Development of a Microgram Scale Video-Microscopic Method to Investigate Dissolution Behavior of Poorly Water-Soluble Drugs.

Poor aqueous solubility is a common characteristic of new drug candidates, which leads to low or inconsistent oral bioavailability. This has sparked an interest in material efficient testing of solubility and dissolution rate. The aim was to develop a microgram scale video-microscopic method to screen the dissolution rates of poorly water-soluble drugs.

Predicting in vivo performance of fenofibrate amorphous solid dispersions using in vitro non-sink dissolution and dissolution permeation setup.

Amorphous solid dispersion (ASD) is emerging as a useful formulation strategy to increase the bioavailability of active pharmaceutical ingredients with poor solubility. In vitro dissolution testing under non-sink conditions has often been used to evaluate the ability of ASDs to generate and maintain supersaturation to predict the in vivo performance. However, such a single compartment dissolution setup can fail to predict the oral bioavailability, due to an interdependence between precipitation and permeation.

Visualizing the Journey of Fenofibrate through the Rat Gastrointestinal Tract by Matrix-Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging.

Mapping the spatial distribution of a drug throughout the gastrointestinal tract (GIT) after oral ingestion can provide novel insights into the interaction between the drug, the oral drug delivery system, and the GIT. Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) is a molecular imaging technique that can analyze molecules in the cryosections of tissues, determining their localization with a spatial resolution of 10-100 μm. The overall aim of this study was to use MALDI-MSI to visualize the distribution and spatial location of a model prodrug (fenofibrate) through the rat GIT.

Exploring the Impact of Intestinal Fluid Components on the Solubility and Supersaturation of Danazol.

Eleven simulated intestinal fluids (SIF) were designed using a Design of Experiment (DoE) approach. The DoE SIF covered a range of compositions of fasted state human intestinal fluid (FaHIF) with regard to pH, bile salt (BS), and phospholipid (PL). Using the model compound danazol, the apparent crystalline solubility (aCS) and apparent amorphous solubility (aAS), as well as the supersaturation propensity was determined in the DoE SIF media.

Comparison of induction methods for supersaturation: Amorphous dissolution versus solvent shift.

Simple solvent shift is often used to induce supersaturation and investigate precipitation kinetics in early drug development as a substitute for amorphous dissolution. This study develops and compares a small-scale non-sink amorphous dissolution method to a solvent shift method as induction methods for supersaturation of the model drugs albendazole, felodipine and tadalafil with respect to the maximum dissolved drug concentration, and the solid form of the precipitate. The study also investigates the effect of pre-dispersed precipitation inhibitors (hydroxypropyl methyl cellulose (HPMC) or polyvinylpyrrolidone (PVP)) on tadalafil supersaturation induced by both amorphous dissolution and solvent shift with respect to maximum dissolved drug concentration, precipitation rate and solid form of the precipitate.

Effect of supersaturation on absorption of indomethacin and tadalafil in a single pass intestinal perfusion rat model, in the absence and presence of a precipitation inhibitor.

The effect of the degree of supersaturation (DS) on absorption of the model drugs indomethacin and tadalafil was elucidated in a single-pass intestinal perfusion (SPIP) model in rats. In addition, the performance of the precipitation inhibitor (PI) hydroxypropylmethylcellulose (HPMC) was evaluated when added at a concentration of 0.1% (w/v) to fasted state simulated intestinal fluid (FaSSIF and FaSSIF) used as perfusion medium.

Using in vitro lipolysis and SPECT/CT in vivo imaging to understand oral absorption of fenofibrate from lipid-based drug delivery systems.

Using lipid-based drug delivery systems (LbDDS) is an efficient strategy to enhance the low oral bioavailability of poorly water-soluble drugs. Here the oral absorption of fenofibrate (FF) from LbDDS in rats was investigated in pharmacokinetic, in vitro lipolysis, and SPECT/CT in vivo imaging studies. The investigated formulations were soybean oil solution (SBO), a mixture of soybean oil and monoacyl phosphatidylcholine (MAPC) (SBO-MAPC), self-nanoemulsifying drug delivery systems with and without MAPC (SNEDDS-MAPC and SNEDDS, respectively), and an aqueous suspension (SUSP) as a reference.

Comparison of induction methods for supersaturation: pH shift versus solvent shift.

In order to investigate the supersaturation propensity of drugs in a simple and small-scale setup, induction of supersaturation is often performed via solvent shift. For weak bases, a potentially more biorelevant induction method would be a pH shift, as it is often hypothesized that the induction method will impact the supersaturation and precipitation. However, this has not been investigated systematically in a pharmaceutical context.

Developing a predictive in vitro dissolution model based on gastrointestinal fluid characterisation in rats.

The influence of physiological factors on the solubility of drug compounds has been thoroughly investigated in humans. However, as these factors vary between species and since many in vivo studies are carried out in rats or mice, it has been difficult to establish sufficient in vitro in vivo relations. The aim of this study was to develop a physiologically relevant in vitro dissolution model simulating the gastrointestinal (GI) fluids of fasted rats and compare it to previously published in vitro and in vivo data.

Characterization of the Hydrodynamics in a Miniaturized Dissolution Apparatus.

The hydrodynamics of a miniaturized dissolution apparatus was characterized using computational fluid dynamics simulations and analyzed in relation to the biorelevance and robustness of measurements of drug dissolution and precipitation kinetics from supersaturated drug solutions. The effect of using 3 different agitator geometries operated at 50, 100, 150, and 200 rpm as well as different positioning of an UV probe in the vessel was systematically evaluated. The computational fluid dynamics simulations were validated using a particle streak velocimetry experiment.

Investigation of the Intra- and Interlaboratory Reproducibility of a Small Scale Standardized Supersaturation and Precipitation Method.

The high number of poorly water-soluble compounds in drug development has increased the need for enabling formulations to improve oral bioavailability. One frequently applied approach is to induce supersaturation at the absorptive site, e.g.

Development of a Video-Microscopic Tool To Evaluate the Precipitation Kinetics of Poorly Water Soluble Drugs: A Case Study with Tadalafil and HPMC.

Many drug candidates today have a low aqueous solubility and, hence, may show a low oral bioavailability, presenting a major formulation and drug delivery challenge. One way to increase the bioavailability of these drugs is to use a supersaturating drug delivery strategy. The aim of this study was to develop a video-microscopic method, to evaluate the effect of a precipitation inhibitor on supersaturated solutions of the poorly soluble drug tadalafil, using a novel video-microscopic small scale setup.

Studying the Propensity of Compounds to Supersaturate: A Practical and Broadly Applicable Approach.

Supersaturating drug delivery systems can enhance the oral bioavailability of poorly soluble drug compounds. Supersaturation of such compounds has been studied in many different ways; however, a more standardized method is required. The rationale of choosing suitable concentrations of supersaturation to study has previously been very inconsistent.

Interaction of GABA-mimetics with the taurine transporter (TauT, Slc6a6) in hyperosmotic treated Caco-2, LLC-PK1 and rat renal SKPT cells.

The aim of the present study was to investigate if basic GABA-mimetics interact with the taurine transporter (TauT, Slc6a6), and to find a suitable cell based model that is robust towards extracellular changes in osmolality during uptake studies. Taurine uptake was measured in human Caco-2 cells, porcine LLC-PK1 cells, and rat SKPT cells using radiolabelled taurine. Hyperosmotic conditions were obtained by incubation with raffinose (final osmolality of 500mOsm) for 24h prior to the uptake experiments.

The use of supersaturation for the vaginal application of microbicides: a case study with dapivirine.

In this study, we investigated the potential of supersaturation for the formulation of the poorly water-soluble microbicide dapivirine (DPV) in an aqueous vaginal gel in order to enhance its vaginal tissue uptake. Different excipients such as hydroxypropylmethylcellulose, polyethylene glycol 1000, and cyclodextrins were evaluated for their ability to inhibit precipitation of supersaturated DPV in the formulation vehicle as such as well as in biorelevant media. In vitro permeation assessment across HEC-1A cell layers demonstrated an enhanced DPV flux from supersaturated gels compared with suspension gels.

The anti-epileptic drug substance vigabatrin inhibits taurine transport in intestinal and renal cell culture models.

The GABA-mimetic anti-epileptic drug substance vigabatrin is used against infantile spasms. In vitro and in vivo experiments have shown that vigabatrin is transported via the proton coupled amino acid transporter (PAT1) mediating at least parts of the intestinal absorption of the drug. However, such evidence does not preclude the involvement of other transporters.