Isabel Quijada-Garrido

A novel controlled drug delivery system based on pH-responsive hydrogels included in soft gelatin capsules.

pH-sensitive hydrogels based on methacrylic acid (MAA) and poly(ethylene glycol) macromonomer (PEGMEMA) entrapping diltiazem hydrochloride (DIL·HCl) were synthesized inside soft gelatin capsules for use as a new dosage form for oral drug administration. Different monomer compositions were used to evaluate their swelling and release behavior in two media: at low pH, simulating the acid pH of the stomach, and at pH 7, simulating the higher pH environment of the intestine. Both the swelling process and DIL·HCl release strongly depended on pH and monomer composition. Hydrogels with intermediate compositions showed diminished DIL·HCl release at pH 1.2. This fact was related to the formation of an impermeable outer skin, observed by magnetic resonance imaging (MRI). At pH 7 similar shaped release profiles were found for the four hydrogel compositions under investigation. At this neutral pH slow protonation of the carboxylate groups of MAA led to a swelling front and a dry core, also observed by MRI. As a consequence of this anomalous swelling, release curves exhibited a long period of zero order kinetics. This shows that the system could be a suitable candidate to develop a zero order release dosage form for oral administration of DIL·HCl. The swelling and dissolution processes were analyzed by different mathematical approaches.

Acetyl protected thiol methacrylic polymers as effective ligands to keep quantum dots in luminescent standby mode

Herein, we report evidence for the promising potential of 2-(acetylthio)ethylmethacrytale (AcSEMA), a new monomer, which copolymerizes with methyl methacrylate (MMA) by atom transfer radical polymerization (ATRP) leading to well-defined multidentate protected thiol polymer ligands for CdSe QDs capping by simple ligand exchange. Among the different strategies that can be employed for coating QDs, it is found that thioacetylated polymers, in the presence of hydrophobic QDs, are able to replace trioctylphosphine oxide (TOPO) ligands, leading to hybrid CdSe@PMMA nanoparticles without covalent binding of the polymer to the QD surface. These polymer protected QDs exhibit high stability for long periods of time, in a low luminescence standby mode. Moreover, the fluorescence QD activation of these hybrids is easily achieved at any time from thioacetate hydrolysis to free thiol under mild conditions. This subsequent step, which results in the covalent attachment of PMMA thiol groups to the metallic QD surface, produces compact QDs which exhibit amazingly improved photophysical properties, yielding highly photoluminescent new hybrid materials. For comparison, the same procedure was applied to obtain brush-like QDs coated with PMMA obtained by ATRP with a final thioacetate group. It was then established that the multidentate thiolated polymers provide additional protection against external quenchers, such as 4-amino-TEMPO, to a greater extent than the brush-like PMMA coating and the pristine TOPO capping ligand.

Versatile thiolated thermosensitive polymers synthesized by ATRP of MEO2MA and AcSEMA, a new methacrylic monomer with a protected thiol group

Herein, the synthesis of a new monomer containing a protected thiol group, 2-(acetylthio)ethyl methacrylate (AcSEMA), is introduced. The monomer has been copolymerized via atom transfer radical polymerization (ATRP) with 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) to obtain a series of well-defined hidden-thiol functionalized thermosensitive polymers. The new system exhibits a sharp lower critical solubility temperature (LCST) and after hydrolysis of the acetyl group, the thiolated copolymers exhibit pH responsiveness. Moreover, to show the versatility of AcSEMA, P(MEO2MA-co-AcSEMA) copolymers were in situ hydrolyzed and modified by thiol-ene Michael addition with some acrylate compounds. The click reaction was successfully performed as revealed by NMR and the change in the LCST. We finally demonstrate that the addition of these polymer coatings onto gold nanoparticles (AuNPs) results in the formation of stable, colloidal thermosensitive polymer@AuNP complexes due to bridge formation between the thiol groups of AcSEMA and the metallic NP surfaces. The formation of temperature responsive polymer coated plasmonic nanoparticles shows the promise of P(MEO2MA-co-AcSEMA) copolymers for building multifunctional nanostructures for drug-delivery, diagnosis, tagging, catalysis and organic electronics systems.

The influence of the copolymer composition on the diltiazem hydrochloride release from a series of pH-sensitive poly[(N-isopropylacrylamide)-co-(methacrylic acid)] hydrogels.

A series of poly[(N-isopropylacrylamide)-co-(methacrylic acid)] (P[(N-iPAAm)-co-(MAA)]) hydrogels was investigated to determine the composition that exhibits a better pH-modulated release of diltiazem hydrochloride (DIL.HCl). For this purpose hydrogel slabs were loaded with DIL.HCl by the immersion method, and its release under acidic medium (0.1N HCl, pH 1.2) and in phosphate buffer pH 7.2, using United States Pharmacopeia (USP) 24 Apparatus 1, was investigated. According to the results from the slabs, copolymers with 85% mol N-iPAAm content were selected to prepare tablets with different particle size. The effect of pH and particle size changes on DIL.HCl release from these last hydrogel tablets was investigated by a stepwise pH variation of the dissolution medium. The amount of DIL.HCl released from high N-iPAAm content copolymer slabs under acidic pH medium was not only very low but it was also released at a slow rate. In the 85% N-iPAAm tablets, significant differences between and within release profiles were found as a function of particle size and pH, respectively. A relationship between particle size and release rate has been found. The lower DIL.HCl release at acidic pH from enriched N-iPAAm copolymers is interpreted by a cooperative thermal- and pH-collapse. Although for the whole range of copolymer composition a dependence of the equilibrium of swelling on the pH was found, DIL.HCl release experiments indicated that hydrogels with 85% mol N-iPAAm are the more adequate to be used for modulated drug delivery systems. Additionally, the particle size of the tablet can be used to tailor the release rate.

Dynamic mechanical and dielectric behavior of erucamide (13-cis-docosenamide), isotactic poly(propylene), and their blends

Blends of erucamide (13-cis-docosenamide) and isotactic poly(propylene) were analyzed by means of dynamic mechanical (at 3, 10, and 30 Hz) and dielectric (at 1, 6, and 20 kHz) techniques. The dependence of tan δ with temperature for each one of the blends has been fitted to Gaussian functions in order to deconvolute the overlapped relaxations. Three relaxations for i-PP, αi-PP, βi-PP, γi-PP, three for erucamide, αERU, βERU, and γERU, and five for their blends have been observed and assigned. They do not vary appreciably with composition, suggesting that the components are incompatible either as globules in the matrix or in the amorphous regions of the spherulites, and/or in their surroundings.

Solubility of erucamide (13-cis docosenamide) in isotactic poly(propylene) and thermal behaviour of their blends

Abstract Differential scanning calorimetry studies, made on blends prepared by mixing in the melt, have demonstrated that crystallization of erucamide (13- cis -docosenamide) [H 3 C-(-CH 2 -) 7 -HC=CH-(-CH 2 -) 11 -CO-NH 2 ]/ isotactic poly(propylene (i-PP) blends results in separate crystals of the two components, rather than cocrystallization. For low content erucamide blends (less than 29%), two melting peaks for erucamide have been observed. They have been assigned to: i) erucamide crystals situated in the external surfaces of the i-PP and located forming globules, droplets or inclusions whose melting point appears at the higher temperature (Erucamide I); ii) erucamide crystals forming crystalline microdomains of erucamide, located either within the amorphous region of spherulites and/or in the amorphous regions which surround the spherulites (Erucamide II). The enthalpy of these crystals located in these regions, i.e. in the amorphous region of the spherulites and/or their surroundings, has been estimated. A good linear correlation has been found between the solubility of erucamide crystals in the amorphous region of i-PP spherulites and/or the surrounding region of the spherulites and their apparent melting enthalpy. Spherulite radial growth rates, G , for the different blends are lower than for the pure i-PP. They show a characteristic dependence on the erucamide content in the blend. This behaviour is in agreement with theoretical predictions for crystallization in immiscible blends. An additional feature, as an unambiguous test of the incompatibility, is the poor interfacial adhesion, which has been made clear from the large voids left on the fracture surface where the erucamide globules have separated from the matrix and from the smooth surfaces of the exposed erucamide globules. A model is proposed for erucamide/i-PP blends, which is able to explain quantitatively in detail all the thermal and morphological experimental data.

Poly(styrene)/silica hybrid nanoparticles prepared viaATRP as high-quality fillers in elastomeric composites

Organic–inorganic hybrid nanoparticles of poly(styrene) (PSt) and fumed silica have been successfully synthesized via atom transfer radical polymerization (ATRP) and investigated as fillers for styrene–butadiene rubber (SBR). On the one hand, they were prepared by using the grafting from methodology, in which an ATRP initiator was covalently attached onto the silica and subsequently, PSt chains were grown directly from the surface. On the other hand, the grafting to methodology was used to attach onto the silica, a carboxylic acid end-functionalized PSt, previously synthesized by ATRP. Then, these hybrid nanoparticles could be easily incorporated as fillers into SBR elastomeric matrices by conventional methods employed in rubber technology. The properties of these composites, analyzed by strain sweep tests, scanning electron microscopy, dynamic mechanical measurements, 1H low field double quantum NMR and tensile strength tests, were compared with those obtained using unmodified silica as the filler. The presence of silica particles coated with PSt brushes deeply affects the dynamic and physical response of the elastomer composites prepared, due to the high dispersion and excellent compatibility between the SBR matrix and PSt coated silica. Moreover, the experimental results also indicated that hybrid nanoparticles synthesized by the grafting from methodology are much better for filler applications in the SBR matrix than those obtained by using the grafting to methodology.

Fickian diffusion of erucamide (13-cis-docosenamide) in poly(laurolactam) (Nylon 12) (PA-12)

Diffusion of erucamide (13-cis-docosenamide) [H3C— (—CH2—)11—HC=CH—(—CH2—)7—CO— NH2] (eru) in poly(laurolactam) (Nylon 12) (PA-12) has been studied in a temperature range from 343 to 353 K. In previous investigations on the diffusion of eru in isotactic poly(propylene) (i-PP) it was found that the diffusion took place by a non-Fickian mechanism. This feature was explained by taking into account the microstructure of i-PP films and the incompatibility of eru and i-PP. The same experimental method to determine the concentration profiles was previously employed in this system. The experimental profiles have been compared with theoretical curves based on solutions of Ficks diffusion equation for the best fitting, with the appropriate boundary conditions. The measured concentration profiles show a good agreement with the Fickian law. Values of the diffusion coefficient D in the range from 10–10 to 10–11 cm2·s–1 have been obtained. The activation energy for diffusion (Ed) has been calculated from the D values in the temperature range investigated assuming an Arrhenius-type behaviour. The activation energy has been calculated as Ed = 156 kJ·mol–1. The values of diffusion coefficients and activation energy are in the range found for some other additives. By using Fujitas equation a good correlation between diffusion coefficient and free volume fraction estimated by means of the Williams-Landel-Ferry equation have been found.

Surface modification of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) copolymer films for promoting interaction with bladder urothelial cells†‡

Often bladder dysfunction and diseases lead to therapeutic interventions that require partial or complete replacement of damaged tissue. For this reason, the development of biomaterials to repair the bladder by promoting the adhesion and growth of urothelial cells is of interest. With this aim, a modified copolyester of biocompatible and biodegradable poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [P(HB-co-HV)] was used as scaffold for porcine urothelial cell culture. In addition to good biocompatibility, the surface of P(HB-co-HV) substrates was modified to provide both, higher hydrophilicity and a better interaction with urothelial cells. Chemical treatments with ethylenediamine (ED) and sodium hydroxide (NaOH) led to substrate surfaces with decreasing hydrophobicity and provided functional groups that enable the grafting of bioactive molecules, such as a laminin derived YIGSR sequence. Physico-chemical properties of modified substrates were studied and compared with those of the pristine P(HB-co-HV). Urothelial cell morphology on treated substrates was studied. The results showed that focal attachment and cell-related properties were improved for peptide grafted polymer compared with both, the unmodified and functionalized copolyester.

The surface modification of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) copolymers to improve the attachment of urothelial cells.

Biocompatible and biodegradable poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) [P(HB-co-HHx)] substrates were modified to improve the attachment of porcine urothelial cell culture. The pristine copolymer exhibits excellent mechanical properties to replace the bladder tissue, but its surface lacks chemical functionalities to interact with cells. Thus, wet chemical treatments based on NaOH and ethylenediamine in aqueous [ED(aq)] and isopropanol [ED(isoOH)] media to functionalize the P(HB-co-HHx) films surfaces were compared. Among these treatments, short ED(aq) treatment was able to decrease the hydrophobicity, rendering a surface with amino groups and without a significant alteration of the mechanical properties. Furthermore, to enhance the interaction with urothelial cells, laminin derived YIGSR sequence was covalently bound to these amino functionalized substrates. The focal attachment was clearly improved with this last treatment, comparing with those results found with the unmodified and first-step functionalized P(HB-co-HHx).