RESUMEN
The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.
Asunto(s)
Felodipino , Simulación de Dinámica Molecular , Solubilidad , Perros , Animales , Felodipino/administración & dosificación , Felodipino/farmacocinética , Felodipino/química , Probucol/administración & dosificación , Probucol/farmacocinética , Probucol/química , Carvedilol/administración & dosificación , Carvedilol/farmacocinética , Carvedilol/química , Lípidos/química , Líquidos Corporales/química , Líquidos Corporales/metabolismo , Ácidos y Sales Biliares/química , Masculino , Secreciones Intestinales/químicaRESUMEN
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.
Asunto(s)
Micelas , Simulación de Dinámica Molecular , Humanos , Coloides/química , Intestinos/química , Solubilidad , Glicéridos , Absorción IntestinalRESUMEN
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.
Asunto(s)
Bilis/química , Caprilatos/administración & dosificación , Caprilatos/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Decanoatos/administración & dosificación , Decanoatos/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Sustancias Macromoleculares/administración & dosificación , Ácidos y Sales Biliares/metabolismo , Disponibilidad Biológica , Voluntarios Sanos , Humanos , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Simulación de Dinámica Molecular , Fosfolípidos/metabolismoRESUMEN
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.
Asunto(s)
Variación Biológica Poblacional , Líquidos Corporales/química , Duodeno/química , Micelas , Administración Oral , Disponibilidad Biológica , Líquidos Corporales/metabolismo , Duodeno/metabolismo , Voluntarios Sanos , Humanos , Simulación de Dinámica Molecular , Tamaño de la Partícula , SolubilidadRESUMEN
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 lipid-based 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 (1â¯g and 2â¯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 2â¯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. Finally, the in vitro lipolysis-permeation used herein established IVIVC for carvedilol in the presence of LBFs.
Asunto(s)
Carvedilol/administración & dosificación , Sistemas de Liberación de Medicamentos , Absorción Intestinal , Lípidos/química , Administración Oral , Animales , Ácidos y Sales Biliares/metabolismo , Carvedilol/química , Carvedilol/farmacocinética , Digestión/fisiología , Perros , Excipientes/química , Ácidos Grasos no Esterificados/metabolismo , Secreciones Intestinales/metabolismo , Lípidos/administración & dosificación , Lipólisis/fisiología , Masculino , SolubilidadRESUMEN
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.
Asunto(s)
Simulación por Computador , Simulación de Dinámica Molecular , Preparaciones Farmacéuticas/química , SolubilidadRESUMEN
The absorption of hydrophobic drugs and nutrients from the intestine is principally determined by the amount that can be dissolved by the endogenous fluids present in the gut. Human intestinal fluids (HIFs) comprise a complex mixture of bile salts, phospholipids, steroids and glycerides that vary in composition in the fed and fasted state and between subjects. A number of simulated intestinal fluid (SIF) compositions have been developed to mimic fasted and fed state intestinal conditions and allow the in vitro determination of drug solubility as a proxy for the maximum dissolved concentration it is possible to reach. In particular these solvents are used during the development of lipophilic and poorly water-soluble drugs but questions remain around the differences that may arise from the source and methods of preparation of these fluids. In this work, a range of SIFs were studied using small-angle X-ray scattering (SAXS), cryogenic-transmission electron microscopy (cryo-TEM) and molecular dynamics (MD) simulations in order to analyze their structures. In-house prepared SIFs based on sodium taurodeoxycholate (NaTDC) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) formed oblate ellipsoidal micelles irrespective of lipid concentration and preparation conditions. In contrast, commercially available SIFs based on sodium taurocholate and lecithin formed prolate ellipsoidal micelles in the fed state and vesicles in the fasted state. These structural variations are the likely reason for the dramatic differences sometimes observed in the solubility enhancements for hydrophobic drugs, nutrients and digestion products when using different SIFs. However, the structural homogeneity of the NaTDC/DOPC micelles makes them ideal candidates for standardizing SIF formulations as the structures of the solubilizing nanoaggregates therein are not sensitive to the preparation method.