Letícia Cruz

Alkaline Hydrolysis as a Tool to Determine the Association form of Indomethacin in Nanocapsules Prepared with Poly(ε-Caprolactone)

To determine the association form of indomethacin in nanocapsules prepared with poly(eta-caprolactone) as polymer and a triglyceride as oil, two methods were studied. The indomethacin ethyl ester was prepared as control, which showed a higher affinity for the oil than the indomethacin. Two differently loaded nanocapsule formulations were prepared. For both formulations, a burst effect was detected using ethanol as release medium. Light scattering (PCS) and NMR analyses suggested the ethanol diffuses through the nanocapsule polymeric wall promoting the total release of indomethacin and its ester. The results showed the inability of this approach to determine the association form of indomethacin. On the other hand, the alkaline hydrolysis of indomethacin and its ester, followed by their disappearance (HPLC), were evaluated. The nanocapsule suspensions containing indomethacin or its ester were treated with 50 mM NaOH. The total disappearance of indomethacin associated with nanocapsules was determined after 2 min, whereas the ester associated with colloids was consumed during 24 h. The constant particle sizes (264 and 259 nm) during the hydrolysis reactions showed that neither the nanocapsules were dissolved nor the polymer sorbed water during the contact with NaOH aqueous solution. The ester rate hydrolysis was determined by its diffusion from the nanocapsules to the interface particle/water. Finally, the indomethacin association model considers the burst release of drug after the addition of NaOH by the formation of its carboxylate, followed by its hydrolysis in aqueous solution promoted by the excess of NaOH. The adsorption was the mechanism of indomethacin association with nanocapsules.

Formulation and in vivo evaluation of sodium alendronate spray-dried microparticles intended for lung delivery.

Spray-dried powders for lung delivery of sodium alendronate (SA) were prepared from hydroalcoholic solutions. Formulations display geometric particle size below to 12 μm and spherical shape associated to a hollow structure. The addition of leucine and ammonium bicarbonate leads to porous particles with rough surfaces. The tapped density ranges from 0.016 to 0.062 g/cm(3), decreasing with the increase of the leucine concentration. For all formulations, the calculated aerodynamic diameters are lower than 5 μm. The in vitro aerodynamic evaluation shows that all powders present a high emitted fraction of 100%, a fine particle fraction ranging from 34.4% to 62.0% and an alveolar fraction ranging from to 23.7% to 42.6%. An optimized sample was evaluated regarding sodium alendronate acute pulmonary toxicity and lung bioavailability. The bronchoalveolar lavage study shows that the intratracheal administration of sodium alendronate dry powder and sodium alendronate aqueous solution do not induce significant increases of lung toxicity indicators as compared with the positive control. Moreover, the intratracheal administration of sodium alendronate dry powder results in a 6.23 ± 0.83% bioavailability, a 3.5-fold increase as compared to oral bioavailability. Finally, these results suggest that sodium alendronate pulmonary delivery could be a new and promising administration route.

Determining the simultaneous presence of drug nanocrystals in drug-loaded polymeric nanocapsule aqueous suspensions: A relation between light scattering and drug content

The encapsulation of lipophilic drugs in polymeric nanoparticles can form simultaneously both polymeric nanoparticles and drug nanocrystals. The objective was to detect the presence of nanocrystals in the nanoparticle suspensions using a simple methodology, and to determine if the nanocrystals are formed during preparation or by drug leakage from the particles during storage. Indomethacin was chosen as drug model. Unloaded and drug-loaded (1mg/mL) nanocapsules showed diameters close to 280nm and polydispersity lower than 0.20, remaining constant after 120 days. Comparing indomethacin loaded (3mg/mL) and unloaded formulations, variations in the scattered light depolarization degree indicated the simultaneous presence of nanocrystals and nanocapsules in the suspensions. A relation between the scattered light intensities and the drug precipitation was established. As a function of time, when the decrease in the Rayleigh ratios occurred, the drug contents decreased due to precipitation. On the other hand, when the Rayleigh ratios slightly increase, the drug contents are constant. The nanocrystals formed in the oversaturated formulations, agglomerate and precipitate during storage. When the drug is adsorbed on the nanocapsules, but the system is not oversaturated, no nanocrystal was formed and the formulation is physico-chemically stable at least for 150 days of storage.

Gastroresistant microparticles containing sodium alendronate prevent the bone loss in ovariectomized rats.

Sodium alendronate, an antiresorptive drug, primarily used in the treatment of osteoporosis was encapsulated in blended microparticles composed of Eudragit S100 and Methocel K15M. The micropowder obtained by spray-drying technique was characterized in terms of its morphology, particle size, encapsulation efficiency and in vitro drug release. In vivo studies were carried out in order to evaluate the pharmacodynamic effect and the ulcerogenic activity of sodium alendronate-loaded microparticles after oral administration in rats. Drug encapsulation efficiency was close to 80% and particle mean diameter of 13.8 microm. SEM analysis showed spherical collapsed shape particles with smooth surface. At pH 1.2, in vitro experiments showed that <10% of the drug was released from the microparticles. At pH 6.8, the microparticles were able to prolong the sodium alendronate release for 12h. In vivo experiments carried out in ovariectomized rats showed bone mineral density significantly higher for the sodium alendronate-loaded microparticles than for the negative control groups. Furthermore, the microencapsulation of the drug showed a significant reduction in the ulcerative lesion index. In conclusion, the blended microparticles are excellent oral carriers for sodium alendronate since they were able to maintain the drug antiresorptive effect and to reduce the gastrointestinal drug toxicity.

HIGH ENCAPSULATION EFFICIENCY OF SODIUM ALENDRONATE IN EUDRAGIT S100/HPMC BLEND MICROPARTICLES

The hydrophilic drug sodium alendronate was encapsulated in blended microparticles of Eudragit® S100 and Methocel® F4M or Methocel® K100LV. Both formulations prepared by spray-drying showed spherical collapsed shape and smooth surface, encapsulation efficiencies of 85 and 82% and mean diameters of 11.7 and 8.4 µm, respectively. At pH 1.2, in vitro dissolution studies showed good gastro-resistance for both formulations. At pH 6.8, the sodium alendronate release from the microparticles was delayed and was controlled by Fickian diffusion. In conclusion, the prepared microparticles showed high encapsulation efficiency of sodium alendronate presenting gastro-resistance and sustained release suitable for its oral administration.

Microencapsulation of sodium alendronate reduces drug mucosal damage in rats

Sodium alendronate is an effective treatment for osteoporosis, but its oral administration is associated with adverse gastrointestinal effects. The aim of this work was to evaluate gastroresistant sodium alendronate-loaded microparticles prepared by spray-drying using Eudragit® S100 or a blend of Eudragit® S100/Methocel® E4M. Both formulations presented high encapsulation efficiencies, mean diameters below 17 μm, and similar collapsed shape. Dissolution experiments showed good gastro-resistance for the microparticles at pH 1.2. At pH 6.8, the blended microparticles retarded the drug release. In vivo studies showed that the formulations were able to protect the rat stomachs against ulcer formation by sodium alendronate. In conclusion, the microparticles seems to be promising oral carriers for sodium alendronate.

Structural model of polymeric nanospheres containing indomethacin ethyl ester and in vivo antiedematogenic activity

The aim of this work was to establish a structural model for describing the organisation, at a molecular level, of nanospheres prepared by nanoprecipitation using poly(e-caprolactone), sorbitan monostearate and polysorbate 80. Therefore, different techniques were employed to characterise the systems such as dynamic and static light scattering, small angle X-ray scattering and release profile evaluations. The indomethacin ethyl ester that is insoluble in water and presents in vitro anti-inflammatory activity was encapsulated in the nanospheres. Furthermore, the antiedematogenic activity has been studied in rats. The unloaded and loaded nanosphere suspensions presented particle diameters of 186 nm and 208 nm, polydispersity lower than 0.2, ζ-potentials of ?40.7 mV and ?45.3 mV and pH 5.0 and 5.2, respectively. The depolarisation ratio showed constant values that were lower than 0.015 indicating that nanospheres in suspensions are isotropic, then being considered spherically shaped. SAXS analyses showed a partial organisation of the sorbitan monostearate and no peak relative to the crystallinity of the polymer, suggesting that this surfactant is retained in the polymer matrix of nanospheres. The structural organisation, at a molecular level, of those nanospheres corresponds to particles in which aggregates of sorbitan monostearate are stabilised by the polymeric chains. Additionally, the indomethacin ethyl ester-loaded nanospheres presented antiedematogenic activity after oral administration in rats, indicating that even though the ester is insoluble in gastric or intestinal media, those nanospheres were able to deliver it for a pharmacological response.

Influence of Harvest Season and Cultivar on the Variation of Phenolic Compounds Composition and Antioxidant Properties in Vaccinium ashei Leaves

The effect of variation of harvest season and cultivar on the total phenolic content (TPC), total flavonoid content (TFC), HPLC-UV/DAD profile and antioxidant properties in Vaccinium ashei (Rabbiteye blueberry) leaves grown in Brazil was evaluated. The cultivars collected in December and March were Aliceblue, Powderblue, Climax, Bluegem and FloridaM. It was observed that leaves from March had the highest TPC values (222 ± 1 mg gallic acid equivalents/g to Aliceblue cultivar) and highest TFC values (49.8 ± 0.8 and 48.7 ± 0.7 µg rutin/g to Clímax and Powderblue cultivars, respectively). The chromatographic profile was quantitatively similar, however, the proportions of each compound were influenced by cultivar and harvest season. Chlorogenic acid and rutin were the main identified phenolic compounds, but chlorogenic acid was the most abundant in both harvest seasons. Antioxidant capacities values ranged from 5.80 ± 0.04 to 105 ± 2 µg/mL (DPPH) and 178 ± 5 to 431 ± 8 mmol Trolox/100 g (ORAC). The cultivar Bluegem by March had the highest values in both assays. The results indicate that the blueberry leaves from different cultivars and harvest seasons have different phenolic compounds content and different antioxidant capacities. In addition, the antioxidant properties demonstrated a high correlation with rutin content.

Anti-inflammatory action of seed extract and polymeric nanoparticles of Syzygium cumini in diabetic rats infected with Candida albicans

1 Departamento de Análises Clínicas e Toxicológicas, Centro de Ciências da Saúde, Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil. 2 Departamento de Farmácia Industrial, Centro de Ciências da Saúde, Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal de Santa Maria, Santa Maria, Brazil. 3 Departamento de Microbiologia, Centro de Ciências da Saúde, Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal de Santa Maria, Santa Maria, Brazil. 4 Universidade Luterana do Brasil, Santa Maria, Brazil. 5 Programa de Pós-Graduação em Ciências Biológicas: Farmacologia e Terapêutica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Diphenyl diselenide loaded poly(ε-caprolactone) nanocapsules with selective antimelanoma activity: Development and cytotoxic evaluation

Please cite this article as: Luana Mota Ferreira, Verônica Ferrari Cervi, Marcel Henrique Marcondes Sari, Allanna Valentini Barbieri, Andiara Prates Ramos, Priscila Marquezan Copetti, Gerson Fernandes de Brum, Kátia Nascimento, Jessica Mendes Nadal, Paulo Vitor Farago, Michele Rorato Sagrillo, Cristina Wayne Nogueira, Letícia Cruz , Diphenyl diselenide loaded poly(ε-caprolactone) nanocapsules with selective antimelanoma activity: Development and cytotoxic evaluation. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Msc(2017), doi:10.1016/j.msec.2018.05.014