Dual Release Model to Evaluate Dissolution Profiles from Swellable Drug Polyelectrolyte Matrices.

BACKGROUND: Mathematical modeling in modified drug release is an important tool that allows predicting the release rate of drugs in their surrounding environment and elucidates the transport mechanisms involved in the process. OBJECTIVE: The aim of this work was to develop a mathematical model that allows evaluating the release profile of drugs from polymeric carriers in which the swelling phenomenon is present. METHODS: Swellable matrices based on ionic complexes of alginic acid or carboxymethylcellulose with ciprofloxacin were prepared and the effect of adding the polymer sodium salt on the swelling process and the drug release was evaluated. Experimental data from the ciprofloxacin release profiles were mathematically adjusted, considering the mechanisms involved in each stage of the release process. RESULTS: A proposed model, named "Dual Release" model, was able to properly fit the experimental data of matrices presenting the swelling phenomenon, characterized by an inflection point in their release profile. This entails applying the extended model of Korsmeyer-Peppas to estimate the percentage of drug released from the first experimental point up to the inflection point and then a model called Lumped until the final time, allowing to adequately represent the complete range of the drug release profile. Different parameters of pharmaceutical relevance were calculated using the proposed model to compare the profiles of the studied matrices. CONCLUSION: The "Dual Release" model proposed in this article can be used to predict the behavior of complex systems in which different mechanisms are involved in the release process.

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease.

Chagas disease is an important public health problem in Latin America, and its treatment by chemotherapy with benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to design new alternative strategies to improve the current etiological treatments, in the present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effects of clomipramine (CMP) (a parasite-trypanothione reductase-specific inhibitor) combined with BZ. In vitro studies, carried out using a checkerboard technique on trypomastigotes (T. cruzi strain Tulahuen), revealed a combination index (CI) of 0.375, indicative of a synergistic effect of the drug combination. This result was correlated with the data obtained in infected BALB/c mice. We observed that during the acute phase (15 days postinfection [dpi]), BZ at 25 mg/kg of body weight/day alone decreased the levels of parasitemia compared with those of the control group, but when BZ was administered with CMP, the drug combination completely suppressed the parasitemia due to the observed synergistic effect. Furthermore, in the chronic phase (90 dpi), mice treated with both drugs showed less heart damage as assessed by the histopathological analysis, index of myocardial inflammation, and levels of heart injury biochemical markers than mice treated with BZ alone at the reference dose (100 mg/kg/day). Collectively, these data support the notion that CMP combined with low doses of BZ diminishes cardiac damage and inflammation during the chronic phase of cardiomyopathy. The synergistic activity of BZ-CMP clearly suggests a potential drug combination for Chagas disease treatment, which would allow a reduction of the effective dose of BZ and an increase in therapeutic safety.

Swellable drug-polyelectrolyte matrices (SDPM). Characterization and delivery properties.

The objective of the study is to develop and characterize the delivery properties of swellable drug-polyelectrolyte matrices (SDPM). Solid complexes (C-D)X of carbomer (C) neutralized with different proportions of model basic drugs (D), in which D is atenolol, lidocaine, and metoclopramide, and X=25, 50, 75 and 100 mol of D per 100 equivalents of carboxylic groups of C, were prepared and characterized by DSC-TG, IR, and X-ray diffraction studies. Mechanistic studies with hydrophilic and hydrophobic basic drugs were conducted to explore the drug release patterns of SDPM. Besides, release and up-take studies were carried out in water and NaCl solution to examine the influence of ionic effects. The authors concluded that drugs can be loaded in a high proportion on to the polymer and therefore the resulting (C-D) material could be diluted with other polymers to modulate delivery properties of SDPM. Matrices of atenolol and lidocaine exhibited robust delivery properties with regard to change in proportion of loading D.