Short communicationFollowing-up skin penetration of lidocaine from different vehicles by Raman spectroscopic mapping
Introduction
Dermal drug delivery systems are getting increasingly more attention these days because their application is beneficial in many conditions. Dermal application is advantageous due to a decrease in potential adverse reactions and the avoidance of first pass metabolism. However, the skin penetration of drugs is a really complex process because many factors have an impact on it, e.g. the physicochemical properties of the API, the carrier system, occlusion, concentration, dosage regimen, skin site on the body, etc. [1]. Furthermore, the stratum corneum (SC), which is the outermost layer of the skin, is almost impermeable and it provides a rate-limiting step in the penetration process [2]. The exact knowledge of drug distribution in the skin would be indispensable for the optimization of dermal formulations by revealing their penetration pathways. Widely used techniques for following-up drug penetration, such as diffusion cells and tape-stripping method, are destructive, labor intense, lacking accuracy and have many issues with establishing adequate experimental conditions [[3], [4], [5]].
Spectroscopic methods can provide molecular information about the structure of skin specimens. Raman spectroscopy is an upcoming spectroscopic technique based on detecting the characteristic vibrational energy levels of a molecule irradiated by laser beam and it provides information about the molecular structure of tissue components without the use of fluorescent labels or chemical stains [[6], [7], [8], [9], [10]]. Therefore, this technique is suitable for detecting changes in the structure of skin components and also for following-up the penetration of exogenous materials [8]. In recent times, Raman microscopy has evolved as an important technique to better understand skin structure and percutaneous drug delivery [4,8,11,12].
In this work, we aimed to track the penetration of lidocaine (LID) from different carrier systems in human skin. We used Raman microscopy to obtain images of the spatial distribution of the drug in ex vivo human skin. Lidocaine is a local anesthectic agent used in pharmacological pain control and management. The site of action for LID is the dermis, which contains the free nerve endings responsible for pain sensation [2]. However, the topical application of this drug is not as effective as administration by subcutaneous injection because its penetration into the dermal layers is limited owing to the barrier function of SC. Using a vehicle which maximizes drug delivery into the skin seems to be a good strategy for optimizing the percutaneous permeation of topically applied drugs. So there is an urgent need for further research in this field, for the development of new systems that allow better penetration and prolonged anesthesia [13]. Thus, the understanding of the exact mechanisms of lidocaine skin penetration from different carrier systems can be a useful tool to develop an effective, innovative, topically used local anesthetic formulation.
We investigated and compared the skin penetration of different carrier systems for lidocaine by using Raman spectroscopy. Hydrogel and oleogel are conventional drug carrier systems with a simpler structure than lyotropic liquid crystals (LLC) and nanostructured lipid carriers (NLC). LLCs with lamellar structure have a unique, skin-similar construction, which makes them capable of penetrating through the SC and becoming candidates for topical drug delivery systems [14]. NLC systems are also promising vehicles for topical application because they are well tolerated, biodegradable and non-toxic, they show improved stability and controlled drug release, and they can have an occlusive effect, which also facilitates skin penetration [[15], [16], [17]].
In our study, the first step was the determination of the spectral features of lidocaine in its solid form and incorporated in the above-mentioned carrier systems. Afterwards, excised human skin was treated with these formulations, frozen and cross-sectioned in order to perform Raman imaging and determine the distinct spatial distribution of the drug in the skin layers.
Section snippets
Materials
Lidocaine base form (LID-B), lidocaine hydrochloride (LID-HCl) and macrogol 400 were purchased from Hungaropharma Ltd. (Budapest, Hungary). Aerosil 200 was obtained from Sigma-Aldrich (Budapest, Hungary). Kolliphor RH40 (PEG-40 Hydrogenated Castor Oil; HLB value: 14–16) and Kolliphor RH60 (PEG-60 Hydrogenated Castor Oil; HLB value: 15–17) were kind gifts from BASF ChemTrade GmbH (Ludwigshafen, Germany). Miglyol 812 N (caprylic/capric triglyceride) was kindly provided by Sasol GmbH (Hamburg,
Spectral signatures of lidocaine as free base or salt
The first part of our study consisted of establishing spectral signatures for lidocaine in solid state and also for the lidocaine-containing formulations Fig. 1. presents the recorded spectra of LID-B and LID-HCl. This enabled us to determine the most pertinent spectral features to detect the drug on the cross-sectioned skin surface. The characteristic bands of different lidocaine forms are presented in Table 1 with the vibrational assignments (cm−1) based on Ref. [18].
Raman spectra of formulations
Fig. 2 depicts the Raman
Conclusion
Understanding how different carrier systems influence the penetration of active agents into/through the skin provides valuable information to the pharmaceutical, personal care, and cosmetic industries. In the current study, the application of Raman spectroscopy provided the visualization of spatial distribution in the skin for different lidocaine-containing formulations. Our results confirmed the raison d'ętre of developing modern carrier systems, as the nanostructured LLC and NLC showed
Declarations of interest
None.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
References (33)
- et al.
Effects of permeation enhancers on flufenamic acid delivery in Ex vivo human skin by confocal Raman microscopy
Int. J. Pharm.
(2016) - et al.
Quantitative detection of caffeine in human skin by confocal Raman spectroscopy – a systematic in vitro validation study
Eur. J. Pharm. Biopharm.
(2015) - et al.
Confocal Raman spectroscopy: in vivo measurement of physiological skin parameters – a pilot study
J. Dermatol. Sci.
(2017) - et al.
Ex-vivo measurement of scalp follicular infundibulum delivery of zinc pyrithione and climbazole from an anti-dandruff shampoo
J. Pharm. Biomed. Anal.
(2017) - et al.
In vivo confocal Raman spectroscopy and molecular dynamics analysis of penetration of retinyl acetate into stratum corneum
Spectrochim. Acta – Part A Mol. Biomol. Spectrosc.
(2017) - et al.
High-speed line-focus Raman microscopy with spectral decomposition of mouse skin
Vib. Spectrosc.
(2016) - et al.
Lyotropic liquid crystal systems in drug delivery
Drug Discov. Today
(2010) - et al.
The conformational stability, solvation and the assignments of the experimental infrared, Raman (1)H and (13)C NMR spectra of the local anesthetic drug lidocaine
Spectrochim. Acta A Mol. Biomol. Spectrosc.
(2015) - et al.
Evaluation of cytotoxicity of surfactants used in self-micro emulsifying drug delivery systems and their effects on paracellular transport in Caco-2 cell monolayer
Eur. J. Pharm. Sci.
(2012) - et al.
Kinetic analysis of the toxicity of pharmaceutical excipients cremophor EL and RH40 on endothelial and epithelial cells
J. Pharm. Sci.
(2013)
Effect of the glyceryl monooleate-based lyotropic phases on skin permeation using invitro diffusion and skin imaging
Asian J. Pharm. Sci.
Guidance document on dermal absorption
Health Consum. Prot. Dir.
Percutaneous dermal drug delivery for local pain control
Ther. Clin. Risk Manag.
Follow-up of drug permeation through excised human skin with confocal Raman microspectroscopy
Eur. Biophys. J.
Detection of skin cancer by classification of Raman spectra
IEEE Trans. Biomed. Eng.
In vivo measurement of the water content in the dermis by confocal Raman spectroscopy
Skin Res. Technol.
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