Preparation and Characterization of Lidocaine-loaded, Microemulsion-Based Topical Gels

Document Type : Research article


1 Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Food Safety Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

4 Protein Technology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.



Microemulsion-based gels (MBGs) were prepared for transdermal delivery of lidocaine and evaluated for their potential for local anesthesia. Lidocaine solubility was measured in various oils, and phase diagrams were constructed to map the concentration range of oil, surfactant, cosurfactant, and water for oil-in-water (o/w) microemulsion (ME) domains, employing the water titration method at different surfactant/cosurfactant weight ratios. Refractive index, electrical conductivity, droplet size, zeta potential, pH, viscosity, and stability of fluid o/w MEs were evaluated. CarbomerÒ 940 was incorporated into the fluid drug-loaded MEs as a gelling agent. Microemulsion-based gels were characterized for spreadability, pH, viscosity, and in-vitro drug release measurements, and based on the results obtained, the best MBGs were selected and subsequently subjected to ex-vivo rat skin permeation anesthetic effect and irritation studies. Data indicated the formation of nano-sized droplets of MEs ranging from 20-52 nm with a polydispersity of less than 0.5. In-vitro release and ex-vivo permeation studies on MBGs showed significantly higher drug release and permeation in comparison to the marketed topical gel. Developed MBG formulations demonstrated greater potential for transdermal delivery of lidocaine and advantage over the commercially available gel product, and therefore, they may be considered as potential vehicles for the topical delivery of lidocaine.

Graphical Abstract

Preparation and Characterization of Lidocaine-loaded, Microemulsion-Based Topical Gels


  1. Shah J, Votta-Velis EG and Borgeat A. New local anesthetics. Best Pract. Res. Clin. Anaesthesiol. (2018) 32: 179-85.
  2. Heavner JE. Local anesthetics. Opin. Anaesthesiol. (2007) 20: 336-42.
  3. Shrestha M and Chen A. Modalities in managing postherpetic neuralgia. Korean J Pain. (2018) 31: 235-43.
  4. Alster T. Review of lidocaine/tetracaine cream as a topical anesthetic for dermatologic laser procedures. Pain Ther. (2013) 2: 11-9.
  5. de Araújo DR, da Silva DC, Barbosa RM, Franz-Montan M, Cereda CM, Padula C, Santi P and de Paula E. Strategies for delivering local anesthetics to the skin: focus on liposomes, solid lipid nanoparticles, hydrogels and patches. Expert Opin. Drug Deliv. (2013) 10: 1551-63.
  6. Shipton EA. New formulations of local anaesthetics-part I. Anesthesiol Res. Pract. (2012) 2012: 546409.
  7. Shainhouse T and Cunningham BB. Topical anesthetics. J. Drug Deliv. (2004) 2: 89-99.
  8. Dogrul A, Arslan SA and Tirnaksiz F. Water/oil type microemulsion systems containing lidocaine hydrochloride: in-vitro and in-vivo J. Microencapsul. (2014) 31: 448-60.
  9. Wang Y, Su W, Li Q, Li C, Wang H, Li Y, Cao Y, Chang J and Zhang L. Preparation and evaluation of lidocaine hydrochloride-loaded TAT-conjugated polymeric liposomes for transdermal delivery. J. Pharm. (2013) 441: 748-56.
  10. Yuan JS, Ansari M, Samaan M and Acosta EJ. Linker-based lecithin microemulsions for transdermal delivery of lidocaine. J. Pharm. (2008) 349: 130-43.
  11. Baek SH, Shin JH and Kim YC. Drug-coated microneedles for rapid and painless local anesthesia. Microdevices. (2017) 19: 2.
  12. Shipton EA. New delivery systems for local anaesthetics-part 2. Anesthesiol Res Pract. (2012) 2012: 289373.
  13. Negi P, Singh B, Sharma G, Beg S, Raza K and Katare OP. Phospholipid microemulsion-based hydrogel for enhanced topical delivery of lidocaine and prilocaine: QbD-based development and evaluation. Drug Deliv. (2016) 23: 951-67.
  14. Hoar TP and Schulman JH. Transparent water-in-oil dispersions: the Oleopathic Hydro-Micelle. Nature (1943) 152: 102-3.
  15. Tashtoush BM, Bennamani AN and Al-Taani BM. Preparation and characterization of microemulsion formulations of nicotinic acid and its prodrugs for transdermal delivery. Dev. Technol. (2013) 18: 834-43.
  16. Baroli B, López-Quintela MA, Delgado-Charro MB, Fadda AM and Blanco-Méndez J. Microemulsions for topical delivery of 8-methoxsalen. Control. Release. (2000) 69: 209-18.
  17. Coneac G, Vlaia V, Olariu I, Muţ AM, Anghel DF, Ilie C, Popoiu C, Lupuleasa D and Vlaia L. Development and evaluation of new microemulsion-based hydrogel formulations for topical delivery of fluconazole. AAPS PharmSciTech. (2015) 16: 889-904.
  18. Formariz TP, Sarmento VH, Silva-Junior AA, Scarpa MV, Santilli CV and Oliveira AG. Doxorubicin biocompatible O/W microemulsion stabilized by mixed surfactant containing soya phosphatidylcholine. Colloids Surf. B. Biointerfaces (2006) 51: 54-61.
  19. Chhibber T, Wadhwa S, Chadha P, Sharma G and Katare OP. Phospholipid structured microemulsion as effective carrier system with potential in methicillin sensitive Staphylococcus aureus (MSSA) involved burn wound infection. Drug Target. (2015) 23: 943-52.
  20. Reis MY, Santos SM, Silva DR, Silva MV, Correia MT, Navarro D, Ferraz MA, Santos GK, Hallwass F, Bianchi O and Silva AG. Anti-inflammatory activity of babassu oil and development of a microemulsion system for topical delivery. Based Complementary Altern. Med. (2017) 2017: 3647801.
  21. Tessema EN, Gebre-Mariam T, Paulos G, Wohlrab J and Neubert RH. Delivery of oat-derived phytoceramides into the stratum corneum of the skin using nanocarriers: Formulation, characterization and in-vitro and ex-vivo penetration studies. J. Pharm. Biopharm. (2018) 127: 260-9.
  22. Delgado-Charro MB, Iglesias-Vilas G, Blanco-Méndez J, López-Quintela MA, Marty JP and Guy RH. Delivery of a hydrophilic solute through the skin from novel microemulsion systems. J. Pharm. Biopharm. (1997) 43: 37-42.
  23. Sah AK, Jain SK and Pandey RS. Microemulsion based hydrogel formulation of methoxsalen for the effective treatment of psoriasis. Asian J. Pharm. Clin. Res. (2011) 4: 140-5.
  24. Cavalcanti AL, Reis MY, Silva GC, Ramalho ÍM, Guimarães GP, Silva JA, Saraiva KL and Damasceno BP. Microemulsion for topical application of pentoxifylline: In-vitro release and in-vivo Int. J. Pharm. (2016) 506: 351-60.
  25. Savić V, Todosijević M, Ilić T, Lukić M, Mitsou E, Papadimitriou V, Avramiotis S, Marković B, Cekić N and Savić S. Tacrolimus loaded biocompatible lecithin-based microemulsions with improved skin penetration: structure characterization and in-vitro/in vivo Int. J. Pharm. (2017) 529: 491-505.
  26. Patel HK, Barot BS, Parejiya PB, Shelat PK and Shukla A. Topical delivery of clobetasol propionate loaded microemulsion based gel for effective treatment of vitiligo: Ex-vivo permeation and skin irritation studies. Colloids Surf. B. Biointerfaces. (2013) 102: 86-94.
  27. Yang C, Shen Y, Wang J, Ouahab A, Zhang T and Tu J. Cationic polymer-based micro-emulgel with self-preserving ability for transdermal delivery of diclofenac sodium. Drug Deliv. (2015) 22: 814-22.
  28. Djekic L, Martinovic M and Primorac M. Microemulsion Hydrogels – Properties and current applications in drug delivery. In: Torres T. (ed.) Microemulsions: systems, properties and applications. 1st Nova Science Publishers, New York, USA (2016) 1-36.
  29. Patel RR, Patel ZK, Patel KR and Patel MR. Micro emulsion based gel: recent expansions for topical drug delivery system. Med. Pharm. Allied Sci. (2014) 1: 1-15.
  30. Djekic L, Martinovic M, Stepanović-PetrovićR, Micov A, TomićM and Primorac M. Formulation of hydrogel-thickened nonionic microemulsions with enhanced percutaneous delivery of ibuprofen assessed in-vivo in rats. J. Pharm. Sci. (2016) 92: 255-65.
  31. Vlaia L, Olariu I, Coneac G, Muţ AM, Popoiu C, Corina S, Anghel DF, Maxim ME, Kalas S and Vlaia VI. Development of microemulsion-loaded hydrogel formulations for topical delivery of metoprolol tartrate: Physicochemical characterization and ex-vivo FARMACIA (2016) 64: 901-13.
  32. Wani RR, Patil MP, Dhurjad P, Chaudhari CA and Kshirsagar SJ. Microemulsion based gel: A novel approach in delivery of hydrophobic drugs. J. Pharm. Res. Scholars. (2015) 4: 398-410.
  33. Zhao L, Wang Y, Zhai Y, Wang Z, Liu J and Zhai G. Ropivacaine loaded microemulsion and microemulsion-based gel for transdermal delivery: preparation, optimization, and evaluation. J. Pharm. (2014) 477: 47-56.
  34. Okur NÜ, Çağlar EŞ, Arpa MD and Karasulu HY. Preparation and evaluation of novel microemulsion-based hydrogels for dermal delivery of benzocaine. Dev. Technol. (2017) 22: 500-10.
  35. Ghai D and Sinha VR. Nanoemulsions as self-emulsified drug delivery carriers for enhanced permeability of the poorly water-soluble selective β1-adrenoreceptor blocker Talinolol. Nanomedicine (2012) 8: 618-26.
  36. Chhatrani BM and Shah DP. A review on microemulsion based gel: A novel approach for enhancing topical delivery of hydrophobic drug. J. Pharm. Pharm. Res. (2017) 8: 19-35.
  37. Kaur A, Sharma G, Gupta V, Ratho RK, Shishu and Katare OP. Enhanced acyclovir delivery using w/o type microemulsion: preclinical assessment of antiviral activity using murine model of zosteriform cutaneous HSV-1 infection. Cells Nanomed. Biotechnol. (2018) 46: 346-54.
  38. Baboota S, Alam MS, Sharma S, Sahni JK, Kumar A and Ali J. Nanocarrier-based hydrogel of betamethasone dipropionate and salicylic acid for treatment of psoriasis. J. Pharm. Investig. (2011) 1: 139-47.
  39. Almeida IF and Bahia MF. Evaluation of the physical stability of two oleogels. J. Pharm. (2006) 327: 73-7.
  40. Farghaly DA, Aboelwafa AA, Hamza MY and Mohamed MI. Microemulsion for topical delivery of fenoprofen calcium: in-vitro and in-vivo J. Liposome Res. (2018) 28: 126-36.
  41. Zeb A, Qureshi OS, Kim HS, Cha JH, Kim HS and Kim JK. Improved skin permeation of methotrexate via nanosized ultradeformable liposomes. J. Nanomedicine. (2016) 11: 3813-24.
  42. Deuis JR, Dvorakova LS and Vetter I. Methods used to evaluate pain behaviors in rodents. Mol. Neurosci. (2017) 10: 284.
  43. Test No. 404: Acute Dermal Irritation/Corrosion. OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris (2015) Avaiable from URL:
  44. Shafiq-un-Nabi S, Shakeel F, Talegaonkar S, Ali J, Baboota S, Ahuja A, Khar RK and Ali M. Formulation development and optimization using nanoemulsion technique: a technical note. AAPS PharmSciTech. (2007) 8: Article 28.
  45. Mishra R, Prabhavalkar KS and Bhatt LK. Preparation, optimization, and evaluation of zaltoprofen-loaded microemulsion and microemulsion-based gel for transdermal delivery. Liposome Res. (2016) 26: 297-306.
  46. Tadros T. Principles of emulsion stabilization with special reference to polymeric surfactants. Cosmet .Sci. (2006) 57: 153-69.
  47. Olariu I, Coneac G, Vlaia L, Vlaia V, Anghel DF, Ilie C, Popoiu C and Lupuleasa D. Development and evaluation of microemulsion-based hydrogel formulations for topical delivery of propranolol hydrochloride. J. Nanomater. Biostruct. (2014) 9: 395-412.
  48. Chen L, Zhao X, Cai J, Guan Y, Wang S, Liu H, Zhu W and Li J. Triptolide-loaded microemulsion-based hydrogels: physical properties and percutaneous permeability. Acta Pharm. Sin. B (2013) 3: 185–92.
  49. Patel MR, Patel RB, Parikh JR and Patel BG. Novel microemulsion-based gel formulation of tazarotene for therapy of acne. Dev. Technol. (2016) 21: 921-32.
  50. Abd E, Yousef SA, Pastore MN, Telaprolu K, Mohammed YH, Namjoshi S, Grice JE and Roberts MS. Skin models for the testing of transdermal drugs. Pharmacol. (2016) 8: 163-76.
  51. Morimoto Y, Hatanaka T, Sugibayashi K and Omiya H. Prediction of skin permeability of drugs: comparison of human and hairless rat skin. Pharm. Pharmacol. (1992) 44: 634-9.
  52. Godin B and Touitou E. Transdermal skin delivery: Predictions for humans from in vivo, ex-vivo and animal models. Drug Deliv. Rev. (2007) 59: 1152-61.
  53. Kweon JH, Chi SC and Park ES. Transdermal delivery of diclofenac using microemulsions. Pharmacal Res. (2004) 27: 351-6.
  54. Higuchi T. Physical chemical analysis of percutaneous absorption process from creams and ointments. Soc. Cosmet. Chem. (1960) 11: 85-97.
  55. Radwan SA, ElMeshad AN and Shoukri RA. Microemulsion loaded hydrogel as a promising vehicle for dermal delivery of the antifungal sertaconazole: Design, optimization and ex-vivo Drug Dev. Ind. Pharm. (2017) 43: 1351-65.
  56. Cao M, Ren L and Chen G. Formulation, optimization and ex-vivo and in vivo evaluation of celecoxib microemulsion-based gel for transdermal delivery. AAPS PharmSciTech. (2017) 18: 1960-71.
  57. Shakeel F, Baboota S, Ahuja A, Ali J, Aqil M and Shafiq S. Nanoemulsions as vehicles for transdermal delivery of aceclofenac. AAPS PharmSciTech. (2007) 8: Article 104.
  58. Zhang YT, Li Z, Zhang K, Zhang HY, He ZH, Xia Q, Zhao JH and Feng NP. Co-delivery of evodiamine and rutaecarpine in a microemulsion-based hyaluronic acid hydrogel for enhanced analgesic effects on mouse pain models. J. Pharm. (2017) 528: 100-6.
  59. Williams AC and Barry BW. Penetration enhancers. Drug Deliv. Rev. (2012) 64: 128-37.
  60. Starýchová L, Žabka M, Spaglová M, Čuchorová M, Vitková M, Čierna M, Bartoníková K and Gardavská K. In-vitro liberation of indomethacin from chitosan gels containing microemulsion in different dissolution mediums. Pharm. Sci. (2014) 103: 3977-84.
  61. Çelebi N, Ermiş S and Özkan S. Development of topical hydrogels of terbinafine hydrochloride and evaluation of their antifungal activity. Drug Dev. Ind. Pharm. (2015) 41: 631-9.
  62. Chudasama A, Patel V, Nivsarkar M, Vasu K and Shishoo C. Investigation of microemulsion system for transdermal delivery of itraconazole. Adv. Pharm. Technol. Res. (2011) 2: 30-8.
  63. Aliberti AL, de Queiroz AC, Praça FS, Eloy JO, Bentley MV and Medina WS. Ketoprofen microemulsion for improved skin delivery and in-vivo anti-inflammatory effect. AAPS PharmSciTech. (2017) 18: 2783-91.
  64. Gohel MC and Nagori SA. Fabrication and evaluation of hydrogel thickened microemulsion of ibuprofen for topical delivery. Indian J. Pharm. Edu. Res. (2010) 44: 189-96.
  65. Bachhav YG and Patravale VB. Microemulsion-based vaginal gel of clotrimazole: formulation, in-vitro evaluation, and stability studies. AAPS PharmSciTech. (2009) 10: 476-81.
  66. Mishra B, Sahoo SK and Sahoo S. Liranaftate loaded xanthan gum based hydrogel for topical delivery: Physical properties and ex-vivo Int. J. Biol. Macromol. (2018) 107: 1717-23.
  67. Aggarwal N, Goindi S and Khurana R. Formulation, characterization and evaluation of an optimized microemulsion formulation of griseofulvin for topical application. Colloids Surf. B Biointerfaces. (2013) 105: 158-66.
  68. Tasdighi E, Jafari Azar Z and Mortazavi SA. Development and in-vitro evaluation of a contraceptive vagino-adhesive propranolol hydrochloride gel. J. Pharm. Res. (2012) 11: 13-26.