| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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