Skip to main content

Advertisement

Log in

Delivery of Methotrexate and Characterization of Skin Treated by Fabricated PLGA Microneedles and Fractional Ablative Laser

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

Abstract

Purpose

This study investigated in vitro transdermal delivery of methotrexate through dermatomed porcine ear and cadaver human skin treated with poly (D,L-lactide-co-glycolide) acid microneedles or fractional ablative laser.

Methods

PLGA microneedles were fabricated and characterized using scanning electron microscopy and mechanical assessment techniques. The integrity of treated skin was evaluated by rheometer, transepidermal water loss, and skin electrical resistance measurements. Successful skin microporation was demonstrated by dye binding, histology, pore uniformity, confocal laser microscopy, and DermaScan studies. In vitro permeation experiment was performed on Franz diffusion cells to determine drug delivery into and across the skin.

Results

Both physical treatments resulted in a considerable decrease in skin resistance and an increase in transepidermal water loss value. The laser-created microchannels were significantly larger than those formed by microneedles (p < 0.05). An effective force of 41.04 ± 18.33 N was required to achieve 100% penetration efficiency of the microneedles. For both porcine ear and human skin, laser ablation provided a significantly higher methotrexate permeability into the receptor chamber and skin layers compared to microneedle poration and untreated skin (p < 0.05).

Conclusions

Both fractional ablative laser and polymeric microneedles markedly enhanced in vitro transdermal delivery of methotrexate into and across skin.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14

Similar content being viewed by others

Abbreviations

FTIR:

Fourier transform infrared spectrophotometer

MN:

Microneedles

MTX:

Methotrexate

PBS:

Phosphate buffered saline

PDMS:

Polydimethylsiloxane

PLGA:

Poly Lactic-co-Glycolic Acid

PPI:

Pore permeability index

RP-HPLC:

Reversed-phase high performance liquid chromatography

SD:

Standard deviation

SEM:

Scanning electron microscopy

TEWL:

Transepidermal water loss

References

  1. Abla MJ, Chaturvedula A, O’Mahony C, Banga AK. Transdermal delivery of methotrexate for pediatrics using silicon microneedles. Ther Deliv. 2013;4:543–51.

    Article  CAS  PubMed  Google Scholar 

  2. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26:1261–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Banga AK. Microporation applications for enhancing drug delivery. Expert Opin. Drug Deliv. 2009;6:343–54.

    Article  CAS  PubMed  Google Scholar 

  4. Haq MI, Smith E, John DN, Kalavala M, Edwards C, Anstey A, et al. Clinical administration of microneedles: skin puncture, pain and sensation. Biomed Microdevices. 2009;11:35–47.

    Article  CAS  PubMed  Google Scholar 

  5. Kalluri H, Banga AK. Microneedles and transdermal drug delivery. J Drug Delivery Sci Technol. 2009;19:303–10.

    Article  CAS  Google Scholar 

  6. Heinrich A, Vizhanyo A, Krammer P, Summer S, Gross S, Bragagna T, et al. Next generation Er:YAG fractional ablative laser. 2011 [cited 2016 Sep 22]. p. 78830M–78830M–6. Available from: doi:https://doi.org/10.1117/12.873522.

  7. Weiss R, Hessenberger M, Kitzmüller S, Bach D, Weinberger EE, Krautgartner WD, et al. Transcutaneous vaccination via laser microporation. J Control Release. 2012;162:391–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sklar LR, Burnett CT, Waibel JS, Moy RL, Ozog DM. Laser assisted drug delivery: a review of an evolving technology. Lasers Surg Med. 2014;46:249–62.

    Article  PubMed  Google Scholar 

  9. Hantash BM, Bedi VP, Kapadia B, Rahman Z, Jiang K, Tanner H, et al. In vivo histological evaluation of a novel ablative fractional resurfacing device. Lasers Surg Med. 2007;39:96–107.

    Article  PubMed  Google Scholar 

  10. Taudorf EH, Haak CS, Erlendsson AM, Philipsen PA, Anderson R, Paasch U, et al. Fractional ablative erbium YAG laser: histological characterization of relationships between laser settings and micropore dimensions. Lasers Surg Med. 2014;46:281–9.

    Article  PubMed  Google Scholar 

  11. Erlendsson AM, Taudorf EH, Eriksson AH, Haak CS, Zibert JR, Paasch U, et al. Ablative fractional laser alters biodistribution of ingenol mebutate in the skin. Arch Dermatol Res. 2015;307:515–22.

    Article  CAS  PubMed  Google Scholar 

  12. Taudorf EH, Lerche CM, Erlendsson AM, Philipsen PA, Hansen SH, Janfelt C, et al. Fractional laser-assisted drug delivery: laser channel depth influences biodistribution and skin deposition of methotrexate. Lasers Surg Med. 2016;48:519–29.

  13. Dadlani C, Orlow SJ. Treatment of children and adolescents with methotrexate, cyclosporine, and etanercept: review of the dermatologic and rheumatologic literature. J Am Acad Dermatol. 2005;52:316–40.

    Article  PubMed  Google Scholar 

  14. Patiño-García A, Zalacaín M, Marrodán L, San-Julián M, Sierrasesúmaga L. Methotrexate in pediatric osteosarcoma: response and toxicity in relation to genetic polymorphisms and dihydrofolate reductase and reduced folate carrier 1 expression. J Pediatr. 2009;154:688–93.

    Article  PubMed  Google Scholar 

  15. Vemulapalli V, Yang Y, Friden PM, Banga AK. Synergistic effect of iontophoresis and soluble microneedles for transdermal delivery of methotrexate. J Pharm Pharmacol. 2008;60:27–33.

    Article  CAS  PubMed  Google Scholar 

  16. Kelly A, Ramanan AV. The principles of pharmacological treatment of juvenile idiopathic arthritis. Paediatr Child Health. 2011;21:563–8.

    Article  Google Scholar 

  17. Van Outryve S, Schrijvers D, Van Den Brande J, Wilmes P, Bogers J, Van Marck E, et al. Methotrexate-associated liver toxicity in a patient with breast cancer: case report and literature review. Neth J Med. 2002;60:216–22.

    PubMed  Google Scholar 

  18. Vagace JM, de la Maya MD, Caceres-Marzal C, de Murillo SG, Gervasini G. Central nervous system chemotoxicity during treatment of pediatric acute lymphoblastic leukemia/lymphoma. Crit Rev Oncol Hematol. 2012;84:274–86.

    Article  PubMed  Google Scholar 

  19. Fang J-Y, Liu P-F, Huang C-M. Decreasing systemic toxicity via transdermal delivery of anticancer drugs. Curr Drug Metab. 2008;9:592–7.

    Article  CAS  PubMed  Google Scholar 

  20. Alvarez-Figueroa MJ, Blanco-Mendez J. Transdermal delivery of methotrexate: iontophoretic delivery from hydrogels and passive delivery from microemulsions. Int J Pharm. 2001;215:57–65.

    Article  CAS  PubMed  Google Scholar 

  21. Sutton L, Swinehart JM, Cato A, Kaplan AS. A clinical study to determine the efficacy and safety of 1% methotrexate/Azone®(MAZ) gel applied topically once daily in patients with psoriasis vulgaris. Int J Dermatol. 2001;40:464–7.

    Article  CAS  PubMed  Google Scholar 

  22. Ali MFM, Salah M, Rafea M, Saleh N. Liposomal methotrexate hydrogel for treatment of localized psoriasis: preparation, characterization and laser targeting. Med Sci Monit. 2008;14:PI66–74.

    PubMed  Google Scholar 

  23. Prasad R, Anand S, Koul V. Biophysical assessment of DC iontophoresis and current density on transdermal permeation of methotrexate. Int J Pharm Investig. 2011;1:234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee W-R, Shen S-C, Fang C-L, Zhuo R-Z, Fang J-Y. Topical delivery of methotrexate via skin pretreated with physical enhancement techniques: low-fluence erbium: YAG laser and electroporation. Lasers Surg Med. 2008;40:468–76.

    Article  PubMed  Google Scholar 

  25. Wong T-W, Zhao Y-L, Sen A, Hui SW. Pilot study of topical delivery of methotrexate by electroporation. Br J Dermatol. 2005;152:524–30.

    Article  CAS  PubMed  Google Scholar 

  26. Stewart WD, Wallace SM, Runikis JO. Absorption and local action of methotrexate in human and mouse skin. Arch Dermatol. 1972;106:357–61.

    Article  CAS  PubMed  Google Scholar 

  27. Taudorf EH, Lerche CM, Vissing A-C, Philipsen PA, Hannibal J, D’Alvise J, et al. Topically applied methotrexate is rapidly delivered into skin by fractional laser ablation. Expert Opin Drug Deliv. 2015;12:1059–69.

    Article  CAS  PubMed  Google Scholar 

  28. Park J-H, Allen MG, Prausnitz MR. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J Control Release. 2005;104:51–66.

    Article  CAS  PubMed  Google Scholar 

  29. Nguyen HX, Banga AK. Enhanced skin delivery of vismodegib by microneedle treatment. Drug Deliv Transl Res. 2015;5:407–23.

    Article  CAS  PubMed  Google Scholar 

  30. Nguyen HX, Banga AK. Fabrication, characterization and application of sugar microneedles for transdermal drug delivery. Ther Deliv. 2017;8:249–64.

    Article  CAS  PubMed  Google Scholar 

  31. Donnelly RF, McCrudden MT, Alkilani AZ, Larrañeta E, McAlister E, Courtenay AJ, et al. Hydrogel-forming microneedles prepared from “super swelling” polymers combined with lyophilised wafers for transdermal drug delivery. PLoS One. 2014;9:e111547.

    Article  PubMed  PubMed Central  Google Scholar 

  32. McCrudden MTC, Alkilani AZ, McCrudden CM, McAlister E, McCarthy HO, Woolfson AD, et al. Design and physicochemical characterisation of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs. J Control Release. 2014;180:71–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kalluri H, Kolli CS, Banga AK. Characterization of microchannels created by metal microneedles: formation and closure. AAPS J. 2011;13:473–81.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kolli CS, Banga AK. Characterization of solid maltose microneedles and their use for transdermal delivery. Pharm Res. 2008;25:104–13.

    Article  CAS  PubMed  Google Scholar 

  35. Kalluri H, Banga AK. Formation and closure of microchannels in skin following microporation. Pharm Res. 2011;28:82–94.

    Article  CAS  PubMed  Google Scholar 

  36. Davis SP, Landis BJ, Adams ZH, Allen MG, Prausnitz MR. Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force. J Biomech. 2004;37:1155–63.

    Article  PubMed  Google Scholar 

  37. Hasanovic A, Winkler R, Resch GP, Valenta C. Modification of the conformational skin structure by treatment with liposomal formulations and its correlation to the penetration depth of aciclovir. Eur J Pharm Biopharm Off J Arbeitsgemeinschaft Für Pharm Verfahrenstechnik EV. 2011;79:76–81.

    CAS  Google Scholar 

  38. Sviridov AP, Zimnyakov DA, Sinichkin YP, Butvina LN, Omelchenko AJ, Shakh GS, et al. Attenuated total reflection Fourier transform infrared and polarization spectroscopy of in vivo human skin ablated, layer by layer, by erbium:YAG laser. J Biomed Opt. 2004;9:820–7.

    Article  CAS  PubMed  Google Scholar 

  39. Larrañeta E, Moore J, Vicente-Pérez EM, González-Vázquez P, Lutton R, Woolfson AD, et al. A proposed model membrane and test method for microneedle insertion studies. Int J Pharm. 2014;472:65–73.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Enfield J, O’Connell M-L, Lawlor K, Jonathan E, O’Mahony C, Leahy M. In-vivo dynamic characterization of microneedle skin penetration using optical coherence tomography. J Biomed Opt. 2010;15:46001.

    Article  Google Scholar 

Download references

Acknowledgments and Disclosures

The authors would like to thank Michelle Vu, College of Pharmacy, Mercer University for her contribution in proof-reading the manuscript. The authors do not have any conflicts of interest to report for this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ajay K. Banga.

Electronic supplementary material

ESM 1

(DOCX 2764 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nguyen, H.X., Banga, A.K. Delivery of Methotrexate and Characterization of Skin Treated by Fabricated PLGA Microneedles and Fractional Ablative Laser. Pharm Res 35, 68 (2018). https://doi.org/10.1007/s11095-018-2369-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-018-2369-6

Key Words

Navigation