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- 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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| 2. |
- 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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