Revistas
Revista:
DRUG DELIVERY AND TRANSLATIONAL RESEARCH
ISSN:
2190-393X
Año:
2024
Vol.:
14
N°:
5
Págs.:
1189-1205
The oral administration of therapeutic proteins copes with important challenges (mainly degradation and poor absorption) making their potential therapeutic application extremely difficult. The aim of this study was to design and evaluate the potential of the combination between mucus-permeating nanoparticles and permeation enhancers as a carrier for the oral delivery of the monoclonal antibody bevacizumab, used as a model of therapeutic protein. For this purpose, bevacizumab was encapsulated in PEG-coated albumin nanoparticles as a hydrophobic ion-pairing complex with either sodium deoxycholate (DS) or sodium docusate (DOCU). In both cases, complex formation efficiencies close to 90% were found. The incorporation of either DS or DOCU in PEG-coated nanoparticles significantly increased their mean size, particularly when DOCU was used. Moreover, the diffusion in mucus of DOCU-loaded nanoparticles was significantly reduced, compared with DS ones. In a C. elegans model, DS or DOCU (free or nanoencapsulated) disrupted the intestinal epithelial integrity, but the overall survival of the worms was not affected. In rats, the relative oral bioavailability of bevacizumab incorporated in PEG-coated nanoparticles as a complex with DS (B-DS-NP-P) was 3.7%, a 1000-fold increase compared to free bevacizumab encapsulated in nanoparticles (B-NP-P). This important effect of DS may be explained not only by its capability to transiently disrupt tight junctions but also to their ability to increase the fluidity of membranes and to inhibit cytosolic and brush border enzymes. In summary, the current strategy may be useful to allow the therapeutic use of orally administered proteins, including monoclonal antibodies.
Revista:
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
ISSN:
0141-8130
Año:
2023
Vol.:
249
Págs.:
126111
This study aims to provide a thorough characterization of Brij O2-stabilized gliadin nanoparticles to be used for the potential oral administration of various compounds. Different techniques were used in order to evaluate their physico-chemical features and then in vivo studies in rats were performed for the investigation of their biodistribution and gastrointestinal transit profiles. The results showed that the gliadin nanoparticles accumulated in the mucus layer of the bowel mucosa and evidenced their ability to move along the digestive systems of the animals. The incubation of the nanosystems with Caenorhabditis elegans, used as an additional in vivo model, confirmed the intake of the particles and evidenced their presence along the entire gastrointestinal tract of these nematodes. The gliadin nanoparticles influenced neither the egg-laying activity of the worms nor their metabolism of lipids up to 10 & mu;g/mL of nanoformulation. The systems decreased the content of the age-related lipofuscin pigment in the nematodes in a dose-dependent manner, demonstrating a certain antioxidant activity. Lastly, dihydroethidium staining showed the absence of oxidative stress upon incubation of the worms together with the formulations, confirming their safe profile. This data paves the way for the future application of the proposed nanosystems regarding the oral delivery of various bioactives.
Revista:
INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN:
0378-5173
Año:
2023
Vol.:
643
Págs.:
123216
In this study, the ability of zein nanospheres (NS) and zein nanocapsules containing wheat germ oil (NC) to enhance the bioavailability and efficacy of quercetin was evaluated. Both types of nanocarriers had similar physico-chemical properties, including size (between 230 and 250 nm), spherical shape, negative zeta potential, and surface hydrophobicity. However, NS displayed a higher ability than NC to interact with the intestinal epithelium, as evidenced by an oral biodistribution study in rats. Moreover, both types of nanocarriers offered similar loading efficiencies and release profiles in simulated fluids. In C. elegans, the encapsulation of quercetin in nanospheres (Q-NS) was found to be two twice more effective than the free form of quercetin in reducing lipid accumulation. For nanocapsules, the presence of wheat germ oil significantly increased the storage of lipids in C. elegans; although the incorporation of quercetin (Q-NC) significantly counteracted the presence of the oil. Finally, nanoparticles improved the oral absorption of quercetin in Wistar rats, offering a relative oral bioavailability of 26% and 57% for Q-NS and Q-NC, respectively, compared to a 5% for the control formulation. Overall, the study suggests that zein nanocarriers, particularly nanospheres, could be useful in improving the bioavailability and efficacy of quercetin.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN:
1422-0067
Año:
2022
Vol.:
23
N°:
24
Págs.:
16119
Gemfibrozil (GEM) is a hypolipidemic agent, which is effective in reducing serum cholesterol and triglyceride levels. Complexation of GEM with native ß-cyclodextrin (ß-CD) and with the derivatives hydroxypropyl-ß- and randomly methylated ß-CD (HPß-CD and Meß-CD) was studied in aqueous solution of pH 2.8 and 7.0. The stability constants were determined by spectrofluorimetry, 1H-NMR spectroscopy and solubility assays. Considering the well-known difficulties to obtain similar stability constants by different techniques, the agreement of the values obtained supports the reliability of the results presented. The advantages and drawbacks of each analytical technique for the study of inclusion complexation were discussed as well. In addition, the thermodynamic parameters of complexation, enthalpy (¿H) and entropy (¿S), were determined and related to the type of molecular interactions that take place between GEM and the different cyclodextrins. Finally, solid dispersions were prepared by co-evaporation, kneading, vacuum desiccation, and coprecipitation, and complexation was evaluated by X-ray diffraction.
Autores:
Anjani, Q. K.; Domínguez-Robles, J.; Utomo, E.; et al.
Revista:
PHARMACEUTICALS
ISSN:
1424-8247
Año:
2022
Vol.:
15
N°:
1
Págs.:
20
Inclusion complexation of rifampicin (RIF) with several types of cyclodextrins (beta CD, hydroxypropyl-beta CD, gamma CD, hydroxypropyl-gamma CD) in aqueous solutions at different pH values was investigated to assess the interactions between RIF and cyclodextrins (CDs). Molecular modeling was performed to determine the possible interactions between RIF and CDs at several pH values. The inclusion complexes were characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffractometry, and scanning electron microscopy. Moreover, this study evaluated the dissolution profile and antibacterial activity of the formed complexes. Phase solubility analysis suggested the formation of RIF-CD affirmed 1:1 stoichiometry at all pH values (except RIF-beta CD at pH 4.0 and both beta CD and gamma CD at pH 9.0). The inclusion complexation of RIF with CD successfully increased the percentage of RIF released in in vitro studies. The inclusion complexes of RIF exhibited more than 60% of RIF released in 2 h which was significantly higher (p < 0.05) than release of pure RIF, which was only less than 10%. Antibacterial activity of RIF-CD complexes (measured by the minimum inhibitory concentration of RIF against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus) was lower for both RIF-beta CD and RIF-HP gamma CD at pH 7.0 to pure RIF suspension. In conclusion, this work reports that both beta CD and gamma CD can be used to enhance the solubility of RIF and thus, improve the effectivity of RIF by decreasing the required daily dose of RIF for the treatment of bacterial infections.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN:
1422-0067
Año:
2022
Vol.:
23
N°:
23
Págs.:
15367
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 mu m), 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 mu m) 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.
Revista:
PHARMACEUTICS
ISSN:
1999-4923
Año:
2022
Vol.:
14
N°:
1
Págs.:
39
Zein, the major storage protein from corn, has a GRAS (Generally Regarded as Safe) status and may be easily transformed into nanoparticles, offering significant payloads for protein materials without affecting their stability. In this work, the capability of bare zein nanoparticles (mucoadhesive) and nanoparticles coated with poly(ethylene glycol) (mucus-permeating) was evaluated as oral carriers of insulin (I-NP and I-NP-PEG, respectively). Both nanocarriers displayed sizes of around 270 nm, insulin payloads close to 80 mu g/mg and did not induce cytotoxic effects in Caco-2 and HT29-MTX cell lines. In Caenorhabditis elegans, where insulin decreases fat storage, I-NP-PEG induced a higher reduction in the fat content than I-NP and slightly lower than the control (Orlistat). In diabetic rats, nanoparticles induced a potent hypoglycemic effect and achieved an oral bioavailability of 4.2% for I-NP and 10.2% for I-NP-PEG. This superior effect observed for I-NP-PEG would be related to their capability to diffuse through the mucus layer and reach the surface of enterocytes (where insulin would be released), whereas the mucoadhesive I-NP would remain trapped in the mucus, far away from the absorptive epithelium. In summary, PEG-coated zein nanoparticles may be an interesting device for the effective delivery of proteins through the oral route.
Revista:
INTERNATIONAL JOURNAL OF PHARMACEUTICS. X
ISSN:
2590-1567
Año:
2021
Vol.:
3
Págs.:
100104
Camptothecin (CPT) exhibits a number of challenges for its oral administration, including a low aqueous solu-bility, a lactone ring susceptible to hydrolysis, and an affinity to the intestinal P-gp. The aim of this work was to evaluate nanoparticles from Gantrez-based conjugates as carriers for the oral delivery of CPT. For this purpose two different conjugates (G-mPEG and G-HPCD), obtained by the covalent binding of either HP-beta-CD or methoxy-PEG (m-PEG) to the polymer backbone of GantrezTM AN, were synthetized and characterized. Both excipients (m -PEG and HPCD) were selected due to their reported abilities to stabilize the lactone ring of CPT and disturb the effect of intestinal P-gp. The resulting nanoparticles (G-mPEG-NP and G-HPCD-NP) presented a similar size (about 200 nm) and zeta potential (close to-35 mV); although, G-mPEG-NP presented a higher CPT payload than G-HPCD-NP. On the contrary, in rats, nanoparticles based on Gantrez conjugates appeared to be capable of crossing the protective mucus layer and reach the intestinal epithelium, whereas conventional Gantrez nano-particles displayed a mucoadhesive profile. Finally, the pharmacokinetic study revealed that both formulations were able to enhance the relative oral bioavailability of CPT; although this value was found to be 2.6-times higher for G-mPEG-NP than for G-HPCD-NP.
Revista:
INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN:
0378-5173
Año:
2021
Vol.:
597
Págs.:
120287
The aim was to produce PEG-coated nanoparticles (NP-PEG), with mucus-permeating properties, for oral drug delivery purposes by using simple procedures and regulatoryapproved compounds in order to facilitate a potential clinical development. For this purpose, zein nanoparticles were prepared by desolvation and, then, coated by incubation with PEG 35,000. The resulting nanocarriers displayed a mean size of about 200 nm and a negative zeta potential. The presence of PEG on the surface of nanoparticles was evidenced by electron microscopy and confirmed by FTIR analysis. Likely, the hydrophobic surface of zein nanoparticles (NP) was significantly reduce by their coating with PEG. This increase of the hydrophilicity of PEG-coated nanoparticles was associated with an important increase of their mobility in pig intestinal mucus. In laboratory animals, NP-PEG (fluorescently labelled with Lumogen® Red 305) displayed a different behavior when compared with bare nanoparticles. After oral administration, NP appeared to be trapped in the mucus mesh, whereas NP-PEG were capable of crossing the protective mucus layer and reach the epithelium. Finally, PEGcoated zein nanoparticles, prepared by a simple and reproducible method without employing reactive reagents, may be adequate carriers for promoting the oral bioavailability of biomacromolecules and other biologically active compounds with low permeability properties.
Revista:
COLLOIDS AND SURFACES B-BIOINTERFACES
ISSN:
0927-7765
Año:
2018
Vol.:
163
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.
Revista:
INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN:
0378-5173
Año:
2018
Vol.:
547
N°:
1 - 2
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.
Revista:
INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN:
0378-5173
Año:
2018
Vol.:
541
N°:
1 - 2
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.
Revista:
INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN:
0378-5173
Año:
2018
Vol.:
543
N°:
1 - 2
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.
Revista:
PHARMACOLOGICAL RESEARCH
ISSN:
1043-6618
Año:
2017
Vol.:
126
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.
Revista:
INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN:
0378-5173
Año:
2017
Vol.:
519
N°:
1 - 2
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.
Revista:
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
ISSN:
0939-6411
Año:
2017
Vol.:
121
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.
Revista:
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
ISSN:
0021-8561
Año:
2017
Vol.:
65
N°:
24
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.
Revista:
INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN:
0378-5173
Año:
2017
Vol.:
530
N°:
1 - 2
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.
Revista:
JOURNAL OF PHARMACEUTICAL SCIENCES
ISSN:
0022-3549
Año:
2014
Vol.:
103
N°:
1
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.
Revista:
INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN:
0378-5173
Año:
2014
Vol.:
467
N°:
1 - 2
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.
Revista:
JOURNAL OF INCLUSION PHENOMENA AND MACROCYCLIC CHEMISTRY
ISSN:
1388-3127
Año:
2013
Vol.:
75
N°:
3-4
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.
Revista:
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
ISSN:
0021-8561
Año:
2013
Vol.:
61
N°:
50
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.
Revista:
JOURNAL OF INCLUSION PHENOMENA AND MACROCYCLIC CHEMISTRY
ISSN:
1388-3127
Año:
2011
Vol.:
70
N°:
3 - 4
Págs.:
415 - 419
Complexation of ebastine (EB) with hydroxypropyl and methyl-beta-cyclodextrin (HP-beta-CD and Me-beta-CD) was studied in aqueous solutions and in the solid state. The formation of inclusion complexes in aqueous solutions was analysed by the solubility method. The assays were designed using low CD concentrations compared with the solubility of these derivatives in order to avoid non-inclusion phenomena and to obtain a linear increase in EB solubility as a function of CD concentration. The values of complexation efficiency for HP-beta-CD and Me-beta-CD were 1.9 x 10(-2) and 2.1 x 10(-2), respectively. It seems that the non polar character of the methyl moiety slightly favoured complexation. In relation to solid state complexation, 1: 1 EB: CD systems were prepared by kneading, and by heating a drug-CD mixture at 90 degrees C. They were analysed using X ray diffraction analysis by comparison with their respective physical mixtures. A complex with a characteristic diffraction pattern similar to that of the channel structure of beta-CD was formed with Me-beta-CD in 1: 1 melted and 1: 2 EB: CD kneaded systems. Complexation with HP-beta-CD was not clearly evidenced because only a slight reduction of drug crystallinity was detected. Finally, the loading of EB in two beta-CD polymers cross-linked with epichlorohydrin yielded 7.3 and 7.7 mg of EB/g polymer respectively.
Revista:
JOURNAL OF INCLUSION PHENOMENA AND MACROCYCLIC CHEMISTRY
ISSN:
1388-3127
Año:
2011
Vol.:
69
N°:
3-4
Págs.:
411 - 415
The mechanisms of sorption and release of solutes from polymeric materials synthesised by cross-linking ß-cyclodextrin (ß-CD) with epichlorohydrin have been investigated. Gemfibrozil (pKa 4.7) was chosen as model solute. The polymers were obtained by suspension (P1) and block polymerisation (P2). Both P1 and P2 had similar ß-CD contents (65 and 64%) and their swelling capacities were 5.0 and 5.8 cm3/g, respectively. The sorption of gemfibrozil kinetic data in water and in aqueous solutions at pH 2.8 and 7.0 were fitted to a hyperbolic equation and they were studied by applying the Weber and Morris and the Elovich equations. P2 presented faster rates and higher sorption capacities in water and at pH 2.8. The mechanisms of sorption were pH-dependent. In water, the sorption rate was determined by the diffusion of gemfibrozil in the polymer network and fitted the Weber and Morris equation. At pH 2.8 a better adjustment to the Elovich equation suggested a significant influence of the inclusion in the ß-CD cavities. The release kinetics at pH 7.0 was controlled by drug solubilisation and presented maximum release values of 90 (P1) and 95% (P2), with a suitable regeneration of the loaded polymer. In water, the release was slower, fitted a hyperbole and the mechanism was controlled by drug solubility and also by the polymeric geometry. Finally, release assays were carried out from discs of loaded polymer in a medium that simulated the gastrointestinal tract.
