome formulations compared to topical latanoprost [58,59]. Blazaki et al. developed a novel liposome aggregate platform system for calcein, FITC-dextran-4000, and flurbiprofen, which is encapsulated in a negatively charged liposome; this study showed that liposome is one of the most promising and safe approaches for ocular delivery [60].
6. Various Approaches for Drug Delivery
Novel formulations are incorporated into these various approaches, such as contact lenses, implants, microneedle, etc., for sustaining the drug release [35].
6.1. Contact Lenses
The first contact lenses were developed for glaucoma in 1974 by soaking vinyl pyrrolidone or acrylic co-polymer contact lenses for three days in 1% pilocarpine eye drops. Some of the studies show that soft contact lenses give a sustainable drug release and they are transparent, and therefore do not impair vision [61]. Soft contact lenses were made of the cross-linking of a hydrogel with a water-soluble polymer [62]. Contact lenses can be loaded with vitamin E to improve the drug release. Five marketed silicone contact lenses are ACUVUE ADVANCE and ACUVUA OASYS by Johnson and Johnson vision care; O2OPTIX by Alcon, Fort Worth; NIGHT and DAY by Alcon, Fort Worth; and pure vision by Bausch and Lomb, Bridgewater; these were used to increase the release of dexamethasone [62]. Kang et al. developed contact lenses of oxidized hydroxyethyl cellulose and an allyl co-polymer-based hydrogel [63].
6.2. Ocular Inserts
The first ocular insert reported is a small portion of filter paper impregnated with drug solutions such as pilocarpine HCL and atropine sulfate [64]. The ocular insert was of three types: soluble, insoluble, and bio-erodible. The soluble and bio-erodible differ in their underlying chemical processes [65]. The polymers used for the formulation of inserts are methyl cellulose (MC), hydroxypropyl methylcellulose (HPMC), ethyl cellulose (EC), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), chitosan (CS), and gelatin [62]. The shape of the insert is the major challenge for the preparation of inserts, as the shape of the insert affects the capacity of drug loading, comfort, and retention time. The human volunteers show that rod-shaped inserts are well tolerable [66]. Marketed ocular inserts are ozurdex, surodex, iluvien, mydriasert, retisert, and lacrisert, and others are in clinical trials [67]. Franca et al. developed chitosan/hydroxyethyl cellulose inserts for delivery of dorzolamide for the treatment of glaucoma [68].
6.3. Intraocular Implants
Intraocular implants are inserted into the eye by a surgical process, and drug release is extended for a long period. The implants are not biodegradable so there is a need to remove the implant by surgery, which has many risks with this type of delivery system. However, in biodegradable polymeric implants, there is no need to remove the implants by surgery [51]. Implants can also be made as stimuli-responsive delivery systems, but the currently marketed implants extended the release but do not change the rate of the drug release. There are many ongoing studies related to stimuli-responsive polymeric implants [37,69–71]. Felipe et al. prepared an implant for the delivery of bimatoprost for treatment of glaucoma and ocular hypertension; in a 12-week study, they showed that a bimatoprost implant was not inferior to timolol and it has potential for improved adherence and decrease the treatment of glaucoma [72].

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6.4. Microneedles
Microneedles are one of the delivery systems; they are made of metals or polymers and have a length of 15–1500 µm, thickness of 1 to 25 µm, and width of 50 to 250 µm [73]. It is less invasive than the injection due to the micron dimension of the device and also provides a targeted release [74]. Jiang et al. used a microneedle of 500 to 750 µm to deliver pilocarpine by intrascleral route in the anterior region. They found an increase in absorption of 45 fold compared to eye drops [59]. Roy et al. developed a microneedle patch containing liposomal or free amphotericin-B as a treatment for fungal keratitis because it is a less invasive delivery system compared to ocular injections [75].
7. Strategies for Enhancing Ocular Drug Delivery System
To overcome the disadvantage of topical ocular delivery, researchers have given two strategies, such as enhancing the corneal residence time by the use of a viscosity enhancer, in situ gel, and a mucoadhesive agent [76]. Some delivery systems give a prolonged retention time with a decreased frequency of drug dosing. A low viscous preparation has more patient compliance; however, enhancing the viscosity of the formulation increases the retention time and improves the bioavailability of the drug [76]. Natural and synthetic polymers and biopolymer are used due to their viscosity-enhancing activity [44]. These polymers cause a slower elimination of the drug; examples are cellulose derivatives such as protein (collagen, silk, gelatin), polysaccharide (chitosan, starch, alginate), polyesters (polycaprolactone, polylactide, polylactide/polyglycolic copolymer) [35], and cellulose derivatives such as HPMC [77], hydroxyethyl cellulose [78], and methylcellulose. In situ gels are delivered as a solution or suspension and rapidly undergoes sol-gel transition [79] upon external stimuli such pH, temperature, and ionic strength [80]. This has merits such as reproducible and accurate dosing. Low vision impairment, being easy to administer, and a prolonged residence time decreases the frequency of administration and has low nasolacrimal drainage. Depending on the physiological mechanism, the three categories of polymers are (1) pH-triggered in situ gels: this polymer has weakly basic and acidic groups which accept and release protons in response to a pH change. (2) Temperature-triggered in situ gel, the low critical system temperature (LCST) is the phase-transition temperature; below this point the hydrogen bonds between the polymer and water molecules increase the dissolution of the polymer, but above this point, when the temperature increases, the hydrogen bonds breaks and a hydrophobic interaction appears that is a sol-gel transition. Finally, (3) ion-triggered in situ gelling polymers, because of the mono and divalent cation in tears, cross-linking of the sensitive polymer occurs [81]. The mucoadhesive agent adheres to the mucous membrane; this adhesion enhances the retention time of the drug and controls the drug release along with enhancing the bioavailability and more patient compliance [82]. The mechanism of muco-adhesion is the contact phase and the consolidation phase. The former involves the contact between the agent and mucus that causes the spreading and swelling of the preparation. In the latter phase, the mucoadhesive polymer is activated in the presence of moisture, which causes molecules to break freely and be joined by the force of van der Waals and hydrogen bonding [83].
Secondly, by increasing the corneal permeability, through the use of prodrugs, penetration enhancers, and a colloidal system, such as nanoparticles and liposomes [84]. Prodrugs are inactive substances; they need to be transformed chemically or enzymatically [85]. The active compound has carboxyl or hydroxyl groups that are esterified to give a lipophilic substance. The corneal epithelium, esterase, is 2.5-fold more as compared to the endothelium and stroma [86]. An example is the nepafenac prodrug, used for inflammation and the pain associated with cataract surgery [87]. This shows that lipid vesicles are compatible with the corneal epithelium and leads to enhanced solubility and ease of transportation, across the cornea. Permeation enhancers can improve drug permeability in the corneal epithelium, reducing the corneal barrier resistance. Permeation enhancers decrease the dose size and enhance the bioavailability [88]. For example, Benzalkonium chloride alters the ocular barrier, but it has a toxic effect when used for several days by accumulating in

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the cornea [89] and EDTA acts by altering the tight junction of superficial cells and cause paracellular transport of the drug. Cyclodextrin, by complexing with the drug, solubilizes the lipophilic molecules [90] and results in increased permeation [91]. The colloidal system provides controlled drug release and prolonged pharmacological effects. On localized retention in a cul-de-sac, the drug can be delivered under external stimuli such as light or by diffusion. NP can overcome the ocular barriers, maintaining an optimal concentration and drug permeability [92]. Liposomes are large in size as they contain electrostatic attraction between the positive and negative charges of polymers and phospholipids [93].
Topical formulations are the most widely used treatment approach for ocular drug delivery. The vehicles or bases of topical formulations, such as a solution, suspension, or ointment, are very critical in determining the drug delivery to the eye. Vehicles should not irritate the eye and should be compatible with the rest of the ingredients as well as the packaging material [94]. Ophthalmic solutions and suspensions have purified water or most preferably sterile water for injection as their vehicle. In the case of topical ointment, a mixture of white petrolatum and liquid paraffin is the most widely used vehicle. However, because of the advantages of water-soluble bases over petrolatum bases, such as better spreadability, pH, lubricity, stability, and low irritability, the use of water-soluble bases, such as gels containing PEG 200, PEG 400, carboxymethylcellulose, and Carbopol, has increased. It is necessary to increase the viscosity of the formulation to get a prolonged residence time and improved bioavailability [95,96]. Vehicles containing viscosity enhancers, such as CMC, MC, HPMC, and HMC, improve the retention time of topical ophthalmic formulations. Vehicles containing mucoadhesive polymers interact with the mucin layer and increase the residence of the formulation while also successfully increasing the bioavailability [97]. In all ophthalmic formulations, sterility is an absolute requirement. Various sterilization methods, such as an autoclave, dry heat, membrane filtration, ethylene oxide, gas plasma, and irradiation, can be employed, depending on the feasibility and thermal stability of the formulation. Most of the formulations are terminally sterilized by either dry heat method, autoclave, or irradiation. In the case of a liquid vehicle, the formulation can also be sterilized by filtering it through a 0.22micron membrane filter in a sterile container [98]. Aseptic preparation involves pre-sterilization of the vehicles or ointment bases and all the ingredients involved in the formulation. The production takes place in a clean room. It is convenient to perform terminal sterilization rather than an aseptic production process [98,99].
The antimicrobial preservative is a very crucial component of the ocular drug delivery system. Preservatives should be chosen based on properties such as efficacy against a wide range of organisms at extremely low concentrations, compatibility with packing components, long shelf-life, stability, and solubility [100]. The quaternary ammonium compounds, such as benzalkonium chloride, 2-poly(ethyl alcohol), chloro-butanol, and parabens, are commonly used preservatives that meet most of the criteria discussed above [101]. The presence of preservatives in ocular formulations is considered to be the cause of epithelium damage but they are necessary, especially in a multi-dose container. Preservative such as benzalkonium chloride is well known for causing ocular cytotoxicity, therefore some newer preservatives such as Polyquaternium-1, sodium perborate, and stabilized oxy chloro-complex are being explored. In some instances, a preservative-free single-dose container was used, usually in the case of patients with serious allergies or surgical conditions. Preservative-free containers need to be very carefully sterilized and stored to avoid bacterial growth [102].
8. Cellulose and Its Derivatives in Ocular Drug Delivery System
Cellulose is one of the most widely used polymers in ophthalmic formulations. In the 1940s, methylcellulose (MC) was first used in ocular formulations as a viscosity enhancer. Since then, cellulosic polymers have been widely studied in animals, as well as in humans, for ocular administration [103]. As pure cellulose is insoluble in water, various cellulosic derivatives are employed extensively in ocular formulations. The cellulosic derivatives that

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are most commonly used in ocular formulations are methylcellulose (MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and carboxymethylcellulose (CMC) [104]. Cellulosic derivatives have valuable viscosityincreasing properties, which are very useful in polymer-based ophthalmic formulations for improved bioavailability. These macromolecules also have evident potential as a carrier in ocular drug delivery. Additionally, the swelling properties, chemical properties, and structural morphology of these derivatives influence the release mechanism of the drugs loaded in these systems to a great extent [105–107]. It can be obtained from various natural sources, such as vegetables, cotton fiber, woods, and even from marine animals such as tunicates, as well as found in bacteria such as algae, fungi, and invertebrates, or may even be synthesized in labs [108,109]. The extensive production of cellulose, which is 7.5 × 1010 t annually, shows that there is an abundant reservoir of this polysaccharide, which helps in reducing the overall cost of the formulation [108,110]. Cellulose, as a raw material, is suitable for the large-scale manufacturing of various products. Cellulose can be altered easily utilizing chemical reactions; therefore, many derivatives of cellulose are produced for application in various ophthalmic preparations. It can be further modified to meet specific requirements [110]. Easy accessibility and the valuable properties of cellulosic polymers have made them a very attractive choice of polymer for ophthalmic formulation.
Cellulose is a sustainable natural polymer in the world and it is a primary component of plants [108,110]. It has very good mechanical properties that give strength to plants [108]. In the past few decades, the development and innovation of various delivery systems in formulations, science, medicine, and technology brought forward the application of this natural molecule globally [111]. Production of cellulose is 7.5 × 1010 t annually, showing that there is an abundant reservoir of this polysaccharide [108,110]. Cellulose is suitable for the large-scale manufacturing of various chemicals and products as a raw material. Cellulose can alter, easily utilizing chemical reactions, and therefore many derivatives of cellulose are produced for application in various preparation. It even can be modified to meet the various properties [110]. It can be obtained from various natural sources such as vegetables, cotton fiber, woods, and even from marine animals such as tunicates, and also found in bacteria such as algae, fungi, invertebrates, or may be synthesized in labs [108,109].
Cellulose was discovered by the French chemist Anselme Payene in 1838 [109]. Cellulose is a high-molecular-weight homopolysaccharide and composed of β-1,4-anhydroD-glucopyranose units, which is linked to an acetal molecule by covalent bonds between the C4 of the hydroxyl group and C1 of carbon. Anhydro glucose molecules contain one primary and two secondary hydroxyl groups [95,112]. This hydroxyl group forms the hydrogen bonds that are inter and intramolecular bonds; because of the very strong bond, cellulose is not soluble in aqueous and organic solvents [108,113]. Two glucose moieties are linked through the β-1-4 bond and forms cellobiose units [109], with a high molecular weight (162.14 g mol−1), and the degree of crystallinity makes cellulose aqueous insoluble. The hydroxyl group of D glucose is the favorable site for modification and to form different derivatives [114].
9. Properties of Cellulosic Polymers
Cellulose can be modified by esterification or etherification methods; this modification can lead to water solubility, viscosity enhancer, water binding ability, adhesiveness, film former, thickening agent, swelling, and emulsifying properties. These properties of modified or derivatives of cellulose lead to its wide applications [115,116]. Cellulose derivatives are preferred over cellulose because of their aqueous and organic solvents solubility [109]. Cellulose derivatives are green molecules, have a low cost, and have very good properties such as a high chemical stability and good solubility, as well as having a very good biological affinity, moldability, porosity, and are physiologically safe molecules [111,117]. These molecules also have good biodegradability and are biocompatible; for example, carboxymethyl cellulose degrade in a few days in the presence of enzymes such as cellu-

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Cellulosic Polymers for Enhancing Drug Bioavailability in Ocular