Preparation of pellets containing Pothomorphe umbellata extracts by extrusion-spheronization: improvement of 4-nerolidylcatechol photostability

Pothomorphe umbellata (L.) Miq., Piperaceae, has been extensively used in Brazilian folk medicine and it is well known for its strong antioxidant properties. However, its main active constituent, 4-nerolydilcatechol (4-NC), is sensitive to ultraviolet and visible light, which can limit the use of intermediate and final herbal preparations of this species. In the present work, coated multiparticulate solid dosage forms of P. umbellata were obtained with the purpose of increasing the stability of 4-NC. P. umbellata extract was used as a wetting liquid for the preparation of pellets by extrusion-spheronization. Pellets were coated in a fluidized bed by three different polymers (hydroxypropylmethylcellulose (HPMC), polyvynilpirrolidone K-30 (PVP-K30), and polyvinyl alcohol-polyethylene glycol graft-copolymer (PVAPEG)). 4-NC photostability was evaluated by an accelerated photostability protocol. Pellets showed a narrow size distribution and low friability. 4-NC photodegradation followed a second order degradation kinetics with similar k values for the percolate, uncoated pellets and HPMC coated pellets. Photoprotection was higher in pellets coated with PVP-K30 and PVA-PEG. PVA-PEG coated pellets with 6 and 9% weight gain resulted in a final concentration of 4-NC approximately cinco times higher than uncoated pellets or liquid extracts, suggesting the potential of this formulation as a multiparticulate solid dosage form for P. umbellata extracts.

Development and characterization of PLGA nanocapsules of grandisin isolated from Virola surinamensis: in vitro release and cytotoxicity studies

The most studied phyto constituent isolated from Virola surinamensis (Rol. ex Rottb.) Warb., Myristicaceae, is the tetrahydrofuran neolignan grandisin, which exhibits a series of biological activities, including trypanocidal, larvicidal and antitumoral. Due to its extremely low solubility, additional studies, including in vivo investigations are challenged by the difficulties in the development of an effective drug delivery system for grandisin. The encapsulation in polymeric nanoparticles is a very attractive alternative for overcoming some of these limitations. In this work, PLGA nanocapsules loaded with grandisin were developed in an attempt to optimize the efficacy of grandisin as an antitumoral drug, with high drug loading and efficiency, prolonged drug release and increased physical-chemical stability. Mean diameter of the nanocapsules was lower than 200 nm, with very low polydispersity. Encapsulation efficiency was above 90%. A sustained in vitro drug release was achieved for up to twenty days and cytotoxicity was markedly increased (IC50 for grandisin-NC and grandisin were 0.005 µM and 0.078 µM, respectively), indicating that polymeric nanocapsules are a potential drug delivery system for grandisin allowing the preparation of formulations viable for further in vivo studies.

Preparation and characterization of solid oral dosage forms containing soy isoflavones

Soy isoflavones have been extensively used for menopausal symptoms and prevention of hormone-related cancer, osteoporosis and cardiovascular diseases. Commercially available forms of isoflavones include supplements, capsules and tablets. However, the non-standardization of soy isoflavones extracts and different dissolution profiles of these solid dosage forms highlight the need of additional studies on the development of well characterized pharmaceutical dosage forms of isoflavones. In this work, immediate release oral tablets of soy isoflavones were obtained and evaluated. Genistein and daidzein, were the main constituents of the dried soy extract. Preparation of the tables was accomplished in a rotary tableting machine following either a dry mixture for direct compression or wet granulation with different excipients. Powder, granules and tablets were evaluated for several parameters, including flow properties, Carr and Hausner indexes, hardness, friability, disintegration time and drug release profile. Also, a fast and validated HPLC analytical method for both genistein and daidzein was developed. Formulations containing sodium croscarmellose and sodium dodecyl sulfate resulted in better flowability as indicated by the flow rate and angle of repose, faster disintegration time and immediate release dissolution profile.

Atividade citotóxica e antiangiogênica de Punica granatum L., Punicaceae / Cytotoxic and antiangiogenic activities of Punica granatum L., Punicaceae

Punica granatum L., Punicaceae, amplamente usada no Brasil, foi avaliada quanto ao seu potencial antitumoral in vitroe in vivo. Investigou-se in vitro a citotoxicidade do extrato etanólico do fruto e folha da P. granatumutilizando células K-562 e células do Tumor Ascítico de Ehrlich (TAE), pelos métodos de redução do MTT e exclusão do azul de tripano. Nos estudos in vivoavaliou-se o aumento da sobrevida de animais portadores do TAE e tratados, por via oral, com diferentes doses dos extratos etanólicos da P. granatum(12,5; 25; 50 e 100 mg/kg) por dez dias consecutivos. Além disso, nestes animais analisou-se o potencial de inibição tumoral e a atividade antiangiogênica da P. granatum. Os resultados dos estudos in vitrodemonstraram uma redução na viabilidade das células K-562 e do TAE, concentração-dependente, nos métodos investigados. Os resultados in vivo demonstraram aumento da sobrevida dos animais portadores do TAE tratados, de forma dose-dependente. Em paralelo, observou-se diminuição do número de células tumorais na cavidade peritoneal dos animais portadores e tratados. Além disto, os tratamentos empregados reduziram o padrão de vascularização da parede abdominal. Dessa forma, os dados apresentados revelaram que o extrato de P. granatumpossui atividade antitumoral in vitroe in vivo em paralelo a redução da angiogênese peritoneal.

Punica granatum L., a plant widely used in Brazil, was tested for its antitumor and antiangiogenic activities in vitroand in vivo. In this work, the in vitrocytotoxicity was evaluated using the K-562 cell line and Ehrlich ascites tumour cells, by MTT tetrazolium reduction test and the trypan blue exclusion test. In vivostudies investigated the increase in the survival time of Ehrlich tumour-bearing mice after treatment with different doses of Punica granatumL. ethanol extract (12.5; 25; 50 e and 100 mg/kg), by gavages, for ten consecutive days. In addition, we also investigated the tumour inhibition potential and antiangiogenic activity of this plant. In vitroresults demonstrated a decrease of K-562 and Ehrlich ascites tumour cells viability, with both methods used, in a dependent-manner concentration. In vivoresults showed a significant antitumor activity against Ehrlich ascites tumour growth, increasing survival time. In parallel, we detected a significant inhibition of the tumour growth, along with a decrease in the vascular pattern of the peritoneal wall. Thus, the data presented herein clearly showed that Punica granatum L. has antitumor and antiangiogenic activities.

Avaliação da toxicidade aguda e subaguda, em ratos, do extrato etanólico das folhas e do látex de Synadenium umbellatum Pax / Acute and subacute toxicity studies of the latex and of the ethanolic extract of the leaves of Synadenium umbellatum Pax in rats

O uso de plantas medicinais tem sido muito significativo nos últimos anos, sendo incentivado pela Organização Mundial de Saúde (OMS). Synadenium umbellatum Pax, Euphorbiacea (vulgo cola-nota, cancerola, milagrosa) tem o látex usado empiricamente como antitumoral e antiinflamatório. Por existir espécies tóxicas nesta família e visando à segurança no uso de extratos vegetais, tal estudo avaliou a toxicidade pré-clínica do látex e do extrato etanólico das folhas (EEF) de S. umbellatum, por via oral, em ratas Wistar. O estudo seguiu diretrizes do Guideline 423 (toxicidade aguda) e Guideline 407 (toxicidade subaguda) da OECD (Organisation for Economic Cooperation and Development). Na toxicidade aguda do látex e do EEF, não se observou letalidade nem alterações fisiológicas e comportamentais das ratas na dose de 2000 mg/kg, sendo praticamente atóxico. Porém, na análise histopatológica, o látex ocasionou congestão e infiltrado leucocitário nos rins, fígado e pulmões, efeitos não observados com o EEF. Na toxicidade subaguda, doses de 50, 100 e 200 mg/kg de EEF não produziram alterações dose-dependentes significativas nos parâmetros laboratoriais e fisiológicos, nem alterações macroscópicas e histopatológicas nos órgãos das ratas. Contudo, o uso crônico da planta S. umbellatum merece mais estudos.

The use of medicinal plants has been being very significant in the last years, being the use encouraged by WHO. Synadenium umbellatum Pax, Euphorbiacea (popularly known as cola-note, cancerola, miraculous) has the latex used empirically as anti-cancerous and anti-inflammatory. For there being toxic species in this family and aiming at the safety in the use of vegetable extracts, such study evaluated the pre-clinical toxicity of the latex and of the ethanolic extract of the leaves (EEL) of S. umbellatum, administrated by oral route, in Wistar female rats. The study followed OECD's Guidelines for test of acute toxicity (Guideline 423) and for subacute toxicity (Guideline 407). In the acute toxicity of latex and EEL, behavioral and physiological alterations were not observed neither animal's death in the dose level of 2,000 mg/kg. However, the latex caused congestion and leukocytes infiltration of the kidneys, liver and lungs, effects not observed with EEL. In the subacute toxicity, dose levels of 50, 100 and 200 mg/kg of EEL did not produced significant dose-dependent alterations in the lab results and no physiologic, macroscopic and hystopathological alterations. EEL of S. umbellatum is practically poisonless in acute exposure; already the latex can cause hystological damages. The chronic use of S. umbellatum needs more specific studies.