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1、Colloids and Surfaces B: Biointerfaces 115 (2014) 391399Contents lists available at ScienceDirectColloids and Surfaces B: Biointerfacesj o ur nal ho me pa ge: of NMR spectroscopy in the development of a biomimeticapproach for hydrophobic drug association with physical hydrogelsRita Lpez-Cebrala, Man
2、uel Martin-Pastorb, Patrizia Paolicellic,Maria Antonietta Casadeic, Bego na Seijoa,d, Alejandro Sancheza,d,aDepartment of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Santiago de Compostela (USC), Campus Vida, 15782Santiago de Compostela, SpainbMagnetic Resonance Unit,
3、RIAIDT, Campus Vida, University of Santiago de Compostela, Santiago de Compostela, A Coru na 15706, SpaincDepartment of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, ItalydMolecular Image Group, IDIS, Santiago de Compostela University Hospital Complex (CHUS), A Choupana,
4、15706 Santiago de Compostela, Spaina r t i c l e i n f oArticle history:Received 2 August 2013Received in revised form11 December 2013Accepted 14 December 2013Available online 19 December 2013Keywords:HydrogelAlbuminHydrophobic drugBinding interactionNMR-STDNMR double titrationa b s t r a c tThe cli
5、nical application of sparingly soluble drugs is hampered by the wide range of problems associatedto their delivery. Herein we present a new physical hydrogel as a delivery system for these drugs. Thestrategy behind the design of this delivery system involved the incorporation of the protein albumini
6、nto the hydrogel with the aim of exploiting its intrinsic capacity to bind small hydrophobic molecules.Prednisolone and ketoconazole were used as model drug molecules. A combination of the saturationtransfer difference (STD) spectra and a novel double titration assay followed by NMR was applied to s
7、tudyall of the possible binding modes between albumin and each drug. Finally, the ability of the hydrogelsystem to release the two model drugs was corroborated. The results of the release studies were inagreement with the drug binding capacities derived from the NMR studies, thus confirming that the
8、potential of the NMR approach as a predictive technique could be useful in evaluating the designs of newdrug delivery systems. 2014 Elsevier B.V. All rights reserved.1. IntroductionReduced aqueous solubility is a property of many effective drugsthat severely limits their clinical use due to various
9、problemsrelated to their delivery 13. Therefore, considerable efforts havebeen devoted to the inclusion of sparingly soluble drugs into ade-quate drug delivery systems. This is a difficult task and, in manycases, a significant amount of either surfactant excipients or organicsolvents are required fo
10、r this purpose 2,4.Hydrogel formulations are three-dimensional networks that areable to absorb large quantities of water and aqueous fluids 5.These formulations possess a series of remarkable characteristics(mass transfer capability, flexibility, porosity or high water con-tent), which make them sim
11、ilar to living tissues 6,7 and, therefore,suitable for a wide range of applications in the biomedical field,Corresponding author at: Department of Pharmacy and Pharmaceutical Tech-nology, Faculty of Pharmacy, University of Santiago de Compostela (USC), CampusVida, 15782 Santiago de Compostela, Spain
12、. Tel.: +34 881815105;fax: +34 981 547 148.E-mail address: alejandro.sanchezusc.es (A. Sanchez).among which drug delivery is considered extremely important8. However, the hydrophilic nature of these matrices repre-sents a handicap in the entrapment of poorly soluble therapeuticmolecules 9,10. As a c
13、onsequence, many research efforts in recentyears have been devoted to overcoming this limitation 1113.Herein we present the use of a new generation of physicalhydrogels recently patented by our group 14, as pharmaceuticaldelivery vehicles for hydrophobic drugs of high therapeutic inter-est. Based on
14、 naturally occurring polymers, these hydrogels areprepared using the ionotropic gelation technique, which is gentle,simple, scalable and rapid.In this work, the potential of albumin as a tool to incor-porate water-insoluble drugs into the aforementioned hydrogelformulation was evaluated. Albumin is
15、a protein of fundamentalimportance and accounts for approximately 60% of the total proteincontent in the blood. Albumin is the primary carrier of both endoge-nous (e.g., fatty acids, hormones, bilirubin, etc.) and exogenous(e.g., fatty acids, drugs, etc.) hydrophobic molecules throughoutthe systemic
16、 circulation 1517. The interaction between differ-ent therapeutic drugs and albumin has attracted significant interestin biomedicine. Albumin can bind to a large variety of drugs and,therefore, it can influence their pharmacokinetics and, ultimately,0927-7765/$ see front matter 2014 Elsevier B.V. All rights reserved.http:/dx.doi.org/10.1016/j.colsurfb.2013.12.022392 R. Lpez-Cebral et al. / Colloids and Surfaces B: Biointerfaces 115 (2014) 391399their effectiveness. For instance, strong binding c