Insights into the small intestinal colloids and their impact on drug solubility

Oral administration is the preferred route for drug delivery because it has high patient compliance and is cost effective. The aqueous solubility of modern drug candidates is often poor, but a drug delivered orally must dissolve in the intestine so that it can be absorbed into the circulation. Advanced formulations can be used to improve the solubility, but the possible improvement in bioavailability from formulation varies among drug molecules. In vitro methods can be used to assess solubility, but these are slow and consume valuable drug material that is often rare early in development. As a non-destructive alternative, in silico methods have the potential to predict solubility, but methods available are in need of improvement, especially for predictions of drug solubility in intestinal fluid and for refining drug formulations.  The goal of this thesis is to use molecular dynamics (MD) simulations to investigate the colloidal structures in intestinal fluids that affect drug solubility, and to simulate processes that affect solubility on the molecular level. Coarse-grained MD simulation protocols for biorelevant media, human and dog duodenal fluids, and lipid-based formulations were established based on concentrations measured in vivo. In the simulations, colloids self-assembled to micelles and vesicles depending on concentration and component input. Simulations with biorelevant media resulted in micelles qualitatively similar to those experimentally measured by small-angle X-rays. The structure of the colloids in the simulations were described in detail, and used to qualitatively assess drug solubility enhancement in model compounds with poor water solubility. These assessments were made by looking at the displacement of drugs and the drugs’ interactions with molecules in small intestinal fluid. The MD simulations were not able replace current solubility-predicting in silico models, but do show that coarse-grained MD simulations can be used for investigating the relevant processes involving intestinal fluids and lipid-based formulations

Insights into the small intestinal colloids and their impact on drug solubility

Oral administration is the preferred route for drug delivery because it has high patient compliance and is cost effective. The aqueous solubility of modern drug candidates is often poor, but a drug delivered orally must dissolve in the intestine so that it can be absorbed into the circulation. Advanced formulations can be used to improve the solubility, but the possible improvement in bioavailability from formulation varies among drug molecules. In vitro methods can be used to assess solubility, but these are slow and consume valuable drug material that is often rare early in development. As a non-destructive alternative, in silico methods have the potential to predict solubility, but methods available are in need of improvement, especially for predictions of drug solubility in intestinal fluid and for refining drug formulations.  The goal of this thesis is to use molecular dynamics (MD) simulations to investigate the colloidal structures in intestinal fluids that affect drug solubility, and to simulate processes that affect solubility on the molecular level. Coarse-grained MD simulation protocols for biorelevant media, human and dog duodenal fluids, and lipid-based formulations were established based on concentrations measured in vivo. In the simulations, colloids self-assembled to micelles and vesicles depending on concentration and component input. Simulations with biorelevant media resulted in micelles qualitatively similar to those experimentally measured by small-angle X-rays. The structure of the colloids in the simulations were described in detail, and used to qualitatively assess drug solubility enhancement in model compounds with poor water solubility. These assessments were made by looking at the displacement of drugs and the drugs’ interactions with molecules in small intestinal fluid. The MD simulations were not able replace current solubility-predicting in silico models, but do show that coarse-grained MD simulations can be used for investigating the relevant processes involving intestinal fluids and lipid-based formulations

Molecular Dynamics Simulations of Self-Assembling Colloids in Fed-State Human Intestinal Fluids and Their Solubilization of Lipophilic Drugs

Bioavailability of oral drugs often depends on how soluble the active pharmaceutical ingredient is in the fluid present in the small intestine. For efficient drug discovery and development, computational tools are needed for estimating this drug solubility. In this paper, we examined human intestinal fluids collected in the fed state, with coarse-grained molecular dynamics simulations. The experimentally obtained concentrations in aspirated duodenal fluids from five healthy individuals were used in three simulation sets to evaluate the importance of the initial distribution of molecules and the presence of glycerides in the simulation box when simulating the colloidal environment of the human intestinal fluid. We observed self-assembly of colloidal structures of different types: prolate, elongated, and oblate micelles, and vesicles. Glycerides were important for the formation of vesicles, and their absence was shown to induce elongated micelles. We then simulated the impact of digestion and absorption on the different colloidal types. Finally, we looked at the solubilization of three model compounds of increasing lipophilicity (prednisolone, fenofibrate, and probucol) by calculating contact ratios of drug–colloid to drug–water. Our simulation results of colloidal interactions with APIs were in line with experimental solubilization data but showed a dissimilarity to solubility values when comparing fasted-/fed-state ratios between two of the APIs. This work shows that coarse-grained molecular dynamics simulation is a promising tool for investigation of the intestinal fluids, in terms of colloidal attributes and drug solubility.Title in the list of papers of Albin Parrow's thesis: Molecular dynamics simulations of self-assembling colloids in fed state human intestinal fluids and their solubilization of lipophilic drugs</p

Molecular Dynamics Simulations on Interindividual Variability of Intestinal Fluids : Impact on Drug Solubilization

Efficient delivery of oral drugs is dependent on their solubility in human intestinal fluid, a complex and dynamic fluid that contains colloidal structures composed of small molecules. These structures solubilize poorly water-soluble compounds, increasing their apparent solubility, and possibly their bioavailability. In this study, we conducted coarse-grained molecular dynamics simulations with data from duodenal fluid samples previously acquired from five healthy volunteers. In these simulations, we observed the self-assembly of mixed micelles of bile salts, phospholipids, and free fatty acids. The micelles were ellipsoids with a size range of 4-7 nm. Next, we investigated micelle affinities of three model drugs. The affinities in our simulation showed the same trend as literature values for the solubility enhancement of drugs in human intestinal fluids. This type of simulations is useful for studies of events and interactions taking place in the small intestinal fluid

Molecular simulation as a computational pharmaceutics tool to predict drug solubility, solubilization processes and partitioning

In this review we will discuss how computational methods, and in particular classical molecular dynamics simulations, can be used to calculate solubility of pharmaceutically relevant molecules and systems. To the extent possible, we focus on the non-technical details of these calculations, and try to show also the added value of a more thorough and detailed understanding of the solubilization process obtained by using computational simulations. Although the main focus is on classical molecular dynamics simulations, we also provide the reader with some insights into other computational techniques, such as the COSMO-method, and also discuss Flory-Huggins theory and solubility parameters. We hope that this review will serve as a valuable starting point for any pharmaceutical researcher, who has not yet fully explored the possibilities offered by computational approaches to solubility calculations

Explicit-pH Coarse-Grained Molecular Dynamics Simulations Enable Insights into Restructuring of Intestinal Colloidal Aggregates with Permeation Enhancers

Permeation enhancers (PEs) can increase the bioavailability of drugs. The mechanisms of action of these PEs are complex, but, typically, when used for oral administration, they can transiently induce the alteration of trans- and paracellular pathways, including increased solubilization and membrane fluidity, or the opening of the tight junctions. To elucidate these mechanistic details, it is important to understand the aggregation behavior of not only the PEs themselves but also other molecules already present in the intestine. Aggregation processes depend critically on, among other factors, the charge state of ionizable chemical groups, which is affected by the pH of the system. In this study, we used explicit-pH coarse-grained molecular dynamics simulations to investigate the aggregation behavior and pH dependence of two commonly used PEs&mdash;caprate and SNAC&mdash;together with other components of fasted- and fed-state simulated intestinal fluids. We also present and validate a coarse-grained molecular topology for the bile salt taurocholate suitable for the Martini3 force-field. Our results indicate an increase in the number of free molecules as a function of the system pH and for each combination of FaSSIF/FeSSIF and PEs. In addition, there are differences between caprate and SNAC, which are rationalized based on their different molecular structures and critical micelle concentrations

Explicit-pH Coarse-Grained Molecular Dynamics Simulations Enable Insights into Restructuring of Intestinal Colloidal Aggregates with Permeation Enhancers

Permeation enhancers (PEs) can increase the bioavailability of drugs. The mechanisms of action of these PEs are complex, but, typically, when used for oral administration, they can transiently induce the alteration of trans- and paracellular pathways, including increased solubilization and membrane fluidity, or the opening of the tight junctions. To elucidate these mechanistic details, it is important to understand the aggregation behavior of not only the PEs themselves but also other molecules already present in the intestine. Aggregation processes depend critically on, among other factors, the charge state of ionizable chemical groups, which is affected by the pH of the system. In this study, we used explicit-pH coarse-grained molecular dynamics simulations to investigate the aggregation behavior and pH dependence of two commonly used PEs&amp;mdash;caprate and SNAC&amp;mdash;together with other components of fasted- and fed-state simulated intestinal fluids. We also present and validate a coarse-grained molecular topology for the bile salt taurocholate suitable for the Martini3 force-field. Our results indicate an increase in the number of free molecules as a function of the system pH and for each combination of FaSSIF/FeSSIF and PEs. In addition, there are differences between caprate and SNAC, which are rationalized based on their different molecular structures and critical micelle concentrations

Effect of lipids on absorption of carvedilol in dogs : Is coadministration of lipids as efficient as a lipid-based formulation?

Lipid-based formulations (LBFs) is a formulation strategy for enabling oral delivery of poorly water-soluble drugs. However, current use of this strategy is limited to a few percent of the marketed products. Reasons for that are linked to the complexity of LBFs, chemical instability of pre-dissolved drug and a limited understanding of the influence of LBF intestinal digestion on drug absorption. The aim of this study was to explore intestinal drug solubilization from a long-chain LBF, and evaluate whether coadministration of LBF is as efficient as a lipidbased drug formulation containing the pre-dissolved model drug carvedilol. Thus, solubility studies of this weak base were performed in simulated intestinal fluid (SIF) and aspirated dog intestinal fluid (DIF). DIF was collected from duodenal stomas after dosing of water and two levels (1 g and 2 g) of LBF. Similarly, the in vitro SIF solubility studies were conducted prior to, and after addition of, undigested or digested LBF. The DIF fluid was further characterized for lipid digestion products (free fatty acids) and bile salts. Subsequently, carvedilol was orally administered to dogs in a lipid-based drug formulation and coadministered with LBF, and drug plasma exposure was assessed. In addition to these studies, in vitro drug absorption from the different formulation approaches were evaluated in a lipolysis-permeation device, and the obtained data was used to evaluate the in vitro in vivo correlation. The results showed elevated concentrations of free fatty acids and bile salts in the DIF when 2 g of LBF was administered, compared to only water. As expected, the SIF and DIF solubility data revealed that carvedilol solubilization increased by the presence of lipids and lipid digestion products. Moreover, coadministration of LBF and drug demonstrated equal plasma exposure to the lipid-based drug formulation. Furthermore, evaluation of in vitro absorption resulted in the same rank order for the LBFs as in the in vivo dog study. In conclusion, this study demonstrated increased intestinal solubilization from a small amount of LBF, caused by lipid digestion products and bile secretion. The outcomes also support the use of coadministration of LBF as a potential dosing regimen in cases where it is beneficial to have the drug in the solid form, e.g. due to chemical instability in the lipid vehicle. LBFs

Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers

Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, the effects are variable across individuals and classes of macromolecular drugs and biologics. Here, we examined the influence of bile compositions on the ability of membrane incorporation of three transient PEs-caprylate, caprate, and SNAC-using coarse-grained molecular dynamics (CG-MD). The availability of free PE monomers, which are important near the absorption site, to become incorporated into the membrane was higher in fasted-state fluids than that in fed-state fluids. The simulations also showed that transmembrane perturbation, i.e., insertion of PEs into the membrane, is a key mechanism by which caprylate and caprate increase permeability. In contrast, SNAC was mainly adsorbed onto the membrane surface, indicating a different mode of action. Membrane incorporation of caprylate and caprate was also influenced by bile composition, with more incorporation into fasted- than fed-state fluids. The simulations of transient PE interaction with membranes were further evaluated using two experimental techniques: the quartz crystal microbalance with dissipation technique and total internal reflection fluorescence microscopy. The experimental results were in good agreement with the computational simulations. Finally, the kinetics of membrane insertion was studied with CG-MD. Variation in micelle composition affected the insertion rates of caprate monomer insertion and expulsion from the micelle surface. In conclusion, this study suggests that the bile composition and the luminal composition of the intestinal fluid are important factors contributing to the interindividual variability in the absorption of macromolecular drugs administered with transient PEs