RESUMO
In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro-in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.
Assuntos
Benchmarking/normas , Indústria Farmacêutica/normas , Preparações Farmacêuticas/normas , Tecnologia Farmacêutica/normas , Animais , Química Farmacêutica/normas , Preparações de Ação Retardada/normas , Aprovação de Drogas , Indústria Farmacêutica/métodos , Excipientes/química , Excipientes/normas , Humanos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/química , Farmacocinética , Controle de Qualidade , Medição de Risco , Solubilidade , Tecnologia Farmacêutica/métodos , Toxicologia/normas , Estados Unidos , United States Food and Drug AdministrationRESUMO
Divalproex sodium is a narrow therapeutic index drug that is widely used for the treatment of epilepsy, the manic episodes associated with bipolar disorder, and prophylaxis of migraine headaches. The present investigation was undertaken to design an oral dosage form that would provide once-daily administration with improved therapy and to explore the relationships between in vitro drug release and in vivo absorption. Controlled release hydrophilic matrix formulations of divalproex sodium were designed and evaluated via in vitro and in vivo studies. The release rate of divalproex sodium was modulated by varying different rate-controlling hydrophilic polymers and measured in vitro using a USP apparatus II dissolution method. Formulations with differing release rates were studied in beagle dogs and in healthy subjects. A selected formulation given once-daily was further evaluated against the commercial enteric tablet dosed twice-daily in a multiple dose study, and shown to provide desired nearly constant therapeutic plasma concentrations over the entire 24-h dosing interval. Preliminary linear relationships between in vitro dissolution and in vivo absorption were observed in both the animal model and in humans. However, the relationships were formulation dependent, indicating a need for further studies.