Development and characterization of thermopressed polyvinyl alcohol films for buccal delivery of benznidazole.

Given that oral preparations of benznidazole (BZN) have demonstrated limited efficacy in the treatment of Chagas' disease due to pharmacokinetic or toxicological problems, the development of buccal polymeric films was purposed in this study. These systems ensure high patient acceptability and direct access to the systemic circulation, improving drug bioavailability and toxicological profile. Polymer films were prepared through a thermopressing method by mixing BZN and polyvinyl alcohol (PVAL). In some preparations, propylene glycol (PG) and thymol (TM) were also included as plasticizer and chemical absorption enhancer, respectively. Morphology, X-ray diffraction, spectroscopic, thermal, mechanical, and water uptake properties, as well as ex vivo permeability studies, were performed to characterize the film formulations. BZN remained stable and in an amorphous form over 90 days. The addition of PG and TM improved the mechanical properties of the films, making them soft, flexible and tear-resistant. Also, these additives increased the water sorption rate of the films at 50 and 75% relative humidity and the TM increased the film erosion properties and drug permeability (close to 6×) compared to control. It was hypothesized that the permeability improvement of thymol-based films that follow a drug release profile through erosion is also associated with the inhibition of the crystallization of BNZ when the film is in contact with the buccal mucosa. Once the thymol has previously demonstrated a significant in vivo and in vitro trypanocidal action and even improved film characteristics, these systems may be considered promising for Chagas' disease treatment.

Transbuccal Delivery of Isoniazid: Ex Vivo Permeability and Drug-Surfactant Interaction Studies.

The oral administration of isoniazid (INH) may lead to discontinuation of tuberculosis treatment due to drug-related hepatotoxicity events, and thus, the transbuccal delivery of this drug was investigated, for the first time, as an alternative administration route. Ex vivo permeability assays were performed in Franz-type diffusion chambers, applying INH alone and in combination with sodium dodecyl sulfate (SDS) and sodium taurocholate (ST). After confirming the formation of micelle structures by dynamic light scattering analysis, UV-visible spectroscopy and zeta potential analyses were used to investigate drug-micelle interactions. In zeta potential analyses, no electrostatical interactions were identified for both surfactants in saliva buffer pH 6.8. Spectrophotometric analyses, in turn, indicated chemical interactions between INH and SDS in both pH values (2.0 and 6.8) whereas no interaction between the drug and ST was observed. Despite the interaction between SDS and drug, this surfactant increased the buccal transport rate of INH by approximately 11 times when compared with the control. In contrast, ST did not increase the drug permeability. The INH retention in SDS-treated mucosa was significantly higher when compared with the control and an effect on intercellular lipids was suggested. In vivo studies are needed to confirm the high INH absorption found here. Grapical abstract.

Transbuccal delivery of metal complexes of isoniazid as an alternative to overcome antimicrobial resistance problems.

In isolated isoniazid (INH)-resistant strains, deletion or mutations in thekatGgene have been identified, which result in loss of catalase-peroxidase activity. This enzyme plays a key role in the activation of this prodrug. As an alternative, the coordination of the INH to metal complexes has been purposed to activate it regardless of enzyme functionality. Although pentacyanido(isoniazid)ferrate(II) complexes have shown to be effective against resistant strains of Mycobacterium tuberculosis, low oral bioavailability was found. In this context, buccal mucosa was selected as an alternative route to the metal complex delivery. Moreover, oral manifestations of tuberculosis(TB) have been observed in some patients, particularly when resistant strains are present, and no therapeutic options are currently available on the market. Pentacyanidoferrate (PCF-INH) and Prussian-blue (PB-INH) complexes were initially prepared and characterized, followed by buccal permeability studies in Franz-type diffusion cells. The electrochemical potential of the complexes demonstrated their ability to self-activate. Job's method suggested the presence of structural defects in PB-INH complexes, which was correlated with permeability results. In fact, PB-INH showed a higher dissociation rate in salt-rich aqueous medium and thus a high transport rate of INH through the buccal mucosa. Its passage through the tissue would not be possible due to the high molecular size. PCF-INH, in turn, presented a lower dissociation rate in the salt-rich aqueous medium, justifying its slower transport rate through the tissue. Taken together, these results suggest that INH-based metal complexes may be efficiently administered through the buccal route, impacting on both oral bioavailability and microbial resistance.

Transbuccal delivery of benznidazole associated with monoterpenes: permeation studies and mechanistic insights.

Benznidazole (BZN) represents the only drug currently available for the treatment of Chagas disease in most endemic countries. When administered orally, high doses are required due to its extensive hepatic metabolism and its toxicity represents the main reason for treatment withdrawals. Because of these complications, transbuccal administration of BZN was investigated. This route avoids the first-pass hepatic metabolism and presents high permeability, with direct access to the systemic circulation. BZN was applied on porcine buccal mucosa after pretreatment with pure eugenol, carvacrol or limonene. Thermal (DSC) and spectroscopic (FT-IR) analyzes were performed to investigate the mechanisms of drug absorption enhancement. The permeability coefficient values of BZN increased 2.6, 2.9 and 4.9-fold after pretreatment with eugenol, carvacrol and limonene, respectively. The lag time, in turn, was shortened in the pretreated samples. The DSC and FT-IR analyzes suggested that transport of BZN through the buccal mucosa is associated with log P and size of monoterpenes. Limonene, the most effective absorption enhancer, contributed to greater interaction with non-polar domains of the buccal epithelium. Overall, BZN showed to be efficiently transported through the buccal route, but in vivo pharmacokinetic studies should be performed to confirm these findings.