{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:58:33Z","timestamp":1790405913420,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T00:00:00Z","timestamp":1617840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC-PC_17167"],"award-info":[{"award-number":["MC-PC_17167"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Council United Kingdom Grand Challenges Research Funder","award":["MR\/P027989\/1"],"award-info":[{"award-number":["MR\/P027989\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>In cutaneous leishmaniasis (CL), parasites reside in the dermis, creating an opportunity for local drug administration potentially reducing adverse effects and improving treatment adherence compared to current therapies. Polymeric film-forming systems (FFSs) are directly applied to the skin and form a thin film as the solvent evaporates. In contrast to conventional topical dosage forms, FFSs strongly adhere to the skin, favouring sustained drug delivery to the affected site, reducing the need for frequent applications, and enhancing patient compliance. This study reports the first investigation of the use of film-forming systems for the delivery of DNDI-0690, a nitroimidazole compound with potent activity against CL-causing Leishmania species. A total of seven polymers with or without plasticiser were evaluated for drying time, stickiness, film-flexibility, and cosmetic attributes; three FFSs yielded a positive evaluation for all test parameters. The impact of each of these FFSs on the permeation of the model skin permeant hydrocortisone (hydrocortisone, 1% (w\/v) across the Strat-M membrane was evaluated, and the formulations resulting in the highest and lowest permeation flux (Klucel LF with triethyl citrate and Eudragit RS with dibutyl sebacate, respectively) were selected as the FFS vehicle for DNDI-0690. The release and skin distribution of the drug upon application to Leishmania-infected and uninfected BALB\/c mouse skin were examined using Franz diffusion cells followed by an evaluation of the efficacy of both DNDI-0690 FFSs (1% (w\/v)) in an experimental CL model. Whereas the Eudragit film resulted in a higher permeation of DNDI-0690, the Klucel film was able to deposit four times more drug into the skin, where the parasite resides. Of the FFSs formulations, only the Eudragit system resulted in a reduced parasite load, but not reduced lesion size, when compared to the vehicle only control. Whereas drug delivery into the skin was successfully modulated using different FFS systems, the FFS systems selected were not effective for the topical application of DNDI-0690. The convenience and aesthetic of FFS systems alongside their ability to modulate drug delivery to and into the skin merit further investigation using other promising antileishmanial drugs.<\/jats:p>","DOI":"10.3390\/pharmaceutics13040516","type":"journal-article","created":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T21:27:44Z","timestamp":1617917264000},"page":"516","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Film-Forming Systems for the Delivery of DNDI-0690 to Treat Cutaneous Leishmaniasis"],"prefix":"10.3390","volume":"13","author":[{"given":"Katrien","family":"Van Bocxlaer","sequence":"first","affiliation":[{"name":"Department of Biology, York Biomedical Research Institute, University of York, York YO10 5DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3106-6171","authenticated-orcid":false,"given":"Kerri-Nicola","family":"McArthur","sequence":"additional","affiliation":[{"name":"Pharmidex Pharmaceutical Services Ltd., London EC2V 8AU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Harris","sequence":"additional","affiliation":[{"name":"Pharmidex Pharmaceutical Services Ltd., London EC2V 8AU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mo","family":"Alavijeh","sequence":"additional","affiliation":[{"name":"Pharmidex Pharmaceutical Services Ltd., London EC2V 8AU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6354-3059","authenticated-orcid":false,"given":"St\u00e9phanie","family":"Braillard","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases <i>initiative<\/i> (DND<i>i<\/i>), 1202 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles E.","family":"Mowbray","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases <i>initiative<\/i> (DND<i>i<\/i>), 1202 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon L.","family":"Croft","sequence":"additional","affiliation":[{"name":"Faculty of Infectious and Tropical Diseases, London School of Hygiene &amp; Tropical Medicine, London WC1E 7HT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alvar, J., Velez, I.D., Bern, C., Herrero, M., Desjeux, P., Cano, J., Jannin, J., and den Boer, M. (2012). Leishmaniasis Worldwide and Global Estimates of Its Incidence. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035671"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(18)31204-2","article-title":"Leishmaniasis","volume":"392","author":"Burza","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Choi, H.L., Jain, S., Ruiz Postigo, J.A., Borisch, B., and Dagne, D.A. (2021). The global procurement landscape of leishmaniasis medicines. PLoS Negl. Trop. Dis., 15.","DOI":"10.1371\/journal.pntd.0009181"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Rivas, L., and Gil, C. (2018). Leishmaniasis\u2014Impact and therapeutic needs. Drug Discovery for Leishmaniasis, The Royal Society of Chemistry.","DOI":"10.1039\/9781788010177"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Bailey, F., Mondragon-Shem, K., Haines, L.R., Olabi, A., Alorfi, A., Ruiz-Postigo, J.A., Alvar, J., Hotez, P., Adams, E.R., and V\u00e9lez, I.D. (2019). Cutaneous leishmaniasis and co-morbid major depressive disorder: A systematic review with burden estimates. PLoS Negl. Trop. Dis., 13.","DOI":"10.1371\/journal.pntd.0007092"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Pires, M., Wright, B., Kaye, P.M., da Concei\u00e7\u00e3o, V., and Churchill, R.C. (2019). The impact of leishmaniasis on mental health and psychosocial well-being: A systematic review. PLoS ONE, 14.","DOI":"10.1101\/637132"},{"key":"ref_7","unstructured":"(2021, February 02). DNDi Visceral Leishmaniasis: Target Product Profile. Available online: https:\/\/dndi.org\/diseases\/visceral-leishmaniasis\/target-product-profile\/."},{"key":"ref_8","unstructured":"(2021, February 02). DNDi Cutaneous Leishmaniasis: Target Product Profile. Available online: https:\/\/dndi.org\/diseases\/cutaneous-leishmaniasis\/target-product-profile\/."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejpb.2015.01.002","article-title":"Formulation considerations in the design of topical, polymeric film-forming systems for sustained drug delivery to the skin","volume":"91","author":"Frederiksen","year":"2015","journal-title":"Eur. J. Pharm. Biopharm. Off. J. Arb. Pharm. Verfahr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0190-9622(92)70175-F","article-title":"Topical treatment of Old World cutaneous leishmaniasis caused by Leishmania major: A double-blind control study","volume":"27","author":"Halevy","year":"1992","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1086\/516267","article-title":"Topical paromomycin\/methylbenzethonium chloride plus parenteral meglumine antimonate as treatment for American cutaneous leishmaniasis: Controlled study","volume":"26","author":"Soto","year":"1998","journal-title":"Clin. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S0035-9203(97)90290-X","article-title":"Non-ulcerative cutaneous leishmaniasis in Honduras fails to respond to topical paromomycin","volume":"91","author":"Neva","year":"1997","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1056\/NEJMoa1202657","article-title":"Topical paromomycin with or without gentamicin for cutaneous leishmaniasis","volume":"368","author":"Guedri","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sosa, N., Pascale, J.M., Jim\u00e9nez, A.I., Norwood, J.A., Kreishman-Detrick, M., Weina, P.J., Lawrence, K., McCarthy, W.F., Adams, R.C., and Scott, C. (2019). Topical paromomycin for New World cutaneous leishmaniasis. PLoS Negl. Trop. Dis., 13.","DOI":"10.1371\/journal.pntd.0007253"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.3109\/03639045.2011.653362","article-title":"Influence of the hydrophilic\u2013lipophilic balance of sunscreen emulsions on their water resistance property","volume":"38","author":"Couteau","year":"2012","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1159\/000074057","article-title":"Factors affecting the formation of a skin reservoir for topically applied","volume":"17","author":"Roberts","year":"2004","journal-title":"Skin Pharmacol. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/j.1468-3083.2012.04525.x","article-title":"Adherence to topical treatment in psoriasis: A systematic literature review","volume":"26","author":"Devaux","year":"2012","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e14833","DOI":"10.1111\/dth.14833","article-title":"Patient-reported outcomes of topical therapies in actinic keratosis: A systematic review","volume":"34","author":"Grada","year":"2021","journal-title":"Dermatol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1185\/030079907X199664","article-title":"Stratum corneum pharmacokinetics of the anti-fungal drug, terbinafine, in a novel topical formulation, for single-dose application in dermatophytoses","volume":"23","author":"Kienzler","year":"2007","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3109\/09546634.2010.512952","article-title":"Efficacy of clobetasol spray: Factors beyond patient compliance","volume":"23","author":"Bhutani","year":"2012","journal-title":"J. Dermatol. Treat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ijpddr.2019.02.002","article-title":"Novel benzoxaborole, nitroimidazole and aminopyrazoles with activity against experimental cutaneous leishmaniasis","volume":"11","author":"Caridha","year":"2019","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"ref_22","first-page":"4454","article-title":"Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis","volume":"26","author":"Fairlamb","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e00829-19","DOI":"10.1128\/AAC.00829-19","article-title":"Pharmacokinetics and Pharmacodynamics of the Nitroimidazole DNDI-0690 in Mouse Models of Cutaneous Leishmaniasis","volume":"63","author":"Wijnant","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.ejpb.2006.07.015","article-title":"Development and characterization of film forming polymeric solutions for skin","volume":"65","author":"Schroeder","year":"2007","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.ijpharm.2018.06.012","article-title":"Strat-M\u00ae synthetic membrane: Permeability comparison to human cadaver skin","volume":"547","author":"Haq","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_26","unstructured":"Ashland Global Specialty Chemicals Inc (2021, February 08). Klucel\u2122 hydroxypropylcellulose\u2014Physical and Chemical Properties. Available online: www.ashland.com\/Documents\/PC_11229_Klucel_HPC."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.cplett.2005.02.095","article-title":"Glass transition temperature of a cationic polymethacrylate dependent on the plasticizer content\u2014Simulation vs. experiment","volume":"406","author":"Wagner","year":"2005","journal-title":"Chem. Phys. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1208\/s12249-009-9275-5","article-title":"Influence of an acrylic polymer blend on the physical stability of film-coated theophylline pellets","volume":"10","author":"Kucera","year":"2009","journal-title":"Aaps Pharmscitech"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.jconrel.2006.12.013","article-title":"Delivery of ethinylestradiol from film forming polymeric solutions across human epidermis in vitro and in vivo in pigs","volume":"118","author":"Franke","year":"2007","journal-title":"J. Control. Release Off. J. Control. Release Soc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1517\/17425247.2016.1124412","article-title":"The potential of polymeric film-forming systems as sustained delivery platforms for topical drugs","volume":"13","author":"Frederiksen","year":"2016","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1080\/09546630701247971","article-title":"Short-duration topical treatment of tinea pedis using terbinafine emulsion gel: Results of a dose-ranging clinical trial","volume":"18","author":"James","year":"2007","journal-title":"J. Dermatolog. Treat."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Van Bocxlaer, K., and Croft, S.L. (2021). Pharmacokinetics and pharmacodynamics in the treatment of cutaneous leishmaniasis\u2013Challenges and opportunities. RSC Med. Chem.","DOI":"10.1039\/D0MD00343C"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1093\/jac\/dkw012","article-title":"Drug permeation and barrier damage in Leishmania-infected mouse skin","volume":"71","author":"Yardley","year":"2016","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e00631-18","DOI":"10.1128\/AAC.00631-18","article-title":"Local Skin Inflammation in Cutaneous Leishmaniasis as a Source of Variable Pharmacokinetics and Therapeutic Efficacy of Liposomal Amphotericin B","volume":"62","author":"Wijnant","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jconrel.2015.06.015","article-title":"Biophysical elucidation of the mechanism of enhanced drug release and topical delivery from polymeric film-forming systems","volume":"212","author":"Frederiksen","year":"2015","journal-title":"J. Control. 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