{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:22:38Z","timestamp":1770078158918,"version":"3.49.0"},"reference-count":203,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SA NRF","award":["129785"],"award-info":[{"award-number":["129785"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Topical treatment of cutaneous tuberculosis (CTB) requires reliable models to evaluate dermal drug release and diffusion, particularly for fixed-dose combinations (FDCs) with contrasting physicochemical properties. Human skin remains the reference standard but poses ethical, logistical, and reproducibility challenges. This study investigated the suitability of Strat-M\u00ae synthetic membranes as an alternative to human skin for assessing the simultaneous release and diffusion of clofazimine (CFZ) and pyrazinamide (PZA) from a topical FDC, and aimed to develop an optimized dermal emulsion using a Quality-by-Design (QbD)-informed formulation development tool. Methods: Self-emulsifying dermal emulsions containing CFZ and PZA were developed following QbD principles. Preformulation studies included drug solubility screening, oil phase selection, and pseudoternary phase diagram construction to identify stable emulsion regions. Formulations were characterized for droplet size, polydispersity index, zeta potential, viscosity, self-emulsification efficiency, and thermodynamic stability. Eight stable emulsions were identified, of which four were selected for in vitro drug release studies. The peppermint oil-based emulsion (PPO415) was further evaluated in comparative diffusion studies using Strat-M\u00ae membranes and ex vivo human skin (Caucasian and African). Results: PPO415 demonstrated favorable physicochemical properties, including high CFZ solubility, uniform droplet distribution, and suitability for dermal application. Comparative diffusion studies showed that Strat-M\u00ae underestimated the partitioning of lipophilic CFZ while overestimating the diffusion of hydrophilic PZA relative to human skin. These differences were attributed to compositional and structural disparities between synthetic membranes and biological skin. Conclusions: Strat-M\u00ae membranes show potential as a reproducible and ethical in vitro screening tool during early-stage formulation development for topical FDCs. However, ex vivo human skin remains essential for accurately predicting dermal drug distribution and therapeutic performance.<\/jats:p>","DOI":"10.3390\/ph19020255","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T12:00:47Z","timestamp":1770033647000},"page":"255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quality-by-Design Development of a Clofazimine\u2013Pyrazinamide Dermal Emulsion and Its Diffusion Behavior in Strat-M\u00ae and Human Skin"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4688-6737","authenticated-orcid":false,"given":"Francelle","family":"Bouwer","sequence":"first","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences (Pharmacen\u2122), Building G16, Faculty of Health Sciences, North-West University, Potchefstroom 2520, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0197-300X","authenticated-orcid":false,"given":"Marius","family":"Brits","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences (Pharmacen\u2122), Building G16, Faculty of Health Sciences, North-West University, Potchefstroom 2520, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8652-3205","authenticated-orcid":false,"given":"Dani\u00e9lle","family":"van Staden","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences (Pharmacen\u2122), Building G16, Faculty of Health Sciences, North-West University, Potchefstroom 2520, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2489-1616","authenticated-orcid":false,"given":"Joe M.","family":"Viljoen","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Pharmaceutical Sciences (Pharmacen\u2122), Building G16, Faculty of Health Sciences, North-West University, Potchefstroom 2520, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Costa Gagosian, V.S., Coronel, R., Buss, B.C., Dos Santos, M.L.F., Liste, I., Anta, B., and Foti, L. (2025). In vitro skin models as non-animal methods for dermal drug development and safety assessment. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17101342"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Neupane, R., Boddu, S.H.S., Renukuntla, J., Babu, R.J., and Tiwari, A.K. (2020). Alternatives to biological skin in permeation studies: Current trends and possibilities. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12020152"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dragicevic, N., and Maibach, H.I. (2017). Efficacy, safety and targets in topical and transdermal active and excipient delivery. Percutaneous Penetration Enhancers Drug Penetration into\/Through the Skin: Methodology and General Considerations, Springer. [1st ed.].","DOI":"10.1007\/978-3-662-53270-6"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101252","DOI":"10.1016\/j.plipres.2023.101252","article-title":"The skin barrier: An extraordinary interface with an exceptional lipid organization","volume":"92","author":"Bouwstra","year":"2023","journal-title":"Prog. Lipid Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105630","DOI":"10.1016\/j.tiv.2023.105630","article-title":"Parallel evaluation of alternative skin barrier models and excised human skin for dermal absorption studies in vitro","volume":"91","author":"Salminen","year":"2023","journal-title":"Toxicol. Vitr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s12403-023-00558-9","article-title":"Permeability of dimethyl phthalate through human skin models\u2014Health risk assessment","volume":"16","author":"Olkowska","year":"2024","journal-title":"Expo. Health"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Todo, H. (2017). Transdermal permeation of drugs in various animal species. Pharmaceutics, 9.","DOI":"10.3390\/pharmaceutics9030033"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1208\/s12249-025-03143-2","article-title":"Optimizing in vitro skin permeation studies to obtain meaningful data in topical and transdermal drug delivery","volume":"26","author":"Nair","year":"2025","journal-title":"AAPS PharmSciTech"},{"key":"ref_9","unstructured":"United States Food and Drug Administration (2025, October 11). Implementing Alternative Methods, Available online: https:\/\/www.fda.gov\/science-research\/advancing-alternative-methods-fda\/implementing-alternative-methods."},{"key":"ref_10","unstructured":"ICH (2025, October 11). ICH M3 (R2) Non-Clinical safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals\u2014Scientific Guideline. Available online: https:\/\/www.ema.europa.eu\/en\/ich-m3-r2-non-clinical-safety-studies-conduct-human-clinical-trials-pharmaceuticals-scientific-guideline."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1208\/s12249-022-02352-3","article-title":"Evaluation of an anhydrous permeation-enhancing vehicle for percutaneous absorption of hormones","volume":"23","author":"Song","year":"2022","journal-title":"AAPS PharmSciTech"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"123488","DOI":"10.1016\/j.ijpharm.2023.123488","article-title":"Strat-M\u00ae positioning for skin permeation studies: A comparative study including EpiSkin\u00ae RHE, and human skin","volume":"647","author":"Kichou","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Arce, F.J., Asano, N., See, G.L., Itakura, S., Todo, H., and Sugibayashi, K. (2020). Usefulness of artificial membrane, Strat-M\u00ae, in the assessment of drug permeation from complex vehicles in finite dose conditions. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12020173"},{"key":"ref_14","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_15","doi-asserted-by":"crossref","unstructured":"Kov\u00e1cs, A., Zsik\u00f3, S., Falusi, F., Cs\u00e1nyi, E., Budai-Sz\u0171cs, M., Cs\u00f3ka, I., and Berk\u00f3, S. (2021). Comparison of synthetic membranes to heat-separated human epidermis in skin permeation studies In vitro. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13122106"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bouwer, F., Brits, M., and Viljoen, J.M. (2025). Cracking the Skin Barrier: Models and Methods Driving Dermal Drug Delivery. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17121586"},{"key":"ref_17","first-page":"710","article-title":"Cutaneous tuberculosis: A comprehensive review of etiopathogenesis, clinical subtypes, diagnostic modalities, and contemporary therapeutic approaches","volume":"5","author":"Almanza","year":"2025","journal-title":"Int. J. Med. Sci. Clin. Res. Stud."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nguyen, K.H., Alcantara, C.A., Glassman, I., May, N., Mundra, A., Mukundan, A., Urness, B., Yoon, S., Sakaki, R., and Dayal, S. (2023). Cutaneous manifestations of Mycobacterium tuberculosis: A literature review. Pathogens, 12.","DOI":"10.3390\/pathogens12070920"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.tube.2014.12.006","article-title":"Cutaneous tuberculosis overview and current treatment regimens","volume":"95","author":"Viljoen","year":"2015","journal-title":"Tuberculosis"},{"key":"ref_20","first-page":"793","article-title":"Recognising cutaneous tuberculosis","volume":"23","author":"Gramminger","year":"2025","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.clindermatol.2019.01.008","article-title":"Cutaneous tuberculosis: A great imitator","volume":"37","author":"Chen","year":"2019","journal-title":"Clin. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.abd.2021.07.004","article-title":"Cutaneous tuberculosis: Epidemiological, clinical, diagnostic and therapeutic update","volume":"97","author":"Brito","year":"2022","journal-title":"An. Bras. Dermatol."},{"key":"ref_23","first-page":"141","article-title":"Extrapulmonary tuberculosis\u2014An update on the diagnosis, treatment and drug resistance","volume":"1","author":"Gopalaswamy","year":"2021","journal-title":"J. Respir."},{"key":"ref_24","first-page":"206","article-title":"Advancements in tuberculosis treatment: From epidemiology to innovative therapies","volume":"13","author":"Thakur","year":"2024","journal-title":"Int. J. Sci. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15347","DOI":"10.1038\/s41598-019-51695-8","article-title":"Retrospective analysis of 28 cases of tuberculosis in pregnant women in China","volume":"9","author":"Li","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1016\/j.biopha.2018.06.023","article-title":"Clofazimine: A useful antibiotic for drug-resistant tuberculosis","volume":"105","author":"Mirnejad","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e00636-18","DOI":"10.1128\/AAC.00636-18","article-title":"Impact of clofazimine dosing on treatment shortening of the first-line regimen in a mouse model of tuberculosis","volume":"62","author":"Ammerman","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/14737167.2020.1734456","article-title":"Fixed dose drug combinations\u2014Are they pharmacoeconomically sound? Findings and implications especially for lower- and middle-income countries","volume":"20","author":"Godman","year":"2020","journal-title":"Expert Rev. Pharmacoecon. Outcomes Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.cmi.2018.11.010","article-title":"Clofazimine for the treatment of multidrug-resistant tuberculosis","volume":"25","author":"Lange","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"311","DOI":"10.4103\/2230-8210.152739","article-title":"Triple fixed drug combinations in type 2 diabetes","volume":"19","author":"John","year":"2015","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1128\/JB.181.7.2044-2049.1999","article-title":"Role of acid pH and deficient efflux of pyrazinoic acid in unique susceptibility of Mycobacterium tuberculosis to pyrazinamide","volume":"181","author":"Zhang","year":"1999","journal-title":"J. Bacteriol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.1021\/acsinfecdis.0c00507","article-title":"The acid-base equilibrium of pyrazinoic acid drives the pH dependence of pyrazinamide-induced Mycobacterium tuberculosis growth inhibition","volume":"6","author":"Fontes","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1164\/rccm.201410-1801OC","article-title":"Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline","volume":"191","author":"Diacon","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Van Deventer, M., Haynes, R.K., Brits, M., and Viljoen, J.M. (2025). Formulation of topical drug delivery systems containing a fixed-dose isoniazid-rifampicin combination using the self-emulsification mechanism. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17060680"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4683","DOI":"10.1016\/j.apsb.2024.08.027","article-title":"Solubilization techniques used for poorly water-soluble drugs","volume":"14","author":"Xie","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ait-Touchente, Z., Zine, N., Jaffrezic-Renault, N., Errachid, A., Lebaz, N., Fessi, H., and Elaissari, A. (2023). Exploring the versatility of microemulsions in cutaneous drug delivery: Opportunities and challenges. Nanomaterials, 13.","DOI":"10.3390\/nano13101688"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nrd2197","article-title":"Lipids and lipid-based formulations: Optimizing the oral delivery of lipophilic drugs","volume":"6","author":"Porter","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_38","first-page":"e541101220308","article-title":"Vegetable oils as skin penetration enhancer in topical and transdermal anti-inflammatory formulations: An integrative review","volume":"10","author":"Feitosa","year":"2021","journal-title":"Res. Soc. Dev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3480","DOI":"10.1021\/acs.molpharmaceut.7b00521","article-title":"Design and solidification of fast-releasing clofazimine nanoparticles for treatment of cryptosporidiosis","volume":"14","author":"Zhang","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1073\/pnas.1416951112","article-title":"Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis","volume":"112","author":"Tyagi","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.5588\/ijtld.12.0144","article-title":"Systematic review of clofazimine for the treatment of drug-resistant tuberculosis","volume":"17","author":"Gopal","year":"2013","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e04239","DOI":"10.1016\/j.heliyon.2020.e04239","article-title":"Chemical reactivity and bioactivity properties of pyrazinamide analogs of acetylsalicylic acid and salicylic acid using conceptual density functional theory","volume":"6","author":"Villagracia","year":"2020","journal-title":"Heliyon"},{"key":"ref_43","unstructured":"National Center for Biotechnology Information (2025, October 28). PubChem Compound Summary for CID 2794, Clofazimine, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Clofazimine."},{"key":"ref_44","unstructured":"National Center for Biotechnology Information (2025, October 28). PubChem Compound Summary for CID 1046, Pyrazinamide, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Pyrazinamide."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.2147\/IJN.S236277","article-title":"Novel approach for transdermal delivery of rifampicin to induce synergistic antimycobacterial effects against cutaneous and systemic tuberculosis using a cationic nanoemulsion gel","volume":"15","author":"Hussain","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"113941","DOI":"10.1016\/j.jpba.2021.113941","article-title":"Evaluation of the effect of temperature on the stability and antimicrobial activity of rifampicin quinone","volume":"197","author":"Sutradhar","year":"2021","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jconrel.2020.02.026","article-title":"Antitubercular nanocarrier monotherapy: Study of In vivo efficacy and pharmacokinetics for rifampicin","volume":"321","author":"Trousil","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1208\/s12248-015-9743-7","article-title":"Applying biopharmaceutical classification system (BCS) criteria to predict oral absorption of drugs in dogs: Challenges and pitfalls","volume":"17","author":"Papich","year":"2015","journal-title":"AAPS J."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Van Staden, D., Lemmer, H.J.R., Liebenberg, W., and Hamman, J.H. (2025). Novel liquid-based approaches for transmucosal drug delivery. Acta Pharm. Sin. B, in press.","DOI":"10.1016\/j.apsb.2025.12.042"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Van Staden, D., Haynes, R.K., and Viljoen, J.M. (2022). Adapting clofazimine for treatment of cutaneous tuberculosis by using self-double-emulsifying drug delivery systems. Antibiotics, 11.","DOI":"10.3390\/antibiotics11060806"},{"key":"ref_51","first-page":"1000130","article-title":"Self-emulsifying drug delivery systems (SEDDS) in pharmaceutical development","volume":"5","author":"Zanchetta","year":"2015","journal-title":"J. Adv. Chem. Eng."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"21010","DOI":"10.3390\/molecules201219745","article-title":"Development and evaluation of liquid and solid self-emulsifying drug delivery systems for atorvastatin","volume":"20","author":"Szekalska","year":"2015","journal-title":"Molecules"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1021\/sc500667n","article-title":"Formation and characterization of fully dilutable microemulsion with fatty acid methyl esters as oil phase","volume":"3","author":"Wang","year":"2015","journal-title":"ACS Sustain. Chem. Eng."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/1475-2875-12-202","article-title":"Determination of artemether and lumefantrine in anti-malarial fixed-dose combination tablets by microemulsion electrokinetic chromatography with short-end injection procedure","volume":"12","author":"Amin","year":"2013","journal-title":"Malar. J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s11743-013-1497-6","article-title":"Enlargement of nanoemulsion region in pseudo-ternary mixing diagrams for a drug delivery system","volume":"17","author":"Wang","year":"2014","journal-title":"J. Surfact. Deterg."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Van Staden, D., Du Plessis, J., and Viljoen, J.M. (2020). Development of a self-emulsifying drug delivery system for optimized topical delivery of clofazimine. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12060523"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Topalovi\u0107, I.A., Markovi\u0107, O.S., Pe\u0161i\u0107, M.P., Kathawala, M.H., Kuentz, M., Avdeef, A., Serajuddin, A.T.M., and Verbi\u0107, T. (2024). Effects of different weak small organic acids on clofazimine solubility in aqueous media. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16121545"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Queiroz, L.H., Lage, M.R., Dos Santos, C.C., Sarragu\u00e7a, M.C., and Ribeiro, P.R. (2025). Thermodynamic and structural characterization of a mechanochemically synthesized pyrazinamide\u2013acetylsalicylic\u2013acid eutectic mixture. Pharmaceuticals, 18.","DOI":"10.3390\/ph18020211"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/jps.20765","article-title":"Biowaiver monographs for immediate release solid oral dosage forms: Isoniazid","volume":"96","author":"Becker","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1208\/s12249-019-1335-x","article-title":"Self-emulsifying oral lipid drug delivery systems: Advances and challenges","volume":"20","author":"Rani","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"169","DOI":"10.15171\/apb.2018.021","article-title":"Chemical enhancer: A simplistic way to modulate barrier function of the stratum corneum","volume":"8","author":"Haque","year":"2018","journal-title":"Adv. Pharm. Bull."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.3109\/03639045.2015.1047847","article-title":"Penetration enhancing effects of selected natural oils utilized in topical dosage forms","volume":"41","author":"Viljoen","year":"2015","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Alhasso, B., Ghori, M.U., and Conway, B.R. (2022). Systematic review on the effectiveness of essential and carrier oils as skin penetration enhancers in pharmaceutical formulations. Sci. Pharm., 90.","DOI":"10.3390\/scipharm90010014"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1900347","DOI":"10.1002\/ejlt.201900347","article-title":"Characterization of extra virgin olive oil from Southern Brazil","volume":"122","author":"Crizel","year":"2020","journal-title":"Eur. J. Lipid Sci. Technol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Jimenez-Lopez, C., Carpena, M., Louren\u00e7o-Lopes, C., Gallardo-Gomez, M., Lorenzo, J.M., Barba, F.J., Prieto, M.A., and Simal-Gandara, J. (2020). Bioactive compounds and quality of extra virgin olive oil. Foods, 9.","DOI":"10.3390\/foods9081014"},{"key":"ref_66","first-page":"1012","article-title":"Physicochemical properties of olive oil and its stability at different storage temperatures","volume":"6","author":"Chinnaraja","year":"2018","journal-title":"Int. J. Chem. Stud."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Rotondi, A., Morrone, L., Bertazza, G., and Neri, L. (2021). Effect of duration of olive storage on chemical and sensory quality of extra virgin olive oils. Foods, 10.","DOI":"10.3390\/foods10102296"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s10787-024-01588-8","article-title":"Therapeutic applications of eucalyptus essential oils","volume":"33","author":"Shiekh","year":"2025","journal-title":"Inflammopharmacology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"123953","DOI":"10.1016\/j.jchromb.2023.123953","article-title":"Comprehensive quality assessment of peppermint oils and commercial products: An integrated approach involving conventional and chiral GC\/MS coupled with chemometrics","volume":"1232","author":"Wang","year":"2024","journal-title":"J. Chromatogr. B"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"100217","DOI":"10.1016\/j.fochx.2022.100217","article-title":"Terpenes and terpenoids as main bioactive compounds of essential oils, their roles in human health and potential application as natural food preservatives","volume":"13","author":"Masyita","year":"2022","journal-title":"Food Chem. X"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1007\/s000110050639","article-title":"Terpinen-4-ol, the main component of the essential oil of Melaleuca alternifolia (tea tree oil), suppresses inflammatory mediator production by activated human monocytes","volume":"49","author":"Hart","year":"2000","journal-title":"Inflamm. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.jscs.2018.01.008","article-title":"Recent progress in photochemical reaction on main components of some essential oils","volume":"22","author":"Khayyat","year":"2018","journal-title":"J. Saudi Chem. Soc."},{"key":"ref_73","first-page":"416","article-title":"Strategies to improve stability of essential oils","volume":"13","author":"Vaishnavi","year":"2021","journal-title":"J. Pharm. Sci. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/1541-4337.12006","article-title":"Stability of essential oils: A review","volume":"12","author":"Turek","year":"2013","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Shelepova, O.V., Dilovarova, T.A., Gulevich, A.A., Olekhnovich, L.S., Shirokova, A.V., Ushakova, I.T., Zhuravleva, E.V., Konovalova, L.N., and Baranova, E.N. (2021). Chemical components and biological activities of essential oils of Mentha \u00d7 piperita L. from field-grown and field-acclimated after in vitro propagation plants. Agronomy, 11.","DOI":"10.3390\/agronomy11112314"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Hubert-Sch\u00f6ler, C., Tsiaparas, S., Luhmer, K., Moll, M.D., Passon, M., W\u00fcst, M., Schieber, A., and Pude, R. (2024). Essential oil composition and physiology of three mentha genotypes under shaded field conditions. Plants, 13.","DOI":"10.3390\/plants13223155"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Thormar, H. (2011). Chapter 9: Chemistry and bioactivity of essential oils. Lipids and Essential Oils as Antimicrobial Agents, John Wiley & Sons.","DOI":"10.1002\/9780470976623"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Boskou, D. (2006). Olive Oil: Chemistry and Technology, AOCS Publishing.","DOI":"10.1201\/9781439832028"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"531","DOI":"10.3109\/10717544.2014.891270","article-title":"Role of lipid-based excipients and their composition on the bioavailability of antiretroviral self-emulsifying formulations","volume":"22","author":"Chudasama","year":"2015","journal-title":"Drug Deliv."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"S93","DOI":"10.1016\/S0928-0987(00)00167-6","article-title":"Lipid formulations for oral administration of drugs: Non-emulsifying, self-emulsifying and \u2018self-microemulsifying\u2019 drug delivery systems","volume":"11","author":"Pouton","year":"2000","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1080\/10717544.2022.2083724","article-title":"Self-emulsifying drug delivery systems: A novel approach to deliver drugs","volume":"29","author":"Salawi","year":"2022","journal-title":"Drug Deliv."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"103289","DOI":"10.1016\/j.jddst.2022.103289","article-title":"Supersaturable self-emulsifying drug delivery system: A strategy for improving the loading and oral bioavailability of quercetin","volume":"71","author":"Sirvi","year":"2022","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Viljoen, J.M., Cilliers, L., and Du Plessis, L.H. (2024). Developing self-nanoemulsifying drug delivery systems comprising an artemether-lumefantrine fixed-dose combination to treat malaria. Front. Biosci., 16.","DOI":"10.31083\/j.fbe1603025"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Seo, E.B., Du Plessis, L.H., and Viljoen, J.M. (2022). Solidification of self-emulsifying drug delivery systems as a novel approach to the management of uncomplicated malaria. Pharmaceuticals, 15.","DOI":"10.3390\/ph15020120"},{"key":"ref_85","first-page":"171","article-title":"Transdermal drug delivery: Principles and opioid therapy","volume":"7","author":"Margetts","year":"2007","journal-title":"Contin. Educ. Anaesth. Crit. Care Pain"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.ejps.2017.09.001","article-title":"Development and in vitro\/in vivo performance of self-nanoemulsifying drug delivery systems loaded with candesartan cilexetil","volume":"109","author":"AboulFotouh","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_87","first-page":"459","article-title":"Development of jojoba oil (Simmondsia chinensis (Link) C.K. Schneid.) Based nanoemulsions","volume":"33","author":"Costa","year":"2014","journal-title":"Lat. Am. J. Pharm."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1590\/S0102-695X2012005000127","article-title":"HLB value, an important parameter for the development of essential oil phytopharmaceuticals","volume":"23","author":"Fernandes","year":"2013","journal-title":"Rev. Bras. Farmacogn."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.jcis.2008.10.077","article-title":"Design and optimization of a new self-nanoemulsifying drug delivery system","volume":"330","author":"Wang","year":"2009","journal-title":"J. Colloid Interface Sci."},{"key":"ref_90","unstructured":"(2025, October 28). Magis Pharma. Available online: https:\/\/magis-pharma.be\/en\/hbl-values."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Colucci, G., Santamaria-Echart, A., Silva, S.C., Fernandes, I.P.M., Sipoli, C.C., and Barreiro, M.F. (2020). Development of water-in-oil emulsions as delivery vehicles and testing with a natural antimicrobial extract. Molecules, 25.","DOI":"10.3390\/molecules25092105"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Kampa, J., Frazier, R., and Rodriguez-Garcia, J. (2022). Physical and chemical characterisation of conventional and nano\/emulsions: Influence of vegetable oils from different origins. Foods, 11.","DOI":"10.3390\/foods11050681"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Kaspute, G., Ivaskiene, T., Ramanavicius, A., Ramanavicius, S., and Prentice, U. (2025). Terpenes and essential oils in pharmaceutics: Applications as therapeutic agents and penetration enhancers with advanced delivery systems for improved stability and bioavailability. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17060793"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.ijpharm.2019.02.011","article-title":"Combination of microneedles and microemulsions to increase celecoxib topical delivery for potential application in chemoprevention of breast cancer","volume":"560","author":"Mojeiko","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.ijpharm.2018.09.002","article-title":"Development of a skin-friendly microemulsion for dermal allergen-specific immunotherapy","volume":"550","author":"Kiselmann","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Van Staden, D., Haynes, R.K., and Viljoen, J.M. (2023). The development of dermal self-double-emulsifying drug delivery systems: Preformulation studies as the keys to success. Pharmaceuticals, 16.","DOI":"10.3390\/ph16101348"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ijpharm.2019.01.072","article-title":"Tailoring novel soft nano-vesicles \u2018flexosomes\u2019 for enhanced transdermal drug delivery: Optimization, characterization and comprehensive ex vivo\u2014In vivo evaluation","volume":"560","author":"Ishak","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_98","first-page":"826798","article-title":"Microemulsion: New insights into the ocular drug delivery","volume":"2013","author":"Hegde","year":"2013","journal-title":"Int. Sch. Res. Not."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.ijpharm.2010.06.034","article-title":"Role of edge activators and surface charge in developing ultradeformable vesicles with enhanced skin delivery","volume":"397","author":"Awad","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Uttreja, P., Karnik, I., Adel Ali Youssef, A., Narala, N., Elkanayati, R.M., Baisa, S., Alshammari, N.D., Banda, S., Vemula, S.K., and Repka, M.A. (2025). Self-emulsifying drug delivery systems (SEDDS): Transition from liquid to solid\u2014A comprehensive review of formulation, characterization, applications, and future trends. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17010063"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"50640","DOI":"10.1039\/C6RA06027G","article-title":"Effects of interfacial tension and emulsification on displacement efficiency in dilute surfactant flooding","volume":"6","author":"Pu","year":"2016","journal-title":"RSC Adv."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1021\/ja9095158","article-title":"The interfacial tension of nanoscopic oil droplets in water is hardly affected by SDS surfactant","volume":"132","author":"Strader","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"360","DOI":"10.11113\/mjfas.v14n3.1070","article-title":"Formulation and characterization of self-nano emulsifying drug delivery systems of lemongrass (cymbopogon citratus) essential oil","volume":"14","author":"Ujilestari","year":"2018","journal-title":"Malays. J. Fundam. Appl. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ijpharm.2018.06.005","article-title":"Development of self-emulsifying drug delivery systems (SEDDS) for ciprofloxacin with improved mucus permeating properties","volume":"547","author":"Zaichik","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"117","DOI":"10.2147\/DDDT.S95905","article-title":"Self-emulsifying drug delivery systems as a tool to improve solubility and bioavailability of resveratrol","volume":"10","author":"Balata","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_106","first-page":"546","article-title":"Self-emulsifying drug delivery systems (SEDDS): An update from formulation development to therapeutic strategies","volume":"6","author":"Mahapatra","year":"2014","journal-title":"Int. J. PharmTech Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/ics.12841","article-title":"Development of SEDDS formulation containing caffeine for dermal delivery","volume":"45","author":"Simon","year":"2023","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Gul, S., Sridhar, S.B., Jalil, A., Akhlaq, M., Arshad, M.S., Sarwar, H.S., Usman, F., Shareef, J., and Thomas, S. (2024). Solid self-nanoemulsifying drug delivery systems of furosemide: In vivo proof of concept for enhanced predictable therapeutic response. Pharmaceuticals, 17.","DOI":"10.3390\/ph17040500"},{"key":"ref_109","first-page":"8139","article-title":"Self-emulsifying drug delivery system for enhanced oral delivery of tenofovir: Formulation, physicochemical characterization, and bioavailability assessment","volume":"9","author":"Mahajan","year":"2024","journal-title":"ACS Omega"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"104956","DOI":"10.1016\/j.ejps.2019.104956","article-title":"Transdermal delivery of fluvastatin loaded nanoemulsion gel: Preparation, characterization and in vivo anti-osteoporosis activity","volume":"136","author":"Kaur","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Danaei, M., Dehghankhold, M., Ataei, S., Hasanzadeh Davarani, F., Javanmard, R., Dokhani, A., Khorasani, S., and Mozafari, M.R. (2018). Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10020057"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.cis.2003.10.023","article-title":"Formation and stability of nano-emulsions","volume":"108\u2013109","author":"Tadros","year":"2004","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1039\/C2SM06903B","article-title":"Nanoemulsions versus microemulsions: Terminology, differences, and similarities","volume":"8","author":"McClements","year":"2012","journal-title":"Soft Matter"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1021\/acs.langmuir.4c03812","article-title":"Nonspherical particle stabilized emulsions formed through destabilization and arrested coalescence","volume":"41","author":"Lobel","year":"2025","journal-title":"Langmuir"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1208\/s12249-018-1251-5","article-title":"Topical delivery of artemisone, clofazimine and decoquinate encapsulated in vesicles and their in vitro efficacy against Mycobacterium tuberculosis","volume":"20","author":"Viljoen","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Jamous, Y.F., Altwaijry, N.A., Saleem, M.T., Alrayes, A.F., Albishi, S.M., and Almeshari, M.A. (2023). Formulation and characterization of solid lipid nanoparticles loaded with troxerutin. Processes, 11.","DOI":"10.3390\/pr11103039"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Qiu, H., Chen, X., Wei, X., Liang, J., Zhou, D., and Wang, L. (2020). The emulsifying properties of hydrogenated rosin xylitol ester as a biomass surfactant for food: Effect of pH and salts. Molecules, 25.","DOI":"10.3390\/molecules25020302"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Kupikowska-Stobba, B., Domaga\u0142a, J., and Kasprzak, M.M. (2024). Critical review of techniques for food emulsion characterization. Appl. Sci., 14.","DOI":"10.3390\/app14031069"},{"key":"ref_119","unstructured":"Grumezescu, A.M. (2018). Lipid Nanocarriers for Drug Targeting, William Andrew."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.jcis.2017.03.085","article-title":"The role of surface active species in the fabrication and functionality of edible solid lipid particles","volume":"500","author":"Zafeiri","year":"2017","journal-title":"J. Colloid Interface Sci."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Liu, F., He, W., Huang, X., Yin, J., and Nie, S. (2024). The emulsification and stabilization mechanism of an oil-in-water emulsion constructed from tremella polysaccharide and citrus pectin. Foods, 13.","DOI":"10.3390\/foods13101545"},{"key":"ref_122","unstructured":"Alpha Chemique (2025, October 18). Polysorbate 60: Properties, Functions, and Applications. Available online: https:\/\/www.alphachem.biz\/polysorbate-60-properties-functions-and-applications\/#:~:text=Stabilizer:%20Polysorbate%2060%20acts%20as,creams%2C%20lotions%2C%20and%20cosmetics."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.ejpb.2016.09.001","article-title":"Antibacterial action of lipid nanocapsules containing fatty acids or monoglycerides as co-surfactants","volume":"108","author":"Umerska","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ijpharm.2018.11.032","article-title":"Biocompatible nanoparticles and vesicular systems in transdermal drug delivery for various skin diseases","volume":"555","author":"Carter","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_125","unstructured":"Grumezescu, A.M. (2017). Multifunctional Systems for Combined Delivery, Biosensing and Diagnostics, William Andrew."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s11095-009-9985-0","article-title":"Efficiency of fatty acids as chemical penetration enhancers: Mechanisms and structure enhancement relationship","volume":"27","author":"Ibrahim","year":"2010","journal-title":"Pharm. Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1559-4106-8-3","article-title":"Studying the penetration of fatty acids into human skin by ex vivo TOF-SIMS imaging","volume":"8","author":"Kezutyte","year":"2013","journal-title":"Biointerphases"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s40257-017-0301-1","article-title":"Natural oils for skin-barrier repair: Ancient compounds now backed by modern science","volume":"19","author":"Vaughn","year":"2018","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.xphs.2015.11.032","article-title":"Essential fatty acids as transdermal penetration enhancers","volume":"105","author":"Gerber","year":"2016","journal-title":"J. Pharm. Sci."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ijpharm.2013.02.040","article-title":"Skin penetration enhancers","volume":"447","author":"Lane","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1016\/j.scispo.2017.03.009","article-title":"A wearable sweat rate sensor to monitor the athletes\u2019 performance during training","volume":"33","author":"Salvo","year":"2018","journal-title":"Sci. Sports"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Asghar, A.A., Akhlaq, M., Jalil, A., Azad, A.K., Asghar, J., Adeel, M., Albadrani, G.M., Al-Doaiss, A.A., Kamel, M., and Altyar, A.E. (2022). Formulation of ciprofloxacin-loaded oral self-emulsifying drug delivery system to improve the pharmacokinetics and antibacterial activity. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.967106"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"104428","DOI":"10.1016\/j.yrtph.2019.104428","article-title":"Percutaneous penetration of drugs applied in transdermal delivery systems: An in vivo based approach for evaluating computer generated penetration models","volume":"108","author":"Keurentjes","year":"2019","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_134","first-page":"487","article-title":"Film forming systems for topical and transdermal drug delivery","volume":"12","author":"Kathe","year":"2017","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.ejpb.2011.01.025","article-title":"Uptake of phenothiazines by the harvested chylomicrons ex vivo model: Influence of self-nanoemulsifying formulation design","volume":"79","author":"Shahnaz","year":"2011","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.cocis.2016.03.002","article-title":"Spontaneous emulsification","volume":"22","author":"Solans","year":"2016","journal-title":"Curr. Opin. Colloid Interface Sci."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.cmi.2016.10.008","article-title":"Clinical management of adults and children with multidrug-resistant and extensively drug-resistant tuberculosis","volume":"23","author":"Dheda","year":"2017","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.cmi.2018.07.012","article-title":"Clofazimine improves clinical outcomes in multidrug-resistant tuberculosis: A randomized controlled trial","volume":"25","author":"Duan","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"135902","DOI":"10.1016\/j.ijbiomac.2024.135902","article-title":"Effect of gel composition interaction on rheological, physicochemical and textural properties of methyl cellulose oleogels and lard replacement in ham sausage","volume":"280","author":"Wu","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.colsurfb.2014.11.022","article-title":"Self emulsifying drug delivery system for enhanced solubility and dissolution of glipizide","volume":"126","author":"Agrawal","year":"2015","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"10522","DOI":"10.1021\/acsomega.3c08700","article-title":"Preparation and evaluation of a self-emulsifying drug delivery system for improving the solubility and permeability of ticagrelor","volume":"9","author":"Aziz","year":"2024","journal-title":"ACS Omega"},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Smail, S.S., Ghareeb, M.M., Omer, H.K., Al-Kinani, A.A., and Alany, R.G. (2021). Studies on surfactants, cosurfactants, and oils for prospective use in formulation of ketorolac tromethamine ophthalmic nanoemulsions. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13040467"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/j.xphs.2018.01.005","article-title":"Surfactant effects on lipid-based vesicles properties","volume":"107","author":"Bnyan","year":"2018","journal-title":"J. Pharm. Sci."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Cort\u00e9s, H., Hern\u00e1ndez-Parra, H., Bernal-Ch\u00e1vez, S.A., Prado-Audelo, M.L.D., Caballero-Flor\u00e1n, I.H., Borbolla-Jim\u00e9nez, F.V., Gonz\u00e1lez-Torres, M., Maga\u00f1a, J.J., and Leyva-G\u00f3mez, G. (2021). Non-ionic surfactants for stabilization of polymeric nanoparticles for biomedical uses. Materials, 14.","DOI":"10.3390\/ma14123197"},{"key":"ref_145","unstructured":"(2026, January 07). Creaming. ScienceDirect Topics. Available online: https:\/\/www.sciencedirect.com\/topics\/agricultural-and-biological-sciences\/creaming."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Loi, C.C., Eyres, G.T., and Birch, E.J. (2019). Protein-stabilised emulsions. Encyclopedia of Food Chemistry, Elsevier.","DOI":"10.1016\/B978-0-08-100596-5.22490-6"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"5001","DOI":"10.1021\/acsomega.0c06142","article-title":"Influence of Surfactant and Weak-Alkali Concentrations on the Stability of O\/W Emulsion in an Alkali-Surfactant-Polymer Compound System","volume":"6","author":"Zhang","year":"2021","journal-title":"ACS Omega"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"102792","DOI":"10.1016\/j.fochx.2025.102792","article-title":"Advances in emulsion stability: A review on mechanisms, role of emulsifiers, and applications in food","volume":"29","author":"Xiao","year":"2025","journal-title":"Food Chem. X"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1208\/s12249-019-1362-7","article-title":"In vitro drug dissolution\/permeation testing of nanocarriers for skin application: A comprehensive review","volume":"20","author":"Sheshala","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Hwang, J.H., Lee, S., Lee, H.G., Choi, D., and Lim, K.M. (2022). Evaluation of skin irritation of acids commonly used in cleaners in 3D-reconstructed human epidermis model, KeraSkin\u2122. Toxics, 10.","DOI":"10.3390\/toxics10100558"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1002\/1873-3468.70023","article-title":"Unraveling Mycobacterium tuberculosis acid resistance and pH homeostasis mechanisms","volume":"599","author":"Laudouze","year":"2025","journal-title":"FEBS Lett."},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Leister, N., and Karbstein, H.P. (2023). Determination of the dominating coalescence pathways in double emulsion formulations by use of microfluidic emulsions. Processes, 11.","DOI":"10.3390\/pr11010234"},{"key":"ref_153","first-page":"561","article-title":"Nanoparticles\u2014A review","volume":"5","author":"Mohanraj","year":"2006","journal-title":"Trop. J. Pharm. Res."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"s587","DOI":"10.5530\/ijper.53.4s.154","article-title":"Development and bioavailability assessment of ramipril nanoparticle formulation","volume":"54","author":"Pereira","year":"2019","journal-title":"Indian J. Pharm. Educ. Res."},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Qian, K., Lin, Y., Zhao, B., and Liu, X. (2025). Droplet size reduction of self-emulsifying drug delivery system (SEDDS) using the hybrid of medium and long-chain triglycerides. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17070822"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Jacob, S., Kather, F.S., Boddu, S.H.S., Shah, J., and Nair, A.B. (2024). Innovations in nanoemulsion technology: Enhancing drug delivery for oral, parenteral, and ophthalmic applications. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16101333"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"102541","DOI":"10.1016\/j.cis.2021.102541","article-title":"Emulsion characterization via microfluidic devices: A review on interfacial tension and stability to coalescence","volume":"299","author":"Ho","year":"2022","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Bhalani, D.V., Nutan, B., Kumar, A., and Singh Chandel, A.K. (2022). Bioavailability enhancement techniques for poorly aqueous soluble drugs and therapeutics. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092055"},{"key":"ref_159","first-page":"195727","article-title":"Drug solubility: Importance and enhancement techniques","volume":"2012","author":"Savjani","year":"2012","journal-title":"Int. Sch. Res. Not."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jconrel.2012.02.027","article-title":"In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS)","volume":"160","author":"Thomas","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Park, H., Ha, E.S., and Kim, M.S. (2020). Current status of supersaturable self-emulsifying drug delivery systems. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12040365"},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Sharma, A., Arora, K., Mohapatra, H., Sindhu, R.K., Bulzan, M., Cavalu, S., Paneshar, G., Elansary, H.O., El-Sabrout, A.M., and Mahmoud, E.A. (2022). Supersaturation-based drug delivery systems: Strategy for bioavailability enhancement of poorly water-soluble drugs. Molecules, 27.","DOI":"10.3390\/molecules27092969"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.2174\/1381612821666150428125046","article-title":"Supersaturation as a tool for skin penetration enhancement","volume":"21","author":"Cilurzo","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Kunita, R., Nishijima, T., Todo, H., Sugibayashi, K., and Sakaguchi, H. (2022). A mathematical approach using Strat-M\u00ae to predict the percutaneous absorption of chemicals under finite dose conditions. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14071370"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"124071","DOI":"10.1016\/j.ijpharm.2024.124071","article-title":"Parafilm\u00ae M and Strat-M\u00ae as skin simulants in in vitro permeation of dissolving microarray patches loaded with proteins","volume":"655","author":"Anjani","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.jid.2017.09.031","article-title":"The physicochemical basis of clofazimine-induced skin pigmentation","volume":"138","author":"Murashov","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ejps.2014.11.002","article-title":"Prediction of skin permeation by chemical compounds using the artificial membrane, Strat-M\u2122","volume":"67","author":"Uchida","year":"2015","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1007\/s44174-022-00041-0","article-title":"Lipid-Based Drug Delivery System (LBDDS): An Emerging Paradigm to Enhance Oral Bioavailability of Poorly Soluble Drugs","volume":"1","author":"Kesharwani","year":"2023","journal-title":"Biomed. Mater. Devices"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0928-0987(01)00167-1","article-title":"Novel mechanisms and devices to enable successful transdermal drug delivery","volume":"14","author":"Barry","year":"2001","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_170","doi-asserted-by":"crossref","unstructured":"Bhushan, B. (2012). Dermal and Transdermal Delivery. Encyclopedia of Nanotechnology, Springer.","DOI":"10.1007\/978-90-481-9751-4"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.ijpharm.2016.08.052","article-title":"Comparative evaluation of rivastigmine permeation from a transdermal system in the Franz cell using synthetic membranes and pig ear skin with in vivo-in vitro correlation","volume":"512","author":"Simon","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Brito, S., Baek, M., and Bin, B.-H. (2024). Skin structure, physiology, and pathology in topical and transdermal drug delivery. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16111403"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1248\/cpb.c22-00533","article-title":"Distribution of domains formed by lateral packing of intercellular lipid in the stratum corneum","volume":"71","author":"Ohnari","year":"2023","journal-title":"Chem. Pharm. Bull."},{"key":"ref_174","first-page":"67","article-title":"Transdermal drug delivery systems: A focused review of the physical methods of permeation enhancement","volume":"14","author":"Vaseem","year":"2024","journal-title":"Adv. Pharm. Bull."},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Hmingthansanga, V., Singh, N., Banerjee, S., Manickam, S., Velayutham, R., and Natesan, S. (2022). Improved topical drug delivery: Role of permeation enhancers and advanced approaches. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14122818"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"438","DOI":"10.3390\/pharmaceutics7040438","article-title":"Transdermal drug delivery: Innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum","volume":"7","author":"Alkilani","year":"2015","journal-title":"Pharmaceutics"},{"key":"ref_177","first-page":"2274","article-title":"Transdermal drug delivery system: A review","volume":"7","author":"Tanwar","year":"2016","journal-title":"Int. J. Pharm. Sci. Res."},{"key":"ref_178","unstructured":"Williams, A. (2003). Transdermal and Topical Drug Delivery from Theory to Clinical Practice, Pharmaceutical Press."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/j.jcis.2021.06.097","article-title":"Skin hydration as a tool to control the distribution and molecular effects of intermediate polarity compounds in intact stratum corneum","volume":"603","author":"Pham","year":"2021","journal-title":"J. Colloid Interface Sci."},{"key":"ref_180","first-page":"80","article-title":"Anatomical and functional differences of the skin in various ethnic groups","volume":"74","author":"Helbig","year":"2023","journal-title":"Die Dermatol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jdermsci.2010.06.003","article-title":"Structural and functional differences in barrier properties of African American, Caucasian and East Asian skin","volume":"59","author":"Muizzuddin","year":"2010","journal-title":"J. Dermatol. Sci."},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Brits, M., Bouwer, F., and Viljoen, J.M. (2026). RP-DAD-HPLC Method for the Quantitative Analysis of Clofazimine and Pyrazinamide for inclusion in a Fixed-dose Combination Topical Drug Delivery System. Methods Protoc., 9.","DOI":"10.3390\/mps9010016"},{"key":"ref_183","doi-asserted-by":"crossref","unstructured":"Van Staden, D., Haynes, R.K., Van Der Kooy, F., and Viljoen, J.M. (2023). Development of a HPLC method for analysis of a combination of clofazimine, isoniazid, pyrazinamide, and rifampicin incorporated into a dermal self-double-emulsifying drug delivery system. Methods Protoc., 6.","DOI":"10.3390\/mps6060104"},{"key":"ref_184","unstructured":"ICH (2025, October 11). Validation of Analytical Procedures Q2(R2). Available online: https:\/\/database.ich.org\/sites\/default\/files\/ICH_Q2-R2_Document_Step2_Guideline_2022_0324.pdf."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1007\/s11696-023-03216-1","article-title":"Optimization of capsaicin microemulgel: A comprehensive in vitro evaluation and pseudo ternary diagram","volume":"78","author":"Mohamed","year":"2024","journal-title":"Chem. Pap."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"16766","DOI":"10.1021\/acs.iecr.3c02345","article-title":"Understanding the effect of the oil-to-surfactant ratio on eugenol oil-in-water nanoemulsions using experimental and molecular dynamics investigations","volume":"62","author":"Debraj","year":"2023","journal-title":"Ind. Eng. Chem. Res."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"e17667","DOI":"10.1016\/j.heliyon.2023.e17667","article-title":"An experimental workflow to assess the applicability of microemulsions for conformance improvement in oil-bearing reservoir","volume":"9","author":"Pal","year":"2023","journal-title":"Heliyon"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1007\/s13346-021-01071-9","article-title":"Lipid-based emulsion drug delivery systems\u2014A comprehensive review","volume":"12","author":"Dhaval","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_189","first-page":"572","article-title":"Tizanidine nano emulsion: Formulation and in-vitro characterization","volume":"13","author":"Fadhel","year":"2022","journal-title":"J. Pharm. Negat. Results"},{"key":"ref_190","first-page":"1314","article-title":"Optimization of nano-emulsion formulations for certain emollient effect","volume":"4","author":"Abdellatif","year":"2015","journal-title":"World J. Pharm. Pharm. Sci."},{"key":"ref_191","first-page":"301","article-title":"Identification of phases of various oil, surfactant\/co-surfactants and water system by ternary phase diagram","volume":"71","author":"Syed","year":"2014","journal-title":"Acta Pol. Pharm."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ijpharm.2003.12.028","article-title":"Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs","volume":"274","author":"Kang","year":"2004","journal-title":"Int. J. Pharm."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"231","DOI":"10.22270\/jddt.v10i3.3981","article-title":"Self-emulsifying formulations: A pharmaceutical review","volume":"10","author":"Agubata","year":"2020","journal-title":"J. Drug Deliv. Ther."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1007\/s11095-017-2171-x","article-title":"Characterization of temperature profiles in skin and transdermal delivery system when exposed to temperature gradients in vivo and in vitro","volume":"34","author":"Zhang","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_195","first-page":"623","article-title":"A novel approach\u2014Self emulsifying drug delivery systems","volume":"12","author":"Sri","year":"2023","journal-title":"World J. Pharm. Res."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"122159","DOI":"10.1016\/j.ijpharm.2022.122159","article-title":"In vitro release test (IVRT): Principles and applications","volume":"15","author":"Shah","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/nbt.1504","article-title":"Transdermal drug delivery","volume":"26","author":"Prausnitz","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_198","unstructured":"U.S. Food and Drug Administration (US FDA) (2025, November 25). In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs. Guidance for Industry, Available online: https:\/\/www.fda.gov\/media\/162476\/download."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1461-5347(00)00295-9","article-title":"Transdermal drug delivery: Overcoming the skin\u2019s barrier function","volume":"3","author":"Naik","year":"2000","journal-title":"Pharm. Sci. Technol. Today"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1208\/s12249-010-9522-9","article-title":"Validation of a Static Franz Diffusion Cell System for In Vitro Permeation Studies","volume":"11","author":"Ng","year":"2010","journal-title":"AAPS PharmSciTech"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.colsurfb.2018.07.011","article-title":"Monoolein liquid crystalline phases for topical delivery of crocetin","volume":"171","author":"Esposito","year":"2018","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_202","unstructured":"Mattiasson, J. (2020). Method Development of an In Vitro Vertical Franz Diffusion Cell System to Assess Permeation of Cosmetic Active Ingredients. [Master\u2019s Thesis, Uppsala University]."},{"key":"ref_203","doi-asserted-by":"crossref","unstructured":"Van Staden, D., Du Plessis, J., and Viljoen, J.M. (2020). Development of topical\/transdermal self-emulsifying drug delivery systems, not as simple as expected. Sci. Pharm., 88.","DOI":"10.3390\/scipharm88020017"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/2\/255\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T12:06:39Z","timestamp":1770033999000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/2\/255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,1]]},"references-count":203,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ph19020255"],"URL":"https:\/\/doi.org\/10.3390\/ph19020255","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,1]]}}}