Microneedle-Mediated Permeation Enhancement of Chlorhexidine Digluconate: Mechanistic Insights Through Imaging Mass Spectrometry

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2022 Jun 10

PMID 35689005

Authors

Melissa Kirkby

Akmal Bin Sabri

David Scurr

Gary Moss

Affiliations

Soon will be listed here.

Abstract

Purpose: Chlorhexidine digluconate (CHG) is a first-line antiseptic agent typically applied to the skin as a topical solution prior to surgery due to its efficacy and safety profile. However, the physiochemical properties of CHG limits its cutaneous permeation, preventing it from reaching potentially pathogenic bacteria residing within deeper skin layers. Thus, the utility of a solid oscillating microneedle system, Dermapen®, and a CHG-hydroxyethylcellulose (HEC) gel were investigated to improve the intradermal delivery of CHG.

Methods: Permeation of CHG from the commercial product, Hibiscrub®, and HEC-CHG gels (containing 1% or 4% CHG w/w) was assessed in intact skin, or skin that had been pre-treated with microneedles of different array numbers, using an Franz diffusion cells and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS).

Results: Gels containing 1% and 4% CHG resulted in significantly increased depth permeation of CHG compared to Hibiscrub® (4% w/v CHG) when applied to microneedle pre-treated skin, with the effect being more significant with the higher array number. ToF-SIMS analysis indicated that the depth of dermal penetration achieved was sufficient to reach the skin strata that typically harbours pathogenic bacteria, which is currently inaccessible by Hibiscrub®, and showed potential lateral diffusion within the viable epidermis.

Conclusions: This study indicates that HEC-CHG gels applied to microneedle pre-treated skin may be a viable strategy to improve the permeation CHG into the skin. Such enhanced intradermal delivery may be of significant clinical utility for improved skin antisepsis in those at risk of a skin or soft tissue infection following surgical intervention.

Citing Articles

Using Oscillation to Improve the Insertion Depth and Consistency of Hollow Microneedles for Transdermal Insulin Delivery with Mechanistic Insights.

Smith F, Kotowska A, Fiedler B, Cerny E, Cheung K, Rutland C Mol Pharm. 2024; 22(1):316-329.

PMID: 39625848 PMC: 11707737. DOI: 10.1021/acs.molpharmaceut.4c00942.

Regulatory Standard for Determining Preoperative Skin Preparation Efficacy Underreports True Dermal Bioburden in a Porcine Model.

Duffy H, Ashton N, Blair A, Hooper N, Stulce P, Williams D Microorganisms. 2024; 12(11).

PMID: 39597757 PMC: 11596398. DOI: 10.3390/microorganisms12112369.

Visualizing the transdermal delivery of berberine loaded within chitosan microneedles using mass spectrometry imaging.

Cui X, Geng H, Guo H, Wang L, Zhu Z, Zhang Y Anal Bioanal Chem. 2024; 416(29):6869-6877.

PMID: 39400576 DOI: 10.1007/s00216-024-05584-3.

References

Karpanen T, Worthington T, Conway B, Hilton A, Elliott T, Lambert P . Penetration of chlorhexidine into human skin. Antimicrob Agents Chemother. 2008; 52(10):3633-6. PMC: 2565868. DOI: 10.1128/AAC.00637-08. View

Farkas E, Kiss D, Zelko R . Study on the release of chlorhexidine base and salts from different liquid crystalline structures. Int J Pharm. 2007; 340(1-2):71-5. DOI: 10.1016/j.ijpharm.2007.03.038. View

HUGO W, LONGWORTH A . SOME ASPECTS OF THE MODE OF ACTION OF CHLORHEXIDINE. J Pharm Pharmacol. 1964; 16:655-62. DOI: 10.1111/j.2042-7158.1964.tb07384.x. View

Owens C, Stoessel K . Surgical site infections: epidemiology, microbiology and prevention. J Hosp Infect. 2008; 70 Suppl 2:3-10. DOI: 10.1016/S0195-6701(08)60017-1. View

Touitou E, Meidan V, Horwitz E . Methods for quantitative determination of drug localized in the skin. J Control Release. 1998; 56(1-3):7-21. DOI: 10.1016/s0168-3659(98)00060-1. View

Kirkby M, Sabri A, Scurr D, Moss G . Dendrimer-mediated permeation enhancement of chlorhexidine digluconate: Determination of in vitro skin permeability and visualisation of dermal distribution. Eur J Pharm Biopharm. 2020; 159:77-87. DOI: 10.1016/j.ejpb.2020.12.014. View

Kim Y, Park J, Prausnitz M . Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev. 2012; 64(14):1547-68. PMC: 3419303. DOI: 10.1016/j.addr.2012.04.005. View

Permana A, Paredes A, Volpe-Zanutto F, Anjani Q, Utomo E, Donnelly R . Dissolving microneedle-mediated dermal delivery of itraconazole nanocrystals for improved treatment of cutaneous candidiasis. Eur J Pharm Biopharm. 2020; 154:50-61. DOI: 10.1016/j.ejpb.2020.06.025. View

Peng K, Vora L, Tekko I, Permana A, Dominguez-Robles J, Ramadon D . Dissolving microneedle patches loaded with amphotericin B microparticles for localised and sustained intradermal delivery: Potential for enhanced treatment of cutaneous fungal infections. J Control Release. 2021; 339:361-380. DOI: 10.1016/j.jconrel.2021.10.001. View

10.

Sabri A, Anjani Q, Utomo E, Ripolin A, Donnelly R . Development and characterization of a dry reservoir-hydrogel-forming microneedles composite for minimally invasive delivery of cefazolin. Int J Pharm. 2022; 617:121593. DOI: 10.1016/j.ijpharm.2022.121593. View

11.

Starr N, Hamid K, Wibawa J, Marlow I, Bell M, Perez-Garcia L . Enhanced vitamin C skin permeation from supramolecular hydrogels, illustrated using in situ ToF-SIMS 3D chemical profiling. Int J Pharm. 2019; 563:21-29. DOI: 10.1016/j.ijpharm.2019.03.028. View

12.

Sabri A, Cater Z, Gurnani P, Ogilvie J, Segal J, Scurr D . Intradermal delivery of imiquimod using polymeric microneedles for basal cell carcinoma. Int J Pharm. 2020; 589:119808. DOI: 10.1016/j.ijpharm.2020.119808. View

14.

Kezutyte T, Desbenoit N, Brunelle A, Briedis V . Studying the penetration of fatty acids into human skin by ex vivo TOF-SIMS imaging. Biointerphases. 2014; 8(1):3. DOI: 10.1186/1559-4106-8-3. View

15.

Sjovall P, Greve T, Clausen S, Moller K, Eirefelt S, Johansson B . Imaging of distribution of topically applied drug molecules in mouse skin by combination of time-of-flight secondary ion mass spectrometry and scanning electron microscopy. Anal Chem. 2014; 86(7):3443-52. DOI: 10.1021/ac403924w. View

17.

Lu C, Wucher A, Winograd N . Molecular depth profiling of buried lipid bilayers using C(60)-secondary ion mass spectrometry. Anal Chem. 2010; 83(1):351-8. PMC: 3075603. DOI: 10.1021/ac102525v. View

18.

Bich C, Touboul D, Brunelle A . Cluster TOF-SIMS imaging as a tool for micrometric histology of lipids in tissue. Mass Spectrom Rev. 2013; 33(6):442-51. DOI: 10.1002/mas.21399. View

19.

Nygren H, Malmberg P, Kriegeskotte C, Arlinghaus H . Bioimaging TOF-SIMS: localization of cholesterol in rat kidney sections. FEBS Lett. 2004; 566(1-3):291-3. DOI: 10.1016/j.febslet.2004.04.052. View

21.

Lazar A, Bich C, Panchal M, Desbenoit N, Petit V, Touboul D . Time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging reveals cholesterol overload in the cerebral cortex of Alzheimer disease patients. Acta Neuropathol. 2012; 125(1):133-44. DOI: 10.1007/s00401-012-1041-1. View

22.

Larraneta E, Moore J, Vicente-Perez E, Gonzalez-Vazquez P, Lutton R, Woolfson A . A proposed model membrane and test method for microneedle insertion studies. Int J Pharm. 2014; 472(1-2):65-73. PMC: 4111867. DOI: 10.1016/j.ijpharm.2014.05.042. View

23.

Jacobi U, Kaiser M, Toll R, Mangelsdorf S, Audring H, Otberg N . Porcine ear skin: an in vitro model for human skin. Skin Res Technol. 2007; 13(1):19-24. DOI: 10.1111/j.1600-0846.2006.00179.x. View