Guillermo Torrado

Release of amoxicillin from polyionic complexes of chitosan and poly(acrylic acid). study of polymer/polymer and polymer/drug interactions within the network structure

Polyionic complexes of chitosan (CS) and poly(acrylic acid) (PAA) were prepared in a wide range of copolymer composition and with two kind of drugs. Release of amoxicillin trihydrate and amoxicillin sodium from these different complexes were studied. The swelling behavior of and solute transport in swellable hydrogels were investigated to check the effect of polymer/polymer and polymer/drugs interactions. The electrostatic polymer/polymer interactions take place between the cationic groups from CS and the anionic ones from PAA. The diffusion of amoxicillin trihydrate was controlled only by the swelling/eroding ratio of the polyionic complexes. The swelling degree of amoxicillin sodium hydrogels was more extensive when compared to the swelling degree of amoxicillin trihydrate formulations. It was concluded that the water uptake was mainly governed by the degree of ionization. Restriction of amoxicillin sodium diffusion could be achieved by polymer/ionized-drug interaction that retards the drug release. Freeze-dried polyionic complexes could serve as suitable candidates for amoxicillin site-specific delivery in the stomach.

A novel formulation of albendazole solution: oral bioavailability and efficacy evaluation

To improve the oral bioavailability of albendazole, a poorly water-soluble drug, a new liquid formulation was investigated in mice. The liquid formulation studied was a solvent system of Transcutol® (40% w/w) in 1.2 pH buffer. A significant (p<0.05) increased relative bioavailability was obtained with this albendazole solution as compared with an albendazole suspension. A Trichinella/mouse model was used to evaluate the efficacy of the formulation against the different stages of the parasite. The higher concentration–time plasma profile of the albendazole solution would explain the greater therapeutic effect obtained with this new formulation against the systemic phases of the Trichinella model studied. This albendazole solution presented an efficacy against the migrating larvae phase twice that of the albendazole suspension. The efficacy of the solution (95.5%) in the encysted phase was significantly (p<0.05) higher than the efficacy obtained with the albendazole suspension (2.4%).

Process-induced crystallite size and dissolution changes elucidated by a variety of analytical methods

The purpose of this work was the study, by multiple analytical techniques, of the physico-chemical changes and the dissolution behaviour of various recrystallized forms obtained through different recrystallization methods. Scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction and infra-red spectroscopy were applied to evaluate the samples. These analytical techniques showed changes in particle morphology, and ruled out the possibility of the existence of polymorphs, pseudopolymorphs, totally amorphous forms or chemical structural changes. The powder X-ray diffraction technique showed great reductions in the drug crystallite sizes induced by both recrystallization methods. The decreased drug crystallite sizes can explain the faster dissolution rates of the recrystallized samples as compared to the non-recrystallized drug acetylsalicylic acid (ASA), or to the physical mixtures of drug (ASA) and carrier (mannitol).

Quantitative determination of dimethicone in commercial tablets and capsules by Fourier transform infrared spectroscopy and antifoaming activity test

Fourier transform infrared (FTIR) spectroscopy and antifoaming activity test have been employed for the quantitative analysis of dimethicone. Linearity, accuracy and precision are presented for both methods. These methods have been also used to compare different dimethicone-containing proprietary medicines. FTIR spectroscopy has shown to be adequate for quantitation of dimethicone in commercial tablets and capsules in order to comply with USP requirements. The antifoaming activity test is able to detect incompatibilities between dimethicone and other constituents. The presence of certain enzymes in some medicinal products increases the defoaming properties of these formulations.

Characterization and superficial transformations on mini-matrices made of interpolymer complexes of chitosan and carboxymethylcellulose during in vitro clarithromycin release

Different interpolymer complexes (IPCs) of chitosan (CS) and carboxymethylcellulose sodium salt (CMC) were used to elaborate mini-matrices containing clarithromycin (CAM). IPCs were characterized by FTIR, DSC and powder X-ray (XRD). Compression processes did not modify the physical state of CAM which was in its polymorph Form II. However, during tableting, polymer/polymer interactions occurred to form matrix systems that were confirmed by DSC. When mini-matrices were placed in acetate buffer (pH 4.2), the formation of a CAM solvate was determined by XRD, FTIR and DSC, showing the presence of incorporated crystallizing solvent molecules. Grazing incidence X-ray diffraction (GID) enabled us to profile transformations of CAM on surfaces of mini-matrices when it is in intimate contact with dissolution medium, and its conversion to a solvate form prior to its dissolution process. Besides, FTIR and DSC revealed polymer-polymer electrostatic interactions during dissolution process. Furthermore, swelling and eroding studies and in vitro drug release exhibited that when increasing the amount of CS within IPCs, swelling and erosion rates were greater and CAM release was faster. Zero-order kinetics from drug release profiles were related to linear erosion kinetics, and highlighted that erosion played an important role in drug release due to CAM poor solubility at this pH.

Correlation of in vitro and in vivo acetaminophen availability from albumin microaggregates oral modified release formulations

The aim of this study was to develop albumin microaggregated oral formulations for controlled drug release, and to reveal the possible influence of the release site on drug absorption. Acetaminophen was chosen as the model drug, which is included in the Class 1 group of the Biopharmaceutics Classification System (BCS). Albumin micro aggregates were formulated into tablets to obtain different drug release rates: Immediate Release (IR) tablets, multiparticulate systems with an intermediate release rate, and matrix systems showing slow release rate. The properties of the products were initially tested via dissolution studies, and then via bioavailability studies in healthy volunteers. Controlled release albumin microaggregated acetaminophen formulations for oral administration were obtained. The extent of drug absorption was comparable for all formulations, suggesting that the differences found in saliva concentration and urine cumulative profiles could be attributed merely to differences in drug release kinetics, as confirmed by the in vitro-in vivo correlation study. Therefore, it can be concluded that extended release of acetaminophen does not influence its absorption via intestinal heterogeneity.

Clinical trial evaluating amoxicillin and clarithromycin hydrogels (Chitosan-polyacrylic acid polyionic complex) for H. pylori eradication.

Aim It has been suggested that enhancement of amoxicillin or clarithromycin concentration at the gastric tissue may improve the anti-Helicobacter pylori effect of these drugs. This could be achieved by allowing the drug to remain longer in the stomach using dried hydrogels. Our aim was to evaluate the efficacy of an H. pylori eradication regimen including both amoxicillin and clarithromycin hydrogels. Methods Design: prospective clinical trial. Patients: with peptic ulcer or functional dyspepsia. Intervention: 7-day rabeprazole-amoxicillin-clarithromycin regimen. In addition, amoxicillin and clarithromycin hydrogels were administered twice daily during the 7 days. The polyionic complex hydrogel was prepared with Chitosan and polyacrylic acid. Outcome: H. pylori eradication was defined as a negative 13C-urea breath test 8 weeks after completing therapy. Results Forty patients were included. One patient did not return for follow-up. Ninety percent of the patients took all the medications correctly. Per-protocol and intention-to-treat eradication rates were 74% (95% CI=58%–86%) and 70% (55%–82%). Mild adverse effects were reported in 4 (10%) patients (diarrhea in 3, and nausea/heartburn in 1). Conclusions Although dried polyionic complexes could serve as suitable candidates for amoxicillin and clarithromycin site-specific delivery in the stomach, its addition does not increase the eradication efficacy of the generally prescribed proton pump inhibitor plus amoxicillin and clarithromycin regimen.

Enhanced bioavailability and anthelmintic efficacy of mebendazole in redispersible microparticles with low-substituted hydroxypropylcellulose

Background Mebendazole (MBZ) is an extremely insoluble and therefore poorly absorbed drug and the variable clinical results may correlate with blood concentrations. The necessity of a prolonged high dose treatment of this drug increases the risk of adverse effects. Methods In the present study we prepared redispersible microparticles (RDM) containing MBZ, an oral, poorly water-soluble drug, in different proportions of low-substituted hydroxypropylcellulose (L-HPC). We investigated the microparticulate structures that emerge spontaneously upon dispersion of an RDM in aqueous medium and elucidated their influence on dissolution, and also on their oral bioavailability and therapeutic efficiency using a murine model of infection with the nematode parasite Trichinella spiralis. Results Elevated percentages of dissolved drug were obtained with RDM at 1:2.5 and 1:5 ratios of MBZ: L-HPC. Thermal analysis showed an amorphization of MBZ in the RDM by the absence of a clear MBZ melting peak in formulations. The rapid dissolution behavior could be due to the decreased drug crystallinity, the fast dissolution time of carriers as L-HPC, together with its superior dispersibility and excellent wetting properties. RDM-1:2.5 and RDM-1:5 resulted in increased maximum plasma concentration and area(s) under the curve (AUC)0-∞ values. Likewise, after oral administration of the RDM-1:2.5 and RDM-1:5 the AUC0-∞ were 2.67- and 2.97-fold higher, respectively, compared to those of pure MBZ. Therapeutic activity, assessed on the Trichinella spiralis life cycle, showed that RDM-1:5 was the most effective in reducing the number of parasites (4.56-fold) as compared to pure MBZ, on the encysted stage. Conclusion The MBZ: L-HPC RDM might be an effective way of improving oral bioavailability and therapeutic activity using low doses of MBZ (5 mg/kg), which implies a low degree of toxicity for humans.

Innovación Pedagógica y Elaboración de una Guía de Aprendizaje en Tecnología Farmacéutica Industrial

Resumen El objetivo del presente trabajo, es disenar un plan didactico siguiendo estrategias de ensenanza-aprendizaje marcadas por las orientaciones europeas y plantear un sistema de evaluacion que responde a las exigencias del modelo de formacion implantado. Se incluye en el estudio aspectos relacionados con la formacion por competencias. La aplicacion de esta guia consigue incluir mejoras adaptadas a las necesidades detectadas a partir de sucesivos cursos academicos y que pueden seguir usandose hasta que se pongan en marcha los nuevos planes de estudio. Ademas, en el ambito del alumnado se obtuvo un gran interes por la asignatura con un alto grado de motivacion y compromiso. Muchas de estas cuestiones sirven como punto de partida y de reflexion previa, e incluso ayudan a mejorar el plan docente de la asignatura. Palabras clave: guia de aprendizaje, competencias, evaluacion, plan didactico, innovacion Pedagogical Innovation and Elaboration of a Learning Guide In Industrial Pharmaceutical Technology