{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:52:33Z","timestamp":1791827553428,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Research and Graduate Studies at King Khalid University","award":["RGP2\/402\/45"],"award-info":[{"award-number":["RGP2\/402\/45"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Various routes of drug administration are available for psoriasis treatment. However, there is an urgent need for novel and improved therapeutic options. Hence, our study aimed to develop a nanostructured lipid carrier (NLC) gel of hesperidin (HPD) using a systemic QbD approach for an effective treatment of psoriasis. Methods: Initially, HPD-NLC was optimized with independent variables (drug content, amount of liquid lipid, total lipid, and surfactant concentration) using Box\u2013Behnken Design to assess dependent variables (particle size, size distribution, and entrapment efficiency). HPD-NLC was developed using the high-shear homogenization technique. The characteristics of nanoformulation such as particle size, morphology [transmission electron microscopy (TEM) and differential scanning calorimetry (DSC)], crystallinity [powder X-ray diffraction (XRD)], and chemical interactions [Fourier transform infrared spectroscopy (FTIR)], the drug entrapment efficiency (%EE), and the drug release were investigated. Franz-diffusion cell was utilized to perform in vitro diffusion study, and an imiquimod-induced psoriasis model was used for in vivo study. Results: The optimized HPD-NLC exhibited a spherical shape with particle size of 125.7 nm, polydispersity index (PDI) of 0.36, and entrapment efficiency of 52.26% w\/w. Further, different techniques validated the reduced crystallinity of the hesperidin. The in vitro diffusion study highlighted the sustained and anomalous diffusion of the drug from NLC gel. In the in vivo study, the HPD-NLC-Gel-treated group displayed normal skin with minimal keratosis, while the drug-loaded gel group exhibited signs of hyperkeratosis and parakeratosis signs. Conclusions: HPD-NLC gel showed promising advancement in nanotechnology-based psoriasis treatment and the results of this study open the door for the application of topical HPD-NLC-Gel clinically.<\/jats:p>","DOI":"10.3390\/pharmaceutics17040478","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T05:59:00Z","timestamp":1744091940000},"page":"478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Nanostructured Lipid Carriers (NLC)-Based Topical Formulation of Hesperidin for Effective Treatment of Psoriasis"],"prefix":"10.3390","volume":"17","author":[{"given":"Anita","family":"Rani","sequence":"first","affiliation":[{"name":"Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1697-9562","authenticated-orcid":false,"given":"Rajwinder","family":"Kaur","sequence":"additional","affiliation":[{"name":"Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5073-2088","authenticated-orcid":false,"given":"Afaf","family":"Aldahish","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajalakshimi","family":"Vasudevan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6882-2233","authenticated-orcid":false,"given":"Prasanalakshmi","family":"Balaji","sequence":"additional","affiliation":[{"name":"Department of Computer Science, College of Computer Science, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6718-5183","authenticated-orcid":false,"given":"Chander Parkash","family":"Dora","sequence":"additional","affiliation":[{"name":"Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4198-8679","authenticated-orcid":false,"given":"Balakumar","family":"Chandrasekaran","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Philadelphia University, P.O. Box 1, Amman 19392, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2979-1590","authenticated-orcid":false,"given":"Thakur Gurjeet","family":"Singh","sequence":"additional","affiliation":[{"name":"Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Sharma","sequence":"additional","affiliation":[{"name":"Gateway College of Pharmacy, Sonepat 131001, Haryana, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Almenara-Blasco, M., Gracia-Caza\u00f1a, T., Poblador-Plou, B., Laguna-Berna, C., Carmona-P\u00edrez, J., Navarro-Bielsa, A., Prados-Torres, A., Gimeno-Miguel, A., and Gilaberte, Y. (2024). Multimorbidity of Psoriasis: A Large-Scale Population Study of Its Associated Comorbidities. J. Clin. Med., 13.","DOI":"10.3390\/jcm13020492"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lee, H.J., and Kim, M. (2023). Challenges and Future Trends in the Treatment of Psoriasis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713313"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gendrisch, F., Haarhaus, B., Krieger, N., Quirin, K.-W., Schempp, C.M., and W\u00f6lfle, U. (2021). The Effect of Herbal Medicinal Products on Psoriasis-Like Keratinocytes. Biomolecules, 11.","DOI":"10.3390\/biom11030371"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Alam, M., Rizwanullah, M., Mir, S.R., and Amin, S. (2023). Statistically Optimized Tacrolimus and Thymoquinone Co-Loaded Nanostructured Lipid Carriers Gel for Improved Topical Treatment of Psoriasis. Gels, 9.","DOI":"10.3390\/gels9070515"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.lfs.2019.01.019","article-title":"Hesperidin Inhibits Keratinocyte Proliferation and Imiquimod-Induced Psoriasis-Like Dermatitis via the IRS-1\/ERK1\/2 Pathway","volume":"219","author":"Li","year":"2019","journal-title":"Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1002\/jsfa.8734","article-title":"Enhancement of the Water Solubility and Antioxidant Activity of Hesperidin by Chitooligosaccharide","volume":"98","author":"Cao","year":"2018","journal-title":"J. Sci. Food Agric."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"617","DOI":"10.3109\/21691401.2016.1167699","article-title":"Optimization of Nanostructured Lipid Carriers for Topical Delivery of Nimesulide Using Box\u2013Behnken Design Approach","volume":"45","author":"Moghddam","year":"2017","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"601","DOI":"10.3109\/10717544.2014.923958","article-title":"Nanostructured Lipid Carriers of Pioglitazone for Transdermal Application: From Experimental Design to Bioactivity Detail","volume":"23","author":"Alam","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"554","DOI":"10.3109\/10837450.2015.1026605","article-title":"A Novel Nanogel Formulation of Methotrexate for Topical Treatment of Psoriasis: Optimization, In Vitro and In Vivo Evaluation","volume":"21","author":"Avasatthi","year":"2016","journal-title":"Pharm. Dev. Technol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Azhar, S.N.A., Ashari, S.E., Zainuddin, N., and Hassan, M. (2022). Nanostructured Lipid Carriers-Hydrogels System for Drug Delivery: Nanohybrid Technology Perspective. Molecules, 27.","DOI":"10.3390\/molecules27010289"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"G\u00fcndo\u011fdu, E., Demir, E.-S., Ekinci, M., \u00d6zgenc, E., Ilem-\u00d6zdemir, D., \u015eenyigit, Z., and Bermejo, M. (2022). An Innovative Formulation Based on Nanostructured Lipid Carriers for Imatinib Delivery: Pre-Formulation, Cellular Uptake, and Cytotoxicity Studies. Nanomaterials, 12.","DOI":"10.3390\/nano12020250"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ajiboye, A.L., Nandi, U., Galli, M., and Trivedi, V. (2021). Olanzapine Loaded Nanostructured Lipid Carriers via High Shear Homogenization and Ultrasonication. Sci. Pharm., 89.","DOI":"10.3390\/scipharm89020025"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"61","DOI":"10.22159\/ijpps.2018v10i4.23142","article-title":"Influence of Formulation Factors on the Size of Nanostructured Lipid Carriers and Nanoemulsions Prepared by High Shear Homogenization","volume":"10","author":"Gardouh","year":"2018","journal-title":"Int. J. Pharm. Pharm. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"522","DOI":"10.22146\/ijp.1552","article-title":"Box-Behnken Design for Optimization of Nanostructured Lipid Carrier Sonication Conditions from Mixtures of Palm Stearin and Palm Olein","volume":"32","author":"Solikah","year":"2021","journal-title":"Indones. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1080\/10717544.2020.1858997","article-title":"Statistical Optimization of Hyaluronic Acid-Enriched Ultra-Deformable Elastomers for Ocular Delivery of Voriconazole via Box\u2013Behnken Design: In Vitro Characterization and In Vivo Evaluation","volume":"28","author":"Fahmy","year":"2021","journal-title":"Drug Deliv."},{"key":"ref_16","first-page":"961","article-title":"Formulation, Optimization, and Evaluation of Nanostructured Lipid Carriers of Resveratrol","volume":"7","author":"Teja","year":"2022","journal-title":"Int. J. Pharm. Res. Appl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.colsurfb.2017.03.006","article-title":"Nanostructured Lipid Carriers of Olmesartan Medoxomil with Enhanced Oral Bioavailability","volume":"154","author":"Kaithwas","year":"2017","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_18","first-page":"64","article-title":"Development of Nanostructured Lipid Carriers Loaded Caffeic Acid Topical Cream for Prevention of Inflammation in a Wistar Rat Model","volume":"13","author":"Kamath","year":"2023","journal-title":"J. Appl. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102911","DOI":"10.1016\/j.jddst.2021.102911","article-title":"Design and Development of Surface-Modified Epigallocatechin 3-Gallate NanoCubogel for Localized Delivery to Oral Submucous Fibrosis Therapy","volume":"66","author":"Mehta","year":"2021","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"58","DOI":"10.22270\/jddt.v13i3.5762","article-title":"Design, Development and Characterization of Nanostructured Lipid Carriers (NLCs) by HPH Method Loaded with Anticancer Drug","volume":"13","author":"Gorle","year":"2023","journal-title":"J. Drug Deliv. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Raza, H., Shah, S.U., Ali, Z., Khan, A.U., Rajput, I.B., Farid, A., Mohaini, M.A., Alsalman, A.J., Al Hawaj, M.A., and Mahmood, S. (2022). In Vitro and Ex Vivo Evaluation of Fluocinolone Acetonide\u2013Acitretin Coloaded Nanostructured Lipid Carriers for Topical Treatment of Psoriasis. Gels, 8.","DOI":"10.3390\/gels8110746"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ortiz, A.C., Ya\u00f1ez, O., Salas-Huenuleo, E., and Morales, J.O. (2021). Development of a Nanostructured Lipid Carrier (NLC) by a Low-Energy Method, Comparison of Release Kinetics and Molecular Dynamics Simulation. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13040531"},{"key":"ref_23","first-page":"191","article-title":"Formulation and Evaluation of Topical Gel Containing Nanostructured Lipid Carriers Dispersion of an Antifungal Drug","volume":"57","author":"Gujjar","year":"2019","journal-title":"Acta Pharm. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"102","DOI":"10.2174\/2211738506666180523112513","article-title":"Topical Nanostructured Lipid Carrier-Based Hydrogel of Mometasone Furoate for the Treatment of Psoriasis","volume":"6","author":"Kaur","year":"2018","journal-title":"Pharm. Nanotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e13370","DOI":"10.1111\/dth.13370","article-title":"Formulation, Optimization, and In Vitro Evaluation of Nanostructured Lipid Carriers for Topical Delivery of Apremilast","volume":"33","author":"Madan","year":"2020","journal-title":"Dermatol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"125","DOI":"10.4103\/ijp.IJP_506_19","article-title":"Development of a psoriatic-like skin inflammation rat model using imiquimod as an inducing agent","volume":"53","author":"Parmar","year":"2021","journal-title":"Indian J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gul, M., Shah, F.A., Sahar, N.U., Malik, I., Din, F.U., Khan, S.A., Aman, W., Choi, H.I., Lim, C.W., and Noh, H.Y. (2022). Formulation Optimization, In Vitro and In Vivo Evaluation of Agomelatine-Loaded Nanostructured Lipid Carriers for Augmented Antidepressant Effects. Colloids Surf. B Biointerfaces, 216.","DOI":"10.1016\/j.colsurfb.2022.112537"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Reena, K., Mittal, S., Faizan, M., Jahan, I., Rahman, Y., Khan, R., Singh, L., Alhalmi, A., Noman, O.M., and Alahdab, A. (2023). Enhancement of Curcumin\u2019s Anti-Psoriatic Efficacy via Formulation into Tea Tree Oil-Based Emulgel. Gels, 9.","DOI":"10.3390\/gels9120973"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4763","DOI":"10.2147\/IJN.S247007","article-title":"Methotrexate-Loaded Nanostructured Lipid Carrier Gel Alleviates Imiquimod-Induced Psoriasis by Moderating Inflammation: Formulation, Optimization, Characterization, In Vitro and In Vivo Studies","volume":"15","author":"Agrawal","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Agrawal, M., Saraf, S., Pradhan, M., Patel, R.J., Singhvi, G., and Ajazuddin, A.A. (2021). Design and optimization of curcumin loaded nano lipid carrier system using Box-Behnken design. Biomed. Pharmacother., 141.","DOI":"10.1016\/j.biopha.2021.111919"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ejpb.2009.06.002","article-title":"Design for Optimization of Nanoparticles Integrating Biomaterials for Orally Dosed Insulin","volume":"73","author":"Woitiski","year":"2009","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5582","DOI":"10.1007\/s11694-023-02070-9","article-title":"Optimization of hesperidin extraction using hot methanol method assisted with ultrasound waves from the peel wastes of bitter orange (Citrus aurantium) and Persian orange (Citrus reticulata)","volume":"17","author":"Rajabi","year":"2023","journal-title":"Food Meas."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"102458","DOI":"10.1016\/j.jddst.2021.102458","article-title":"Enhanced Anti-Psoriatic Activity of Tacrolimus Loaded Nanoemulsion Gel via Omega-3\u2014Fatty Acid (EPA and DHA) Rich Oils\u2014Fish Oil and Linseed Oil","volume":"63","author":"Mittal","year":"2021","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ejps.2016.12.005","article-title":"Phospholipid Complex Enriched Micelles: A Novel Drug Delivery Approach for Promoting the Antidiabetic Effect of Repaglinide","volume":"99","author":"Kassem","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"749","DOI":"10.3797\/scipharm.1202-12","article-title":"Nanostructured Lipid Carriers (NLC)-Based Gel for the Topical Delivery of Aceclofenac: Preparation, Characterization, and In Vivo Evaluation","volume":"80","author":"Patel","year":"2012","journal-title":"Sci. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1208\/s12249-021-02108-5","article-title":"Primaquine Loaded Solid Lipid Nanoparticles (SLN), Nanostructured Lipid Carriers (NLC), and Nanoemulsion (NE): Effect of Lipid Matrix and Surfactant on Drug Entrapment, In Vitro Release, and Ex Vivo Hemolysis","volume":"22","author":"Wu","year":"2021","journal-title":"AAPS PharmSciTech"},{"key":"ref_37","first-page":"794","article-title":"Formulation, Development and Evaluation of Nanostructured Lipid Carrier (NLC) Based Gel for Topical Delivery of Diacerein","volume":"11","author":"Pawbake","year":"2020","journal-title":"Syst. Rev. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Dos Santos, R.S., da Silva, J.B., Rosseto, H.C., Vecchi, C.F., Campanholi, K.S.S., Caetano, W., and Bruschi, M.L. (2021). Emulgels Containing Propolis and Curcumin: The Effect of Type of Vegetable Oil, Poly(Acrylic Acid) and Bioactive Agent on Physicochemical Stability, Mechanical and Rheological Properties. Gels, 7.","DOI":"10.3390\/gels7030120"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5836","DOI":"10.4049\/jimmunol.0802999","article-title":"Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23\/IL-17 axis","volume":"182","author":"Mourits","year":"2009","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1007\/s10787-023-01198-w","article-title":"Diosmin nanocrystal gel alleviates imiquimod-induced psoriasis in rats via modulating TLR7, 8\/NF-\u03baB\/micro RNA-31, AKT\/mTOR\/P70S6K milieu, and Tregs\/Th17 balance","volume":"31","author":"Shahine","year":"2023","journal-title":"Inflammopharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Alhalmi, A., Amin, S., Khan, Z., Beg, S., Al kamaly, O., Saleh, A., and Kohli, K. (2022). Nanostructured Lipid Carrier-Based Codelivery of Raloxifene and Naringin: Formulation, Optimization, In Vitro, Ex Vivo, In Vivo Assessment, and Acute Toxicity Studies. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14091771"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/BF00257745","article-title":"Effects of Polysorbate 80 on the Absorption and Distribution of Oral Methotrexate (MTX) in Mice","volume":"9","author":"Azmin","year":"1982","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.ejps.2006.04.016","article-title":"Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system","volume":"29","author":"Pouton","year":"2006","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0378-5173(79)90025-5","article-title":"The rheological properties of carbopol gels I: Continuous shear and creep properties of carbopol gels","volume":"2","author":"Barry","year":"1979","journal-title":"Int. J. Pharm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"654","DOI":"10.5530\/ijper.53.4.127","article-title":"Formulation and Characterization of pH Induced in situ Gels Containing Sulfacetamide Sodium for Ocular Drug Delivery: A Combination of Carbopol\u00ae\/HPMC Polymer","volume":"53","author":"Sheshala","year":"2019","journal-title":"Indian J. Pharm. Educat. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1002\/art.23835","article-title":"Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: A literature review and potential mechanisms of action","volume":"59","author":"Collamer","year":"2008","journal-title":"Arthritis Rheum."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/4\/478\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:11:19Z","timestamp":1760029879000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/4\/478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,7]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["pharmaceutics17040478"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17040478","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,7]]}}}