Role of Microstructure in Drug Release from Chitosan Amorphous Solid Dispersions.

The unexpected dissolution behaviour of amorphous diflunisal-chitosan solid dispersions (kneading method) with respect to the crystalline co-evaporated systems is the starting point of this research. This work is an in-depth study of the diflunisal release behaviour from either chitosan or carboxymethylchitosan dispersions. The microstructure is not usually considered when designing this type of products; however, it is essential to understand the process of solvent penetration and subsequent drug release through a polymeric system, as has been evidenced in this study. In accordance with the kinetic data analysed, it is possible to conclude that the porous structure, conditioned by the sample preparation method, can be considered the main factor involved in diflunisal release. The low mean pore size (1-2 µm), low porosity, and high tortuosity of the amorphous kneaded products are responsible for the slow drug release in comparison with the crystalline coevaporated systems, which exhibit larger pore size (8-10 µm) and lower tortuosity. Nevertheless, all diflunisal-carboxymethylchitosan products show similar porous microstructure and overlapping dissolution profiles. The drug release mechanisms obtained can also be related to the porous structure. Fickian diffusion was the main mechanism involved in drug release from chitosan, whereas an important contribution of erosion was detected for carboxymethylchitosan systems, probably due to its high solubility.

High-resolution time-dependent probabilistic assessment of the hydraulic performance for historic coastal structures: application to Luarca Breakwater.

Historic coastal structures have played a key role in small- to medium-size ports, being the driving force for the local development of coastal communities. Because coastal managers require reliable risk-based analysis of the whole life cycle of these coastal structures, previous lifetimes should be studied. This is a differentiating factor with respect to the newly built breakwaters. For this reason, in this work, a methodology for assessing how the hydraulic performance of an expired lifetime has evolved over the years is presented. It is performed following a probabilistic approach due to the uncertainty related to both the involved variables (wave climate, geometrical and structural breakwater variables) and the hydraulic response of the structure. The first ones are characterized by reliable probability distribution functions. The second ones are characterized by reliable formulae for the analysis of the hydraulic response. However, their non-conventional designs located in shallow-water locations require site-dependent formulae. To overcome this problem, a novel methodology to apply CFD numerical models is presented. Finally, it is integrated in a high-resolution time-dependent probabilistic methodology which takes into account the stochastic behaviour of all the involved variables, coastal and structural processes with a good uncertainty level. This article is part of the theme issue 'Environmental loading of heritage structures'.

Cyclodextrin-grafted poly(anhydride) nanoparticles for oral glibenclamide administration. In vivo evaluation using C. elegans.

The aim of this work was to prepare and evaluate cyclodextrins-modified poly(anhydride) nanoparticles to enhance the oral administration of glibenclamide. A conjugate polymer was synthesized by incorporating hydroxypropyl-ß-cyclodextrin to the backbone of poly(methylvinyl ether-co-maleic anhydride) via Steglich reaction. The degree of substitution of anhydride rings by cyclodextrins molecules was calculated to be 4.9% using H-NMR spectroscopy. A central composite design of experiments was used to optimize the preparative process. Under the optimal conditions, nanoparticles displayed a size of about 170 nm, a surface charge of -47 mV and a drug loading of 69 µg GB/mg. X-ray diffraction studies confirmed the loss of the crystalline structure of GB due to its dispersion into the nanoparticles, either included into cyclodextrin cavities or entrapped in the polymer chains. Glibenclamide was mainly release by Fickian-diffusion in simulated intestinal fluid. GB-loaded nanoparticles produced a hypolipidemic effect over C. elegans N2 wild-type and daf-2 mutant. The action mechanism included daf-2 and daf-28 genes, both implicated in the insulin signaling pathway of C. elegans. In summary, the covalent linkage of cyclodextrin to the poly(anhydride) backbone could be an interesting strategy to prepare nanoparticles for the oral administration of glibenclamide.

Coencapsulation of cyclodextrins into poly(anhydride) nanoparticles to improve the oral administration of glibenclamide. A screening on C. elegans.

This work describes the feasibility of poly(anhydride) nanoparticles as carriers for the oral administration of glibenclamide (GB) as well as the in vivo evaluation of their hypolipidemic effect in a C. elegans model. For this purpose, and in order to increase the GB payload, the drug was encapsulated in nanoparticles in presence of cyclodextrins (either ßCD or HPßCD). The optimized nanoparticles displayed a size of about 220 nm and a negative zeta potential (-40 mV), with a drug loading up to 52 µg/mg. Small-angle neutron scattering studies suggested an internal fractal-like structure, based on the repetition of spherical blocks of polymeric units (about 5 nm) grouped to form the nanoparticle. X-ray diffraction study confirmed the absence of crystalline GB molecules due to its dispersion into the nanoparticles, either entrapped in the polymer chains and/or included into cyclodextrin cavities. GB-loaded nanoparticles induced a significant reduction in the fat content of C. elegans. This hypolipidemic effect was slightly higher for the nanoparticles prepared with coencapsulated HPßCD (8.2%) than for those prepared with ßCD (7.9%) or in the absence of cyclodextrins (7.0%). In summary, the coencapsulation of cyclodextrins into poly(anhydride) nanoparticles could be an interesting strategy to develop new oral formulations of glibenclamide.

Optimization and evaluation of zein nanoparticles to improve the oral delivery of glibenclamide. In vivo study using C. elegans.

The aim of this work was to evaluate the capability of zein nanoparticles as oral carriers for glibenclamide (GB). Nanoparticles were prepared by a desolvation procedure in the presence of lysine as stabilizer. A central composite design was used to optimize this preparative process. Under the selected conditions, nanoparticles displayed a size of about 190 nm, a surface charge of -37mV and a payload of 45µg GB/mg. Small-angle neutron scattering and X-ray diffraction techniques suggested an internal fractal-like structure, based on the repetition of spherical blocks of zein units (about 20nm) grouped to form the nanoparticles. This structure, stabilized by lysine molecules located at the surface, would determine the release of GB (molecularly trapped into the nanoparticles) by a pure diffusion mechanism. Moreover, GB-loaded nanoparticles induced a significant hypolipidemic effect with a reduction of about 15% in the fat content of C. elegans worms. In addition, did not induce any significant modification in the lifespan of worms. In summary, the employment of zein nanoparticles as delivery systems of glibenclamide may be an interesting approach to develop new oral formulations of this antidiabetic drug.

Supramolecular structure of glibenclamide and ß-cyclodextrins complexes.

Glibenclamide is an antidiabetic drug showing low bioavailability as consequence of its low solubility. To solve this drawback, the interaction with cyclodextrins has been proposed. The formation of GB-ßCDs inclusion complexes was carried out using different methods, ßCD derivatives and drug-to-cyclodextrin ratios. The structures of the corresponding complexes have been studied by molecular modelling, X-ray diffraction and differential thermal analysis. The dissolution behavior of inclusion complexes has been compared to that of pure GB. Dimeric inclusion complexes were obtained with different CD disposals, head-to-head for ßCD and head-to-tail for HPßCD and RMßCD. Amorphous inclusion complexes were obtained by employing methods of freeze-drying or coevaporation in ammonia-water. However, crystalline structures were formed by kneading and coevaporation in ethanol/water in the case of GB-ßCD complexes. The arrangement of these structures depended on the GB:ßCD ratio, yielding cage type structures for 1:3 and 1:5 ratios and channel-type structures for higher GB contents. The amount of GB released and its dissolution rate was considerably increased by the use of amorphous inclusion complexes; whereas, slower GB release rates were found from crystalline inclusion complexes formed by kneading or coevaporation in ethanol/water. In addition, it was found that the porous structure strongly conditioned the GB dissolution rate from crystalline products.

Nanoaggregation of inclusion complexes of glibenclamide with cyclodextrins.

Glibenclamide is a sulfonylurea used for the oral treatment of type II diabetes mellitus. This drug shows low bioavailability as consequence of its low solubility. In order to solve this problem, the interaction with cyclodextrin has been proposed. This study tries to provide an explanation about the processes involved in the formation of GB-ßCDs complexes, which have been interpreted in different ways by several authors. Among native cyclodextrins, ßCD presents the most appropriate cavity to host glibenclamide molecules showing AL solubility diagrams (K1:1≈1700M-1). However, [Formula: see text] solubility profiles were found for ßCD derivatives, highlighting the coexistence of several phenomena involved in the drug solubility enhancement. At low CD concentration, the formation of inclusion complexes can be studied and the stability constants can be calculated (K1:1≈1400M-1). Whereas at high CD concentration, the enhancement of GB solubility would be mainly attributed to the formation of nanoaggregates of CD and GB-CD complexes (sizes between 100 and 300nm). The inclusion mode into ßCD occurs through the cyclohexyl ring of GB, adopting a semi-folded conformation which maximizes the hydrogen bond network. As consequence of all these phenomena, a 150-fold enhancement of drug solubility has been achieved using ß-cyclodextrin derivatives. Thus, its use has proven to be an interesting tool to improve the oral administration of glibenclamide in accordance with dosage bulk and dose/solubility ratio requirements.

Influence of chitosan and carboxymethylchitosan on the polymorphism and solubilisation of diflunisal.

The interactions of diflunisal (DF) with chitosans (CS) of different molecular weights and carboxymethylchitosan (CMCS), a water-soluble derivative, have been investigated. The interactions in solution have been studied by solubility assays in which the highest solubilisation (13-fold) was obtained with CMCS. Solid dispersions were prepared by coevaporation and kneading methods. Solid state characterisation was performed by X-ray diffraction analysis, scanning electron microscopy, thermomicroscopy, differential thermal analysis and infrared spectroscopy. Drug-polymer electrostatic interactions and hydrogen bonds are the main binding forces in these systems. The kneading method gave rise to amorphous systems regardless of the polymer employed. However, coevaporation resulted in the formation of different polymorphs of diflunisal (form II or III) depending on the type of polymer used. Therefore, it seems that drug-polymer interactions determine the crystallization pattern of the drug. Finally, diflunisal release from these systems improved markedly with CMCS and significantly in the presence of low molecular weight CS.