{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T09:51:56Z","timestamp":1782467516015,"version":"3.54.5"},"reference-count":24,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T00:00:00Z","timestamp":1689638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Saud University, Riyadh, Saudi Arabia","award":["RSP2023R457"],"award-info":[{"award-number":["RSP2023R457"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Despite several novel and innovative approaches, clinical translation of oral insulin delivery into commercially viable treatment is still challenging due to its poor absorption and rapid degradation in GIT. Thus, an insulin-SDS hydrophobic ion pair loaded self-microemulsifying drug delivery system (SMEDDS) was formulated to exploit the hypoglycemic effects of orally delivered insulin. Insulin was initially hydrophobically ion paired with sodium dodecyl sulphate (SDS) to enhance its lipophilicity. The successful complexation of Insulin-SDS was confirmed by FTIR and surface morphology was evaluated using SEM. Stability of insulin after its release from HIP complex was evaluated using SDS PAGE. Subsequently, Ins-SDS loaded SMEDDS was optimized using two factorial designs. In vitro stability of insulin entrapped in optimized SMEDDS against proteolytic degradation was also assessed. Further, antidiabetic activity of optimized Ins-SDS loaded SMEDDS was evaluated in diabetic rats. Insulin complexed with SDS at 6:1 (SDS\/insulin) molar ratio with almost five-fold increased lipophilicity. The SMEDDS was optimized at 10% Labraphil M2125 CS, 70% Cremophore EL, and 20% Transcutol HP with better proteolytic stability and oral antidiabetic activity. An Ins-SDS loaded SMEDDS was successfully optimized. Compared with insulin and Ins-SDS complex, the optimized SMEDDS displayed considerable resistance to GI enzymes. Thus, the SMEDDS showed potential for effective delivery of macromolecular drugs with improved oral bioavailability.<\/jats:p>","DOI":"10.3390\/pharmaceutics15071973","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:54:01Z","timestamp":1689728041000},"page":"1973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Design and Evaluation of Hydrophobic Ion Paired Insulin Loaded Self Micro-Emulsifying Drug Delivery System for Oral Delivery"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7308-6509","authenticated-orcid":false,"given":"Jahanzeb","family":"Mudassir","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afsheen","family":"Raza","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5703-2730","authenticated-orcid":false,"given":"Mahtab Ahmad","family":"Khan","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, University of Central Punjab (UCP), Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8636-8644","authenticated-orcid":false,"given":"Huma","family":"Hameed","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, University of Central Punjab (UCP), Lahore 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gamal A.","family":"Shazly","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8977-3303","authenticated-orcid":false,"given":"Ali","family":"Irfan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadia Jafar","family":"Rana","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7343-078X","authenticated-orcid":false,"given":"Khizar","family":"Abbas","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9807-5841","authenticated-orcid":false,"given":"Muhammad Sohail","family":"Arshad","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajjad","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Medical Faculty, Heinrich Heine University, Moorenstrasse-5, 40225 D\u00fcsseldorf, Germany"},{"name":"Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3302-4036","authenticated-orcid":false,"given":"Yousef A.","family":"Bin Jardan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1517\/17425247.2015.1068287","article-title":"Self-emulsifying drug delivery systems in oral (poly) peptide drug delivery","volume":"12","author":"Leonaviciute","year":"2015","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.jconrel.2021.08.060","article-title":"Bile acid transporter-mediated oral absorption of insulin via hydrophobic ion-pairing approach","volume":"338","author":"Bashyal","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s40005-021-00549-5","article-title":"Recent progress in hydrophobic ion-pairing and lipid-based drug delivery systems for enhanced oral delivery of biopharmaceuticals","volume":"52","author":"Noh","year":"2022","journal-title":"J. Pharm. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"112285","DOI":"10.1016\/j.colsurfb.2021.112285","article-title":"Cationic nanocarrier of rhein based on hydrophobic ion pairing approach as intra-articular targeted regenerative therapy for osteoarthritis","volume":"211","author":"Ebada","year":"2022","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.ijbiomac.2022.11.155","article-title":"Assessment of hydrophobic-ion paired insulin incorporated SMEDDS for the treatment of diabetes mellitus","volume":"225","author":"Noh","year":"2023","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4895","DOI":"10.2147\/IJN.S199507","article-title":"Self-assembled insulin and nanogels polyelectrolyte complex (Ins\/NGs-PEC) for oral insulin delivery: Characterization, lyophilization and in-vivo evaluation","volume":"14","author":"Mudassir","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4207","DOI":"10.1039\/C9NA00308H","article-title":"Hydrophobic ion pairing: Encapsulating small molecules, peptides, and proteins into nanocarriers","volume":"1","author":"Ristroph","year":"2019","journal-title":"Nanoscale Adv."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nazl\u0131, H., Mesut, B., and \u00d6zsoy, Y. (2021). In vitro evaluation of a solid supersaturated self nanoemulsifying drug delivery system (Super-SNEDDS) of aprepitant for enhanced solubility. Pharmaceuticals, 14.","DOI":"10.3390\/ph14111089"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"106159","DOI":"10.1016\/j.ejps.2022.106159","article-title":"Formulation development, optimization by Box-Behnken design, characterization, in vitro, ex-vivo, and in vivo evaluation of bosentan-loaded self-nanoemulsifying drug delivery system: A novel alternative dosage form for pulmonary arterial hypertension treatment","volume":"174","author":"Usta","year":"2022","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1080\/10717544.2022.2118399","article-title":"Enhanced oral absorption of insulin: Hydrophobic ion pairing and a self-microemulsifying drug delivery system using a D-optimal mixture design","volume":"29","author":"Goo","year":"2022","journal-title":"Drug Deliv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ijpharm.2017.02.019","article-title":"Hydrophobic ion pairing: Key to highly payloaded self-emulsifying peptide drug delivery systems","volume":"520","author":"Griesser","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.jconrel.2017.04.038","article-title":"Lipophilic peptide character\u2013What oral barriers fear the most","volume":"255","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ijpharm.2006.11.035","article-title":"Characterization of physiochemical and biological properties of an insulin\/lauryl sulfate complex formed by hydrophobic ion pairing","volume":"336","author":"Dai","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4677","DOI":"10.2147\/IJN.S318092","article-title":"Facilitated buccal insulin delivery via hydrophobic ion-pairing approach: In vitro and ex vivo evaluation","volume":"16","author":"Bashyal","year":"2021","journal-title":"Int. J. Nanomed."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1021\/ja00057a006","article-title":"Structure and stability of insulin dissolved in 1-octanol","volume":"115","author":"Matsuura","year":"1993","journal-title":"J. Am. Chem. Soc."},{"key":"ref_16","first-page":"1","article-title":"Design and evaluation of hydrophobic ion-pairing complexation of lysozyme with sodium dodecyl sulfate for improved encapsulation of hydrophilic peptides\/proteins by lipid-polymer hybrid nanoparticles","volume":"6","author":"Devrim","year":"2015","journal-title":"J. Nanomed. Nanotechnol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"717","DOI":"10.2217\/nnm-2017-0307","article-title":"Amikacin-containing self-emulsifying delivery systems via pulmonary administration for treatment of bacterial infections of cystic fibrosis patients","volume":"13","author":"Griesser","year":"2018","journal-title":"Nanomedicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.ijpharm.2019.03.001","article-title":"Self-emulsifying drug delivery systems: Impact of stability of hydrophobic ion pairs on drug release","volume":"561","author":"Nazir","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_19","first-page":"1","article-title":"Preparation and Evaluation of Self-emulsifying Drug Delivery System (SEDDS) of Cepharanthine","volume":"22","author":"Yang","year":"2021","journal-title":"AAPS PharmSciTech"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"102026","DOI":"10.1016\/j.jddst.2020.102026","article-title":"Development, optimization and evaluation of losartan potassium loaded Self Emulsifying Drug Delivery System","volume":"60","author":"Kommana","year":"2020","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s13346-016-0289-8","article-title":"Formulation and evaluation of self-emulsifying orlistat tablet to enhance drug release and in vivo performance: Factorial design approach","volume":"6","author":"Gade","year":"2016","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"609","DOI":"10.15171\/apb.2019.070","article-title":"Assessment of fractional factorial design for the selection and screening of appropriate components of a self-nanoemulsifying drug delivery system formulation","volume":"9","author":"Kuncahyo","year":"2019","journal-title":"Adv. Pharm. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s40005-016-0279-3","article-title":"Application of factorial design approach in development and evaluation of self microemulsifying drug delivery system (SMEDDS) of mebendazole","volume":"47","author":"Parakh","year":"2017","journal-title":"J. Pharm. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/s41578-019-0156-6","article-title":"Materials for oral delivery of proteins and peptides","volume":"5","author":"Brown","year":"2020","journal-title":"Nat. Rev. Mater."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/7\/1973\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:13:56Z","timestamp":1760127236000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/7\/1973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,18]]},"references-count":24,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["pharmaceutics15071973"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15071973","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,18]]}}}