| 1. |
- Edueng, Khadijah, et al.
(författare)
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Pharmaceutical Profiling and Molecular Dynamics Simulations Reveal Crystallization Effects in Amorphous Formulations
- 2021
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Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 613
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Tidskriftsartikel (refereegranskat)abstract
- Robust and reliable in vivo performance of medicines based on amorphous solid dispersions (ASDs) depend on maintenance of physical stability and efficient supersaturation. However, molecular drivers of these two kinetic processes are poorly understood. Here we used molecular dynamics (MD) simulations coupled with experimental assessments to explore supersaturation, nucleation, and crystal growth. The effect of drug loading on physical stability and supersaturation potential was highly drug specific. Storage under humid conditions influenced crystallization, but also resulted in morphological changes and particle fusion. This led to increased particle size, which significantly reduced dissolution rate. MD simulations identified the importance of nano-compartmentalization in the crystallization rate of the ASDs. Nucleation during storage did not inherently compromise the ASD. Rather, the poorer performance resulted from a combination of properties of the compound, nanostructures formed in the formulation, and crystallization.
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| 2. |
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| 3. |
- Hossain, Md Shakhawath, et al.
(författare)
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Explicit-pH Coarse-Grained Molecular Dynamics Simulations Enable Insights into Restructuring of Intestinal Colloidal Aggregates with Permeation Enhancers
- 2022
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Ingår i: Processes. - : MDPI. - 2227-9717. ; 10:1, s. 29-
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Tidskriftsartikel (refereegranskat)abstract
- 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—caprate and SNAC—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.
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| 4. |
- Hossain, Md Shakhawath, et al.
(författare)
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Molecular simulation as a computational pharmaceutics tool to predict drug solubility, solubilization processes and partitioning
- 2019
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER SCIENCE BV. - 0939-6411 .- 1873-3441. ; 137, s. 46-55
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 5. |
- Jacobsen, Ann-Christin, et al.
(författare)
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Intrinsic lipolysis rate for systematic design of lipid-based formulations
- 2023
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Ingår i: Drug Delivery and Translational Research. - : Springer Nature. - 2190-393X .- 2190-3948. ; 13:5, s. 1288-1304
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Tidskriftsartikel (refereegranskat)abstract
- Lipid-based formulations (LBFs) are used by the pharmaceutical industry in oral delivery systems for both poorly water-soluble drugs and biologics. Digestibility is key for the performance of LBFs and in vitro lipolysis is commonly used to compare the digestibility of LBFs. Results from in vitro lipolysis experiments depend highly on the experimental conditions and formulation characteristics, such as droplet size (which defines the surface area available for digestion) and interfacial structure. This study introduced the intrinsic lipolysis rate (ILR) as a surface area-independent approach to compare lipid digestibility. Pure acylglycerol nanoemulsions, stabilized with polysorbate 80 at low concentration, were formulated and digested according to a standardized pH–stat lipolysis protocol. A methodology originally developed to calculate the intrinsic dissolution rate of poorly water-soluble drugs was adapted for the rapid calculation of ILR from lipolysis data. The impact of surfactant concentration on the apparent lipolysis rate and lipid structure on ILR was systematically investigated. The surfactant polysorbate 80 inhibited lipolysis of tricaprylin nanoemulsions in a concentration-dependent manner. Coarse-grained molecular dynamics simulations supported these experimental observations. In the absence of bile and phospholipids, tricaprylin was shielded from lipase at 0.25% polysorbate 80. In contrast, the inclusion of bile salt and phospholipid increased the surfactant-free area and improved the colloidal presentation of the lipids to the enzyme, especially at 0.125% polysorbate 80. At a constant and low surfactant content, acylglycerol digestibility increased with decreasing acyl chain length, decreased esterification, and increasing unsaturation. The calculated ILR of pure acylglycerols was successfully used to accurately predict the IRL of binary lipid mixtures. The ILR measurements hold great promise as an efficient method supporting pharmaceutical formulation scientists in the design of LBFs with specific digestion profiles.
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| 6. |
- Kabedev, Aleksei, et al.
(författare)
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Endothelial glycocalyx permeability for nanoscale solutes
- 2022
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Ingår i: Nanomedicine. - : Future Medicine Ltd. - 1743-5889 .- 1748-6963. ; 17:13, s. 979-996
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Tidskriftsartikel (refereegranskat)abstract
- Glycocalyx has a great impact on the accessibility of the endothelial cell membranes. Although the specific interactions play a crucial role in cross-membrane solute transport, nonspecific interactions cannot be neglected. In this work, we used computational modeling to quantify the nonspecific interactions that control the distribution of nanosized solutes across the endothelial glycocalyx. We evaluated the probabilities of various nanoparticles' passage through the luminal layer to the membrane. The calculations demonstrate that excluded volume and electrostatic interactions are decisive for the solute transport as compared with van der Waals and hydrodynamic interactions. Damaged glycocalyx models showed a relatively weak efficiency in sieving plasma solutes. We estimated the energy barriers and corresponding mean first passage times for nanoscale solute transport through the model glycocalyx.
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| 7. |
- Kabedev, Aleksei, et al.
(författare)
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Molecular Dynamics Simulations as a Tool to Understand Drug Solubilization in Pharmaceutical Systems
- 2023
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Ingår i: Reference Module in Chemistry, Molecular Sciences and Chemical Engineering. - : Elsevier.
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Bokkapitel (refereegranskat)abstract
- This chapter aims to explore the use of molecular dynamics (MD) simulations to investigate the solubilization of drugs by various surfactants and excipients. Examples from the literature are presented to demonstrate that MD simulations provide valuable insights into the solubilization mechanisms, and several metrics for predicting drug solubility in complex formulations are also presented and discussed. We also indicate the potential that is to be found in this area by the combination of MD simulations with machine learning methods.
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| 8. |
- Kabedev, Aleksei, et al.
(författare)
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Molecular dynamics simulations reveal membrane interactions for poorly water-soluble drugs : impact of bile solubilization and drug aggregation
- 2021
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier. - 0022-3549 .- 1520-6017. ; 110:1, s. 176-185
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Tidskriftsartikel (refereegranskat)abstract
- Molecular transport mechanisms of poorly soluble hydrophobic drug compounds to lipid membranes were investigated using molecular dynamics (MD) simulations. The model compound danazol was used to investigate the mechanism(s) by which bile micelles delivered it to the membrane. The interactions between lipid membrane and pure drug aggregates—in the form of amorphous aggregates and nanocrystals—were also studied. Our simulations indicate that bile micelles formed in the intestinal fluid may facilitate danazol incorporation into cellular membranes through two different mechanisms. The micelle may be acting as: i) a shuttle that presents the danazol directly to the membrane or ii) an elevator that moves the solubilized danazol with it as the colloidal structure itself becomes incorporated and solubilized within the membrane. The elevator hypothesis was supported by complementary lipid monolayer adsorption experiments. In these experiments, colloidal structures formed with simulated intestinal fluid were observed to rapidly incorporate into the monolayer. Simulations of membrane interaction with drug aggregates showed that both the amorphous aggregates and crystalline nanostructures incorporated into the membrane. However, the amorphous aggregates solubilized more quickly than the nanocrystals into the membrane, thereby improving the danazol absorption.
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| 9. |
- Kabedev, Aleksei, et al.
(författare)
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Molecular dynamics study on micelle-small molecule interactions : developing a strategy for an extensive comparison
- 2024
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Ingår i: Journal of Computer-Aided Molecular Design. - : Springer Nature. - 0920-654X .- 1573-4951. ; 38:1
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Tidskriftsartikel (refereegranskat)abstract
- Theoretical predictions of the solubilizing capacity of micelles and vesicles present in intestinal fluid are important for the development of new delivery techniques and bioavailability improvement. A balance between accuracy and computational cost is a key factor for an extensive study of numerous compounds in diverse environments. In this study, we aimed to determine an optimal molecular dynamics (MD) protocol to evaluate small-molecule interactions with micelles composed of bile salts and phospholipids. MD simulations were used to produce free energy profiles for three drug molecules (danazol, probucol, and prednisolone) and one surfactant molecule (sodium caprate) as a function of the distance from the colloid center of mass. To address the challenges associated with such tasks, we compared different simulation setups, including freely assembled colloids versus pre-organized spherical micelles, full free energy profiles versus only a few points of interest, and a coarse-grained model versus an all-atom model. Our findings demonstrate that combining these techniques is advantageous for achieving optimal performance and accuracy when evaluating the solubilization capacity of micelles.Graphical abstractAll-atom (AA) and coarse-grained (CG) umbrella sampling (US) simulations and point-wise free energy (FE) calculations were compared to their efficiency to computationally analyze the solubilization of active pharmaceutical ingredients in intestinal fluid colloids.
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| 10. |
- Kabedev, Aleksei, et al.
(författare)
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Stabilizing Mechanisms of β-Lactoglobulin in Amorphous Solid Dispersions of Indomethacin
- 2022
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 19:11, s. 3922-3933
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Tidskriftsartikel (refereegranskat)abstract
- Proteins, and in particular whey proteins, have recently been introduced as a promising excipient class for stabilizing amorphous solid dispersions. However, despite the efficacy of the approach, the molecular mechanisms behind the stabilization of the drug in the amorphous form are not yet understood. To investigate these, we used experimental and computational techniques to study the impact of drug loading on the stability of protein-stabilized amorphous formulations. β-Lactoglobulin, a major component of whey, was chosen as a model protein and indomethacin as a model drug. Samples, prepared by either ball milling or spray drying, formed single-phase amorphous solid dispersions with one glass transition temperature at drug loadings lower than 40–50%; however, a second glass transition temperature appeared at drug loadings higher than 40–50%. Using molecular dynamics simulations, we found that a drug-rich phase occurred at a loading of 40–50% and higher, in agreement with the experimental data. The simulations revealed that the mechanisms of the indomethacin stabilization by β-lactoglobulin were a combination of (a) reduced mobility of the drug molecules in the first drug shell and (b) hydrogen-bond networks. These networks, formed mostly by glutamic and aspartic acids, are situated at the β-lactoglobulin surface, and dependent on the drug loading (>40%), propagated into the second and subsequent drug layers. The simulations indicate that the reduced mobility dominates at low (<40%) drug loadings, whereas hydrogen-bond networks dominate at loadings up to 75%. The computer simulation results agreed with the experimental physical stability data, which showed a significant stabilization effect up to a drug fraction of 70% under dry storage. However, under humid conditions, stabilization was only sufficient for drug loadings up to 50%, confirming the detrimental effect of humidity on the stability of protein-stabilized amorphous formulations.
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| 11. |
- Liu, Kang-Cheng, et al.
(författare)
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Membrane insertion mechanism of the caveola coat protein Cavin1
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:25
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are small plasma membrane invaginations, important for control of membrane tension, signaling cascades, and lipid sorting. The caveola coat protein Cavin1 is essential for shaping such high curvature membrane structures. Yet, a mechanistic understanding of how Cavin1 assembles at the membrane interface is lacking. Here, we used model membranes combined with biophysical dissection and computational modeling to show that Cavin1 inserts into membranes. We establish that initial phosphatidylinositol (4, 5) bisphosphate [PI(4,5)P2]-dependent membrane adsorption of the trimeric helical region 1 (HR1) of Cavin1 mediates the subsequent partial separation and membrane insertion of the individual helices. Insertion kinetics of HR1 is further enhanced by the presence of flanking negatively charged disordered regions, which was found important for the coassembly of Cavin1 with Caveolin1 in living cells. We propose that this intricate mechanism potentiates membrane curvature generation and facilitates dynamic rounds of assembly and disassembly of Cavin1 at the membrane.
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| 12. |
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| 13. |
- Salo-Ahen, Outi M. H., et al.
(författare)
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Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
- 2021
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Ingår i: Processes. - : MDPI. - 2227-9717. ; 9:1
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Forskningsöversikt (refereegranskat)abstract
- Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.
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| 14. |
- Zhuo, Xuezhi, et al.
(författare)
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Analysis of stabilization mechanisms in β-lactoglobulin-based amorphous solid dispersions by experimental and computational approaches
- 2024
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier. - 0928-0987 .- 1879-0720. ; 192
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Tidskriftsartikel (refereegranskat)abstract
- Our previous work shows that β-lactoglobulin-stabilized amorphous solid dispersion (ASD) loaded with 70 % indomethacin remains stable for more than 12 months. The stability is probably due to hydrogen bond networks spread throughout the ASD, facilitated by the indomethacin which has both hydrogen donors and acceptors. To investigate the stabilization mechanisms further, here we tested five other drug molecules, including two without any hydrogen bond donors. A combination of experimental techniques (differential scanning calorimetry, X-ray power diffraction) and molecular dynamics simulations was used to find the maximum drug loadings for ASDs with furosemide, griseofulvin, ibuprofen, ketoconazole and rifaximin. This approach revealed the underlying stabilization factors and the capacity of computer simulations to predict ASD stability. We searched the ASD models for crystalline patterns, and analyzed diffusivity of the drug molecules and hydrogen bond formation. ASDs loaded with rifaximin and ketoconazole remained stable for at least 12 months, even at 90 % drug loading, whereas stable drug loadings for furosemide, griseofulvin and ibuprofen were at a maximum of 70, 50 and 40 %, respectively. Steric confinement and hydrogen bonding to the proteins were the most important stabilization mechanisms at low drug loadings (≤ 40 %). Inter-drug hydrogen bond networks (including those with induced donors), ionic interactions, and a high Tg of the drug molecule were additional factors stabilizing the ASDs at drug loading greater than 40 %.
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| 15. |
- Zhuo, Xuezhi, et al.
(författare)
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Mechanisms of Drug Solubility Enhancement Induced by β-Lactoglobulin-Based Amorphous Solid Dispersions
- 2023
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 20:10, s. 5206-5213
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Tidskriftsartikel (refereegranskat)abstract
- Protein-based amorphous solid dispersions (ASDs) have emerged as a promising approach for enhancing solubility in comparison to crystalline drugs. The dissolution behavior of protein-based amorphous solid dispersions (ASDs) was investigated in various pH media. ASDs of four poorly soluble model drugs with acidic ( furosemide and indomethacin), basic (carvedilol), and neutral (celecoxib) properties were prepared by spray drying at 30 wt % drug loading with the protein ss-lactoglobulin (BLG). The effect of spray-dried BLG (SD-BLG) solubility and protein binding ability with dissolved drugs in solution were investigated to retrieve the mechanisms governing the improvement of drug solubility from the BLG-based ASDs. Powder dissolution results showed that all ASDs obtained a higher maximum concentration (C-max) compared to the respective pure crystalline drugs. It was found that the solubility increase of the drugs from the ASDs was to a large extent dependent on the solubility of the pure SD-BLG at the investigated pH values (low solubility at pH near the isoelectric point (pI) of BLG). Furthermore, drug-protein interactions in a solution were observed, in particular at pH values where the drugs were neutral. These drug-protein interactions also resulted, to some extent, in the stabilization of the drug in supersaturation.
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