{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:04:18Z","timestamp":1791378258985,"version":"4.3.2"},"reference-count":63,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"S\u00e3o Paulo Research Foundation","doi-asserted-by":"publisher","award":["#2020\/03786-9"],"award-info":[{"award-number":["#2020\/03786-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"S\u00e3o Paulo Research Foundation","doi-asserted-by":"publisher","award":["#2019\/07245-5"],"award-info":[{"award-number":["#2019\/07245-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"FAPESP","doi-asserted-by":"publisher","award":["#2020\/03786-9"],"award-info":[{"award-number":["#2020\/03786-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"FAPESP","doi-asserted-by":"publisher","award":["#2019\/07245-5"],"award-info":[{"award-number":["#2019\/07245-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Local anesthesia is essential for most dental procedures, but its parenteral administration is often painful. Topical anesthetics are commonly used to minimize local anesthesia pain; however, commercial formulations fail to fully prevent the discomfort of local anesthetic injection. Methods: We developed and characterized a novel lidocaine and epinephrine co-loaded liquid crystalline precursor system (LCPS) for topical anesthesia. The formulation was structurally characterized using polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). Rheological behavior was assessed through continuous and oscillatory rheological analyses. Texture profile analysis, in vitro mucoadhesive force evaluation, in vitro drug release and permeation studies, and an in vivo toxicity assay using the chicken chorioallantoic membrane (CAM) model were also conducted. Results: PLM and SAXS confirmed the transition of the LCPS from a microemulsion to a lamellar liquid crystalline structure upon contact with artificial saliva. This transition enhanced formulation consistency by over 100 times and tripled mucoadhesion strength. The LCPS also provided controlled drug release, reducing permeation flow by 93% compared to the commercial formulation. Importantly, the CAM assay indicated that the LCPS exhibited similar toxicity to the commercial product. Conclusions: The developed LCPS demonstrated promising physicochemical and biological properties for topical anesthesia, including enhanced mucoadhesion, controlled drug delivery, and acceptable biocompatibility. These findings support its potential for in vivo application and future clinical use to reduce pain during dental anesthesia procedures.<\/jats:p>","DOI":"10.3390\/ph18081166","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T13:25:11Z","timestamp":1754486711000},"page":"1166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In Vitro Proof-of-Concept Study: Lidocaine and Epinephrine Co-Loaded in a Mucoadhesive Liquid Crystal Precursor System for Topical Oral Anesthesia"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1041-5835","authenticated-orcid":false,"given":"Giovana Maria Fioramonti","family":"Calixto","sequence":"first","affiliation":[{"name":"Department of Biosciences, Piracicaba Dental School, Universidade Estadual de Campinas, Av. Limeira, 901, Piracicaba 13414-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aylla Mesquita","family":"Pestana","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Piracicaba Dental School, Universidade Estadual de Campinas, Av. Limeira, 901, Piracicaba 13414-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur Antunes Costa","family":"Bezerra","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Piracicaba Dental School, Universidade Estadual de Campinas, Av. Limeira, 901, Piracicaba 13414-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela Tavares","family":"Luiz","sequence":"additional","affiliation":[{"name":"Department of Drugs and Medicines, School of Pharmaceutical Sciences, S\u00e3o Paulo State University\u2014UNESP, Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7276-3686","authenticated-orcid":false,"given":"Jonatas Lobato","family":"Duarte","sequence":"additional","affiliation":[{"name":"Department of Drugs and Medicines, School of Pharmaceutical Sciences, S\u00e3o Paulo State University\u2014UNESP, Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6698-0545","authenticated-orcid":false,"given":"Marlus","family":"Chorilli","sequence":"additional","affiliation":[{"name":"Department of Drugs and Medicines, School of Pharmaceutical Sciences, S\u00e3o Paulo State University\u2014UNESP, Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0760-1389","authenticated-orcid":false,"given":"Michelle","family":"Franz-Montan","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Piracicaba Dental School, Universidade Estadual de Campinas, Av. Limeira, 901, Piracicaba 13414-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e18031","DOI":"10.1016\/j.heliyon.2023.e18031","article-title":"Paresthesia in Dentistry: The Ignored Neurotoxicity of Local Anesthetics","volume":"9","author":"Tan","year":"2023","journal-title":"Heliyon"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.oooo.2018.05.009","article-title":"Efficacy of a Glycopolymer-Based Oral Rinse Upon Pain Associated with Ulcerative and Erosive Lesions of the Oral Mucosa: A within-Subject Pilot Study","volume":"126","author":"Epstein","year":"2018","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_3","unstructured":"Malamed, S.F. (2019). Handbook of Local Anesthesia, 7e: South Asia Edition-E-Book, Elsevier."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1007\/s10266-015-0221-6","article-title":"Dexmedetomidine (12.5 \u039cg\/Ml) Improves Tissue Distribution, Anesthetic Action, and Hemodynamic Effects of Lidocaine after Palatal Infiltration in Rats","volume":"104","author":"Akimoto","year":"2016","journal-title":"Odontology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1080\/17425247.2016.1227784","article-title":"Recent Advances and Perspectives in Topical Oral Anesthesia","volume":"14","author":"Ribeiro","year":"2017","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.diabres.2017.12.001","article-title":"Scientific Evidence on the Links between Periodontal Diseases and Diabetes: Consensus Report and Guidelines of the Joint Workshop on Periodontal Diseases and Diabetes by the International Diabetes Federation and the European Federation of Periodontology","volume":"137","author":"Sanz","year":"2018","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.2169\/internalmedicine.56.7322","article-title":"Periodontal Treatment and the Risks of Cardiovascular Disease in Patients with Type 2 Diabetes: A Retrospective Cohort Study","volume":"56","author":"Peng","year":"2017","journal-title":"Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.adaj.2017.06.019","article-title":"Intrapocket Topical Anesthetic Versus Injected Anesthetic for Pain Control During Scaling and Root Planing in Adult Patients: Systematic Review and Meta-Analysis","volume":"148","author":"Wambier","year":"2017","journal-title":"J. Am. Dent. Assoc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ejps.2015.09.021","article-title":"Evaluation of Different Pig Oral Mucosa Sites as Permeability Barrier Models for Drug Permeation Studies","volume":"81","author":"Serpe","year":"2016","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_10","first-page":"ZC85","article-title":"Comparative Effects of Clonidine and Adrenaline with Lignocaine During Maxillary Infiltration Anaesthesia for Dental Extraction","volume":"9","author":"Jimson","year":"2015","journal-title":"J. Clin. Diagn. Res. JCDR"},{"key":"ref_11","first-page":"445","article-title":"Updates of Topical and Local Anesthesia Agents","volume":"60","author":"Boyce","year":"2016","journal-title":"Dent. Clin."},{"key":"ref_12","unstructured":"U.S. Food and Drug Administration (2004). Xylocaine\u00ae\u00ae (Lidocaine Hydrochloride and Epinephrine) Injection, Usp\u2014Prescribing Information, U.S. Food and Drug Administration."},{"key":"ref_13","unstructured":"European Medicines Agency (EMA) (2017). Guideline on Clinical Development of Fixed Combination Medicinal Products, European Medicines Agency. Ema\/Chmp\/158268\/2017."},{"key":"ref_14","unstructured":"(2024). Rela\u00e7\u00e3o Nacional de Medicamentos Essenciais, RENAME, Minist\u00e9rio da Sa\u00fade (Brasil)."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"90","DOI":"10.2344\/0003-3006-59.2.90","article-title":"Local Anesthetics: Review of Pharmacological Considerations","volume":"59","author":"Becker","year":"2012","journal-title":"Anesth. Prog."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1007\/s12663-023-01945-0","article-title":"Comparative Evaluation of the Efficacy and Onset of Local Anesthesia Using Buffered 2% Lidocaine with 1: 100,000 Adrenaline, Non-Buffered 2% Lidocaine with 1: 100,000 Adrenaline, Buffered 4% Articaine with 1: 100,000 Adrenaline and Non-Buffered 4% Articaine with 1: 100,000 Adrenaline in Dental Extraction","volume":"23","author":"Kalra","year":"2024","journal-title":"J. Maxillofac. Oral Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ejpb.2016.05.012","article-title":"Rnai Mediated Il-6 in Vitro Knockdown in Psoriasis Skin Model with Topical Sirna Delivery System Based on Liquid Crystalline Phase","volume":"105","author":"Depieri","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ejps.2015.04.017","article-title":"An in Situ Gelling Liquid Crystalline System Based on Monoglycerides and Polyethylenimine for Local Delivery of Sirnas","volume":"74","author":"Depieri","year":"2015","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1208\/s12249-021-01951-w","article-title":"Liquid Crystalline Phases for Enhancement of Oral Bioavailability","volume":"22","author":"Zhang","year":"2021","journal-title":"AAPS PharmSciTech"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1208\/s12249-017-0890-2","article-title":"Polyethyleneimine and Chitosan Polymer-Based Mucoadhesive Liquid Crystalline Systems Intended for Buccal Drug Delivery","volume":"19","author":"Calixto","year":"2018","journal-title":"AAPS PharmSciTech"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1166\/jbn.2021.3025","article-title":"Innovative Mucoadhesive Precursor of Liquid Crystalline System Loading Anti-Gellatinolytic Peptide for Topical Treatment of Oral Cancer","volume":"17","author":"Calixto","year":"2021","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"103739","DOI":"10.1016\/j.pdpdt.2023.103739","article-title":"Mucoadhesive Liquid Crystal Precursor System for Photodynamic Therapy of Oral Cancer Mediated by Methylene Blue","volume":"44","author":"Balian","year":"2023","journal-title":"Photodiagnosis Photodyn. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1021\/acs.molpharmaceut.8b00507","article-title":"Curcumin-Loaded Liquid Crystalline Systems for Controlled Drug Release and Improved Treatment of Vulvovaginal Candidiasis","volume":"15","author":"Rodero","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Amin, M.K., and Boateng, J.S. (2022). Enhancing Stability and Mucoadhesive Properties of Chitosan Nanoparticles by Surface Modification with Sodium Alginate and Polyethylene Glycol for Potential Oral Mucosa Vaccine Delivery. Mar. Drugs, 20.","DOI":"10.3390\/md20030156"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115080","DOI":"10.1016\/j.molliq.2020.115080","article-title":"Curcumin-Loaded Polyethyleneimine and Chitosan Polymer-Based Mucoadhesive Liquid Crystalline Systems as a Potential Platform in the Treatment of Cervical Cancer","volume":"325","author":"Victorelli","year":"2021","journal-title":"J. Mol. Liq."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1007\/BF00659290","article-title":"Saxs Data Analysis of a Lamellar Two-Phase System. Layer Statistics and Compansion","volume":"271","author":"Stribeck","year":"1993","journal-title":"Colloid Polym. Sci."},{"key":"ref_27","unstructured":"ECVAM, and EURL (2010). DB-ALM Method Summary No 96: Hen\u2019s Egg Test on the Chorioallantoic Membrane (HET-CAM), ECVAM."},{"key":"ref_28","unstructured":"ECVAM (2019). DB-ALM and Protocol No. 96: Hen\u2019s Egg Test on the Chorioallantoic Membrane (HET-CAM). EURL ECVAM DB-ALM: Protocol, EURL ECVAM DB-ALM."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.toxlet.2024.03.003","article-title":"Advancing Ocular Safety Research: A Comprehensive Examination of Benzocaine Acute Exposure without Animal Testing","volume":"394","author":"Lenze","year":"2024","journal-title":"Toxicol. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lorenzo-Veiga, B., Sigurdsson, H.H., Loftsson, T., and Alvarez-Lorenzo, C. (2019). Cyclodextrin\u2013Amphiphilic Copolymer Supramolecular Assemblies for the Ocular Delivery of Natamycin. Nanomaterials, 9.","DOI":"10.3390\/nano9050745"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Alsaidan, O.A., Zafar, A., Yasir, M., Alzarea, S.I., Alqinyah, M., and Khalid, M. (2022). Development of Ciprofloxacin-Loaded Bilosomes in-Situ Gel for Ocular Delivery: Optimization, in-Vitro Characterization, Ex-Vivo Permeation, and Antimicrobial Study. Gels, 8.","DOI":"10.3390\/gels8110687"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1177\/10454411950060020501","article-title":"Biochemical Composition of Human Saliva in Relation to Other Mucosal Fluids","volume":"6","author":"Schenkels","year":"1995","journal-title":"Crit. Rev. Oral Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1007\/s12247-020-09470-0","article-title":"Incorporation of Ursolic Acid in Liquid Crystalline Systems Improves the Antifungal Activity against Candida sp.","volume":"16","author":"Marena","year":"2021","journal-title":"J. Pharm. Innov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102429","DOI":"10.1016\/j.jddst.2021.102429","article-title":"The Promising Antischistosomal Activity of Oleic Acid-Loaded Polymeric Nanocapsules for Oral Administration","volume":"63","author":"Campos","year":"2021","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"683","DOI":"10.2147\/JPR.S158695","article-title":"Bupivacaine in Alginate and Chitosan Nanoparticles: An in Vivo Evaluation of Efficacy, Pharmacokinetics, and Local Toxicity","volume":"11","author":"Cereda","year":"2018","journal-title":"J. Pain Res."},{"key":"ref_36","first-page":"4815","article-title":"A Curcumin-Loaded Liquid Crystal Precursor Mucoadhesive System for the Treatment of Vaginal Candidiasis","volume":"10","author":"Salmazi","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"75","DOI":"10.18256\/2238-510X\/j.oralinvestigations.v6n1p75-84","article-title":"Sais Anest\u00e9sicos Utilizados Na Odontologia: Revis\u00e3o De Literatura","volume":"6","author":"Parise","year":"2017","journal-title":"J. Oral Investig."},{"key":"ref_38","first-page":"174","article-title":"Comparative Evaluation of the Efficacy of Lidocaine with Adrenaline and Lidocaine with Clonidine in Maxillary Infiltration Anesthesia","volume":"2","author":"Yajurvedi","year":"2017","journal-title":"Int. J. Innov. Res. Dent. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13223-019-0324-7","article-title":"A Systematic Review of Epinephrine Stability and Sterility with Storage in a Syringe","volume":"15","author":"Parish","year":"2019","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0378-5173(86)90112-2","article-title":"Interaction of Lidocaine and Lidocaine-Hcl with the Liquid Crystal Structure of Topical Preparations","volume":"29","author":"Frank","year":"1986","journal-title":"Int. J. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0378-5173(92)90102-8","article-title":"Phase Behaviour of the Lidocaine-Monoolein-Water System","volume":"79","year":"1992","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1208\/s12249-011-9725-8","article-title":"In Vitro Characterization of Chitosan Gels for Buccal Delivery of Celecoxib: Influence of a Penetration Enhancer","volume":"13","author":"Cid","year":"2012","journal-title":"AAPS PharmSciTech"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.ijbiomac.2020.01.235","article-title":"Mucin-Polysaccharide Interactions: A Rheological Approach to Evaluate the Effect of Ph on the Mucoadhesive Properties","volume":"149","author":"Cardoso","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"116268","DOI":"10.1016\/j.carbpol.2020.116268","article-title":"Thermoresponsive Systems Composed of Poloxamer 407 and Hpmc or Nacmc: Mechanical, Rheological and Sol-Gel Transition Analysis","volume":"240","author":"Cook","year":"2020","journal-title":"Carbohydr. Polym."},{"key":"ref_45","unstructured":"Batistuzzo, J., Itaya, M., and Eto, Y. (2006). Formul\u00e1rio M\u00e9dico Farmac\u00eautico, Editora Pharmabooks. [3rd ed.]."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0939-6411(97)00073-8","article-title":"A Comparison of Different in Vitro Methods for Measuring Mucoadhesive Performance","volume":"44","author":"Tamburic","year":"1997","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1177\/00220345870660080201","article-title":"The Surface Area of the Adult Human Mouth and Thickness of the Salivary Film Covering the Teeth and Oral Mucosa","volume":"66","author":"Collins","year":"1987","journal-title":"J. Dent. Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Bassi da Silva, J., Ferreira, S.B.S., Reis, A.V., Cook, M.T., and Bruschi, M.L. (2018). Assessing Mucoadhesion in Polymer Gels: The Effect of Method Type and Instrument Variables. Polymers, 10.","DOI":"10.3390\/polym10030254"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.foodhyd.2017.05.043","article-title":"Mucoadhesion: A Food Perspective","volume":"72","author":"Cook","year":"2017","journal-title":"Food Hydrocoll."},{"key":"ref_50","first-page":"50","article-title":"Mucoadhesive Drug Delivery Systems: A Review of Recent Developments","volume":"2","author":"Alawdi","year":"2021","journal-title":"J. Sci. Res. Med. Biol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.ejpb.2012.11.021","article-title":"Nasal Administration of Liquid Crystal Precursor Mucoadhesive Vehicle as an Alternative Antiretroviral Therapy","volume":"84","author":"Carvalho","year":"2013","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Muniz, B.V., Baratelli, D., Di Carla, S., Serpe, L., da Silva, C.B., Guilherme, V.A., de Morais Ribeiro, L.N., Cereda, C.M.S., de Paula, E., and Volpato, M.C. (2018). Hybrid Hydrogel Composed of Polymeric Nanocapsules Co-Loading Lidocaine and Prilocaine for Topical Intraoral Anesthesia. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-36382-4"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Barboza, A.d.S., Ribeiro de Andrade, J.S., Ferreira, M.L., Pe\u00f1a, C.L.D., da Costa, J.S., Fajardo, A.R., and Lund, R.G. (2023). Propolis Controlled Delivery Systems for Oral Therapeutics in Dental Medicine: A Systematic Review. Dent. J., 11.","DOI":"10.3390\/dj11070162"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Amato, M., Santonocito, S., Polizzi, A., Tartaglia, G.M., Ronsivalle, V., Viglianisi, G., Grippaudo, C., and Isola, G. (2023). Local Delivery and Controlled Release Drugs Systems: A New Approach for the Clinical Treatment of Periodontitis Therapy. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15041312"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1208\/s12249-021-02101-y","article-title":"Biorelevant in Vitro Skin Permeation Testing and in Vivo Pharmacokinetic Characterization of Lidocaine from a Nonaqueous Drug-in-Matrix Topical System","volume":"22","author":"Emileigh","year":"2021","journal-title":"AAPS PharmSciTech"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"8345","DOI":"10.2147\/IJN.S219670","article-title":"Micelles Loaded with Puerarin and Modified with Triphenylphosphonium Cation Possess Mitochondrial Targeting and Demonstrate Enhanced Protective Effect against Isoprenaline-Induced H9c2 Cells Apoptosis","volume":"18","author":"Li","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"287","DOI":"10.2174\/1568026618666180412153214","article-title":"Alternative Methods to Animal Studies for the Evaluation of Topical\/Transdermal Drug Delivery Systems","volume":"18","author":"Garcia","year":"2018","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/0278-6915(85)90030-4","article-title":"Hen\u2019s Egg Chorioallantoic Membrane Test for Irritation Potential","volume":"23","author":"Luepke","year":"1985","journal-title":"Food Chem. Toxicol."},{"key":"ref_59","unstructured":"Bezerra, A.A.C. (2023). Avalia\u00e7\u00e3o Da Toxicidade De Anest\u00e9sicos T\u00f3picos De Uso Odontol\u00f3gico Por Meio Do Modelo Da Membrana Corioalant\u00f3ica Do Embri\u00e3o De Galinha. [Master\u2019s Dissertation, Universidade Estadual de Campinas (UNICAMP)]. Available online: https:\/\/hdl.handle.net\/20.500.12733\/13469."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"15","DOI":"10.14227\/DT180311P15","article-title":"Simulated Biological Fluids with Possible Application in Dissolution Testing","volume":"18","author":"Marques","year":"2011","journal-title":"Dissolut. Technol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0378-5173(97)04904-1","article-title":"Textural, Viscoelastic and Mucoadhesive Properties of Pharmaceutical Gels Composed of Cellulose Polymers","volume":"151","author":"Jones","year":"1997","journal-title":"Int. J. Pharm."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0168-3659(97)00060-6","article-title":"Mucoadhesive, Syringeable Drug Delivery Systems for Controlled Application of Metronidazole to the Periodontal Pocket: In Vitro Release Kinetics, Syringeability, Mechanical and Mucoadhesive Properties","volume":"49","author":"Jones","year":"1997","journal-title":"J. Control. Release"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"de Araujo, J.S.M., Volpato, M.C., Muniz, B.V., Xavier, G.G.A., Martinelli, C.C.M., Lopez, R.F.V., Groppo, F.C., and Franz-Montan, M. (2021). Resistivity Technique for the Evaluation of the Integrity of Buccal and Esophageal Epithelium Mucosa for in Vitro Permeation Studies: Swine Buccal and Esophageal Mucosa Barrier Models. 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