{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:23:25Z","timestamp":1787732605885,"version":"build-2784847793"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373825"],"award-info":[{"award-number":["82373825"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82373825"],"award-info":[{"award-number":["82373825"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Science and Technology Innovation Action Plan of Shanghai","award":["22DX1900400"],"award-info":[{"award-number":["22DX1900400"]}]},{"name":"Qingfeng Scholar Fund of Shanghai Medical College, Fudan University"},{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Objective: Conventional progesterone (P4) formulations suffer from low bioavailability, severe local irritation, and poor patient adherence due to P4\u2019s poor aqueous solubility. This work aimed to develop and screen a biodegradable PLGA\/NMP (Poly(lactic-co-glycolic acid)\/N-methyl-2-pyrrolidone) injectable in situ gel for sustained P4 delivery to overcome these clinical limitations. Significance: Commercial oral, vaginal, and oil-based intramuscular P4 preparations cannot maintain stable long-term drug exposure, and they cause injection-site pain\/inflammation. The screened in situ depot system reduces administration frequency and local tissue irritation, supporting convenient luteal phase support and pregnancy maintenance. Methods: Nine formulations with variable P4 loading (10\u201350% w\/w) and PLGA concentration (15\u201355% w\/w) were fabricated. Formulations were screened via three core endpoints: injectability (injection force and discharge rate), in vitro sustained release in 10% Hydroxypropyl-\u03b2-cyclodextrin (HP-\u03b2-CD)-Phosphate-buffered saline (PBS) sink medium, and 7-day subcutaneous histocompatibility in rats. high-performance liquid chromatography (HPLC) was validated for progesterone quantification; Hematoxylin and eosin (H&amp;E) staining assessed local inflammatory responses. Results: Formulations with progesterone \u2264 30% w\/w and PLGA \u2264 35% w\/w exhibited acceptable injectability (injection force &lt; 50 N; discharge rate &gt; 79%). Higher PLGA concentrations suppressed initial burst release (16.74% at 8 h for 35% PLGA vs. 29.8% for 20% PLGA). All formulations formed stable ellipsoidal subcutaneous depots and completed progesterone release within 4 days. Histopathology revealed only mild local inflammation (histological score = 1) without severe necrosis, superior to highly irritating oil injections in formulation control groups. Conclusions: The screened PLGA-based progesterone in situ gel resolves critical drawbacks of traditional progesterone dosage forms. This low-irritation, sustained-release injectable platform provides a scalable industrial formulation candidate for long-acting hormone therapy.<\/jats:p>","DOI":"10.3390\/ph19091347","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:11:15Z","timestamp":1787731875000},"page":"1347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Formulation Screening and Characterization of PLGA-Based Injectable In Situ Gel Loaded with Progesterone"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0104-1950","authenticated-orcid":false,"given":"Zhihan","family":"Zhu","sequence":"first","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8526-3122","authenticated-orcid":false,"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China"},{"name":"State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linglin","family":"Feng","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","unstructured":"(2026, March 06). UNICEF Data: Monitoring the Situation of Children and Women. Born Too Soon: Decade of Action on Preterm Birth. Available online: https:\/\/data.unicef.org\/resources\/born-too-soon-decade-of-action-on-preterm-birth\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jconrel.2018.12.046","article-title":"Development of a mucoinert progesterone nanosuspension for safer and more effective prevention of preterm birth","volume":"295","author":"Hoang","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1542\/peds.2007-2012","article-title":"Infant and childhood growth patterns, insulin sensitivity, and blood pressure in prematurely born young adults","volume":"122","author":"Rotteveel","year":"2008","journal-title":"Pediatrics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105187","DOI":"10.1016\/j.earlhumdev.2020.105187","article-title":"An overview of adult health outcomes after preterm birth","volume":"150","author":"Crump","year":"2020","journal-title":"Early Hum. Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"405","DOI":"10.5468\/ogs.2017.60.5.405","article-title":"Use of progesterone supplement therapy for prevention of preterm birth: Review of literatures","volume":"60","author":"Choi","year":"2017","journal-title":"Obstet. Gynecol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1055\/a-0854-6472","article-title":"Progesterone for the prevention of preterm birth\u2014An update of evidence-based indications","volume":"79","author":"Kuon","year":"2019","journal-title":"Geburtshilfe Frauenheilkd."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1007\/s10973-025-14712-9","article-title":"Preformulation studies of progesterone: An instrumental approach","volume":"151","author":"Ridichie","year":"2026","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_8","first-page":"62","article-title":"Effect of PEG-400 and cyclodextrins on the solubility of progesterone","volume":"28","author":"Joshi","year":"2004","journal-title":"Pharm. Technol."},{"key":"ref_9","first-page":"104930","article-title":"Preparation and pharmacokinetics study of albumin-coated crystalline progesterone long-acting microcapsules for injection","volume":"88","author":"Sun","year":"2023","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_10","unstructured":"DailyMed (2026, August 05). PROGESTERONE Injection, USP [Package Insert], Available online: https:\/\/dailymed.nlm.nih.gov\/dailymed\/drugInfo.cfm?setid=a479b395-1e1a-4d2a-8feb-68a15c47225f."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1016\/S0015-0282(03)01170-1","article-title":"Hypersensitivity to progesterone-in-oil after in vitro fertilization and embryo transfer","volume":"80","author":"Phy","year":"2003","journal-title":"Fertil. Steril."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15761\/COGRM.1000296","article-title":"Subcutaneous progesterone (Prolutex) for luteal phase support in cycles of in vitro fertilization\u2013embryo transfer\u2014A retrospective cohort study","volume":"6","author":"Hibshi","year":"2020","journal-title":"Clin. Obstet. Gynecol. Reprod. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/aogs.12765","article-title":"Pharmaceutical and clinical development of a novel progesterone formulation","volume":"94","author":"Cometti","year":"2015","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.jconrel.2022.03.057","article-title":"Non-oral routes, novel formulations and devices of contraceptives: An update","volume":"345","author":"Gupta","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/S0015-0282(16)56031-2","article-title":"The absorption of oral micronized progesterone: The effect of food, dose proportionality, and comparison with intramuscular progesterone","volume":"60","author":"Simon","year":"1993","journal-title":"Fertil. Steril."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Coombes, Z., Plant, K., Freire, C., Basit, A.W., Butler, P., Conlan, R.S., Thong, K.L., Chatzimichail, S., Stringer, A.M., and Gershkovich, P. (2021). Progesterone metabolism by human and rat hepatic and intestinal tissue. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13101707"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/S0015-0282(99)00553-1","article-title":"Comparison of the pharmacokinetics of Crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women","volume":"73","author":"Levine","year":"2000","journal-title":"Fertil. Steril."},{"key":"ref_18","first-page":"137","article-title":"The pharmacodynamics and safety of progesterone","volume":"52","author":"Piette","year":"2018","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1007\/s11095-014-1616-8","article-title":"Thermosensitive progesterone hydrogel: A safe and effective new formulation for vaginal application","volume":"32","author":"Almomen","year":"2015","journal-title":"Pharm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1097\/00003081-199538040-00024","article-title":"Micronised progesterone: Vaginal and oral uses","volume":"38","author":"Simon","year":"1995","journal-title":"Clin. Obstet. Gynecol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5349","DOI":"10.1039\/C6RA27676H","article-title":"Hydrophobic mixed solvent induced PLGA-based in situ forming systems for smooth long-lasting delivery of Radix Ophiopogonis polysaccharide in rats","volume":"7","author":"Wang","year":"2017","journal-title":"RSC Adv."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115003","DOI":"10.1016\/j.addr.2023.115003","article-title":"Polymeric in situ forming depots for long-acting drug delivery systems","volume":"200","author":"Pandya","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"121021","DOI":"10.1016\/j.ijpharm.2021.121021","article-title":"Novel injectable progesterone-loaded nanoparticles embedded in SAIB-PLGA in situ depot system for sustained drug release","volume":"607","author":"Cao","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.jconrel.2012.01.043","article-title":"PLGA-based nanoparticles: An overview of biomedical applications","volume":"161","author":"Danhier","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jconrel.2013.08.024","article-title":"PLGA in situ implants formed by phase inversion: Critical physicochemical parameters to modulate drug release","volume":"172","author":"Parent","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.jconrel.2023.08.029","article-title":"In situ forming risperidone implants: Effect of PLGA attributes on product performance","volume":"361","author":"Wang","year":"2023","journal-title":"J. Control. Release"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ejpb.2023.06.017","article-title":"Evaluating the injectability of injectable microparticle delivery systems on the basis of injection force and discharge rate","volume":"190","author":"Zhao","year":"2023","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3525","DOI":"10.1016\/j.xphs.2024.09.026","article-title":"Injectability of high concentrated suspensions using model microparticles","volume":"113","author":"Kowsari","year":"2024","journal-title":"J. Pharm. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1007\/s13346-018-0491-y","article-title":"In situ forming phase-inversion implants for sustained ocular delivery of triamcinolone acetonide","volume":"9","author":"Sheshala","year":"2019","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"104014","DOI":"10.1016\/j.xphs.2025.104014","article-title":"Progesterone-PLGA in situ formed implants: Structural parameters correlations with in vitro and in vivo mathematical models","volume":"114","author":"Karp","year":"2025","journal-title":"J. Pharm. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ijpharm.2011.05.049","article-title":"The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems\u2014A review","volume":"415","author":"Fredenberg","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Omidian, H., and Wilson, R.L. (2025). PLGA implants for controlled drug delivery and regenerative medicine: Advances, challenges, and clinical potential. Pharmaceuticals, 18.","DOI":"10.3390\/ph18050631"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1053\/j.semperi.2017.08.004","article-title":"17-alpha hydroxyprogesterone caproate for preterm birth prevention: Where have we been, how did we get here, and where are we going?","volume":"41","author":"Manuck","year":"2017","journal-title":"Semin. Perinatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1080\/10717544.2021.1943056","article-title":"Poly(lactic-co-glycolic acid) microsphere production based on quality by design: A review","volume":"28","author":"Hua","year":"2021","journal-title":"Drug Deliv."},{"key":"ref_35","first-page":"657","article-title":"Review: Approaches to develop PLGA based in situ gelling system with low initial burst","volume":"28","author":"Ahmed","year":"2015","journal-title":"Pak. J. Pharm. Sci."},{"key":"ref_36","first-page":"325","article-title":"Preparation and in vitro release of progesterone thermosensitive in situ gel","volume":"45","author":"Lin","year":"2014","journal-title":"J. China Pharm. Univ."},{"key":"ref_37","first-page":"1203","article-title":"Sustained-release progesterone nanosuspension following intramuscular injection in ovariectomized rats","volume":"7","author":"Salem","year":"2012","journal-title":"Int. J. Nanomed."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3252","DOI":"10.1002\/jps.21091","article-title":"Sucrose acetate isobutyrate as an in situ forming system for sustained risperidone release","volume":"96","author":"Lu","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.ejpb.2004.03.003","article-title":"In situ forming parenteral drug delivery systems: An overview","volume":"58","author":"Packhaeuser","year":"2004","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_40","first-page":"271","article-title":"Injectability of biodegradable in situ forming microparticle systems (ISM)","volume":"73","author":"Rungseevijitprapa","year":"2009","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1002\/jps.22033","article-title":"The solubility\u2013permeability interplay in using cyclodextrins as pharmaceutical solubilizers: Mechanistic modeling and application to progesterone","volume":"99","author":"Dahan","year":"2010","journal-title":"J. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Beig, A., Agbaria, R., and Dahan, A. (2013). Oral delivery of lipophilic drugs: The tradeoff between solubility increase and permeability decrease when using cyclodextrin-based formulations. PLoS ONE, 8.","DOI":"10.1371\/annotation\/10ae05dc-90cb-46f1-aa2b-e63eb4a132e2"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"120494","DOI":"10.1016\/j.ijpharm.2021.120494","article-title":"In vitro\u2013in vivo correlation in the effect of cyclodextrin on oral absorption of poorly soluble drugs","volume":"600","author":"Aihara","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1111\/jphp.13277","article-title":"Release rate determination from in situ gel forming PLGA implant: A novel \u2018shape-controlled basket in tube\u2019 method","volume":"72","author":"Zhang","year":"2020","journal-title":"J. Pharm. Pharmacol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/9\/1347\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:17:08Z","timestamp":1787732228000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/9\/1347"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ph19091347"],"URL":"https:\/\/doi.org\/10.3390\/ph19091347","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]}}}