Stimulated Raman scattering (SRS) microscopy enables label-free and quantitative imaging of active pharmaceutical ingredients within the skin, with superior chemical specificity and spatial and temporal resolution. Here, we present a method to study topical formulations on ex vivo human skin using two modalities, SRS and near-infrared light (NIR) transmission. NIR transmission is used to compensate for the SRS signal variance caused by differences in skin thickness and formulation properties. Optical co-registration of the two modalities enables recording the variance in each pixel. The developed method helps to evaluate the cutaneous pharmacokinetics of tretinoin from tretinoin-containing solution and cream formulations.
Systemic drug delivery for dermatological conditions yields little drug to the intended site of action resulting in adverse effects. Topical drug delivery is a viable alternative yet the local cutaneous pharmacokinetics (cPK) is relatively under-explored. Product dosing is dependent upon the knowledge of the dose-cPK relationship, which coincides with the pharmacodynamic (PD) activity. Coherent Raman imaging (CRI) can quantify tissue-specific drug localization and elucidate micro-scale cPK estimates, affording a clinically relevant cPK-PD relationship. This demonstration of a dose-cPK relationship utilizing CRI offers a stepping stone for additional formulation evaluation ex vivo.
Cutaneous pharmacokinetics (cPK) can be quantified utilizing a myriad of in vitro and in vivo approaches. However, these techniques provide macroscale cPK for long experimental durations and do not provide cPK information from the moments directly after a topical formulation application, thus missing critical product dosing insight. Furthermore, formulations are typically applied for 5-10 minutes in the clinic and then removed (purposely or accidentally), which requires a high temporal and spatial resolution estimate of the early timepoint cPK. We have developed a 3-D printed applicator to address the unmet need for early time-point cPK quantification pertinent to the clinic.
Stimulated Raman scattering (SRS) is a rapid, nondestructive technique for imaging biomedical specimens with label-free chemical specificity. Here, we demonstrate a sparse spectral sampling SRS imaging approach where a rapidly-tunable dual-output all-fiber optical parametric oscillator is automatically tuned into specific vibrational modes across >1400cm-1. We demonstrate this system via simultaneously monitoring an active pharmaceutical ingredient and excipient within a single formulation, tracking penetration and permeation through distinct layers of ex vivo mouse skin over time with Raman fingerprint and high wavenumber spectral contrast. This novel method is ideally suited to monitor spatiotemporal dynamic changes during topical drug delivery.
Stimulated Raman Scattering (SRS) is a powerful method for quantifying the uptake, flow, and flux of active pharmaceutical ingredients (APIs). While there are numerous APIs that have unique structures and vibrational spectra, the majority do not have strong or unique vibrational bands. We have developed a sparse spectral sampling SRS imaging system to address these needs that can rapidly and specifically tune into specific Raman shifts from the fingerprint to high wavenumber region in < 5 ms per step. These hyperspectral SRS images can be analyzed using computational analytical approaches to visualize and quantify the dynamics of multiple molecular species simultaneously.
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