RESUMO
Literature data on the properties of zidovudine relevant to waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate-release (IR) solid oral dosage forms containing zidovudine alone or in combination with other active pharmaceutical ingredients (APIs) are reviewed. Solubility, dissolution, and permeability data for zidovudine, along with its dosing schedule, therapeutic index and pharmacokinetic properties, and reports related to BE/bioavailability were all taken into consideration. Data for solubility and permeability suggest that zidovudine belongs to Class I according to the Biopharmaceutics Classification System. Also, zidovudine is not a narrow therapeutic index drug. Although five out of 13 formulations tested in vivo (mostly of unreported composition) failed to show BE, it appears that in vitro studies performed according to biowaiver methods could predict in vivo behavior. Nevertheless, it is highly recommended that if a biowaiver is to be applied, excipient choices be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form (Table 2 of this monograph), in their usual amounts. These conclusions apply to products containing zidovudine as the only API and also to fixed combination products containing zidovudine with respect to the zidovudine component of the formulation.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Zidovudina/administração & dosagem , Zidovudina/farmacocinética , Administração Oral , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/toxicidade , Células CACO-2 , Linhagem Celular , Cães , Excipientes/química , Infecções por HIV/tratamento farmacológico , Humanos , Permeabilidade , Solubilidade , Equivalência Terapêutica , Zidovudina/química , Zidovudina/toxicidadeRESUMO
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing metronidazole are reviewed. Metronidazole can be assigned to Biopharmaceutics Classification System Class I. Most BE studies that were identified reported the investigated formulations to be bioequivalent, indicating the risk of bioinequivalence to be low. Formulations showing differences in bioavailability showed dissimilarities in in vitro dissolution profiles. Furthermore, metronidazole has a wide therapeutic index. It is concluded that a biowaiver for solid IR formulations is justified, provided: (a) the test product and its comparator are both rapidly dissolving; (b) meet similarity of the dissolution profiles at pH 1.2, 4.5, and 6.8; (c) the test product contains only excipients present in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form; and (d) if the test product contains sorbitol, sodium laurilsulfate, or propylene glycol, the test product needs to be qualitatively and quantitatively identical to its comparator with respect to these excipients [corrected]..
Assuntos
Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/farmacocinética , Metronidazol/administração & dosagem , Metronidazol/farmacocinética , Administração Oral , Animais , Anti-Infecciosos/química , Controle de Medicamentos e Entorpecentes , Humanos , Metronidazol/química , Solubilidade , Comprimidos , Equivalência TerapêuticaRESUMO
The instability of polysaccharide/protein mixtures occurs because of either thermodynamic incompatibility or complexation. We studied which instability mechanism dominated given the external conditions. Therefore the effect of temperature, pH, and biopolymer concentration on the phase separation of pectin/caseinate mixtures was investigated. At pH > 6, thermodynamic incompatibility with spinodal decomposition was observed in pectin/caseinate mixtures resulting in the formation of water-in-water emulsions in intermediate stages of the phase separation process. The demixing rate of these emulsions and appearance of two macroscopic phases (lower phase enriched with caseinate and upper phase with pectin) was retarded when the pectin concentration increased or when the storage temperature decreased due to a higher viscosity of the mixtures at those conditions. As the pH of the mixture was lowered below 6, pectin accumulated in the caseinate-rich phase. Complexation of pectin and caseinate led to the formation of microparticles (approximately 3 microm), whose shape depends on the biopolymer concentration ratio and rate of acidification. These pectin/caseinate particles do not coalesce and are insensitive to salt addition.