Pharmaceutical development of tablets containing a spray-dried optimized extract from Lippia origanoides H. B. K.: influence of excipients and toxicological assessment

ABSTRACT Lippia origanoides is a honey shrub which has showed hypotensive potential assessed by in vivo studies. The aim of this work is the development of a pharmaceutical formulation composed by an optimized extract obtained from aerial parts of L. origanoides. The quantification of the naringenin marker in the dry extract and tablets developed was performed, as well as the assessment of the oral acute toxicity in rats. The hydroalcoholic extract of L. origanoides was spray-dried with the addition of colloidal silicon dioxide (Lo-HAE/CSD), and then applied in the preparation of eight different lots of tablets. The influence of the diluent (cellulose or babassu mesocarp), the presence of binder, and the percentage of lubricant, as well as organoleptic and physicochemical characteristics were screened. For the quantification of the marker content both in Lo-HAE/CSD and in the tablets, an analytical curve of the naringenin standard was fitted, and the samples were then analyzed in UFLC. The toxicological assessment was performed in female Wistar rats according to the Acute Toxic Class Method from OECD. The developed tablets produced meet acceptable macroscopic characteristics, and the presence of babassu as diluent provided improved physicochemical properties. The best content of Lo-HAE/CSD in the tablet (100.27%) was identified for the lot containing babassu, composed by 1.0% magnesium stearate, without PVP binder in its formulation. Moreover, Lo-HAE/CSD showed no signs of toxicity. Therefore, the babassu mesocarp powder is a promising pharmaceutical excipient for the development of herbal tablets containing the Lippia origanoides extract.

Avaliação dos processos de mistura de pós em farmácias magistrais utilizando planejamento fatorial: caso clonidina / Assessment of powder mixing processes in pharmacies by factorial planning: clonidine case study

O cloridrato de clonidina é um α2-adrenérgico que reduz a pressão sanguínea e retarda a estimulação cardíaca simpaticomimética. Esse fármaco é uma substância de baixo índice terapêutico que possui alta potência, sendo utilizado em baixas concentrações. Pode ser preparado em farmácias magistrais, seguindo-se rigorosos critérios de Boas Práticas de Manipulação estipulados pela Anvisa. Esse controle surgiu em razão de diversos acidentes possivelmente associados ao uso de cloridrato de clonidina manipulado. Diante disso, o objetivo deste trabalho foi avaliar o processo de mistura de pós na manipulação magistral da clonidina, buscando segurança e reprodutibilidade no referido processo. Para tanto, foram produzidas 60 cápsulas de cada lote, seguindo o planejamento fatorial 2³, em que foram estabelecidas as seguintes variáveis de entrada: processo de mistura (diluição geométrica e misturador Mixer Plus®), tamanho do invólucro gelatinoso (n°03 e 02) e concentração do fármaco (0,1 e 0,2 mg). A variável resposta para o planejamento foi o teor do fármaco nas cápsulas. Além disso, foram verificados outros parâmetros de qualidade, como o peso médio e uniformidade de conteúdo. As cápsulas obtidas encontraram-se dentro dos limites especificados pelos compêndios oficiais. Por isso, os resultados sinalizam que apesar do processo de obtenção das cápsulas ser crítico é possível obter produtos com qualidade e segurança comprovada...

Clonidine hydrochloride is an α2-adrenergic agonist that reduces the blood pressure and delays cardiac sympathomimetic stimulation. This drug has a low therapeutic index, high potency and is commonly used at low concentrations. It can be prepared at compounding pharmacies, as long as the rigorous criteria of Good Handling Practices stipulated by Anvisa are followed. This control had its origins in several accidents possibly associated with the use of compounded clonidine hydrochloride. In this context, the present study was designed to assess the powder-mixing process during the compounding of clonidine, so as to optimize its safety and repeatability. To this end, 60 capsules were produced in each batch, following 23 factorial planning, using the following input variables: mixing process (geometric dilution or Mixer Plus®), size of gelatin shell(number 03 or 02) and drug concentration (0.1 and 0.2mg). The response variable for the planning was the amount of drug inside the capsules. In addition, other quality parameters were determined, such as the average weight and content uniformity. The capsules produced were within the limits specified by official compendia. Therefore, the results indicate that, although the process of compounding capsules is critical, it is possible to have products with assured quality and safety...

Modulation of antimicrobial metabolites production by the fungus Aspergillus parasiticus

Biosynthesis of active secondary metabolites by fungi occurs as a specific response to the different growing environments. Changes in this environment alter the chemical and biological profiles leading to metabolites diversification and consequently to novel pharmacological applications. In this work, it was studied the influence of three parameters (fermentation length, medium composition and aeration) in the biosyntheses of antimicrobial metabolites by the fungus Aspergillus parasiticus in 10 distinct fermentation periods. Metabolism modulation in two culturing media, CYA and YES was evaluated by a 2² full factorial planning (ANOVA) and on a 2³ factorial planning, role of aeration, medium composition and carbohydrate concentration were also evaluated. In overall, 120 different extracts were prepared, their HPLC profiles were obtained and the antimicrobial activity against A. flavus, C. albicans, E. coli and S. aureus of all extracts was evaluated by microdilution bioassay. Yield of kojic acid, a fine chemical produced by the fungus A. parasiticus was determined in all extracts. Statistical analyses pointed thirteen conditions able to modulate the production of bioactive metabolites by A. parasiticus. Effect of carbon source in metabolites diversification was significant as shown by the changes in the HPLC profiles of the extracts. Most of the extracts presented inhibition rates higher than that of kojic acid as for the extract obtained after 6 days of fermentation in YES medium under stirring. Kojic acid was not the only metabolite responsible for the activity since some highly active extracts showed to possess low amounts of this compound, as determined by HPLC.