{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:06:59Z","timestamp":1779340019562,"version":"3.51.4"},"reference-count":32,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Teva Pharmaceutical Industries, Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: TV-44749 is a subcutaneous (sc) long-acting injectable (LAI) formulation of olanzapine that recently demonstrated efficacy and safety as a treatment for schizophrenia in adults without the occurrence of post-injection delirium\/sedation syndrome (PDSS) in the phase 3 SOLARIS trial (NCT05693935). TV-44749\u2019s sc route of administration and formulation were designed to provide prolonged olanzapine release over a monthly dosing interval and to avoid the risk of post-injection delirium\/sedation syndrome (PDSS). It was designed as a copolymer in situ-forming depot technology to provide a LAI formulation that could withstand physiological and environmental factors that could affect controlled-release kinetics. Methods: To evaluate the robustness of the TV-44749 formulation, an in vitro release (IVR) study in human plasma was conducted, comparing TV-44749 to the commercially available intramuscular (im) long-acting injection formulation of olanzapine pamoate monohydrate. In addition, in vivo studies in rats were conducted to assess the effect of injection site manipulation following TV-44749 sc injection on olanzapine release from the depot. Results: The IVR study showed that upon contact with human plasma, copolymers comprising TV-44749 formulation instantly precipitate and form a solid matrix that entraps olanzapine particles. This prevents an uncontrolled release of olanzapine. Additionally, in vivo rat studies found that manipulation of the injection site after TV-44749 administration, by either heating or rubbing at different time-points, resulted in no meaningful effect on overall olanzapine exposure. Conclusions: The presented findings support the robustness of the TV-44749 formulation in maintaining controlled-release properties, even under conditions that could otherwise compromise release performance.<\/jats:p>","DOI":"10.3390\/pharmaceutics18050601","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T16:39:34Z","timestamp":1779295174000},"page":"601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Olanzapine for Extended-Release Injectable Suspension for Subcutaneous Use (TV-44749) Designed to Avoid the Risk of PDSS: In Vitro Release Studies in Human Plasma and In Vivo Impact of Extrinsic Factors on Pharmacokinetics"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9174-5690","authenticated-orcid":false,"given":"David","family":"Bibi","sequence":"first","affiliation":[{"name":"Innovative Research and Development, Teva Pharmaceutical Industries Ltd., Netanya 4250400, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilach","family":"Steiner","sequence":"additional","affiliation":[{"name":"Innovative Research and Development, Teva Pharmaceutical Industries Ltd., Netanya 4250400, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5649-3535","authenticated-orcid":false,"given":"Iva","family":"Krtalic","sequence":"additional","affiliation":[{"name":"Research and Development, PLIVA Croatia Ltd., Teva, 10000 Zagreb, Croatia"},{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kova\u010di\u0107a 1, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3912-2429","authenticated-orcid":false,"given":"Marina","family":"Juretic","sequence":"additional","affiliation":[{"name":"Research and Development, PLIVA Croatia Ltd., Teva, 10000 Zagreb, Croatia"},{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kova\u010di\u0107a 1, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1227-9024","authenticated-orcid":false,"given":"Biserka","family":"Cetina-Cizmek","sequence":"additional","affiliation":[{"name":"Research and Development, PLIVA Croatia Ltd., Teva, 10000 Zagreb, Croatia"},{"name":"Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kova\u010di\u0107a 1, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Komlosi","sequence":"additional","affiliation":[{"name":"R&D Bioanalytical Laboratory, Teva Pharmaceutical Works P. Ltd., Co. (TPW), 4042 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pippa","family":"Loupe","sequence":"additional","affiliation":[{"name":"Innovative Research and Development, Teva Pharmaceutical Industries Ltd., Netanya 4250400, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7883-1769","authenticated-orcid":false,"given":"Kristina","family":"Ferderber","sequence":"additional","affiliation":[{"name":"Research and Development, PLIVA Croatia Ltd., Teva, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1685-1374","authenticated-orcid":false,"given":"Hussein","family":"Hallak","sequence":"additional","affiliation":[{"name":"Innovative Research and Development, Teva Pharmaceutical Industries Ltd., Netanya 4250400, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"ref_1","unstructured":"National Institute of Mental Health (NIMH) (2026, April 07). Schizophrenia, Available online: https:\/\/www.nimh.nih.gov\/health\/statistics\/schizophrenia."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"MS21078COM5","DOI":"10.4088\/JCP.MS21078COM5","article-title":"The epidemiology and global burden of schizophrenia","volume":"84","author":"Velligan","year":"2023","journal-title":"J. Clin. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5319","DOI":"10.1038\/s41380-023-02138-4","article-title":"Incidence, prevalence, and global burden of schizophrenia: Data, with critical appraisal, from the Global Burden of Disease 2019","volume":"28","author":"Solmi","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zhang, S., Chen, Y., Zhang, L., Yang, X., Dong, J., Lu, M., Zhou, N., Feng, Y., Zhang, Y., and Zhou, Y. (2026). Global lifetime prevalence of schizophrenia: A systematic review and meta-analysis. Mol. Psychiatry, 31.","DOI":"10.1038\/s41380-026-03533-3"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/wps.20516","article-title":"What is the risk\u2013benefit ratio of long-term antipsychotic treatment in people with schizophrenia?","volume":"17","author":"Correll","year":"2018","journal-title":"World Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1080\/13696998.2017.1379412","article-title":"Medication adherence and discontinuation of long-acting injectable versus oral antipsychotics in patients with schizophrenia or bipolar disorder","volume":"21","author":"Greene","year":"2018","journal-title":"J. Med. Econ."},{"key":"ref_7","first-page":"HS1","article-title":"A practical review of long-acting injectable antipsychotics","volume":"49","author":"Hu","year":"2024","journal-title":"US Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1007\/s40120-025-00838-3","article-title":"The use of long-acting injectables for people with schizophrenia: Consensus panel recommendations for overcoming barriers and implementing treatment","volume":"14","author":"Kane","year":"2025","journal-title":"Neurol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"773","DOI":"10.3122\/jabfm.2022.220425R2","article-title":"A comprehensive guide to long-acting injectable antipsychotics for primary care clinicians","volume":"37","author":"Krishna","year":"2024","journal-title":"J. Am. Board. Fam. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Markowicz-Plasecka, M., Kubisiak, M., Asendrych-Wicik, K., Kolodziejczyk, M., Grzelinska, J., Fabijanska, M., and Pietrzak, T. (2023). Long-acting injectable antipsychotics-a review on formulation and in vitro dissolution. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16010028"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0893-133X(94)00129-N","article-title":"Radioreceptor binding profile of the atypical antipsychotic olanzapine","volume":"14","author":"Bymaster","year":"1996","journal-title":"Neuropsychopharmacology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1176\/ajp.154.4.457","article-title":"Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: Results of an international collaborative trial","volume":"154","author":"Tollefson","year":"1997","journal-title":"Am. J. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1192\/bjp.172.6.499","article-title":"Oral olanzapine versus oral haloperidol in the maintenance treatment of schizophrenia and related psychoses","volume":"172","author":"Tran","year":"1998","journal-title":"Br. J. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/S0140-6736(08)60486-9","article-title":"Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: A randomized clinical trial","volume":"371","author":"Kahn","year":"2008","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/0893-133X(95)00069-P","article-title":"Olanzapine versus placebo and haloperidol: Acute phase results of the North American double-blind olanzapine trial","volume":"14","author":"Beasley","year":"1996","journal-title":"Neuropsychopharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1176\/ajp.155.7.914","article-title":"Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia","volume":"155","author":"Conley","year":"1998","journal-title":"Am. J. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1111\/j.1600-0447.2004.00450.x","article-title":"Effectiveness of antipsychotic treatment for schizophrenia: 6-month results of the Pan-European Schizophrenia Outpatient Health Outcomes (SOHO) study","volume":"111","author":"Haro","year":"2005","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1056\/NEJMoa051688","article-title":"Effectiveness of antipsychotic drugs in patients with chronic schizophrenia","volume":"353","author":"Lieberman","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(13)60733-3","article-title":"Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis","volume":"382","author":"Leucht","year":"2013","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"473","DOI":"10.2165\/00023210-200216070-00004","article-title":"Relapse and rehospitalisation rates in patients with schizophrenia: Effects of second generation antipsychotics","volume":"16","author":"Csernansky","year":"2002","journal-title":"CNS Drugs"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1001\/jamapsychiatry.2015.2955","article-title":"Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-Analysis","volume":"73","author":"Samara","year":"2016","journal-title":"JAMA Psychiatry"},{"key":"ref_22","first-page":"39","article-title":"Remission, response, and relapse rates in patients with acute schizophrenia treated with olanzapine monotherapy or other atypical antipsychotic monotherapy: 12-month prospective observational study","volume":"6","author":"Takahashi","year":"2015","journal-title":"Pragmat. Obs. Res."},{"key":"ref_23","unstructured":"CHEPLAPHARM (2026, January 01). Zyprexa Relprevv. Registration GmbH 2023. Greifswald, Germany. Available online: https:\/\/www.zyprexarelprevvprogram.com\/public\/Default.aspx."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"McDonnell, D.P., Detke, H.C., Bergstrom, R.F., Kothare, P., Johnson, J., Stickelmeyer, M., Sanchez-Felix, M.V., Sorsaburu, S., and I Mitchell, M. (2010). Post-injection delirium\/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, II: Investigations of mechanism. BMC Psychiatry, 10.","DOI":"10.1186\/1471-244X-10-45"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9613","DOI":"10.1038\/s41598-017-10110-w","article-title":"Effective method for drug injection into subcutaneous tissue","volume":"7","author":"Kim","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","first-page":"55","article-title":"Injection technique 2: Administering drugs via the subcutaneous route","volume":"114","author":"Shepherd","year":"2018","journal-title":"Nurs. Times"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.jconrel.2020.01.022","article-title":"BEPO\u00ae: Bioresorbable diblock mPEG-PDLLA and triblock PDLLA-PEG-PDLLA based in situ forming depots with flexible drug delivery kinetics modulation","volume":"319","author":"Roberge","year":"2020","journal-title":"J. Control Release"},{"key":"ref_28","unstructured":"Krasenbaum, L. (2026, January 01). Long-Term Effectiveness With Subcutaneous Long-Acting Injectable Olanzapine (TV-44749) in Adults With Schizophrenia: Results From up to 48 Weeks Open Label Treatment in the Phase 3 SOLARIS Trial US Psych Congress 2025. Poster #96. Available online: https:\/\/www.hmpgloballearningnetwork.com\/node\/347624."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s40261-025-01507-x","article-title":"Safety, Tolerability, and Pharmacokinetics of Subcutaneous Extended Release Injectable Olanzapine in Patients with Schizophrenia and Schizoaffective Disorder","volume":"46","author":"Cherniakov","year":"2026","journal-title":"Clin. Drug Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1192\/bjpo.bp.116.004382","article-title":"Postinjection delirium\/sedation syndrome in patients with schizophrenia receiving olanzapine long-acting injection: Results from a large observational study","volume":"3","author":"Meyers","year":"2017","journal-title":"BJPsych Open"},{"key":"ref_31","unstructured":"Vandenhende, F., Burton, I., Ahrweiler, S., and Buchheit, V. (2014). Analyses and Displays Associated to Non-Compartmental Pharmacokinetics\u2014With a Focus on Clinical Trials, PhUSE CSS. A White Paper by the PhUSE CSS Development of Standard Scripts for Analysis and Programming Working Group; Version 1.0\u2014Final."},{"key":"ref_32","unstructured":"Correll, C.U., Shulman, K., Bar-Nur, T., Gidron-Budovsky, R., Sharon, N., Jehassi, A., Franzenburg, K.R., Suett, M., Pelleg, O., and Knebel, H. (2026, January 01). Long-Term Safety of Subcutaneous Long-Acting Injectable Olanzapine (TV-44749) in Schizophrenia: Results From the Phase 3 SOLARIS Trial. Presentation at US Psych Congress 2025. Available online: https:\/\/www.hmpgloballearningnetwork.com\/node\/371691."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/5\/601\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:15:54Z","timestamp":1779336954000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/5\/601"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,14]]},"references-count":32,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["pharmaceutics18050601"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18050601","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,14]]}}}