Angel Concheiro

Light‐sensitive Intelligent Drug Delivery Systems

Drug delivery systems (DDS) capable of releasing an active molecule at the appropriate site and at a rate that adjusts in response to the progression of the disease or to certain functions/biorhythms of the organism are particularly appealing. Biocompatible materials sensitive to certain physiological variables or external physicochemical stimuli (intelligent materials) can be used for achieving this aim. Light‐responsiveness is receiving increasing attention owing to the possibility of developing materials sensitive to innocuous electromagnetic radiation (mainly in the UV, visible and near‐infrared range), which can be applied on demand at well delimited sites of the body. Some light‐responsive DDS are of a single use (i.e. the light triggers an irreversible structural change that provokes the delivery of the entire dose) while others able to undergo reversible structural changes when cycles of light/dark are applied, behave as multi‐switchable carriers (releasing the drug in a pulsatile manner). In this review, the mechanisms used to develop polymeric micelles, gels, liposomes and nanocomposites with light‐sensitiveness are analyzed. Examples of the capability of some polymeric, lipidic and inorganic structures to regulate the release of small solutes and biomacromolecules are presented and the potential of light‐sensitive carriers as functional components of intelligent DDS is discussed.

Crosslinked ionic polysaccharides for stimuli-sensitive drug delivery.

Polysaccharides are gaining increasing attention as components of stimuli-responsive drug delivery systems, particularly since they can be obtained in a well characterized and reproducible way from the natural sources. Ionic polysaccharides can be readily crosslinked to render hydrogel networks sensitive to a variety of internal and external variables, and thus suitable for switching drug release on-off through diverse mechanisms. Hybrids, composites and grafted polymers can reinforce the responsiveness and widen the range of stimuli to which polysaccharide-based systems can respond. This review analyzes the state of the art of crosslinked ionic polysaccharides as components of delivery systems that can regulate drug release as a function of changes in pH, ion nature and concentration, electric and magnetic field intensity, light wavelength, temperature, redox potential, and certain molecules (enzymes, illness markers, and so on). Examples of specific applications are provided. The information compiled demonstrates that crosslinked networks of ionic polysaccharides are suitable building blocks for developing advanced externally activated and feed-back modulated drug delivery systems.

Contact lenses for drug delivery

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.

Soft contact lenses functionalized with pendant cyclodextrins for controlled drug delivery.

The aim of this work was to develop acrylic hydrogels with high proportions of cyclodextrins maintaining the mechanical properties and the biocompatibility of the starting hydrogels, but notably improving their ability to load drugs and to control their release rate. Poly(hydroxyethylmethacrylate) hydrogels were prepared by copolymerization with glycidyl methacrylate (GMA) at various proportions and then beta-cyclodextrin (betaCD) was grafted to the network by reaction with the glycidyl groups under mild conditions. This led to networks in which the betaCDs form no part of the structural chains but they are hanging on 2-3 ether bonds through the hydroxyl groups. The pendant betaCDs did not modify the light transmittance, glass transition temperature, swelling degree, viscoelasticity, oxygen permeability, or surface contact angle of the hydrogels, but decreased their friction coefficient by 50% and improved diclofenac loading by 1300% and enhanced drug affinity 15-fold. The hydrogels were able to prevent drug leakage to a common conservation liquid for soft contact lenses (SCLs) and to sustain drug delivery in lacrimal fluid for two weeks. To summarize, the hydrogels with pendant betaCDs are particularly useful for the development of cytocompatible medicated implants or biomedical devices, such as drug-loaded SCLs.

Poly(hydroxyethyl methacrylate-co-methacrylated-β-cyclodextrin) hydrogels: Synthesis, cytocompatibility, mechanical properties and drug loading/release properties

Copolymerization of hydroxyethyl methacrylate (HEMA) with a methacrylated-derivative of beta-cyclodextrin (beta-CD) was evaluated as a way to obtain hydrogels with tunable mechanical and drug loading and release properties, particularly for preparing medicated soft contact lenses. A fully methacrylated beta-CD monomer was synthesized and added to the HEMA and cross-linker solution at concentrations ranging from 0.042 to 0.333 g ml(-1) (i.e. 0.23-1.82 mol.%). Thermal polymerization led to transparent hydrogels with a degree of conversion above 74%, which showed a high cytocompatibility and did not induce macrophage response. The greater the content in methacrylated beta-CD was, the higher the glass transition temperature, the lower the degree of swelling and free water proportion, and the greater the storage and loss moduli of the swollen disks. These findings are directly related to the increase in the degree of cross-linking caused by the methacrylated beta-CD. Loading studies were carried out with hydrocortisone and acetazolamide, both able to form complexes with CDs in water and in lacrimal fluid. Hydrocortisone loading progressively decreased as the content in methacrylated beta-CD rose due to a decrease in the volume of aqueous phase of the hydrogel. Acetazolamide loading showed a maximum for an intermediate content in beta-CD (0.125-0.167 g ml(-1)) owing to a balance between complexation with beta-CD and hydrogel mesh size. The hydrogels sustained drug delivery for several days, the acetazolamide release rate being dependent on the beta-CD content. An adequate selection of the content in beta-CD enables pHEMA-co-beta-CD hydrogels suitable for specific biomedical applications to be obtained.

New Cyclodextrin Hydrogels Cross-Linked with Diglycidylethers with a High Drug Loading and Controlled Release Ability

PurposeThe goal of the study is to develop new hydrogels based on cyclodextrins cross-linked with ethyleneglycol diglycidylether (EGDE) under mild conditions, to be used as carriers of amphiphilic drugs. Also, it aims to characterize the cross-linking and the drug loading and release processes.MethodsThe cross-linking of hydroxypropyl-β-cyclodextrin (HPβCD) with EGDE, in the absence or presence of hydroxypropylmethylcellulose (HPMC) Methocel® K4M, was optimized applying oscillatory rheometry and Fourier transform infrared. Hydrogels were characterized regarding swelling in water, ability to load diclofenac, and release after different drying treatments.ResultsSolutions of HPβCD (14.28%), without or with HPMC (0.2–1.0%), provided firm and transparent hydrogels after cross-linking with EGDE (14.28%), in which around two thirds of the OH groups were cross-linked. The incorporation of HPMC progressively reduced the gel time and the swelling degree of hydrogels. HPβCD hydrogels efficiently loaded diclofenac and sustained the release for several hours. The presence of HPMC slowed the release from swollen hydrogels, but promoted it from hydrogels dried before the loading and also before the release.ConclusionsHPβCD hydrogels with good mechanical properties and tunable loading and release ability can be obtained by direct cross-linking with EGDE.

Cyclodextrin-based nanogels for pharmaceutical and biomedical applications

Hydrophilic nanogels combine the advantages of hydrogels with certain advantages that are inherent in their nanoscale size. Similar to macrogels, nanogels can contain and protect drugs and regulate their release by incorporating high-affinity functional groups, stimuli-responsive conformations and biodegradable bonds into the polymer network. Similar to nanoparticles, nanogels can easily be administered in liquid form for parenteral drug delivery. The nanoscale size of nanogels gives them a high specific surface area that is available for further bioconjugation of active targeting agents. Biodistribution and drug release can be modulated through size adjustments. The incorporation of hydrophilic cyclodextrin (CD) moieties into the polymeric network of the nanogels provides them with a drug loading and release mechanism that is based on the formation of inclusion complexes without decreasing the hydrophilicity of the network. The covalent attachment of CD molecules to the chemically crosslinked networks may enable the CDs to display fully their ability to form complexes, while simultaneously preventing drug release upon media dilution. The preparation, characterization and advantages for pharmaceutical and biomedical applications of CD-based nanogels are reviewed in this article.

Incorporation of small quantities of surfactants as a way to improve the rheological and diffusional behavior of carbopol gels

This paper analyzes the effects of Tween 80, Pluronic F-127, sodium dodecylsulfate (SDS), and benzalkonium chloride on the macro and microviscosity of Carbopol 934NF (0.25-0.50 g/dl) pharmaceutical gels. Carbopol/surfactant interactions, which were reflected in changes in the intrinsic viscosity of the polymer and in shifts of IR spectra bands of films, considerably modified the rheological properties of the gel (flow and oscillatory rheometry) and the diffusion coefficients of polystyrene particles (dynamic light scattering, DLS). At pH 4, any surfactant at a concentration of 0.01 g/dl promoted interpolymer connections producing an open three-dimensional network with maximum viscous and elastic moduli, which does not disturb the diffusive movement of polystyrene particles. An increase in non-ionic surfactant (0.05-0.50 g/dl) gradually decreased viscosity and elasticity since there were more surfactant molecules to surround each carbopol particle, forming intrapolymeric micelles and breaking the interpolymer connections. This macroscopic effect is, however, not reflected in a decrease but in an increase in microviscosity (estimated by DLS) owing to the formation of larger carbopol/surfactant aggregates and free micelles that contribute significantly to the obstruction of the diffusional path. Both ionic surfactants decreased macroviscosity owing to ionic aggregation (benzalkonium chloride) or increase in ionic strength (mainly SDS), while the repercussion on the diffusion of polystyrene particles was dramatically different, and was hindered (due to the carbopol/surfactant aggregates) or enhanced (due to the shrinking of carbopol microgels), respectively. At pH 7.4, the ionization of the carboxylic groups produced an expansion of the polymer chains accompanied by a huge increase in viscosity and elasticity and a decrease in diffusion coefficients in comparison with those obtained at pH 4. The effects of the surfactants were similar to those observed at pH 4 but less intense. Chloramphenicol release studies (Franz-Chien cells) revealed that 0.01 g/dl surfactant did not affect the diffusion while a change in pH dramatically altered the process. The results show that by choosing the appropriate proportion of the most suitable surfactant, it is possible to modulate the flow behavior, elastic properties, and diffusional microenvironment of carbopol gels, without losing the pH-dependent gelling ability, which could improve the suitability of carbopol gels for drug delivery through different routes.

Chemically cross-linked and grafted cyclodextrin hydrogels: from nanostructures to drug-eluting medical devices.

The unique ability of cyclodextrins (CDs) to form inclusion complexes can be transmitted to polymeric networks in which CDs are chemically grafted or cross-linked. Combination of CDs and hydrogels in a single material leads to synergic properties: the hydrophilic network enhances biocompatibility and prevents dilution in the physiological medium increasing the stability of the inclusion complexes, while CDs finely tune the mechanical features and the stimuli-responsiveness and provide affinity-based regulation of drug loading and release. Therefore, CD-functionalized materials are opening new perspectives in pharmacotherapy, emerging as advanced delivery systems (DDS) for hydrophobic and hydrophilic drugs to be administered via almost any route. Medical devices (catheters, prosthesis, vascular grafts, bone implants) can also benefit from surface grafting or thermofixation of CDs. The present review focuses on the approaches tested to synthesize nano- to macro-size covalently cross-linked CD networks: i) direct cross-linking through condensation with di- or multifunctional reagents, ii) copolymerization of CD derivatives with acrylic/vinyl monomers, and iii) grafting of CDs to preformed medical devices. Examples of the advantages of having the CDs chemically bound among themselves and to substrates are provided and their applicability in therapeutics discussed.

Self-Associative Behavior and Drug-Solubilizing Ability of Poloxamine (Tetronic) Block Copolymers

The incidence of the structural features on the self-assembly of different poloxamines (the conventional sequential Tetronic 304, 901, 904, 908, 1107, 1301, and 1307; a reverse-sequential counterpart Tetronic 150R1; and a chemically modified derivative, N-methylated Tetronic 1107) was thoroughly studied in 10 mM HCl by means of pi-A isotherm, surface tension, and pyrene fluorescence measurements. The size and size distribution of the aggregates were investigated by dynamic and static light scattering, and the morphology was probed by transmission electron microscopy. The abilities of the different derivatives to solubilize the drug simvastatin were also evaluated. Poloxamines with both higher PO/EO ratio and molecular weight (T1301 and T150R1) led to micelles with larger and more hydrophobic cores, particularly adequate for hosting hydrophobic molecules and protecting the labile lactone form of simvastatin from hydrolysis. On the other hand, the hydroxy acid form of simvastatin interacted with the central ethylenediamine group under alkaline pH (T304) or when a permanent positive charge due to methylation was present. Micelles of long poloxamine molecules containing large PPO blocks (with 23-29 units, namely, T1301, T1307, and T150R1), particularly the one that also has long PEO blocks, were the most physically stable toward dilution.