Skip to main content

Advertisement

SpringerLink
Log in

Examination of the Rate and Extent of Drug Released from Commercial Topical Delivery Systems During Wear: An Example with Lidocaine Topical Systems

  • Original Research Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Objective

This study aimed to determine the extent and rate of lidocaine released in vivo from two bioequivalent topical delivery systems (TDS) by using complementary assessments: pharmacokinetic analysis in healthy human volunteers, and residual lidocaine in TDS following 12 h of wear. The goal was to explore a potentially more clinically meaningful strength presentation than percent active pharmaceutical ingredient loaded in topical systems.

Methods

A three-arm, open-label, crossover clinical study was conducted in 23 human subjects, with 5% lidocaine topical systems from two manufacturers, and intravenous lidocaine administration. Residual drug and LC–MS/MS analyses were performed on worn TDS and serum samples. The rate and extent of drug released from the TDS during wear were determined through (1) calculations of consumed lidocaine via analysis of residual drug in worn TDS, and (2) a pharmacokinetic approach via derivation of the absolute clearance and serum lidocaine concentration at steady state.

Results

Overall the pharmacokinetic approach underestimated the amount transferred to the subject and exhibited greater variability, which may relate to natural inter-subject variability in pharmacokinetic parameters. Further, lidocaine TDS are intended for localized, not systemic, delivery and this may also explain some of the variability seen in the systemic serum concentrations.

Conclusions

The residual drug and pharmacokinetic approaches align well for transdermal formulations, but the differences in administration route (topical versus transdermal) all but eliminates the potential use of the pharmacokinetic approach unless additional compartmental modeling is explored.

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

Similar content being viewed by others

Abbreviations

AIC:

Akaike information criteria

API:

Active pharmaceutical ingredient

AUC:

Area under the concentration–time curve

CL:

Absolute clearance

Cmax :

Maximum serum concentration

Css :

Concentration at steady state

Cp:

Serum drug concentration

IV:

Intravenous

Kel :

Elimination rate constant

LC–MS/MS:

Liquid chromatography-tandem mass spectrometry

LLE:

Liquid liquid extraction

NCA:

Non-compartmental analysis

PK:

Pharmacokinetic

RSD:

Relative standard deviation

SBC:

Schwarz Bayesian criteria

SD:

Standard deviation

SE:

Standard error

TDS:

Topical delivery system

T max :

Time of maximum serum concentration

T1/2 :

Elimination half-life

UPLC:

Ultra-performance liquid chromatography

Vss :

Volume of distribution

WSSR:

Weighted sum square residuals

References

  1. Transdermal and topical delivery systems - product development and quality considerations. Draft guidance for industry. 2019:1–25. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/transdermal-and-topical-deliverysystems-product-development-and-quality-considerations. Accessed 9 Oct 2023.

  2. Swaminathan SK, Strasinger C, Kelchen M, Carr J, Ye W, Wokovich A, et al. Determination of Rate and Extent of Scopolamine Release from Transderm Scōp® Transdermal Drug Delivery Systems in Healthy Human Adults. AAPS PharmSciTech. 2020;21(3):117.

    Article  CAS  PubMed  Google Scholar 

  3. Lidoderm® package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020612s012lbl.pdf. Accessed 21 Aug 2023.

  4. ZTLIDO package insert. https://www.ztlido.com/wp-content/uploads/2022/12/ZTlido-LABEL.pdf. Accessed 21 Aug 2023.

  5. Lidocaine patch 5% package insert. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5c66f3b9-6e04-47ab-8d94-21e89ceec154. Accessed 21 Aug 2023.

  6. Farage MA, Maibach HI, Andersen KE, Lachapelle JM, Kern P, Ryan C, et al. Historical perspective on the use of visual grading scales in evaluating skin irritation and sensitization. Contact Dermatitis. 2011;65(2):65–75.

    Article  PubMed  Google Scholar 

  7. Kondamudi PK, Tirumalasetty PP, Malayandi R, Mutalik S, Pillai R. Lidocaine Transdermal Patch: Pharmacokinetic Modeling and In Vitro-In Vivo Correlation (IVIVC). AAPS PharmSciTech. 2016;17(3):588–96.

    Article  CAS  PubMed  Google Scholar 

  8. Bhatt JA, Wei H, Azarpanah A, Morris KR, Cai Q. Quantitative chromatographic method development for residual lidocaine in topical systems and biological samples. Bioanalysis. 2023;15(10):553–66.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang Y, Huo M, Zhou J, Xie S. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed. 2010;99(3):306–14.

    Article  PubMed  Google Scholar 

  10. Sani SN, Siwale RC. Multicompartment Models: Intravenous Bolus Administration. In: Shargel L, Yu ABC, editors. Applied Biopharmaceutics & Pharmacokinetics, 7e. New York, NY: McGraw-Hill Education; 2016.

  11. Shin SH, Thomas S, Raney SG, Ghosh P, Hammell DC, El-Kamary SS, et al. In vitro-in vivo correlations for nicotine transdermal delivery systems evaluated by both in vitro skin permeation (IVPT) and in vivo serum pharmacokinetics under the influence of transient heat application. J Control Release. 2018;270:76–88.

    Article  CAS  PubMed  Google Scholar 

  12. Draft Guidance on Lidocaine. Nov 2022. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_207962.pdf. Accessed 19 Sep 2023.

  13. Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA Guidance for Industry. Aug 2021. https://www.fda.gov/media/87219/download. Accessed 19 Sep 2023.

  14. Larsen RH, Nielsen F, Sorensen JA, Nielsen JB. Dermal penetration of fentanyl: inter- and intraindividual variations. Pharmacol Toxicol. 2003;93(5):244–8.

    Article  CAS  PubMed  Google Scholar 

  15. Singh I, Morris AP. Performance of transdermal therapeutic systems: Effects of biological factors. Int J Pharm Investig. 2011;1(1):4–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shin SH, Yu M, Hammell DC, Ghosh P, Raney SG, Hassan HE, et al. Evaluation of in vitro/in vivo correlations for three fentanyl transdermal delivery systems using in vitro skin permeation testing and human pharmacokinetic studies under the influence of transient heat application. J Control Release. 2022;342:134–47.

    Article  CAS  PubMed  Google Scholar 

  17. Cilurzo F, Gennari CG, Minghetti P. Adhesive properties: a critical issue in transdermal patch development. Expert Opin Drug Deliv. 2012;9(1):33–45.

    Article  CAS  PubMed  Google Scholar 

  18. Durand C, Alhammad A, Willett KC. Practical considerations for optimal transdermal drug delivery. Am J Health-Syst Pharm. 2012;69:116–24.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This project was funded by the following grants: National Institute for Pharmaceutical Technology and Education U01 Critical Patch Manufacturing Sector Research Initiative (5U01FD004275), and NIH/NCATS CTSA U54R001356.

Author information

Authors and Affiliations

  1. Lachman Institute for Pharmaceutical Analysis, Long Island University, Brooklyn, NY, USA

    Qing Cai, Armita Azarpanah, Jayshil A. Bhatt, Hui Wei & Kenneth R. Morris

  2. Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA

    Qing Cai, Armita Azarpanah, Jayshil A. Bhatt, Hui Wei & Kenneth R. Morris

  3. Samuel J. and Joan B. Williamson Institute for Pharmacometrics, Long Island University, Brooklyn, NY, USA

    Armita Azarpanah

  4. Institute for Clinical and Translational Sciences, University of Iowa, Hospitals and Clinics, Iowa City, IA, USA

    Jamie Carr

  5. United States Food and Drug Administration, CDER, Office of Pharmaceutical Quality, Silver Spring, MD, USA

    Caroline Strasinger

  6. Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa College of Pharmacy, 180 South Grand Avenue, 552 CPB, Iowa City, IA, 52242-1112, USA

    Nicole K. Brogden

  7. Department of Dermatology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA

    Nicole K. Brogden

Authors
  1. Qing Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Armita Azarpanah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jayshil A. Bhatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jamie Carr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenneth R. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Caroline Strasinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nicole K. Brogden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicole K. Brogden.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Disclaimer

Views expressed in this manuscript do not necessarily reflect official policies of the United States Food and Drug Administration; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.

Additional information

Publisher's Note

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

Qing Cai and Armita Azarpanah are Co-first author.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 25 KB)

Supplementary file2 (DOCX 25 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

Cai, Q., Azarpanah, A., Bhatt, J.A. et al. Examination of the Rate and Extent of Drug Released from Commercial Topical Delivery Systems During Wear: An Example with Lidocaine Topical Systems. Pharm Res 41, 39–50 (2024). https://doi.org/10.1007/s11095-023-03617-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-023-03617-7

Keywords

Search

Navigation