{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:32:28Z","timestamp":1792524748112,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,16]],"date-time":"2025-02-16T00:00:00Z","timestamp":1739664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008770","name":"Scientific Research Coordination Unit of Anadolu University","doi-asserted-by":"publisher","award":["1907S132"],"award-info":[{"award-number":["1907S132"]}],"id":[{"id":"10.13039\/501100008770","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Polymers"],"abstract":"<jats:p>Many antifungal agents, including isoconazole nitrate (ISN), suffer from low aqueous solubility and inconsistent dissolution kinetics, which limit their therapeutic potential. To address these challenges, this study aimed to enhance the solubility and stability of ISN through the development of inclusion complexes with hydroxypropyl-\u03b2-cyclodextrin (HP-\u03b2-CD). HP-\u03b2-CD inclusion complexes were prepared using a spray-drying technique and characterized through phase-solubility studies, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (1H-NMR), and differential scanning calorimetry (DSC). The inclusion complex significantly improved ISN solubility, increasing from 0.5088 mg\/mL to 3.6550 mg\/mL. These complexes were incorporated into a thermosensitive, mucoadhesive in situ gel system using Pluronic\u00ae F127 and hydroxypropyl methylcellulose (HPMC) to optimize vaginal drug delivery. The formulations were evaluated for gelation temperature, viscosity, swelling behavior, and pH, confirming their suitability for vaginal application. Antimicrobial studies demonstrated that the ISN\/HP-\u03b2-CD gels exhibited superior activity against Candida albicans, C. glabrata, and C. krusei compared to ISN alone. In vitro release studies further revealed sustained drug release following Peppas-Sahlin kinetics, supporting enhanced bioavailability and prolonged therapeutic action. This study demonstrates that the ISN\/HP-\u03b2-CD-loaded in situ gel system offers a promising and effective approach for improving the solubility, stability, and antifungal efficacy of ISN for the treatment of vaginal infections.<\/jats:p>","DOI":"10.3390\/polym17040514","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T10:26:12Z","timestamp":1739787972000},"page":"514","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Development of Vaginal In Situ Gel Containing ISN\/HP-\u03b2-CD Inclusion Complex for Enhanced Solubility and Antifungal Efficacy"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9501-6863","authenticated-orcid":false,"given":"Tarek","family":"Alloush","sequence":"first","affiliation":[{"name":"Institute of Health Sciences, Istanbul University, 34216 Istanbul, T\u00fcrkiye"},{"name":"Department of Pharmaceutical Technology, Graduate School of Health Sciences, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8897-0885","authenticated-orcid":false,"given":"G\u00fclsel","family":"Yurtda\u015f K\u0131r\u0131ml\u0131o\u011flu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, Anadolu University, 26470 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.bj.2015.11.005","article-title":"A pilot study on Trichomonas vaginalis in women with recurrent urinary tract infections","volume":"39","author":"Chang","year":"2016","journal-title":"Biomed. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1517\/17425247.2.1.335","article-title":"Cyclodextrins in drug delivery","volume":"2","author":"Loftsson","year":"2005","journal-title":"Expert. Opin. Drug Deliv."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Willems, H.M.E., Ahmed, S.S., Liu, J., Xu, Z., and Peters, B.M. (2020). Vulvovaginal candidiasis: A current understanding and burning questions. J. Fungi, 6.","DOI":"10.3390\/jof6010027"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1258\/095646202760159639","article-title":"Facts and myths on recurrent vulvovaginal candidosis\u2014A review on epidemiology, clinical manifestations, diagnosis, pathogenesis and therapy","volume":"13","author":"Rodrigues","year":"2002","journal-title":"Int. J. STD AIDS"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Osma\u0142ek, T., Froelich, A., Jadach, B., Tatarek, A., Gadzi\u0144ski, P., Falana, A., Grali\u0144ska, K., Ekert, M., Puri, V., and Wroty\u0144ska-Barczy\u0144ska, J. (2021). Recent advances in polymer-based vaginal drug delivery systems. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13060884"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"102961","DOI":"10.1016\/j.amjoto.2021.102961","article-title":"Efficacy of topical isoconazole nitrate in the treatment of otomycosis","volume":"42","author":"Abakay","year":"2021","journal-title":"Am. J. Otolaryngol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.1439-0507.2008.01615.x","article-title":"The advantages of topical combination therapy in the treatment of inflammatory dermatomycoses","volume":"51","author":"Havlickova","year":"2008","journal-title":"Mycoses"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1208\/s12249-022-02218-8","article-title":"Formulation of Apigenin-Cyclodextrin-Chitosan ternary complex: Physicochemical characterization, in vitro and in vivo studies","volume":"23","author":"Jafar","year":"2022","journal-title":"AAPS PharmSciTech"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1515\/jbcpp-2021-0008","article-title":"The thermodynamic study of p-methoxycinnamic acid inclusion complex formation using \u03b2-cyclodextrin and hydroxypropyl-\u03b2-cyclodextrin","volume":"32","author":"Isadiartuti","year":"2021","journal-title":"J. Basic Clin. Physiol. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Peimanfard, S., Zarrabi, A., Trotta, F., Matencio, A., Cecone, C., and Caldera, F. (2022). Developing novel hydroxypropyl-\u03b2-cyclodextrin-based nanosponges as carriers for anticancer hydrophobic agents: Overcoming limitations of host-guest complexes in a comparative evaluation. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14051059"},{"key":"ref_11","first-page":"693","article-title":"Host-guest inclusion complex of desloratadine with 2-(hydroxy)propyl-\u03b2-cyclodextrin (HP-\u03b2-CD): Preparation, binding behaviors, and dissolution properties","volume":"24","year":"2020","journal-title":"J. Res. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e20126","DOI":"10.17795\/jjnpp-20126","article-title":"In situ gelling systems for drug delivery","volume":"9","author":"Kouchak","year":"2014","journal-title":"Jundishapur J. Nat. Pharm. Prod."},{"key":"ref_13","first-page":"1398","article-title":"In-situ gel: New trends in controlled and sustained drug delivery system","volume":"2","author":"Nirmal","year":"2010","journal-title":"Int. J. PharmTech Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"762","DOI":"10.12991\/mpj.2017.3","article-title":"Development of in situ poloxamer-chitosan hydrogels for vaginal drug delivery of benzydamine hydrochloride: Textural, mucoadhesive and in vitro release properties","volume":"21","year":"2017","journal-title":"Marmara Pharm. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1208\/s12249-014-0118-7","article-title":"Comparative study to investigate the effect of meloxicam or minocycline HCl in situ gel system on local treatment of periodontal pockets","volume":"15","author":"Kassem","year":"2014","journal-title":"AAPS PharmSciTech"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Takacs, P., Kozma, B., R\u00e1tonyi, D., Kozma, B., Attila, K.S., Fenyvesi, F., and Sipos, A.G. (2024). Development and bioavailability assessment of an estriol-containing vaginal hydrogel. Gels, 10.","DOI":"10.3390\/gels10120823"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1208\/pt070238","article-title":"Mucoadhesive, thermosensitive, prolonged-release vaginal gel for clotrimazole: \u03b2-cyclodextrin complex","volume":"7","author":"Bilensoy","year":"2006","journal-title":"AAPS PharmSciTech"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bouchemal, K., Aka-Any-Grah, A.D., Dereuddre-Bosquet, N., Martin, L., Lievin-Le-Moal, V., Le Grand, R., Nicolas, V., Gibellini, D., Lembo, D., and Po\u00fcs, C. (2015). Thermosensitive and mucoadhesive Pluronic-hydroxypropylmethylcellulose hydrogel containing the Mini-CD4 M48U1 is a promising efficient barrier against HIV diffusion through macaque cervicovaginal mucus. Antimicrob. Agents Chemother., 59.","DOI":"10.1128\/AAC.03503-14"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s10847-010-9922-1","article-title":"Inclusion complexes of fluconazole with \u03b2-cyclodextrin: Physicochemical characterization and in vitro evaluation of its formulation","volume":"70","author":"Demirel","year":"2011","journal-title":"J. Incl. Phenom. Macrocycl. Chem."},{"key":"ref_20","first-page":"117","article-title":"Phase solubility techniques","volume":"4","author":"Higuchi","year":"1965","journal-title":"Adv. Anal. Chem. Instrum."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.rinphs.2015.06.001","article-title":"Development and characterization of in-situ gel for ophthalmic formulation containing ciprofloxacin hydrochloride","volume":"6","author":"Makwana","year":"2016","journal-title":"Results Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Krishnamoorthy, S., Noorani, B., and Xu, C. (2019). Effects of encapsulated cells on the physical\u2013mechanical properties and microstructure of gelatin methacrylate hydrogels. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205061"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.ejpb.2015.04.032","article-title":"New prostaglandin analog formulation for glaucoma treatment containing cyclodextrins for improved stability, solubility, and ocular tolerance","volume":"95","author":"Guinchard","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0040-6031(01)00665-7","article-title":"Thermal analysis of cyclodextrins and their inclusion compounds","volume":"380","author":"Giordano","year":"2001","journal-title":"Thermochim. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1208\/s12249-008-9143-8","article-title":"Preparation and solid-state characterization of inclusion complexes formed between miconazole and methyl-\u03b2-cyclodextrin","volume":"9","author":"Ribeiro","year":"2008","journal-title":"AAPS PharmSciTech"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s10847-010-9922-1","article-title":"Inclusion complexes of ketoconazole with \u03b2-cyclodextrin: Physicochemical characterization and in vitro dissolution behaviour of its vaginal suppositories","volume":"70","author":"Demirel","year":"2011","journal-title":"J. Incl. Phenom. Macrocycl. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.molliq.2017.04.098","article-title":"Inclusion complex of antiasthmatic compound with 2-hydroxypropyl-\u03b2-cyclodextrin: Preparation and physicochemical properties","volume":"237","author":"Sharapova","year":"2017","journal-title":"J. Mol. Liq."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.clay.2012.07.004","article-title":"Preparation and characterization of nanocontainers of corrosion inhibitor based on layered double hydroxides","volume":"67\u201368","author":"Hang","year":"2012","journal-title":"Appl. Clay Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nakamoto, K. (2008). Applications in Coordination Chemistry. Infrared and Raman Spectra of Inorganic and Coordination Compounds, Part B: Applications in Coordination, Organometallic, and Bioinorganic Chemistry, Wiley-Interscience.","DOI":"10.1002\/9780470405888"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Drabi\u0144ska, B., Dettlaff, K., Ratajczak, T., Kossakowski, K., Chmielewski, M.K., Cielecka-Piontek, J., and Kujawski, J. (2023). Structural and Spectroscopic Properties of Isoconazole and Bifonazole\u2014Experimental and Theoretical Studies. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010520"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Han, D., Han, Z., Liu, L., Wang, Y., Xin, S., Zhang, H., and Yu, Z. (2020). Solubility enhancement of myricetin by inclusion complexation with heptakis-O-(2-hydroxypropyl)-\u03b2-cyclodextrin: A joint experimental and theoretical study. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030766"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s10847-016-0635-y","article-title":"Study of the solubility, photostability, and structure of inclusion complexes of carvedilol with \u03b2-cyclodextrin and (2-hydroxypropyl)-\u03b2-cyclodextrin","volume":"86","year":"2016","journal-title":"J. Incl. Phenom. Macrocycl. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.foodchem.2015.10.023","article-title":"Characterization of \u03b2-cyclodextrin inclusion complexes containing an essential oil component","volume":"196","author":"Abarca","year":"2016","journal-title":"Food Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Radeva, L., Yordanov, Y., Spassova, I., Kovacheva, D., Tibi, I.P., Zaharieva, M.M., Kaleva, M., Najdenski, H., Petrov, P.D., and Tzankova, V. (2024). Incorporation of resveratrol-hydroxypropyl-\u03b2-cyclodextrin complexes into hydrogel formulation for wound treatment. Gels, 10.","DOI":"10.3390\/gels10050346"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1016\/j.carbpol.2012.07.057","article-title":"Investigation of inclusion complex of cilnidipine with hydroxypropyl-\u03b2-cyclodextrin","volume":"90","author":"Hu","year":"2012","journal-title":"Carbohydr. Polym."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"134168","DOI":"10.1016\/j.molstruc.2022.134168","article-title":"Preparation, characterization, and physicochemical property of the inclusion complexes of Cannabisin A with \u03b2-cyclodextrin and hydroxypropyl-\u03b2-cyclodextrin","volume":"1272","author":"Xu","year":"2023","journal-title":"J. Mol. Struct."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0378-5173(01)00622-6","article-title":"Combined hydroxypropyl-\u03b2-cyclodextrin and poly(alkylcyanoacrylate) nanoparticles intended for oral administration of saquinavir","volume":"218","author":"Boudad","year":"2001","journal-title":"Int. J. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.ejps.2007.09.010","article-title":"Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-\u03b2-cyclodextrin inclusion complex","volume":"33","author":"Tsuneda","year":"2008","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s40005-018-0395-3","article-title":"Novel and effectual delivery of an antifungal agent for the treatment of persistent vulvovaginal candidiasis","volume":"49","author":"Sarwal","year":"2019","journal-title":"J. Pharm. Investig."},{"key":"ref_40","first-page":"551","article-title":"Mucoadhesive in situ gel formulation for vaginal delivery of clotrimazole: Formulation, preparation, and in vitro\/in vivo evaluation","volume":"22","author":"Karavana","year":"2016","journal-title":"Pharm. Dev. Technol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0378-5173(02)00232-6","article-title":"Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions","volume":"241","author":"Chang","year":"2002","journal-title":"Int. J. Pharm."},{"key":"ref_42","first-page":"391","article-title":"Development of thermosensitive gel of fluconazole for vaginal candidiasis","volume":"8","author":"Deshkar","year":"2015","journal-title":"Int. J. Pharm. Pharm. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1007\/s10973-020-10460-0","article-title":"A promising approach to design thermosensitive in situ gel based on solid dispersions of desloratadine with Kolliphor\u00ae 188 and Pluronic\u00ae F127","volume":"147","year":"2022","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ijpharm.2014.02.001","article-title":"Synthesis of oxidized glycerol monooleate-chitosan polymer and its hydrogel formation for sustained release of trimetazidine hydrochloride","volume":"465","author":"Zhang","year":"2014","journal-title":"Int. J. Pharm."}],"container-title":["Polymers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4360\/17\/4\/514\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:35:43Z","timestamp":1760027743000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4360\/17\/4\/514"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,16]]},"references-count":44,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["polym17040514"],"URL":"https:\/\/doi.org\/10.3390\/polym17040514","relation":{},"ISSN":["2073-4360"],"issn-type":[{"value":"2073-4360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,16]]}}}