José Lamartine Soares-Sobrinho

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.

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.

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.

Palygorskite organophilic for dermopharmaceutical application

Due to the growing interest of the population in natural treatments, the clays represent a good alternative to the treatment of wounds. Its modification by organophilization happens when the same inorganic cations are exchanged for organic cations of the surfactant used in the process. Thus, the clay has the properties of its surface modified from being hydrophilic to hydrophobic, improving its functionality on the skin. In order to determine changes in surface palygorskite and to assess its healing action, this clay was organophilizated by two cationic surfactants: dimethyl benzyl ammonium chloride alkyl, and cetyl trimethyl ammonium chloride, and characterized by sieve analysis, property flow, test oil adsorption, and the techniques of X-ray fluorescence, X-ray diffraction, infrared Fourier transform, thermogravimetric analysis, scanning calorimetry—differential and histological of cutaneous wounds in rats. The results indicate that the attapulgite has good rheological properties, a high capacity of adsorption of oil, and the presence of clay minerals that reduce inflammation. The analysis by X-ray fluorescence is not observing any change in the crystal structure of palygorskite organophilizated but through infrared spectroscopy Fourier transform, verifying the interaction and incorporation of the clay ammonium salts, as well as thermoanalytical analysis also suggests that the organophilic process reduces the hydrophilic character of palygorskite. The histological analysis showed healing effect after topical application of natural and organophilizated clay in skin wounds in rats. These analyses favor a good prospect of its application in dermopharmaceuticals, because the use of palygorskite provides greater interaction with skin and heals wounds.

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).

Biopolymers and pilocarpine interaction study for use in drug delivery systems (DDS)

This work aimed at the investigation of pilocarpine’s interaction in the association of cashew gum (CG) and chitosan (CH) biopolymers because of mucoadhesive and prolonged release properties of this polymeric system. To elucidate this issue, characterization techniques, such as DSC, TG, XRD, IR, were applied besides DFT B3LYP/6-31++G(d,p) computational calculations. According to this approach, CG interacts with pilocarpine having a protective thermal effect on the drug and CH can reduce its thermal stability. These interactions occur, preferably, between a carbonyl group from pilocarpine and hydroxyl groups from biopolymers in which hydrogen bonds are involved. Thus, this work was able to identify interactions between the drug and the biopolymers and how, in a molecular approach, they occur. These results allow for the full understanding of the influence of each biopolymer for future pilocarpine-release systems.

A study of photostability and compatibility of the anti-chagas drug Benznidazole with pharmaceutics excipients

Abstract Context: Benznidazole (BNZ) is an antiparasitic with trypanocidal properties for the etiological treatment of Chagas disease since 1973. Monitoring the stability of this drug is one of the most effective methods of assessment, forecasting and prevention of problems related to quality product. Objective: To investigate the direct and indirect photodegradation of BNZ and to evaluate the interference of the excipients used in the forms dosage solid as well as to shed light on the chemical structure of the degradation products obtained. Materials and methods: To perform this work we adopted the “ICH Harmonised Tripartite Guideline: Photostability Testing of New Drug Substances and Products Q1B” (Guideline Q1B). We used benzonidazole (BNZ) (N-benzil-2-(2-nitroimidazol-1-il) acetamide) (LAFEPE®, Recife, Brazil) and various excipients; beyond high-performance liquid chromatography (HPLC), differential scanning calorimetry (DSC), infrared spectroscopy (IR) and mass spectrometry/mass spectrometry (MS/MS). The indirect photodegradation of BNZ was carried out using physical mixtures with 13 pharmaceutical excipients commonly used in the preparation of solid dosage forms. Results: HPLC and MS/MS techniques were selected for the identification of two photoproducts (PPs) and photoreactions found in direct and indirect tests with the microcrystalline cellulose, considered a critical excipient. Discussion: Despite variations in the infrared spectrometry, differential scanning calorimetry and differential thermogravimetry curves, these techniques are not conclusive since the study of photodegradation of the drug caused decay of 30%, according to the ICH. Conclusions: The results show that BNZ only undergoes direct photodegradation, since no new PPs were found for a combination of the drug and excipients.

Molecular dynamics simulations reveal the influence of dextran sulfate in nanoparticle formation with calcium alginate to encapsulate insulin

Molecular dynamics simulations reveal the influence of dextran sulfate in nanoparticle formation with calcium alginate to encapsulate insulin Daniela Nadvorny* , José Lamartine Soares-Sobrinho, Monica F. de La Roca Soares, Antônio José Ribeiro , Francisco Veiga and Gustavo M. Seabra Núcleo de Controle de Qualidade de Medicamentos e Correlatos, Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco, Recife, Brazil; Faculdade de Farmácia, Universidade de Coimbra, Coimbra, Portugal; Departamento de Química Fundamental, Universidade Federal de Pernambuco, Recife, Brazil