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Design of advanced contact lenses (CLs) demands materials that are safe and comfortable for the wearers and that preserve the normal eye microbiota, avoiding chronic inflammation and biofilm development. This work aimed to combine the natural antibiofouling phosphorylcholine and the antioxidant and prebiotic resveratrol as integral components of CLs that may have the additional performance of preventing oxidative-stress related eye diseases. Different from previous uses of 2-methacryloyloxyethyl phosphorylcholine (MPC) as coating, we explored the feasibility of adding MPC at high proportions as a comonomer of 2-hydroxyethyl methacrylate (HEMA)-based hydrogels while still allowing for the loading of the hydrophobic resveratrol. Homogeneous distribution of MPC along the hydrogel depth (confirmed by Raman spectroscopy) notably increased solvent uptake and the proportion of free water while it decreased Young's modulus. Relevantly, MPC did not hinder the uptake of resveratrol by CLs (>10 mg/g), which indeed showed network/water partition coefficients of >100. Protocols for CLs sterilization and loading of resveratrol under aseptic conditions were implemented, and the effects of tear proteins on resveratrol release rate were investigated. CLs sustained resveratrol release for more than 24 h in vitro , and sorption of albumin onto the hydrogel, although attenuated by MPC, slowed down the release. The combination of MPC and resveratrol reduced P. aeruginosa and S. aureus growth as tested in a novel hydrogel disk-agar interface biofilm growth setup. The developed CLs showed excellent anti-inflammatory properties and biocompatibility in in ovo and rabbit tests and provided higher and more prolonged levels of resveratrol in tear fluid, which favored resveratrol biodistribution in anterior and posterior eye segments compared to eye drops. Correlations between the release profiles of resveratrol in vitro and in vivo were assessed. Relevantly, the CLs preserved the antioxidant properties of resveratrol during the entire 8 h of wearing. In sum, CLs prepared with high proportion in MPC may help address safety and comfort requirements while having drug releasing capabilities.

Oral administration of cholesterol-lowering statins, HMG-CoA reductase inhibitors, is associated with beneficial effects on eye conditions. This work aims to design contact lenses (CLs) that can sustainedly deliver pravastatin and thus improve the ocular efficacy while avoiding systemic side effects of statins. Bioinspired hydrogels were prepared with monomers that resemble hydrophobic (ethylene glycol phenyl ether methacrylate) and amino (2-aminoethyl methacrylamide hydrochloride) functionalities of the active site of HMG-CoA. Best performing CLs loaded >6 mg/g, in vitro fulfilled the release demands for daily wearing, and showed anti-inflammatory activity (lowering TNF-α). High hydrostatic pressure sterilization preserved the stability of both the drug and the hydrogel network. Ex vivo tests revealed the ability of pravastatin to accumulate in cornea and sclera and to penetrate through transscleral route. In vivo tests (rabbits) confirmed that, compared to eye drops and for the same dose, CLs provided significantly higher pravastatin levels in tear fluid within 1 to 7 h of wearing. Moreover, after 8 h wearing pravastatin was present in cornea, sclera, aqueous humour and vitreous humour. Strong correlations between percentages of drug released in vitro and in vivo were found. Effects of volume and proteins on release rate and Levy plots were identified., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Contact lenses (CLs) offer a wide variety of advantages as ocular drug-releasing platforms, but the feasibility of medicated CL development is constrained by numerous scientific, technological, and regulatory challenges. One main difficulty is the setting of release rate specifications for each drug, since at present there are no standardized in vitro release models that can appropriately predict the performance of drug-eluting CLs once placed onto the eye. CL-adapted release tests may provide knowledge on how the drug release pattern should perform in vivo to trigger and maintain the therapeutic effects for both anterior and posterior ocular tissues. Moreover, in vitro release tests are valuable tools for quality assessment during production and to investigate the effect of a change in composition or process variables. This review aims to shed light on biorelevant ways of evaluating in vitro drug release from CLs and the feasibility of establishing in vitro-in vivo correlations (IVIVC) to predict in vivo performance. First, general guidelines and Pharmacopeia release tests for topical ophthalmic formulations as well as in vitro release tests implemented for drug-CLs in the last two decades are analyzed. Then, development of an appropriate method to investigate IVIVC is attempted from the few papers simultaneously reporting in vitro release profiles and either in vivo release or therapeutic response. Finally, key points to be considered for in vitro testing drug release from a medicated CL are suggested to pave the way to the clinical arena., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Contact lenses may act as drug release platforms for the treatment of ocular infections, but there is still the need for extending their typical release periods and enhancing ocular bioavailability. The present study aimed to develop a molecularly imprinted silicone-based hydrogel to be used in the manufacturing of contact lenses that can be loaded efficiently and be able to release the antibiotic moxifloxacin hydrochloride (MXF) in a sustained way. A set of hydrogels was prepared by the molecular imprinting method using acrylic acid (AA) as the functional monomer for the specific recognition of MXF. The modified hydrogels loaded a higher amount of MXF, which was released for a longer time. In vitro experiments, using a microfluidic cell to mimic the ocular surface fluid turnover, showed that the imprinted hydrogel TRIS(300)-I prepared with the highest content in AA led to MXF concentrations in the release medium which were effective against S. aureus and S. epidermidis for about 2 weeks. Furthermore, some important properties such as water uptake, wettability, transmittance, ionic permeability, and Young´s modulus of the modified hydrogel remained within the range of values recommended for contact lenses. No cytotoxicity and no potential ocular irritancy effect were detected. Such hydrogel seems to be a promising alternative to the current options for the treatment of ocular infections., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Unlabelled: Combination of the ability of contact lenses (CLs) to act as a physical barrier against airborne antigen and to serve as a sustained depot of antihistaminic drugs may improve the efficiency of treatments of some ocular allergic diseases. The aim of this work was to develop CLs that exhibit affinity to olopatadine by mimicking the composition of the natural H1-receptor for which olopatadine behaves as a selective antagonist. Functional monomers that match the chemical groups of the receptor and application of the molecular imprinting technology led to hydrogels able to load high amounts of olopatadine and to sustain the release once in contact with lachrymal fluid. Optimized hydrogels prepared with acrylic acid, 2-acrylamido-2-methyl-1-propanesulfonic acid and benzylmethacrylate as functional monomers provided in few hours olopatadine concentrations similar to those of commercially available eye drops but the levels could be sustained for a whole day, demonstrating their efficacy. Olopatadine-loaded CLs successfully passed the HET-CAM test of ocular irritancy and showed good compatibility with mast cells. They were able to inhibit the release of histamine and TNF-α from sensitized mast cells, proving their potential application in preventing and treating allergic conjunctivitis., Statement of Significance: Contact lenses (CLs) with affinity for antiallergic drugs may constitute an advantageous alternative to eye drops in management of ocular allergies for both contact lens wearers and patients who eventually use neutral CLs as therapeutic platforms. The present work represents a step forward in the state of the art of drug-CL combo products by (i) mimicking the composition of the human receptor of the drug, (ii) exploring combinations of functional monomers that include a monomer (2-acrylamido-2-methyl-1-propanesulfonic acid; AMPSA) with a strong acid group (pKa<4) able to enhance the interaction of the network with olopatadine in the saline environment of the lachrymal fluid, and (iii) analysing in detail the antihistamic effects provided by olopatadine released from the CLs on sensitized mast cells., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The aim of this work was to develop an innovative supercritical fluid (SCF)-assisted molecular imprinting method to endow commercial soft contact lenses (SCLs) with the ability to load specific drugs and to control their release. This approach seeks to overcome the limitation of the common loading of preformed SCLs by immersion in concentrated drug solutions (only valid for highly water soluble drugs) and of the molecular imprinting methods that require choice of the drug before polymerization and thus to create drug-tailored networks. In particular, we focused on improving the flurbiprofen load/release capacity of daily wear Hilafilcon B commercial SCLs by the use of sequential SCF flurbiprofen impregnation and extraction steps. Supercritical carbon dioxide (scCO2) impregnation assays were performed at 12.0 MPa and 40 °C, while scCO2 extractions were performed at 20.0 MPa and 40 °C. Conventional flurbiprofen sorption and drug removal experiments in aqueous solutions were carried out for comparison purposes. SCF-processed SCLs showed a recognition ability and a higher affinity for flurbiprofen in aqueous solution than for the structurally related ibuprofen and dexamethasone, which suggests the creation of molecularly imprinted cavities driven by both physical (swelling/plasticization) and chemical (carbonyl groups in the network with the C-F group in the drug) interactions. Processing with scCO2 did not alter some of the critical functional properties of SCLs (glass transition temperature, transmittance, oxygen permeability, contact angle), enabled the control of drug loaded/released amounts (by the application of several consecutive processing cycles) and permitted the preparation of hydrophobic drug-based therapeutic SCLs in much shorter process times than those using conventional aqueous-based molecular imprinting methods., (Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

(1) Background: The purpose of this study was to synthesize melatonin-eluting contact lenses (CLs) and evaluate both the ocular kinetics of the released melatonin and its effect on tear volume and intraocular pressure. (2) Methods: In vitro, melatonin-eluting CLs were synthesized by using non-functionalized (HEMA) and functionalized (HEMA/APMA) monomers. In vivo, a short-term prospective and randomized study was performed on 15 rabbits divided into two groups: 12 rabbits wearing functionalized CLs and 3 rabbits without CLs as a control. The melatonin levels in tears, aqueous humor, vitreous body and retina, tear volume, and intraocular pressure were measured for 8 h. (3) Results: In vitro, both monomers did not show differences in terms of melatonin loading and release (p ≥ 0.05). In vivo, the melatonin concentration was elevated in tears and aqueous humor after 2 and 4 h of wearing CLs, respectively (p < 0.05). Additionally, the CLs increased tear volume for 2 h (p < 0.05). (4) Conclusions: The melatonin-eluting CLs released their content over the ocular surface for at least 2 h, which was associated with a secretagogue effect on tear volume. However, the increased amount of melatonin found in the aqueous humor had no effect on intraocular pressure. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Efficient ocular drug delivery that can overcome the challenges of topical application has been largely pursued. Contact lenses (CLs) may act as light-transparent cornea/sclera bandages for prolonged drug release towards the post-lens tear fluid, if their composition and inner architecture are fitted to the features of the drug molecules. In this review, first the foundations and advantages of using CLs as ocular drug depots are revisited. Then, pros and cons of common strategies to prepare drug-loaded CLs are analyzed on the basis of recent examples, and finally the main section focuses on bioinspired strategies that can overcome some limitations of current designs. Most bioinspired strategies resemble a reverse engineering process to create artificial receptors for the drug inside the CL network by mimicking the human natural binding site of the drug. Related bioinspired strategies are being also tested for designing CLs that elute comfort ingredients mimicking the blinking-associated renewal of eye mucins. Other bioinspired approaches exploit the natural eye variables as stimuli to trigger drug release or take benefit of bio-glues to specifically bind active components to the CL surface. Overall, biomimicking approaches are being revealed as valuable tools to fit the amounts loaded and the release profiles to the therapeutic demands of each pathology. Statement of Significance Biomimetic and bioinspired strategies are remarkable tools for the optimization of drug delivery systems. Translation of the knowledge about how drugs interact with the natural pharmacological receptor and about components and dynamics of anterior eye segment may shed light on the design criteria for obtaining efficient drug-eluting CLs. Current strategies for endowing CLs with controlled drug release performance still require optimization regarding amount loaded, drug retained in the CL structure during storage, regulation of drug release once applied onto the eye, and maintenance of CL physical properties. All these limitations may be addressed through a variety of recently growing bioinspired approaches, which are expected to pave the way of medicated CLs towards the clinics. [ABSTRACT FROM AUTHOR]

[Display omitted] • Soaking of contact lenses in HAuCl 4 solution followed by steam heat renders AuNPs. • Silicone hydrogels spontaneously trigger anisotropic AuNPs formation at RT under dark in a controllable way. • F moieties hinder AuNP formation at 20 °C, but the reaction still proceeds under steam heat. • AuNPs@hydrogels absorb from green to NIR light developing versatile photothermal outcomes. • Reagent-free AuNPs-containing hydrogels are wettable and stable in water for months. This work describes for first time how anisotropic gold nanoparticles (AuNPs) can be spontaneously formed inside preformed contact lenses (CLs) avoiding the use of additional reductant agents (reagent-free) through a precise tunning of the monomeric composition, the saline concentration, and the application of steam heat sterilization. Protocols to generate AuNPs in solution using inorganic or small organic reductants are widely available. Differently, gold precursors interactions with polymer networks have been overlooked and, thus, the interest of chemically cross-linked hydrogels as organic reductants is still to be elucidated. In the ocular field, incorporation of AuNPs to CLs may expand their applications in prophylaxis, therapy and diagnosis. To carry out the work, a variety of hydrogels and commercially available CLs were incubated with gold salt solution without any other chemical reagent. AuNPs formation was monitored by changes in localized surface plasmon resonance (LSPR) bands and quantifying the gold sorbed. Only silicone hydrogels induced AuNPs formation at room temperature in few days; methacrylic acid red-shifted the LSPR band (550–600 nm), while monomers bearing F hindered the reduction. Storage of hydrogels in the gold precursor solution allowed a gradual formation of anisotropic AuNPs, which could be stopped at any time by washing the hydrogel with water. The developed CLs behave as efficient filters against highly penetrant light and also exhibit photoresponsiveness as demonstrated as rapid (10 s), focused mild hyperthermia when irradiated with green, red and NIR lasers. [ABSTRACT FROM AUTHOR]

Abstract: Soft contact lenses are receiving an increasing attention not only for correcting mild ametropia but also as drug delivery devices. To provide poly(hydroxyethyl methacrylate), PHEMA, lenses with the ability to load norfloxacin (NRF) and to control its release, functional monomers were carefully chosen and then spatially ordered applying the molecular imprinting technology. Isothermal titration calorimetry (ITC) studies revealed that maximum binding interaction between NRF and acrylic acid (AA) occurs at a 1:1, and that the process saturates at 1:4 molar ratio. Hydrogels were synthesized using different NRF:AA molar ratios (1:2 to 1:16), at two fix AA total concentrations (100 and 200 mM), and using moulds of different thicknesses (0.4 and 0.9 mm). The cross-linker molar concentration was 1.6 times that of AA. Control (non-imprinted) hydrogels were prepared similarly but with the omission of NRF. All hydrogels showed a similar degree of swelling (55%) and, once hydrated, presented adequate optical and viscoelastic properties. After immersion in 0.025, 0.050 and 0.10 mM drug solutions, imprinted hydrogels loaded greater amounts of NRF than the non-imprinted ones. Imprinted hydrogels synthesized using NRF:AA 1:3 and 1:4 molar ratios showed the greatest ability to control the release process, sustaining it for more than 24 h. These results prove that ITC is a useful tool for the optimization of the structure of the imprinted cavities in order to obtain efficient therapeutic soft contact lenses. [Copyright &y& Elsevier]

Currently, approximately 100 million people are estimated to be wearing contact lenses, and the number is increasing exponentially. Although the main use of contact lenses is for correcting ametropia problems, they also hold interest as therapeutic devices for the relief of ocular pain, promotion of corneal healing, mechanical protection and support, maintenance of corneal epithelial hydration, and drug delivery. Ocular drug administration is particularly challenging and recent research has been directed towards the design of novel drug delivery systems capable of prolonging the permanence of the drug in the precorneal area and, thus, potentially increasing bioavailability and minimizing adverse effects.Conventional hydrogel soft contact lenses have the ability to absorb some drugs and release them into the post-lens lacrimal fluid, minimizing clearance and sorption through the conjunctiva. Their ability to be a drug reservoir strongly depends on the water content and thickness of the lens, the molecular weight of the drug, the concentration of the drug loading solution and the time the lens remains in it. However, the ability of contact lenses to load drugs and to control their release is in general inadequate and the following approaches, based on modifications of the polymer network, are currently under evaluation: (i) covalent binding of the drug to the lens network via labile bonds; (ii) inclusion of the drug in colloidal structures that are dispersed in the lens and are responsible for controlling drug release; (iii) functionalization of the network with chemical groups that work as ion-exchange resins; and (iv) creation in the lens structure of imprinted pockets that memorize the spatial features and bonding preferences of the drug and provide the lens with a high affinity and selectivity for a given drug. In this review, the possibilities and the advantages/drawbacks of these new types of contact lenses as drug delivery systems are critically analyzed. [ABSTRACT FROM AUTHOR]

The aim of this work was to evaluate the utility of molecular imprinting for improving the loading capability of weakly cross-linked hydrogels, with a view to their use as soft contact lenses for administration of timolol. Imprinted hydrogels were prepared considering preformation of complexes between methacrylic acid (functional monomers) and timolol (target molecules), and polymerization with N,N-diethylacrylamide and ethylenglycol dimethacrylate (EGDMA, cross-linker) after injection in moulds (0.3 mm thickness) and UV irradiation at room temperature. After polymerization, timolol molecules were removed by washing. When the gels were immersed in timolol solutions, the imprinted gels adsorbed much more timolol than the corresponding non-imprinted ones, especially above 60 mM EGDMA. The minimum cross-linker concentration for the imprinting to be effective was 80 mM EGDMA. The imprinted contact lenses improved significantly the affinity of the hydrogels for timolol, estimated after fitting Langmuir equation to the adsorption isotherms. These results indicated that adsorption sites capable of capturing the target molecules were encoded effectively into the polymer network by the molecular imprinting technique and, in consequence, improved the drug loading capacity of the gels. Loaded imprinted contact lenses were able to prolong timolol release, in 0.9% NaCl aqueous solution, for more than 24 h. [Copyright &y& Elsevier]

Statins are receiving increasing attention in the ophthalmic field. Their activity as 3-hydroxy-3-methylglutaryl–CoA (HMG–CoA) reductase inhibitors is clinically used to regulate cholesterol levels and leads to pleiotropic effects, which may help in the management of diabetes-related ocular pathologies. This work aims to design bioinspired contact lenses (CLs) with an affinity for atorvastatin by mimicking the active site of HMG–CoA reductase. Sets of imprinted and nonimprinted 2-hydroxyethyl methacrylate (HEMA) hydrogels were synthesized, varying the contents in functional monomers that bear chemical groups that resemble those present in HMG–CoA reductase, namely, ethylene glycol phenyl ether methacrylate (EGPEM), 2-aminoethyl methacrylate hydrochloride (AEMA), and N-(3-aminopropyl) methacrylamide hydrochloride (APMA). The hydrogels were characterized in terms of suitability as CLs (solvent uptake, light transmission, mechanical properties, and biocompatibility) and capability to load and release atorvastatin. Three sterilization protocols (steam heat, gamma radiation, and high hydrostatic pressure) were implemented and their effects on hydrogel properties were evaluated. Copolymerization of AEMA and, particularly, APMA endowed the hydrogels with a high affinity for atorvastatin (up to 11 mg/g; KN/W > 200). Only high hydrostatic pressure sterilization preserved atorvastatin stability and hydrogel performance. Permeability studies through the porcine cornea and sclera tissues revealed that the amount of atorvastatin accumulated in the cornea and sclera could be effective to treat ocular surface diseases. [ABSTRACT FROM AUTHOR]

Contact lenses (CLs) are prone to biofilm formation, which may cause severe ocular infections. Since the use of antibiotics is associated with resistance concerns, here, two alternative strategies were evaluated to endow CLs with antibiofilm features: copolymerization with the antifouling monomer 2-methacryloyloxyethyl phosphorylcholine (MPC) and loading of the antioxidant resveratrol with known antibacterial activity. MPC has, so far, been used to increase water retention on the CL surface (Proclear® 1 day CLs). Both poly(hydroxyethyl methacrylate) (HEMA) and silicone hydrogels were prepared with MPC covering a wide range of concentrations (from 0 to 101 mM). All hydrogels showed physical properties adequate for CLs and successfully passed the hen's egg-chorioallantoic membrane (HET-CAM) test. Silicone hydrogels had stronger affinity for resveratrol, with higher loading and a slower release rate. Ex vivo cornea and sclera permeability tests revealed that resveratrol released from the hydrogels readily accumulated in both tissues but did not cross through. The antibiofilm tests against Pseudomonas aeruginosa and Staphylococcus aureus evidenced that, in general, resveratrol decreased biofilm formation, which correlated with its concentration-dependent antibacterial capability. Preferential adsorption of lysozyme, compared to albumin, might also contribute to the antimicrobial activity. In addition, importantly, the loading of resveratrol in the hydrogels preserved the antioxidant activity, even against photodegradation. Overall, the designed hydrogels can host therapeutically relevant amounts of resveratrol to be sustainedly released on the eye, providing antibiofilm and antioxidant performance. [ABSTRACT FROM AUTHOR]

A variety of ocular diseases are caused by viruses, and most treatments rely on the use of systemic formulations and eye drops. The efficient ocular barriers that oppose antiviral drug penetration have prompted the development of improved topical delivery platforms. The aim was to design hydrogel contact lenses endowed with an affinity for acyclovir (ACV) and its prodrug valacyclovir (VACV), first-choice drugs against herpes simplex virus (HSV) ocular keratitis, and that can sustain the release of therapeutic doses during daily wearing. Functional monomers suitable for interaction with these drugs were screened using computational modeling. Imprinted and non-imprinted hydrogels were prepared with various contents in the functional monomer methacrylic acid (MAA) and characterized in terms of swelling, transmittance, mechanical properties, and ocular compatibility (hen's egg test on chorioallantoic membrane (HET-CAM) assay). The values were in the range typical of soft contact lenses. Compared to ACV, the capability to load VACV was remarkably higher due to stronger electrostatic interactions with MAA. The advantages of the imprinting technology were evidenced for VACV. Stability of VACV loading solution/hydrogels under steam heat sterilization and subsequent drug release was investigated. Permeability studies through bovine and porcine cornea and sclera of the drug released from the hydrogels revealed that VACV accumulates in the cornea and can easily cross the sclera, which may facilitate the treatment of both anterior and posterior eye segments diseases. [ABSTRACT FROM AUTHOR]

As an alternative to eye drops and ocular injections for gene therapy, the aim of this work was to design for the first time hydrogel contact lenses that can act as platforms for the controlled delivery of viral vectors (recombinant adeno-associated virus, rAAV) to the eye in an effective way with improved patient compliance. Hydrogels of hydroxyethyl methacrylate (HEMA) with aminopropyl methacrylamide (APMA) (H1: 40, and H2: 80 mM) or without (Hc: 0 mM) were synthesized, sterilized by steam heat (121 °C, 20 min), and then tested for gene therapy using rAAV vectors to deliver the genes to the cornea. The hydrogels showed adequate light transparency, oxygen permeability, and swelling for use as contact lenses. Loading of viral vectors (rAAV-lacZ, rAAV-RFP, or rAAV-hIGF-I) was carried out at 4 °C to maintain viral vector titer. Release in culture medium was monitored by fluorescence with Cy3-rAAV-lacZ and AAV Titration ELISA. Transduction efficacy was tested through reporter genes lacZ and RFP in human bone marrow derived mesenchymal stem cells (hMSCs). lacZ was detected with X-Gal staining and quantified with Beta-Glo®, and RFP was monitored by fluorescence. The ability of rAAV-hIGF-I-loaded hydrogels to trigger cell proliferation in hMSCs was evaluated by immunohistochemistry. Finally, the ability of rAAV-lacZ-loaded hydrogels to transduce bovine cornea was confirmed through detection with X-Gal staining of β-galactosidase expressed within the tissue. [ABSTRACT FROM AUTHOR]

Most treatments for diabetic eye conditions rely on systemic (oral) or intravitreal administration, and there is still a demand of efficient and comfortable ocular dosage forms. Our purpose was to design contact lenses (CLs) suitable for local prophylaxis/treatment of diabetes-related ocular pathologies, by means of the incorporation of bioinspired functional groups that can reversibly interact with epalrestat, an aldose reductase inhibitor. Several sets of silicone hydrogels were synthesized varying the contents in 2-hydroxyethyl methacrylate (HEMA), monomethacryloxypropyl-sym-polydimethylsiloxane hydroxypropyl terminated (MCS-MC12), and aminopropyl methacrylamide (APMA). Epalrestat was incorporated before or after polymerization, and loading and release profiles compared. All sets were evaluated regarding optical properties, oxygen permeability, swelling, cytocompatibility, ocular irritation, and corneal drug penetration (using a drug solution as reference). Designed silicone hydrogels showed adequate properties to be used as CLs. Affinity for epalrestat strongly depended on the content in APMA, which endowed the hydrogels with prolonged release in 0.9% NaCl for one week, both after synthesis and after being re-loaded. Bovine corneal permeability tests demonstrated that epalrestat released from the hydrogels can efficiently accumulate into the cornea in spite the concentrations provided on cornea surface were lower than those attained after instillation of concentrated eyedrops. Epalrestat-loaded hydrogels also demonstrated anti-cataract activity in an in vitro model of diabetic eye. Overall, silicone hydrogel CLs functionalized with bioinspired chemical groups represent a first attempt to design CLs adapted to the needs of diabetic eyes, acting as controlled release platforms of epalrestat, promoting drug accumulation and diffusion through cornea. [ABSTRACT FROM AUTHOR]

The aim of this work was to develop drug-soft contact lens combination products suitable for controlled release of antimicrobial peptides on the ocular surface. Incorporation of functional monomers and the application of molecular imprinting techniques were explored to endow 2-hydroxyethyl methacrylate ( HEMA) hydrogels with the ability to load and to sustain the release of polymyxin B and vancomycin. Various HEMA-drug-functional monomer-cross-linker molar ratios were evaluated to prepare polymyxin B imprinted and non-imprinted hydrogels. Acrylic acid-functionalized and imprinted hydrogels loaded greater amounts of polymyxin B and led to more sustained release profiles, in comparison with non-functionalized and non-imprinted networks. Polymyxin B-loaded hydrogels showed good biocompatibility in hen's egg test-chorioallantoic membrane tests. Functionalized hydrogels also loaded vancomycin and sustained its release, but the imprinting effect was only exhibited with polymyxin B, as demonstrated in rebinding tests. Microbiological assays carried out with Pseudomonas aeruginosa allowed identification of the most suitable hydrogel composition for efficient bacteria eradication; some hydrogels being able to stand several continued challenges against this important bacterial pathogen. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3386-3394, 2015 [ABSTRACT FROM AUTHOR]

Contact lenses (CLs) constitute an advantageous platform for the topical release of corticosteroids due to their prolonged contact with the eye. However, the lipophilic nature of corticosteroids hampers CLs' ability to release therapeutic amounts. Two approaches to improve loading and release of triamcinolone acetonide (TA) from poly(2-hydroxyethyl methacrylate)-based hydrogels were investigated: adding 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) to the monomers solution before polymerization (HEMA/i-CD) and an hydrogels' post-treatment with HP-β-CD (HEMA/p-CD). The effect of HP-β-CD and sterilization by high hydrostatic pressure (HHP) on the hydrogel properties (water content, oxygen and ion permeability, roughness, transmittance, and stiffness) was evaluated. The HEMA/i-CD hydrogels had stronger affinity for TA, sustaining its release for one day. HHP sterilization promoted the formation of cyclodextrin-TA complexes within the hydrogels, improving their drug-loading capacity »60 %. Cytotoxicity and irritability tests confirmed the safety of the therapeutic CLs. TA released from the hydrogels permeated through ocular tissues ex vivo and showed anti-inflammatory activity. Finally, a previously validated mathematical model was used to estimate the ability of the TA-loaded CLs to deliver therapeutic drug concentrations to the posterior part of the eye. Overall, HP-β-CD-containing CLs are promising candidates for the topical ocular application of TA as an alternative delivery system to intraocular injections. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Knowledge about the microstructure and the release rate of hydrophilic macromolecules is required for a rational development of comfortable and safe contact lenses. Semi-interpenetrating networks of poly(hydroxyethyl methacrylate) (pHEMA) with poly(vinyl pyrrolidone) (PVP) were prepared by free radical polymerization of HEMA in the presence of PVP K30 or K90F, under anhydrous conditions or after addition of water, and evaluated in terms of swelling, porosity, PVP release rate, air–water surface tension, and friction coefficient. The greater water content was during polymerization, the higher was the swelling degree and porosity. Microphase separation above a certain volume of water resulted in hydrogels with bumpy surface and interconnected pores. All hydrogels showed a high optical clarity and slowly released PVP (20% after 9 days). In general, the greater the content of PVP or the higher its molecular weight was, the lower the friction coefficients were. In the case of hydrogels prepared with water, the friction was influenced by the balance between the ability to hold water in the network (which contributes to the sliding and PVP release) and the deleterious effect of an irregular surface. Controlled delivery of PVP revealed as a critical factor for improving the frictional behavior of pHEMA contact lenses. [Copyright &y& Elsevier]

Abstract: Post-processing drug impregnation of commercially available polymer-based devices is a recent and attractive approach for the development of multifunctional biomedical devices and implants, drug release systems and tissue scaffolds. Therapeutic ophthalmic articles, such as drug-loaded contact lenses, are already known to improve ocular bioavailability in the treatment of several eye diseases, namely glaucoma, as well as to minimize undesired systemic side-effects. In this work, commercial silicone-based hydrogel contact lenses (Balafilcon A) were impregnated with two anti-glaucoma drugs (acetazolamide and timolol maleate) using a discontinuous supercritical solvent impregnation (SSI) methodology. Pressure and temperature, as well as impregnation time and depressurization rate, were kept constant (17MPa, 40°C, 90min, 0.06MPa/min, respectively) in order to evaluate the effects of nature and concentration of cosolvents (ethanol and water at 5, 10 and 15% molar) on the impregnation efficiencies and the properties of the contact lenses. Glass-transition temperature (DSC), oxygen permeability, contact angle, apparent morphological changes (SEM) and in vitro drug release kinetics were studied in detail. Results demonstrated the feasibility of preparing acetazolamide and timolol maleate impregnated therapeutic Balafilcon A contact lenses using CO2 +EtOH and CO2 +H2O solvent mixtures. Valuable information about how the nature and the composition of the employed solvent mixtures influence drug loading, drug release profiles and contact lenses physical and thermomechanical properties was obtained. [Copyright &y& Elsevier]

The aim of this study was to evaluate “in vivo” the usefulness of molecular imprinting technology to obtain therapeutic soft contact lenses capable of prolonging the permanence of timolol in the precorneal area, compared to conventional contact lenses and eyedrops. Soft contact lenses (diameter 14 mm, center thickness 0.08 mm) consisted of N,N-diethylacrylamide (DEAA; main component of the matrix), methacrylic acid (MAA; functional monomer) and ethylene glycol dimethacrylate (EGDMA; cross-linker) were prepared by the conventional methodology (non-imprinted) or by applying a molecular imprinting technique using timolol as the template (imprinted ones). After washing and reloading, timolol release studies carried out in rabbits showed that the soft contact lenses made by the molecular imprinting method (34 μg dose) provided measurable timolol concentrations in the tear fluid for 2.0- and 3.0-fold longer than the non-imprinted contact lenses (21 μg dose) and eyedrops (doses of 34 and 125 μg), respectively. Furthermore, the area under the timolol concentration–time curve (AUC) was 3.3- and 8.7-fold greater for imprinted contact lenses than non-imprinted contact lenses and eyedrops, respectively. The timolol concentration of the eyedrops did not affect the precorneal residence time of drug significantly. On the other hand, timolol loading capacity of the contact lenses was improved by the molecular imprinting method; the sustaining of the drug levels in the tear fluid being proportional to the loading capacity of the contact lenses. These results indicate that imprinted soft contact lenses are promising drug devices able to provide greater and more sustained drug concentrations in tear fluid with lower doses than conventional eyedrops. [Copyright &y& Elsevier]

Naltrexone (NTX) is a potent opioid growth factor receptor (OGFR) antagonist proved to be useful for treatment of ocular surface complications. The aim of this work was to explore the feasibility of designing NTX-imprinted 2-hydroxyethyl methacrylate-based hydrogels for sustained drug release on the ocular surface. Acrylic acid (AAc) and benzyl methacrylate (BzMA) were chosen as functional monomers able to form binding cavities mimicking OGFR binding sites for NTX. Imprinted hydrogels containing functional monomers loaded higher amounts of NTX compared to non-imprinted ones by simple soaking in drug aqueous solution. In addition, possibility of carrying out the loading and sterilization processes in one step was investigated. NTX release was evaluated both under agitated sink conditions and in a microfluidic flow chamber mimicking the hydrodynamic conditions of the eye, namely the small volume of lachrymal fluid and its renovation rate. Sustained release profiles together with adequate swelling degree (46 to 57% w/w), light transparency (over 85%) and oxygen permeability may make these hydrogels suitable candidates to NTX-eluting contact lenses. NTX-loaded and non-loaded discs successfully passed the chorioallantoic membrane test for potential ocular irritation and were cytocompatible with human mesenchymal stem cells. Finally, NTX-imprinted hydrogels tested in the bovine corneal permeability assay provided therapeutically relevant amounts of NTX inside the cornea, reaching drug levels similar to those attained with a concentrated aqueous solution in spite the discs showed sustained release. Unlabelled Image • Acrylic acid (AAc) played a main role in forming naltrexone binding points. • The imprinting enhanced drug loading, which could be carried out during autoclaving. • Sustained release was recorded in both agitated sink medium and microfluidic chamber. • Imprinted hydrogels provided therapeutic drug amounts inside the cornea. [ABSTRACT FROM AUTHOR]