{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:17:07Z","timestamp":1786979827453,"version":"build-2736575974"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Medizinische Fakult\u00e4t Heidelberg der Universit\u00e4t Heidelberg"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Clin Pharmacol"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>The use of two-dimensional (2D) printing technologies of drugs on orodispersible films (ODF) can promote dose individualization and facilitate drug delivery in vulnerable patients, including children. We investigated midazolam pharmacokinetics after the administration of 2D-printed ODF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Midazolam doses of 0.03 and 3\u00a0mg were printed on an ODF using a 2D drug printer. We investigated the bioavailability of the two midazolam doses with ODF swallowed immediately (ODF-IS) or delayed after 2\u00a0min (ODF-DS) by comparing their pharmacokinetics with intravenous and oral midazolam solution in 12 healthy volunteers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The relative bioavailability of ODF-IS 0.03\u00a0mg was 102% (90% confidence interval: 89.4\u2013116) compared to oral solution and for 3\u00a0mg 101% (86.8\u2013116).\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      of ODF-IS 0.03\u00a0mg was 95.5% (83.2\u2013110) compared to oral solution and 94.3% (78.2\u2013114) after 3\u00a0mg. Absolute bioavailability of ODF-IS 0.03\u00a0mg was 24.9% (21.2\u201329.2) and for 3\u00a0mg 28.1% (23.4\u201333.8) (oral solution: 0.03\u00a0mg: 24.4% (22.0\u201327.1); 3\u00a0mg: 28.0% (25.0\u201331.2)). Absolute bioavailability of ODF-DS was significantly larger than for ODF-IS (0.03\u00a0mg: 61.4%; 3\u00a0mg: 44.1%; both\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This trial demonstrates the tolerability and unchanged bioavailability of midazolam printed on ODF over a 100-fold dose range, proving the suitability of ODF for dose individualization. Midazolam ODF-IS AUC\n                      <jats:sub>0\u2013\u221e<\/jats:sub>\n                      in both doses was bioequivalent to the administration of an oral solution. However,\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      of the therapeutic dose of ODF-IS missed bioequivalence by a clinically not relevant extent. Prolonged mucosal exposure increased bioavailability. (Trial Registration\u00a0EudraCT: 2020\u2013003984-24, August 10, 2020).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00228-022-03406-y","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T17:02:40Z","timestamp":1666112560000},"page":"1965-1972","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Oral bioavailability of microdoses and therapeutic doses of midazolam as a 2-dimensionally printed orodispersible film in healthy volunteers"],"prefix":"10.1007","volume":"78","author":[{"given":"Mareile H.","family":"Breithaupt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Krohmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenka","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Koerner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Hoppe-Tichy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2190-1698","authenticated-orcid":false,"given":"Juergen","family":"Burhenne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin I.","family":"Foerster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Dachtler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Huber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Venkatesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Eggenreich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1217-5134","authenticated-orcid":false,"given":"David","family":"Czock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1783-133X","authenticated-orcid":false,"given":"Gerd","family":"Mikus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Blank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0672-6876","authenticated-orcid":false,"given":"Walter E.","family":"Haefeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"issue":"1","key":"3406_CR1","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s002280050420","volume":"54","author":"JT Backman","year":"1998","unstructured":"Backman JT, Kivist\u00f6 KT, Olkkola KT, Neuvonen PJ (1998) The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. 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The study protocol was approved by the responsible Ethics Committee of the Medical Faculty of Heidelberg University (AFmo-012\/2021) and the German competent authority (EudraCT 2020\u2013003984-24, August 10, 2020). The trial was performed in accordance with Good Clinical Practice, the 1964 Declaration of Helsinki and its later amendments, and all pertinent legal requirements of Germany.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from all individual participants prior to inclusion in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"IMP manufacturing was conducted and financed by Gen-Plus GmbH (MD, RV, and KE) and printed on a 2D Flexdose printer manufactured by DiHeSys (GH). Data analysis and interpretation were not influenced by the involvement of Gen-Plus GmbH. All other authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}