Darío Leonardi

Effects of benznidazole:cyclodextrin complexes on the drug bioavailability upon oral administration to rats.

Benznidazole (BZL) is the drug of choice for the treatment of Chagas disease, a neglected parasitic infection. It is poorly soluble in water, which may have a direct impact into its bioavailability. Thus, the aim of this study was to evaluate the impact of stoichiometric and non-stoichiometric BZL-cyclodextrins (CDs) complexes on the bioavailability of BZL. The interaction of BZL with the CDs was investigated using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffractometry (XRD), phase solubility and dissolution studies. The oral bioavailability of BZL from these complexes was examined in rats. Both BZL solubility and dissolution increased by CD complexation. The inclusion complexes were found to improve the dissolution rate of BZL by 4.3-fold in comparison with BZL alone. Complexation of BZL with CDs derivatives increased its plasma concentrations when fed to rats, with AUC0-5 values increasing up to 3.7-fold and Cmax increasing 2.5-fold in comparison with BZL alone. It should be note that a remarkable increase in these parameters was observed in the case of the non-stoichiometric complexes. Thus, these CDs complexes could be used to efficiently deliver BZL in patients suffering from Chagas disease.

In vivo evaluation of albendazole microspheres for the treatment of Toxocara canis larva migrans.

Albendazole is a benzimidazole derivative with proven efficacy against many parasites such as intestinal helminths. Toxocariasis is one of the important parasitic diseases in humans and animals caused by Toxocara canis. It is well known that T. canis larvae migrate in paratenic hosts, including humans where it may cause visceral larva migrans. Thus, the present research was carried out using in vivo experiments with the aim of finding whether novel albendazole microparticles would be active against migrating larvae of the parasite. Albendazole-chitosan microparticles were prepared by ionotropic gelation with sodium lauryl sulphate or by a liquid-liquid phase separation with sodium hydroxide. Mice were infected with T. canis and then treated with both albendazole-chitosan microparticles. After treatment (28days post-infection), it was examined the anthelmintic effect in mice after oral administration of microparticulate preparations. The number of larvae recovered from mice treated with albendazole formulations were compared with placebo. The results showed that albendazole microparticles were easily prepared in high yield using both aqueous solutions of sodium lauryl sulphate or sodium hydroxide. In vivo evaluation of larva migration showed that albendazole microparticles exhibited a greater anthelmintic effect in the brain (0 larva/mouse). In addition, it was also found that liver and lung showed a significant decrease in the number of larvae. Therefore, these data suggest that albendazole-chitosan microparticles are effective formulations for the treatment of toxocariasis infection by reducing the number of larvae in liver and lung. Particularly, these polymeric preparations were able to totally prevent migration of larvae to the mice brain.

Multiresponse optimization of the properties of albendazole-chitosan microparticles.

The loading of albendazole into biodegradable polymeric microparticles provides an attractive alternative to improve the drug dissolution rate. Experimental design and optimization techniques were implemented for the development of albendazole-chitosan microparticles using the ionic interaction method. The effect of seven different factors (chitosan concentration, pH of chitosan solution, stirring rate, stirring time, temperature, ionic agent and pH of ionic solutions) were studied on six responses: the yield, pH, morphology, size, dissolution rate and encapsulation efficiency of the microparticles. During the screening phase, the factors were evaluated at three levels each, in order to identify those which exert a significant effect. Multiple response simultaneous optimization by using the desirability function was then used to find experimental conditions where the system shows the most adequate results. The optimal conditions were found to be: NaOH as ionic agent at a pH value of 13.0, chitosan concentration, 0.50% (w/v) at a pH value of 1.0 and stirring rate, 1,000 rpm.

Preparation, characterization and dissolution studies of fast release diclofenac sodium tablets from PVP solid dispersions

Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used in the treatment of ankylosing spondylitis, rheumatoid arthritis and osteoarthritis. In this context, a rapid onset of action is required. Thus, the aim of this study was to formulate diclofenac sodium-PVP K-30 fast release tablets from solid dispersions. The physical state and drug:carrier interactions were analyzed by X-ray diffraction and scanning electron microscopy and stability upon storage was also studied. Dissolution rate of diclofenac sodium from solid dispersions was markedly enhanced by increasing the polymer concentration.

Development and in vitro/in vivo evaluation of a novel benznidazole liquid dosage form using a quality‐by‐design approach

To develop an alcohol‐free solution suitable for children of benznidazole, the drug of choice for treatment of Chagas disease.

Solving the Delivery Problems of Triclabendazole Using Cyclodextrins

Triclabendazole is the first-line drug of choice to treat and control fasciolasis, a neglected parasitic human disease. It is a class II/IV compound according to the Biopharmaceutics Classification System. Thus, the aim of this study was to improve aqueous solubility and dissolution rate of triclabendazole complexed with 2-hydroxylpropyl-β-cyclodextrin (HP-β-CD) and methyl-β-cyclodextrin (Me-β-CD) at 1:1 and 1:2xa0M ratio. The impact of storage on the solubility, dissolution profile, and solid-state properties of such complexes was also investigated. Drug-carrier interactions were characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy. The solubility of triclabendazole improved up to 256- and 341-fold using HP-β-CD and Me-β-CD, respectively. In particular, the drug complexed with Me-β-CD showed a positive deviation from linearity, suggesting that its solubility increases with an increasing concentration of Me-β-CD concentration in a nonlinear manner. The drug dissolution was found to be improved through complex formation with HP-β-CD and Me-β-CD. In particular, the 1:2xa0M ratio complexes exhibited higher dissolution than the corresponding 1:1xa0M ratio complexes. The physicochemical characterization of the systems showed strong evidence of amorphous phases and/or of the formation of an inclusion complex. Stored at 25xa0°C, 60% RH for 24xa0months, drug complexed with β-cyclodextrins (CDs) at 1:2xa0M ratio remained amorphous. Based on these findings, it is postulated that the formation of triclabendazole-CD inclusion complexes produced significant enhancement in both the dissolution and solid-state properties of the drug, which may lead to the development of triclabendazole novel formulations with improved biopharmaceutical characteristics.

Structural Elucidation of Poloxamer 237 and Poloxamer 237/Praziquantel Solid Dispersions: Impact of Poly(Vinylpyrrolidone) over Drug Recrystallization and Dissolution

Praziquantel (PZQ) is the recommended, effective, and safe treatment against all forms of schistosomiasis. Solid dispersions (SDs) in water-soluble polymers have been reported to increase solubility and bioavailability of poorly water-soluble drugs like PZQ, generally due to the amorphous form stabilization. In this work, poloxamer (PLX) 237 and poly(vinylpyrrolidone) (PVP) K30 were evaluated as potential carriers to revert PZQ crystallization. Binary and ternary SDs were prepared by the solvent evaporation method. PZQ solubility increased similarly with PLX either as binary physical mixtures or SDs. Such unpredicted data correlated well with crystalline PZQ and PLX as detected by solid-state NMR (ssNMR) and differential scanning calorimetry in those samples. Ternary PVP/PLX/PZQ SDs showed both ssNMR broad and narrow superimposed signals, thus revealing the presence of amorphous and crystalline PZQ, respectively, and exhibited the highest PZQ dissolution efficiency (up to 82% at 180xa0min). SDs with PVP provided a promising way to enhance solubility and dissolution rate of PZQ since PLX alone did not prevent recrystallization of amorphous PZQ. Based on ssNMR data, novel evidences on PLX structure and molecular dynamics were also obtained. As shown for the first time using ssNMR, propylene glycol and ethylene glycol constitute the PLX amorphous and crystalline components, respectively.

Repositioning of Anti-parasitic Drugs in Cyclodextrin Inclusion Complexes for Treatment of Triple-Negative Breast Cancer

Drug repositioning refers to the identification of new therapeutic indications for drugs already approved. Albendazole and ricobendazole have been used as anti-parasitic drugs for many years; their therapeutic action is based on the inhibition of microtubule formation. Therefore, the study of their properties as antitumor compounds and the design of an appropriate formulation for cancer therapy is an interesting issue to investigate. The selected compounds are poorly soluble in water, and consequently, they have low and erratic bioavailability. In order to improve their biopharmaceutics properties, several formulations employing cyclodextrin inclusion complexes were developed. To carefully evaluate the in vitro and in vivo antitumor activity of these drugs and their complexes, several studies were performed on a breast cancer cell line (4T1) and BALB/c mice. In vitro studies showed that albendazole presented improved antitumor activity compared with ricobendazole. Furthermore, albendazole:citrate-β-cyclodextrin complex decreased significantly 4T1 cell growth both in in vitro and in vivo experiments. Thus, new formulations for anti-parasitic drugs could help to reposition them for new therapeutic indications, offering safer and more effective treatments by using a well-known drug.