F.J. Otero-Espinar

Chitosan and chondroitin microspheres for oral-administration controlled release of metoclopramide

This study investigated the usefulness of chitosan and chondroitin sulphate microspheres for controlled release of metoclopramide hydrochloride in oral administration. Microspheres were prepared by spray drying of aqueous polymer dispersions containing the drug and different amounts of formaldehyde as cross-linker. Drug release kinetics were investigated in vitro in media of different pH. Chondroitin sulphate microspheres scarcely retarded drug release, regardless of cross-linker concentration and medium pH, and were thus not further characterized. Chitosan microspheres prepared with more than 15% formaldehyde (w/w with respect to polymer) showed good control release (more than 8 h), and release rates were little affected by medium pH. Release from chitosan microspheres prepared with 20% formaldehyde was independent of pH, suggesting that this may be the most appropriate formulation. The size distribution of the chitosan microparticles was clearly bimodal, with the smaller-diameter subpopulation corresponding to microsphere fragments and other particles. Electron microscopy showed the chitosan microspheres to be almost-spherical, though with shallow invaginations. The kinetics of drug release from chitosan microspheres were best fitted by models originally developed for systems in which release rate is largely governed by rate of diffusion through the matrix.

In-vitro bioadhesion of carbopol hydrogels

Abstract The main goal of this work was to study the adhesive capacity of hydrogels obtained from carbopol, this was achieved using a tensile tester in which adhesion work was the main parameter. The intended use of these hydrogels was the buccal administration of propanolol HC1. The adhesion assays were carried out under two hydration conditions, in order to evaluate the influence of water on adhesion. Results showed that adhesion capacity was considerably increased when water was limited in the system. The influence exerted on adhesion work by the polymer molecular weight and the crosslinking percentage were also studied and results showed that an increase in either of the mentioned parameters gave rise to a decrease in adhesion. Finally, propranolol HC1 was included into the hydrogels. It was observed that when water was limited in the system there was an increase in adhesion due to the increase in elasticity caused by the formation of a complex between the polymer and the drug. However, when there was no water limitation there was a slight decrease in adhesion caused by the precipitation of the complex carbopol-propranolol HC1.

A proton nuclear magnetic resonance study of the inclusion complex of naproxen with β-cyclodextrin

We report a 1H-NMR study of the complex formed between naproxen (NAP) and β-cyclodextrin (β-CD) in aqueous medium. Our results confirm that inclusion occurs. Analysis of our data by the continuous variation method shows that the complex has 1 : 1 stoicheiometry. Using Scotts modification of the Benesi-Hildebrand method, we estimate the apparent stability constant of the complex at 298 K in alkaline medium to be 420 M−1. Finally, with the aid of a molecular modelling program, we have determined the most probable structure of the complex. In general our results confirm those of previous studies, although our estimate of the apparent stability constant differs slightly from that reported on the basis of phase solubility results.

Cyclodextrins in drug delivery systems

Cyclodextrins are one of the most versatile aids in pharmaceutical technology, being of interest for the formulation of a wide range of delivery devices from the most classical dosage forms to the newest drug carriers. Their unique structural conformation together with the variety of substituents which can replace some of their hydroxyl groups endow cyclodextrins with versatile physicochemical features and the ability to form inclusion complexes with a wide range of drugs and macromolecules. Better knowledge of the reactivity of the cyclodextrins on forming supramolecular structures with a variety of architectures (self-assembled systems, poly(pseudo)rotaxanes, cross-linked networks, drug-conjugates) makes it possible to use cyclodextrins not only as drug solubilizers but also as true delivery systems. This review aims to summarize examples of the performance of cyclodextrins mainly in solid and semi-solid drug delivery systems, from the macro to the nanoparticulate scale, focusing on the information reported over the last 15 years.

Interaction of naproxen with β-cyclodextrin in solution and in the solid state

Abstract The behaviour of the inclusion complex of naproxen with β-cyclodextrin was studied by molecular modelling using interactive computer graphics, solubility diagrams at different temperatures and pH values, infrared spectroscopy and differential scanning calorimetry. The complex was prepared by freeze-drying, spray-drying and kneading. Three-dimensional modelling shows that naproxen lies totally enclosed in the interior of the β-cyclodextrin cavity. The energy calculated for the model indicates a high stability. The dependency of the stability in solution on pH and temperature, and the thermodynamic parameters calculated show the possible existence of intermolecular hydrogen bonds that are less stable with increasing pH. Infrared spectra show a shift to lower wavenumber in the carbonyl-stretching bands of naproxen for the products prepared by freeze-drying and spray-drying. This may be due to the formation of hydrogen bonds between the host and guest. Thermal analysis confirmed that freeze-drying and spray-drying led to complex formation. The kneading method, however, gives poor drug complexation; only one-third of the naproxen penetrates the cyclodextrin cavity, the rest remaining freely dispersed between uncomplexed host and inclusion compound.

Hydrosoluble cyclodextrin/poloxamer polypseudorotaxanes at the air/water interface, in bulk solution, and in the gel state.

The interactions between poloxamer 407 (Pluronic F127, PF127) and two hydrophilic derivatives of beta-cyclodextrin, i.e., hydroxypropyl-beta-cyclodextrin (HPbetaCD; molar substitution (MS) 0.65) and methylated-beta-cyclodextrin (MbetaCD; MS 0.57), were characterized by means of surface tension measurements, pi-A isotherms, isoperibol microcalorimetry, 1H NMR, and rheometry. An effective complexation of poloxamer with the two CDs was evidenced as a change in the surface pressure of the pi-A isotherm of PF127 on a subphase of CD solution, with a positive excess being observed at the expanded region and a negative excess at the collapsed region. Such changes indicated that when the CD lies with the main axis perpendicular to the interface at low pressure no complexation occurs, but as the pressure increases and the CDs eventually change their arrangement to be with the main axis parallel to the interface, the amphiphilic copolymer can form polypseudorotaxanes. Addition of CDs to PF127 micellar solutions led to the exothermic rupture of micelles, a shift in the cmc toward higher values, changes in the chemical shifts of H3, H4, and H5 of MbetaCD and of the methyl groups of PF127, and an increase in the gel temperature. The interaction was stronger between poloxamer and MbetaCD, compared to HPbetaCD, with the stoichiometry of the polypseudorotaxanes being preferably ca. 1:20 in both cases. SEM images revealed formation of nanorods of stacked polypseudorotaxanes. Complexation with a high affinity constant between unimers and CDs in bulk solution was also evidenced by competitive displacement of methyl orange. Feasible structural models of the PF127:CD polypseudorotaxanes at both the air-water interface and in the bulk solution are proposed.

Hydration and N-acetyl-l-cysteine alter the microstructure of human nail and bovine hoof: Implications for drug delivery

This work aimed to (a) characterize the microstructure and porosity of human nail and bovine hoof by mercury intrusion porosimetry and SEM image analysis, (b) study the effects of hydration and of N-acetyl-l-cysteine treatment on the microstructure of both membranes, and (c) determine whether the microstructural modifications were associated with changes in drug penetration measured by standard diffusion studies. Bovine hoof surface is more porous than nail surface although there were no differences between the mean surface pore sizes. Hydration and N-acetyl-l-cysteine increased the roughness and apparent surface porosity, and the porosity determined by mercury intrusion porosimetry of both membranes. Pore-Cor™ was used to generate tridimensional structures having percolation characteristics comparable to nail and hooves. The modeled structures were horizontally banded having an inner less-porous area which disappeared upon treatment. Treatment increased the predicted permeability of the simulated structures. Triamcinolone permeation increased significantly for hooves treated N-acetyl-l-cysteine, i.e., the membranes for which microstructural and permeability changes were the largest. Thus, microstructural changes determined via mercury intrusion porosimetry and subsequently modeled by Pore-Cor™ were related to drug diffusion. Further refinement of the technique will allow fast screening of penetration enhancers to be used in ungual drug delivery.

Formulation of triamcinolone acetonide pellets suitable for coating and colon targeting

Spherical pellets containing 5% of triamcinolone acetonide (TA) were formed by extrusion/spheronization following formulation with microcrystalline cellulose (MCC) and/or a hydrophilic excipient (lactose, sodium carboxymethylcellulose or beta-cyclodextrin, beta-CD). Their suitability for coating, with a view to colonic drug delivery, was assessed in terms of their size, sphericity and dissolution test response. Best results were afforded by 5:90:5 MCC-beta-CD-TA pellets obtained by complexation of TA with beta-CD prior to addition of MCC, extrusion and spheronization.

Design and evaluation of buccoadhesive metoclopramide hydrogels composed of poly(acrylic acid) crosslinked with sucrose

Abstract We evaluated the effects of polyacrylic acid (PAA) molecular weight and crosslinking agent (sucrose) concentration on swelling and drug (metoclopramide) release characteristics of PAA (Carbopol) hydrogels. Both factors, and the interactions between them, were found to have significant effects on both hydrogel swelling and drug release. In particular, increased sucrose concentration led to reduced swelling and reduced drug release efficiency.

In vitro and in vivo ocular safety and eye surface permanence determination by direct and Magnetic Resonance Imaging of ion-sensitive hydrogels based on gellan gum and kappa-carrageenan

Gellan gum, kappa-carrageenan and alginates are natural polysaccharides able to interact with different cations that can be used to elaborate ion-activated in situ gelling systems for different uses. The interaction between fluid solutions of these polysaccharides and cations presents into the tear made these biopolymers very interesting to elaborate ophthalmic drug delivery systems. The main purpose of this study is to evaluate the ability of mixtures of these polymers to obtain ion-activated ophthalmic in situ gelling systems with optimal properties for ocular use. To achieve this purpose different proportion of the biopolymers were analyzed using a mixture experimental design evaluating their transparency, mechanical properties and bioadhesion in the absence and presence of simulated tear fluid. Tear induces a rapid sol-to-gel phase transition in the mixtures forming a consistent hydrogel. The solution composed by 80% of gellan gum and 20% kappa-carrageenan showed the best mechanical and mucoadhesive properties. This mixture was evaluated for rheological behavior, microstructure, cytotoxicity, acute corneal irritancy, ex-vivo and in vivo ocular toxicity and in vivo corneal contact time using Magnetic Resonance Images (MRI) techniques. Result indicates that the system is safe at ophthalmic level and produces an extensive ocular permanence higher than 6h.