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We previously developed liposome-encapsulated midazolam (LE-midazolam) for oral administration, but midazolam is metabolized in the liver, and for clinical use the encapsulation of the liposomes needed to be improved to increase the bioavailability of midazolam. The surfaces of pharmaceutical liposomes are generally coated with polyethylene glycol (PEGylation) because it prevents their capture by phagocytes and helps them to avoid the reticuloendothelial system. Therefore, we considered that PEGylation could reduce the metabolism of orally administered encapsulated midazolam in the liver.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Midazolam solution, LE-midazolam solution, and PEGylated liposome-encapsulated midazolam (PEG-LE-midazolam) solution were prepared, and the characteristics of the liposomes in these solutions were evaluated. Furthermore, these solutions were orally administered to rabbits, and the resultant plasma midazolam concentrations were measured. The effects of the PEGylation of LE-midazolam on the plasma concentration and bioavailability of orally administered midazolam were also evaluated.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The PEG-LE-midazolam solution contained a higher percentage of larger liposomes than the LE-midazolam solution. The area under the concentration-time curve (AUC) of the LE-midazolam solution was significantly higher than that of the midazolam solution, but there was no difference between the AUC values of the PEG-LE-midazolam and midazolam solutions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>These findings suggest that liposome encapsulation may reduce the first-pass effect following oral administration, but PEGylation is not expected to improve the bioavailability of orally administered midazolam.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s40360-025-00993-1","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T09:58:41Z","timestamp":1760522321000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["PEGylation of liposome-encapsulated midazolam does not improve the bioavailability of midazolam when administered orally"],"prefix":"10.1186","volume":"26","author":[{"given":"Yukiko","family":"Nishioka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Higuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saki","family":"Miyake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Fujimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Midori","family":"Hamaoka-Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Tanimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitomi","family":"Ujita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Maeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Miyawaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"993_CR1","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/1556-276x-8-102","volume":"8","author":"A Akbarzadeh","year":"2013","unstructured":"Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Joo SW, Zarghami N, Hanifehpour Y, Samiei M, Kouhi M, Nejati-Koshki K. 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