Pedro José Rolim-Neto

Inclusion complex of methyl-β-cyclodextrin and olanzapine as potential drug delivery system for schizophrenia.

Olanzapine (OLP), the most important atypical antipsychotic drug of the new generation, a high cost drug, has low aqueous solubility, affecting its dissolution and absorption. Its complexation with modified cyclodextrins (CDs) is designed to achieve novel vectorization systems with higher solubility, consequently higher bioavailability. From the CD selection, among β-CD, methyl-β-CD (MβCD) and hydroxypropyl-β-CD, it was obtained a phase solubility diagram suggesting a 1:1 (mol:mol) OLP-CD stoichiometry and complexation constants of 966.9, 149.4 and 91.1 L/mol, respectively. The MβCD was selected for the inclusion complexes (IC) attainment, a physical mixture (PM) and a rotatory evaporator product (ROE). The analysis showed differences in the structure, morphology and performance of OLP, MβCD, PM and ROE, revealing the occurrence of interactions between drug and CD. The ROE presented the higher dissolution efficiency and stability. The results suggest that the IC was formation, being a technological resource efficient and profitable for drug delivery.

The Use of Solid Dispersion Systems in Hydrophilic Carriers to Increase Benznidazole Solubility

The present study investigates the release mechanism of benznidazole (BNZ) in solid dispersions with polyethylene glycol 6000 (PEG 6000) and polyvinylpirrolydone K-30 (PVP K-30), with a view to observing the increase in solubility of BNZ in water in the presence of these two hydrophilic polymers. The interaction of BNZ with the polymers was evaluated using scanning electron microscopy, Fourier-transformation infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and in vitro dissolution tests, and a theoretical study of molecular modeling was also carried out. The drug-polymer interaction was studied trough molecular modeling, using density functional theory with the B3LYP exchange correlation function. The corrected interaction energies were calculated to be -20.9 kJ/mol with PVP and -6.6 kJ/mol with PEG. The experimental and theoretical results indicate that a powerful interaction occurred between BNZ and the polymers, which was especially strong in the case of PVP, and that this interaction contributed to improvement of BNZ solubility.

Induction of cancer cell death by apoptosis and slow release of 5-fluoracil from metal-organic frameworks Cu-BTC.

This study aimed to evaluate the mechanism associated with cytotoxic activity displayed by the drug 5-fluorouracil incorporated in Cu-BTC MOF and its slow delivery from the Cu-BTC MOF. Structural characterization encompasses elemental analysis (CHNS), differential scanning calorimetry (DSC), thermogravimetric analysis (TG/DTG), Fournier transform infrared (FIT-IR) and X-ray diffraction (XRD) was performed to verify the process of association between the drug 5-FU and Cu-BTC MOF. Flow cytometry was done to indicate that apoptosis is the mechanism responsible for the cell death. The release profile of the drug 5-FU from Cu-BTC MOF for 48 hours was obeisant. Also, the anti-inflammatory activity was evaluated by the peritonitis testing and the production of nitric oxide and pro-inflammatory cytokines were measured. The chemical characterization of the material indicated the presence of drug associated with the coordination network in a proportion of 0.82 g 5-FU per 1.0 g of Cu-BTC MOF. The cytotoxic tests were carried out against four cell lines: NCI-H292, MCF-7, HT29 and HL60. The Cu-BTC MOF associated drug was extremely cytotoxic against the human breast cancer adenocarcinoma (MCF-7) cell line and against human acute promyelocytic leukemia cells (HL60), cancer cells were killed by apoptosis mechanisms. The drug demonstrated a slow release profile where 82% of the drug was released in 48 hours. The results indicated that the drug incorporated in Cu-BTC MOF decreased significantly the number of leukocytes in the peritoneal cavity of rodents as well as reduced levels of cytokines and nitric oxide production.

Benznidazole drug delivery by binary and multicomponent inclusion complexes using cyclodextrins and polymers

Benznidazole (BNZ) is the drug of choice for Chagas disease treatment, which affects about 9.8 million people worldwide. It has low solubility and high toxicity. The present study aimed to develop and characterize inclusion complexes (IC) in binary systems (BS) with BNZ and randomly methylated-β-cyclodextrin (RMβCD) and in ternary systems (TS) with BNZ, RMβCD and hydrophilic polymers. The results showed that the solid BS had a large increase in dissolution rate (Q>80%). For the solid IC obtained, the kneading method, in ratio of 1:0.17 (77.8% in 60 min), appeared to be the most suitable for the development of a solid oral pharmaceutical product, with possible industrial scale-up and low concentration of CD. The solid TS containing 0.1% of hydroxypropylmethylcellulose (HPMC) showed no significant advantages compared to the binary IC in solid state. The use of cyclodextrins proved to be a viable tool for effective, standardized and safe drug delivery.

Study of stability and drug-excipient compatibility of diethylcarbamazine citrate

Diethylcarbamazine citrate (DEC) is the main drug used in the lymphatic filariasis treatment. This study aimed to evaluate drug-excipient compatibility of binary mixtures (BMs) (1:1, w/w), initially by differential scanning calorimetry (DSC), and subsequently, if there were any interaction evidence, by complementary techniques, such as thermogravimetric (TG), non-isothermal kinetics, Fourier transform infrared (FT-IR), and X-ray diffraction (XRD). For the analyses of the BMs by DSC, we selected those with Tabletose®, representing the excipients containing lactose, polivinilpirrolidona (PVP), and magnesium stearate (MgS). The additional analyses by FT-IR and XRD showed no interaction evidence. The TG curves of DEC–Tabletose® showed no signs of interaction, unlike the TG curves of PVP and MgS, confirming the results of non-isothermal kinetics, in which the BMs with PVP and MgS decreased the reaction activation energy. Thus, it was concluded after evaluation that the excipients, especially the PVP and MgS, should be avoided.

Avaliação de procedimentos para quantificação espectrofotométrica de flavonoides totais em folhas de Bauhinia forficata Link

Interest in analytical methods for quality control of herbal drugs has grown sharply due to the scarcity of monographs in official manuals. Thus, the aim of the present study was to evaluate analytical procedures for quantitative determination of flavonoids from leaves of Bauhinia forficata Link (pata-de-vaca). Two procedures for quantification of total flavonoids (with and without acid hydrolysis) by spectrophotometry were tested. The proposed methods proved to be specific, sensitive, precise, accurate and robust, being suitable for routine laboratory use.

Study of benznidazole-cyclodextrin inclusion complexes, cytotoxicity and trypanocidal activity

The current chemotherapy for Chagas disease is still based on benznidazole, which has low solubility, but complexation with cyclodextrins provides a way of increasing the solubility. The objective of this work was to characterize the inclusion complexes formed between benznidazole (BNZ) and randomly 2-methyled-β-cyclodextrin (RM-β-CD) in aqueous solution and study cytotoxicity and trypanocidal. BNZ:RM-β-CD solution complex systems were prepared and characterized using the phase solubility diagram, nuclear magnetic resonance and a photostability assays, also to investigate the in vitro trypanocidal activity with epimastigote forms of Trypanossoma cruzi and the study of cytotoxicity against mammal cells. The phase-solubility diagram displayed an AL-type feature, providing evidence of the formation of soluble inclusion complexes. The continuous variation method showed the existence of a complex with 1:1 stoichiometry. Toxicity assays demonstrated that inclusion complexes were able to reduce the toxic effects caused by benznidazole alone and that this did not interfere with the trypanocidal activity of the benznidazole. The use of inclusion complexes benznidazole:cyclodextrin is thus a promising alternative for the development of a safe and stable liquid formulation and a new option for the treatment of Chagas disease.

Development and Evaluation of Stability of a Gel Formulation Containing the Monoterpene Borneol.

Borneol is a bicyclic monoterpenoid alcohol commonly used in traditional Chinese and Indian medicine. It is extracted from the essential oil of various medicinal plants. It has antibacterial, analgesic, and anti-inflammatory action proven in studies that used oral and intraperitoneal applications of this monoterpene in mice. The current study was designed to develop a topical gel formulation containing the monoterpene borneol using carbopol as gel base and to evaluate its stability. The prepared formulation was subjected to physical characterization and physical-chemistry assessment. The gel was prepared from carbopol and 5% of borneol. The prepared gel was subjected to pharmacotechnical tests such as its pH, viscosity, conductivity, spreadability, centrifugation, and accelerated stability with freezing-thaw cycle. The borneol was successfully incorporated into the carbopol formulation. Borneol gel (BG5) showed good stability after eight months of its development and after 12 days in the freeze-thaw cycle, not showing statistical difference in pH value, conductivity, and viscosity before and after test. Furthermore, the formulation showed a good spreadability. Therefore, it was concluded that the formulation could be very promising alternative for the topical or transdermal treatment of skin diseases.

Multicomponent systems with cyclodextrins and hydrophilic polymers for the delivery of Efavirenz

Efavirenz (EFZ) is one of the most used drugs in the treatment of AIDS and is the first antiretroviral choice. However, since it has low solubility, it does not exhibit suitable bioavailability, which interferes with its therapeutic action and is classified as a class II drug according Biopharmaceutical Classification System (low solubility and high permeability). Among several drug delivery systems, the multicomponent systems with cyclodextrins and hydrophilic polymers are a promising alternative for increasing the aqueous solubility of the drug. The present study aimed to develop and characterize in a ternary system of EFZ, MβCD and PVP K30. The results showed that the solid ternary system provided a large increase in the dissolution rate which was greater than 80% and was characterized by DSC, TG, XRD, FT-IR and SEM. The use of the ternary system (EFZ, MβCD and PVP K30 1%) proved to be a viable, effective and safe delivery of the drug. The addition of the hydrophilic polymer appeared to be suitable for the development of a solid oral pharmaceutical product, with possible industrial scale-up and with low concentration of CDs (cyclodextrins).

Phytochemical analysis and evaluation of antioxidant and photoprotective activities of extracts from flowers of Bromelia laciniosa (Bromeliaceae)

ABSTRACT In this study, the phytochemical profile of extracts from the flowers of Bromelia laciniosa was characterized. The total phenolic and flavonoids contents were determined and the antioxidant and photoprotective activities were evaluated using in vitro assays. Phytochemical analysis demonstrated that the extracts were found to be positive for the presence of anthracene derivatives, anthraquinones, coumarins, flavonoids and tannins, lignans, mono and diterpenes. The ethanol extract (Bl-EtOH) presented the most significant total phenolic content (53.75 ± 1.25 mg GAE/g). The dichloromethane extract (Bl-CH2Cl2) showed the highest flavonoid content (46.06 ± 1.18 mg CE/g). The methanol extract (Bl-MeOH) was the most effective extract in the DPPH (2,2-diphenyl-1-picrylhydrazil) assay (EC50 141.90 ± 3.01 μg/mL). Bl-EtOH and Bl-MeOH showed higher sun protection factor at a concentration of 100 mg/L (3.38 ± 0.04 and 3.78 ± 0.11, respectively). Therefore, the extracts proved to be interesting for the development of new studies aiming their incorporation into photoprotective cosmetic formulations.