24 research outputs found
Food effect risk assessment in preformulation stage using material sparing μFLUX methodology1
The intake of food and meal type can strongly impact the bioavailability of orally administered drugs and can consequently impact drug efficacy and safety. During the early stages of drug development, only a small amount of drug substance is available, and the solubility difference between fasted state simulated intestinal fluid and fed state simulated intestinal fluid may provide an early indication about the probable food effect. But higher drug solubility in fed state simulated intestinal fluid may not always results in an increased oral absorption. In the present research, we demonstrated using 11 model compounds that in addition to the drug dissolution in biorelevant media, the evaluation of the diffusion flux of a drug in solution, across artificial lipid coated membrane, where only the unbound drug crosses the membrane, is a reliable way to predict the food effect. Although, the combination of dissolution and diffusion flux may not reliably predict the food effect in case of drugs undergoing intestinal metabolism or when transporters are involved in the drug absorption, the technique generally provides good information about the food effect at very early stages of drug development that may help in designing a clinical plan by adjusting the drug dose in the fed state
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, pKa, 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. © 2016 American Chemical Society
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
Human skin models: From healthy to disease‐mimetic systems; characteristics and applications
Workshop report: USP workshop on exploring the science of drug absorption
In October 2018, the United States Pharmacopeia (USP) hosted a two-day workshop to explore the science of drug absorption. Experts from around the globe presented some of the challenges associated with drug product development from the perspective of the physiological attributes of the patient (human or canine) and the body site for drug activity. Included in the discussions were methods and approaches for answering complex questions, providing insights into the strengths and challenges of methods available in our biopharmaceutical tool chest. The following is a synopsis of the presentations and the highlights of the discussions that ensued. Disclaimer: This article reflects the views of the authors and should not be construed as representing the views or policies of the United States Food and Drug Administration. © 2019, Dissolution Technologies Inc. All rights reserved