The aim of this study was to investigate the influence of experimental conditions on levothyroxine sodium release from two immediate-release tablet formulations which narrowly passed the standard requirements for bioequivalence studies. The in vivo study was conducted as randomised, single-dose, two-way cross-over pharmacokinetic study in 24 healthy subjects. The in vitro study was performed using various dissolution media, and obtained dissolution profiles were compared using the similarity factor value. Drug solubility in different media was also determined. The in vivo results showed narrowly passing bioequivalence. Considering that levothyroxine sodium is classified as Class III drug according to the Biopharmaceutics Classification System, drug bioavailability will be less sensitive to the variation in its dissolution characteristics and it can be assumed that the differences observed in vitro in some of investigated media probably do not have significant influence on the absorption process, as long as rapid and complete dissolution exists. The study results indicate that the current regulatory criteria for the value of similarity factor in comparative dissolution testing, as well as request for very rapid dissolution (more than 85% of drug dissolved in 15 min), are very restricted for immediate-release dosage forms containing highly soluble drug substance and need further investigation. The obtained results also add to the existing debate on the appropriateness of the current bioequivalence standards for levothyroxine sodium products.
The aim of this case study was to develop a drug-specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus™ software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration-time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate-release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro-in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets.
The aim of the study was to present an example of experimental design application to set up the dissolution test conditions for the two immediaterelease products of levothyroxine sodium (L-Na) with proven bioequivalence: the generic product A and the reference product B [1,2]. The description of the dissolution profiles by using model-independent methods included the calculation of mean dissolution time (MDT) from the in vitro data for both formulations. MDT for the products were compared one to each other as well as with mean absorption time (MAT), calculated from the in vivo data [3]. The experimental factorial design 2 3 was applied with following independent variables: concentration of surfactant used (X 1 ), volume of dissolution medium (X 2 ), and paddle stirring speed (X 3 ). Dependent variables were set up as a difference between the MDT observed under various experimental conditions for the investigated products (Y 1 ), as well as the difference between MDT and MAT for each product (Y 2 = MDT prod. A − MAT prod. A ; Y 3 =MDT prod. B − MAT prod. B ). The obtained results showed that the paddle rotation speed was the most significant drug release factor. The medium volume had very small effect on responses Y 1 and Y 2 but its impact could not be regarded as negligible in the case of response Y 3 . The surfactant used for dissolution testing showed significant effect on the tested parameters, but the observed effects were contradictory and general conclusion could not be made. This study showed the limited applicability of experimental design in the optimization of the dissolution conditions for two different L-Na formulations. The significant differences among in vitro release profiles were obtained and there was not unique dissolution test model applicable to both investigated products. Malinowski HJ, Smith WE. Use of factorial design to evaluate granulations prepared by spheronization.
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