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Sökning: WFRF:(Kabedev Aleksei) > Stabilizing Mechani...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00004714naa a2200481 4500
001oai:DiVA.org:uu-490610
003SwePub
008221213s2022 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4906102 URI
0247 a https://doi.org/10.1021/acs.molpharmaceut.2c003972 DOI
040 a (SwePub)uu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Kabedev, Alekseiu Uppsala universitet,Institutionen för farmaci4 aut0 (Swepub:uu)aleka155
2451 0a Stabilizing Mechanisms of β-Lactoglobulin in Amorphous Solid Dispersions of Indomethacin
264 c 2022-09-22
264 1b American Chemical Society (ACS),c 2022
338 a electronic2 rdacarrier
520 a 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.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
653 a amorphous solid dispersion
653 a β-lactoglobulin
653 a molecular dynamics simulation
653 a stability
653 a hydrogen bonds
653 a mobility
653 a poorly soluble drugs
7001 a Zhuo, Xuezhiu Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark4 aut
7001 a Leng, Dongleiu Zerion Pharma A/S, Blokken 11, 3460 Birkerød, Denmark4 aut
7001 a Foderà, Vitou Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark4 aut
7001 a Zhao, Minu School of Pharmacy, Queen’s University Belfast, Belfast BT9 7BL, U.K.;Queen’s University Belfast Joint College (CQC), China Medical University, Shenyang 110000, China4 aut
7001 a Larsson, Peru Uppsala universitet,Institutionen för farmaci4 aut0 (Swepub:uu)pelar499
7001 a Bergström, Christel,d 1973-u Uppsala universitet,Institutionen för farmaci4 aut0 (Swepub:uu)cjo29958
7001 a Löbmann, Korbinianu Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark;Zerion Pharma A/S, Blokken 11, 3460 Birkerød, Denmark4 aut
7102 a Uppsala universitetb Institutionen för farmaci4 org
7730 t Molecular Pharmaceuticsd : American Chemical Society (ACS)g 19:11, s. 3922-3933q 19:11<3922-3933x 1543-8384x 1543-8392
8564 u https://doi.org/10.1021/acs.molpharmaceut.2c00397y Fulltext
8564 u https://uu.diva-portal.org/smash/get/diva2:1718565/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-490610
8564 8u https://doi.org/10.1021/acs.molpharmaceut.2c00397

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