RESUMO

Diabetic retinopathy (RD) is a microvascular disease that can cause the formation of fragile neovessels, increasing the risk of hemorrhages and leading to vision loss. Current therapies are based on the intravitreal injection of anti-VEGF (vascular endothelial growth factor), which is invasive and can cause secondary effects. The development of new treatments that complement the current therapies is necessary to improve the patient's outcomes. Nanostructured formulations offer several advantages regarding drug delivery and penetration. In this research, a resveratrol nanosuspension (RSV-NS) was prepared and characterized using dynamic light scattering, field emission scanning electron microscopy, and infrared spectroscopy. The RSV-NS had an average particle size of 304.0 ± 81.21 nm with a PDI of 0.225 ± 0.036, and a spherical-like morphology and uniform particle distribution. Cell viability, proliferation, and migration were tested on endothelial cells (HMRECs). RSV-NS in a concentration of less than 18.75 µM did not have a cytotoxic effect on HMRECs. Likewise, proliferation and migration were significantly reduced compared to the unstimulated control at 37.5 µM. The RSV-NS did not present cytotoxic effects but decreased cell proliferation and migration, indicating that it could provide an important contribution to future medical implementations and could have a high potential to treat this disease.

RESUMO

This work aimed to evaluate the influence of the mechanical defibrillation technique on the pinhão nanosuspensions production obtained from the whole pinhão, its coat, and almond. The nanosuspensions were characterized concerning their composition, morphology, thermal stability, rheological behavior, compound profiling, and cytotoxicity. The results revealed a significant fiber content in pinhão coat nanosuspension (63.12 ± 0.52 %) and non-fiber carbohydrates in whole pinhão (59.00 ± 0.13 %) and almond (74.39 ± 0.23 %) nanosuspensions. The defibrillation process led to micro/nano-sized fibers in pinhão coat nanosuspensions and small-size starch granules in almond nanosuspensions. The nanosuspensions containing pinhão coat exhibited a gel-like behavior, while almond nanosuspensions displayed liquid-like characteristics. Pinhão coat nanosuspensions presented a significant content of flavonoids and phytosterols, whereas almond-based nanosuspensions contained substantial sugar amounts. No cytotoxicity was observed at the concentrations evaluated. These findings demonstrated that the defibrillation technique impacted the properties of pinhão constituents, allowing their application in new product development.

Assuntos

Araucaria , Nanopartículas , Flavonoides , Sementes , Amido , Suspensões , Tamanho da Partícula

RESUMO

BACKGROUND: Ursodeoxycholic acid (UDCA) is a therapeutic agent used for the treatment of cholestatic hepatobiliary diseases in pediatric patients. It is a bile acid that presents high lipophilicity, and it belongs to Class II of the Biopharmaceutical Classification System (BCS), which exhibits low water solubility and high intestinal permeability, which leads to poor oral absorption. The objective of this work was to design and optimize UDCA nanosuspensions by means of the precipitation-ultrasonication method to improve the solubility, dissolution, and oral bioavailability of UDCA. METHODS: A three-level, three-factor Box-Behnken design was used to optimize formulation variables and obtain uniform, small-particle-size UDCA nanosuspensions. The independent variables were: stabilizer percentage (X1), amplitude (X2), and sonication time (X3), and the dependent variable was the particle size (Y1). In the precipitation-ultrasonication method, UDCA was dissolved in acetone:PEG 400 (1:1 v/v) and quickly incorporated into the antisolvent (pre-cooled aqueous dispersion of HPMC E-15 0.3%), by means of intense sonication at 50 W for 5 min, controlling temperature through an ice water bath. The lyophilization efficacy was evaluated by means of a cryoprotective efficacy test, working with 10% maltose at -80 °C. The nanosuspensions were characterized by dynamic light scattering (DLS), X-ray diffraction, and scanning electron microscopy (SEM). The physicochemical stability was determined at 25 °C and 4 °C at 7, 14, 30, and 60 days, and the UDCA content was analyzed via HPLC-UV. An in vitro dissolution assay and an oral bioavailability study were performed in male Wistar rats. RESULTS: A significant impact was achieved in the optimized nanosuspension with 0.3% (stabilizer), 50 W (amplitude), and 5 min (sonication time), with a particle size of 352.4 nm, PDI of 0.11, and zeta potential of -4.30 mV. It presented adequate physicochemical stability throughout the study and the UDCA content was between 90% and 110%. In total, 86% of UDCA was dissolved in the in vitro dissolution test. The relative oral bioavailability was similar without significant statistical differences when comparing the lyophilized nanosuspension and the commercial tablet, the latter presenting a more erratic behavior. The pharmacokinetic parameters of the nanosuspension and the commercial tablet were Tmax (1.0 ± 0.9 h vs. 2.0 ± 0.8 h, respectively), Cmax (0.558 ± 0.118 vs. 0.366 ± 0.113 µM, respectively), ΔCmax (0.309 ± 0.099 vs. 0.232 ± 0.056, respectively), AUC (4.326 ± 0.471 vs. 2.188 ± 0.353 µg/mL.h, respectively, p < 0.02), and IAUC0-24h (2.261 ± 0.187 µg/mL.h vs. 1.924 ± 0.440 µg/mL.h, respectively). CONCLUSIONS: The developed nanosuspension presents an appropriate dosage and administration for pediatric patients. On the other hand, it exhibits an adequate absorption and UDCA oral bioavailability.

RESUMO

Dapsone (DAP)is a dual-function drug substance; however, its limited water solubility may impair its bioavailability. Drug nanocrystals are an alternative to overcome this limitation. Herein, a DAP nanosuspension was prepared using adesign space approach aiming to investigate the influence of raw material properties and process parameters on the critical quality attributes of the drugnanocrystals. Optimized nanocrystals with 206.3 ± 6.7 nm using povacoat™ as stabilizer were made. The nanoparticles were characterized by dynamic light scattering, laser diffraction, scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, and saturation solubility. Compared to the raw material, the nanocrystals were 250-times smaller. Meanwhile, its crystalline state remained basically unchanged even after milling and drying. The nanosuspension successfully maintained its physical stability inlong-termandaccelerated stability studiesover, 4 and 3 months. Furthermore, toxicity studiesshowed low a toxicity at a20 mg/kg. As expected for nanocrystals, the size reduction improvedsaturation solubility3.78 times in water. An attempt to scale up from lab to pilot scale resulted nanocrystals of potential commercial quality. In conclusion, the present study describes the development of dapsone nanocrystals for treating infectious and inflammatory diseases. The nanocrystal formuation can be scaled up for commercial use.

Assuntos

Nanopartículas , Água , Tamanho da Partícula , Água/química , Dapsona , Solubilidade , Disponibilidade Biológica , Nanopartículas/química , Difração de Raios X , Varredura Diferencial de Calorimetria

RESUMO

Tuberculosis (TB) is one of the top ten causes of death worldwide and a leading cause of death in HIV patients. Rifampicin (Rif), a low water-soluble drug, is a critical first-line treatment and the most effective drug substance for therapy of drug-susceptible TB. However, Rif has high interindividual pharmacokinetic variability, mainly due to its highly variable absorption caused by its poor solubility. Drug nanocrystals are a promising technology to overcome this variability by increasing the surface area. This strategy allows for increasing the dissolution rate and improving the bioavailability of this BCS class II drug. In this study, Rif nanocrystals were prepared by a wet-bead milling method. A 3-factor, 3-level Box-Behnken design was used to investigate the independent variables: the concentration of rifampicin, the concentration of the stabilizing agent (Povacoat® type F), and the mass of zirconia beads. Two optimized formulations, F1-Rif and F2-Rif, were characterized by determining their particle size and size distribution, morphology, crystal properties, and antimicrobial activity. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) revealed that rifampicin's polymorph II crystal structure was unchanged. The reduced particle size of <500 nm (100-fold decrease) increased the saturation solubility and dissolution rate up to 1.74-fold. The novel polymer, Povacoat®, demonstrated to be a suitable stabilizer to maintain the physical stability of nanosuspensions over two years. The Rif nanocrystals showed antimicrobial activity (0.25 µg/mL) not significantly different from standard rifampicin powder. However, the low cytotoxicity of the nanosuspensions in HepG2 cells was determined. When compared to the commercial product, the nanosuspension increased the rifampicin concentration 2-fold. In conclusion, the Rif nanosuspension allows half the needed volume of administration, which might increase compliance among children and elderly patients throughout the long-term treatment of TB.

Assuntos

Antibióticos Antituberculose/química , Nanopartículas/química , Rifampina/química , Antibióticos Antituberculose/farmacologia , Varredura Diferencial de Calorimetria , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura , Mycobacterium tuberculosis/efeitos dos fármacos , Tamanho da Partícula , Rifampina/farmacologia , Solubilidade , Viscosidade

RESUMO

Sodium alendronate is a nitrogen-containing bisphosphonate, widely used for osteoporosis treatment. However, due to its several oral administration drawbacks, the transdermal route represents an interesting option. The aim of this study was to formulate sodium alendronate in two submicron delivery systems, microemulsions, and solid-in-oil nanosuspensions, both systems possessing permeation enhancing properties. The composition of microemulsions was determined through the construction of pseudo-ternary phase diagrams. Solid-in-oil nanosuspensions were prepared by an emulsification-freeze-drying method, evaluating the effect of sonication time and the type of surfactant. According to the results of drug loading capacity, droplet/particle size, and polydispersity index, two microemulsions and two nanosuspensions were selected to perform the subsequent evaluations. The results showed that microemulsions allowed a faster release of alendronate than nanosuspensions. The permeation capacity of alendronate formulations was assessed through the synthetic membrane Strat M®, as well as through pigskin, finding higher fluxes with microemulsions than with nanosuspensions. In order to elucidate the effect of the formulations on the permeability barrier of the stratum corneum, techniques such as ATR-FTIR and TEWL were used. Finally, measurements of erythema intensity showed that neither of the two nanosystems caused skin irritation after 2 h of contact. The results suggest that alendronate formulated in a microemulsion can be a viable transdermal nanocarrier for osteoporosis treatment.

Assuntos

Alendronato/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Portadores de Fármacos , Excipientes/química , Nanopartículas , Administração Cutânea , Alendronato/química , Alendronato/metabolismo , Alendronato/toxicidade , Animais , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/metabolismo , Conservadores da Densidade Óssea/toxicidade , Composição de Medicamentos , Liberação Controlada de Fármacos , Emulsões , Eritema/induzido quimicamente , Excipientes/toxicidade , Cinética , Permeabilidade , Pele/metabolismo , Absorção Cutânea , Sus scrofa , Perda Insensível de Água

RESUMO

Purpose: Loratadine is used as antihistaminic without side effects in nervous systems. This drug is a weak base and it is absorbed from the intestine. The nitrogen of the pyridine ring is protonated in the stomach affecting the oral bioavailability. The aim of this paper was obtaining, characterize and evaluate the release profiles and the stability of a gastroresistant loratadine nanosuspension. Methods: The nanosuspension was prepared by the solvent displacement evaporation method, using three different polymers (Eudragit® L 100 55, Kollicoat® MAE 100P and PEG 4000) and Polysorbate 80. Dynamic Light Scattering was used for evaluating the particle size (PS), zeta potential, and conductivity of the nanosuspension. Loratadine release profiles were evaluated in simulated gastrointestinal fluids. The shelf and accelerated stability were assessed during three months. Results: Nanosuspension particle size was 45.94 ± 0.50 nm, with a low polydispersion index (PdI, 0.300). Kollicoat® MAE 100P produced a hard and flexible coating layer. In simulated intestinal fluids, the 100 percent of loratadine was released in 40 min, while in simulated stomach fluids the release was lesser than 5%. Nanosuspension presented a good physicochemical stability showing a reduction in PS and PdI after three months (43.29 ± 0.16 and 0.250; respectively). Conclusions: A promissory loratadine nanosuspension for loratadine intestinal delivery was obtained, by using a low energy method, which is an advantage for a possible scale up for practical purpose.

RESUMO

This study investigated the effects of nanosuspension and inclusion complex techniques on in vitro trypsin inhibitory activity of naproxen—a member of the propionic acid derivatives, which are a group of antipyretic, analgesic, and non-steroidal anti-inflammatory drugs. Nanosuspension and inclusion complex techniques were used to increase the solubility and anti-inflammatory efficacy of naproxen. The evaporative precipitation into aqueous solution (EPAS) technique and the kneading methods were used to prepare the nanosuspension and inclusion complex of naproxen, respectively. We also used an in vitro protease inhibitory assay to investigate the anti-inflammatory effect of modified naproxen formulations. Physiochemical properties of modified naproxen formulations were analyzed using UV, IR spectra, and solubility studies. Beta-cyclodextrin inclusion complex of naproxen was found to have a lower percentage of antitryptic activity than a pure nanosuspension of naproxen did. In conclusion, nanosuspension of naproxen has a greater anti-inflammatory effect than the other two tested formulations. This is because the nanosuspension formulation reduces the particle size of naproxen. Based on these results, the antitryptic activity of naproxen nanosuspension was noteworthy; therefore, this formulation can be used for the management of inflammatory disorders.

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O objetivo do presente estudo foi investigar a atividade anti-inflamatória in vitro de nanossuspensões e do complexo de inclusão contendo naproxeno. Esse fármaco é derivado de ácido propiônico, com ação analgésica, antipirética e antiinflamatória. A obtenção dessas formulações teve por finalidade o aumento da solubilidade e da atividade anti-inflamatória do fármaco. Os métodos por precipitação em solução aquosa por evaporação e por empastagem foram modificados para a obtenção da nanossuspensão e do complexo de inclusão, respectivamente. Para a avaliação da atividade anti-inflamatória das formulações utilizou-se ensaio in vitro modificado de inibição de tripsina. As propriedades físico-químicas das formulações propostas foram determinadas utilizando espectroscopia UV e de infravermelho, além de estudos de solubilidade. O complexo de inclusão de naproxeno apresentou menor atividade antitripsina, quando comparado ao composto livre e à nanossuspensão. Em conclusão, entre as formulações avaliadas, a nanossuspensão de naproxeno apresentou maior efeito anti-inflamatório. Esse efeito foi devido à redução da dimensão das partículas de naproxeno para a escala nanométrica. Com base nos resultados obtidos, a atividade da nanossuspensão de naproxeno foi notável. Dessa forma, essa formulação apresenta potencial para o tratamento de distúrbios inflamatórios.

Assuntos

Inibidores de Proteases/farmacocinética , Naproxeno/farmacocinética , Solubilidade/efeitos dos fármacos , Excipientes/farmacocinética

RESUMO

The present study was performed to design and evaluate the famotidine loaded mucoadhesive nanosuspension for aspirin induced ulcer. A 3-factor, 3-level Box-Behnken design was applied to study the effects of amount of the beads (X1), PVPK-30(X2) and Tween-80 (X3) on the particle size (Y1), and cumulative percentage drug released after 1h (Y2). The optimization was performed using the desirability function and contour plots. The scanning electron microscopy (SEM) showed the nanoparticles as spherical in shape. The differential scanning calorimetry (DSC) analysis indicated that there was substantial crystallinity change in the nanoparticle compared with the pure drug. Ex-vivo mucoadhesion study showed that famotidine mucoadhesive nanoparticles possessed higher mucoadhesion than the famotidine nanoparticles. The in vivo studies on aspirin-induced rats indicated the lowering in ulcer index for famotidine mucoadhesive nanoparticles was 0.46+0.011, which was significantly better than the effect of traditional famotidine suspension (0.66+0.035). Famotidine mucoadhesive nanosuspension could be prepared using the media milling technique and allowing significant reduction in ulcer index compared to famotidine suspension.