Skip to main content

Advertisement

SpringerLink
Log in

Enhanced Topical Co-delivery of Acyclovir and Lidocaine Gel Formulation Across Dermatomed Human Skin

  • Research Article
  • Active and Passive Permeation Enhancement Strategies for Transdermal Delivery of Bioactive Compounds
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Acyclovir a widely used drug in the treatment of herpes simplex virus (HSV) infections and lidocaine a local anesthetic were combined in a topical gel formulation. The topical gel with Transcutol P (TP) or N-methyl 2-pyrrolidone (NMP) was prepared and tested for in vitro skin permeation across the intact and microneedle-treated human cadaver skin. The topical gels containing 5% each of acyclovir and lidocaine showed optimal pH, spreadability, and 100% drug release. The transdermal flux and skin retention of the gels were significantly higher compared to Generic 5% acyclovir ointment (Zovirax) (p < 0.001), and 5% lidocaine gel (numb gel) (p < 0.05). As expected, topical gels showed a very high increase in the skin permeation across microporated skin versus intact skin. In viral infections, skin is inflamed, and barrier integrity may be disrupted. The results of the present study are significant because the co-delivery formulation showed a very high increase in the skin permeation across intact and microporated skin (versus respective commercial formulations). The results of this study demonstrate enhanced co-delivery of acyclovir and lidocaine in a topical formulation across skin (intact or barrier compromised) for the treatment of herpes virus infections.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Hasler-Nguyen N, Shelton D, Ponard G, Bader M, Schaffrik M, Mallefet P. Evaluation of the in vitro skin permeation of antiviral drugs from penciclovir 1% cream and acyclovir 5% cream used to treat herpes simplex virus infection. BMC Dermatol. 2009;9(1):1–10.

    Article  Google Scholar 

  2. Herpes simplex virus [updated 10 Mar 2022]. [cited July 31, 2022]. Available from: https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus#hsv1.

  3. Wald A. Herpes simplex virus type 2 transmission: risk factors and virus shedding. Herpes: the journal of the IHMF. 2004;11:130A-7A.

  4. Rasoanirina BNV, Lassoued MA, Kamoun A, Bahloul B, Miladi K, Sfar S. Voriconazole-loaded self-nanoemulsifying drug delivery system (SNEDDS) to improve transcorneal permeability. Pharm Dev Technol. 2020;25(6):694–703.

    Article  CAS  PubMed  Google Scholar 

  5. Goldberg LH, Sperber J. Acyclovir prophylaxis for herpes simplex virus infection. Antimicrobial agents and chemotherapy. 1987;31(11):1865.

  6. Shukla C, Friden P, Juluru R, Stagni G. In vivo quantification of acyclovir exposure in the dermis following iontophoresis of semisolid formulations. J Pharm Sci. 2009;98(3):917–25.

    Article  CAS  PubMed  Google Scholar 

  7. Spruance SL, Rea TL, Thoming C, Tucker R, Saltzman R, Boon R. Penciclovir cream for the treatment of herpes simplex labialis: a randomized, multicenter, double-blind, placebo-controlled trial. JAMA. 1997;277(17):1374–9.

    Article  CAS  PubMed  Google Scholar 

  8. Product Monograph. Ontario: GlaxoSmithKline Inc.; 2008. Contract No.: 184897

  9. Spruance S, Aoki FY, Tyring S, Stanberry L, Whitley R, Hamed K. Short-course therapy for recurrent genital herpes and herpes labialis: entering an era of greater convenience, better treatment adherence, and reduced cost. J Fam Pract. 2007;56(1):30–7.

    PubMed  Google Scholar 

  10. Gusai T, Dhavalkumar M, Soniwala M, Dudhat K, Vasoya J, Chavda J. Formulation and optimization of microsponge-loaded emulgel to improve the transdermal application of acyclovir—a DOE based approach. Drug Deliv Transl Res. 2021;11(5):2009–29.

    Article  CAS  PubMed  Google Scholar 

  11. Hamuy R, Berman B. Treatment of herpes simplex virus infections with topical antiviral agents. Eur J Dermatol. 1998;8(5):310–9.

    CAS  PubMed  Google Scholar 

  12. de Jalón EG, Blanco-Prı́eto MaJ, Ygartua P, Santoyo S. Topical application of acyclovir-loaded microparticles: quantification of the drug in porcine skin layers. Journal of controlled release. 2001;75(1–2):191–7.

  13. O’Brien JJ. Campoli-Richards DM. Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1989;37:233–309.

  14. Lembo D, Donalisio M, Civra A, Argenziano M, Cavalli R. Nanomedicine formulations for the delivery of antiviral drugs: a promising solution for the treatment of viral infections. Expert Opin Drug Deliv. 2018;15(1):93–114.

    Article  CAS  PubMed  Google Scholar 

  15. Chávez-Iñiguez JS, Medina-Gonzalez R, Aguilar-Parra L, Torres-Vázquez EJ, Maggiani-Aguilera P, Cervantes-Pérez E, et al. Oral acyclovir induced hypokalemia and acute tubular necrosis a case report. BMC Nephrol. 2018;19(1):1–5.

    Article  Google Scholar 

  16. Spruance SL, Crumpacker CS. Topical 5 percent acyclovir in polyethylene glycol for herpes simplex labialis: antiviral effect without clinical benefit. Am J Med. 1982;73(1):315–9.

    Article  CAS  PubMed  Google Scholar 

  17. Leowattana W. Antiviral drugs and acute kidney injury (AKI). Infectious Disorders-Drug Targets (Formerly Current Drug Targets-Infectious Disorders). 2019;19(4):375–82.

  18. Helldén A, Odar-Cederlöf I, Diener P, Barkholt L, Medin C, Svensson JO, et al. High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovir-related neuropsychiatric side effects: an observational study. Nephrol Dial Transplant. 2003;18(6):1135–41.

    Article  PubMed  Google Scholar 

  19. Volpato NM, Nicoli S, Laureri C, Colombo P, Santi P. In vitro acyclovir distribution in human skin layers after transdermal iontophoresis. J Control Release. 1998;50(1–3):291–6.

    Article  CAS  PubMed  Google Scholar 

  20. Effendy I, Maibach HI. Surfactants and experimental irritant contact dermatitis. Contact Dermatitis. 1995;33(4):217–25.

    Article  CAS  PubMed  Google Scholar 

  21. Thomas RD, Behbehani MM, Coyle DE, Denson DD. Cardiovascular toxicity of local anesthetics: an alternative hypothesis. Anesth Analg. 1986;65(5):444–50.

    Article  CAS  PubMed  Google Scholar 

  22. Stoopler ET, Balasubramanlam R. Topical and systemic therapies for oral and perioral herpes simplex virus infections. California Dental Association Journal. 2013;41(4):259.

    Google Scholar 

  23. Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain. 1996;65(1):39–44.

    Article  CAS  PubMed  Google Scholar 

  24. Mulabagal V, Annaji M, Kurapati S, Dash RP, Srinivas NR, Tiwari AK, et al. Stability-indicating HPLC method for acyclovir and lidocaine in topical formulations. Biomed Chromatogr. 2020;34(3): e4751.

    Article  CAS  PubMed  Google Scholar 

  25. Whitley RJ, Roizman B. Herpes simplex virus infections. The lancet. 2001;357(9267):1513–8.

    Article  CAS  Google Scholar 

  26. Gudin J, Nalamachu S. Utility of lidocaine as a topical analgesic and improvements in patch delivery systems. Postgrad Med. 2020;132(1):28–36.

    Article  CAS  PubMed  Google Scholar 

  27. Glasnapp A. General Pharmacy Compounding. 2021. [cited 2022 Sept 28, 2022]. Available from: https://www.pccarx.com/Blog/lidocaine-vs-lidocaine-hcl.

  28. Kamal NS, Krishnaiah YSR, Xu X, Zidan AS, Raney S, Cruz CN, et al. Identification of critical formulation parameters affecting the in vitro release, permeation, and rheological properties of the acyclovir topical cream. Int J Pharm. 2020;590: 119914.

    Article  CAS  PubMed  Google Scholar 

  29. Freeman DJ, Sheth NV, Spruance SL. Failure of topical acyclovir in ointment to penetrate human skin. Antimicrob Agents Chemother. 1986;29(5):730–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jones DS, Woolfson AD, Djokic J. Texture profile analysis of bioadhesive polymeric semisolids: mechanical characterization and investigation of interactions between formulation components. J Appl Polym Sci. 1996;61(12):2229–34.

    Article  CAS  Google Scholar 

  31. Froelich A, Osmałek T, Snela A, Kunstman P, Jadach B, Olejniczak M, et al. Novel microemulsion-based gels for topical delivery of indomethacin: formulation, physicochemical properties and in vitro drug release studies. J Colloid Interface Sci. 2017;507:323–36.

    Article  CAS  PubMed  Google Scholar 

  32. Cevher E, Sensoy D, Taha MAM, Araman A. Effect of thiolated polymers to textural and mucoadhesive properties of vaginal gel formulations prepared with polycarbophil and chitosan. AAPS PharmSciTech. 2008;9(3):953–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Singh S, Singh M, Tripathi CB, Arya M, Saraf SA. Development and evaluation of ultra-small nanostructured lipid carriers: novel topical delivery system for athlete’s foot. Drug Deliv Transl Res. 2016;6(1):38–47.

    Article  PubMed  Google Scholar 

  34. Das B, Nayak AK, Nanda U. Topical gels of lidocaine HCl using cashew gum and Carbopol 940: preparation and in vitro skin permeation. Int J Biol Macromol. 2013;62:514–7.

    Article  CAS  PubMed  Google Scholar 

  35. Pawar KR, Smith F, Kolli CS, Babu RJ. Effect of lipophilicity on microneedle-mediated iontophoretic transdermal delivery across human skin in vitro. J Pharm Sci. 2013;102(10):3784–91.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang S, Qiu Y, Gao Y. Enhanced delivery of hydrophilic peptides in vitro by transdermal microneedle pretreatment. Acta Pharmaceutica Sinica B. 2014;4(1):100–4.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Pawar K, Kolli CS, Rangari VK, Babu RJ. Transdermal iontophoretic delivery of lysine-proline-valine (KPV) peptide across microporated human skin. J Pharm Sci. 2017;106(7):1814–20.

    Article  CAS  PubMed  Google Scholar 

  38. Kelchen MN, Brogden NK. In vitro skin retention and drug permeation through intact and microneedle pretreated skin after application of propranolol loaded microemulsions. Pharm Res. 2018;35(12):1–12.

    Article  CAS  Google Scholar 

  39. Osborne DW, Musakhanian J. Skin penetration and permeation properties of Transcutol®—neat or diluted mixtures. AAPS PharmSciTech. 2018;19(8):3512–33.

    Article  CAS  PubMed  Google Scholar 

  40. Li X, Pan W, Ju C, Liu Z, Pan H, Zhang H, et al. Evaluation of Pharmasolve® corneal permeability enhancement and its irritation on rabbit eyes. Drug Deliv. 2009;16(4):224–9.

    Article  CAS  PubMed  Google Scholar 

  41. Heuschkel S, Goebel A, Neubert RHH. Microemulsions—modern colloidal carrier for dermal and transdermal drug delivery. J Pharm Sci. 2008;97(2):603–31.

    Article  CAS  PubMed  Google Scholar 

  42. Gujjar M, Banga AK. Vehicle influence on permeation through intact and compromised skin. Int J Pharm. 2014;472(1–2):362–8.

    Article  CAS  PubMed  Google Scholar 

  43. Guy RH, Hadgraft J. Physicochemical aspects of percutaneous penetration and its enhancement. Pharm Res. 1988;5(12):753–8.

    Article  CAS  PubMed  Google Scholar 

  44. Kim Y-C, Park J-H, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Del Rev. 2012;64(14):1547–68.

    Article  CAS  Google Scholar 

Download references

Acknowledgement

Authors acknowledge Auburn University Presidential Awards for Interdisciplinary Research (PAIR) grants for financial support for graduate students (M. Annaji and I Poudel).

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Author information

Authors and Affiliations

  1. Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama , 36849, USA

    Manjusha Annaji, Nur Mita, Shivani Rangari, Ishwor Poudel & R. Jayachandra Babu

  2. Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia

    Mohammed F. Aldawsari & Ahmed Alsaqr

  3. Department of Biosystems Engineering, Samuel Ginn College of Engineering, Auburn University, Auburn, Alabama, 36849, USA

    Oladiran Fasina

Authors
  1. Manjusha Annaji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nur Mita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shivani Rangari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammed F. Aldawsari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahmed Alsaqr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ishwor Poudel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Oladiran Fasina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Jayachandra Babu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, RJ Babu; Research methodology, M. Annaji, N Mita, S Rangari, MF Aldawsari, A Alsaqr, I Poudel, Formal analysis, M. Annaji, RJ Babu; Resources, RJ Babu, OO Fasina, Supervision, RJ Babu, OO Fasina, Writing—original draft, M. Annaji, RJ Babu; Writing—review and editing, M. Annaji, N. Mita, I Poudel, RJ Babu. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to R. Jayachandra Babu.

Ethics declarations

Conflict of Interest

The authors have no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Communicated by Jayachandra Babu Ramapuram and Ashana Puri.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 153 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Annaji, M., Mita, N., Rangari, S. et al. Enhanced Topical Co-delivery of Acyclovir and Lidocaine Gel Formulation Across Dermatomed Human Skin. AAPS PharmSciTech 23, 305 (2022). https://doi.org/10.1208/s12249-022-02458-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-022-02458-8

Keywords

Search

Navigation