Drug Delivery

ISSN: 1071-7544 (Print) 1521-0464 (Online) Journal homepage: http://www.tandfonline.com/loi/idrd20

A review on therapeutic contact lenses for ocular drug delivery Furqan A. Maulvi, Tejal G. Soni & Dinesh O. Shah To cite this article: Furqan A. Maulvi, Tejal G. Soni & Dinesh O. Shah (2016): A review on therapeutic contact lenses for ocular drug delivery, Drug Delivery, DOI: 10.3109/10717544.2016.1138342 To link to this article: http://dx.doi.org/10.3109/10717544.2016.1138342

Published online: 29 Jan 2016.

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Date: 01 February 2016, At: 00:17

http://informahealthcare.com/drd ISSN: 1071-7544 (print), 1521-0464 (electronic) Drug Delivery, Early Online: 1–10 ! 2016 Taylor & Francis. DOI: 10.3109/10717544.2016.1138342

CRITICAL REVIEW

A review on therapeutic contact lenses for ocular drug delivery Furqan A. Maulvi1, Tejal G. Soni2, and Dinesh O. Shah3,4,5 1

Maliba Pharmacy College, Uka Tarsadia University, Gujarat, India, 2Faculty of Pharmacy, Dharmsinh Desai University, Gujarat, India, Shah-Schulman Center for Surface Science and Nanotechnology, Dharmsinh Desai University, Gujarat, India, 4Department of Chemical Engineering and Department of Anaesthesiology, University of Florida, FL, USA, and 5School of Earth and Environmental Sciences, Columbia University, New York, USA

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Abstract

Keywords

Contact lenses for ophthalmic drug delivery have become very popular, due to their unique advantages like extended wear and more than 50% bioavailability. To achieve controlled and sustained drug delivery from contact lenses, researchers are working on various systems like polymeric nanoparticles, microemulsion, micelle, liposomes, use of vitamin E, etc. Numerous scientists are working on different areas of therapeutic contact lenses to treat ocular diseases by implementing techniques like soaking method, molecular imprinting, entrapment of drugladen colloidal nanoparticles, drug plate/film, ion ligand polymeric systems, supercritical fluid technology, etc. Though sustained drug delivery was achieved using contact lens, the critical properties such as water content, tensile strength (mechanical properties), ion permeability, transparency and oxygen permeability were altered, which limit the commercialization of therapeutic contact lenses. Also issues like drug stability during processing/fabrication (drug integrity test), zero order release kinetics (prevent burst release), drug release during monomer extraction step after fabrication (to remove un-reacted monomers), protein adherence, drug release during storage in packaging solution, shelf life study, cost-benefit analysis, etc. are still to be addressed. This review provides an expert opinion on different methodology to develop therapeutic contact lenses with special remark of their advantages and limitations.

Challenges, critical lens property, ophthalmic drug delivery, sustained drug delivery, therapeutic contact lenses

Introduction Drug delivery to the anterior chamber of eye is a very challenging task for scientists, due to the complex anatomy of eye and resistance to foreign substances, including drugs (Shell, 1982; Lang, 1995; Ding, 1998; Gaudana et al., 2010). At present, majority of the ocular medications are instilled topically either through eye drop solutions or suspensions. However, the conventional eye drop therapy commonly shows low bioavailability to target ocular tissue, due to various precorneal loss factors, such as tearing and blinking (tear dynamics), non-productive absorption through conjunctiva, nasolacrimal drainage and also due to low permeability of the corneal membrane (Prausnitz & Noonan, 1998; Yokoi & Komuro, 2004; Zhu & Chauhan, 2005; Urtti, 2006; Del Amo & Urtti, 2008). Thus, due to physiological and anatomical restrictions, the eye drop solution shows a reduced-drug residence time of 1–3 minutes in the tear film and consequently a very-low bioavailability of 1–3%. To compensate for the low bioavailability, clinicians are forced to prescribe eye drops with frequent doses at high-drug loading, to attain desired therapeutic drug level at the target tissue (Chrai et al., *Address for correspondence: Furqan A. Maulvi, Maliba Pharmacy College, Uka Tarsadia University, Bardoli – Mahuva Road, Tarsadi, Dist. Surat 394350, Gujarat, India. Tel: +91 8238651055. Fax: +91 02625 255882. Email: [email protected]

History Received 17 November 2015 Revised 31 December 2015 Accepted 02 January 2016

1974; Burns & Mulley, 1992; Stone et al., 2009). High-dosing frequency exaggerates the side effects and reduces patient compliance, especially in treatment of chronic diseases like glaucoma and dry eye syndrome (Patel & Spaeth, 1995; Frishman et al., 2000; Fechtner & Realini, 2004; Sˇklubalova´ & Zatloukal, 2005). To overcome the limitations associated with conventional eye drop therapy, novel delivery systems and devices have being explored by many researchers (Nicolson & Vogt, 2001; Shah et al., 2003; Alvarez-Lorenzo et al., 2006a). The ideal drug delivery system delivers a required amount of drug to the ocular tissue with comfort, easy to administer, and does not interfere with vision or normal eye functioning. In this context, therapeutic contact lenses have being proposed for controlled and sustained ocular drug delivery, due to their unique properties like extended wear and more than 50% bioavailability in comparison to eye drop formulation (Li & Chauhan, 2006; Peng et al., 2010, 2012; Gonza´lez-Chomo´n et al., 2013,). Drug releases from therapeutic contact lenses in pre- and post-lens tear film, leading to a residence time of more than 30 minutes, in comparison to just 1–3 minutes for eye drop solutions (Mcnamara et al., 1999; Creech et al., 2001). The high drug residence time increases the bioavailability up to 50%, which eventually reduces the dose, dosing frequency, systemic drug absorption and its associated side effects (Jain, 1988; Li & Chauhan, 2006; Li & Chauhan,

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2007; Xinming et al., 2008). There are many innovations on therapeutic contact lenses to treat anterior ocular diseases which uses soaking method, molecular imprinting, entrapment of drug-laden colloidal nanoparticles, drug plate, ion ligand polymeric systems, supercritical fluid technology, etc. (Xinming et al., 2008; Guzman-Aranguez et al., 2013; Hsu et al., 2014; Carvalho et al., 2015). Scientists do achieve controlled and sustained drug delivery using contact lenses, but the critical properties such as swelling, storage modulus, ion permeability, transparency and oxygen permeability was affected, thus limiting the use of therapeutic contact lenses. This review provides a detailed discussion on different methodology to develop therapeutic contact lenses highlighting their advantages and disadvantages.

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Methodology to design therapeutic contact lenses Soaking method The most simple, cost effective and conventional way to load drug into the contact lenses is by soaking method, which involves soaking the preformed contact lenses in the drug solution, followed by drug uptake and release in pre- and post-lens tear film (Hehl et al., 1999; Sedlacek, 1999; Peterson et al., 2006; Bengani et al., 2013). Contact lenses have internal channels/cavity for receiving/accommodating the drug molecules. Their drug reservoir ability strongly depends on the water content, thickness of lenses, the molecular weight of the drug, soaking time period and concentration of drug in soaking solution (Xinming et al., 2008). As an alternative, one can also insert contact lenses into the eyes and then apply eye drops. By this means, drugs can be absorbed and released by the contact lens (Schrader et al., 2006). Use of therapeutic contact lenses prepared by soaking method, to deliver ophthalmic drugs like timolol (Li & Chauhan, 2007), pilocarpine (Ruben & Watkins, 1975), dexamethasone (Kim & Chauhan, 2008), hyaluronic acid (Maulvi et al., 2015), brimonidine tartrate (Schultz et al., 2009), etc. have been explored by many researchers. Anthony Soluri and co-workers investigated soaking technology using ketotifen fumarate, and found that lenses with charged surfaces [Balafilcon A, Etafilcon A, and Etafilcon A (daily disposable)] showed improvement in drug uptake and release duration. The contact lenses were able to exceed the total amount of drug instilled in eye drop therapy (twice-daily, 0.025%w/v ketotifen fumarate solution). The lenses showed burst release and reached a plateau concentration of drug quickly within few hours (Soluri et al., 2012). Jinku-Xu evaluated soaking method, by loading ketotifen fumarate in silicon hydrogel contact lenses. The drug uptake and in-vitro release kinetics were dependent on the hydrogel composition (hydrophilic/hydrophobic monomers) of the contact lenses. The lenses showed higher drug uptake with increase in hydrophilic phase, while sustained release was observed with increase in hydrophobic phase in the contact lens matrix. In animal study, a more stable drug concentration (424 hours) was observed in tear fluid, in comparison to eye drop therapy (Xu et al., 2011). Schultz investigated uptake and release of timolol maleate and brimonidine tartrate from soaking solution using contact lenses. In-vitro release showed burst

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release of drug attaining plateau within 1 h, while clinical data in glaucoma patients (30 minutes wear per day for two weeks) showed reduction in IOP, which was equivalent to eye drop treatment with 10-times lower dose (Schultz et al., 2009). To extend the release duration, Jinah Kim developed extended wear silicone contact lenses to deliver drugs (timolol, dexamethasone, and dexamethasone 21-acetate) for a period of weeks to months by varying ratios of monomers. Lenses showed diffusion-limited transport and extended release which varied from 20 days to 3 months depending on the composition of hydrophobic and hydrophilic monomers of silicone hydrogels (Kim et al., 2008). Eva Garcia and coworkers improved the drug-loading capacity of triamcinolone acetonide and modulated release profile from soft contact lenses by optimizing hydrogel monomer composition and microstructural modifications using water during the fabrication process (Garcı´a-Milla´n et al., 2015). Though soaking method is simple and cost effective, it has several limitations. High molecular weight drugs or polymers like hyaluronic acid, do not penetrate the aqueous channels of contact lenses and remain on the surface only, which shows failure in sustained drug delivery for the treatment of dry eye syndrome (Maulvi et al., 2015). Contact lenses have low affinity for most of the ophthalmic drugs like timolol maleate, olopatadine HCl, brimonidine tartrate, etc. (Schultz et al., 2009; Maulvi et al., 2014). Due to low affinity, the drug is poorly retained by the contact lenses and released quickly (burst release) followed by a steep decline, indicating that the therapeutic levels were not attained, and drug (extended release) was not released within therapeutic window (Gonza´lez-Chomo´n et al., 2013). For example, drugs like prednisolone, pilocarpine, ciprofloxacin, ketotifen fumarate, timolol, hyaluronic acid were released from hydrogel lenses within few hours (Hull et al., 1974; Ruben & Watkins, 1975; Lesher & Gunderson, 1993; Karlgard et al., 2003). Also, only few scientists have focused on the effects of sterilization and packaging processes on the stability of therapeutic contact lenses, which may cause premature release of the drug. Molecular imprinting Molecular imprinting (MI) is one of the advanced methodologies explored by Alvarez-Lorenzo and co-workers using hydrogel contact lenses for high drug loading and controlled drug delivery (Andrade Vivero et al., 2007). In this technique, the target drug is mixed with functional monomers, which rearrange and interact with drug molecules. After polymerization, the drug from contact lens is removed, which results in formation of tailored active sites or imprinted pockets called macromolecular memory sites, i.e. the 3D structure of drug is left behind within a flexible macromolecular network. The monomers in the hydrogel matrix are organized in such a way that high drug affinity molecular sites are created. These molecular imprinted sites mimic the drug’s receptors or its structurally similar analogy, which increase drug loading capacity (Alvarez Lorenzo et al., 2002; Hiratani et al., 2005b; White & Byrne, 2010). Drug affinity and its release profile are therefore governed by the type of functional monomers used as well as their ratio in the polymeric matrix. Thus one can tailor the release pattern based on monomer composition.

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Stable imprinted cavities can be achieved, by increasing the degree of cross-linking in hydrogel matrix (Alvarez-Lorenzo et al., 2006b; Ali et al., 2007; Venkatesh et al., 2007; Venkatesh et al., 2008; Tieppo et al., 2012). Carmen Alvarez-Lorenzo evaluated the influence of monomers like HEMA, methacrylic acid (MAA) and methyl methacrylate (MMA; 100–400 mM) on drug-loading capacity and release of drug from molecular imprinted contact lenses. They found that, incorporation of MAA as co-monomer (100 mM MAA) in hydrogels increased the timolol-loading capacity (Alvarez Lorenzo et al., 2002). Later Haruyuki Hiratani uncovered the influence of MAA/drug ratio on the conformation of the imprinted cavities. Two-fold increase in release duration was observed with increase in the ratio of MAA/drug (1:16–1:32) (Hiratani et al., 2005b). Likewise, Fernando studied the effect of norfloxacin to acrylic acid ratio (1:2 to 1:16) on drug uptake and release from imprinted hydrogels. Imprinted hydrogels synthesized using 1:4 molar ratio showed maximum sustained release up to 24 h (AlvarezLorenzo et al., 2006b). The effect of different monomer to template ratios and ionic non-covalent interactions was also explored by Arianna Tieppo, to develop molecular imprinted diclofenac-poly(HEMA-co-DEAEM-co-PEG200DMA) soft contact lenses. Zero-order release kinetic was achieved when ratio was increased up to 10.5 (release rate decreases from 11.72 mg/h to 6.75 mg/h during the first 48 hours) (Tieppo et al., 2012). Instead of single monomer use in MI technology, Siddarth demonstrated the use of multiple functional monomers which showed eight times higher drug loading and sustained drug delivery, (Venkatesh et al., 2008). The in-vivo performance of MI contact lenses was evaluated by Hiratani et al. (2005a), they found that lenses developed by the MI technology with 34 mg dose delivered timolol concentrations in the tear fluid for a duration 2- and 3-fold longer than the non-MI lenses with 21 mg dose and eye drops with 125 mg dose respectively. Molecular imprinting strategy was also used by Charles J. White to treat dry eye syndrome, using 120 kDa Hydroxypropyl methylcellulose (HPMC). Extended release up to 60 days was achieved with the rate of 16 mg/day, which significantly varied with functional monomer to template ratio (M/T) (White et al., 2011b). Maryam Ali demonstrated biomimetic MI technology, to deliver hyaluronic acid for 24 h with 6 mg/h release rate (Ali & Byrne, 2009). In summary, the results clearly suggest the influence of functional monomers like MMA, MAA and AA on drug uptake and release kinetics in molecular imprint technology. The limitation of molecular imprinting methodology is the highly cross-linked structure of hydrogel which affects the optical and physical performance of contact lens (White et al., 2011a). The drug-loading capacity is limited by the template molecules and functional monomers, and the deformation (change in dimension) of contact lenses after release of drug was also noted (Schrader et al., 2006). The fall in water content (decrease in swelling) leads to an insufficient ion and oxygen permeability which limit the use of contact lenses for extended wear (Byrne & Salian, 2008). Lei Tang and coworkers developed crowding-assisted molecularly imprinted polymer using polystyrene to achieve zero order release kinetics of drug from contact lenses. The effective diffusivity

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was two-fold smaller in magnitude than conventional molecular imprinting (Tang et al., 2015). Tailoring molar ratios of HEMA-drug-functional monomer-cross-linker, Malakooti coworkers et al., (2015) developed imprinted contact lenses, to achieve sustain the release of polymyxin B and vancomycin. Colloidal nanoparticles laden therapeutic contact lens The technique is based on the ability of colloidal nanoparticles (polymeric nanoparticles, liposomes, niosomes, microemulsion, micelles, etc.) to entrap or encapsulate drug and control its release rate from contact lenses (Gupta & Chauhan, 2010; Jung et al., 2013; Hsu et al., 2014). Such formulated nanoparticular system (10 to 100 nm) is dispersed in HEMA monomers and polymerized using ethylene glycol-dimethacrylate (EGDMA) and photo initiator (DarocurÕ ) to fabricate therapeutic contact lenses (Gulsen & Chauhan, 2004; Bazzaz et al., 2014). Drug laden nanoparticles prevent the interaction of drug with polymerization mixture and also offer additional resistance to drug release. Thus the nanoparticles loaded contact lenses can deliver drugs at controlled rate for extended period of time. Drug loaded nanoparticles or globules (microemulsion) also bypass, to some extent, drug metabolism from the enzymes like lysosomes, present in the tear/corneal epithelial surface (Gulsen & Chauhan, 2005; Gulsen et al., 2005; Jung et al., 2013). The researchers have being successful in developing therapeutic contact lenses for extended drug delivery, while at the same time the transparency (optical), oxygen permeability, ion permeability, mechanical properties, and swelling behavior of contact lenses was altered for comfort wear. Polymeric nanoparticles Many researchers have focused on polymeric nanoparticles using biodegradable and non-biodegradable polymers, to develop therapeutic contact lenses to treat ocular diseases. To treat glaucoma, Hyun Jung and co-workers developed therapeutic contact lenses, by dispersing timolol loaded propoxylated glyceryl triacylate (PGT) nanoparticles in contact lenses. In-vitro release profile shows the presence of drug for one month, and animal studies in Beagle dogs confirmed the reduction in IOP. Although the system showed sustained release, the incorporation of nanoparticle in the silicone hydrogel contact lenses caused reduction in both ion and oxygen permeability, and an increase in storage modulus, suggesting the limitation of the technique (Jung et al., 2013). In another work by Anuj Chauhan and co-workers, timolol encapsulated highly cross-linked nanoparticles (3.5 nm in size) was dispersed in contact lenses which showed increase in drug release duration up to four weeks. The cross-linked nanoparticles were prepared from monomers with multivinyl functionalities such as EGDMA (ethylene glycol dimethacrylate) and PGT (propoxylated glyceryl triacylate). They proposed the mechanism of drug transport, as hydrolysis of ester bonds that link timolol to the particle matrix. The results were very encouraging, though the increase in storage modules (mechanical property) and decrease in water content was observed with increase in particle loading (Jung & Chauhan, 2012). Bibi Sedigheh and co-workers assessed the antimicrobial effects of silver nanoparticles (NP) impregnated

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in hydrogels. They evaluated the antimicrobial effect against Pseudomonas aeruginosa and Staphylococcus aureus, and concluded that, the antimicrobial effect was sufficient to decrease the risk of microbial-related adverse events for extended contact lens wear (Bazzaz et al., 2014). Hardik Chandasana designed corneal targeted nanoparticles laden contact lenses, in order to reduce dose and dosing frequency of natamycin. In-vitro release studies showed extended release up to 8 hours and in-vivo results, showed significant improvement in AUC and MRT in comparison with the marketed preparation (Chandasana et al., 2014). Wenji and co-workers dispersed bovine serum albumin-coated meloxicam nanocrystals (nanoaggregates) in contact lens material to treat post-cataract endophthalmitis. The developed contact lenses showed reduction in ocular irritancy and sustained drug delivery for five days (Zhang et al., 2014). Cyclodextrins In another approach, polymers like cyclodextrins (CDs) and their derivatives were used to achieve sustained drug delivery of hydrophobic drugs. CDs can accommodate many different hydrophobic molecules in their hydrophobic interior (ringshaped structure), to achieve controlled drug delivery (Loftsson et al., 2004). Jinku Xu developed pHEMA/b-CD hydrogels by copolymerization of HEMA with puerarin-b-CD complex. The incorporation of b-CD in the hydrogels resulted in increased swelling and tensile strength. The animal study data revealed increase in drug residence time, with higher concentration of the drug in the tear fluid and vitreous humor in comparison with conventional hydrogel lenses or eye drops therapy (Xu et al., 2010). Garcı´a-Ferna´ndez and co-workers developed therapeutic contact lenses with drug-poly-CD laden hydrogels, crossed linked using citric acid, to achieve sustained delivery of acetazolamide to treat glaucoma. Invitro studies, reported an increase in the drug solubility in poly-CD, an increase of its concentration in the cornea and an extended release over several weeks (Garcı´a-Ferna´ndez et al., 2013). Santos and co-workers copolymerized hydroxyethyl methacrylate with a methacrylated-beta-CD to tailor mechanical, drug (hydrocortisone and acetazolamide) loading and release rate from hydrogel contact lenses. They also observed changes in swelling and storage moduli, with increase in betaCD in contact lenses (Dos Santos et al., 2008). Contact lenses functionalized with cyclodextrins for controlled drug delivery have been generated by Jose-Fernando and co-workers. Hydrogels were copolymerized with glycidyl methacrylate (GMA) and grafted with b-cyclodextrin (b-CD). The b-CDs do not participate or interfere in the hydrogel fabrication process, and thus do not significantly change the optical and physical properties of hydrogel matrix. Improvement in drug (diclofenac) loading by 1300% and sustained drug delivery up to two weeks was detected in lacrimal fluids (Dos Santos et al., 2009). Antimicrobial (5,6-dimethoxy-1- indanone N-4allyl thiosemicarbazone) therapeutic contact lenses were developed by Romina J. Glisoni and co-workers, by engineering pHEMA-co-b-CD, to deliver antimicrobial agent for 2 weeks. Uptake and release profiles were influenced by proportion of b-CD units, mesh size, and degree of swelling of hydrogels (Glisoni et al., 2013). Arslan and co-workers

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achieved controlled release of puerarin from hydrogels fabricated using thiol-modified b-cyclodextrin and allylterminated PEGs via the radical thiolene click chemistry. The swelling, morphology and rheological behavior of hydrogels were modified by tailoring the PEG chain length or by varying the amount of b-CD cross-linker (Arslan et al., 2015). Xiaohong improved the performance of hydrogels for ocular drug delivery by using b-cyclodextrin functionalized hydrogels. Along with sustained drug delivery, b-CD functionalization hydrogels also showed increase in hydrophilicity and reduction in protein adherence (Hu et al., 2016). Liposomes Liposomes are biocompatible and biodegradable, due to their biological membrane-like structure and used in numerous drug delivery applications including ophthalmic drug delivery through contact lenses. Derya Gulsen encapsulated lidocaineloaded dimyristoyl phosphatidylcholine liposomes in the contact lens material. The results show that the hydrogel laden liposomes are transparent and releases lidocaine for a period of about eight days (Gulsen et al., 2005). Drug-eluting contact lenses prepared by Roonal (Jain & Shastri, 2011) using ciprofloxacin-loaded unilamellar liposomes (RELs) and multilamellar liposomes (MLs), were prepared using reversephase evaporation and lipid film hydration method respectively. ML liposomes showed greater sustained release in comparison to REL liposomes, because of the presence of several lipid bilayers. Also, the amount of drug entrapped and released was found to be affected by cholesterol content. Danion immobilized levofloxacin-liposomes on contact lens. In step 1 polyethylenimine was covalently bound onto the hydroxyl groups present on surface contact lens, followed by attachment of NHS-PEG-biotin molecules onto the surface amine groups by carbodiimide chemistry. In step 2, NeutrAvidin was bonded onto the polyethylene glycol (PEG)-biotin layer, and liposomes containing PEG-biotinylated lipids were docked onto the surface-immobilized NeutrAvidin. Subsequent addition of further NeutrAvidin and liposome layers enabled formation of multilayers (Danion et al., 2007b; Guzman-Aranguez et al., 2013). Liposomeladen contact lenses were found to be biocompatible in cytotoxicity study (Danion et al., 2007c). Hydrogel contact lenses with two layers of liposomes showed drug release up to 30 hours, while with 10 layers the drug was released up to 120 hours (Danion et al., 2007a). Though liposomes laden contact lenses showed promising results in extended drug delivery, the presence of multilayer liposomes decreased oxygen and carbon dioxide permeability. Microemulsion and micelles Drug-loaded microemulsion and micelles laden therapeutic contact lenses showed promising results, due to their thermodynamic stability, easy preparation, high drug-loading capacity, increased wettability (low protein adherence) and easy tailoring of drug release pattern. Due to nano size (5100 nm) the optical property of hydrogels remained unaltered. Many researchers focused on the use of microemulsions. Chi-Chung developed timolol-contact lenses with o/w type

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microemulsions using ethyl butyrate and Pluronic F127. The microemulsion showed controlled release of timolol, due to the presence of a tightly packed surfactant at the oil–water interface (Li et al., 2007). Lokendrakumar and co-workers Õ developed ACUVUE contact lenses with ionic surfactants to increase the affinity of ionic dexamethasone 21-disodium phosphate on the charged surface of contact lens. The presence of surfactant did not alter the optical property of the contact lenses, and also had the advantage of increase in wettability, i.e. reduction in protein absorption on contact lens surface. With 10% surfactant loading, the drug release duration was increased from 2 h to 50 h, demonstrating the viability of using surfactant to increase drug-release durations (Bengani & Chauhan, 2013). Derya Gulsen encapsulated timolol in microemulsion which was further stabilized with a silica shell using octadecyltrimethoxysilane (OTMS), followed by dispersion in hydrogels. The fabricated hydrogels showed extended drug release over eight days without affecting the transparency of hydrogels (Gulsen & Chauhan, 2005). Yash Kapoor and co-workers developed nanostructured microemulsions or micelles of Brij 97 laden hydrogels for extended delivery of cyclosporine. The in-vitro release profiles for both micelles and microemulsion-laden hydrogels were relatively similar, with parallel surfactant loading. The article also claims that the developed hydrogels retained their effectiveness even after exposure to all the processing conditions like removal of un-reacted monomers (extraction step), sterilization and packaging (Kapoor & Chauhan, 2008b). Hydrogel contact lenses loaded with silica shell crosslinked methoxy(polyethylene glycol)-block-polycaprolactone (MePEG-b-PCL) micelles (rod-like morphology) were developed by Changhai Lu, for sustained release of dexamethasone acetate. Drug was loaded into the silica shell micelles before fabricating the hydrogels. In-vitro release study showed extended release over a month without altering transparency of hydrogel material for contact lens wear (Lu et al., 2013). Using Brij 98 as the surfactant, Kapoor and co-workers developed and validated a model by varying hydrogel thickness and surfactant loading, to tune the drug release rates from drug-surfactant-hydrogels. The model proposed that, increase in surfactant loading by four fold, can cause reduction in percentage release by two folds (Kapoor & Chauhan, 2008a). To increase the bioavailability of cyclosporine, Chauhan and co-workers developed Brij-laden hydrogels that can release drug at a controlled rate. The hydrogels were found to be effective for cyclosporine, but not as effective for dexamethasone and dexamethasone 21 acetate because of lower partitioning inside the surfactant aggregatesladen contact lenses (Kapoor et al., 2009). Yu Jin Cho and coworkers successfully reduced protein adsorption on hydrogel material by synthesizing a novel tri-branched PEG-substituted hydrazide on hydrogel materials (Cho & Jee, 2015). Use of vitamin E To improve the drug-release duration, Chauhan and his coworkers proposed an approach of in-situ creation of Vitamin E as transport barriers for drug molecules. The release of timolol was significantly extended by increasing Vitamin E

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loading from 10 to 40% in contact lenses, while at the same time complicating oxygen and ion permeability (Peng et al., 2010). Jinah and co-workers developed dexamethasone contact lenses with 30% Vitamin E loading. The drug-release duration was extended for 9 days, which was 16 folds higher compared to the drug-release duration by contact lens without Vitamin E (Kim et al., 2010). Cheng-Chun Peng also developed cyclosporine-laden contact lenses, using Vitamin E as barrier. The in-vitro flux results showed sustained drug release for about a month, using silicon hydrogel contact lenses, due to high partition coefficient of drug in gel, in Õ comparison to hydrogel ACUVUE lens, which showed release for only 24 hrs (due to hydrophilic nature). Such silicon contact lenses demonstrate the promising potential of delivering cyclosporine for the treatment of chromic dry eyes (Peng & Chauhan, 2011). Kuan-Hui Hsu and co-workers incorporated vitamin E as diffusion barriers into the contact lenses to increase the release duration of cysteamine. They observed that loading vitamin E increases the release duration from 10 min to 3 h, thus allowing the possibility of extended drug delivery. In addition to control of drug-release rate, vitamin E also prevented oxidation of cysteamine (Hsu et al., 2013). Cheng-Chun Peng used nano sized hydrophobic vitamin E aggregates as diffusion barrier in silicone contact lenses to extend the release duration for 7 days, for charged (at physiologic pH) esthetic drugs (lidocaine, bupivacaine, and tetracaine). The developed therapeutic contact lenses can be useful for post-operative pain, after photorefractive keratectomy surgery (Peng et al., 2011). Cheng also incorporated Õ vitamin E as a diffusion barrier in ACUVUE TruEyeÔ contact lenses. They found significant reduction in IOP in beagle dogs, with only 20% of drug dose when compared with eye drops therapy (Peng et al., 2012). Kuan-Hui Hsu and coworkers developed drug-eluting contact lenses for treatment of glaucoma by releasing two drugs (timolol and dorzolamide) from single contact lens. The sustained drug release was achieved by using vitamin E as physical barrier (Hsu et al., 2015). Vitamin E, due to its powerful anti-oxidant property protects cornea from UV radiations, and also prevents oxidation of many susceptible drugs. (Nagata et al., 1999; Bilgihan et al., 2001; Yılmaz et al., 2007) Although vitamin E was found to be a promising biocompatible diffusion barrier, which retards the release of many hydrophilic drugs, the researchers should keep in mind the limitations of vitamin E, such as reduction in ion permeability, oxygen permeability, increase in storage module, i.e. change in mechanical properties, protein adsorption due to hydrophobic nature of vitamin E, etc. which may limit the use of vitamin E for development of therapeutic contact lenses. Supercritical fluid technology Supercritical fluid technology (SCF) is one of the mosteffective technologies to load/impregnate both hydrophilic and hydrophobic drug in contact lenses using supercritical solvent like CO2. Impregnation process involve dissolution of drug in supercritical solvent like CO2 (at subcritical or supercritical conditions), followed by interaction with hydrogel contact lenses. The drug loading amount and its release

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kinetics are controlled by tailoring operational parameters like pressure, temperature, processing time and depressurization rate. Viviana P. Costa impregnated acetazolamide and timolol maleate in Balafilcon A contact lenses using a discontinuous supercritical solvent (CO2 + EtOH and CO2 +H2O) impregnation (SSI) methodology. By modifying the co-solvent type and/or its composition, different level of drug impregnation is possible, which can tailor the amount of drug loading and release pattern from the contact lenses without altering the optical and physical properties (Costa et al., 2010a). To overcome the limited application of soaking (can be used for water soluble drugs only) and molecular imprinting techniques, Fernando Yanez developed novel supercritical fluid (SCF)-assisted molecular imprinting technique to endow contact lenses (Hilafilcon B) with the ability to load specific drugs and to control/tailor their release profile. Flurbiprofenloading capacity was increased by sequential SCF flurbiprofen impregnation. The process showed a recognition ability and higher affinity for flurbiprofen in aqueous solution than for the structurally-related ibuprofen and dexamethasone, which propose the formation of molecularly imprinted cavities driven by both physical and chemical interactions. Application of SCF technique, did not alter the critical functional properties of contact lens and showed improved drug loading and extended release, in comparison to conventional molecular imprinting methodology (Yan˜ez et al., 2011). Viviana also studied the effects and interactions of different polymers (hydrogels), operational pressure, impregnation duration and addition of a co-solvent (ethanol) on overall drug loading (amount/yield) in supercritical solvent impregnation technology (SSI). The author demonstrated that, drug impregnation can be easily controlled by tailoring operational conditions, without altering critical lens properties. Such therapeutic contact lenses can be used for extended delivery of both hydrophilic and hydrophobic drugs (Costa et al., 2010b). Ana Rita fabricated molecularly imprinted contact lenses of two template drugs (salicylic acid and acetylsalicylic acid) using supercritical fluid technology. Poly(diethylene glycol dimethacrylate) was synthesized using supercritical CO2 and carboxylic acid end-capped perfluoropolyether oil as stabilizer. The release profile data suggested a correlation between the amount of drug present during the fabrication step, the percentage of impregnated drug and hence the drug release rate (Duarte et al., 2006). Ana Rita also impregnated flurbiprofen in poly(methyl methacrylate-co ethyl hexyl acrylate co- ethylene glycol dimethacrylate), P(MMA-EHAEGDMA) contact lens matrix, and achieved controlled release for 3 months (Duarte et al., 2007). Yuta and co-workers investigated the influence of temperature and pressure on impregnation of salicylic acid using supercritical CO2. They observed that, increase in temperature and low pressure during impregnation process lead to sustained drug delivery from the contact lenses (Yokozaki et al., 2015). Other techniques To circumvent the alterations in optical property of contact lenses, Ciolino and co-workers impregnated ciprofloxacinPLGA (poly[lactic-co-glycolic acid]) films in contact lenses.

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Prototype contact lenses showed nominal initial burst release and demonstrated controlled release for 4 weeks under infinite sink conditions. The release rate from lenses was tailored by changing the drug: PLGA ratios (Ciolino et al., 2009). Later on, they designed latanoprost-eluting contact lens for the treatment of glaucoma, by encapsulating film in methafilcon lenses. In-vivo results showed sustained release for one month. Though the issues associated with alterations in mechanical properties, ion and oxygen permeability, protein adherence, etc. are yet to be addressed (Ciolino et al., 2014). To overcome the limitation of drug release during storage and the loss in mechanical properties, Ho-Joong Kim embedded timolol-loaded Nano-Diamond in contact lenses, which releases timolol only in presence of lysozyme (enzyme-triggered chitosan degradation) (Kim et al., 2014). Koji Kakisu and co-workers investigated the uptake and release of gatifloxacin and moxifloxacin from novel synthesized hydrogel contact lenses (anionic group monomers) using an ion ligand mechanism. Antibiotic uptake and release duration was increased with increase in anionic group monomers in hydrogels. Burst release was observed with all the batches at initial hour, followed by sustained release up to 72 h. In-vivo results showed improvement in penetration of drug into the eye, as well as prevention of bacterial proliferation, in comparison to eye drop therapy (Kakisu et al., 2013). Isabelle and co-workers grafted nisin (an antimicrobial peptide) on hyaluronic acid to achieve an antimicrobial biopolymer in various applications such as wound dressings, contacts lenses, cosmetics formulations, etc. The grafted biomaterial showed antimicrobial activity against Staphylococcus epidermidis, S. aureus and P. aeruginosa (Lequeux et al., 2014). P. Ferreira and co-workers developed a new vancomycin chlorhydrate-eluting contact lens to prevent inflammation after corneal substitution (keratoprosthesis) (Carreira et al., 2014). Table 1 summarizes the methodologies used to develop therapeutic contact lenses for ocular drug delivery with limitations.

Conclusion The therapeutic contact lenses are an excellent alternative to treat chronic ocular diseases, due to their ability to release the drug for extended period of time. In the last 25 years, many novel drug delivery systems have been developed to increase the drug-loading capacity and control the drug-release rate. However the commercialization of such products is still limited. Researchers need to address the issues like impact on critical lens properties such as transparency, mechanical property, water content, ion and oxygen permeability for comfort day and night wear contact lenses. Also issues like lack of drug stability during processing/fabrication (drug integrity test), zero-order release kinetics (prevention of burst release), drug release during monomer extraction step, protein adherence, drug release during storage in packaging solution, shelf-life study, cost-benefit analysis, etc. need to be addressed. Further advancement and improvement in contact lens technology is expected to develop to optimize therapeutic contact lenses, which can be used for extended period of time, without altering optical and physical properties. Once these

Triamcinolone acetonide

Hyaluronic acid (HA)

Aminoglutethimide

Meloxicam

Timolol

Puerarin

Orfloxacin

Ciprofloxacin

Timolol

Timolol

Soaking method

Molecular imprinting

Polymeric nanoparticles

Polymeric nanoparticles

Cyclodextrins

Cyclodextrins

Liposomes

Microemulsion

Microemulsion

Model drug

Soaking method

Methodology

Findings/Results

Fabricated poly(ethylene glycol) (PEG) based chemically cross-linked hydrogels containing discrete b-cyclodextrin. Controlled release up to 8 hours. Improved the performance of hydrogels for ocular drug delivery by using b-cyclodextrin functionalized hydrogels. Increased hydrophilicity and reduce protein adherence. Biocompatible and biodegradable. Better control of release rate. Multilamellar liposomes showed greater sustained release in comparison to unilamellar liposomes. Drug release was affected by cholesterol content. Ethyl butyrate/water microemulsions stabilized by Pluronic F127. Controlled release up to weeks in distilled water. High drug loading was achieved. High drug loading using microemulsion, which was further stabilized with silica shell coating.

High drug loading. Crowding-assisted molecularly imprinted contact lenses using polystyrene. Zero order release kinetics. Sustained drug delivery up to 18 hours. Developed bovine serum albumin-coated meloxicam nanocrystals laden contact lenses to treat postcataract endophthalmitis. Exhibited reduction in ocular irritancy and sustained drug delivery for five days Dispersed timolol loaded propoxylated glyceryl triacylate nanoparticles in contact lenses. One month release (in vitro). Reduction in IOP (Beagle dogs study).

Surface adsorption of high molecular weight polymer (HA). No significant alterations in critical lens property.

Simple and cost effective method. Improved drug loading capacity, by optimizing hydrogel composition and micro structure modification using water during polymerization step. Incorporation of 40% v/v of water in hydrogel showed highest drug loading.

Table 1. Summary of methodology used in drug delivery by contact lenses.

(Maulvi et al., 2015)

(Tang et al., 2015)

(Zhang et al., 2014)

(Jung et al., 2013)

(Arslan et al., 2015)

Low affinity of HA for contact lens. First order release kinetics. Testing mechanical property of lenses is required. Changes in dimension after drug leaching. Presence of nanoparticles showed reduction in storage modulus and swelling behavior. Reduction in both ion and oxygen permeability. Increase in storage modulus. Need sufficient in vivo data, to prove the efficacy and safety of hydrogels. Testing mechanical property of contact lenses is required.

(continued )

(Gulsen & Chauhan, 2005)

(Li et al., 2007)

Rapid release of drug in saline and buffer media. Need to establish animal safety data.

(Jain & Shastri, 2011) Presence of multilayer liposomes decreased oxygen and carbon dioxide permeability.

(Hu et al., 2016)

(Garcı´a-Milla´n et al., 2015)

Reference

High burst release. Drug release up to 24 hours.

Comments/Notes

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DOI: 10.3109/10717544.2016.1138342

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(Kim et al., 2014)

(Ciolino et al., 2014)

(Yokozaki et al., 2015)

(Hsu et al., 2015)

Reference

issues are resolved, the therapeutic contact lenses will change the way ocular diseases are treated.

Declaration of interest The authors report no conflicts of interest and have no proprietary or commercial interests in any concept or product or material discussed in this paper.

Intra subject variability in release rate profile could be observed, as the level of lysozyme may vary from person to person and diseases status. Lack of in vivo data to support concept.

Need supporting data of oxygen permeability, mechanical property, effect of packaging solution, etc.

Studies like mechanical properties, ion and oxygen permeability are needed, to confirm the effectiveness of system. Drug release up to 8 h. Salicylic acid

Latanoprost

Timolol

Supercritical fluid technology

Impregnation of film in contact lens

Enzyme triggered

Simultaneous loading of timolol and dorzolamide. Inclusion of Vitamin E aggregates showed controlled drug delivery. Reduction in IOP for 4 days was observed in Beagle dog. Improved drug loading capacity. Higher temperature and low pressure in the impregnation process resulted in sustained release from contact lens. Fickian controlled release. Designed latanoprost-eluting contact lens. In-vivo results showed sustained release for one month. The contact lens appeared safe in both cell culture and animal studies. Synthesized timolol loaded nano-diamond nanogels by cross-linking polyethyleneimine coated nanodiamonds and partially N-acetylated chitosan. Delay release up to 48 h was noted in presence of lacrimal fluid lysozyme. Timolol and Dorzolamide Vitamin E

Extended drug release over 8 days without affecting the optical property of hydrogels.

Comments/Notes Findings/Results Model drug Methodology

Table 1. Continued

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