Alexandre C.C. Vieira

Solid dispersion of efavirenz in PVP K-30 by conventional solvent and kneading methods.

Efavirenz (EFV) used as a part of the treatment of first choice in antiretroviral therapy for AIDS has low aqueous solubility and presents problems of absorption. We thus initially present a phase solubility diagram with carriers of different classes. With a view to obtaining a solid dispersion (SD) with suitable consistency to that of a solid formulation, we chose to use PVP K-30, since polymers present some of the best results. The kneading (KN) and solvent evaporation (EV) methods were thus used at different rates. These were characterized by the way of DSC, FT-IR, SEM, DR-X and dissolution. SD EV proved unsatisfactory, resulting in a decreased dissolution rate, despite the amorphous state of the samples, while the SD KN 4:1 (EFV:polymer) and physical mixtures (PM) had a higher rate of dissolution. SD KN and PM 4:1 were also evaluated for stability after storage, with benefits being observed in relation to EFV.

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.

Design of a nanostructured lipid carrier intended to improve the treatment of tuberculosis

This work aimed to design, develop, and characterize a lipid nanocarrier system for the selective delivery of rifabutin (RFB) to alveolar macrophages. Lipid nanoparticles, specifically nanostructured lipid carriers (NLC), were synthetized by the high-shear homogenization and ultrasonication techniques. These nanoparticles were designed to exhibit both passive and active targeting strategies to be efficiently internalized by the alveolar macrophages, traffic to the acidified phagosomes and phagolysosomes, and release bactericidal concentrations of the antituberculosis drug intracellularly. NLC that could entrap RFB were prepared, characterized, and further functionalized with mannose. Particles’ diameter, zeta potential, morphology, drug% entrapping efficiency, and drug release kinetics were evaluated. The mannose coating process was confirmed by Fourier transform infrared. Further, the cytotoxicity of the formulations was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay in A549, Calu-3, and Raw 264.7 cells. The diameter of NLC formulations was found to be in the range of 175–213 nm, and drug entrapping efficiency was found to be above 80%. In addition, high storage stability for the formulations was expected since they maintained the initial characteristics for 6 months. Moreover, the drug release was pH-sensitive, with a faster drug release at acidic pH than at neutral pH. These results pose a strong argument that the developed nanocarrier can be explored as a promising carrier for safer and more efficient management of tuberculosis by exploiting the pulmonary route of administration.

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).

Development of PLGA nanoparticles loaded with clofazimine for oral delivery: Assessment of formulation variables and intestinal permeability

ABSTRACT The use of polymeric nanoparticles as delivery systems is a promising tool to overcome drawbacks related to low aqueous solubility of drugs, which limit their in vivo bioavailability. The aim of this study was to decrease clofazimine (CLZ) toxicity using experimental design to formulate CLZ loaded in PLGA nanoparticles (NPs‐CLZ) through a Plackett–Burman design (PBD). A screening PBD was constructed with twelve formulations involving six variables among process and formulation parameters and the selected responses were particle size, polydispersity index (PDI), association efficiency (AE) and drug loading (DL). The formulation was achieved based on the desirability tool, and the obtained NPs‐CLZ formulation was characterized regarding morphology, physicochemical properties, in vitro release and cellular studies. Particle size, PDI, AE and DL were found to be 211 ± 3 nm, 0.211 ± 0.009, 70 ± 5% and 12 ± 1%, respectively. Physicochemical studies confirmed the absence of chemical interactions between CLZ and other nanoparticles constituents and the amorphous state of CLZ, while morphological analysis revealed the spherical shape of the particles. In vitro release profile of CLZ from NPs‐PLGA showed a slow pattern of drug release. Cell viability studies towards intestinal cells revealed that NPs‐CLZ did not show CLZ toxicity on Caco‐2 and HT29‐MTX cells compared to free CLZ solutions. Moreover, CLZ could permeate Caco‐2 monolayers substantially at the end of 8 h. It can be concluded that the proposed NPs‐CLZ represent a promising platform to the oral delivery of CLZ as they were able to decrease its intrinsic toxicity, with improved absorption. Graphical abstract Figure. No Caption available.

Mucoadhesive chitosan-coated solid lipid nanoparticles for better management of tuberculosis

Taking into consideration the potential mucoadhesion properties of systems in lung delivery, this paper describes the preparation and characterization of chitosan-coated solid lipid nanoparticles (C-SLNs) loaded with rifampicin (RIF) as anti-tuberculosis (anti-TB) drug. The process of development and characterization of the NPs in terms of size, surface charge, encapsulation efficiency (EE), morphology, in vitro drug release, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), in vitro assessment of mucoadhesive property, cell viability and permeability studies are documented. Results showed that the SLNs had a smooth spherical shape with a size of ca. 245-344 nm and with a zeta potential around -30 mV for SLNs and +40 mV for C-SLNs. The surface charge variation from negative to positive charge and FTIR analysis demonstrated the successful process of coating the nanoparticles (NPs) surface with chitosan. The DSC thermograms were in agreement with the nanostructure of the SLNs. The EE of drug was found to be higher than 90% and the loading capacity (LC) around 4.5%. C-SLNs show higher in vitro muchoadesive properties and a higher permeability in alveolar epithelial cells A549 than uncoated SLNs, indicating that the developed C-SLNs can be used as a promising carrier for sasfer and efficient management of TB.

Mannosylated solid lipid nanoparticles for the selective delivery of rifampicin to macrophages

Abstract Tuberculosis (TB) is still a devastating disease and more people have died of TB than any other infectious diseases throughout the history. The current therapy consists of a multidrug combination in a long-term treatment, being associated with the appearance of several adverse effects. Thus, solid lipid nanoparticles (SLNs) were developed using mannose as a lectin receptor ligand conjugate for macrophage targeting and to increase the therapeutic index of rifampicin (RIF). The developed SLNs were studied in terms of diameter, polydispersity index, zeta potential, encapsulation efficiency (EE) and loading capacity (LC). Morphology, in vitro drug release and differential scanning calorimetry studies, macrophage uptake studies, cell viability and storage stability studies were also performed. The diameter of the SLNs obtained was within the range of 160–250 nm and drug EE was above 75%. The biocompatibility of M-SLNs was verified and the internalization in macrophages was improved with the mannosylation. The overall results suggested that the developed mannosylated formulations are safe and a promising tool for TB therapy targeted for macrophages.

Rational and precise development of amorphous polymeric systems with dapsone by response surface methodology

This work aimed to design dapsone (DAP) amorphous Polymeric Dispersions (PD) using design of experiments (DoE) and response surface methodology (RSM) as optimization tools in order to tailor the biopharmaceutical properties toward its oral delivery. A two-factor, three-level (3(2)) statistical design was implemented to study the influence of input variables (amount of PVP K30 and Pluronic F68) on the equilibrium solubility of DAP of the physical mixture (PM), kneaded (KN) and freeze dried (FD) PDs. Through the analysis, it was found that equilibrium solubility of DAP was improved with increasing of PVP K30, mainly for FD PDs, but decreased with increasing Pluronic F68 concentration. XRD and FTIR spectrum revealed the amorphous characteristic of FD PDs and SEM confirmed the homogeneity of the system leading to enhanced surface area and consequent dissolution rate. The in vitro dissolution rate of PDs was significantly faster compared to DAP and PM, and all the similarity factors (f2) were below 50, demonstrating the differences on the dissolution profiles. The results established the effectiveness of PDs for improvement of dissolution and solubility of DAP and the success in the implementation of DoE and RSM as QbD tools in the design of PDs.

Quality by Design: Discussing and Assessing the Solid Dispersions Risk

The poor water solubility tops the list of undesirable physicochemical properties in the drug discovery and Solid Dispersions (SDs) has been frequently used to enhance dissolution of such compounds. Although, some challenges limit the studies of SD commercial application. During recent years, the Quality by Design (QbD) approach has begun to change drug development, and focus on pharmaceutical production, which shifted from an univariate empirical understanding for a systematic multivariate process. In this review, some possible variables during the development process, formulation and production of SDs were defined, introducing and applying the QbD concept. The proposed work presented important definitions as well as its application in the pharmaceutical product and process design, especially the challenges encountered during the development of formulations of poorly soluble drugs. In this aspect, the SD technique was deeply discussed, in which some important parameters during SD design and production were mentioned as method of production, polymers commonly used, methods for characterization and stability evaluation, in addition of biopharmaceutical considerations. Finally, a specific risk assessment for the design and production of SD and critical points were discussed, which was a positive evolution and may lead to better understanding of SD for a rational formulation.

Folate-targeted nanostructured lipid carriers for enhanced oral delivery of epigallocatechin-3-gallate

The well-known pleiotropic health benefits of green tea are mainly attributed to epigallocatechin-3-gallate (EGCG), a polyphenolic compound from the group of catechins. EGCGs poor stability and intestinal permeability, however, can strongly impair its biological activities. In this work, EGCG-loaded nanostructured lipid carriers (NLC) functionalized with folic acid were optimized through a Box-Behnken design intended to provide an enhanced oral absorption and increased bioavailability of EGCG. Size, zeta potential and encapsulation efficiency (EE) of the produced spherical nanoparticles were evaluated. NLC were further characterized by Differential Scanning Calorimetry (DSC). An in vitro release study in simulated gastric and intestinal fluids was conducted and the storage stability of the nanoparticles was evaluated over a period of 8weeks. The overall results demonstrated the suitability of the developed formulation for the oral delivery of EGCG and its potential for applications in food industry.