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Publicaciones científicas más recientes (desde 2010)

Autores: Luis de Redín, Inés; Boiero, C.; Martínez-Oharriz, M.C.; et al.
ISSN 0378-5173  Vol. 541  Nº 1 - 2  2018  págs. 214 - 223
Bevacizumab-loaded nanoparticles (B-NP) were prepared by a desolvation process followed by freeze-drying, without any chemical, physical or enzymatic cross-linkage. Compared with typical HSA nanoparticles crosslinked with glutaraldehyde (B-NP-GLU), B-NP displayed a significantly higher mean size (310 nm vs. 180 nm) and a lower negative zeta potential (-15 mV vs. -36 mV). On the contrary, B-NP displayed a high payload of approximately 13% when measured by a specific ELISA, whereas B-NP-GLU presented a very low bevacizumab loading (0.1 mu g/mg). These results could be related to the inactivation of bevacizumab after reacting with glutaraldehyde. From B-NP, bevacizumab was released following an initial burst effect, proceeded by a continuous release of bevacizumab at a rate of 6 mu g/h. Cytotoxicity studies in ARPE cells were carried out at a single dose up to 72 h and with repeated doses over a 5-day period. Neither bevacizumab nor B-NP altered cell viability even when repeated doses were used. Finally, B-NP were labeled with Tc-99m and administered as eye drops in rats. Tc-99m-B-NP remained in the eye for at least 4 h while Tc-99m-HSA was rapidly drained from the administration point. In summary, HSA nanoparticles may be an appropriate candidate for ocular delivery of bevacizumab.
Autores: Moreno, L. C. G. E. A. I.; Solas, Maite; Martínez-Oharriz, M.C.; et al.
ISSN 0378-5173  Vol. 543  Nº 1 - 2  2018  págs. 245 - 256
Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of nimodipine and test their capability to both reverse the anxiety and protect against cognitive impairment of in stressed mice. Pegylated nanoparticles (NMD-NP/PEG), with a size of 190 nm and a payload of 68 mu g/mg, significantly improve the oral bioavailability of nimodipine; about 7-times higher than for the control drug solution (62% vs 9%). The effect of oral nimodipine on the anxiety and cognitive capabilities in a model of stressed mice was also evaluated. NMD-NP/PEG displayed a poor effect on the anxiety-like behavior of animals. Nevertheless, only the treatment with NMD-NP/PEG exerted a protective effect against the memory impairments induced by chronic corticosterone administration, improving the cognitive capabilities of animals when compared with controls. These pegylated nanocarriers may represent a useful strategy to develop new oral treatments for preventing from cognitive impairments.
Autores: Lucio, David; Martínez-Oharriz, M.C.; González-Navarro, CJ; et al.
ISSN 0927-7765  Vol. 163  2018  págs. 64 - 72
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¿¿g/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.
Autores: Lucio, David, (Autor de correspondencia); Martínez-Oharriz, M.C.; Gu, Z. W.; et al.
ISSN 0378-5173  Vol. 547  Nº 1 - 2  2018  págs. 97 - 105
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-beta-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 mu g 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.
Autores: Lucio, David; Irache, Juan M.; Font, María ; et al.
ISSN 0378-5173  Vol. 519  Nº 1 - 2  2017  págs. 263 - 271
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-beta CDs complexes, which have been interpreted in different ways by several authors. Among native cyclodextrins, beta CD presents the most appropriate cavity to host glibenclamide molecules showing A(L) solubility diagrams (K-1:1 approximate to 1700 M-1). However, A(L)- solubility profiles were found for pa) 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 (K-1:1 approximate to 1700 M-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 300 nm). The inclusion mode into beta CD 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 beta-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. (C) 2017 Elsevier B.V. All rights reserved.
Autores: García-Padial, Marcos; Martínez-Oharriz, M.C.; Isasi, José Ramón; et al.
ISSN 0021-8561  Vol. 65  Nº 24  2017  págs. 4905 - 4910
The sorption and release of tyrosol and caffeic acid, two biophenolic antioxidants with known health benefits, in different insoluble cyclodextrin polymers have been studied. Cyclodextrin polymers were synthesized by cross-linking, beta-cyclodextrin or 50:50 w/w nominal mixtures of alpha- and beta-cyclodextrins using either epichlorohydrin (EP) or toluene-2,4-diisocyanate (TDI) as cross-linking agents. An analogous sucrose polymer was prepared using EP as cross-linking reagent. Freundlich isotherms and isosteric heats of sorption for tyrosol and caffeic acid in the insoluble beta-cyclodextrin polymer cross-linked with epichlorohydrin at 50 degrees C were obtained and discussed. Finally, the release of tyrosol and caffeic acid has been studied from loaded polymer disks, the microstructures of which were characterized by mercury intrusion porosimetry. Caffeic acid shows greater affinity than tyrosol for the polymeric matrices as it presents a higher sorption and a lower and slower release. However, tyrosol has a higher isosteric heat of sorption for low coverages.
Autores: Calleja, P.; Irache, Juan M.; Zandueta, C.; et al.
ISSN 1043-6618  Vol. 126  2017  págs. 77 - 83
IDO is an enzyme that tumors use to create a state of immunosupression. 1-d-methyltryptophan (1-MT) is an IDO pathway inhibitor. After being successfully evaluated in preclinical studies, current clinical trials are actually analyzing its efficacy as monotherapy or in combination with multiple chemotherapeutic agents such as paclitaxel. 1-MT very poor solubility in water and many other solvents precludes its ease parenteral administration. It is currently administered by oral route because high daily doses were well-tolerated and effectively inhibited the IDO activity although only 25% of dose was recovered in plasma. The present work describes the preparation and characterization of 1-MT nanocrystals in order to enhance its solubility, dissolution rate, biodisponibility as well as facilitate its administration by parenteral route. A bottom-down approach of nanoprecipitation with an antisolvent was used for the fabrication of the nanocrystals and the choice of stabilizers was critical for reducing the size. Thermal analysis and x-ray diffraction indicated modifications in the drug crystalline state by the process. Through the reduction size and crystalline state modifications the dissolution characteristics of raw material were significantly increased. In a Lewis Lung cancer mice model, the nanocrystals strategy facilitated the sc administration and its antitumoral activity was similar to that of i.v. paclitaxel. The best efficacy was achieved when sc 1-MT nanocrystals were administered in combination with oral paclitaxel loaded in poly(anhydride) nanoparticles. Take together, 1-MT nanocrystals delivery performs a nanotechnological strategy suitable to modify the current route and schedule for its administration.
Autores: Lucio, David; Martínez-Oharriz, M.C.; Jaras, G.; et al.
ISSN 0939-6411  Vol. 121  2017  págs. 104 - 112
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 -37 mV and a payload of 45 mu g 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 20 nm) 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.
Autores: Lucio, David; Irache, Juan M.; Font, María ; et al.
ISSN 0378-5173  Vol. 530  Nº 1 - 2  2017  págs. 377 - 386
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-beta CDs inclusion complexes was carried out using different methods, beta CD 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 beta CD and head-to-tail for HP beta CD and RM beta CD. 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-beta CD complexes. The arrangement of these structures depended on the GB:beta CD 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.
Autores: Martínez-Oharriz, M.C.; Vélaz, I.; et al.
ISSN 0022-3549  Vol. 103  Nº 1  2014  págs. 197 - 206
Gels obtained by complexation of octablock star polyethylene oxide/polypropylene oxide copolymers ( Tetronic 90 R4) with alpha-cyclodextrin (alpha- CD) were evaluated as matrices for drug release. Both molecules are biocompatible so they can be potentially applied to drug delivery systems. Two different types of matrices of Tetronic 90 R4 and alpha-CD were evaluated: gels and tablets. These gels are capable to gelifying in situ and show sustained erosion kinetics in aqueous media. Tablets were prepared by freeze-drying and comprising the gels. Using these two different matrices, the release of two model molecules, L-tryptophan ( Trp), and a protein, bovine serum albumin ( BSA), was evaluated. The release profiles of these molecules from gels and tablets prove that they are suitable for sustained delivery. Mathematical models were applied to the release curves from tablets to elucidate the drug delivery mechanism. Good correlations were found for the fittings of the release curves to different equations. The results point that the release of Trp from different tablets is always governed by Fickian diffusion, whereas the release of BSA is governed by a combination of diffusion and tablet erosion.
Autores: Lucio, David; Zornoza, Arantza; Martínez-Oharriz, M.C.;
ISSN 0378-5173  Vol. 467   Nº 1 - 2  2014  págs. 19 - 26
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.
Autores: García-Padial, Marcos; Martínez-Oharriz, M.C.; Isasi, José Ramón; et al.
ISSN 1388-3127  Vol. 75  Nº 3-4  2013  págs. 241 - 246
Tyrosol (TY), 4-(2-hydroxyethyl)phenol, is an olive oil biophenol with antioxidant activity and positive effects on human health. This study has investigated the interactions of TY with cyclodextrins (CD) and a CD polymer. Complexation of TY with beta-CD, hydroxypropyl-beta-CD (HP-beta-CD), and methyl-beta-CD (Me-beta-CD) has been evaluated both in aqueous solution and in the solid state. The techniques employed in solution to determine the apparent stability constants of the respective complexes were fluorescence and UV-visible spectroscopies. Complexation with beta-CD and its derivatives involved an increase of both the UV absorbance and the intrinsic fluorescence of TY; a bathochromic shift of the UV spectrum was detected as well. The apparent stability constants obtained with native beta-CD, Me-beta-CD and HP-beta-CD presented similar values. Complexes in the solid state were obtained by coevaporation and kneading. They were characterised by X-ray diffraction analysis and differential thermal analysis. The interaction of TY with beta-CD led to a crystalline complex; the same diffraction pattern was obtained by coevaporation and kneading. The complexes obtained with methyl- and HP-beta-CD were amorphous irrespective of the preparation method. In addition, the retention of TY in an insoluble polymer of CD crosslinked with epichlorohydrin has been quantified. In approximately 20 min, 1 mg of TY per gram of polymer was retained.
Autores: García-Padial, Marcos; Martínez-Oharriz, M.C.; Navarro-Blasco, I.; et al.
ISSN 0021-8561  Vol. 61  Nº 50  2013  págs. 12260 - 122604
Tyrosol and caffeic acid are biophenols that contribute to the beneficial properties of virgin olive oil. The influence of hydroxypropyl-beta-cyclodextrin (HP beta-CD) on their respective antioxidant capacities was analyzed. The ORAC antioxidant activity of tyrosol (expressed as mu M Trolox equivalents/mu M Tyrosol) was 0.83 +/- 0.03 and it increased up to 1.20 +/- 0.11 in the presence of 0.8 mM HP beta-CD. However, the ORAC antioxidant activity of caffeic acid experienced no change. The different effect of HP beta-CD on each compound was discussed. In addition, the effect of increasing concentrations of different cyclodextrins in the development of ORAC-fluorescence (ORAC-FL) assays was studied. The ORAC signal was higher for HP beta-CD, followed by M beta-CD, beta-CD, gamma-CD and finally alpha-CD. These results could be explained by the formation of inclusion complexes with fluorescein.
Autores: Fernández, L.; Zornoza, Arantza; et al.
Revista: Journal of Inclusion Phenomena and Macrocyclic Chemistry
ISSN 1388-3127  Vol. 69  Nº 3-4  2011  págs. 411 - 415
Autores: Maddens, T.; Vélaz, I.; et al.
Revista: Journal of Inclusion Phenomena and Macrocyclic Chemistry
ISSN 1388-3127  Vol. 70  Nº 3-4  2011  págs. 415 - 419
Autores: Luis de Redín, Inés; Agüeros, Maite; et al.
Libro:  XI International forum on advances in pharmaceutical technology
2018  págs. 70 - 71
Autores: Lucio, David; Martínez-Oharriz, M.C.;
Libro:  Biological activities and application of marine polysaccharides
2017  págs. 107-127
Marine organisms have been under research for the last decades as a source for different active compounds with various biological activities and application in agriculture, pharmacy, medicine, environment, and industries. Marine polysaccharides from these active compounds are used as antibacterial, antiviral, antioxidant, anti-inflammation, bioremediations, etc. During the last three decades, several important factors that control the production of phytoplankton polysaccharides have been identified such as chemical concentrations, temperature, light, etc. The current book includes 14 chapters contributed by experts around the world; the chapters are categorized into three sections: Marine Polysaccharides and Agriculture, Marine Polysaccharides and Biological Activities, and Marine Polysaccharides and Industries.