12 research outputs found
Prediction of Bioequivalence and Food Effect Using Flux- and Solubility-Based Methods
In this work, two different approaches have been developed to predict the food effect and the bioequivalence of marketed itraconazole (ITRA) formulations. Kinetic solubility and simultaneous dissolution–permeation tests of three (ITRA) formulations (Sporanox capsules and solution and SUBA-ITRA capsules) were carried out in simulated fasted and fed states. Fraction of dose absorbed ratios estimating food effect and bioequivalence were calculated based on these results and were compared to the in vivo study results published by Medicines Agencies. The comparison demonstrated that kinetic solubility and flux values could be used as input parameters for biopharmaceutics modeling and simulations to estimate food effect and bioequivalence. Both prediction methods were able to determine a slightly negative food effect in the case of the Sporanox solution and also a pronounced positive food effect for the Sporanox capsule. Superior bioavailability was predicted when the Sporanox solution was compared to the Sporanox capsule (in agreement with in vivo data)
Ranking Itraconazole Formulations Based on the Flux through Artificial Lipophilic Membrane
Purpose: The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (μFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature. Method: Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of μFLUX™ apparatus. Donor and acceptor chambers were divided from each other by a lipophilic membrane. In addition to the flux evaluations, changes in solid state as a function of time were investigated to gain further insight into the flux changes observed over time for the solid dispersion formulations. Results: Initial flux values from Sporanox®, the nanosuspension and the micronized ITZ showed ratios of 52/4/1 with a decreasing flux from nanosuspension and both solid dispersions after 2.5–3 h. Although the initial flux from the Soluplus® formulation was 2.2 times lower than the one observed for Sporanox®, the decrease in flux observed was milder and became ~ 2 times higher than Sporanox® after approximately 2.5 h. The total amounts of ITZ in the receiver compartment after 240 min showed the same rank order as the rodent AUCs of these formulations reported in literature. Conclusions: It was demonstrated that in vitro flux measurements using lipophilic artificial membranes could correctly reproduce the rank order of PK results for ITZ formulations. The drop in flux over time for solid dispersions could be backed by experimental indications of crystallization
The effect of formulation additives on in vitro dissolution-absorption profile and in vivo bioavailability of telmisartan from brand and generic formulations
In this study, brand and four generic formulations of telmisartan, an antihypertensive drug, were used in in vitro simultaneous dissolution-absorption, investigating the effect of different formulation additives on dissolution and on absorption through an artificial membrane. The in vitro test was found to be sensitive enough to show even small differences between brand and generic formulations caused by the use of different excipients. By only changing the type of filler from sorbitol to mannitol in the formulation, the flux through the membrane was reduced by approximately 10%. Changing the salt forming agent as well resulted in approximately 20% of flux reduction compared to the brand formulation. This significant difference was clearly shown in the published in vivo results as well. The use of additional lactose monohydrate in the formulation also leads to approximately 10% reduction in flux. The results show that by changing excipients, the dissolution of telmisartan was not altered significantly, but the flux through the membrane was found to be significantly changed.
These results pointed out the limitations of traditional USP dissolution tests and emphasized the importance of simultaneously measuring dissolution and absorption, which allows the complex effect of formulation excipients on both processes to be measured. Moreover, the in vivo predictive power of the simultaneous dissolution-absorption test was demonstrated by comparing the in vitro fluxes to in vivo bioequivalence study results
Effect of Formulation Additives on Drug Transport through Size-Exclusion Membranes
The aim of this research was to investigate
the driving force of
membrane transport through size-exclusion membranes and to provide
a concentration-based mathematical description of it to evaluate whether
it can be an alternative for lipophilic membranes in the formulation
development of amorphous solid dispersions. Carvedilol, an antihypertensive
drug, was chosen and formulated using solvent-based electrospinning
to overcome the poor water solubility of the drug. Vinylpyrrolidone–vinyl
acetate copolymer (PVPVA64) and Soluplus were used to create two different
amorphous solid dispersions of the API. The load-dependent effect
of the additives on dissolution and permeation through regenerated
cellulose membrane was observed by a side-by-side diffusion cell,
μFLUX. The solubilizing effect of the polymers was studied by
carrying out thermodynamic solubility assays. The supersaturation
ratio (SSR, defined as the ratio of dissolved amount of the drug to
its thermodynamic solubility measured in exactly the same medium)
was found to be the driving force of membrane transport in the case
of size-exclusion membranes. Although the transport through lipophilic
and size-exclusion membranes is mechanistically different, in both
cases, the driving force of membrane transport in the presence of
polymer additives was found to be the same. This finding may enable
the use of size-exclusion membranes as an alternative to lipid membranes
in formulation development of amorphous solid dispersions
Investigation and Mathematical Description of the Real Driving Force of Passive Transport of Drug Molecules from Supersaturated Solutions
The aim of this study
was to investigate the impact of formulation
excipients and solubilizing additives on dissolution, supersaturation,
and membrane transport of an active pharmaceutical ingredient (API).
When a poorly water-soluble API is formulated to enhance its dissolution,
additives, such as surfactants, polymers, and cyclodextrins, have
an effect not only on dissolution profile but also on the measured
physicochemical properties (solubility, p<i>K</i><sub>a</sub>, permeability) of the drug while the excipient is present, therefore
also affecting the driving force of membrane transport. Meloxicam,
a nonsteroidal anti-inflammatory drug, was chosen as a poorly water-soluble
model drug and formulated in order to enhance its dissolution using
solvent-based electrospinning. Three polyvinylpyrrolidone (PVP) derivatives
(K30, K90, and VA 64), Soluplus, and (2-hydroxypropyl)-β-cyclodextrin
were used to create five different amorphous solid dispersions of
meloxicam. Through experimental design, the various formulation additives
that could influence the characteristics of dissolution and permeation
through artificial membrane were observed by carrying out a simultaneous
dissolution–permeation study with a side-by-side diffusion
cell, μFLUX. Although the dissolution profiles of the formulations
were found to be very similar, in the case of Soluplus containing
formulation the flux was superior, showing that the driving force
of membrane transport cannot be simplified to the concentration gradient.
Supersaturation gradient, the difference in degree of supersaturation
(defined as the ratio of dissolved amount of the drug to its thermodynamic
solubility) between the donor and acceptor side, was found to be the
driving force of membrane transport. It was mathematically derived
from Fick’s first law, and experimentally proved to be universal
on several meloxicam containing ASDs and DMSO stock solution