Alvaro F. Jimenez-Kairuz

Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives

The hydrochlorides of the 1:3 aluminum:norfloxacin and aluminum:ciprofloxacin complexes were characterized according to the Biopharmaceutics Classification System (BCS) premises in comparison with their parent compounds. The pH-solubility profiles of the complexes were experimentally determined at 25 and 37 degrees C in the range of pH 1-8 and compared to that of uncomplexed norfloxacin and ciprofloxacin. Both complexes are clearly more soluble than the antibiotics themselves, even at the lowest solubility pHs. The increase in solubility was ascribed to the species controlling solubility, which were analyzed in the solid phases at equilibrium at selected pHs. Additionally, permeability was set as low, based on data reported in the scientific literature regarding oral bioavailability, intestinal and cell cultures permeabilities and also considering the influence of stoichiometric amounts of aluminum. The complexes fulfill the BCS criterion to be classified as class 3 compounds (high solubility/low permeability). Instead, the active pharmaceutical ingredients (APIs) currently used in solid dosage forms, norfloxacin and ciprofloxacin hydrochloride, proved to be BCS class 4 (low solubility/low permeability). The solubility improvement turns the complexes as potential biowaiver candidates from the scientific point of view and may be a good way for developing more dose-efficient formulations. An immediate release tablet showing very rapid dissolution was obtained. Its dissolution profile was compared to that of the commercial ciprofloxacin hydrochloride tablets allowing to dissolution of the complete dose at a critical pH such as 6.8.

Equilibrium properties and mechanism of kinetic release of metoclopramide from carbomer hydrogels

Equilibrium properties and kinetics of metoclopramide release of carbomer-metoclopramide (C-M) hydrogels are reported. A set of (C-M)(X) (x=moles percent of M=50, 75, 100) that covers a pH range between 6.49 and 8.40 was used. Hydrogels exhibited a high negative electrokinetic potential (zeta). Concentrations of ion pair [R-COO(-)MH(+)] and free species [M] and [MH(+)] were determined by the selective extraction of M with 1,2-dichloroethane (DCE) together with pH measurements. The system (C-M) is characterized by a high proportion of drug present in the form of ion pairs and a negative zeta potential that attracts MH(+) and H(+) and repeals OH(-), providing a microenvironment of higher acidity than the bulk medium. Delivery rates of M were measured in a Franz type bi-compartmental device using water and NaCl 0.9% solution as receptor media. (C-M) hydrogels behave as a reservoir that releases the drug at a slow rate to water; the rate increases 14 times as water is replaced by NaCl solution. The pH effect on delivery rate suggests that, under the main conditions assayed, the rate of dissociation of R-COO(-)MH(+) together with the low change of pH in the polyelectrolyte environment are the factors that control releasing rates.

Release kinetics and up-take studies of model fluoroquinolones from carbomer hydrogels

Hydrogels of carbomer (C) loaded with model slightly soluble fluoroquinolone antimicrobials (AMFQ), norfloxacin (I) and ciprofloxacin (II) were prepared to evaluate their physical and delivery properties. Thus, dispersions of 0.25% of C loaded with 0.2-0.5 mol equivalents of AMFQ and 0.2-0.5 mol equivalents of NaOH yielded pseudoplastic hydrogels with a high negative electrokinetic potential and good physical stability. Concentration of AMFQ in the hydrogels was, respectively, 7.2 and 34 times higher than I and II aqueous solubility, indicating a high increase in aqueous compatibility. Release of AMFQ in bicompartimetal Franz type cell occurred by zero order kinetics. Delivery rate constant (k(0)) was five to six times higher as water was replaced by NaCl solution as receptor medium. Release in agar dishes revealed that, even under high dilution, delivery remains modulated. Intestinal absorption flux coefficient in everted rat intestine (k(U)) were measured with reference solutions (RS) of free AMFQ (k(U)(RS) II>k(U)(RS) I) and with hydrogels (H), in which the pattern was reversed since k(U)(H) I>k(U)(H) II. As expected k(U)(H) II was 0.55 times lower than k(U)(RS) II. However, k(U)(H) I was 1.37 times higher than its reference, which cannot be explained from the analysis of k(0) and k(U)(RS) alone. Hydrogels C-AMFQ behave as a reservoir of AMFQ able to deliver it at a constant rate and would be useful to design topical and or systemic dosage forms.

Comparative study of three structurally related acid polyelectrolytes as carriers of basic drugs: Carbomer, Eudragit L-100 and S-100

A detailed description of equilibrium and drug release properties of aqueous dispersions of complexes of model basic drugs (D) [lidocaine (Ld), atenolol and metoclopramide (Me)] with three structurally related acid polyelectrolytes (PE) is reported. Thus, affinity constants for ionic pair formation (K ip) of dispersions of polymetacrylates, Eudragit L-100 and Eudragit S-100, neutralised with increasing proportions of Ld and Me, were determined and compared with those of Carbomer previously reported. Affinity constants were calculated from the concentration of D condensed with PE (RCOO− DH+) and those of free species (D and DH+). In agreement with the high degree of counterionic condensation observed, the three PE–D complexes placed on Franz-type cells released D at slow rates as water was placed as receptor medium. Rates increased over three times as water was replaced by 0.9% NaCl solution. Similar average of diffusional exponent n (water, 0.61 and NaCl, 0.69) was found in both media. The overall kinetic behaviour suggests that, under the conditions assayed, the dissociation of RCOO− DH+ is the factor that controls releasing rates. Structure-related properties of the PE–D systems were identified in order to expand their potential uses as drug carriers.

A novel gel based on an ionic complex from a dendronized polymer and ciprofloxacin: Evaluation of its use for controlled topical drug release

The development and characterization of a novel, gel-type material based on a dendronized polymer (DP) loaded with ciprofloxacin (CIP), and the evaluation of its possible use for controlled drug release, are presented in this work. DP showed biocompatible and non-toxic behaviors in cultured cells, both of which are considered optimal properties for the design of a final material for biomedical applications. These results were encouraging for the use of the polymer loaded with CIP (as a drug model), under gel form, in the development of a new controlled-release system to be evaluated for topical administration. First, DP-CIP ionic complexes were obtained by an acid-base reaction using the high density of carboxylic acid groups of the DP and the amine groups of the CIP. The complexes obtained in the solid state were broadly characterized using FTIR spectroscopy, XRP diffraction, DSC-TG analysis and optical microscopy techniques. Gels based on the DP-CIP complexes were easily prepared and presented excellent mechanical behaviors. In addition, optimal properties for application on mucosal membranes and skin were achieved due to their high biocompatibility and acute skin non-irritation. Slow and sustained release of CIP toward simulated physiological fluids was observed in the assays (in vitro), attributed to ion exchange phenomenon and to the drug reservoir effect. An in vitro bacterial growth inhibition assay showed significant CIP activity, corresponding to 38 and 58% of that exhibited by a CIP hydrochloride solution at similar CIP concentrations, against Staphylococcus aureus and Pseudomonas aeruginosa, respectively. However, CIP delivery was appropriate, both in terms of magnitude and velocity to allow for a bactericidal effect. In conclusion, the final product showed promising behavior, which could be exploited for the treatment of topical and mucosal opportunistic infections in human or veterinary applications.

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

ABSTRACT 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.

Bioadhesive and biocompatible films as wound dressing materials based on a novel dendronized chitosan loaded with ciprofloxacin

The bioadhesive polymeric films as topical drug delivery systems are interesting alternatives to improve the pharmacotherapy and patient compliances. New derivate biomaterials based on weisocyanate- dendronized PVP- crosslinked chitosan and loaded with ciprofloxacin (CIP), as model drug, were used to prepare bioadhesive films. Relevant in vitro/in vivo attributes to define main physicochemical and biopharmaceutical characteristics for topical wound-healing applications were evaluated. A high proportion of CIP, uniformly dispersed along throughout the film, was loaded. An extended release of CIP and different behaviors of release profiles, depending on the presence of dendron, were observed. The films loaded with CIP were effective in inhibiting the growth of both Gram positive and Gram negative bacteria. In addition, biocompatibility and bioadhesion into conjuntival-sacs of the rabbits suggests that these films have good properties to be applied over skin wounds for topical applications, allowing a reduction of the frequency of administration and improving the residence time of the films.

Polyelectrolytes as Drug Carriers. Analysis by Dynamic Light Scattering of Reconstituted and in-situ Prepared Model Polymethacrylate-Drug Aqueous Dispersions

This article reports dynamic light scattering (DLS) data, and electrokinetic � -potentials of aqueous dispersions of two linear flexible polymethacrylic acid derivatives Eudragit ® L100 (EuL) and S100 (EuS) loaded with two model drugs (D), lidocaine (Ld) and atenolol (At). Dispersions of EuL and EuS at 1,0 % neutralized with increasing percentages (50, 75 and 100 mole %) of each D exhibited a unimodal scattering distribution rendering diffusion coefficients (DC) in the interval of 4 to 9. 10 -9 cm 2 /s. All dispersions 50% neutralized exhibited quite similar DC. However, the effect of in- creasing neutralization followed a different pattern in each Eudragit ® . All dispersions exhibited high negative � -potentials that were lower at 100% with respect to 50% loading. Both, DC and � -potentials, of redispersed lyophilized samples of (EuL-D) and (EuS-D) remained identical to those of in situ prepared while those of analog samples prepared by solvent evaporation exhibited some slight differences. The behavior of (EuL-D) and (EuS-D) systems examined here through DLS appears to be quite similar to that reported for polyelectrolytes neutralized with monovalent inorganic cations. Last, it has been shown that DLS provides valuable information about the reversibility from solid to dispersion states of these nanometric drug carrier systems.

Polyelectrolyte-drug ionic complexes as nanostructured drug carriers to design solid and liquid oral delivery systems

Aqueous dispersions of acid or basic polyelectrolytes (PE) loaded with ionizable drugs (D) of opposite charge are characterized by a high degree of counterionic condensation. In solid state, these PE-D complexes are stable amorphous materials that, in many cases, quickly swell reverting to the original dispersion in the presence of aqueous fluids. Such systems exhibit a set of unique properties. Among them, the reversibility of the PE-D association modulates the release of D when dispersions are in contact with biological fluids. Besides, some of them exhibit interesting bioadhesive properties. By compaction of solid complexes swellable PE-D matrices (SPDM) are obtained. Kinetics and rate of D delivery from SPDM can be modulated by changes in their composition to satisfy the design of extended delivery systems. Among the factors that control the delivery of D, the rate of swelling, complex dissociation of ionic pairs and further diffusion of D, as well as hydrogel layer erosion, are mainly involved. PE-D complexes formulated as matrices, multiparticulate or dispersed systems play an important role in the design of drug delivery systems.

Extemporaneous benznidazole oral suspension prepared from commercially available tablets for treatment of Chagas disease in paediatric patients

To develop an extemporaneous 1% benznidazole (BNZ) suspension, with masked taste and adequate stability starting from available commercial tablets. The quality of compounding was evaluated through content uniformity measurement and physical and microbiological stability evaluation, under different storage conditions during 90 days.