RESUMO
The pharmaceutical equivalence between test (generic or similar) and reference medicine is evaluated through in vitro quality tests involving multiple compliance parameters. Despite efforts to ensure the reliability of the analytical results obtained in the pharmaceutical equivalence studies, measurement uncertainties lead to a risk of false decisions. Thus, the aim of this work was to evaluate the measurement uncertainties associated with the analytical results obtained in the pharmaceutical equivalence studies of different pharmaceutical forms and to estimate the risks of false decisions in the evaluation of pharmaceutical equivalence. The measurement uncertainties associated with the test results were evaluated using the bottom-up and top-down approaches. The consumer's or producer's combined particular risks and combined total risks were estimated using the Monte Carlo method implemented in MS-Excel spreadsheet (available as supplemental material). Considering the seven pharmaceutical equivalence studies performed in this work, three studies were not conclusive (risk of false pharmaceutical equivalence decisions higher than 5 %). Moreover, we concluded pharmaceutical equivalence and pharmaceutical non-equivalence in one and three studies, respectively. The particular and total combined risks are useful to make decisions regarding the evaluation of pharmaceutical equivalence between the test (generic or similar) and reference medicines. Regulatory bodies and pharmaceutical equivalence centers are very interested in the estimation of the risks of false decisions, particularly to evaluate the quality of medicines that are not submitted to bioequivalence studies.
Assuntos
Medicamentos Genéricos , Método de Monte Carlo , Reprodutibilidade dos Testes , IncertezaRESUMO
O acesso a medicamentos pode ser facilitado por programas globais de desenvolvimento farmacêutico, mas há necessidade de que as agencias regulatórias e as indústrias farmoquímicas e farmacêuticas interajam e haja um consenso quanto as exigências para o registro de medicamentos. Este artigo examinou a legislação especifica sobre bi isenção com base no Sistema de Classificação Biofarmacêutica, comparando os cenários do Brasil e do mundo. A partir dessa análise, identificou os entraves a aplicação dos critérios internacionais na realidade regulatória nacional, identificando algumas fragilidades da legislação, como no caso de pro-fármacos. Analisaram-se os critérios de cinco organismos regulatórios (Agência Europeia de Medicamentos, Food and Drug Administration, Health Canada, Conselho Internacional para Harmonização de Requisitos Técnicos para Medicamentos de Uso Humano e Organização Mundial da Saúde) frente aos requisitos da Agência Nacional de Vigilância Sanitária, pontuando as diferenças e o que já se encontra pacificado no tocante a classe do Sistema de Classificação Biofarmacêutica aceita, a comparabilidade entre formulação teste e de referência, solubilidade, permeabilidade intestinal e perfil de dissolução in vitro. Concluiu--se que a Agência Nacional de Vigilância Sanitária deve internalizar os preceitos e critérios da bioisenção com base no Sistema de Classificação Biofarmacêutica por meio de um novo marco regulatório. Além disso, para que esse marco regulatório seja bem-sucedido e produza resultados palpáveis, em especial na área de saúde publica e vigilância sanitária, a agência brasileira deve estar aberta ao diálogo com o setor regulado e as inovações e orientações da academia, sem desviar o foco de sua missão institucional.
Access to medicines can be facilitated by global pharmaceutical development programs, but there is a need for regulatory agencies and the pharmochemical and pharmaceutical industries to interact and to have a consensus on the requirements for drug registration. This article examined the specific legislation concerning to biowaiver based on the Biopharmaceutical Classification System, comparing the scenario in Brazil and worldwide. Based on this analysis, it identified the obstacles to the application of international criteria in the national regulatory reality, identifying some weaknesses of the legislation, as in the case of prodrugs. The criteria of five regulatory bodies (European Medicines Agency, Food and Drug Administration, Health Canada, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and World Health Organization) were analyzed in relation to the requirements of the Brazilian Health Regulatory Agency (Anvisa), pointing out the differences and what has already been settled regarding the accepted class of the Biopharmaceutical Classification System, the comparability between test and reference formulations, solubility, intestinal permeability and in vitro dissolution profile. It was concluded that Anvisa should internalize the percepts and criteria of the biowaiver based on Biopharmaceutical Classification System, through a new regulatory framework. Moreover, for this regulatory framework to be successful and produce tangible results, especially in the area of public health and health surveillance, Anvisa must be open to dialogue with the regulated sector and to innovations and guidance from academia, without losing focus of its institutional mission.
RESUMO
BACKGROUND: The aim of this paper is to evaluate a simple in vitro skin penetration experiment in which the drug is extracted from the whole skin piece as a test valid for formulation screening and optimization during development process, equivalence assessment during quality control or postapproval after changes to the product. METHODS: Twelve clobetasol propionate (CP) formulations (six creams and six ointments, being five generics and one reference from each formulation type) from the local market were used as a model to challenge the evaluated methodology in comparison to in vitro skin penetration following tape-stripping for drug extraction. To support the results, physicochemical tests for pH, viscosity, density and assay, as well as in vitro release were performed. RESULTS: Both protocols, extracting the drug from the skin using the tape-stripping technique or extracting from the full skin were capable of differentiating CP formulations. Only one formulation did not present statistical difference from the reference drug product in penetration tests and only other two oitments presented equivalent release to the reference. The protocol is straightforward and reproducible. CONCLUSION: Results suggest the bioinequavalence of tested CP formulations reinforcing the necessity of such evaluations.
Assuntos
Clobetasol/farmacocinética , Medicamentos Genéricos/farmacocinética , Glucocorticoides/farmacocinética , Pomadas/farmacocinética , Creme para a Pele/farmacocinética , Pele/metabolismo , Administração Tópica , Animais , Química Farmacêutica , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Absorção Cutânea , Solubilidade , Suínos , Equivalência Terapêutica , ViscosidadeRESUMO
ABSTRACT Spironolactone (SPR) is a steroidal drug administered as a potassium-sparing diuretic for high blood pressure treatment. The drug shows incomplete gastrointestinal absorption due to its poor aqueous solubility. The physicochemical properties of SPR in crystal forms I and II suggest that differences in their aqueous solubility may lead to a lack of bioequivalence between solid-state formulations. In this study, SPR polymorphs in five batches of active pharmaceutical ingredients (APIs) from three manufacturers were characterized using powder X-ray diffraction, infrared spectroscopy, thermal analysis, and solubility measurements. SPR tablets (50 mg) were manufactured in our laboratory using API in pure form II, and API in form II contaminated with form I, which was found in a commercial batch. Physicochemical quality evaluations of the manufactured tablets, along with five SPR tablets marketed in Brazil, were performed, and results indicated differences in their dissolution profiles. In the manufactured tablets, differences were associated with the increased solubility of API in form II contaminated with form I compared to API in pure form II. In the marketed SPR tablets, the formulation composition demonstrated an important role in the dissolution rate of the drug, leading to lack of pharmaceutical equivalence among the drug products.
Assuntos
Solubilidade , Espironolactona/análise , Comprimidos/farmacologia , Cromatografia Líquida de Alta Pressão/instrumentação , Dissolução/análiseRESUMO
ABSTRACT The evaluation of drug permeation/penetration of semisolid formulations into animal skin can be useful to supplement the pharmaceutical equivalence. This paper describes the in vitro assessment of acyclovir (ACV) into porcine skin from commercial formulations with etermination of drug concentration in different layers of cutaneous tissue to correlate with effective antiviral concentration in order to improve the equivalence decision. Studies were conducted using Franz cells and porcine skin. Selected pharmaceutical creams containing ACV had identical (reference and generic) and different (similar) excipients. A software program was employed for the simulation of antiviral effectiveness in the skin. Regarding ACV skin penetration, the first batch of the generic product showed a significant difference from reference and similar products, while in the second batch all products demonstrated equivalent drug penetration in the skin. Simulation studies suggest that formulations analysed exhibit a pharmacological effect even when in contact with Herpes simplex strains of high IC50 (inhibitory concentration required to reduce viral replication by 50%). According to results, it can be assumed that the in vitro cutaneous permeation/penetration study does not supply sensitivity information regarding small alterations of ACV semisolid formulations due to the variability inherent to the method, although it can be relevant to pharmaceutical equivalence studies in the development of semisolid products.
Assuntos
Antivirais/classificação , Aciclovir/farmacocinética , Preparações Farmacêuticas/análiseRESUMO
In Brazil, in order for a pharmaceutical company to register a drug form as generic or ?similar? with the Brazilian food and drug agency (Anvisa), it must be proved bioequivalent to its innovatory branded form (reference drug). This requires comparative trials, carried out in conformity with official compendia (Brazilian Pharmacopeia or another officially recognized code). Additionally, according to the Anvisa resolution RDC 31/2010, the dissolution profile of the drug must be tested and compared with that of the branded reference, as a benchmark of quality. The aim of this study was to assess the quality of 500 mg sodium metamizole (dipyrone) tablets produced by seven different laboratories in Brazil: three generic drugs (G1, G2, G3), three (branded) similar drugs (S1, S2, S3) and their reference branded product (Novalgina®, Sanofi-Aventis, drug R). All tests were carried out by methods specified in the Brazilian Pharmacopeia 4th edition (Farmacopeia Brasileira IV). The following tests were performed: uniformity of mass, friability, disintegration time, hardness, assay, uniformity of dosage units, salicylic acid limit assay, dissolution and identification. The dissolution profile was also recorded, as recommended in RDC 31/2010. Whereas every sample was approved in all the Farmacopeia Brasileira IV tests, the results in the dissolution profile test showed that four of the test drugs (G1, G2, S1 and S2) were not pharmaceutically equivalent to drug R. Thus, only drugs G3 and S3 showed dissolution profiles similar to that of drug R and the other four drugs could not be considered equivalent to it and were not approved.
No Brasil, para que uma indústria farmacêutica registre um produto como genérico ou similar, o medicamento deve ser bioequivalente a seu medicamento de referência. Isto requer a realização de estudos comparativos, seguindo um compêndio oficial (Farmacopeia Brasileira ou outra reconhecida oficialmente). Além disso, de acordo com a RDC 31/2010, também deve ser realizado o estudo do perfil de dissolução em relação ao seu medicamento de referência. Este estudo teve como objetivo avaliar a qualidade de comprimidos de metamizol sódico (ou dipirona) com teor de 500mg produzidos por sete diferentes laboratórios brasileiros: três medicamentos genéricos (G1, G2, G3), três similares (S1, S2, S3) e o medicamento de referência (Novalgina®, Sanofi-Aventis, R). Todos os testes seguiram os métodos descritos na Farmacopeia Brasileira IV. Os seguintes ensaios foram realizados: uniformidade de massa, friabilidade, tempo de desintegração, dureza, doseamento, uniformidade de doses unitárias, ensaio limite de ácido salicílico e identificação. O perfil de dissolução foi realizado como recomendado pela RDC 31/2010. Apesar das amostras terem sido aprovadas em todos os ensaios farmacopéicos, os resultados do perfil de dissolução indicaram que quatro medicamentos (G1, G2, S1 e S2) não são equivalentes farmacêuticos de R. Apenas G3 e S3 mostraram perfis similares a R. Assim, quatro medicamentos foram reprovados.
Assuntos
Dipirona , Avaliação de Medicamentos , Medicamentos Genéricos/farmacocinética , Medicamentos Similares , Solubilidade , BrasilRESUMO
O presente trabalho tem por objetivos validar métodos por espectrofotometria de absorção no ultravioleta e cromatografia líquida de alta eficiência para o doseamento de metronidazol em solução injetável e aplicá-los em estudo de equivalência farmacêutica entre medicamento de referência, genérico e similar. Os métodos propostos para doseamento de metronidazol em solução injetável por espectrofotometria de absorção no ultravioleta e por cromatografia líquida de alta eficiência foram validados, mostrando especificidade / seletividade, linearidade e faixa linear, limite de detecção /quantificação, exatidão e precisão adequados para o uso pretendido. Os medicamentos foram avaliados quanto aos testes de determinação de pH, volume médio, identificação por espectrofotometria de absorção no infravermelho, identificação por cromatografia líquida de alta eficiência, esterilidade, endotoxinas bacterianas e doseamento por espectrofotometria de absorção no ultravioleta e por cromatografia líquida de alta eficiência. Os três medicamentos atenderam as especificações para os testes avaliados e, portanto, podem ser considerados apresentando equivalência farmacêutica.
The aim of this study was to validate analytical methods, based on UV absorption spectrophotometry and high performance liquid chromatography (HPLC), to assay metronidazole supplied in injectable solutions, and to employ these methods in a study of the pharmaceutical equivalence of the original brand name medicine (?reference?), generic and similar (brand) medicines. The methods proposed for the metronidazole assay were validated, showing adequate specificity/selectivity, linearity, linear range, detection and quantitation limits, accuracy and precision for the intended purpose. The injectable solutions were then tested to determine pH, volume and identity (by IR spectrophotometry), to verify sterility, detect bacterial endotoxins and assay the drug by the proposed UV spectrophotometric and HPLC methods. All three medicines met the requirements in all tests performed and, therefore, can be considered pharmaceutically equivalent.
Assuntos
Humanos , Avaliação de Medicamentos , Metronidazol/administração & dosagem , Soluções FarmacêuticasRESUMO
Gabapentin is widely used as an oral anti-epileptic agent. However, owing to its high crystallinity and poor compaction properties, it is difficult to form tablets of this drug by direct compression. The aim of this study was to develop gabapentin tablets, pharmaceutically equivalent to the brand-name pioneer product Neurontin® (marketed in USA). Gabapentin 800mg tablets were produced by wet granulation with a constant concentration of intragranular binder and a varying concentration of extragranular binders (A = polyvinylpyrrolidone K30, B = hydroxypropylmethylcellulose 15 cps, C = Kollidon VA64, D =Klucel EXF). The tablets that did not vary in weight, thickness or hardness and had appropriate friability and disintegration profiles were coated with a 3% film-coating solution. Seven formulations F1 (A 3%), F2 (A 6%), F3 (B 3%), F4 (B 6%), F5 (C 3%), F6 (C 3%) and F7 (D 3%) were prepared. Among these, F6 exhibited adequate hardness, friability, disintegration, uniformity of content and total drug dissolution after 45minutes. Comparing the F6 dissolution profile with that of the brand-name tablets, the difference factor (f1) was 5.93 and the similarity factor (f2) 67.85. Hence, formulation F6 was found to be equivalent to Neurontin®.
Gabapentina é uma droga de alta dosagem por via oral amplamente usada como agente antiepilético. Devido a sua alta cristalinidade e baixo poder de compactação é difícil formar comprimidos por compressão direta. O objetivo desse estudo foi desenvolver comprimidos de gabapentina, farmaceuticamente equivalente ao produto de referencia Neurontina (vendido nos Estados Unidos). Comprimidos de gabapentina de 800 mg foram produzidos por granulação molhada usando concentrações constantes e variáveis dos ligantes intragranulares (A=PVPK 30, B=HPMC 15 cps, C=Kollidon VA 64, D=Klucel EXF). Os comprimidos sem variação de peso, densidade , dureza , com friabilidade e com perfil de desintegração apropriados foram revestidos com uma solução de revestimento de 3%. Foram feitas sete formulações: F1 (A em baixa concentração), F2 (A em alta concentração), F3 (B em baixa concentração) , F4 ( B em alta concentração), F5 (C em baixa concentração), F6 (C em alta concentração ), F7 ( D em baixa concentração). Dentre essas formulações a F6 demonstrou dureza adequada, friabilidade, desintegração, uniformidade de conteúdo e total dissolução após 45 minutos. O fator de dissimilaridade (f1) foi de 5,93 e o fator de similaridade (f2) foi de 67,85. Portanto, F6 pode ser considerado equivalente a Neurontina.
RESUMO
O presente trabalho teve por objetivos validar método para o doseamento de aciclovir em creme por espectrofotometria de absorção no ultravioleta e aplicá-lo em estudo de equivalência farmacêutica entre medicamento de referência, genérico e similar. O método proposto para doseamento de aciclovir em creme por espectrofotometria de absorção no ultravioleta foi validado, mostrando especificidade/ seletividade, linearidade e faixa linear, limite de detecção /quantificação, exatidão e precisão adequados para o uso pretendido. Os medicamentos foram avaliados quanto aos testes de peso médio, limite de guanina por cromatografia em camada delgada, identificação por espectrofotometria de absorção no ultravioleta, contagem microbiana de bactérias e fungos, pesquisa de microrganismos patógenos e doseamento por espectrofotometria de absorção no ultravioleta. Os três medicamentos atenderam as especificações para os testes avaliados e, portanto, podem ser considerados equivalentes farmacêuticos.
The aim of this study was to validate a UV absorption spectrophotometric method to assay acyclovir in cream and to use it to verify the pharmaceutical equivalence of the original brand-name, generic and similar (brand) medicines. The method proposed for acyclovir cream was validated, showing adequate specificity/selectivity, linearity and linear range, detection and quantitation limits, accuracy and precision. The medicines were tested for average weight, guanine contents within limits (by thin-layer chromatography), drug identity (by UV spectrophotometry), bacterial and fungal counts and presence of pathogens, and were assayed by UV spectrophotometry. All medicines met the requirements in all these tests and can, therefore, be considered equivalent.