{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T19:24:32Z","timestamp":1780514672391,"version":"3.54.1"},"reference-count":34,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scilex Pharmaceutical Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Topical delivery systems (TDSs) enable the direct transport of analgesics into areas of localized pain and thus minimize the side effects of administration routes that rely on systemic drug distribution. For musculoskeletal pain, clinicians frequently prescribe topical products containing lidocaine or diclofenac. This study assessed whether drug delivery from a TDS into muscle tissue occurs mainly via direct diffusion or systemic transport. An investigational TDS containing 108 mg lidocaine (SP-103, 5.4% lidocaine), a commercially available TDS containing 36 mg lidocaine (ZTlido\u00ae, 1.8% lidocaine), and a topical pain relief gel (Pennsaid\u00ae, 2% diclofenac) were tested. Using open flow microperfusion (OFM), interstitial fluid from the dermis, subcutaneous adipose tissue (SAT), and muscle was continuously sampled to assess drug penetration in all tissue layers. Ex vivo and in vivo experiments showed a higher diffusive transport of lidocaine compared to diclofenac. The data showed a clear contribution of diffusive transport to lidocaine concentration, with SP-103 5.4% resulting in a significantly higher lidocaine concentration in muscle tissue than commercially available ZTlido\u00ae (p = 0.008). These results indicate that SP-103 5.4% is highly effective in delivering lidocaine into muscle tissue in areas of localized pain for the treatment of musculoskeletal pain disorders (e.g., lower back pain).<\/jats:p>","DOI":"10.3390\/pharmaceutics15112563","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T12:44:03Z","timestamp":1698756243000},"page":"2563","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Topical Delivery Systems Effectively Transport Analgesics to Areas of Localized Pain via Direct Diffusion"],"prefix":"10.3390","volume":"15","author":[{"given":"Thomas","family":"Birngruber","sequence":"first","affiliation":[{"name":"HEALTH\u2014Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kip","family":"Vought","sequence":"additional","affiliation":[{"name":"Scilex Holding Company, Palo Alto, CA 94303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Schwingenschuh","sequence":"additional","affiliation":[{"name":"HEALTH\u2014Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Reisenegger","sequence":"additional","affiliation":[{"name":"HEALTH\u2014Institute for Biomedical Research and Technologies, Joanneum Research Forschungsgesellschaft mbH, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Maibach","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitri","family":"Lissin","sequence":"additional","affiliation":[{"name":"Scilex Holding Company, Palo Alto, CA 94303, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Leppert, W., Malec\u2013Milewska, M., Zajaczkowska, R., and Wordliczek, J. (2018). Transdermal and Topical Drug Administration in the Treatment of Pain. Molecules, 23.","DOI":"10.3390\/molecules23030681"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1080\/00325481.2013.1110567111","article-title":"Topical Therapies in the Management of Chronic Pain","volume":"125","author":"Stanos","year":"2013","journal-title":"Postgrad. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1080\/00325481.2019.1702296","article-title":"Utility of Lidocaine as a Topical Analgesic and Improvements in Patch Delivery Systems","volume":"132","author":"Gudin","year":"2020","journal-title":"Postgrad. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.anclin.2007.07.004","article-title":"Topical Analgesics","volume":"25","author":"McCleane","year":"2007","journal-title":"Anesthesiol. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.pmr.2014.01.007","article-title":"Side Effects of Commonly Prescribed Analgesic Medications","volume":"25","author":"Carter","year":"2014","journal-title":"Phys. Med. Rehabil. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"53","DOI":"10.2165\/11630080-000000000-00000","article-title":"Adverse Effects Associated with Non-Opioid and Opioid Treatment in Patients with Chronic Pain","volume":"32","author":"Labianca","year":"2012","journal-title":"Clin. Drug Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/jcpt.12484","article-title":"Non-Steroidal Anti-Inflammatory Drug-Induced Cardiovascular Adverse Events: A Meta-Analysis","volume":"42","author":"Gunter","year":"2017","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/S0140-6736(13)60900-9","article-title":"Vascular and Upper Gastrointestinal Effects of Non-Steroidal Anti-Inflammatory Drugs: Meta-Analyses of Individual Participant Data from Randomised Trials","volume":"382","author":"Baigent","year":"2013","journal-title":"Lancet"},{"key":"ref_9","first-page":"642","article-title":"Topical Analgesics: A Review of Recent Clinical Trials and Their Application to Clinical Practice","volume":"3","author":"Argoff","year":"2003","journal-title":"Adv. Stud. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1002\/jps.20666","article-title":"Deep Percutaneous Penetration into Muscles and Joints","volume":"95","author":"Lee","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.pmr.2020.02.002","article-title":"Topical Analgesics","volume":"31","author":"Stanos","year":"2020","journal-title":"Phys. Med. Rehabil. Clin. N. Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1157977","DOI":"10.3389\/fphar.2023.1157977","article-title":"Evaluation of the in Vitro Permeation Parameters of Topical Ketoprofen and Lidocaine Hydrochloride from Transdermal Pentravan\u00ae Products through Human Skin","volume":"14","author":"Nowak","year":"2023","journal-title":"Front. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"114293","DOI":"10.1016\/j.addr.2022.114293","article-title":"Advances and Future Perspectives in Epithelial Drug Delivery","volume":"186","author":"Mohammed","year":"2022","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.ejps.2012.08.016","article-title":"Comparison of the Efficacy and Skin Permeability of Topical NSAID Preparations Used in Europe","volume":"47","author":"Komatsu","year":"2012","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1097\/EJA.0b013e328330e989","article-title":"Long-Term Treatment of Neuropathic Pain with a 5% Lidocaine Medicated Plaster","volume":"27","author":"Wilhelm","year":"2010","journal-title":"Eur. J. Anaesthesiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.2147\/JPR.S270169","article-title":"Characteristics of Analgesic Patch Formulations","volume":"13","author":"Nalamachu","year":"2020","journal-title":"J. Pain Res."},{"key":"ref_17","first-page":"175","article-title":"Dermal and Transdermal Drug Delivery Systems: Current and Future Prospects","volume":"13","author":"Brown","year":"2006","journal-title":"Drug Deliv. J. Deliv. Target. Ther. Agents"},{"key":"ref_18","first-page":"E401","article-title":"Direct Access to Interstitial Fluid in Adipose Tissue in Humans by Use of Open-Flow Microperfusion","volume":"276","author":"Schaupp","year":"1999","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1080\/03007995.2017.1352497","article-title":"Skin Penetration and Tissue Permeation after Topical Administration of Diclofenac","volume":"33","author":"Hagen","year":"2017","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"121737","DOI":"10.1016\/j.ijpharm.2022.121737","article-title":"Optimization of Topical Formulations Using a Combination of in Vitro Methods to Quantify the Transdermal Passive Diffusion of Drugs","volume":"620","author":"Hummer","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/978-1-4614-4815-0_15","article-title":"Open Flow Microperfusion: An Alternative Method to Microdialysis?","volume":"Volume 4","year":"2013","journal-title":"Microdialysis in Drug Development"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Reisfeld, B., and Mayeno, A.N. (2012). Computational Toxicology. Methods in Molecular Biology Vol 929, Humana Press.","DOI":"10.1007\/978-1-62703-050-2"},{"key":"ref_23","first-page":"366","article-title":"The Effect of Protein Binding on the Deep Tissue Penetration and Efflux of Dermally Applied Salicylic Acid, Lidocaine and Diazepam in the Perfused Rat Hindlimb","volume":"277","author":"Cross","year":"1996","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"603","DOI":"10.5414\/CP203922","article-title":"Microdialysis as a Potential Tool for Comparative Assessment of Tissue Pharmacokinetics of Two Different Patches Containing Lidocaine: A Crossover Pilot Study","volume":"59","author":"Matzneller","year":"2021","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1177\/1090820X12442672","article-title":"Comparison of Five Commonly-Available, Lidocaine-Containing Topical Anesthetics and Their Effect on Serum Levels of Lidocaine and Its Metabolite Monoethylglycinexylidide (MEGX)","volume":"32","author":"Oni","year":"2012","journal-title":"Aesthetic Surg. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1021\/js950346l","article-title":"A Comparative Study of the Transdermal Penetration of a Series of Nonsteroidal Antiinflammatory Drugs","volume":"86","author":"Cordero","year":"1997","journal-title":"J. Pharm. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s40265-015-0392-z","article-title":"Advances in NSAID Development: Evolution of Diclofenac Products Using Pharmaceutical Technology","volume":"75","author":"Altman","year":"2015","journal-title":"Drugs"},{"key":"ref_28","first-page":"545","article-title":"Diclofenac Sodium. A Reappraisal of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy","volume":"35","author":"Todd","year":"1988","journal-title":"Drugs"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1085\/jgp.20028651","article-title":"Molecular Action of Lidocaine on the Voltage Sensors of Sodium Channels","volume":"121","author":"Sheets","year":"2003","journal-title":"J. Gen. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17","DOI":"10.5313\/wja.v4.i2.17","article-title":"Pharmacokinetics and Pharmacodynamics of Lignocaine: A Review","volume":"4","author":"Weinberg","year":"2015","journal-title":"World J. Anesthesiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"393","DOI":"10.2165\/00044011-200929060-00003","article-title":"Topical 5% Lidocaine (Lignocaine) Medicated Plaster Treatment for Post-Herpetic Neuralgia: Results of a Double-Blind, Placebo-Controlled, Multinational Efficacy and Safety Trial","volume":"29","author":"Binder","year":"2009","journal-title":"Clin. Drug Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S0304-3959(98)00244-9","article-title":"Topical Lidocaine Patch Relieves Postherpetic Neuralgia More Effectively than a Vehicle Topical Patch: Results of an Enriched Enrollment Study","volume":"80","author":"Galer","year":"1999","journal-title":"Pain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0304-3959(95)00146-8","article-title":"Lidocaine Patch: Double-Blind Controlled Study of a New Treatment Method for Post-Herpetic Neuralgia","volume":"65","author":"Rowbotham","year":"1996","journal-title":"Pain"},{"key":"ref_34","unstructured":"Scilex Pharmaceuticals (2023, June 23). ZTLidoTM Prescribing Information, Available online: www.fda.gov\/medwatch."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/11\/2563\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:15:08Z","timestamp":1760130908000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/11\/2563"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,31]]},"references-count":34,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["pharmaceutics15112563"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15112563","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,31]]}}}