Stratum Corneum Sampling to Assess Bioequivalence between Topical Acyclovir Products

Pensado, Andrea; Chiu, Wing Sin; Cordery, Sarah F.; Rantou, Elena; Bunge, Annette L.; Delgado‐Charro, M. Begoña; Guy, Richard H.

doi:10.1007/s11095-019-2707-3

Cited by 29 publications

(43 citation statements)

References 31 publications

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“…Values of R 2 were also assessed (see Table II) directly from the experimental measurements of drug in the SC following uptake and after the shorter clearance period, as indicated in Eq. 5 (6)(7)(8)(9). It is worth emphasising that, when using the tape-stripping method, drug clearance from the SC is measured after the drug formulation has been removed from the skin surface.…”

Section: Resultsmentioning

confidence: 99%

“…A second approach that has been reported in the literature (6,8,9) estimates the input rate (R 2 ) from the difference between the amounts of drug in the SC after 'uptake' (M UP ) and after a period of 'clearance' (M CL ) divided by the time elapsed between the two measurements (Δt):…”

Section: Analysis and Interpretation Of In Vivo Skin Uptake And Penetmentioning

confidence: 99%

“…The idea behind this approach was first indicated and justified through mathematical modelling (7), and further illustrated in later publications on diclofenac (8) and metronidazole (9). Specifically, the clearance phase, where the drug diffuses from the SC into the deeper layers of the viable skin below, provides valuable information about a topical drug's input function into the viable tissue (6)(7)(8)(9). It follows that the mass of drug in the viable tissue depends on the flux of drug from the SC and the rate of its subsequent transfer to the presystemic blood compartment.…”

Section: Introductionmentioning

confidence: 99%

“…Hence, for drugs with their site of action in the viable epidermis, the SC sampling methodology, as recently described (6)(7)(8)(9), is targeted at eliciting information directly pertinent to the assessment of topical bioavailability (and by extrapolation, eventually, to bio(in)equivalence between different formulations). As such, the new approach to the interpretation of SC sampling data responds directly to an early and still-voiced criticism of tape-stripping that it cannot provide a useful metric related to the rate and extent of drug delivery to sites of action that are found elsewhere in the skin (such as the viable epidermis).…”

Section: Introductionmentioning

confidence: 99%

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Assessment of Drug Delivery Kinetics to Epidermal Targets In Vivo

Hoppel

Tabosa

Bunge

et al. 2021

AAPS J

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It has proven challenging to quantify ‘drug input’ from a formulation to the viable skin because the epidermal and dermal targets of topically applied drugs are difficult, if not impossible, to access in vivo. Defining the drug input function to the viable skin with a straightforward and practical experimental approach would enable a key component of dermal pharmacokinetics to be characterised. It has been hypothesised that measuring drug uptake into and clearance from the stratum corneum (SC) by tape-stripping allows estimation of a topical drug’s input function into the viable tissue. This study aimed to test this idea by determining the input of nicotine and lidocaine into the viable skin, following the application of commercialised transdermal patches to healthy human volunteers. The known input rates of these delivery systems were used to validate and assess the results from the tape-stripping protocol. The drug input rates from in vivo tape-stripping agreed well with the claimed delivery rates of the patches. The experimental approach was then used to determine the input of lidocaine from a marketed cream, a typical topical product for which the amount of drug absorbed has not been well-characterised. A significantly higher delivery of lidocaine from the cream than from the patch was found. The different input rates between drugs and formulations in vivo were confirmed qualitatively and quantitatively in vitro in conventional diffusion cells using dermatomed abdominal pig skin.

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Section: Resultsmentioning

confidence: 99%

Section: Analysis and Interpretation Of In Vivo Skin Uptake And Penetmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Assessment of Drug Delivery Kinetics to Epidermal Targets In Vivo

Hoppel

Tabosa

Bunge

et al. 2021

AAPS J

Self Cite

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“…To date, however, only a few experimental approaches have been established to have such reliability. Among them, the in vitro permeation test (IVPT) in human skin is considered a “gold-standard” method for studying percutaneous absorption, with good correlations with human in vivo data [ 14 , 15 , 16 , 17 ]. In addition to the use of IVPT to screen and optimize topical formulations, the method has also been proposed for the bioequivalence testing of topical formulations.…”

Section: Introductionmentioning

confidence: 99%

Franz Cell Diffusion Testing and Quantitative Confocal Raman Spectroscopy: In Vitro-In Vivo Correlation

2020

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Previously, we reported the use of Confocal Raman Spectroscopy (CRS) to investigate the topical delivery of actives and excipients. We have also correlated the results from CRS with findings from in vitro diffusion studies in human skin. However, until now CRS has only been used as a semi-quantitative method of determining the skin uptake of molecules, with results expressed as arbitrary units of signal intensity. Clearly, this posed challenges for using CRS to determine skin delivery and to assess the drug bioavailability and bioequivalence of topical formulations. In the present work, the permeation of niacinamide (NIA) from various formulations in human skin was studied in vitro using conventional Franz cells and in vivo using a quantitative CRS method under finite dose conditions. The selection of NIA was based on its wide use in pharmaceutical and personal care formulations for many years. This is the first fully quantitative study to compare these methods. The vehicles investigated were neat Transcutol® P (TC); binary combinations of propylene glycol (PG) with propylene glycol monolaurate (PGML); and ternary mixtures of PG, PGML, and isopropyl myristate (IPM). These solvents were selected to encompass a range of physicochemical properties. NIA permeation was evident from all formulations in vitro and in vivo. The vehicles PG:PGML and PG:PGML:IPM delivered comparable amounts across the skin in vitro at 24 h (100.3–106.7 µg/cm2, p > 0.05) that were significantly higher compared with those of TC (1.3 µg/cm2, p < 0.05). An excellent in vitro in vivo correlation (R2 = 0.98) was found following the linear regression of the cumulative amounts of NIA permeated in vitro and the amounts of NIA at 2 μm in the skin measured with CRS. A very good correlation between the cumulative permeation of NIA in vitro and the total amount of NIA that penetrated the stratum corneum (SC) per unit of surface area (μg/cm2) in vivo was also observed, with a Pearson correlation coefficient (R2) of 0.94. The findings support the use of CRS for the quantitative measurement of actives delivered to the skin in vivo. Future studies will focus on exploring the reproducibility and reliability of the method by investigating the delivery of different actives from a wider range of vehicles. Additionally, quantitative CRS will be evaluated further as a method for assessing the bioequivalence of topical formulations.

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Physiologically‐Based Pharmacokinetic Modeling to Support Determination of Bioequivalence for Dermatological Drug Products: Scientific and Regulatory Considerations

Tsakalozou

Alam

Babiskin

et al. 2021

Clin Pharma and Therapeutics

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Physiologically‐based pharmacokinetic (PBPK) modeling and simulation provides mechanism‐based predictions of the pharmacokinetics of an active ingredient following its administration in humans. Dermal PBPK models describe the skin permeation and disposition of the active ingredient following the application of a dermatological product on the skin of virtual healthy and diseased human subjects. These models take into account information on product quality attributes, physicochemical properties of the active ingredient and skin (patho)physiology, and their interplay with each other. Regulatory and product development decision makers can leverage these quantitative tools to identify factors impacting local and systemic exposure. In the realm of generic drug products, the number of US Food and Drug Administratioin (FDA) interactions that use dermal PBPK modeling to support alternative bioequivalence (BE) approaches is increasing. In this report, we share scientific considerations on the development, verification and validation (V&V), and application of PBPK models within the context of a virtual BE assessment for dermatological drug products. We discuss the challenges associated with model V&V for these drug products stemming from the fact that target‐site active ingredient concentrations are typically not measurable. Additionally, there are no established relationships between local and systemic PK profiles, when the latter are quantifiable. To that end, we detail a multilevel model V&V approach involving validation for the model of the drug product of interest coupled with the overall assessment of the modeling platform in use while leveraging in vitro and in vivo data related to local and systemic bioavailability.

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Stratum Corneum Sampling to Assess Bioequivalence between Topical Acyclovir Products

Cited by 29 publications

References 31 publications

Assessment of Drug Delivery Kinetics to Epidermal Targets In Vivo

Assessment of Drug Delivery Kinetics to Epidermal Targets In Vivo

Franz Cell Diffusion Testing and Quantitative Confocal Raman Spectroscopy: In Vitro-In Vivo Correlation

Physiologically‐Based Pharmacokinetic Modeling to Support Determination of Bioequivalence for Dermatological Drug Products: Scientific and Regulatory Considerations

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