AAPS PharmSciTech

, Volume 19, Issue 7, pp 3219–3227 | Cite as

Third-Generation Transdermal Delivery Systems Containing Zidovudine: Effect of the Combination of Different Chemical Enhancers and a Microemulsion System

  • André Luis Menezes Carvalho
  • José Alexsandro Silva
  • Ana Amélia Moreira LiraEmail author
  • Ellen Denise Prado Almeida
  • Rogéria de Souza Nunes
  • Victor Hugo Vitorino Sarmento
  • Leiz Maria Costa Veras
  • José Roberto de Almeida Leite
  • Leila Bastos Leal
  • Davi Pereira de Santana
Research Article


This study aimed to examine the influence of the combination of chemical enhancers and a microemulsion on the transdermal permeation of zidovudine (AZT). Ethanol, 1,8-cineole, and geraniol were incorporated in a microemulsion. The droplet size, zeta potential, rheology, and SAXS analysis were performed. The permeation enhancer effect was evaluated using pig ear skin. Snake skin (Boa constrictor) treated with the formulations was also used as a stratum corneum model and studied by attenuated total reflectance-infrared spectroscopy. As a result, it was observed that the incorporation of the chemical enhancers promoted a decrease of the droplet size and some rheological modifications. The 1,8-cineole associated with the microemulsion significantly increased the permeated amount of AZT. Conversely, ethanol significantly increased the quantity of the drug retained in the skin. The probable mechanism for the cineole and ethanol effects was respectively: fluidization and increasing of the diffusion coefficient, and increasing of the partition coefficient. Surprising, geraniol + microemulsion drastically decreased both the permeated and the retained amount of AZT into the skin. Thus, the adequate association of microemulsion and chemical enhancers showed to be a crucial step to enable the topical or transdermal use of drugs.


microemulsion chemical enhancer skin permeation transdermal delivery 



We also acknowledge the Laboratório Nacional de Luz Síncroton (LNLS, Campinas SP, Brazil) for provision of synchrotron radiation facilities. We would like to thank SAXS staff for assistance in using beamline SAXS1 through the approved project number 20160301.

Funding Information

The authors thank CNPq/MCT and CT-FVA for their financial support and the LAFEPE for the AZT donation.

Supplementary material

12249_2018_1160_MOESM1_ESM.png (9.4 mb)
ESM 1 (PNG 9606 kb)


  1. 1.
    Souza JD, Storpirtis S. Antiretroviral activity and pharmacokinetics properties of lamivudine and zidovudine association. Revista Brasileira de Ciências Farmacêuticas. 2004;40(1):9–19.CrossRefGoogle Scholar
  2. 2.
    Beach JW. Chemotherapeutic agents for human immunodeficiency virus infection: mechanism of action, pharmacokinetics, metabolism, and adverse reactions. Clin Ther. 1998;20(1):2–25.CrossRefGoogle Scholar
  3. 3.
    Barry B. Novel mechanisms and devices to enable successful transdermal drug delivery. Eur J Pharm Sci. 2001;14:101–14. Scholar
  4. 4.
    Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26:1261–8. Scholar
  5. 5.
    Wiedersberg S, Guy RH. Transdermal drug delivery: 30+ years of war and still fighting! J Control Release. 2014;190:150–6. Scholar
  6. 6.
    Zhai Y, Zhai G. Advances in lipid-based colloid systems as drug carrier for topic delivery. J Control Release. 2014;193:90–9. Scholar
  7. 7.
    Karande P, Jain A, Mitragotri S. Discovery of transdermal penetration enhancers by high-throughput screening. Nat Biotechnol. 2004;22:192–7. Scholar
  8. 8.
    Kogan A, Garti N. Microemulsions as transdermal drug delivery vehicles. Adv Colloid Interf Sci. 2006;123:369–85. Scholar
  9. 9.
    Fanun M. Microemulsions as delivery systems. Curr Opin Colloid Interface Sci. 2012;17:306–13. Scholar
  10. 10.
    Montenegro L, Lai F, Offerta A, Sarpietro MG, Micicchè L, Maccioni AM, et al. From nanoemulsions to nanostructured lipid carriers: a relevant development in dermal delivery of drugs and cosmetics. J Drug Deliv Sci Technol. 2016;32:100–12. Scholar
  11. 11.
    Hathout RM, Nasr M. Transdermal delivery of betahistine hydrochloride using microemulsions: physical characterization, biophysical assessment, confocal imaging and permeation studies. Colloids Surf B Biointerfaces. 2013;110:254–60. Scholar
  12. 12.
    Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2004;56:603–18. Scholar
  13. 13.
    Aqil M, Ahad A, Sultana Y, Ali A. Status of terpenes as skin penetration enhancers. Drug Discov Today. 2007;12:1061–7. Scholar
  14. 14.
    Sapra B, Jain S, Tiwary AK. Percutaneous permeation enhancement by terpenes: mechanistic view. AAPS J. 2008;10:120–32. Scholar
  15. 15.
    Pham QD, Björklund S, Engblom J, Topgaard D, Sparr E. Chemical penetration enhancers in stratum corneum—relation between molecular effects and barrier function. J Control Release. 2016;232:175–87. Scholar
  16. 16.
    El-Kattan AF, Asbill CS, Michniak BB. The effect of terpene enhancer lipophilicity on the percutaneous permeation of hydrocortisone formulated in HPMC gel systems. Int J Pharm. 2000;198:179–89. Scholar
  17. 17.
    Carvalho ALM, da SJA, Lira AAM, Conceição TMF, Nunes R de S, de Albuquerque Junior RLC, et al. Evaluation of microemulsion and lamellar liquid crystalline systems for transdermal zidovudine delivery. J Pharm Sci. 2016;105:2188–93. Scholar
  18. 18.
    Brito MB, Barin GB, Araújo AAS, de SDP, Cavalcanti SCHS, Lira AAM, et al. The action modes of Lippia sidoides (Cham) essential oil as penetration enhancers on snake skin. J Therm Anal Calorim. 2009;97:323–7. Scholar
  19. 19.
    Vaddi HK, Ho PC, Chan SY. Terpenes in propylene glycol as skin-penetration enhancers: permeation and partition of haloperidol, Fourier transform infrared spectroscopy, and differential scanning calorimetry. J Pharm Sci. 2002;91:1639–51. Scholar
  20. 20.
    Formariz TP, Chiavacci LA, Sarmento VHV, Santilli CV, Tabosa do Egito ES, Oliveira AG. Relationship between structural features and in vitro release of doxorubicin from biocompatible anionic microemulsion. Colloids Surf B Biointerfaces. 2007;60:28–35. Scholar
  21. 21.
    Formariz TP, Chiavacci LA, Sarmento VHV, Franzini CM, Silva- AA, Scarpa MV, et al. Structural changes of biocompatible neutral microemulsions stabilized by mixed surfactant containing soya phosphatidylcholine and their relationship with doxorubicin release. Colloids Surf B Biointerfaces. 2008;63:287–95. Scholar
  22. 22.
    El Maghraby GM. Self-microemulsifying and microemulsion systems for transdermal delivery of indomethacin: effect of phase transition. Colloids Surfaces B Biointerfaces. 2010;75:595–600. Scholar
  23. 23.
    Zhang J, Michniak-Kohn B. Investigation of microemulsion microstructures and their relationship to transdermal permeation of model drugs: ketoprofen, lidocaine, and caffeine. Int J Pharm. 2011;421:34–44. Scholar
  24. 24.
    Godwin DA, Michniak BB. Influence of drug lipophilicity on terpenes as transdermal penetration enhancers. Drug Dev Ind Pharm. 1999;25:905–15. Scholar
  25. 25.
    Edwardson PAD, Walker M, Breheny C. Quantitative FT-IR determination of skin hydration following occlusion with hydrocolloid containing adhesive dressings. Int J Pharm. 1993;91:51–7. Scholar
  26. 26.
    Mak VHW, Potts RO, Guy RH. Oleic acid concentration and effect in human stratum corneum: non-invasive determination by attenuated total reflectance infrared spectroscopy in vivo. J Control Release. 1990;12:67–75. Scholar
  27. 27.
    Hathout RM, Mansour S, Mortada ND, Geneidi AS, Guy RH. Uptake of microemulsion components into the stratum corneum and their molecular effects on skin barrier function. Mol Pharm. 2010;7:1266–73. Scholar
  28. 28.
    Hathout RM, Mansour S, Geneidi AS, Mortada ND. Visualization, dermatopharmacokinetic analysis and monitoring the conformational effects of a microemulsion formulation in the skin stratum corneum. J Colloid Interface Sci. 2011;354:124–30. Scholar
  29. 29.
    Balázs B, Sipos P, Danciu C, Avram S, Soica C, Dehelean C, et al. ATR-FTIR and Raman spectroscopic investigation of the electroporation-mediated transdermal delivery of a nanocarrier system containing an antitumour drug. Biomed Opt Express. 2016;7:67–78. Scholar
  30. 30.
    Herman A, Herman AP. Essential oils and their constituents as skin penetration enhancer for transdermal drug delivery: a review. J Pharm Pharmacol. 2015;67:473–85. Scholar
  31. 31.
    Ge S, Lin Y, Lu H, Li Q, He J, Chen B, et al. Percutaneous delivery of econazole using microemulsion as vehicle: formulation, evaluation and vesicle-skin interaction. Int J Pharm. 2014;465:120–31. Scholar
  32. 32.
    Xie F, Chai J, Hu Q, Yu Y, Ma L, Liu L, et al. Transdermal permeation of drugs with differing lipophilicity: effect of penetration enhancer camphor. Int J Pharm. 2016;507:90–101. Scholar
  33. 33.
    Alvarez-Román R, Merino G, Kalia YN, Naik A, Guy RH. Skin permeability enhancement by low frequency sonophoresis: lipid extraction and transport pathways. J Pharm Sci. 2003;92:1138–46. Scholar
  34. 34.
    Furuishi T, Fukami T, Suzuki T, Takayama K, Tomono K. Synergistic effect of isopropyl myristate and glyceryl monocaprylate on the skin permeation of pentazocine. Biol Pharm Bull. 2010;33:294–300.CrossRefGoogle Scholar
  35. 35.
    Narishetty STK, Panchagnula R. Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action. J Control Release. 2004;95:367–79. Scholar
  36. 36.
    Amnuaikit C, Ikeuchi I, Ogawara K, Higaki K, Kimura T. Skin permeation of propranolol from polymeric film containing terpene enhancers for transdermal use. Int J Pharm. 2005;289:167–78. Scholar
  37. 37.
    Narishetty STK, Panchagnula R. Effect of l-menthol and 1,8-cineole on phase behavior and molecular organization of SC lipids and skin permeation of zidovudine. J Control Release. 2005;102:59–70. Scholar
  38. 38.
    Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128–37. Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • André Luis Menezes Carvalho
    • 1
    • 2
  • José Alexsandro Silva
    • 3
  • Ana Amélia Moreira Lira
    • 4
    • 5
    Email author
  • Ellen Denise Prado Almeida
    • 4
  • Rogéria de Souza Nunes
    • 4
  • Victor Hugo Vitorino Sarmento
    • 6
  • Leiz Maria Costa Veras
    • 7
  • José Roberto de Almeida Leite
    • 8
  • Leila Bastos Leal
    • 1
  • Davi Pereira de Santana
    • 1
  1. 1.Núcleo de Desenvolvimento Farmacêutico e Cosmético, Departamento de Ciências FarmacêuticasUniversidade Federal de PernambucoRecifeBrazil
  2. 2.Curso de FarmáciaUniversidade Federal do PiauíTeresinaBrazil
  3. 3.Department of Agrarian and Exact Sciences, Postgraduate Program in Agroindustry SystemsFederal University of Campina Grande - Campus IVPombalBrazil
  4. 4.Departamento de FarmáciaUniversidade Federal de SergipeSão CristóvãoBrazil
  5. 5.Department of PharmacyFederal University of SergipeSão CristóvãoBrazil
  6. 6.Departamento de QuímicaUniversidade Federal de SergipeItabaianaBrazil
  7. 7.Laboratório de Biodiversidade e BiotecnologiaUniversidade Federal do PiauíParnaíbaBrazil
  8. 8.Faculdade de MedicinaUniversidade de BrasíliaBrasíliaBrazil

Personalised recommendations