Abstract
Chagas disease is a neglected tropical disease caused by the flagellate protozoan Trypanosoma cruzi (T. cruzi). Endemic in underdeveloped and developed countries, due to the migratory movement, it is considered a serious public health problem. Endemic in underdeveloped countries and due to the migratory movement, in developed countries as well, it is considered a serious public health problem. One of the reasons for this is a weak therapeutic arsenal, represented only by the drug benznidazole (BNZ) which, although it promotes significant cure rates in the acute phase of the disease, presents serious problems of toxicity and bioavailability, mainly due to its low aqueous solubility. Several studies have presented several drug delivery systems (DDS) based on BNZ aiming at enhancing its solubility in aqueous medium and, with this, promoting an increase in the dissolution rate and, consequently, in its bioavailability. However, the present work is a pioneer in using a zeolitic imidazolate framework as a carrier agent for a DDS in order to promote a pH-sensitive modulation of the drug. Thus, this work aimed to develop a novel DDS based on BNZ and the ZIF-8 to use it in development of prolonged-release dosage forms to alternative treatment of Chagas disease. The BNZ@ZIF-8 system was obtained through an ex situ method selected due to its higher incorporation efficiency (38%). Different characterization techniques corroborated the obtainment and drug release data were analyzed by in vitro dissolution assay under sink and non-sink conditions and setting the kinetic results through both model dependent and independent methods. Under sink conditions, at pH 4.5, BNZ and BNZ@ZIF-8 showed similar release profile, but the DDS was effective in promoting a prolonged release. At pH 7.6, after 7 h, BNZ showed a lower release than BNZ@ZIF-8. On the other hand, in non-sink conditions at pH 4.5 the BNZ presented 80% of drug release in 3 h, while the DDS in 6 h. At pH 7.6, BNZ presented a release of 80% in 2 h, while the DDS reaches it in only at 12 h. Therefore, at pH 4.5 the DDS BNZ@ZIF-8 showed a faster release with a burst effect, while at pH 7.6 it showed a prolonged and controlled release. Finally, it is evident that a promising DDS pH-sensitive was obtained as a novel carrier that might be able to prolongs BNZ release in dosage forms intended for the alternative treatment of Chagas disease.
Highlights
IntroductionKnown as American trypanosomiasis, is a neglected tropical disease endemic in 27 countries of the American continent
Chagas disease, known as American trypanosomiasis, is a neglected tropical disease endemic in 27 countries of the American continent
A recent study by Khalid and collaborators [41] showed similar behavior when evaluating the mechanism of release of flurbiprofen-based mucoadhesive tablets. These results found in the non-sink condition are more expressive than those obtained in sink conditions, since at an acidic pH the Zeolitic Imidazolate Framework (ZIF)-8 dissociates more rapidly
Summary
Known as American trypanosomiasis, is a neglected tropical disease endemic in 27 countries of the American continent. It is estimated that 65 million people on the American continent live in exposure areas and are at risk of contracting the disease. Fatal, the disease is caused by the parasite protozoan Trypanosoma cruzi (T. cruzi), and among neglected diseases, is the parasitic infection with the greatest socioeconomic impact in Latin America, being responsible for an annual loss of about US $1.2 billion, mainly due to the loss of productivity [1,2,3,4,5]. Benznidazole (BNZ) (N-benzyl-2-nitroimidazole-1-acetamide) is a broad spectrum nitroimidazole derivative of antiprotozoal and antibacterial pharmacological activity, and it is the first-choice drug and the only one in the therapeutic arsenal against the disease. The drug may cause toxic reactions and undesirable side effects like metronidazole, such as nausea, headache, anorexia, abdominal pain, weight loss, dizziness, asthenia, vomiting, rash, and ataxia [6,7,8]
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