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Gupta et al: Nanotechnology-based Strategies for Ocular Drug Delivery Systems 4073

Review Article

Nanotechnology-based Strategies for Ocular Drug Delivery Systems

Aashu Gupta, Kritika Nayak and Manju Misra* Department of Pharmaceutics, NIPER-Ahmedabad, Gandhinagar-382355, Gujarat, India.

Received February 15, 2017; accepted March 26, 2018

ABSTRACT This review describes current nanotechnology-based delivery systems for ocular targeting. Amongst all the drug delivery systems existing today, ocular drug delivery is one such delivery approach which is having great endeavours due to the challenges faced by it. Many new as well as exciting treatment options have emerged in this field. The major cause behind development of new treatment alternatives in this field are the limitations raised by the conventional approaches. Currently, researchers are working on development of novel nano techniques to overcome these challenges. The major hurdle is associated with the complicated anatomy and physiology of eye having various static (cornea, conjunctiva, retinal pigmental epithelium) as well as dynamic barriers (blood aqueous barrier, blood retinal barrier) which reduce the

overall bioavailability of the drugs. These membranous and fluidic barriers make drug delivery to eye a very challenging task. Hence, current research focuses on developing a system, which is least invasive and able to surpass ocular barriers to maintain sufficient drug levels within the ocular tissue. Nanotechnology based delivery systems play a vital role in this. Many vesicular as well as particulate systems are attempted for the same for anterior as well as posterior segment targeting which can easily overcome limitations of conventional drug delivery systems. Current momentum and ongoing research in this field holds a significant level of promise towards development of improved therapies for treating vision related ailments.

KEYWORDS: Nanotechnology; Ocular drug delivery systems; Retinal barrier; Ophthalmic.

Introduction Eye is a major sense organ of human body having

complex anatomy as well as physiology. One-third portion of it is known as the anterior segment, while the rest is known as the posterior segment. Progression has been made in the current therapies for the treatment of several ocular segment related diseases like diabetic retinopathy, diabetic macularoedema, age related macular degeneration, glaucoma, uveitis, conjunctivitis, etc. which affects the anterior as well as the posterior segment of the eye. These recent advances help in increasing patient compliance as these all are having minimal invasion and side effects to the eye. But, despite several efforts, still targeting to eye remains a major challenge for the scientists (Achouri et al., 2013). The major reason behind this is the anatomical and physiological barriers associated with the eye which results in poor ocular bioavailability. These include static barrier of cornea, conjunctiva and retinal pigmental epithelium (RPE) and dynamic barrier of blood aqueous barrier (BAB) in the anterior segment as well as the

blood retinal barrier (BRB) in the posterior segment (Chen et al., 2008). Conventional techniques like topical eye drops do exist but has limitations in terms of poor patient compliance (Patel et al., 2013). In addition, these types of formulations have short residence time within the eye and are eliminated in no time due to the physiological processes associated with the eye in terms of lachrymal secretion and blinking which causes formulation to drain out and to get diluted. Thus, frequent administration is required, which increases the chances of toxicity and incompliance.

Nanotechnology comes as a very recent approach for ocular targeting and remains an important segment of applied science. By nanotechnology, the use and exploitation of material at their micro- and nano-level is possible and it can be manipulated to achieve incorporation of poorly water soluble drugs, provide protection to drug from degradation, achievement of targeted as well as controlled drug release, better permeation/penetration of tissue, improved pharmaco-kinetics and pharmacodynamics, elimination/mitigation

International Journal of Pharmaceutical Sciences and Nanotechnology

Volume 11 • Issue 3 • May – June 2018MS ID: IJPSN-2-15-18-GUPTA

ABBREVIATIONS: RPE, Retinal Pigment Epithelium; BAB, Blood Aqueous Barrier; BRB, Blood Retinal Barrier; NS, Nanosuspension; NP, Nanoparticle; NM – Nanomicelles; CMC - Critical Micellar Concentration; NE – Nanoemulsion; ME – Microemulsion; HDL - High Density Lipoprotein; SLN - Solid lipid nanoparticles; NLC - Nanostructured lipid carriers; MP – Microparticles; PLA - Polylactic acid; PGA - Polyglycolic acid; PLGA - Polylactic-co-glycolic acid; VEGF - Vascular endothelial growth factor; PNIPAAm - Poly(N isopropylacrylamide); PAMAM - Poly (amidoamine); VEGF - Vascular endothelial growth factor; AMD - Age related maculardegeneration; DME - Diabetic macular edema; HA-VS - Vinylsulfone functionalized Hyaluronic acid; Dex- SH - Thiolated dextran; EVA - Ethylene Vinyl Acetate; PVA - Polyvinyl Alcohol

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4074 Int J Pharm Sci Nanotech Vol 11; Issue 3 • May− June 2018

of toxicity and improvement in therapeutic efficacy of the drugs (Sahoo et al., 2008). It is able to overcome the ocular barriers and is able to release drug within the eye as shown in figure 1. Nanotechnology includes variety of delivery systems ranging from simple lipids to complex polymers. In this review, we have tried to discuss all the recent developments associated with the nanosystems attempted for the eye covering nano-based suspensions, particles, emulsions and micelles, micro based systems particles and emulsions, lipid based systems like lipidic nanoparticles and liposomes, niosomes, along with discussion on recent trends like dendrimers, cyclodextrins, hydrogels, implants, inserts, microneedles and contact lensesbased on the advantages offered by them as shown in Figure 2.

Fig. 1. Comparison between nanoformulations over conventional formulations to pass across the corneal barriers and release the drug.

Fig. 2. Advantages of nanotechnology in ocular drug delivery.

Fig. 3. Nanotechnology in ocular drug delivery.

Various Nanotechnology-based Drug Delivery Systems for Ocular Targeting

Tilldate, many techniques have been tried for ocular targeting, all of which are discussed below along with the recent advancement in them and the drugs for which the system is developed. Figure 3 depicts all the nanotechniques, which are described in the following section.

Nanosuspension (NS)

Nanosuspension is dispersion of water insoluble/ sparingly soluble drugs in suitable vehicle with appropriate suspending agent. It is specifically used for those drugs, which form crystals with high-energy content. Mostly inert materials/resin/polymer is used for this purpose to avoid any kind of incompatibility and irritation. NS formulations have been utilized for different categories of drugs methylprednisolone acetate, triamcinolone acetonide, piroxicam (Stabilizer/ suspending agent: Eudragit RS and RL 100, Eudragit RLPM and RSPM) (Adibkia et al., 2007a; 2007b; Sabzevari et al., 2013), flurbiprofen (Pignatello et al., 2002), ibuprofen (Pignatello et al., 2002) amphotericin B (Eudragit RS100) (Das and Suresh, 2011), acyclovir (pluronic F68) (Dandagi et al., 2009; El-Feky et al., 2013), itraconazole (Ahuja et al., 2015) (poloxamer 188, chitosan), diclofenac (Poly Lactic Glutamic Acid) (Agnihotri and Vavia, 2009), hydrocortisone (poly vinyl alcohol, tween 80, hydroxy-propyl methyl cellulose) (Ali et al., 2011), dexamethasone (crosslinked copolymer of N-isopropylacrylamide, vinyl pyrrolidine and methacrylate) (Rafie et al., 2010) for diverse diseases/disorders such as inflammation, uveitis, infection etc. by using variety of preparation methods like co-precipitation method, quasi emulsification solvent diffusion method, milling and microfluidic nano-precipitation method (Ali et al., 2011).

Nanoparticle (NP)

Nanoparticles are most exploited nanosized colloidal system in which drug may be adsorbed, entrapped, encapsulated or conjugated in polymeric matrix. Depending on the preparation method, which can be used, they are of two kinds; nanocapsule and nanospheres with different drug release profile. Nanos-pheres are small spherical polymeric body in which drug is either incorporated or adsorbed on surface while in case of nanocapsules, polymeric shell is present which surrounds the drug. Mostly nanospheres type of NPs have been used in ocular delivery which gives biphasic release pattern; burst release in the initial time followed by sustained release after some time. It can be prepared from variety of polymers. Polylactide co-glycolide (PLGA) is such a biocompatible, biodegradable material utilized for many drugs like sparfloxacin (Gupta et al., 2010), pirfenidone (Chowdhury et al., 2013), oleanolic acid, ursolic acid (Alvarado et al., 2015), flurbiprofen (Vega et al., 2006), cyclosporine A (Aksungur et al., 2011), dexamethasone (Zhang et al., 2009), triamcinolone acetonide (Sabzevari et al., 2013), acyclovir (Jwala et al., 2011), retinoids (Gao et al., 2012) etc. Not only synthetic


drug molecule, biological molecules can also be loaded in PLGA NPs for example cell penetrating peptide (Vasconcelos et al., 2015), and bevacizumab along with albumin (added to improve stability of bevacizumab and PLGA nanoparticle itself) (Varshochian et al., 2013). Various variants are also attempted to improve their efficiency like cationic or mucoadhesive and bio adhesive NP to enhance retention time on ocular surface, PEGylated NP to enhance circulation time within fluidic barrier.

Mucoadhesive NPs improves residence time, allowing drug to release from formulation and diffuse to the required site. Mucoadhesive polymers like chitosan and its admixture with other polymer or its modified variants for example cross-linked chitosan dextran sulphate NP (Chaiyasan et al., 2015), chitosan gelatine NP (Moraru et al., 2014), N-trimethyl chitosan NP (Asasutjarit et al.,

2017), chondroitin sulphate chitosan NP (Abdullah et al., 2016), hyaluronic acid coated chitosan NP (Kalam, 2016), chitosan and eudragit NP (Tayel et al., 2013) etc. are widely reported for several drugs. Polycaprolactone NP with good physicochemical and biocompatibility properties were prepared and successfully attempted to be loaded in contact lens for prolonged and sustained release of drug (Nasra et al., 2015). Similarly, bioadhesive polymer, polyacrylic acid was utilized to obtain nanoparticles by reverse microemulsion polymerization method with size range 50-250nm, stability at 4˚C, and long term release (more than 24 h) in PBS (De and Hoffman, 2001). Although there is no NP in market but there are some NPs and other nanosystems, which are undergoing clinical trials as, illustrated in Table 1.

TABLE 1

Nanosystems under clinical trials.

Drug Indication/route Ingredients Sponsor Phase Specifications Clinical Trials. gov identifier

Nanoparticle Urea Cataract/topical Pluronic F 127 Assuit University, Egypt II Size 140nm, prepared by

ionic gelation method with glutathione

NCT03001466

Paclitaxel Metastatic melanoma/i.v.

Albumin Ohio State University Comprehensive Cancer Center, USA

II Albumin stabilize the NP NCT00738361

Dexamethasone DME/topical Cyclodextrin King Saud University, Saudi Arabia

II Microparicles NCT01523314

Coenzyme Q10 Ataxia with ocular aparaxia type 1/oral

Lecithin, glycerin Assistance Publique Hopitaux de Paris

III NCT02333305

Liposome Latanoprost Ocular hypertension/

subconjunctival injection

Egg phosphatadylcholine

Singapore Eye Research Institute, Singapore

I/II Successful preclinical study on rabbit and monkey

NCT01987323

Levocarnitine Dry eye/topical Soy lecithin, sphingomyelin, cholesterol

Glasgow Caledonian University, UK

Device: Lamelleye Eyedrops

NCT03052140

Vitamin A, vitamin E

Blepharitis/topical Soy lecithin University of Cologne, Germany

Blephacura NCT01115192

Latanoprost Open angle glaucoma/sub conjunctival injection

Paregrine ophthalmic II POLAT-001 NCT02466399

Vincristine Metastatic Malignant Uveal Melanoma/i.v.

Spectrum Pharmaceuticals, In, USA

II Marqibo NCT00506142

Vincristine Reinalblastoma/i.v. Children oncology group, National cancer institute, USA

III Marqibo NCT00335738

TLC399 RVO, ME/intravitreal Taiwan liposome company, Taiwan

II ProDex NCT03093701

Phospholipids Dry eye/topical spray Phospholipids, preservative free

Aston University, UK Tears again NCT02420834

Phospholipids Dry eye/topical Phospholipids Sun Yat-sen University, China

Liposic NCT02992392

Nanoemulsion Cyclosporine Dry eye/topical Taejoon Pharm Co., Ltd.,

Korea III TJCS 0.05% NCT02461719

Microemulsion Omega 3 Dry eye/topical Hypotonic

microemulsion of PUFA, hydrating polymer

TRB Chemedica AG, Germany

REMOGEN®OMEGA NCT02908282


Nanomicelles (NM)

Polymeric micelles range from 10 to 1000nm which is formed through self-assembly of amphiphilic block copolymers and is formed above critical micellar concentration (CMC). They contain a hydrophobic core which can encapsulate lipophilic drugs and hydrophilic shell which can trap hydrophilic drugs (Vadlapudi and Mitra, 2015). The shell provides stability to the system and it can interact with the bio-membranes. Surface modification of amphiphilic block copolymers can be done to induce bio-adhesion or to provide protection against ocular enzymes or to modify or sustain drug release kinetics. The advantages of using NM system are enhanced solubility of hydrophobic drugs, decreased irritation to ocular tissues, lowering down of drug degradation as well as side-effects, and improved drug permeation through ocular epithelia (Vaishya, 2015). NM formulations are often highly clear and transparent and involves use of polymers such as vinyl pyrrolidone, N-isopropylacrylamide, acrylic acid (Gupta et al., 2000), polyhydroxyehtylaspartamide (Civiale et al., 2009), poly (ethyleneglycol)-hexylsubstituted poly(lactides) (Mondon et al., 2011) and surfactants such as Pluronic F127 (Liu et al., 2006; Schopf et al., 2017), Vitamin E TPGS (Cholkar et al., 2014) and octoxynol-40 (Cholkar et al., 2015) for delivering drugs and/or genes to anterior and posterior ocular tissues (Mandal et al., 2017).

Nanoemulsion (NE)

Nano-emulsions are often used due to the major advantages offered by them in terms of its high loading capacity, stability, increased bioavailability, and good spreadability. Also, the surfactants used in NE serve dual purpose by acting as a emulsifying agents as well as penetration enhancers (Ammar et al., 2009). Chitosan, which is a cationic polymer, is most frequently used in the ocular drug delivery as it can increase the drug permeability across the cornea by opening the tight junctions. It can increase the residence time on the precorneal surface by interacting with mucin, which is negatively charged. Even topical application of NE significantly improves bioavailability in the cornea and aqueous humor (Lallemand et al., 2012). Non-ionic and cationic o/w nanoemulsion are preferably used in ophthalmic as non-ionic is inert for negatively charged ocular surface and cationic is adherent to it. Inertness provides easy permeation of flexible nanosized droplets while adherence to cornea imparts longer residence time improving bioavailability (Badawi et al., 2008; Daull et al., 2014; Gallarate et al., 2013; Lallemand et al., 2012b; Liu et al., 2015; Toutounchian et al., 2000). Restasis® is one such preservative-free anionic oil-in-water NE formulation of cyclosporine A launched by Allergan in 2003 containing castor oil as well as polysorbate 80 along with carbomer copolymer as stabiliser. Apart from this, Lacrinmune® by Bausch and Lomb is yet another formulation of cyclosporine A similar to Restasis® having sodium hyaluronate as an additional component for the treatment of mild to moderate eye diseases. Ikervis®

based on Novasorb® technology is another cationic type of ME again for cyclosporine A by Santen used for the treatment of dry eyes as well as glaucoma which due to the presence of net positive charge on the oil droplets, helps to increase residence time as well as ocular bioavailability (Lallemand et al., 2017).

Microemulsion (ME) ME based approach is becoming very popular nowadays due to its associated industrial and research applications (Stubenrauch, 2009). It is based on the fact of formation of reservoir of drug which can limit its drainage and removal from the eye (Vandamme, 2002). The major advantage associated with the same is its ability to deliver both hydrophilic and lipophilic drugs and the nanostructured transparent isotropic system allows easy corneal penetration (Lawrence and Rees, 2000; Habib and Maher, 2012). They are spontaneously formed and are thermodynamically stable. Their formulation depends on the interfacial tension which needs to be decreased using various amphiphiles (Lidich et al., 2016). W/O and O/W, both kind of MEs are utilized in ocular drug delivery but o/w is the preferred over other owing to similarity with eye drops. Major components of ME are oil, surfactant, cosurfactant and water with additional requirement of tonicity modifier, buffer, antioxidant, and preservative in context of ocular delivery (Hegde et al., 2013). Several permeation enhancers could be added in this to increase its ability to cross the cornea as well as retinal barriers.

Liposome

Liposomes are vesicular systems that comprises of phospholipid bilayers (natural or synthetic) of size in the range 10nm to 1μm, or even greater. They consist of concentric layer of lipid bilayers separated by water compartments and drug gets encapsulated either of the two compartments depending on its solubility (Kaur and Kanwar, 2002). Classification of the liposomes is based on the number of phospholipid bilayers and the associated liposomal size (Agarwal et al., 2016). Drug loading capacity of liposomes is governed by a number of factors such as size, nature of lipid, physicochemical properties of active pharmaceutical ingredient, and method of preparation. Liposome encapsulated drug is usually delivered in the case when high density lipoprotein (HDL) or the phospholipase present in blood degrades the phospholipid layers of liposome causing vesicle damage which then releases the encapsulated drug in the cell (Tsukamoto et al., 2013). The rate of drug release is dependent on the stretch of liposomal membrane erosion. It has also been studied that liposomes follow the non-corneal route in order to target the inner regions of the posterior eye (Mishra et al., 2011). The only marketed liposomal formulation for ocular condition via intravenous route is Visudyne® containing photosensitive drug Verteporfin for photodynamic therapy. Ciprofloxacin (Hosny 2010; Taha et al., 2014) ganciclovir (Shen and Tu, 2007), fluconazole (Habib et al., 2008), diclofenac (Fujisawa et al., 2012), bromfenac (Tsukamoto et al., 2013), prednisolone acetate


(Hosseini et al., 2016) etc. have been explored in this formulation. Some of these liposomes formulated for drugs like diclofenac, bromfenac, coumarin 6 etc. showed their easy accessibility to the retina (Hironaka et al., 2009). Recently light sensitive liposomes (Lajunen et al., 2016) and novel use of mucoadhesive polymer (Tsukamoto et al., 2013) are also explored for liposomal delivery to the eye.

Lipid Nanoparticles

Lipid nanoparticles comprise solid lipid nanoparticle (SLN) and Nanostructured lipid carriers (NLC). SLN are made up of solid lipid and surfactant. Their lipidic nature makes them biocompatible and bioadhesive. Different kind of natural lipids are being used for ocular SLN. Using tristearin and stearic acid as solid lipid and poloxamer 188 and sodium taurocholate (bile salt) as surfactant, Kumar et al obtained valacyclovir loaded SLN (size 202.5±2.56nm, PDI 0.252±0.06, zeta potential -34.4±3.04mV, with EE% 58.82±2.45%), which exhibited >60% drug release in 12 h, and corneal permeability of 22.17±1.41 μg/cm2h (Kumar and Sinha, 2016). Different anti-inflammatory drugs like indomethacin (Hippalgaonkar et al., 2013), cyclosporine A were loaded in SLN made up of compritol ATO888, tripalmitin (Basaran et al., 2010; Gokce et al., 2008). Attama et al developed SLN from goat fat and showed its biocompatibility with ocular surface and efficiency to deliver drug for prolonged time period (Attama et al., 2008).

NLC are the enhanced version of solid lipid nanoparticles with controlled nanostructuring of solid lipids with spatially discordant liquids forming the lipid matrix. The result is augmentation of encapsulation efficiency (drug load), and also restriction of its discharge (Luo et al., 2011). These nanoparticles stick to the surface of the eyes and show retention intrinsically as well as by interacting with the epithelium due to their physiochemical characteristics like its shape, size or charge (Shen et al., 2010). The impressive targeting of the posterior eye disease can be achieved through intrinsic characteristics of surface adhesion, improved surface area, and smooth particle size. A mixture of hydrophilic and lipophilic surfactants is observed to increase stability, and also increases the range for combined hydrophilic and lipophilic loading of the drug (Tej et al., 2016). NLC have an edge due to their reduced precorneal drug loss pertaining to bioadhesion, and hence sustained drug delivery. Incorporation of flurbiprofen, ibuprofen, and cyclosporine A for ocular application in NLC have been reported using gellucire 44/14, miglyol, compritol ATO888, castor oil, stearic acid, tween 80, precifac, chitosan, solutol HS15, Transcutol, cremophor EL and were found tolerable to eye and efficacious in maintaining drug level in aqueous humor (Dai et al., 2010; Gonzalez-Mira et al., 2012, 2010; Liu et al., 2012; Luo et al., 2011; Patel et al., 2012; Shen et al., 2010). Araújo et al., also reported NLC for posterior segment of the eye that showed success in preliminary stages.

Microparticle (MP)

Microparticles have been developed for the ocular targeting as they can easily bypass blood ocular barrier and they can provide sustained effect thus, removing the need for multiple injections (Kothuri et al., 2003). It can either be a matrix or a reservoir system made up of polylactic acid (PLA), polglycolic acid (PGA) or their copolymers polylactic-co-glycolic acid (PLGA) (Bin Choy et al., 2008). These PLGA MPs have been developed incorporating drugs like adriamycin and 5-fluorouracil for proliferative vitroretinopathy, dexamethasone for uveitis, budesonide and celecoxib for diabetic retinopathy, anti-vascular endothelial growth factor (VEGF) for age macular degeneration (AMD), and triamcinolone acetonidefor treating diabetic macular edema (Kompella and Edelhauser, 2011). They are preferred as compared to other delivery options as they are biodegradable and thus, they get degraded at the site of administration automatically after delivering the drug. Sterilization of it can be done easily using gamma radiations and thus, are preferred for retinal repair and diseases.

Hydrogels

Hydrogels are network polymer chain that are three dimensional in nature consisting of water, polymers and pendant groups having a cross-linking. Controlled release of the therapeutic agent can be achieved through it based on the change of pH, temperature, electric current, magnetic field or ultrasound (Fathi et al., 2015). They can be formed through both natural and synthetic polymers and its degradation depends on various enzymes, which are present like amylase, alginase, collagenase and dextranase, which can degrade alginate, starch, collagen and dextran respectively. Synthetic polymers are made up of poly(ethylene glycol), poly(2-hydroxyethyl methacrylate), poly(N-isopropylacrylamide) poly(acrylamide) and poly(acrylic acid) (Ahmed, 2013). Cross linking of poly(N-isopropylacrylamide) (PNIPAAm) can be done with poly(ethylene glycol) diacrylate to formulate hydrogel in which PNIPAAm serve as a hydrophobic part whereas PEG serve as a hydrophilic part (Gandhi et al., 2014). This type of drug delivery system provides a very efficient way to deliver drug to the posterior segment of the eye with minimal invasion (Derwent et al., 2008). A study was conducted by Yu et al, where they formulated hydrogel of bevacizumab which was given as an intravitreal injection showing controlled release for 6 months. Hydrogel was formulated by chemical crosslinking of vinylsulfone functionalized hyaluronic acid (HA-VS) with thiolated dextran (Dex-SH) (Yu et al., 2015). The major limitation of such system is its invasive nature. Thus, subconjunctival or transscleral route should be tried to deliver the drug to the posterior segment of the eye as these are less invasive route as compared to intravitreal administration (Ranta and Urtti, 2006).


Cyclodextrin based Ocular Drug Delivery

Cyclodextrins are groups of hydrophilic cyclic oligosaccharide with 6, 7, or 8 glucose molecules namely α, β and γ cyclodextrin. They have hydrophilic outer surface and inner hydrophobic core. They have been utilized in pharmaceutical science as complexing agent, and as solubilising agent to improve aqueous solubility of poorly soluble drugs. These are novel, chemically stable adjuvant that can enhance ocular bioavailability without sacrificing ocular barrier functions. Topical anaesthetic lidocaine HCl has been successfully incorporated in ocular insert developed with β-cyclodextrin with better physicochemical characteristic, prolonged drug release and higher aqueous humor drug level (Shukr, 2014). Cyclodextrins and their derivatives have been utilized for anterior as well as posterior segment of eye. Ex vivo study on sclera of porcine eye with lutein loaded nanoemulsion containing β-cyclodextrin showed 9 fold enhanced permeation than simple lutein suspension (Liu et al., 2015). Complex of doxycycline and hydroxypropyl β-cyclodextrin entrapped in thermosensitive gel made up of poloxamer was found to stabilize drug and increasing its water solubility proving promising in cases of ocular carcinoma (He et al., 2011). Vavia et al, have developed cyclodextrin based nanosponges loaded with dexamethasone and reported drug release for 300min with good corneal permeability (Swaminathan et al., 2013). Retinal delivery of dexamethasone was achieved with randomly methylated β-cyclodextrin and γ –cyclodextrin by Loftsson et al (Loftsson and Stefansson, 2007; Loftsson et al., 2007b). The study indicated higher levels of dexamethasone when combined with β-cyclodextrinor γ-cylcodextrin as compared to marketed preparation Maxidex®, having 0.1%w/v of dexamethasone in form of alcoholic suspension. In-vivo studies were also performed for the same on female albino rabbits, which indicated enhanced drug delivery to the aqueous mucin layer on the surface of the eye along with increase in drug permeability through the various barriers present in the eye.

Dendrimer

Dendrimers are highly branched tree like 3D polymeric nanostructure. They have initiator core and many layers of repeating units with multitudinous terminal groups and are classified by number of branches and terminal functional groups (Abbasi et al., 2014). Drug molecules can entangle within the branches by physical (vander waals, hydrogen bonding) and/or chemical bonds (covalent, ionic bonding) or can bound to terminal group (Kalomiraki et al., 2016). Pilocarpine and tropicamide were incorporated in poly (amidoamine) (PAMAM) dendrimers and found to increase residence time and were found to be tolerable (Vandamme and Brobeck, 2005). Similarly, puerarin was delivered using PAMAM dendrimers for ocular application and was found to exhibit greater loading and compatibility thereby projecting dendrimers as suitable delivery systems for ophthalmic use (Yao et al., 2010). Hybrid of nanoparticle and dendrimers for ocular application

showing combinatorial or synergistic therapeutic benefit were attempted by Yang and Leffler, 2013. Recently, aza-bisphosphonate capped-poly(phosphorhydrazone) dendrimer (Fruchon et al., 2013) and EXP3174 conjugated with PEG and PAMAM dendrimers (Hennig et al., 2015) were utilized against uveitis and retinal neovascularization respectively for posterior segment and were found promising pharmacokinetically as well as pharmaco-dynamically (Fruchon et al., 2013).

Niosome

Niosomes, just like liposomes are nano-vesicular carrier systems which are formed of amphiphilic non-ionic surfactants having size range between 10 to 1000 nm. They are developed to overcome limitations associated with liposomes in terms of its stability and oxidative degradation which occurs due to the presence of phospholipids in it (Kaur and Kanwar, 2002). Surfactants used in this case are essentially bio-degradable, biocompatible, and nonimmunogenic. It can encapsulate both the water soluble as well as insoluble drugs and can increase their stability (Kaur et al., 2012). In addition, they are non-ionic in nature making them less toxic and are quite easy to handle. They can also improve bioavailability as well as control the drug release at the site of action (Nagalakshmi et al., 2015). Prednisolone acetate (Gaafar et al., 2014) and fluconazole (Kaur et al., 2012) have been incorporated in niosome made up of span 60 and cholesterol and found to impact ocular bioavailability drastically as compared to simple drug solution with no toxicity. A new variant of niosome called spanlastics came into existence recently. It is named so because of its composition (made up of spans specifically) and elasticity (Kakkar and Kaur, 2011; Zafar et al., 2016).

Contact Lenses

Contact lenses represent one of the major advancement in ocular drug delivery that covers the cornea fully and adheres to the tear film to release the drug based on the effect of the surface tension. It provides longer residence time along with higher drug influx rate as compared to the conventional eye drops (Maulvi et al., 2016). Particle laden contact lenses have also been developed which consist of nanosystem having drug dispersed in lens like lidocaine loaded micro-emulsion drops (Gulsen and Chauhan, 2004). Even molecular imprinting based soft contact lenses have also been developed which improves the loading of the drug and improves the drug release like the one developed for timolol delivery (Hiratani et al., 2005). Even, pH and temperature sensitive lenses have been designed which works on a very smart approach to deliver the drug based on the fluctuation of pH or temperature. For example, ketotifen fumarate imprinted lenses (Tieppo et al., 2012) works on this approach only. According to one study conducted by Peng et al., silicon-based contact lenses were used for the controlled delivery of cyclosporine. Addition of vitamin E showed further increase in its duration of action as well as therapeutic


efficiency for the treatment of dry eyes and associated problems (Peng and Chauhan, 2011).

Implants

There are many devices that have been designed to provide controlled and sustained drug delivery profile and are generally placed in the vitreous chamber of the eye. They are gaining lots of attention nowadays as they help to overcome the requirement of the frequent drug administration, helps in local drug delivery, reduces the associated side effects and also helps to overcome the BRB(Yasukawa et al., 2006). These can be biodegradable or non-biodegradable. Currently in the market, non-biodegradable implants made of ethylene vinyl acetate (EVA) polyvinyl alcohol (PVA) (Manickavasagam and Oyewumi, 2013) are more prevalent as they offer sustained release showing zero order kinetics. For example, Vitrasert™ (Kaur and Kanwar, 2002), Retisert™ (Christoforidis et al., 2012) and Iluvein®

(Haghjou et al., 2011) are the implants which are useful to treat the posterior segment eye inflammation. Durasert™ is another implant developed by pSivida for sustained drug delivery of molecules upto three years. (Lallemand et al., 2017). I-vation is an implant developed by SurModics Inc. for sustained release of triamcinolone acetinide (Wang et al., 2013).

The major limitation associated with these non-biodegradable devices is the associated problems on long term use like retinal detachment, increase in intraocular pressure and tissue haemorrhage (Rodrigues et al., 2010). Apart from this, the nanotoxicity associated with such systems needs to be taken care off. So, to overcome these limitations, researchers have also tried certain bio-degradable implants which are made up of polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactones and PLGA (Makadia and Siegel, 2011). For example, Surodex™ and Ozurdex™ (Kompella et al., 2010) are the biodegradable implants which have been designed for the long lasting delivery of dexamethasone to treat intraocular inflammation and diabetic macular edema (DME) respectively (Lee, 2015). Both the systems are available in the market due to the distinct advantages offered by them. Most important advantage of them is their ability to target to ocular tissues without the need of surgery and their specific characteristic feature of being heat and light sensitive. Miniaturization of them is possible by developing multi-particulate system to release drug in a controllable manner (Bourges et al., 2006). Recent technologies also indicate use of silicon to prepare implant for chronic ocular hypotony where the use of silicon, provides implant with more mechanical strength as well makes the system more biocompatible. It makes the implant resistant to biological attack in-vivo and the use of silicon oil mimics the mechanism of buoyant force and works as a long-term vitreous substitute (Bayoudh et al., 2016).

Microneedles

It is again an emerging technique used for posterior segment targeting as it can overcome BRB very easily (Khandan et al., 2015) and it can be designed to penetrate sclera and thus, it can easily avoid deeper tissue damage (Jiang et al., 2017). It also helps to lower down the complications associated with the implants and can also serve as a drug reservoir by depositing the drug between the sclera and choroid called the suprachoroidal space (Patel et al., 2011) which facilitates drug diffusion into deeper ocular tissues. For example, microneedle-based surface coating for the drug sulforhodamine (Kompella and Edelhauser, 2011) have been developed which provides minimum invasive route with maximum efficiency.

Inserts

This represents advancement in the therapy for the eye disease consisting of a device directly placed in the cul-de-sac or the conjunctival sac of the eye. These are multi-layered drug impregnated sterile device providing long lasting drug delivery. These inserts can be soluble, insoluble or bioerodible (Kumari et al., 2010). Insoluble inserts work on the mechanism of diffusion or osmosis. Soft contact lenses also fall under the category of insoluble inserts as it consists of covalently cross linked hydrophilic or hydrophobic polymer matrix which can retain water or aqueous solutions (Rathore and Nema, 2009). Soluble ophthalmic inserts are made up of some natural polymer like collagen or of semi-synthetic or synthetic polymers. Drug is absorbed on the insert by soaking it in the drug solution and the release mechanism depends on the diffusion rate of the drug (Madhuri et al., 2012). Lastly, bioerodible inserts consists of poly (orthoesters) and poly (orthocarbonates) (Higuchi et al., 1976) and drug release from these types of devices depends on the contact of the device with the tear fluid which then causes its bioerosion. Even currently bioadhesive type of ophthalmic drug inserts have also been formulated in order to overcome problems faced with the conventional inserts in terms of risk of discharge at the site of application. So, a bioadhesive component is used in the formulation to decrease this risk and it also helps in prolonged drug release combined with drug release which can be controlled (Kaur and Kanwar, 2002). The classic example in this category is pilocarpine sustained release ocu-sert for the treatment of glaucoma. This type of system was checked on around thirty-four patients for seven days period. Enhanced therapeutic effect along with controlled drug release as well as increased patient compliance was obtained with such system. However, the major barrier faced was its cost along with the problem associated with blurring of vision and lack of encouragement within the patients to use such a system which will reside in the eye (Pollack et al., 1976).

A comparative table for all these technologies is given in Table 2.


TABLE 2

Various nanotechnology-based drug delivery system for ocular segment targeting.

Technology Drug Parameters studied In-vitro study Ex-vivo study In-vivo study References

Nanosuspension 1) Methylprednisolone acetate

Size- 380,460 and 580 nm

Study conducted in rabbit showed inhibition of endotoxin using nanosuspension

(Adibkia et al., 2007)

2) Flurbiprofen

Size - 90 nm Zeta potential – 34.8 mV

Study done using dialysis system showed 40% drug release in 3hr

Done in 3 female New Zealand white albino rabbits and it showed an increase in the duration of action

(R. Pignatello et al., 2002)

3) Ibuprofen

Size - 35-125 nm Zeta potential – 35mV

Study done using dialysis system showed 40% drug release in 3hr

Done in male New Zealand white albino rabbits and it showed gradual and prolonged drug release profile

(Rosario Pignatello et al., 2002)

4) Amphotericin B

Size - 150-290 nm Zeta potential – 19-28 mV

Using dialysis membrane and it showed 60% of drug release within 30min

Draize test in four male albino rabbit showed that formulation showed no ocular irritation

(Das and Suresh, 2011)

5) Acyclovir Size - 150-300nm Drug entrapment efficiency – 95.0%

Using dialysis membrane and it showed 92.14% cumulative release after 24hr

Study done on male albino New Zealand rabbit and it showed decrease frequency of administration, prolonged release and avoidance of eye irritation.

(Dandagi et al., 2009)

6) Itraconazole

Size – 301-1922 nm Zeta potential - >20mV Entrapment efficiency – 72-91%

(Ahuja et al., 2015)

7) Diclofenac

Size – 172nm Zeta potential – -23.7 mV Entrapment efficiency – 95.77%

Study done using dialysis sac and % cumulative release obtained was almost 100% in 16hr.

Study in albino rabbits showed higher anti-inflammatory activity

(Ahuja et al., 2011)

8) Hydrocortisone

Size – 300nm PDI – 0.14

Study done on isolated goat cornea showed increased corneal permeation

Study done in five male albino rabbit and it showed increase in ocular bioavailability

(Ali et al., 2011)

9) Dexamethasone

Size – 650nm

Study done using male albino rabbit and it showed that low dose was required and also the number of instillations also decreased

(Kassem et al., 2007)

Nanoparticle 1) Sparfloxacin

Size – 181nm Zeta potential – -22.5mV PDI – 0.238 Drug loading – 12.3%Encapsulation efficiency – 86.6%

Study done using dialysis sac and % cumulative release obtained was almost 85.8% in 24hr.

Study showed no ocular inflammation or toxicity during HET-CAM test

(Gupta et al., 2010)

2) Cyclosporin A

Size –180nm Zeta potential – 25.2mV

Study done using dialysis sac and % cumulative release obtained was almost 90% in 24hr.

Study was conducted on New Zealand white rabbit and it showed higher ocular bioavailability.

(Aksungur et al., 2011)

TABLE 2 Contd…


Technology Drug Parameters studied In-vitro study Ex-vivo study In-vivo study References 3) Flurbiprofen

Size – 232-277 nm Entrapment efficiency – 93.55-94.60%

% cumulative drug release was 100% in 10hr

Study was conducted on New Zealand white rabbit and it showed no toxicity and irritation.

(Vega et al., 2006)

4) Diclofenac

Size – 131-188nm Zeta potential – 6.3-8.9mV

Study showed initial burst release of 24.23 % in 1 h followed by sustained release of 94.36 % in 24 h

(Asasutjarit et al., 2015)

5) Acyclovir

Size – 495-500nm PDI – 0.16-0.37 Zeta potential – 36.7-42.3mV Encapsulation efficiency – 56-80% Loading capacity – 10 to 25%

Study conducted using dialysis bag showed % cumulative release of 90% over a period of 24hr

Study showed no ocular inflammation or toxicity

(Rajendran et al., 2010)

6) Oleanolic acid/ ursolic acid

Mean diameter - <225nm PI – 0.1 Zeta potential – -27mV Entrappment efficiency – 77%

Study done using rabbit cornea showed increase in corneal retention.

(L Alvarado et al., 2015)

7) Bromfenac

Size – 234-380nm PDI – 0.097-0.232 Zeta potential – 27.52-47.25mV Entrapment efficiency – 47.23-60.02%

Fluoroscein study done on goat cornea showed increase in corneal uptake

(Abdullah et al., 2016)

8) Triamcinolone acetonide

Size – 195-208 nm PDI – 0.11-0.13 Zeta potential - -16.8 to -18.1mV

Study was conducted on New Zealand white rabbit and it showed higher ocular bioavailability.

(Sabzevari et al., 2013)

9) Bevacizumab

Size – 190nm PDI – 0.17 Zeta potential - -24.5mV Entrapment efficiency – 84.1% Loading efficiency – 7.4%

Study was conducted on New Zealand white rabbit and it showed higher ocular bioavailabilityand thus reduced the requirement for frequent administration of injection.

(Varshochian et al., 2013)

Nanomicelle α-lipoic acid Size – 84.7 nm Zeta potenetial – -14.1 mV PDI – 0.13

Eyes of bovine cattle- used and it showed increase in corneal permeability

(Concheiro et al., 2016)

Nanoemulsion Dorzolamide Hydrochloride

Size – 9.8 to 11 nm Viscosity – 4.63 mPasSurface tension – 47.6-50.5 mNm Refractive index – 1.356 Osmolality – 687-1050 mOsm/kg

Study done using dialysis bag showed almost 100% release in 350min

Study in rabbit showed increment in therapeutic efficacy and bioavailability as compared to conventional formulation

(Ammar et al., 2009)

TABLE 2 Contd…



Microemulsion 1) Gatifloxacin Droplet size -51.42nm PDI- 0.145 Zeta potential – -26.25mV drug content – 98.99%

Study done using dialysis bag showed almost80% release in 13hr

Ocular retention study done in rabbits using γ-scintigraphy showed an increase in corneal residence time for a period 10hr.

(Kalam et al., 2014)

2) Voriconazole

Globule size – 210.8 -213.7 nm PDI – 0.055-0.293 Drug content – 61.43%-64.52%

Study done using dialysis bag showed almost80% release in 13hr

Study done on goat cornea showed enhance flux and permeation

Study was conducted on New Zealand white rabbit and it showed decrement in miosis in 6hr.

(Kumar and Sinha, 2014)

3) Pilocarpine hydrochloride

Globule size – 0.695 nm PDI – 0.432 Refractive index - 1.442 ± 0.002 Electrical conductivity – 4.50 ± 0.008

Study done using dialysis bag showed almost 1100μg drug release in 12hr

Study was conducted on New Zealand white rabbit and it showed increment in bioavailability and precorneal residence.

(Chan et al., 2007)

4) Dexamethasone Globule size – 46.6-186.1 nm PDI – 0.317-0.366 Zeta potential – 20.3-26.4 mV

Study using dialysis bag showed almost 100% release in 8hr

(Kesavan et al., 2013)

Liposome 1) Ciprofloxacin

Size – 1630-1850 nm

Study showed almost 75% release in 6 hr and transcorneal permeation was 30.6%

(Hosny, 2010)

2) Ganciclovir

3.9-fold higher release obtained as compared to conventional formulation

1.7-fold higher aqueous humor concentration and 2-10 times more ocular distribution as compared to conventional solution.

(Shen and Tu, 2007)

3) Bromfenac

Size – 123-137 nm PDI – 0.109-0.120 Zeta potential – -3.5 to -22.5mV Entrapment efficiency – 95.9-96%

Almost 80% drug release obtained over period of 24hr

(Tsukamoto et al., 2013)

4) Diclofenac

Size – 0.697-0.816 μm Entrapment efficiency – 28.19-33.61%

Enhanced drug absorption obtained with liposomes in rabbits.

(Elnahas, 2013)

5) Fluconazole

The formulation was able to successfully eliminate C.albicans infection when tested on rabbit cornea.

(Habib et al., 2008)

6) Prednisolone acetate

Size –186nm Zeta potential– -20mV Entrapment efficiency – 95.5% Loading efficiency – 9.06%

% cumulative release obtained was 18% over a period of 150hr

Study was conducted on Wistar rats and it showed higher and more prolonged anti-inflammatory activity.

(Hosseini et al., 2016)

TABLE 2 Contd…



Lipid nanoparticles

1) Indomethacin

Size – 140nm PDI – 0.16 Zeta potential – -21 mV Entrapment efficiency – 72%

Study showed 3-4.5- fold increase in transcorneal permeability

(Hippalgaonkar et al., 2013)

2) Cyclosporin Size – 225.9 nm PDI – 0.194 Zeta potential – -23.6 mV

Study in New Zealand male rabbit showed longer precorneal retention time

(Gökçe et al., 2009)

Microparticles Dexamethsone Size – 20.4μm Increased concentration of drug obtained in vitreous humor after 2 hr

(Loftsson et al., 2007)

Niosome 1)Fluconazole

Size – 140 to 280nm

Study showed 24-33% release in 1hr

2) Prednisolone acetate Size – 180nm PDI – 0.25 Entrapment efficiency – 84%

Complete 100% drug release was observed in 2-3 hr.

Study in albino rabbits showed higher ocular bioavailability as well as good ocular tolerability with minimal irritation.

(Fetihg, 2016) (Gaafar et al., 2014)

Contact lenses Timolol, betaxolol, epinephrine, and latanoprost

Size of lens measured by ruler and water content was measured based on mass of fully hydrated lens and mass of dry lens

18.7% drug release obtained over a period of 4hr for timolol

(Lee et al., 2016)

Ocular inserts Chloramphenicol Uniformity of thickness – 0.11-0.31mm Uniformity of weight – 0.015-0.018gm % moisture absorption – 13.33-20.13% % moisture loss – 10.52-11.1% Drug content – 95.5-96.86%

99.97% drug release obtained in 10 hr

(Khokhar, 2015)

Conclusions

Nanotechnology holds a great scope in the field of ophthalmology for delivering of the drug to the target tissue. It can also be used to prepare certain nanodevices, which can work like an aid during complex eye surgeries and could be utilized to solve solubility related issues associated with certain compounds so that they could be developed as a promising drug candidate for effective targeting to the ocular tissue. In terms of drug delivery, the major purpose of all the techniques is to increase the ocular residence time in order to increase the bioavailability within the ocular tissue. Like if we see, nanosuspension then it holds a great promise, particularly the one developed by quasi emulsification technique as it utilizes no toxic solvent and thus, provides a safe formulation for ocular tissue targeting. In addition, the formulations developed have a positive charge on the surface that allows its easy adhesion to the

corneal tissue. Similarly, microparticles and nanoparticles also holds a very bright future in terms of ocular delivery but certain issues which needs to be taken care for this is the problem associated with the blockade of the lachrymal drainage system due to the aggregation of the particles. Still the use of PEG and chitosan, which makes the system-prolonged release along with having negligible toxicity, makes nanoparticle as a suitable candidate for ocular drug delivery. Likewise, solid lipid nanoparticles are also quite famous as they offer enhanced ocular bioavailability. Other systems are the emulsion system which are the most convenient to prepare and could be used easily for topical eye delivery. However, they suffer from a major limitation due to the surfactants and cosurfactants used in its preparation, which increases the toxicity level, associated with the formulation and makes them unsuitable. To solve these issues, currently researchers


are focusing on some non-ionic surfactants, as they are less toxic as compared to the ionic ones. Apart from this, the colloidal systems which have been discussed also holds a great promise for ocular drug delivery provided various issues associated with the same problems associated with stability, reproducibility and entrapment efficiency are looked upon properly. Hydrogels also serve as a good option to achieve effective ocular targeting provided the problems like blurring of vision associated with the same are looked upon properly.

Other techniques like nanomicelles are also quite efficient in terms of improving solubility related issues with the drug, yet it serves from some major limitations due to lack of research to obtain sustained release from them. In case of cyclodextrin, majorly the problem faced is its hydrophilic nature, which hampers its permeation to the lipophilic corneal membrane. Dendrimer use in ocular drug delivery have provided very promising results during the preclinical trials yet, there is lack of research in this field but it possesses significant opportunities if looked upon properly. Apart from this, contact lenses are also a good option in particular if the drug is trapped in its vesicle to improve the residence time. However, the major concern associated with the same is its transparency level maintenance along with oxygen permeability throughout its shelf life. It should cause no patient discomfort or irritation and should have proper wettability as well as water content to have proper physiological compatibility with the ocular tissues. Microneedle provides a new way to deliver drug to intraocular tissue. Also, currently rapidly dissolving polymeric microneedles or titanium-based microneedles have also been tried along with the development of hollow microneedles which could microinfuse drug solution into the sclera for posterior segment targeting. Apart from this, ocular inserts and implants also exist, but they suffer from the problem of being invasive as well causes certain other problems like retinal detachment hemorrhage and thus causes patient discomfort. However, the fact that they could be placed easily in the intraocular, sub-tenon and intrascleral place in the eye makes them a potent therapy for the treatment of several intraocular diseases. On the other hand, implants also face some of the major limitation due to the cost associated with their manufacturing and the reluctance of the patients to use unfamiliar type of ocular medications.

Hence, as discussed in the above manuscript, all the nanotechnology-based approaches have both positive as well as negative attributes associated to them. Yet, they are one of the most important as well as promising tool for ocular targeting offering higher set of advantages as compared to traditional systems. The major reason behind this is their ability to offer protective as well as effective means for the therapy for nearly inaccessible diseases or syndromes of eyes. Apart from this, recent trends also show amalgamation of various techniques into a single system for morecompetent as well as proficient drug targeting like hydrogel loaded on contact lenses. This type of system intensifies the advantages

associated with the drug delivery system and helps overcomes the challenges faced in case of use of only a specific technique for the delivery approach. Thus, the ongoing research in this field will pave a salient path for further research in this field, which will make ocular drug delivery a very efficient as well as paramount technique at industrial as well as commercial level.

Conflict of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of paper

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Address correspondence to: Dr. Manju Misra, Asst. professor, Department of Pharmaceutics, NIPER-Ahmedabad, Palaj, Opp. Air force station Head quarter, Gandhinagar-382355, Gujarat, India. Ph: +91 79 66745555, +91 79 66745501 E-mail: [email protected]; [email protected]; [email protected]; [email protected]

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