Development and evaluation of the in vitro schistosomicidal activity of solid dispersions based on 2-(-5-bromo-1-H-indole-3-yl-methylene)-N-(naphthalene-1-ylhydrazine-carbothiamide.

Among all the neglected diseases, schistosomiasis is considered the second most important parasitic infection after malaria. Praziquantel is the most widely used drug for this disease, but its exclusive use may result in the development of drug-resistant schistosomiasis. To increase the control of the disease, new drugs have been developed as alternative treatments, among them 2-(-5-bromo-1-h-indole-3-yl-methylene)-N-(naphthalene-1-ylhydrazine-carbothiamide (LQIT/LT-50), which showed promising schistosomicidal activity in nonclinical studies. However, LQIT/LT-50 presents low solubility in water, resulting in reduced bioavailability. To overcome this solubility problem, the present study aimed to develop LQIT/LT-50 solid dispersions for the treatment of schistosomiasis. Solid dispersions were prepared through the solvent method using Soluplus©, polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP K-30) as hydrophilic carriers. The formulations with the best results in the compatibility tests, aqueous solubility and preliminary stability studies have undergone solubility tests and physicochemical characterizations by Fourier-transform infrared spectroscopy (FTIR), x-ray diffractometry (XRD), exploratory differential calorimetry (DSC), thermogravimetry (TG) and Raman spectroscopy. Finally, the schistosomicidal activity was evaluated in vitro. The phycochemical analyzes showed that when using PVP K-30, there was an interaction between the PVP K-30 and LQIT/LT-50, proving the successful development of the solid dispersion. Furthermore, an increase in the solubility of the new system was observed (LQIT/LT-50:PVP K-30) in addition to the improvement in the in vitro shistosomidal activity at 1:4 (w/w) molar ratio (i.e., 20% drug loading) when compared to LQIT/LT-50 alone. The development of the LQIT/LT-50:PVP K-30 1:4 solid dispersion is encouraging for the future development of new pharmaceutical solid formulations, aiming the schistosomicidal treatment.

A Systematic Review of Functionalized Polymeric Nanoparticles to Improve Intestinal Permeability of Drugs and Biological Products.

BACKGROUND: The oral route is the most frequently used and the most convenient route of drug administration since it has several advantages, such as ease of use, patient compliance, and better costeffectiveness. However, physicochemical and biopharmaceutical limitations of various active pharmaceutical ingredients (API) hinder suitability for this route, including degradation in the gastrointestinal tract, low intestinal permeability, and low bioavailability. To overcome these problems, while maintaining therapeutic efficacy, polymeric nanoparticles have attracted considerable attention for their ability to increase drug solubility, promote the controlled release, and improve stability. In addition, the functionalization of nanocarriers can increase uptake and accumulation at the target site of action, and intestinal absorption, making it possible to obtain more viable, safe and efficient treatments for oral administration. OBJECTIVE: This systematic review aimed to seek recent advances in the literature on the use of polymeric nanoparticles functionalization to increase intestinal permeability of APIs that are intended for oral administration. METHODS: Two bibliographic databases were consulted (PubMed and ScienceDirect). The selected publications and the writing of this systematic review were based on the guidelines mentioned in the PRISMA statement. RESULTS: Out of a total of 3036 studies, 22 studies were included in this article based on our eligibility criteria. The results were consistent for the application of nanoparticle functionalization to increase intestinal permeability. CONCLUSION: The functionalized polymeric nanoparticles can be considered as carrier systems that improve the intestinal permeability and bioavailability of APIs, with the potential to result, in the future, in the development of oral medicines.

Enhanced Solubility of Albendazole in Cyclodextrin Inclusion Complex: A Molecular Modeling Approach and Physicochemical Evaluation.

BACKGROUND: Albendazole (ABZ) is the drug of choice for the treatment of a variety of human and veterinary parasites. However, it has low aqueous solubility and low bioavailability. Cyclodextrins (CD) are pharmaceutical excipients with the ability to modulate the solubilization property of hydrophobic molecules. OBJECTIVE: The aim of the study was to analyze through in vitro and in silico studies (Autodock Vina software and CycloMolder platform) the formation of inclusion complexes between ABZ, ß-cyclodextrin (ß-CD) and its derivatives Methyl-ß-cyclodextrin (M-ß-CD) and Hydroxypropyl-ß-cyclodextrin (HP-ß-CD). METHODS: The most stable inclusion complexes were produced by the kneading method and characterized by Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD), determination of the ABZ content and in vitro dissolution profile. RESULTS: Molecular modeling revealed that inclusion complexes between HP-ß-CD:ABZ (in the proportion 1:1 and 2:1) presented the lowest formation energy and the highest number of intermolecular interactions, showing that the use of more cyclodextrins does not generate gains in the stability of the complex. On the characterization tests, the complexes experimentally obtained by the kneading method demonstrated highly suggestive parameters, including ABZ in HP-ß-CD in both molar proportions, suppression of bands in the infrared spectrum, displacement of the drug's melting temperature in DSC, crystallinity halos instead of the characteristic peaks of ABZ crystals in the XRD and a release of more than 80% of ABZ in less than 5 minutes, dissolution efficiency of up to 92%. CONCLUSION: In silico studies provided a rational selection of the appropriate complexes of cyclodextrin, enabling the elaboration of more targeted complexes, decreasing time and costs for elaboration of new formulations, thereby increasing the oral biodisponibility of ABZ.

Beta-lapachone: Natural occurrence, physicochemical properties, biological activities, toxicity and synthesis.

ß-Lapachone is an ortho-naphthoquinone originally isolated from the heartwood of Handroanthus impetiginosus and can be obtained through synthesis from lapachol, naphthoquinones, and other aromatic compounds. ß-Lapachone is well known to inhibit topoisomerase I and to induce NAD(P)H: quinone oxidoreductase 1. Currently, phase II clinical trials are being conducted for the treatment of pancreatic cancer. In view of ever-increasing scientific interest in this naphthoquinone, herein, the authors present a review of the synthesis, physicochemical properties, biological activities, and toxicity of ß-lapachone. This natural compound has shown activity against several types of malignant tumors, such as lung and pancreatic cancers and melanoma. Furthermore, this ortho-naphthoquinone has antifungal and antibacterial activities, underscoring its action against resistant microorganisms and providing anti-inflammatory, antiobesity, antioxidant, neuroprotective, nephroprotective, and wound-healing properties. ß-Lapachone presents low toxicity, with no signs of toxicity against alveolar macrophages, dermal fibroblast cells, hepatocytes, or kidney cells.

A Systematic Review of the Anti-inflammatory Effects of Gallium Compounds.

BACKGROUND: Inflammation is an essential response provided by the immune system, ensuring the survival during microbial infection, tissue injury and other noxious conditions. However, prolonged inflammatory processes are often associated with severe side effects on health. OBJECTIVE: This systematic review aimed to provide the evidence in the literature of the preclinical and human anti-inflammatory activity of gallium compounds from 2000 to 2019 focused on elucidating the mechanisms involved in the inflammatory process. METHODS: Seven bibliographical databases were consulted (PubMed, Medline, ScienceDirect, Scopus, Springer, Web of Science, and EBSCOhost). The selection of appropriate publications and writing of this systematic review were based on the guidelines mentioned in the PRISMA statement. Moreover, the assessment of the methodological quality of the selected studies was also performed. RESULTS: From a total of 3018 studies, 16 studies were included in this paper based on our eligibility criteria, which showed promising and consistent results. CONCLUSION: Further research concerning specific inflammatory conditions is required.

ZIF-8 as a promising drug delivery system for benznidazole: development, characterization, in vitro dialysis release and cytotoxicity.

Chagas disease (CD), caused by the flagellate protozoan Trypanosoma cruzi, is one of the major public health problems in developing countries. Benznidazole (BNZ) is the only drug available for CD treatment in most countries, however, it presents high toxicity and low bioavailability. To address these problems this study used Zeolitic Imidazolate Framework-8 (ZIF-8), which has garnered considerable attention due to its potential applications, enabling the controlled delivery of drugs. The present work developed and characterized a BNZ@ZIF-8 system, and the modulation of BNZ release from the ZIF-8 framework was evaluated through the in vitro dialysis release method under sink conditions at different pH values. Moreover, the in vitro evaluation of cell viability and cytotoxicity by MTT assay were also performed. The dissolution studies corroborated that a pH sensitive Drug Delivery System capable of vectorizing the release of BNZ was developed, may leading to the improvement in the bioavailability of BNZ. The MTT assay showed that no statistically significant toxic effects occurred in the developed system, nor significant effects on cell viability.

Lipid Nanoparticles as a Skin Wound Healing Drug Delivery System: Discoveries and Advances.

Chronic wounds are a remarkable cause of morbidity, requiring long-time treatments with a significant impact on the quality of life and high costs for public health. Although there are a variety of topical skin preparations commercially available, they have several limitations that frequently impair wound healing, such as drug instability, toxicity, limited time of action and ineffective skin permeation. In recent years, researchers have focused on the development of new effective treatments for wound healing and shown frequent interest in nanometric drug delivery systems to overcome such obstacles. In dermatology, lipid nanoparticles (LNPs) have received great attention from researchers due to their great functionalities, greater adhesion to the skin and film formation, enabling the hydration and maintenance of skin integrity, as well as present a more effective penetration through the skin barrier. This review provides an update on topical formulations based on Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) as wound healing treatments. Both SLNs and NLCs are able to increase solubility and stability of active pharmaceutical ingredients and increase skin penetration compared to the free drugs. Additionally, SLNs and NLCs can increase pharmacological activity, increase the release profile of the drugs, promote synergistic effects and improve the sensory properties of the final formulation. Topical dosage forms containing nanoparticles have been extensively evaluated for wound healing activity, mainly the dressings, films and scaffolds. Therefore, lipid nanoparticles have contributed in improving wound healing therapies when incorporated into other dosage forms with better efficacy and lesser adverse effects than conventional formulations.