{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T18:00:41Z","timestamp":1785348041206,"version":"3.55.0"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chutian Elite Program of Hubei Province for Health Professionals","award":["2024-09054"],"award-info":[{"award-number":["2024-09054"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Ketorolac tromethamine (KT) is a potent nonsteroidal anti-inflammatory drug (NSAID) used for moderate to severe pain management. Its short elimination half-life necessitates frequent dosing, which can reduce patient compliance. The objective of this study was to formulate, develop, and optimize a novel biphasic-release tablet-in-tablet (TIT) system for KT to provide immediate pain relief followed by extended drug release. A TIT system was designed, comprising an immediate-release (IR) outer layer and an extended-release (ER) core matrix. The ER core was optimized using a 3\n                    <jats:sup>2<\/jats:sup>\n                    full factorial design, with the amounts of HPMC K100M and HPMC K4M as independent variables. Formulations were evaluated for pre- and post-compression parameters, drug-excipient compatibility, and\n                    <jats:italic>in vitro<\/jats:italic>\n                    drug release. The drug release kinetics and mechanism were analyzed using various mathematical models. The optimal ER core formulation (F1) exhibited a drug release of 4.6% at 0.5 h and 66.1% at 12 h, closely matching the theoretical profile (similarity factor\n                    <jats:italic>f<\/jats:italic>\n                    <jats:sub>2<\/jats:sub>\n                    \u2009=\u200951). Release kinetics followed the first-order model and the Korsmeyer-Peppas model indicated an anomalous (non-Fickian) release mechanism (n\u2009=\u20090.831). The corresponding TIT formulation (F11) demonstrated desired physicochemical properties: hardness of 75 N, friability of 0.59%, and rapid outer layer disintegration (&lt;50 s). The TIT provided an initial burst release (~30%) within 30 minutes, followed by sustained release exceeding 90% over 24 hours. This TIT system represents a promising alternative to conventional KT tablets for effective pain management.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0354689","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T17:31:31Z","timestamp":1785346291000},"page":"e0354689","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Formulation development of a biphasic release tablet-in-tablet system containing ketorolac tromethamine"],"prefix":"10.1371","volume":"21","author":[{"given":"Ping","family":"Zou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-ru","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8260-3988","authenticated-orcid":true,"given":"Xiang-yang","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin-ke","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-hui","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"issue":"2","key":"pone.0354689.ref001","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1310\/hpj5002-108","article-title":"The role of subcutaneous ketorolac for pain management","volume":"50","author":"ME Vacha","year":"2015","journal-title":"Hosp Pharm"},{"issue":"9","key":"pone.0354689.ref002","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1517\/17425240903116006","article-title":"Ketorolac tromethamine formulations: an overview","volume":"6","author":"VR Sinha","year":"2009","journal-title":"Expert Opin Drug Deliv"},{"issue":"10","key":"pone.0354689.ref003","doi-asserted-by":"crossref","first-page":"101780","DOI":"10.1016\/j.jsps.2023.101780","article-title":"Study of the effect of active pharmaceutical ingredients of various classes of BCS on the parameters of thermosensitive systems based on poloxamers","volume":"31","author":"EO Bakhrushina","year":"2023","journal-title":"Saudi Pharm J"},{"issue":"6","key":"pone.0354689.ref004","doi-asserted-by":"crossref","first-page":"415","DOI":"10.2165\/00003088-199223060-00003","article-title":"Clinical pharmacokinetics of ketorolac tromethamine","volume":"23","author":"DR Brocks","year":"1992","journal-title":"Clin Pharmacokinet"},{"issue":"9","key":"pone.0354689.ref005","doi-asserted-by":"crossref","first-page":"3633","DOI":"10.1007\/s12325-024-02933-7","article-title":"A Novel Formulation of Ketorolac Tromethamine (NTM-001) in Continuous Infusion in Adults with and without Renal Impairment: A Randomized Controlled Pharmacologic Study","volume":"41","author":"JV Pergolizzi","year":"2024","journal-title":"Adv Ther"},{"issue":"4","key":"pone.0354689.ref006","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1002\/cpdd.319","article-title":"Comparison of the Pharmacokinetics of Ketorolac Tromethamine After Continuous Subcutaneous Infusion and Repeat Intramuscular Bolus Injections in Healthy Adult Subjects","volume":"6","author":"M Burdick","year":"2017","journal-title":"Clin Pharmacol Drug Dev"},{"issue":"9","key":"pone.0354689.ref007","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1002\/jps.2600800915","article-title":"Prolongation of antipyretic action and reduction of gastric ulcerogenicity in the rat by controlled-release granules of bermoprofen, a new nonsteroidal anti-inflammatory drug","volume":"80","author":"M Mori","year":"1991","journal-title":"J Pharm Sci"},{"issue":"1","key":"pone.0354689.ref008","first-page":"19","article-title":"Six-month prospective study to monitor the treatment of rheumatic diseases with sustained-release flurbiprofen","volume":"26","author":"J Rovensk\u00fd","year":"2000","journal-title":"Drugs Exp Clin Res"},{"issue":"1","key":"pone.0354689.ref009","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3390\/ph17010029","article-title":"Novel Opioids in the Setting of Acute Postoperative Pain: A Narrative Review","volume":"17","author":"A Wang","year":"2023","journal-title":"Pharmaceuticals 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