Sustained drug release by contact lenses for glaucoma treatment—A review

    Sustained Drug Release by contact lenses for Glaucoma Treatment– a review I.M. Carvalho, C.S. Marques, R.S. Oliveira, P.B. Coelho, P.C. Costa, D.C. Ferreira PII: DOI: Reference:

S0168-3659(15)00063-2 doi: 10.1016/j.jconrel.2015.01.023 COREL 7532

To appear in:

Journal of Controlled Release

Received date: Revised date: Accepted date:

20 October 2014 20 January 2015 20 January 2015

Please cite this article as: I.M. Carvalho, C.S. Marques, R.S. Oliveira, P.B. Coelho, P.C. Costa, D.C. Ferreira, Sustained Drug Release by contact lenses for Glaucoma Treatment– a review, Journal of Controlled Release (2015), doi: 10.1016/j.jconrel.2015.01.023

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ACCEPTED MANUSCRIPT Sustained Drug Release by contact lenses for Glaucoma Treatment– a review

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Carvalho, I. M. a, Marques, C. S a, Oliveira, R. S. b, Coelho, P. B. b, Costa, P. C. a,

Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto,

Rua Jorge de Viterbo Ferreira, 228, 4050-313 Porto, Portugal b

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a

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Ferreira, D. C. a*

Department of Pharmaceutical Technology, Faculty of Health Sciences, University Fernando Pessoa, Praça 9 de

Abril, 349, 4249-004 Porto, Portugal

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* Corresponding Author: Tel.: +351 919364623, E-mail address: [email protected] (Domingos Carvalho Ferreira)

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Abstract

In the context of ocular pharmacology, there is a growing need for innovative delivery

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platforms for a convenient and sustained drug release into the eye, especially for chronic diseases that require the adoption of a strict insurmountable treatment regimen for a

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large part of the affected population, as in the case of glaucoma. Due to the large residence time of the contact lenses in the eye, its use for sustained drug delivery is

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quite promising. However, and despite the numerous therapeutic advantages arising from its use, the low affinity shown by most ophthalmic drugs for conventional contact lenses hinders the practical application of this technology. In this paper we elaborated a

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review of the various methods exploited so far to improve the contact lenses’ characteristics as mechanisms for controlled and prolonged drug release for topical treatment of ocular diseases, with particular emphasis on the treatment of glaucoma.

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Graphical abstract

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Key words: Contact lenses, Nanoparticles, Ophthalmic, Ocular delivery, Glaucoma.

1. Introduction

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The ocular surface is readily available for the administration of drugs, which makes it

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the preferred route for the treatment of ocular disorders 1. The most common dosage forms for topical administration of drugs are eye drops (sterile solutions or

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suspensions), accounting for over 90% of all ophthalmic formulations 1. These dosage forms have however a major limitation, which is the drug’s short residence time in the cornea due to its rapid clearance and the dilutive effect of tears 2,3. Additionally, due to the fact that between 50-100% of the applied droplet is drained through the nasolacrimal

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duct, the drug can be absorbed in the gastrointestinal tract and exert systemic action 4. Consequently, the drugs have a very low bioavailability (between 1-5%) 5 and a reduced residence time in the tear film, only 2-3 minutes 6, therefore requiring the administration of high drug doses in order to achieve the therapeutic level in the eye. Moreover, the administration of eye drops requires a demanding manual dexterity not easily achieved by certain patients, such as the geriatric population. Noncompliance and therapeutic failure of treatments with eye drops appear to be most significantly related to the patients’ inability to correctly instill the drops in the eye and high dosing frequency that leads to forgetfulness 7,8. With the aim of overcoming such limitations, several strategies have been exploited, namely the use of permeation enhancers, viscous and adhesive polymers shields

14,15

, advanced drug delivery systems such as nanoparticles

9–13 16

, collagen

, colloidal 2

ACCEPTED MANUSCRIPT carriers17-19, liposomes

20–22

or ocular implants

23,24

. These drug delivery systems have

enabled an increase in the drug’s residence time in the cornea and conjunctival sac, an increased ocular permeation and a prolonged drug release, resulting in less frequent

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administrations, irritation and both ocular and systemic side-effects. However,

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regardless of these achievements, all advanced drug delivery systems have limitations. The collagen shields are not individually customized and can reduce visual acuity; as

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for the colloidal systems, nanoparticles which comprise poly(alkyl-cyanoacrylate) can damage the corneal epithelium and the liposomes are quite unstable due to the hydrolysis of the phospholipids which constitute them. Some ocular implants may even

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require surgery and can compromise visual performance (blurred vision), therefore substantially decreasing the patient’s compliance to the treatment 25.

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The appearance of contact lenses (CLs) for vision correction has enabled the possibility of achieving a controlled and sustained drug release in the eye without the risk of compromising the optical performance

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. CLs consist of curved plastic discs, which

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cling to the corneal tear film due to their surface tension. They can be used to correct

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vision problems but also for cosmetic or therapeutic purposes 27. They can be classified into two groups: rigid, mainly consisting of poly(methylmethacrylate) (PMMA) and soft

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(gelatinous), consisting mainly of polymers of hydroxyethyl methacrylate (pHEMA) 28. The FDA also classifies them as hydrophilic (adopting the suffix -filcon) or hydrophobic (adopting the suffix -focon) 29. Due to their superior ability to retain water,

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the hydrophilic CLs can be used for long periods of time (up to 6 nights and 7 days) 30. From the need to increase the gaseous permeability of CLs for continued use during closed-eye intervals stemmed the silicon CLs, allowing their continued use for 29 nights and 30 days without the risk of ocular hypoxia 31,32. Practically since the development of CLs, several studies have demonstrated that they can be suitable drug delivery systems for the treatment of several chronic and acute eye disorders

33–35

. Therapeutic CLs consist of soft lenses formed by pHEMA polymeric

matrices with or without silicone, impregnated with drugs through various techniques: soaking in a solution with the drug, colloidal particle-laden CLs, molecular imprinting, ion ligands or microemulsion-loaded gels

25

. These systems’ mechanism of action

includes drug diffusion into the post-lens tear film followed by dispersion in the tear fluid and subsequent absorption by the cornea (Fig. 1). Due to the constant absorption of the drug through the cornea, the concentration of the post-lens tear fluid remains 3

ACCEPTED MANUSCRIPT lower than its concentration in the CLs, creating a constant and prolonged drug flow from the CLs to the cornea 36. This is called the sink effect 37. This method results in an increased retention of the drug on the surface of the cornea (about 30 minutes) as 39

and a bioavailability equal to or greater

. In fact, it leads to an increased therapeutic efficacy, a reduction of drug

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than 50%

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opposed to around 2 minutes for eye drops

fluctuations and a decrease in the amount of drug administered

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. Furthermore, CLs

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reduce the need for the addition of permeation enhancers and preservatives commonly

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used in multidose eye drops, which may cause ocular irritation 40,41.

Fig 1. Ocular drug release on the ocular surface through the use of drug-eluting contact lenses.

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The benefits provided by the use of CLs therefore enable their use for the treatment of various ophthalmic chronic diseases that require a constant therapeutic level of drug in the eye for an effective control of the disease, as is the case of glaucoma. Glaucoma affects about 60.5 million individuals worldwide 42 and is the second leading cause of blindness following cataract

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. It consists in an increase in the intraocular

pressure (IOP) leading to the degeneration of axons from the retinal ganglion cells. In order to maintain a normal IOP, i.e. between 10 and 21 mmHg

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several classes of

drugs that lower the IOP can be used; beta-adrenergic antagonists such as timolol and betaxolol,

less

selective

sympathomimetic

agents

such

as

epinephrine,

parasympathomimetics miotic agents such as pilocarpine, carbonic anhydrase inhibitors such as dorzolamide or prostaglandin analogues such as latanoprost

45,46

. However,

glaucoma treatment which comprises the administration of eye drops of the drugs 4

ACCEPTED MANUSCRIPT mentioned, in monotherapy or in dual-therapy, has limited effectiveness when instilled incorrectly or with a wrong dosing frequency. Since an accurate drug administration is essential in order to maintain a constant normalized IOP, in a significant amount of

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patients the treatment is ineffective and compliance to the strict therapeutic regimen is

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low, especially in the elderly population who are precisely the most affected by this disease. Several studies show that less than half of the individuals with glaucoma

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treated with topical ocular therapy (eye drops) maintain the IOP between the normal values due to the difficulty of achieving the therapeutic regimen instituted, by forgetting several doses or noncompliance due to underestimation of the adverse effects of this

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disease 47–49.

Commercial contact lenses

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2.1.

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2. Strategies for the use of contact lenses for glaucoma treatment

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The use of conventional CLs for the sustained release of drugs to the eye was first reported about 50 years ago by Wichterle et al.

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. Due to its simplicity, most of the

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initial studies were based on the “soak and release” method, which consists in soaking the contact lens in eye-drop solutions followed by drug uptake and its sustained release to the post-lens tear film

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. However, this simplistic method has several limitations

which are greatly responsible for the limited applicability of this method, namely, the

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CLs’ low affinity for most drugs for ophthalmic use. The affinity of the drug to the contact lens depends on the nature of both, in an ambivalent situation. If the affinity is too high, the formulation exhibits a high stability but the drug is not released, while if the affinity is too low, the drug will be poorly retained by the CLs and will be released very quickly, exhibiting a peak concentration in the eye followed by a steep decline, meaning that therapeutic levels are not attained

30

. The drug-CLs affinity depends also

on the drug’s molecular weight, which for values between 300-500 Da is released from the CLs in the order of minutes to hours

51–55

. Additionally, the sterilization and

packaging processes may cause premature release of the drug leading to loss of therapeutic effectiveness, as well as the degradation of labile drugs. One of the first recorded attempts to use CLs for the treatment of glaucoma was performed by North (1971), who used soft contact lenses previously soaked in a 4% 5

ACCEPTED MANUSCRIPT pilocarpine solution. After this attempt, several researchers evaluated through in vitro and in vivo studies the efficacy of CLs for glaucoma treatment. Kaufman et al. (1971) reported a more effective control of the IOP by using CLs pre-soaked in a 1% 40

. Assef et al. (1973) showed a greater control of the IOP in monkeys

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administration

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pilocarpine solution when compared to an 8% pilocarpine solution for ophthalmic

treated with CLs soaked for 2 minutes in a 1% pilocarpine solution, when compared to 57

. In 1974 Hillman demonstrated the effectiveness

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the usual treatment with eye drops

of this method in patients with glaucoma, also suggesting that an increase in exposure time between the lens and the pilocarpine solution may lead to a higher equilibrium

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between them both and an increased release time. In continuation of the work done by these researchers, several others emerged

58–61

. More recently Schultz et al. (2009)

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determined that the maximum absorption and release for both timolol and brimonidine from hydrogel vasurfilcon A CLs (consisting of methylmethacrylate (MMA) and N-vinylpyrrolidone (NVP)) occurs within 60 minutes. A study comprising a 30 minute

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CLs use per day for 2 weeks demonstrated an IOP control equivalent to the previous 54

. Some ophthalmologists may also

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regimen (eye drops) in volunteers with glaucoma

resort to the placement of the CLs above the ophthalmic drops in the eye. Although it

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does not result in sustained release of the drug, it can reduce its wastage 30. Despite the promising results from this simplistic method, no study showed a prolonged drug release exceeding 2 hours, which implies the need for the production of modified

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CLs with different characteristics.

2.2. Modified medicated contact lenses Molecular diffusion is the main drug release mechanism from the polymeric matrix that constitutes the CL. One of the possible methods to prolong drug release in CLs is to create a barrier to outline the CL matrix which slows down drug diffusion, therefore prolonging its action. However the creation of these barriers on the surface of the CLs is complicated due to the transparency and oxygen permeation requirements 36. Alternatively Chauhan et al. developed vitamin E (VE) CLs for sustained release of several drugs for ophthalmic use

62

. These CLs can be produced by soaking them in a

VE ethanolic solution before drug incorporation, or alternatively, they can both be loaded simultaneously, followed by ethanol extraction with water. This strategy is 6

ACCEPTED MANUSCRIPT especially effective for hydrophilic drugs which do not dissolve in VE, allowing it to act as an obstacle to the progression of the drug, thus prolonging the diffusion time on the cornea (Fig. 2). Among the various drugs tested by Chauhan et al. is timolol, one of the 63

. This drug was chosen due to its

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drugs of choice for the treatment of glaucoma

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potential to cause severe cardiac and pulmonary side-effects, such as cardiac arrhythmias and bronchospasms, when absorbed into the systemic circulation

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. There

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is consequently an increased benefit of using CLs, since this method maintains a constant drug concentration on the corneal surface and therefore reduces the probability of systemic absorption. Various types of CLs were tested with the addition of VE and

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timolol simultaneously during production of the lens. The Lotrafilcon A CLs, consisting of dimethylacrylamide (DMA) and siloxane showed the best results. At a concentration

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of 16% VE there was a 9.8-fold release time increase from the standard eye-drop treatment, while there was a 76-fold and a 341-fold release time increase respectively for a 27% and a 74% VE concentration. These results correspond to a total release time

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of 5.5, 43 and 192 hours respectively.

Fig 2. VE effect in the progression of a hydrophilic drug through the polymeric matrix of a hydrophilic CL.

The "soak and release" method was also tested for the absorption of timolol, and although there was a lower VE loading, this method resulted in a more homogeneous VE distribution in the CLs. In a preliminary in vivo study performed on Beagle dogs with hereditary open-angle glaucoma using timolol-loaded CLs, there was an increase in the therapeutic efficacy as well as a prolonged release profile for timolol in comparison with eye-drops. It was further observed a significant difference in the drug release times between the CLs with and without VE. Conventional CLs released about 80% of the

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ACCEPTED MANUSCRIPT drug within 30 minutes and the remaining drug in 2 hours, while the VE CLs released 75% of the drug in 12 hours and the remainder in approximately 100 hours 65. The successful use of VE-loaded CLs for the extended release of timolol in beagle dogs

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with spontaneous glaucoma was confirmed by Peng et al. (2012b). The lenses were

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either replaced daily (60 g of timolol) or continuously worn for 4 days with or without

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VE (200 g of timolol). The drug’s pharmacodynamics and IOP-lowering effect were compared to the standard treatment with 150 g timolol eye drops twice daily. The in vivo studies showed that all CLs were more effective than eye drops in reducing the

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IOP, in agreement with previous studies. However, only the VE CLs allowed a continuous timolol release for 4 days and an IOP effective control for 3 days, which

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proves their effectiveness for long-term glaucoma treatment. Furthermore, the use of CLs in only one eye had no effect in the untreated eye, indicating a decrease in systemic absorption of timolol in which case it is extremely

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important.

VE also has the advantage of acting as a powerful antioxidant and is thus useful for the prevention of several ocular pathologies and also in enhancing the stability of 66–68

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susceptible drugs

. Additionally, it protects the cornea against UV radiation and its

aggregates do not interfere with the transparency of the CLs and the visual performance,

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since they are smaller than the wavelength size of visible light 30.

2.3. Imprinted medicated contact lenses Molecular imprinting is one of the most recent and promising techniques for controlled drug delivery by CLs. It involves the use of a template drug and functional monomers during the CLs polymerization process which results in the formation of macromolecular memory sites with a suitable size and chemical groups to stably accommodate the drug

30

. The molecularly imprinted pockets mimic the drug’s

receptors and its structurally similar analogs, therefore increasing the drug loading capacity, while providing an adequate release rate

69,70

(Fig. 3). Drug affinity however

greatly depends on the type of functional monomers used as well as their ratio in the polymeric matrix

71,72

. The drug’s releasing behavior can therefore be changed by

modifying the monomer composition as well as the diversity and number of interactions 8

ACCEPTED MANUSCRIPT at the recognition site. A high polymer crosslinking degree also plays an important role in the stability of the imprinted cavities. However, a high crosslinking degree affects the hydrogel’s transparency and optical performance, as well as its flexibility and water

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content. CLs with a reduced transparency and flexibility are not suitable for ocular

diffusion into the surface of the cornea

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application, and a reduced water content leads to an insufficient oxygen dissolution and . Therefore, lower crosslinker concentrations

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(<5%) are usually more desirable for the preparation of CLs 74.

Molecularly imprinted pocket

Drug

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Drug receptor

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Fig 3. Drug release by molecularly imprinted CLs.

This technology has been successful in increasing the loading capacity and optimizing

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the release profile of several active ingredients such as norfloxacin hyaluronic acid

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, hydroxypropylmethylcellulose

78

75

, prednisolone

, diclofenac 70

71,76

,

and ketotifen

fumarate 79. The first attempt to use molecularly-imprinted soft-CLs was conducted for timolol

80

. This study demonstrated the superior ability of the imprinted CLs to

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accommodate the drug compared to conventional CLs. The first in vivo study to demonstrate the effectiveness of these modified CLs was also made for timolol in rabbits 81. The imprinted CLs accommodated a maximum of 34 g of timolol, while the conventional CLs accommodated only 20 g. Simultaneously the timolol release time from 0.068% and 0.25% ophthalmic drops (total dose of 34 g and 125 g respectively) was also evaluated. Both CLs resulted in a maximum ocular concentration peak after 5 minutes followed by a sustained release for 90 minutes and 180 minutes respectively for conventional CLs and imprinted CLs. For both ophthalmic solutions, timolol was completely eliminated from the cornea in less than 60 minutes. This study thereby demonstrates the ability of these CLs of reducing the pre-corneal elimination of timolol and the subsequent need for lower doses of the drug, in addition to displaying a sustained release. A more recent study assessed the ability of imprinted CLs to retain a

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ACCEPTED MANUSCRIPT larger amount and to sustain a prolonged release of dorzolamide, a carbonic anhydrase inhibitor also used in the topical treatment of glaucoma 82. An improvement in the drug

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retention capacity and a more prolonged release were demonstrated.

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2.4. Medicated contact lenses with nanoparticles

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This strategy is based on the ability of nanoparticles (such as liposomes, polymeric nanoparticles and nanosized micelles) to include several drugs and control their release within CLs. Nanoparticles are complex colloidal systems of any shape with dimensions

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in the nanometer scale. These CLs possess nanoparticles incorporated during the production stage, thus ensuring a high concentration in the polymeric matrix, resulting in a high drug loading capacity (Fig. 4). Several nanoparticle types have been studied,

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including lipid nanoparticles, (liposomes, microemulsions, and micelles) and polymeric

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nanoparticles which comprise several biodegradable and non-biodegradable molecules.

Cyclodextrin Liposome

Micelle

Fig 4. Drug release from CLs with nanostructures (liposomes, micelles, cyclodextrins).

2.4.1. Lipid-based nanoparticles The use of lipid nanostructures such as microemulsions and liposomes for drug incorporation within the CL matrix is especially promising due to their thermodynamic stability, which leads to a high drug-loading capacity. In addition they allow for the inclusion of both hydrophilic and hydrophobic drugs, thereby showing great versatility 83. It is however necessary to control the amount of nanoparticles trapped in the CL matrix such that it possesses a large loading capacity without compromising the transparency of the lens. Gulsen & Chauhan (2005) encapsulated various drugs for ophthalmic use in liposomes consisting of dimyristoyl phosphatidylcholine (DMPC) 10

ACCEPTED MANUSCRIPT followed by incorporation into the CL polymeric matrix. It was found that these CLs promote drug release for up to 8 days. In the context of glaucoma treatment, studies are mainly focused on the use of microemulsions. Li et al. (2007) prepared CLs

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incorporated with oil in water microemulsions of ethyl butyrate stabilized with the

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surfactant pluronic F127 in order to assess the retention capacity and the time of release of timolol. In theory the use of surfactant would confer a stronger resistance to the drug

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release from the lipid vesicles. The results demonstrated a high retention capacity of timolol in the basic form, which may be included in the oil phase or form the oil phase itself. Its release was too fast nevertheless, suggesting that Pluronic F127 may have

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been ineffective in prolonging timolol release, which may have also been due to timolol’s low molecular weight.

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The use of micelles has so far demonstrated to be much more promising. Kapoor & Chauhan (2008) produced CLs containing micelles of Brij 97 in order to encapsulate cyclosporine-A. This drug is mostly used to increase the hydration of the dry eye, but 87

. These CLs resisted the autoclaving and conditioning processes without

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glaucoma

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also to reduce ocular inflammation, being therefore useful in the topical treatment of

suffering premature drug release. However, for surfactants to be potentially used, it is

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essential to take into account the partition coefficient of the drug in the micelle. The partition coefficient is the concentration ratio of a drug in two immiscible phases, one of them hydrophilic and the other hydrophobic. This coefficient depends on the

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hydrophobicity of the drug and the micellar core. As evidenced by Kapoor et al. (2009), who evaluated the partition coefficient of a drug for ophthalmic administration using Brij surfactants with different hydrophobicity degrees, if the partition coefficient is too low, the drug is rapidly released from the micelle. The limited number of studies to date on the application of these nanosystems for drug delivery by CLs, including the use of other lipid-based particles such as nanostructured lipid carriers and solid-lipid nanosystems, is largely due to various limitations in terms of physical stability, and the need to preserve the CLs in a saturated drug solution in order to prevent its premature release, which leads to wastage of a large amount of drug 89,90

.

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ACCEPTED MANUSCRIPT 2.4.2. Polymeric nanoparticles Polymeric nanoparticles have been studied for the incorporation of drugs for the treatment of ocular pathologies. The incorporation of this type of nanoparticles in the

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CL polymer matrix for the treatment of glaucoma has only recently been studied. Jung

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& Chauhan (2012) evaluated the retention capacity and the prolonged release of

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nanoparticle-laden CLs with PGT (propoxylated glyceril tryacilate) and EGDMA (ethylene glycol methacrylate) loaded with timolol. These authors found that both mechanisms lead to a sustained release of timolol in therapeutic doses for 2 to 4 weeks in a temperature dependent manner, and the drug was released only on contact with the

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eye at body temperature. This finding is quite significant, as it means that during storage (cooling) the drug does not suffer premature release. Jung et al. (2013) also produced

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CLs with PGT particles with timolol. In vitro studies demonstrated the ability of these CLs to release the drug at a constant rate over about one month. The mechanisms probably involved in this extended release are: hydrolysis of ester bonds between the

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polymeric matrix and timolol and / or diffusion of the drug through the polymer matrix.

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The drug concentration used (5%) had a minimal impact on the critical properties of the lens, such as transparency and oxygen and ion permeability, as in the previous study.

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Preliminary studies performed in vivo in beagle dogs also proved the effectiveness of these CLs in controlling IOP in glaucoma

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. More recently, Ciolino et al. (2014)

developed CLs with nanoparticles located in a film between the lens matrix, consisting

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of the biodegradable polymer PLGA (polylactic glyolic acid) for sustained release of latanoprost. In vitro and in vivo studies in rabbits demonstrated this mechanism’s ability to constantly release the drug in therapeutic doses for 4 weeks, while maintaining a concentration in the vitreous humor similar to that achieved by conventional eye-drop regimens and were more efficient in the control of the IOP. This fact confirms the high capacity of PLGA to control and extend the release of drugs for ophthalmic use, as had previously been shown with eye drops containing brimonidine 13. A different approach to increase the affinity of hydrophobic drugs to the polymer matrix of the CLs, and with the aim of prolonging their release, is the use of cyclodextrins (CDs). CDs are cyclic oligosaccharides which, due to their ring-shaped structure with a hydrophobic interior and hydrophilic exterior, are capable of forming inclusion complexes with various hydrophobic molecules, thus resulting in an increased solubility, stability and bioavailability of the drugs included as well as reduction of the 12

ACCEPTED MANUSCRIPT adverse effects

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. The use of -CD allows for the accommodation and controlled

release of various low molecular weight drugs through various hydrogel matrixes without compromising the mechanical properties and without causing cytotoxicity

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.

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Xu et al. (2010) prepared CLs by promoting the copolymerization of a HEMA hydrogel glaucoma, due to their -blocking effect

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loaded with puerarin--CD complex, a hydrophobic substance used in the treatment of . In vitro and in vivo studies in rabbits

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demonstrated an increased residence time and concentration of the drug in the vitreous humor compared with conventional CLs or eye drops. Through the use of CLs with CD, the concentration in the vitreous humour remained 46.55 g/ml after 6 hours, while for

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the isolated CLs that concentration was only maintained for 1.5 hours and for eye drops only 50 minutes. More recently, García-Fernández et al developed CLs with poly-CD in

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order to increase the retention and prolong the release of acetazolamide, a carbonic anhydrase inhibitor used to lower the IOP

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. By performing in vitro studies, they

reported an increase in the drug solubility, an increase of its concentration in the cornea

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and a prolonged release over several weeks. These results are very promising, especially

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considering that until now this drug is only administered orally, which limits its therapeutic action, while implying the use of high quantities in order to have the desired

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effect in the eye.

3. Conclusion

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Although the use of CLs not only to correct visual problems but also for therapeutic purposes has been postulated for about 50 years

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, the use of this technology is still

fairly limited. However, there are more and more studies and tests to demonstrate the benefits of this new type of therapeutic system, particularly to treat chronic eye diseases that involve maintaining an accurate control of the dose, frequency and mode of administration, such as glaucoma. Considering that non-adherence to glaucoma treatment is one of the biggest risk factors for disease progression, immense advantages are offered by the CLs, in which the most important consist in: improved maintenance and disease control leading to fewer hospitalizations, fewer complications and ocular surgery, and less morbidity (blindness), in addition to smaller quantities of drugs used, with pharmacoeconomic advantages, and much greater therapeutic efficacy and patient convenience. The use of CLs for the treatment of glaucoma may be especially useful in younger patients already receiving optical correction with CLs. In this case there can not 13

ACCEPTED MANUSCRIPT only be a better IOP control in a more convenient way, but also to avoid the need to remove the CLs prior to droplets administration. Despite being a system that the older population is not so used to, which can be seen as a limitation, after habituation, the use

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of CLs has the potential to become much more comfortable and safe. Apart from that, it

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does not require great manual dexterity as required for administration of eye drops. It also has the advantage of displaying prolonged use, and may therefore only be changed

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daily, weekly or monthly as can be seen from current studies in this field.

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Conflicts of interest

The authors report no conflicts of interest and have no proprietary or commercial

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interests in any concept or product discussed in this paper.

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