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Controlled drug release from hydrogels for contact lenses: drug partitioning and diffusion

Publication . Pimenta, A.F.R.; Ascenso, J.; Fernandes, J.C.S.; Colaço, R.; Serro, A.P.; Saramago, B.

Optimization of drug delivery from drug loaded contact lenses assumes understanding the drug transport mechanisms through hydrogels which relies on the knowledge of drug partition and diffusion coefficients. We chose, as model systems, two materials used in contact lens, a poly-hydroxyethylmethacrylate (pHEMA) based hydrogel and a silicone based hydrogel, and three drugs with different sizes and charges: chlorhexidine, levofloxacin and diclofenac. Equilibrium partition coefficients were determined at different ionic strength and pH, using water (pH 5.6) and PBS (pH 7.4). The measured partition coefficients were related with the polymer volume fraction in the hydrogel, through the introduction of an enhancement factor following the approach developed by the group of C. J. Radke (Kotsmar et al., 2012; Liu et al., 2013). This factor may be decomposed in the product of three other factors EHS, Eel and Ead which account for, respectively, hard-sphere size exclusion, electrostatic interactions, and specific solute adsorption. While EHS and Eel are close to 1, Ead > > 1 in all cases suggesting strong specific interactions between the drugs and the hydrogels. Adsorption was maximal for chlorhexidine on the silicone based hydrogel, in water, due to strong hydrogen bonding. The effective diffusion coefficients, De, were determined from the drug release profiles. Estimations of diffusion coefficients of the non-adsorbed solutes D = De × Ead allowed comparison with theories for solute diffusion in the absence of specific interaction with the polymeric membrane.

2016-12Journal article

Open access

Simulation of the hydrodynamic conditions of the eye to better reproduce the drug release from hydrogel contact lenses: experiments and modeling

Publication . Pimenta, A. F. R.; Valente, A.; Pereira, J. M. C.; Pereira, J. C. F.; Filipe, H. P.; Mata, J. L. G.; Colaço, R.; Saramago, B.; Serro, A. P.

Currently, most in vitro drug release studies for ophthalmic applications are carried out in static sink conditions. Although this procedure is simple and useful to make comparative studies, it does not describe adequately the drug release kinetics in the eye, considering the small tear volume and flow rates found in vivo. In this work, a microfluidic cell was designed and used to mimic the continuous, volumetric flow rate of tear fluid and its low volume. The suitable operation of the cell, in terms of uniformity and symmetry of flux, was proved using a numerical model based in the Navier-Stokes and continuity equations. The release profile of a model system (a hydroxyethyl methacrylate-based hydrogel (HEMA/PVP) for soft contact lenses (SCLs) loaded with diclofenac) obtained with the microfluidic cell was compared with that obtained in static conditions, showing that the kinetics of release in dynamic conditions is slower. The application of the numerical model demonstrated that the designed cell can be used to simulate the drug release in the whole range of the human eye tear film volume and allowed to estimate the drug concentration in the volume of liquid in direct contact with the hydrogel. The knowledge of this concentration, which is significantly different from that measured in the experimental tests during the first hours of release, is critical to predict the toxicity of the drug release system and its in vivo efficacy. In conclusion, the use of the microfluidic cell in conjunction with the numerical model shall be a valuable tool to design and optimize new therapeutic drug-loaded SCLs.

2016-12Journal article

Open access

Capture of opiates by ionic liquids

Publication . Restolho, José; Barroso, Mário; Dias, Mário; Afonso, Carlos A. M.; Saramago, Benilde

Room temperature ionic liquids (RTILs) are known to provide efficient extraction media for a variety of systems. In particular, their ability to remove low volatility compounds (including opiate drugs) from the surface of human hair was recently demonstrated by this team. Among many tested ILs, some exhibited high extraction efficiencies for the two studied compounds, morphine and 6-monoacetylmorphine, while others have practically zero efficiency. The aim of the present study was to further understand the special affinity of specific combinations cation/anion towards the opiate drugs, through a systematic study of a limited number of ILs: 1-ethyl-3-methylimidazolium acetate, [C2mim][OAc], 1-butyl-3-methylimidazolium acetate [C4mim][OAc], 1-hexyl-3-methylimidazolium acetate [C6mim][OAc], 1-ethanol-3-methylimidazolium tetrafluoroborate, [C2OHmim][BF4], 1-ethanol-3-methylimidazolium chloride [C2OHmim][Cl], and 1-butyl-3-methylimidazolium tetrafluoroborate, [C4mim][BF4]. Correlations between the efficiency of drug extraction from hair and the water content, surface tension and polarity of the ionic liquids (ILs) were found. The extraction efficiency increased with the IL’s water content, although in a different way for each IL/drug pair. A decrease in the surface tension during the process of drug extraction was detected only for highly efficient ILs. Efficiency was correlated with the polarity parameters defined by Kamlet and Taft: large for ILs of high acidity and low basicity (e.g. [C2OHmim][BF4]) and small for liquids with of low acidity and high basicity (e.g. [C6mim][OAc]).

2015-04Journal article

Restricted access

The effect of albumin and cholesterol on the biotribological behavior of hydrogels for contact lenses

Publication . Silva, D.; Fernandes, A. C.; Nunes, T. G.; Colaço, R.; Serro, A. P.

The irritation/discomfort associated with the use of contact lenses (CLs) is often related to the eyelid-lens friction. Although the use of such devices is widespread, the information about the influence of the lacrimal fluid biomolecules on the tribological behavior of the CLs hydrogels is scarce. In this work, we investigated the effect of the presence of albumin and cholesterol in the lubricant medium, on the frictional response of two model hydrogels for CLs: a hydroxyethylmethacrylate based hydrogel, HEMA/PVP, and a silicone based one, TRIS/NVP/HEMA. Tribological experiments were done in a nanotribometer, in water and in the presence of solutions of those biomolecules. It was observed a significant increase of the friction coefficient (μ) for HEMA/PVP when the lubricant contains cholesterol, and for TRIS/NVP/HEMA when it contains albumin. Solid-state NMR and DSC analysis revealed that HEMA/PVP hydrated in cholesterol solution has a lower amount of free and loosely bound water than the hydrogel hydrated in water. Therefore, a smaller amount of water shall be released into the contact region during the friction tests with cholesterol solution, leading to a thinner film in the contact zone, and consequently to a higher μ. Concerning TRIS/NVP/HEMA, QCM-D studies showed that this hydrogel adsorbs less albumin than HEMA/PVP and that the formed film is more rigid, which can explain the increase of μ. The obtained results contribute to understand the influence of lacrimal fluid composition on the tribological behavior of CLs materials, being relevant for the selection and optimization of these devices.

2015-10Journal article

Restricted access

Diffusion-based design of multi-layered ophthalmic lenses for controlled drug release

Publication . Pimenta, Andreia F. R.; Serro, Ana Paula; Paradiso, Patrizia; Saramago, Benilde; Colaço, Rogério

The study of ocular drug delivery systems has been one of the most covered topics in drug delivery research. One potential drug carrier solution is the use of materials that are already commercially available in ophthalmic lenses for the correction of refractive errors. In this study, we present a diffusion-based mathematical model in which the parameters can be adjusted based on experimental results obtained under controlled conditions. The model allows for the design of multi-layered therapeutic ophthalmic lenses for controlled drug delivery. We show that the proper combination of materials with adequate drug diffusion coefficients, thicknesses and interfacial transport characteristics allows for the control of the delivery of drugs from multi-layered ophthalmic lenses, such that drug bursts can be minimized, and the release time can be maximized. As far as we know, this combination of a mathematical modelling approach with experimental validation of non-constant activity source lamellar structures, made of layers of different materials, accounting for the interface resistance to the drug diffusion, is a novel approach to the design of drug loaded multi-layered contact lenses.

2016-12Journal article

Open access