{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T09:53:29Z","timestamp":1781776409697,"version":"3.54.5"},"reference-count":43,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Agency, Poland","award":["2024\/ABM\/03\/KPO\/KPOD.07.07-IW.07-0135\/24-00"],"award-info":[{"award-number":["2024\/ABM\/03\/KPO\/KPOD.07.07-IW.07-0135\/24-00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: 5-(3\u2032,4\u2032-Dihydroxyphenyl)-\u03b3-valerolactone (DHPV) is a postbiotic gut microbiota-derived flavanol metabolite with reported anti-inflammatory activity. Despite growing interest in its potential dermatological applications, its pharmaceutical properties and suitability for topical delivery have not been systematically investigated. This study aimed to perform the first comprehensive preformulation and formulation-oriented evaluation of DHPV and to develop stable topical ointment formulations suitable for further dermatological research. Methods: The physicochemical properties of DHPV were characterized using powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), quantitative solubility assessment, and excipient compatibility studies. Based on the obtained preformulation data, two anhydrous ointment formulations containing DHPV were developed. The formulations were evaluated for homogeneity, rheological behavior, chemical stability under accelerated storage conditions, and in vitro drug release performance. Results: DHPV was identified as a crystalline compound with heterogeneous particle morphology and limited aqueous solubility. Quantitative solubility studies demonstrated the highest solubility in PEG 300 and glycol-based solvents. Compatibility testing revealed increased impurity formation in hydrophilic environments, whereas lipophilic excipients provided improved chemical stability. Both ointment formulations exhibited acceptable physical characteristics and maintained DHPV stability throughout accelerated storage. However, marked differences in release behavior were observed. The lipid\u2013wax formulation showed significantly higher release rates, lower variability, and more reproducible release profiles than the petrolatum-based reference formulation, indicating more efficient diffusion of DHPV from the semisolid matrix. Conclusions: The physicochemical characteristics of DHPV strongly influence formulation design and performance. Anhydrous lipid-based systems provide a favorable environment for maintaining DHPV stability, while formulation composition significantly affects drug release. The developed lipid\u2013wax formulation represents a promising platform for future skin permeation, pharmacodynamic, and efficacy studies.<\/jats:p>","DOI":"10.3390\/pharmaceutics18060749","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T08:59:38Z","timestamp":1781773178000},"page":"749","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preformulation Studies and Rational Design of an Ointment Containing a Postbiotic Metabolite of Procyanidins for Topical Use"],"prefix":"10.3390","volume":"18","author":[{"given":"Tomasz","family":"Todryk","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry and Biomaterials, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0088-8858","authenticated-orcid":false,"given":"Monika","family":"Budnicka","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry and Biomaterials, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1985-0876","authenticated-orcid":false,"given":"Lukasz","family":"Pajchel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry and Biomaterials, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Kiero\u0144ska","sequence":"additional","affiliation":[{"name":"Pikralida Sp. z.o.o, Uniwersytetu Pozna\u0144skiego 10 Street, 61-614 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7262-5718","authenticated-orcid":false,"given":"Maciej","family":"Dawidowski","sequence":"additional","affiliation":[{"name":"Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4621-1551","authenticated-orcid":false,"given":"Krzysztof Adam","family":"St\u0119pie\u0144","sequence":"additional","affiliation":[{"name":"Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2567-4453","authenticated-orcid":false,"given":"Joanna","family":"Giebu\u0142towicz","sequence":"additional","affiliation":[{"name":"Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1876-1321","authenticated-orcid":false,"given":"Sebastian","family":"Granica","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biology, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4417-5836","authenticated-orcid":false,"given":"Joanna","family":"Kolmas","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry and Biomaterials, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5011-0983","authenticated-orcid":false,"given":"Jakub P.","family":"Piwowarski","sequence":"additional","affiliation":[{"name":"Microbiota Lab, Department of Pharmaceutical Microbiology and Bioanalysis, Medical University of Warsaw, Banacha 1 Street, 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/S0140-6736(15)00149-X","article-title":"Atopic dermatitis","volume":"387","author":"Weidinger","year":"2016","journal-title":"Lancet"},{"key":"ref_2","first-page":"35","article-title":"Atopic dermatitis: An overview","volume":"86","author":"Berke","year":"2012","journal-title":"Am. Fam. Physician"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e70029","DOI":"10.1002\/mco2.70029","article-title":"Atopic dermatitis: Pathogenesis and therapeutic intervention","volume":"5","author":"Yue","year":"2024","journal-title":"MedComm"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.anai.2023.09.009","article-title":"Filaggrin and beyond: New insights into the skin barrier in atopic dermatitis and allergic diseases, from genetics to therapeutic perspectives","volume":"132","author":"Stefanovic","year":"2024","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Moosbrugger-Martinz, V., Leprince, C., M\u00e9chin, M.-C., Simon, M., Blunder, S., Gruber, R., and Dubrac, S. (2022). Revisiting the Roles of Filaggrin in Atopic Dermatitis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105318"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.anai.2023.11.020","article-title":"Diversity of atopic dermatitis and selection of immune targets","volume":"132","author":"Bar","year":"2024","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2721469","DOI":"10.1155\/2016\/2721469","article-title":"Oxidative stress in atopic dermatitis","volume":"2016","author":"Ji","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kvedariene, V., Vaskovic, M., and Semyte, J.B. (2025). Role of oxidative stress and antioxidants in the course of atopic dermatitis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094210"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1111\/cea.70136","article-title":"New topical and systemic treatments for atopic dermatitis","volume":"55","author":"Mirali","year":"2025","journal-title":"Clin. Exp. Allergy"},{"key":"ref_10","first-page":"53","article-title":"Atopic dermatitis\u2014Current state of research on biological treatment","volume":"24","author":"Klasa","year":"2020","journal-title":"J. Mother Child"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.sder.2011.05.002","article-title":"Management of itch in atopic dermatitis","volume":"30","author":"Hong","year":"2011","journal-title":"Semin. Cutan. Med. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wegh, C.A.M., Geerlings, S.Y., Knol, J., Roeselers, G., and Belzer, C. (2019). Postbiotics and their potential applications in early life nutrition and beyond. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194673"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Borrego-Ruiz, A., and Borrego, J.J. (2024). Nutritional and microbial strategies for treating acne, alopecia, and atopic dermatitis. Nutrients, 16.","DOI":"10.3390\/nu16203559"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1007\/s00394-021-02692-z","article-title":"Metabotypes of flavan-3-ol colonic metabolites after cranberry intake: Elucidation and statistical approaches","volume":"61","author":"Mena","year":"2022","journal-title":"Eur. J. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7083","DOI":"10.1021\/jf2020182","article-title":"Synthesis, analytical features, and biological relevance of 5-(3\u2032,4\u2032-dihydroxyphenyl)-\u03b3-valerolactone","volume":"59","author":"Chioua","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hur, J., Kim, A.-R., Kim, H.S., Lim, C., Kim, T., Kim, T.-A., Sim, J., and Suh, Y.-G. (2020). Concise synthesis of catechin metabolites 5-(3\u2032,4\u2032-dihydroxyphenyl)-\u03b3-valerolactones and their stereochemical effects. Molecules, 25.","DOI":"10.3390\/molecules25081970"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6893","DOI":"10.1021\/jf034578e","article-title":"Urinary excretion of 5-(3\u2032,4\u2032-dihydroxyphenyl)-\u03b3-valerolactone","volume":"51","author":"Unno","year":"2003","journal-title":"J. Agric. Food Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1039\/c0fo00132e","article-title":"Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols","volume":"1","author":"Monagas","year":"2010","journal-title":"Food Funct."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1021\/jf803059z","article-title":"Procyanidin dimers are metabolized by human microbiota","volume":"57","author":"Appeldoorn","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"M\u00e1rquez Campos, E., Stehle, P., and Simon, M.-C. (2019). Microbial metabolites of flavan-3-ols and their biological activity. Nutrients, 11.","DOI":"10.3390\/nu11102260"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dufour, C., Villa-Rodriguez, J.A., Furger, C., Lessard-Lord, J., Gironde, C., Rigal, M., Badr, A., Desjardins, Y., and Guyonnet, D. (2022). Cellular antioxidant effect of an Aronia extract. Antioxidants, 11.","DOI":"10.3390\/antiox11081561"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kurebayashi, A.K., Phan, K., Abdoh, A., Andreo-Filho, N., Lopes, P.S., Mohammed, Y., and Leite-Silva, V.R. (2024). Strategic approaches in formulation development for atopic dermatitis. Cosmetics, 11.","DOI":"10.3390\/cosmetics11040113"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Oliveira, R., and Almeida, I.F. (2023). Patient-centric design of topical dermatological medicines. Pharmaceutics, 16.","DOI":"10.3390\/ph16040617"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jin, X., Imran, M., and Mohammed, Y. (2022). Topical semisolid products\u2014Impact of metamorphosis on skin penetration. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112487"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/j.jaci.2023.08.030","article-title":"Topical treatments for atopic dermatitis: Systematic review and network meta-analysis","volume":"152","author":"Chu","year":"2023","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Alnaim, A.S. (2024). Nanocrystals in dermal drug delivery. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16121561"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"133430","DOI":"10.1016\/j.foodchem.2022.133430","article-title":"FT-IR and FT-Raman fingerprints of flavonoids","volume":"393","author":"Krysa","year":"2022","journal-title":"Food Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"118228","DOI":"10.1016\/j.saa.2020.118228","article-title":"FTIR spectroscopy for predicting antioxidant content","volume":"233","author":"Johnson","year":"2020","journal-title":"Spectrochim. Acta A"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Barnes, T.M., Mijaljica, D., Townley, J.P., Spada, F., and Harrison, I.P. (2021). Vehicles for drug delivery and cosmetic moisturizers. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13122012"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S1093-0191(00)00024-1","article-title":"Advanced oxidation of phenolic compounds","volume":"4","author":"Alnaizy","year":"2000","journal-title":"Adv. Environ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1021\/jf0349883","article-title":"LC-MS investigation of oxidation products of phenolic antioxidants","volume":"52","author":"Antolovich","year":"2004","journal-title":"J. Agric. Food Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1007\/s11144-023-02358-3","article-title":"Kinetics and mechanism of caffeic acid autoxidation","volume":"136","year":"2023","journal-title":"Reac. Kinet. Mech. Cat."},{"key":"ref_33","unstructured":"European Medicines Agency (EMA), CHMP (2026, June 03). Guideline on Quality and Equivalence of Locally Applied Cutaneous Products. EMA\/CHMP\/QWP\/708282\/2018 Corr.1. Available online: https:\/\/www.ema.europa.eu\/en\/human-regulatory-overview\/research-development\/scientific-guidelines."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"103586","DOI":"10.1016\/j.fbio.2024.103586","article-title":"Stability and preservation of phenolic compounds","volume":"57","author":"Pasquet","year":"2024","journal-title":"Food Biosci."},{"key":"ref_35","unstructured":"Aulton, M.E., and Taylor, K. (2018). Pharmaceutics: The Design and Manufacture of Medicines, Elsevier. [5th ed.]."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0009-3084(97)00108-4","article-title":"Physical, chemical and functional properties of lipids in the skin","volume":"91","author":"Wertz","year":"1998","journal-title":"Chem. Phys. Lipids"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Tadros, T.F. (2010). Rheology of emulsions. Rheology of Dispersions, Wiley-VCH. [1st ed.].","DOI":"10.1002\/9783527631568"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Brown, M.B., Turner, R., and Lim, S.T. (2012). Topical product formulation development. Topical and Transdermal Drug Delivery, Wiley.","DOI":"10.1002\/9781118140505.ch14"},{"key":"ref_39","first-page":"69","article-title":"Functions of mixed emulsifiers in dermatological lotions","volume":"123\u2013124","author":"Eccleston","year":"1997","journal-title":"Colloids Surf. A"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Otto, A., and du Plessis, J. (2015). Effects of emulsifiers on dermal drug delivery. Percutaneous Penetration Enhancers, Springer.","DOI":"10.1007\/978-3-662-45013-0_16"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ijpharm.2011.03.051","article-title":"Higuchi equation: Derivation and applications","volume":"418","author":"Siepmann","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1080\/10837450.2021.1945625","article-title":"Rheological and in vitro release measurements of acyclovir creams","volume":"26","author":"Miron","year":"2021","journal-title":"Pharm. Dev. Technol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"122159","DOI":"10.1016\/j.ijpharm.2022.122159","article-title":"In vitro release test (IVRT)","volume":"626","author":"Shah","year":"2022","journal-title":"Int. J. Pharm."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/6\/749\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T09:10:08Z","timestamp":1781773808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/6\/749"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":43,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["pharmaceutics18060749"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18060749","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]}}}