Skip to main content

Advertisement

SpringerLink
Log in

Size-Dependent Absorption through Stratum Corneum by Drug-Loaded Liposomes

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Topical treatment of various skin disorders requires drug absorption and penetration through the stratum corneum (SC) into the epidermis and dermis tissues. The use of nano-drug delivery systems including liposomes and lipid nanoparticles (SLNs) have been shown to facilitate SC penetration. The goal of this work was to study the impact of liposome sizes and the resulted drug distribution inside various skin tissue.

Methods

All trans retinoic acid (ATRA) was used as the model drug and loaded into gel phase HSPC/CHOL/DSPE-PEG liposomes (lipo-ATRA) with sizes ranging from 80 nm to more than 300 nm. The percutaneous drug absorption process was monitored and analyzed.

Results

There were significant differences in percutaneous absorption and tissue distribution resulted from liposomes smaller than 100 nm and those bigger than 200 nm. Lipo-ATRA with a mean diameter of 83 nm can deliver the content to epidermis and dermis. But for 200 nm - 300 nm liposomes, the resulted epidermis and dermis ATRA levels were less than about one third, suggesting bigger liposomes had poor penetration through the brick and mortar structure of SC.

Conclusions

Gel phase liposomes with sizes under 100 nm improved encapsulated drug absorption and distribution into the epidermis and dermis tissues. A size dependent mechanism for liposome penetration of the stratum corneum was proposed.

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

Similar content being viewed by others

Abbreviations

ATRA:

All trans retinoic acid

GNP:

Gold nanoparticles

HPLC:

High performance liquid chromatography

ICP-OES:

Inductively coupled plasma emission spectrometer

SC:

Stratum corneum

TEM:

Transmission electron microscope

References

  1. Fantini A, Demurtas A, Nicoli S, Padula C, Pescina S, Santi P. In vitro skin retention of Crisaborole after topical application. Pharmaceutics. 2020;12(6):491–502.

    Article  CAS  Google Scholar 

  2. Zorec B, Pavselj N. Active enhancement methods for intra- and transdermal drug delivery: a review. Zdravniki Vestnik. 2013;82(5):339–56.

    Google Scholar 

  3. Lane ME. Skin penetration enhancers. Int J Pharm. 2013;447(1–2):12–21.

    Article  CAS  Google Scholar 

  4. Zoabi A, Touitou E, Margulis K. Recent Advances in Nanomaterials for Dermal and Transdermal Applications. Colloids Interfaces, 2021.

  5. Sala M, Diab R, Elaissari A, Fessi H. Lipid nanocarriers as skin drug delivery systems: properties, mechanisms of skin interactions and medical applications. ScienceDirect International Journal of Pharmaceutics. 2018;535(1–2):1–17.

    CAS  Google Scholar 

  6. Prow TW, Grice JE, Lin LL, Faye R, Roberts MS. Nanoparticles and microparticles for skin drug delivery. J Adv Drug Deliv Rev. 2011;63(6):470–91.

    Article  CAS  Google Scholar 

  7. Hua S. Lipid-based nano-delivery systems for skin delivery of drugs and bioactives. Front Pharmacol. 2015;6.

  8. Verma DD, Verma S, Blume G, Fahr A. Particle size of liposomes influences dermal delivery of substances into skin. Int J Pharm. 2003;258(1–2):141–51.

    Article  CAS  Google Scholar 

  9. Sentjurc M, Vrhovnik K, Kristl J. Liposomes as a topical delivery system: the role of size on transport studied by the EPR imaging method. Journal of Controlled Release Official Journal of the Controlled Release Society. 1999;59(1):87–97.

    Article  CAS  Google Scholar 

  10. Peralta MF, Guzmán ML, Pérez AP, Apezteguia GA, Fórmica ML, Romero EL, et al. Liposomes can both enhance or reduce drugs penetration through the skin entific. Reports. 2018;8(1):13253–64.

    Google Scholar 

  11. Mbah CC, Builders PF, Attama AA. Nanovesicular carriers as alternative drug delivery systems: ethosomes in focus. Expert Opinion on Drug Delivery. 2014;11(1):45–59.

    Article  CAS  Google Scholar 

  12. Abd El-Alim SH, Kassem AA, Basha M, Salama A. Comparative study of liposomes, ethosomes and transfersomes as carriers for enhancing the transdermal delivery of diflunisal: in vitro and in vivo evaluation. Int J Pharm. 2019;563:293–303.

    Article  CAS  Google Scholar 

  13. Clares B, Calpena AC, Parra A, Abrego G, Alvarado H, Fangueiro JF, et al. Nanoemulsions (NEs), liposomes (LPs) and solid lipid nanoparticles (SLNs) for retinyl palmitate: effect on skin permeation. Int J Pharm. 2014;473(1–2):591–8.

    Article  CAS  Google Scholar 

  14. El-Menshawe SF, Hussein AK. Formulation and evaluation of meloxicam niosomes as vesicular carriers for enhanced skin delivery. Pharm Dev Technol. 2011;18(4):779–86.

    Article  Google Scholar 

  15. Song YK, Hyun SY, Kim HT, KimC K, Oh JM. Transdermal delivery of low molecular weight heparin loaded in flexible liposomes with bioavailability enhancement: comparison with ethosomes. J Microencapsul. 2011;28(3):151–8.

    Article  CAS  Google Scholar 

  16. Trivedi R, Umekar M, Kotagale N, Bonde S, Taksande J. Design, Evaluation and in vivo Pharmacokinetic Study of a Cationic Flexible Liposomes for Enhanced Transdermal Delivery of Pramipexole. Journal of Drug Delivery Science and Technology. 2020;61:102313.

  17. Zeb A, Arif ST, Malik M, Shah FA, Din FU, Qureshi OS, et al. Potential of nanoparticulate carriers for improved drug delivery via skin. Journal of Pharmaceutical Investigation. 2018;49:485–517.

    Article  Google Scholar 

  18. Hubbard BA, Unger JG, Rohrich RJ. Reversal of Skin Aging with Topical Retinoids. Plastic and Reconstructive Surgery. 2014;133(4):481e.

    Article  CAS  Google Scholar 

  19. Mukherjee S, Date A, Patravale V, Korting HC, Weindl G. Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clin Interv Aging. 2006;1(4):327–48.

    Article  CAS  Google Scholar 

  20. Szymański U, Skopek R, Palusińska M, Schenk T, Zelent A. Retinoic acid and its derivatives in skin. Cells. 2020;9(12):2660.

    Article  Google Scholar 

  21. Yamaguchi Y, Nagasawa T, Nakamura N, Takenaga M, Igarashi R. Successful treatment of photo-damaged skin of nano-scale atRA particles using a novel transdermal delivery. Control Release. 2005;104(1):29–40.

    Article  CAS  Google Scholar 

  22. Grabar KC, Freeman RG, Hommer MB, Natan MG. Preparation and characterization of au colloid monolayers. Anal Chem. 1995;67(4):735–43.

    Article  CAS  Google Scholar 

  23. Heba S, Ahmed SM, Omar MM. Liposomal flucytosine capped with gold nanoparticle formulations for improved ocular delivery. Drug Design, Development and Therapy. 2016;10:277–95.

    Google Scholar 

  24. Tsai MJ, Hu YB, Fang JW, Fu YS, Wu PC. Preparation and characterization of Naringenin-loaded elastic liposomes for topical application. PLoS One. 2015;10(7):e0131026.

    Article  Google Scholar 

  25. Trommer H, Neubert R. Overcoming the Stratum Corneum: The Modulation of Skin Penetration. Skin Pharmacology & Physiology. 2006;19(2):106–21.

    Article  CAS  Google Scholar 

  26. Essendoubi M, Gobinet C, Reynaud R, Angiboust JF, Manfait M, Piot O. Human skin penetration of hyaluronic acid of different molecular weights as probed by Raman spectroscopy. Skin Res Technol. 2016;22(1):55–62.

    Article  CAS  Google Scholar 

  27. Kojima C, Hirano Y, Yuba E, Harada A, Kono K. Preparation and characterization of complexes of liposomes with gold nanoparticles. Colloids Surf B Biointerfaces. 2008;66(2):246–52.

    Article  CAS  Google Scholar 

  28. Labouta HI, Liu DC, Lin LL, Butler MK, Grice JE, Raphael AP, et al. Gold nanoparticle penetration and reduced metabolism in human skin by toluene. Pharm Res. 2011;28(11):2931–44.

    Article  CAS  Google Scholar 

  29. Sonavane G, Tomoda K, Sano A, Ohshima H, Terada H, Makino K. In vitro permeation of gold nanoparticles through rat skin and rat intestine: effect of particle size. Colloids Surf B: Biointerfaces. 2008;65(1):1–10.

    Article  CAS  Google Scholar 

  30. Mathes SH, Ruffner H, Graf-Hausner U. The use of skin models in drug development. Adv Drug Deliv Rev. 2014;(69-70):81–102.

  31. Ángeles GH, Brandejsová M, Štěpán P, Pavlík V, Starigazdová J, Orzol P, et al. Retinoic acid grafted to hyaluronan for skin delivery: synthesis, stability studies, and biological evaluation. Carbohydr Polym. 2020;231:115733.

    Article  Google Scholar 

  32. Oliveira DD, Andrade DFD, Oliveira EGD, Beck RCR. Liquid chromatography method to assay tretinoin in skin layers: validation and application in skin penetration/retention studies. Heliyon. 2020;6(1):e03098.

    Article  Google Scholar 

  33. Kitagawa S, Kasamaki M. Enhanced delivery of retinoic acid to skin by cationic liposomes. Chemical & pharmaceutical bulletin. 2006;54(2):242–4.

    Article  CAS  Google Scholar 

  34. Rahman SA, Abdelmalak NS, Badawi A, Elbayoumy T, Sabry N, Ramly AE. Tretinoin-loaded liposomal formulations: from lab to comparative clinical study in acne patients. J Drug Delivery. 2015:1–10.

  35. Chandrashekhar BC, Anitha M, Ruparelia M, Vaidya P, Sanmukhani J. Tretinoin Nanogel 0.025% Versus Conventional Gel 0.025% in Patients with Acne Vulgaris: A Randomized, Active Controlled, Multicentre, Parallel Group, Phase IV Clinical Trial. Journal of Clinical and Diagnostic Research. 2015.

Download references

Acknowledgments and Disclosures

Jun-ye Liu contributed to the design and implementation of the experiments. He also participated in the writing of the manuscript. This study was supported by the National Natural Science Foundation of China. No. 81690262 and funding from the Yunnan Province Sci & Tech Department. An-jie Zheng contributed to the data analysis of experiments and participated in the manuscript writing. Baowei Peng helped with the experiments and analyzed the data. Yuhong Xu contributed to the design and analysis of the experiments and manuscript writing. Ning Zhang contributed to the design and analysis of the experiments and manuscript writing. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. The authors report no conflicts of interest in this work.

Author information

Author notes

  1. Jun-ye Liu and An-jie Zheng contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Dali University, Bai Autonomous Prefecture, Dali, China

    Junye Liu, Baowei Peng & Yuhong Xu

  2. School of Pharmacy, Shanghai Jiaotong University, Shanghai, China

    Anjie Zheng

  3. Center for drug evaluation, NMPA, Beijing, China

    Ning Zhang

Authors
  1. Junye Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anjie Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baowei Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuhong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ning Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yuhong Xu or Ning Zhang.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, J., Zheng, A., Peng, B. et al. Size-Dependent Absorption through Stratum Corneum by Drug-Loaded Liposomes. Pharm Res 38, 1429–1437 (2021). https://doi.org/10.1007/s11095-021-03079-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-021-03079-9

Key Words

Search

Navigation