New Era of Ocular Drug Delivery Systems Based on Contact Lenses

FABAD J. Pharm. Sci., 45, 2, 161-174, 2020

Review Articles New Era of Ocular Drug Delivery Systems Based on Contact Lenses

Panoraia I. SIAFAKA* , Ayşe Pınar YAĞCILAR** , Neslihan ÜSTÜNDAĞ OKUR***º

New Era of Ocular Drug Delivery Systems Based on Contact Kontakt Lenslere Dayalı Oküler İlaç Taşıyıcı Sistemlerde Lenses Yeni Dönem

SUMMARY ÖZ

Ocular drug delivery belongs to the most useful topical adminis- Oküler ilaç taşınması en kullanışlı topikal ilaç uygulama yol- tration routes. Ocular drugs are applied on the eye mostly as ocular larındandır. Oküler ilaçlar, çoğunlukla göz damlaları olarak drops. However, eye drops present many limitations such as poor göze uygulanır. Ancak göz damlaları gözde kalış süresinin kı- eye retention time and rapid drug removal from tear drainage. salığı ve gözyaşı drenajı ile hızlıca ortamdan uzaklaştırılma Currently, contact lenses as ophthalmic drug carriers have become gibi çeşitli sınırlamalar gösterir. Son dönemde, kontakt lensler very popular since they can extent the drug release time and ther- ilaç salım süresini ve terapötik etkinliğini arttırarak oftalmik apeutic efficacy.I t seems that contact lenses which are applied to ilaç taşıyıcı sistemler olarak popüler olmaya başlamıştır. Gözün the anterior chamber present extremely increased bioavailability ön odacığına uygulanan ve düşük biyoyararlanıma sahip göz above 50% which compared to low bioavailability of eye drops is damlalarına kıyasla biyoyararlanımı %50’nin üzerinde artı- highly beneficial. Moreover, via the topical delivery of ocular drug ran kontakt lenslerin son derece faydalı olduğu görülmüştür. contact lenses side effects are diminished whereas patient compli- Ayrıca, oküler ilaç içeren kontakt lenslerin topikal uygulan- ance is improved. Despite their advantages, contact lenses as oph- masıyla yan etkiler azaltılırken hasta uyuncu da artırılmış- thalmic carriers have not been marketed yet. Nonetheless, the last tır. Avantajlarına rağmen oftalmik taşıyıcılar olarak kontakt decade, the research interest focused on developing novel contact lensler henüz piyasada satışa sunulmamıştır. Bununla birlikte, lenses which can deliver controllable the drugs to the eye. In this son on yılda yapılan araştırmalar kontrollü salım sağlayabilen review, we summarize the found on literature ocular drug deliv- yeni geliştirilen kontakt lenslere odaklanmıştır. Bu derlemede, ery systems based on contact lenses according to their compounds, literatürde bulunan bileşimlerine, tasarımlarına ve diğer ka- their designing methods as other characteristics. It can be said that rakteristiklerine göre kontakt lenslere dayalı oküler ilaç taşıyıcı in the foreseeable future more and more topical eye drug delivery sistemleri özetledik. Öngörülen gelecekte daha fazla topikal ilaç systems will be appeared and contact lenses seem to provide the taşıyıcı sistemlerinin ortaya çıkacağı ve kontakt lenslerin iste- most desirable characteristics. Thus, the drug loaded contact lenses nen özellikleri sağlayacağı söylenebilir. Bu yüzden ilaç yüklü will bring a new evolution on the current marketed ocular for- kontakt lensler güncel oküler formülasyonlara yeni gelişmeler mulations. To conclude, this review could be helpful for medical getirecektir. Sonuç olarak, bu derleme sağlık profesyonelleri, of- professionals, ophthalmologists and scientists of every subject who talmolojistler ve yeni oküler kontakt lens geliştirmek isteyen her want to develop novel ocular contact lenses. konudan araştırmacılar için yararlı olacaktır.

Key Words: Ocular, Drug delivery, Contact lenses, Hydrogels, Anahtar kelimeler: Oküler, İlaç taşınması, Kontakt lens- Polymers, Drug design ler, Hidrojeller, Polimerler, İlaç tasarımı

Received: 31.12.2019 Revised: 12.02.2020 Accepted: 12.02.2020

* ORCID: 0000-0001-7256-3230, Aristotle University of Thessaloniki, Faculty of Sciences, School of Chemistry, Thessaloniki, Greece ** ORCID: 0000-0001-5546-4601, University of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Turkey *** ORCID: 0000-0002-3210-3747, University of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Turkey

º Corresponding Author: Neslihan ÜSTÜNDAĞ OKUR Phone: +90 216 418 96 16, E-mail: [email protected] 161 Siafaka, Yağcılar, Üstündağ Okur

INTRODUCTION Üstündağ Okur et al., 2019) and ocular inserts such Ophthalmic diseases can be categorized as acute (R. as contact lenses (Alvarez-Lorenzo, Anguiano-Igea, Gupta, 2003) and chronic (N. Gupta & Kocur, 2014). Varela-García, Vivero-Lopez, & Concheiro, 2019) and In most cases, ocular diseases are not life-threatening, films (Kapoor & Chauhan, 2008; Üstündağ-Okur et however, if they left untreated can lead to blindness al., 2014; Üstündağ-Okur et al., 2015) are applied as or blurred vision. Eye is very complex organ and thus possible sustained release drug carriers. The contact ocular drug delivery belongs to the most challeng- lenses seem to provide various promising character- ing field of drug administration routes (Siafaka et al., istics and thus should be further evaluated in clinical 2015; Üstündağ-Okur et al., 2014; Üstündağ-Okur, trials and in vivo studying. Yoltas, & Yozgatli, 2016; Üstündağ-Okur et al., 2015). Currently, topical application of ocular drugs is pre- Contact lenses (CLs) are ocular prosthetics devic- ferred since the systemic administration cannot reach es placed on the eye surface. They are widely used for eye efficiently (Başaran & Yazan, 2012). As topical eye correcting vision, aesthetics and therapeutic appli- formulations and most marketed products are used cations (Farandos, Yetisen, Monteiro, Lowe, & Yun, the conventional eye drops or suspensions. Howev- 2015). The first corneal lenses were developed, in 1949 er, such formulations demonstrate very low ocular bioavailability and thus should be frequently dosing. whereas on 1960 the first corneal lenses based on poly Their low bioavailability resulted from various factors, (methyl methacrylate)-PMMA were used. In present, such as rapid removal of drug due to nasolacrimal CLs are manufactured by PMMA, poly (hydroxyleth- drainage, tearing and blinking as well as low permea- yl methacrylate)- PHEMA (Achilias & Siafaka, 2017; bility of the corneal membrane (Maulvi, Soni, & Shah, Achilias, Siafaka, & Nikolaidis, 2012) and other ma- 2016; Siafaka et al., 2015; Üstündağ Okur, Yozgat- terials such as silicone and poly (vinyl alcohol)-PVA, lı, Okur, Yoltaş, & Siafaka, 2019). Due to the above, (Musgrave & Fang, 2019) (Figure 1). PMMA was first novel formulations are designed aiming to overcome applied as CL compound however due to its limited such drawbacks. Colloidal suspensions (Siafaka et al., oxygen permeability, it was replaced by PHEMA. The 2015), matrix systems, liposomes (Taha, El-Anazi, El-Bagory, & Bayomi, 2014), microemulsions (Ke- manufacture of optimal CLs associated strictly with savan, Kant, Nath Singh, & Kumar Pandit, 2013), the macromolecule and its polymerization conditions dendrimers (Chaniotakis, Thermos, & Kalomira- such as temperature, initiator type, polymerization ki, 2016), in–situ gels (Üstündağ-Okur et al., 2016; mechanism (Musgrave & Fang, 2019) etc.

Figure 1. The chemical structures of common polymers develop CLs

162 FABAD J. Pharm. Sci., 45, 2, 161-174, 2020

Contact lenses (CLs) as drug delivery systems 3 minutes of eye drops to more than 30 minutes. Thus, were first introduced in 1965 by Sedlacek (Kumar & the ocular bioavailability is also improved whereas Jha, 2011). It has been reported that as drug eluting dose frequency is eliminated and the drug is absorbed CLs, the silicone hydrogels and other hydrogels are of and reaches target ocular tissues. In addition, the drug the most optimal candidates (Jiawen Xu et al., 2018). systemic absorption is avoided and the related side ef- Mostly, CLs are used as therapeutic tools for ocular fects are also diminished (Kumar & Jha, 2011; Maulvi surface and anterior chamber disorders. Besides, CLs et al., 2016). have been reported to be applied as posterior segment The preparation methods for the development of diseases management (Guzman-Aranguez, Colligris, CLs loaded drugs (Figure 2) are: a) soaking meth- & Pintor, 2013). From pharmacological aspect, anti- od, b) molecular imprinting and c) encapsulation of microbials, corticoids, anti-inflammatory, immuno- colloidal nanoparticles into CLs. In case of soaking suppressants, lowering of ocular pressure agents are method, CLs are soaked in drug suspension, followed loaded in contact lenses so as to treat various diseases by drug uptake and release in pre- and post-lens tear (Holgado, Anguiano-Domínguez, & Martín-Ban- film. This method which is the easiest handled tech- deras, 2020). In further, CLs intended to be used as nique presents various disadvantages such as burst drug carriers should possess comfort, cytocompati- effect and rigorous release. On the other hand, the bility and prolonged release (Ciolino et al., 2009). In retention time compared to the conventional formu- fact, CLs present unique features such as increased lations is improved (Bengani, Hsu, Gause, & Chau- bioavailability, extended wear time and improved re- han, 2013; Hehl, Beck, Luthard, Guthoff, & Drewelow, tention time. Considering that the contact lenses are 1999; Peterson, Wolffsohn, Nick, Winterton, & Lally, solid formulation can extent retention time from 1 to 2006).

Figure 2. A schematic illustration of preparation methods of drug loaded CLs

The second technique molecular imprinting polymerized. Afterwards, drug is extracted from con- shows various advantages such as great retention time tact lenses leaving macromolecular memory sited and and controlled drug release. At this case, high drug resulting in printing of 3D structure of drug into the loading is also achieved. During this method, the tar- polymeric network. Thus, an increased drug loading get drug is blended with the chosen monomers and capacity is provided (Alvarez-Lorenzo et al., 2002; Hi-

163 Siafaka, Yağcılar, Üstündağ Okur ratani, Mizutani, & Alvarez-Lorenzo, 2005; White & load drugs into contact lenses. During this technique,

Byrne, 2010). In the third technique, colloid nanopar- the drug is dissolved in supercritical solvent like CO2 ticles i.e. polymeric nanoparticles, liposomes, nio- (at subcritical or supercritical conditions), followed somes, microemulsion, micelles impregnated drug by interaction with hydrogel contact lenses (Costa et and further loaded in CLs. During this method, drug al., 2010). In addition, the drug loading can be con- is released in a prolonged way and also ameliorate the trolled by altering several parameters such as pres- possibility of drug degradation (C. Gupta & Chau- sure, temperature, processing time and depressuriza- han, 2010; K. H. Hsu, Gause, & Chauhan, 2014; Jung, tion rate (Costa et al., 2010). The possible structures Abou-Jaoude, Carbia, Plummer, & Chauhan, 2013). of the developed CLs due to the different preparation Another interesting technique is the supercritical flu- methods are seen in Figure 3. id technology which is widely applied as method to

Figure 3. The possible structures of drug loaded CLs

Aim of this study, was to summarize the current (Sharma, Verma, Prajapati, & Pandey, 2013), can be drug delivery systems based on CLs due to their pos- overcome with the utilization of drug loaded CLs. At sible therapeutic efficacy and disease target. Thus, the first, the position of CLs onto the cornea can separate contact lenses were categorized according to their the tear film from the external environment limiting drug incorporation to systems for glaucoma, inflam- the tear mixing and exchange (Muntz, Subbaraman, matory, allergic and infection ocular disorders. Sorbara, & Jones, 2015). Consequently, the drug can be eluting from the CLs in a sustained manner since ADVANTAGES OF CONTACT LENSES AS the molecule residence time is prolonged (Kakisu, OCULAR DRUG DELIVERY SYSTEMS Matsunaga, Kobayakawa, Sato, & Tochikubo, 2013). The CLs compared to other topical eye drug de- In further, many active molecules can be entrapped livery systems provide greater characteristics. As it in the CLs, generalizing and prolonging their thera- was mentioned, the ocular delivery presents various peutic action. The prolonged release minimizes the limitations due to various eye barriers (Üstündağ frequent dosing improving the patient compliance. Okur et al., 2019). In fact, the continuous tear dilu- As topical system, the drug loaded CLs eliminate the tion, the drug drainage due to blinking and tear flow, drug of being absorbed from systemic circulation the non-specific absorption, and the irregular drug limiting its possible systemic side effects (Güngör, Er- penetration which the conventional eye drops induce dal, & Aksu, 2013). 164 FABAD J. Pharm. Sci., 45, 2, 161-174, 2020

OCULAR DRUG DELIVERY BASED ON CON- various drugs into the eye can be achieved by using TACT LENSES-THERAPEUTIC APPLICATIONS ocular CLs which are capable of loading both hydrophilic and hydrophobic drugs. Biodegradable or In this part, CLs as drug delivery systems are cat- non-biodegradable and biocompatible polymers are egorized according their possible therapy (Figure 4). formulated on CLs aiming to produce conatct lenses As it was already mentioned, CLs can load drugs for with minimize side effects. both acute and chronic diseases. Topical delivery of

Figure 4. Ocular drug delivery based on contact lenses

Glaucoma tact lenses present negative effects (Jung et al., 2013). Similarly, crosslinked NPS based on propoxylated Glaucoma is the second notable cause of optic glyceryl triacylate and ethylene glycol dimethacry- nerve eventual damage and vision loss worldwide late encapsulated TIM and loaded into contact lenses. (Jung et al., 2013). Various drugs are applied for glau- The drug loaded particles were dispersed in hydroxy coma management but topical drops of β-adrenergic methyl methacrylate (HEMA) gels, the common ma- blockers, such as timolol maleate (TIM) (Siafaka et terial for CLs. Herein, the drug was also released in al., 2015), or miotics such as pilocarpine (Karasulu, a prolonged manner for 4 weeks. It was resulted that Ince, Ates, Yavasoglu, & Levent, 2015) are exten- the mechanical strength was improved whereas the sively applied. Many researchers have focused on water uptake was decreased demonstrating promising polymeric nanoparticles using biodegradable and characteristics (Jung & Chauhan, 2012). In another non-biodegradable polymers, to develop therapeu- study, PHEMA CLs entrapped ethyl cellulose micro- tic contact lenses to treat ocular diseases. Therapeu- particles of TIM as therapeutic system for glaucoma. tic silicone hydrogel contact lenses were developed The microparticles were prepared by spray drying by incorporating propoxylated glyceryl triacylate and dispersed in CLs. It was demonstrated that TIM nanoparticles-NPs loaded with TIM. The preparation was released for 48 hours due to its formulation on of nanoparticle-laden silicone hydrogels was accom- microparticles (Maulvi, Soni, & Shah, 2015). Micro- plished by adding particles to the polymerization mix- emulsions (MEs) based contact lenses have been de- ture followed by free radical polymerization. In vivo signed from various researchers. For example, timolol studies on beagle dogs revealed that decrease on in- loaded CLs lenses were loaded with o/w MEs of ethyl traocular pressure whereas in vitro release confirmed butyrate and Pluronic F127. The free radical solu- prolonged release for 30 days. Nonetheless, the use of tion polymerization with UV initiation was applied NPs reduce ion and oxygen permeability and the con- 165 Siafaka, Yağcılar, Üstündağ Okur for the microemulsion-loaded p-HEMA hydrogels. (comfort agent)-loaded semi-circular ring-implanted A controlled release of TIM was also depicted which CLs were developed by Desai et al. The active molecules is essential for glaucoma therapy (Li, Abrahamson, were entrapped using the soaking method. In vitro release Kapoor, & Chauhan, 2007). In another study, TIM studies revealed prolonged release for 4 days while in vivo was incorporated in MEs stabilized by silica shell us- studies in rabbit model exhibited the TIM presence till ing octadecyltrimethoxysilane and were further dis- 3 days after administration. Similarly, in vivo pharma- persed in hydrogels. The CLs were synthesized by free codynamics studies exhibited decrement on intraocular radical solution polymerization of the monomer with pressure with lower dosing than conventional eye drops chemical initiation. A prolonged release over 8 days (Desai et al., 2018). Guidi et al studied hyaluronic acid was achieved (Gulsen & Chauhan, 2005). CLs soaked ability to alter TIM release from 2-hydroxyethyl meth- in TIM and brimonidine tartrate solution were ob- acrylate with 3-methacryloxypropyltris (trimethyl- tained by Schultz et al. As it was expected, a burst siloxy) silane (TRIS) or N,N-dimethylacrylamide phenomenon was provoked followed by sustained re- (DMA) with TRIS molecular imprinted hydrogel CLs. lease. Clinical studies which were accomplished with It can be said that TIM was released for 2 days (Guidi, reduced dose frequency, justified decrement on intra- Korogiannaki, & Sheardown, 2014). Korogiannaki et ocular pressure (Schultz, Poling, & Mint, 2009). An- al. developed CLs from a hydrophilic monomer, either other study evaluated molecular imprinted CLs com- 2-hydroxyethyl methacrylate or N,N-dimethylacryl- prised from hydroxyethyl methacrylate, methacrylic amide and a hydrophobic silicone monomer of meth- acid and methyl methacrylate. The drug loading rate acryloxypropyltris (trimethylsiloxy) silane and loaded of TIM was efficiently increased (Alvarez-Lorenzo et with TIM using as wetting agents hyaluronic acid or al., 2002). However, the study lacks of in vivo results. PVP. The loading was achieved during the synthesis of Anirudhan et al. prepared molecular imprinted CLs the silicone hydrogels via the direct entrapment meth- based on TIM imprinted copolymer of carboxymethyl od. TIM was sustainable released from 4 to 14 days de- chitosan-g-hydroxy ethyl methacrylate-g-polyacryl- pending on wetting agents ratio (Korogiannaki, Guidi, amide impregnated into PHEMA. A sustained release Jones, & Sheardown, 2015). Both studies should be was depicted for TIM loaded CLs which according to further evaluated for their in vivo performance. authors’ opinion can achieve the therapeutic efficacy Besides TIM, also other drugs as latanoprost, needed in glaucomatous patients (Anirudhan, Nair, & travoprost and bimatoprost are applied for Glaucoma Parvathy, 2016). TIM and Acetazolamide were signifi- management. Horne et al. developed silicone hydrogel cantly entrapped in Balafilcon A-silicon hydrogel CLs lenses soaked in latanoprost solution. A controlled re- using a discontinuous supercritical solvent method. lease was achieved for 96 hours (Horne, Judd, & Pitt, It was revealed that drugs were released in moderate 2017). The same group, recently, revealed that more pattern (Costa et al., 2010). Numerous works involved latanoprost could be loaded into silicone hydrogel the use of lipophilic vitamins such as Vitamine A lenses than PHEMA CLs (Horne, Rich, Bradley, & (VitA) and E (VitE) as agent enhancer agents. TIM re- Pitt, 2020). In both cases, a sustained release was de- leased in greater extent when VitE was also incorpo- picted which is desirable for glaucoma therapy. Lata- rated in CLs (Peng, Kim, & Chauhan, 2010). Similar- noprost-eluting low-dose CLs and high-dose CLs were ly, drug-eluting CLs sustained the release of TIM and produced by encapsulating a thin latanoprost-polymer Dorzolamide when VitE was also loaded (Kuan Hui film within the periphery of a methafilcon hydrogel. In Hsu, Carbia, Plummer, & Chauhan, 2015). A recent vivo studies in glaucomatous monkeys demonstrated study, involve the use of VitE and VitA into hydro- sustained release of drug and great intraocular pres- gel CLs based on PHEMA. It was revealed that TIM sure reduction (Ciolino et al., 2016). Previously, Cioli- and brimonidine were loaded in great extent although no et al. produced Latanoprost-eluting contact lenses their hydrophilic nature. However, in vitro release did encapsulating latanoprost–PLGA films in methafilcon not change (Lee, Cho, Park, & Kwon, 2016). A very in- by ultraviolet light polymerization. In vitro and in teresting idea involved the use of light-mediated drug vivo studies showed an early burst of drug release fol- eluting CLs. The prepared CLs released TIM due to lowed by sustained release for one month (Ciolino et natural daylight exposure at more therapeutically op- al., 2014). Conventional PHEMA based CLs and sil- timal doses compared to conventional formulations. icone hydrogel soft CLs were soaked in Latanoprost The cost effective CLs could really act as promising solution and studied for their efficacy. In vitro results and alternative drug delivery system against Glau- showed their possible efficacy as anti-glaucoma agents coma as well as other ocular disorders (Mu, Shi, Liu, (Mohammadi, Jones, & Gorbet, 2014). Chen, & Marriott, 2018). In further, another promising system composed by TIM and hyaluronic acid 166 FABAD J. Pharm. Sci., 45, 2, 161-174, 2020

Anti-inflammatory ocular conditions ity and sustained release of drug to 2 days (Bengani & Chauhan, 2013). Another study, involved the use Inflammatory ocular diseases are disorders of high of hydrogel CLs based on methoxy (polyethylene gly- prevalence and seem to concern high part of popu- col)-block-polycaprolactone micelles for the encapsulation. Dry eye disorder and allergic conjunctivitis lation of DXM acetate. More specifically, the drug was (Jeng, 2018) as well as uveitis which is the inflamma- entrapped on the micelles and then incorporated in tion of the uvea are of the most known. Various active the lenses. The obtained data showed prolonged re- ingredients loaded eye drops have been used as an- lease for more than 30 days (Lu, Yoganathan, Koci- ti-inflammatory agents, which lack of bioavailability. olek, & Allen, 2013). DXM was entrapped in CLs with Ocular allergies are also quite common health prob- 30% VitE so as its release to be extended. The drug was lem. It is believed that the use of CLs as anti-allergic loaded in the CLs via two ways; by direct addition of carriers can act as a physical barrier against airborne the drug in the VitE–ethanol solution before soaking antigens and as drug carriers which can improve the the pure lens in the solution or by soaking the VitE treatment of ocular allergies (González-Chomón, Sil- loaded lenses in a drug-PBS solution. In fact, DXM va, Concheiro, & Alvarez-Lorenzo, 2016). The dry eye was released for 9 days revealing that VitE can act as syndrome is a multifactorial disorder, which is relat- dissolution enhancer agent (Kim, Peng, & Chauhan, ed with patient discomfort, inflammation, visual dis- 2010). A more promising study included the use of turbance, and tear film instability, which can lead to Chitosan NPs which firstly loaded with DXM and af- ocular surface damage. In most cases rewetting can- terwards added in PHEMA CLs. In vitro release pro- didates are utilized as topical installations (McCann, file depicted a sustained rate for 10 days up to 22 days. Tomlinson, Pearce, & Papa, 2012; Vogel, Crockett, This fact induced great ocular bioavailability (Behl, Oden, Laliberte, & Molina, 2010) Iqbal, O’Reilly, McLoughlin, & Fitzhenry, 2016). Kim Endophthalmitis is a serious intraocular infection et al. produced extended wear silicone contact lens- that occurs as post- surgery complications causing es for the delivering of TIM and DXM. The drug was visual impairment or blindness. The utilization of loaded by soaking the gel in drug-PBS solutions. The topical applied nonsteroidal anti-inflammatory either CLs revealed extended release as it is required for oc- prophylactically or as treatment for ocular post-cata- ular inflammatory disorders (Kim, Conway, & Chau- ract surgery inflammation is recommended (Taban, han, 2008). Flurbiprofen is also a common applied 2005). Thus, meloxicam aggregates of nanocrystals non-steroidal anti-inflammatory molecule applied as coated by bovine serum albumin were dispersed in ocular therapeutic. A study involved its loading into PHEMA CLs showing sustained release. However, endow CLs known as Hilafilcon B via supercritical the study should be reinforced with in vivo results fluid (SCF)-assisted molecular imprinting technique. (Zhang et al., 2014). Another corticosteroid used for The promising results revealed great drug loading and reduction of intraocular inflammation is triamcino- prolonged release (Yañez et al., 2011). Another used lone acetonide. This drug was loaded in soft hydrogel drug to reduce ocular inflammation is prednisolone. contact lenses and the drug release was preferably sus- CLs loaded with prednisolone nanoparticles were tained (García-Millán, Koprivnik, & Otero-Espinar, prepared by soaking method. The developed CLs 2015). Diclofenac is an anti-inflammatory drug used were transparent and permeable whereas drug was to treat pain and inflammation after ocular surgeries. sustainable release (ElShaer et al., 2016). A similar The drug was loaded in b-cyclodextrin which fur- study involved the use of prednisolone nanocapsules ther grafted in hydrogels based copolymers glycidyl into CLs demonstrating also prolonged drug release methacrylate. The obtained data demonstrated great (Katzer, Chaves, Pohlmann, Guterres, & Beck, 2017). drug loading and sustained delivery of diclofenac for Pirfenidone known for its use in chemical burns was 15 days (Rosa dos Santos et al., 2009). Molecular im- entrapped in CLs with VitE demonstrating improved printed poly (HEMA-diethylaminoethyl methacry- ocular bioavailability which is highly desirable for oc- lateco-polyethylene glycol (200) dimethacrylate) soft ular drug release (Dixon et al., 2018). CLs were developed as diclofenac carriers. A zero-or- Antihistamines are active molecules used in al- der release was achieved exhibiting desirable poten- lergies. CLs loaded with sodium cromoglycate and tional (Tieppo, Pate, & Byrne, 2012). ketotifen via soaking method and demonstrated great Dexamethasone (DXM) is widely applied for oc- drug release which is desirable for allergies manage- ular inflammation. For example, Bengani et al. pro- ment (Phan, Weber, Mueller, Yee, & Jones, 2018). duced ACUVUE CLs surface coated with ionic DXM Ketotifen also entrapped in silicon hydrogel CLs via 21-disodium phosphate leading to improved wettabil- submerging them in drug solution. The developed

167 Siafaka, Yağcılar, Üstündağ Okur

CLs exhibited improved drug loading and extend- ing technology and the release was extended for 48 h ed release profile. In vivo data showed that drug can (Maulvi et al., 2018). Similarly, MOX also loaded by be found in tear fluid 24 hours after administration soaking in acrylic intraocular lenses and the drug re- (Jinku Xu, Li, & Sun, 2011). Olatapadine, utilized in lease was controlled and sustained for 2 weeks. The allergic conjunctivitis, was also entrapped in molec- rabbit models data showed that the system can pro- ular imprinted CLs exhibiting prolonged release and vide maximum therapeutic levels for endophthalmitis elimination of eye irritation (Kuan Hui Hsu et al., prophylaxis after cataract surgery (Filipe et al., 2019). 2015). Bajgrowicz et al. incorporated MOX and Ciproflox- Hyaluronic acid is widely used as wetting agent for acin to conventional hydrogel and silicone hydrogel dry eye syndrome. In the past, molecular imprinted CLs CLs via soaking method. It was revealed that drug released hyaluronic acid for 1 day improving dry eye loading was optimal whereas release was differentiat- symptoms (Ali & Byrne, 2009). Moreover, these CLs ed by the sued CLs (Bajgrowicz, Phan, Subbaraman, can also act as treatment option in corneal wound heal- & Jones, 2015). According to the study of Paradiso et ing and epithelial cell migration since hyaluronic acid is al. the VitE incorporation in commercial silicone CLs known for its healing properties (Gomes, Amankwah, prolonged the release of Levofloxacin and Chlorhex- Powell-Richards, & Dua, 2004). A more recent work idine, which are used in bacterial keratitis and other evaluated in vivo the use of hyaluronic acid CLs. Rabbit eye infections. Hence, their frequent use can be min- animal models showed sustained release of hyaluronic imized (Paradiso, Serro, Saramago, Colaco, & Chau- acid for 2 weeks whereas a faster and complete healing han, 2016). Ciprofloxacin was loaded in unilamellar was also observed (Maulvi et al., 2017). liposomes and multilamellar liposomes and further incorporated in CLs. Multilamellar liposomes exhib- Cyclosporine A is also a common applied drug ited sustained release as it is required for CLs formu- for dry eye syndrome. The formulation based on an lations (Jain & Shastri, 2011). Corneal targeted NPs of ocular emulsion due to its insolubility (Ames & Ga- natamycin were also loaded in CLs in order to reduce lor, 2015). A study involved the use of Cyclosporine A dose and dosing frequency of the antibiotic drug. loaded in silicone hydrogel CLs with VitE via soaking Gladly, in vitro release profile exhibited prolonged re- method. It was demonstrated that the drug retention lease for 8 hours and great antibacterial potentional time and bioavailability was significantly improved in (Chandasana et al., 2014). The antimicrobial peptide comparison with the conventional eye drops. More- melamine was covalently attached to CLs and studied over, drug release was extended for 30 days (Peng & for its ability to decrease bacterial keratitis in rabbit Chauhan, 2011). model wearing CLs. It was exhibited that P. aerugino- Ocular fungal and antimicrobial infections sa induced bacterial keratitis was ameliorated (Dutta, Vijay, Kumar, & Willcox, 2016). Eye infections are a common health problem (Watson, Cabrera-Aguas, & Khoo, 2018). Various mi- Fungal keratitis, a severe ocular disease, is one of croorganisms have been identified as possible infec- the leading causes of blindness worldwide (Üstündağ tive agents of an eye. Virus, fungi and bacteria are the Okur et al., 2019). Voriconazole, is an antifungal drug most pathogenic microorganisms. Ocular infections with various uses (Siafaka et al., 2016; Üstündağ Okur should be immediately treated and require frequent et al., 2018) and is also applied against fungal keratitis dosing since various side effects can be caused. Blind- in the form of eye drops. Voriconazole loaded hybrid ness is among the possible outcomes if an eye infection hydrogel CLs which were cross-linked through elec- left untreated. Topical eye drops are started as soon as trostatic interactions between quaternized chitosan, possible after setting the diagnosis. However, due to silver nanoparticles, and graphene oxide revealed the eye tear drainage, the most of the drug amount is very promising characteristics such as sustained re- diluting and the therapeutic outcome is delayed. lease, good antimicrobial functions and great antifungal efficacy (Huang et al., 2016). Bacterial keratitis and conjunctivitis are treated by antibacterial drugs. Moxifloxacin (MOX), a quino- CONCLUSION lone is widely applied as topical eye formulation but Drug loaded contact lenses provide a great poten- requires multiple dosing. Phan et al used various tional on ocular drug administration, since they can marketed contact lenses and soaked them in moxi- deliver drug efficiently, show improved retention time floxacin solution of phosphate tamponade and arti- and great patient compliance. It can be said that nu- ficial tears. This solution led to MOX release for 24 merous contact lenses capable of eluting drugs have hours (Phan et al., 2016). MOX also loaded in CLs been developed; nonetheless, their marketing was not with Hyaluronic acid using the modified cast mould- 168 FABAD J. Pharm. Sci., 45, 2, 161-174, 2020 obtained. This fact is highly related with economic, Anirudhan, T. S., Nair, A. S., & Parvathy, J. (2016). processing and other physicochemical parameters is- Extended wear therapeutic contact lens fabricat- sues. Thus, a huge advancement must be done on ad- ed from timolol imprinted carboxymethyl chi- dressing such drawbacks. For example, more efficient tosan-g-hydroxy ethyl methacrylate-g-poly acryl- contact lenses which can be release drug in efficient amide as a onetime medication for glaucoma. time, with high oxygen permeability and the ability European Journal of Pharmaceutics and Biophar- to be used from all age’s patients as well as night and maceutics, 109, 61–71. https://doi.org/10.1016/j. day are of the most critical drawbacks which should ejpb.2016.09.010 be overcome. Nevertheless, contact lenses can play the major role on the ocular drug delivery field since Bajgrowicz, M., Phan, C.-M., Subbaraman, L. N., & they possess high bioavailability and other character- Jones, L. (2015). Release of Ciprofloxacin and istics, which are beneficial on ophthalmology field. Moxifloxacin From Daily Disposable Contact To sum up, designing contact lenses for both chronic Lenses From an In Vitro Eye Model. 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