Jacqueline de Souza

Modelos in vitro para determinação da absorção de fármacos e previsão da relação dissolução/absorção

Farmacos contidos em formas farmaceuticas solidas devem ter adequada solubilidade aquosa e permeabilidade intestinal para serem absorvidos apos administracao oral. A velocidade e a extensao com as quais um farmaco e absorvido podem variar devido as suas caracteristicas fisico-quimicas e fatores relacionados a desintegracao e dissolucao. Segundo o Sistema de Classificacao Biofarmaceutica (SCB), a dissolucao e a permeacao intestinal do farmaco podem limitar a absorcao e, consequentemente, a acao terapeutica. Este trabalho objetiva discutir dados da literatura referentes a previsao da relacao entre a dissolucao de farmacos e sua absorcao empregando sistemas in vitro. Para avaliar a permeacao in vitro sao discutidos modelos com tecidos e segmentos intestinais, vesiculas extraidas de membranas e cultura de celulas. Na literatura existem estudos de permeabilidade utilizando celulas Caco-2, TC-7, 2/4/A1, MDCK e MDCK-MDR1. As celulas Caco-2 sao extraidas de adenocarcinoma de colon humano que, em cultura celular, se diferenciam em enterocitos, podendo ser acopladas a sistemas de dissolucao. Estas tecnicas representam importante ferramenta para estudos de dissolucao/permeacao, porem, ainda sao limitadas e nao conseguem reproduzir adequadamente os mecanismos de transporte ativo.

Caracterização físico-química do fármaco antichagásico benznidazol

Currently, benznidazole (BNZ) is a unique therapeutic alternative available in Brazil to treat Chagas disease. Despite its traditional medical use, little is known about the chemical nature of this drug. A detailed study of the physicochemical properties of BNZ was performed using multiple assays. Thermal, diffractometric, morphological and reological drug profiles were obtained. The partition coefficient and solubility results allowed this drug to be classified as a class IV drug according to the biopharmaceutical classification system. This information will be useful for the development of more effective BNZ formulations and for establishing the quality profile of BNZ.

HPLC–DAD and UV–Spectrophotometry for the Determination of Lychnopholide in Nanocapsule Dosage Form: Validation and Application to Release Kinetic Study

Simple and sensitive methods using high-performance liquid chromatography-diode array detection (HPLC-DAD) and ultraviolet (UV)-spectrophotometry were developed and compared to quantify lychnopholide (LYC) in poly-ε-caprolactone nanocapsules and to study its release kinetics. Both methods were validated concerning their specificity, linearity, limits of detection and quantification, precision, accuracy and stability. HPLC-DAD analyses were conducted using an RP C18 column, isocratic elution with a methanol-water (60:40 v/v) mobile phase at 0.8 mL/min flow rate and detection at 265 nm. The linear response (r(2) > 0.999) was obtained within a concentration range of 2-25 µg/mL using HPLC-DAD and 5-40 µg/mL using spectrophotometry. Intra-day and inter-day precision were obtained with low relative standard deviation values. The accuracy of the methods was within the range 98-101% for HPLC-DAD and from 96-100% for UV-spectrophotometry. Both methods were suitable to be applied for the determination of drug loading percentage (>96%) and encapsulation efficiency (>90%). Furthermore, the sensitivity of HPLC-DAD method allows studies of LYC release/dissolution in sink conditions. LYC presented 100% dissolution after 24 h, whereas only 60% of LYC was released from the nanocapsule dosage form, with no burst effect. The methods fulfilled all validation parameters evaluated for LYC quantification in the polymeric nanocapsules and have proven to be accurate, selective and sensitive in the previously mentioned applications.

Medicamentos genéricos no Brasil: panorama histórico e legislação

The Brazilian generic drugs policy was implemented in 1999 with the aim of stimulating competition in the market, improve the quality of drugs and improve the access of the population to drug treatment. The process of implementing this policy allowed the introduction and discussion of concepts that had never before been used in the context of drug registration in Brazil: bioavailability, bioequivalence, pharmaceutical equivalence, generic drugs, biopharmaceutical classification system, biowaiver. The present article provides definitions for these concepts in the context of Brazilian legislation as well as a historical and chronological description of the implementation of the generic drugs policy in Brazil, including a list of current generic drug legislation. This article contributes to the understanding of the Brazilian generic drugs policy and facilitates the search for information concerning the legal requirements for registration of drugs in Brazil.

Atividade anti-retroviral e propriedades farmacocinéticas da associação entre lamivudina e zidovudina

Lamivudine (3TC) and zidovudine (ZDV) are antiretroviral drugs used in the treatment of HIV infection. They are nucleoside analogues that inhibit HIV-1 reverse transcriptase. These drugs are anabolized intracellularly by a stepwise process and form an active triphosphate anabolite, which is used by HIV-1 reverse transcriptase and effectively terminates chain extension. The use of monotherapy is associated with a delay in the emergence of resistant mutants. The combination therapy would therefore seem to be potentially useful for rapid reduction in virus load. Adverse events were similar in both regimen, with the exception of lower incidence of anemia when used only 3TC. Both drugs are rapidly absorbed by passive diffusion through the intestinal wall. They are distributed into total body fluid and have a good bioavailability. They diffuse freely across the placenta from the maternal circulation to the fetal circulation. The glucuronidation is the main pathway of ZDV metabolism. About 60 to 70% of the drug undergoes biotransformation. The ZDV has a short elimination half-life from 1 to 1.5 hour. The 3TC is primarily eliminated unchanged through by renal excretion. A pharmacologically inactive trans-sulphoxide metabolite has been determined and corresponds to 5% to 10% of 3TC dose. The terminal elimination half-life of 3TC was from 8.5 to 11.5 hours.

Biopharmaceutics classification system: importance and inclusion in biowaiver guidance

O tratamento farmacologico e essencial frente a varias patologias e e fundamental que a politica de medicamentos tenha por objetivo oferecer a populacao tratamento seguro, eficaz e de preco acessivel. Uma forma de alcancar esse objetivo e por meio da bioisencao, definida como a substituicao de estudos de bioequivalencia in vivo por estudos in vitro. Para bioisentar novos medicamentos sob a forma farmaceutica solida oral de liberacao imediata sao utilizados dados de permeabilidade intestinal e solubilidade do farmaco, bem como sua dissolucao a partir da forma farmaceutica. O Sistema de Classificacao Biofarmaceutica (SCB) e um esquema cientifico que divide os farmacos em classes de acordo com a solubilidade e permeabilidade e vem sendo utilizado como criterio para bioisencao em diversas legislacoes. O presente artigo faz uma avaliacao da aplicacao da bioisencao, abordando os conceitos gerais e parâmetros utilizados pelo SCB, fazendo um relato historico da aplicacao da bioisencao, das exigencias pertinentes as legislacoes vigentes, dos beneficios e riscos inerentes a uma tomada de decisao sobre bioisencao baseada neste criterio. Os resultados revelaram que a utilizacao do SCB como criterio amplia enormemente as possibilidades de bioisencao, contribuindo para o maior acesso da populacao em geral a medicamentos com garantida eficacia, seguranca e menor custo.

Folic acid: a biopharmaceutical evaluation

Abstract The aqueous solubility and drug product dissolution are important factors that determine the rate and extent of drug absorption from immediate release solid oral dosage forms. The aim of this article was to perform a folic acid biopharmaceutical study to evaluate the biowaiver of new products containing folic acid. We studied the solubility of its raw material and the dissolution profile of two commercially available products. Three different buffers (pH 1.2, 4.5 and 6.8) were used as the media of the solubility and dissolution tests (apparatus II, at 50 rpm and 900 mL of medium volume). We found that folic acid solubility and its release from tablets are pH dependent. The dissolution profiles of both tablets were compared by dissolution efficiency (%), using t-test or variance analysis (ANOVA). The dissolution profiles obtained for the two products at pH 1.2 medium were similar (p > 0.05), but they were dissimilar at pH 4.5 and 6.8 (p < 0.05). Furthermore, we could observe differences between all the dissolution profiles of folic acid for each product at three different dissolution media used. The results showed that physicochemical characteristics of folic acid affect its dissolution and absorption making it difficult to take a decision on their biowaiver based on BCS.

Development and characterization of multilamellar liposomes containing pyridostigmine

Abstract Pyridostigmine has cardioprotective activity in both free and liposomal forms. This study aimed to develop and characterize liposomal formulations of pyridostigmine. For this, a spectrophotometric ultraviolet (UV) analytical method, at 270 nm, was developed and validated to quantify liposomal pyridostigmine. The method was linear in ranges from 0.02 to 0.09 mg/mL. The accuracy of this method was determined intra- and inter-day; the results of coefficient of variation were of 1.73–2.72% and 0.32–2.32%, respectively. The accuracy ranged between 99.45% and 101.12%. The method has not changed by influence of liposomal matrix and demonstrated being able to quantify pyridostigmine in liposomes. Two liposomal multilamellar formulations were developed: a constituted by dystearoyl-phosphatidylcholine (DSPC) and cholesterol (CHOL) other by dioleil-phosphatidylcholine (DOPC) and CHOL. The encapsulation efficiency was determined as 23.4% and 15.4%, respectively. Analyses of size and release of pyridostigmine from the formulations were made and the results showed that the formulations are viable for future studies in vivo.

The influence of seasonality on the content of goyazensolide and on anti-inflammatory and anti-hyperuricemic effects of the ethanolic extract of Lychnophora passerina (Brazilian arnica)

ETHNOPHARMACOLOGICAL RELEVANCE Lychnophora passerina (Mart ex DC) Gardn (Asteraceae), popularly known as Brazilian arnica, is used in Brazilian folk medicine to treat pain, rheumatism, bruises, inflammatory diseases and insect bites. AIM OF THE STUDY Investigate the influence of the seasons on the anti-inflammatory and anti-hyperuricemic activities of ethanolic extract of L. passerina and the ratio of the goyazensolide content, main chemical constituent of the ethanolic extract, with these activities. MATERIALS AND METHODS Ethanolic extracts of aerial parts of L. passerina were obtained from seasons: summer (ES), autumn (EA), winter (EW) and spring (EP). The sesquiterpene lactone goyazensolide, major metabolite, was quantified in ES, EA, EW and EP by a developed and validated HPLC-DAD method. The in vivo anti-hyperuricemic and anti-inflammatory effects of the ethanolic extracts from L. passerina and goyazensolide were assayed on experimental model of oxonate-induced hyperuricemia in mice, liver xanthine oxidase (XOD) inhibition and on carrageenan-induced paw edema in mice. RESULTS HPLC method using aqueous solution of acetic acid 0.01% (v/v) and acetonitrile with acetic acid 0.01% (v/v) as a mobile phase in a gradient system, with coumarin as an internal standard and DAD detection at 270nm was developed. The validation parameters showed linearity in a range within 10.0-150.0µg/ml, with intraday and interday precisions a range of 0.61-3.82. The accuracy values of intraday and interday analysis within 87.58-100.95%. EA showed the highest goyazensolide content. From the third to the sixth hour after injection of carrageenan, treatments with all extracts at the dose of 125mg/kg were able to reduce edema. Goyazensolide (10mg/kg) showed significant reduction of paw swelling from the second hour assay. This sesquiterpene lactone was more active than extracts and presented similar effect to indomethacin. Treatments with ES, EA and EP (125mg/kg) and goyazensolide (10mg/kg) reduced serum urate levels compared to hyperuricemic control group and were able to inhibit liver XOD activity. One of the mechanisms by which ES, EA, EP and goyazensolide exercise their anti-hyperuricemic effect is by the inhibition of liver XOD activity. Goyazensolide was identified as the main compound present in ES, EA, EW and EP and it is shown to be one of the chemical constituents responsible for the anti-inflammatory and anti-hyperuricemic effects of the ethanolic extracts. CONCLUSION The anti-inflammatory and anti-hyperuricemic activities of the ethanolic extracts from L. passerina were not proportionally influenced by the variation of goyazensolide content throughout the seasons. The involvement of goyazensolide on in vivo anti-inflammatory and anti-hyperuricemic activities of L.passerina extracts was confirmed, as well as the possibility of participation of other constituents on these effects. This study demonstrated that the aerial parts of L. passerina may be collected in any season for use as anti-inflammatory agent. For use in hyperuricemia, the best seasons for the collection are summer, autumn and spring. The ethanolic extract of L. passerina and goyazensolide can be considered promising agents in the therapeutic of inflammation, hyperuricemia and gout.

Evaluation of the losartan solubility in the biowaiver context by shake-flask method and intrinsic dissolution

Abstract This study aimed at evaluating the shake-flask use as a universal method to evaluate drug solubility in a biowaiver context as proposed by FDA, EMA and ANVISA. The solubility of losartan was determined in three buffers using the shake-flask method, intrinsic dissolution (ID) and Quantum Chemistry. Moreover, the evaluation of a losartan dissolution profile from coated tablets was conducted. The losartan low solubility in pH 1.2 and high solubility in pH 6.8 were observed using the shake-flask method. However, the solubility results using ID demonstrated its high solubility in pH 1.2 and 6.8. It was not possible to find conclusive results regarding the solubility of the drug in pH 4.5. The studies conducted by Quantum Chemistry provide molecular and electronic data that helped understand the losartan solvation in different pH values. Our experimental results defined that losartan can be classified as a low-solubility drug. In addition, this work shows that shake-flask cannot be a universal method of solubility studies in biowaiver context. Individual analysis will be necessary. The intrinsic dissolution should be considered as a complementary method.