{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T01:00:07Z","timestamp":1776733207905,"version":"3.51.2"},"reference-count":41,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,6,25]],"date-time":"2023-06-25T00:00:00Z","timestamp":1687651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, Saudi Arabia","award":["RG-28-166-42"],"award-info":[{"award-number":["RG-28-166-42"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Mucoadhesive nanosized crystalline aggregates (NCs) can be delivered by the gastrointestinal, nasal, or pulmonary route to improve retention at particular sites. Itopride hydrochloride (ITH) was selected as a drug candidate due to its absorption from the upper gastrointestinal tract. For drug localization and target-specific actions, mucoadhesive polymers are essential. The current work aimed to use second-generation mucoadhesive polymers (i.e., thiolated polymers) to enhance mucoadhesive characteristics. An ITH-NC formulation was enhanced using response surface methodology. Concentrations of Tween 80 and Polyvinyl pyrrolidone (PVP K-30) were selected as independent variables that could optimize the formulation to obtain the desired entrapment efficacy and particle size\/diameter. It was found that a formulation prepared using Tween 80 at a concentration of 2.55% and PVP K-30 at 2% could accomplish the goals for which an optimized formulation was needed. Either xanthan gum (XG) or thiolated xanthan gum (TXG) was added to the optimized formulation to determine how they affected the mucoadhesive properties of the formulation. Studies demonstrated that there was an initial burst release of ITH from the ITH\/NC\/XG and ITH\/NC\/TXG in the early hours and then a steady release for 24 h. As anticipated, the TXG formulation had a better mucin interaction, and this was needed to ensure that the drug was distributed to tissues that produce mucus. Finally, at the measured concentrations, the ITH\/NC showed minimal cytotoxicity against lung cells, indicating that it may have potential for additional in vivo research. The enhanced bioavailability and mean residence time of the designed mucoadhesive NC formulations were confirmed by pharmacokinetic studies.<\/jats:p>","DOI":"10.3390\/ph16070925","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T05:39:13Z","timestamp":1687757953000},"page":"925","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["RETRACTED: Design and Evaluation of S-Protected Thiolated-Based Itopride Hydrochloride Polymeric Nanocrystals for Functional Dyspepsia: QbD-Driven Optimization, In Situ, In Vitro, and In Vivo Investigation"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0737-1894","authenticated-orcid":false,"given":"Moutaz","family":"Badr","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Umm Al-Qura University, Makkah 24381, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5751-9014","authenticated-orcid":false,"given":"Pratap","family":"Basim","sequence":"additional","affiliation":[{"name":"ThermoFisher Scientific, Cincinnati, OH 45237, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khaled","family":"Hosny","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3088-4084","authenticated-orcid":false,"given":"Waleed","family":"Rizg","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Center of Innovation in Personalized Medicine (CIPM), 3D Bioprinting Unit, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Naveen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B.G Nagara, Karnataka 571448, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8130-7068","authenticated-orcid":false,"given":"Mallesh","family":"Kurakula","sequence":"additional","affiliation":[{"name":"CURE Pharmaceutical, Oxnard, CA 93033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fayez","family":"Alsulaimani","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2184-4339","authenticated-orcid":false,"given":"Awaji","family":"Safhi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1412-5299","authenticated-orcid":false,"given":"Fahad","family":"Sabei","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4045-0810","authenticated-orcid":false,"given":"Mohammed","family":"Alissa","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9028-8225","authenticated-orcid":false,"given":"Abdulmohsin","family":"Alamoudi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,25]]},"reference":[{"key":"ref_1","first-page":"133","article-title":"Drug Delivery and Nanoparticles: Applications and Hazards","volume":"3","author":"Borm","year":"2008","journal-title":"Int. J. Nanomed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.jconrel.2011.06.001","article-title":"Targeted Drug Delivery to Tumors: Myths, Reality and Possibility","volume":"153","author":"Bae","year":"2011","journal-title":"J. Control. Release"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jbiotec.2004.06.007","article-title":"Challenges and Solutions for the Delivery of Biotech Drugs\u2014A Review of Drug Nanocrystal Technology and Lipid Nanoparticles","volume":"113","author":"Muller","year":"2004","journal-title":"Proc. J. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1021\/bc050050z","article-title":"Folate-Conjugated Iron Oxide Nanoparticles for Solid Tumor Targeting as Potential Specific Magnetic Hyperthermia Mediators: Synthesis, Physicochemical Characterization, and in Vitro Experiments","volume":"16","author":"Sonvico","year":"2005","journal-title":"Bioconjugate Chem."},{"key":"ref_5","first-page":"195727","article-title":"Drug Solubility: Importance and Enhancement Techniques","volume":"2012","author":"Savjani","year":"2012","journal-title":"ISRN Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jconrel.2014.03.053","article-title":"An Overview of Clinical and Commercial Impact of Drug Delivery Systems","volume":"190","author":"Anselmo","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ejpb.2005.05.009","article-title":"Drug Nanocrystals of Poorly Soluble Drugs Produced by High Pressure Homogenisation","volume":"62","author":"Keck","year":"2006","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1081\/DDC-120001481","article-title":"Nanoparticle Technology for Drug Delivery across the Blood-Brain Barrier","volume":"28","author":"Lockman","year":"2002","journal-title":"Drug. Dev. Ind. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ijpharm.2010.07.044","article-title":"Nanocrystals: Industrially Feasible Multifunctional Formulation Technology for Poorly Soluble Actives","volume":"399","author":"Shegokar","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"470","DOI":"10.2174\/1567201817666200512104833","article-title":"Drug Nanocrystals: A Comprehensive Review with Current Regulatory Guidelines","volume":"17","author":"Dhaval","year":"2020","journal-title":"Curr. Drug Deliv."},{"key":"ref_11","first-page":"S49","article-title":"UV Spectrophotometric Method for the Estimation of Itopride Hydrochloride in Pharmaceutical Formulation","volume":"7","author":"Gupta","year":"2010","journal-title":"Eur. J. Chem."},{"key":"ref_12","first-page":"106","article-title":"Itopride: A Novel Prokinetic Agent","volume":"6","author":"Gupta","year":"2004","journal-title":"JK Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Alaithan, S., Naveen, N.R., Goudanavar, P.S., Bhavani, P.D., Ramesh, B., Koppuravuri, N.P., Fattepur, S., Sreeharsha, N., Nair, A.B., and Aldhubiab, B.E. (2022). Development of Novel Unfolding Film System of Itopride Hydrochloride Using Box-Behnken Design&mdash;A Gastro Retentive Approach. Pharmaceuticals, 15.","DOI":"10.3390\/ph15080981"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.ejpb.2018.07.010","article-title":"Impact of Mucoadhesive Polymeric Nanoparticulate Systems on Oral Bioavailability of a Macromolecular Model Drug","volume":"130","author":"Fabiano","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Nair, A.B., Sreeharsha, N., Al-Dhubiab, B.E., Hiremath, J.G., Shinu, P., Attimarad, M., Venugopala, K.N., and Mutahar, M. (2019). HPMC-and Plga-Based Nanoparticles for the Mucoadhesive Delivery of Sitagliptin: Optimization and in Vivo Evaluation in Rats. Materials, 12.","DOI":"10.3390\/ma12244239"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3950942","DOI":"10.1155\/2019\/3950942","article-title":"Mucoadhesive Particles: A Novel, Prolonged-Release Nanocarrier of Sitagliptin for the Treatment of Diabetics","volume":"2019","author":"Sreeharsha","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3109\/02652048.2012.720722","article-title":"Design and Formulation of Mucoadhesive Microspheres of Sitagliptin","volume":"30","author":"Harsha","year":"2013","journal-title":"J. Microencapsul."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1016\/S0142-9612(00)00421-X","article-title":"Thiolated Polymers\u2014Thiomers: Development and in Vitro Evaluation of Chitosan-Thioglycolic Acid Conjugates","volume":"22","author":"Kast","year":"2001","journal-title":"Biomaterials"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Alhakamy, N.A., Naveen, N.R., Gorityala, S., Kurakula, M., Hosny, K.M., Safhi, A.Y., Bukhary, D.M., Bukhary, H.A., Sabei, F.Y., and Mushtaq, R.Y. (2022). Development of Novel S-Protective Thiolated-Based Mucoadhesive Tablets for Repaglinide: Pharmacokinetic Study. Polymers, 14.","DOI":"10.3390\/polym14173529"},{"key":"ref_20","first-page":"47","article-title":"A Spotlight on Thiolated Natural Polymers and Their Relevance in Mucoadhesive Drug Delivery System","volume":"4","author":"Naveen","year":"2018","journal-title":"Futur. J. Pharm. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1208\/s12249-008-9041-0","article-title":"Design and Development of Gliclazide Mucoadhesive Microcapsules: In Vitro and In Vivo Evaluation","volume":"9","author":"Prajapati","year":"2008","journal-title":"AAPS PharmSciTech"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ejps.2017.01.008","article-title":"Thiolated Polymers as Mucoadhesive Drug Delivery Systems","volume":"100","author":"Duggan","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3399","DOI":"10.1021\/acs.molpharmaceut.7b00423","article-title":"Expedited Development of Diphenhydramine Orally Disintegrating Tablet through Integrated Crystal and Particle Engineering","volume":"14","author":"Wang","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_24","first-page":"378","article-title":"Formulation Optimization of Scutellarin-Loaded HP-\u03b2-CD\/Chitosan Nanoparticles Using Response Surface Methodology with Box\u2013Behnken Design","volume":"12","author":"Liu","year":"2017","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.chemolab.2011.10.008","article-title":"The Optimal Mixture Design of Experiments: Alternative Method in Optimizing the Aqueous Phase Composition of a Microemulsion","volume":"112","author":"Jeirani","year":"2012","journal-title":"Chemom. Intell. Lab. Syst."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.fuel.2015.03.081","article-title":"Quantifying the Effects of Fuel Compositions on GDI-Derived Particle Emissions Using the Optimal Mixture Design of Experiments","volume":"154","author":"Chen","year":"2015","journal-title":"Fuel"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.carbpol.2014.02.022","article-title":"Ispaghula Mucilage-Gellan Mucoadhesive Beads of Metformin HCl: Development by Response Surface Methodology","volume":"107","author":"Nayak","year":"2014","journal-title":"Carbohydr. Polym."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.ijbiomac.2012.07.030","article-title":"Optimization and Evaluation of Gastroretentive Ranitidine HCl Microspheres by Using Design Expert Software","volume":"51","author":"Hooda","year":"2012","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_29","first-page":"2506","article-title":"Formulation Design and In Vitro Evaluation for Stomach Specific Drug Delivery System of Anti Retroviral Drug\u2013Acyclovir","volume":"4","author":"Naveen","year":"2013","journal-title":"Int. J. Pharm. Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4103\/0973-8398.150032","article-title":"Formulation, Optimization and Characterization of Gemfibrozil Nanocrystals Prepared by Wet Milling Technique","volume":"9","author":"Bastami","year":"2015","journal-title":"Asian J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Rizg, W.Y., Naveen, N.R., Kurakula, M., Bukhary, H.A., Safhi, A.Y., Alfayez, E., Sindi, A.M., Ali, S., Murshid, S.S., and Hosny, K.M. (2022). QbD Supported Optimization of the Alginate-Chitosan Nanoparticles of Simvastatin in Enhancing the Anti-Proliferative Activity against Tongue Carcinoma. Gels, 8.","DOI":"10.3390\/gels8020103"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1080\/10717544.2022.2094500","article-title":"Compression-Coated Pulsatile Chronomodulated Therapeutic System: QbD Assisted Optimization","volume":"29","author":"Aldawsari","year":"2022","journal-title":"Drug Deliv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2716","DOI":"10.1016\/j.matpr.2020.01.491","article-title":"Process Optimization by Response Surface Methodology for Preparation and Evaluation of Methotrexate Loaded Chitosan Nanoparticles","volume":"33","author":"Naveen","year":"2020","journal-title":"Mater. Today Proc."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kurakula, M., Naveen, N.R., Patel, B., Manne, R., and Patel, D.B. (2021). Preparation, Optimization and Evaluation of Chitosan-Based Avanafil Nanocomplex Utilizing Antioxidants for Enhanced Neuroprotective Effect on PC12 Cells. Gels, 7.","DOI":"10.3390\/gels7030096"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"s396","DOI":"10.5530\/ijper.55.2s.111","article-title":"Datura Stramonium Leaves Mucilage Aided Buccoadhesive Films of Aceclofenac Using 32 Factorial Design with Design-Expert Software","volume":"55","author":"Ahad","year":"2021","journal-title":"Indian. J. Pharm. Educ. Res."},{"key":"ref_36","first-page":"573","article-title":"Design and Characterization of Sustained Release Matrix Tablets of Glimepiride by Using Synthetic and Natural Polymers","volume":"3","author":"Naveen","year":"2013","journal-title":"Int. J. Drug. Discov. Herb. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1002\/jps.24448","article-title":"Quality by Design Coupled with near Infrared in Formulation of Transdermal Glimepiride Liposomal Films","volume":"104","author":"Ahmed","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1517\/17425247.2011.605120","article-title":"Developing Oral Drug Delivery Systems Using Formulation by Design: Vital Precepts, Retrospect and Prospects","volume":"8","author":"Singh","year":"2011","journal-title":"Expert. Opin. Drug. Deliv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.jcis.2016.10.090","article-title":"Probing Mucin Interaction Behavior of Magnetic Nanoparticles","volume":"488","author":"Boya","year":"2017","journal-title":"J. Colloid. Interface Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Gatti, T.H.H., Eloy, J.O., Ferreira, L.M.B., da Silva, I.C., Pavan, F.R., Gremi\u00e3o, M.P.D., and Chorilli, M. (2018). Insulin-Loaded Polymeric Mucoadhesive Nanoparticles: Development, Characterization and Cytotoxicity Evaluation. Braz. J. Pharm. Sci., 54.","DOI":"10.1590\/s2175-97902018000117314"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/2008-2231-20-24","article-title":"Formulation and Evaluation of Microsphere Based Oro Dispersible Tablets of Itopride HCL","volume":"20","author":"Shah","year":"2012","journal-title":"DARU J. Pharm. Sci."}],"updated-by":[{"DOI":"10.3390\/ph19040599","type":"retraction","label":"Retraction","source":"publisher","updated":{"date-parts":[[2023,6,25]],"date-time":"2023-06-25T00:00:00Z","timestamp":1687651200000}},{"DOI":"10.3390\/ph19040599","type":"retraction","label":"Retraction","source":"retraction-watch","updated":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"record-id":"70309"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/7\/925\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T08:03:00Z","timestamp":1775721780000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/7\/925"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,25]]},"references-count":41,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["ph16070925"],"URL":"https:\/\/doi.org\/10.3390\/ph16070925","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,25]]}}}