Chitosan: Strategies to Increase and Modulate Drug Release Rate

Chitin is the second most abundant polysaccharide present in nature; however, chitin has more applications when transformed into chitosan (CS). It is biocompatible, biodegradable, mucoadhesive, soluble in acidic-solutions, nontoxic and nonallergenic. The main drawback of chitosan in pharmaceutical procedures is its low solubility in physiological medium. Chitosan shows physicochemical characteristics that allow it to interact with a wide variety of molecules. This is of particular interest when increasing the solubility of poor water-soluble drugs. For this purpose, chitosan can be used in oral, nasal and ocular routes. In order to modulate drug release rate and achieve a proper drug delivery in physiological medium, some parameters can be modified when solid dispersions or nanoparticles (NPs) based on chitosan are being designed. In case of nanoparticles, chitosan can be used as the main component or as a modifying agent. In order to optimize drug loading and drug delivery, response surface methodology (RSM) is an interesting tool usually underestimated in the pharmaceutical field, which allows us to optimize the parameters involved in the process simultaneously and not by different steps, which usually lead to mistakes

A Comprehensive Study of Gemfibrozil Complexation with β-Cyclodextrins in Aqueous Solution Using Different Analytical Techniques

Gemfibrozil (GEM) is a hypolipidemic agent, which is effective in reducing serum cholesterol and triglyceride levels. Complexation of GEM with native β-cyclodextrin (β-CD) and with the derivatives hydroxypropyl-β- and randomly methylated β-CD (HPβ-CD and Meβ-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 (ΔH) and entropy (ΔS), 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

Inclusion Complexes of Rifampicin with Native and Derivatized Cyclodextrins: In Silico Modeling, Formulation, and Characterization

Inclusion complexation of rifampicin (RIF) with several types of cyclodextrins (βCD, hydroxypropyl-βCD, γCD, hydroxypropyl-γCD) 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-βCD at pH 4.0 and both βCD and γCD 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-βCD and RIF-HPγCD at pH 7.0 to pure RIF suspension. In conclusion, this work reports that both βCD and γCD 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

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 −37 mV and a payload of 45 µg 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

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 βCD or HPβCD). 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 HPβCD (8.2%) than for those prepared with βCD (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

Human serum albumin nanoparticles for ocular delivery of bevacizumab

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 cross-linked 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 μg/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 μg/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 99mTc and administered as eye drops in rats. 99mTc-B-NP remained in the eye for at least 4 h while 99mTc-HSA was rapidly drained from the administration point. In summary, HSA nanoparticles may be an appropriate candidate for ocular delivery of bevacizumab.Fil: Luis de Redín, Inés. Universidad de Navarra; EspañaFil: Boiero, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Martínez-Ohárriz, María Cristina. Universidad de Navarra; EspañaFil: Agüeros, Maite. Universidad de Navarra; EspañaFil: Ramos, Rocío. Universidad de Navarra; EspañaFil: Peñuelas, Iván. Universidad de Navarra; EspañaFil: Allemandi, Daniel Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Llabot, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Irache, Juan M.. Universidad de Navarra; Españ