Alternatives to Biological Skin in Permeation Studies: Current Trends and Possibilities

Neupane, Rabin; Boddu, Sai H. S.; Renukuntla, Jwala; Babu, R. Jayachandra; Tiwari, Amit K.

doi:10.3390/pharmaceutics12020152

Cited by 212 publications

(163 citation statements)

References 113 publications

Supporting

Mentioning

130

Contrasting

Unclassified

Order By: Relevance

“…The use of an infinite dose not only enabled identifying the realistic mechanism behind the penetration and permeation of the studied siloxanes, but is used when no such research has been carried out so far. We would also like to point out that according to the guidelines of OECD and WHO, ex vivo human skin studies are the gold standard for transdermal research, and can demonstrate the closest relationship with the in vivo processes [ 61 ].…”

Section: Resultsmentioning

confidence: 99%

Ex Vivo Human Skin is not a Barrier for Cyclic Siloxanes (Cyclic Silicones): Evidence of Diffusion, Bioaccumulation, and Risk of Dermal Absorption Using a New Validated GC-FID Procedure

Krenczkowska

Mojsiewicz‐Pieńkowska

Wielgomas

et al. 2020

Pharmaceutics

View full text Add to dashboard Cite

Cyclic methylsiloxanes D4, D5, D6 (also called cyclic silicones) are widely used in various dermatological products and cosmetics, both for children and adults. As a result of their unique physicochemical properties, the production of cyclic methylsiloxanes has greatly increased over the last few years, which has resulted in increased exposure to mankind. The validated quantitative for gas chromatography-flame ionization detector (GC-FID) analysis with using the transdermal diffusion system with vertical Franz cells demonstrated that ex vivo human skin is not a barrier to cyclic siloxanes. D4, D5, and D6 have a specific affinity to stratum corneum (SC) (especially D6), and can even diffuse into the deeper layers of the skin (epidermis (E) and dermis (D)), or into the receptor fluid as well. An important achievement of this work was the observation of the characteristic ratio partitioning D4, D5, and D6 in skin layers and receptor fluid (RF). The studies have shown that, in order to thoroughly understand the mechanism, it is important to determine not only the differences in the amounts of cumulated doses in total in all skin layers and receptor fluid, but also the mutual ratios of analyte concentrations existing between matrices. For example, in the case of the stratum corneum, the cumulative doses of D4, D5, and D6 were 27.5, 63.9, and 67.2 µg/cm2/24 h, respectively, and in the epidermis, they were 6.9, 29.9, and 10.7 µg/cm2/24 h, respectively, which confirmed the highest affinity of D6 to stratum corneum as the amount diffused into the epidermis was 2.8 times smaller compared to D5. The calculated epidermis-to-stratum corneum ratios of analyte concentrations also confirm this. The largest ratio was identified for D5 (E/SC = 47), followed by D4 (E/SC = 25), and finally by D6 (E/SC = 16). The analysis of the next stage of diffusion from epidermis to dermis revealed that in dermis the highest cumulative dose was observed for D5 (13.9 µg/cm2/24 h), while the doses of D4 and D6 were similar (5.1 and 5.3 µg/cm2/24 h). Considering the concentration gradient, it can be concluded that the diffusion of D5 and D6 occurs at a similar level, while D4 diffuses at a much higher level. These observations were also confirmed by the dermis-to-epidermis concentration ratios. The final stage of diffusion from dermis to the receptor fluid indicated that D4 was able to permeate easily, while D5 exhibited a difficult diffusion and the diffusion of D6 was limited. The receptor fluid-to-dermis concentration ratios (RF/D) were calculated for D4, D5, and D6: 80, 53, and 17, respectively. Our results also revealed the increased risk of D4 and D5 absorption into the blood and lymphatic systems, whereas D6 demonstrated the lowest risk. Therefore, we can argue that, among the three tested compounds, D6 is the safest one that can be used in dermatological, cosmetic, and personal care products. This study demonstrates that the stratum corneum, epidermis, and dermis can be also considered reservoirs of cyclic methylsiloxanes. Therefore, these compounds can demonstrate potential long-term bioaccumulation, and can be absorbed to the bloodstream in a long-term and uncontrolled process.

show abstract

Section: Resultsmentioning

confidence: 99%

Ex Vivo Human Skin is not a Barrier for Cyclic Siloxanes (Cyclic Silicones): Evidence of Diffusion, Bioaccumulation, and Risk of Dermal Absorption Using a New Validated GC-FID Procedure

Krenczkowska

Mojsiewicz‐Pieńkowska

Wielgomas

et al. 2020

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…However, it has been found that simple artificial membranes do not match the characteristics of the skin and, consequently, their use is suggested only in the determination of drug release. Therefore, there is a growing demand for new artificial membranes that model the human skin well to provide relevant and useful results in predicting the permeation of the drug from the dermal drug delivery preparations [1,11].…”

Section: Introductionmentioning

confidence: 99%

Novel In Vitro Investigational Methods for Modeling Skin Permeation: Skin PAMPA, Raman Mapping

et al. 2020

View full text Add to dashboard Cite

The human skin is marked as a standard by the regulatory agencies in the permeation study of dermal formulations. Artificial membranes can substitute human skin to some extent. Academicians and pharmaceutical corporations are focusing their efforts on developing standardized protocols and safe, reliable options to substitute human skin for carrying out permeability studies. Our research aim was to study the applicability of new techniques in the case of different types of dermal formulations. The skin parallel artificial membrane permeability assay (PAMPA) method and Raman mapping were compared to the gold-standard Franz cell method. A hydrogel and two types of creams were investigated as the most generally used dermal preparations. The values of the diffused drug were closer to each other in PAMPA and Franz cell measurement. The diffused amount of drug showed the same order for the different formulations. These results correlate well with the results of Raman mapping. Our conclusions suggest that all early screening examinations can be performed with model tools such as skin PAMPA supplemented with methods like Raman mapping as a semi-quantitative method.

show abstract

“…The limitation of this epiCS model is the lack of a dermal part although the fibroblasts very seldom play a metabolically active role—they are mostly active in wound healing processes ( Chang et al., 2002 ). Besides, the stratum corneum on any reconstructed skin model is likely more permeable than actual intact human skin ( Neupane et al., 2020 ). Novel methods recently became available which are capable of delivering larger substances (peptides and proteins) through the skin ( Asselineau et al., 1990 ; Prow et al., 2011 ).…”

Section: Discussionmentioning

confidence: 99%

The Delivery of α1-Antitrypsin Therapy Through Transepidermal Route: Worthwhile to Explore

et al. 2020

View full text Add to dashboard Cite

Human α1-antitrypsin (AAT) is an abundant acute phase glycoprotein expressing anti-protease and immunomodulatory activities, and is used as a biopharmaceutical to treat patients with inherited AAT deficiency. The pleiotropic properties of AAT provide a rationale for using this therapy outside of inherited AAT deficiency. Therapy with AAT is administrated intravenously, yet the alternative routes are being considered. To examine the putative transepidermal application of AAT we used epiCS®, the 3D human epidermis equivalents reconstructed from human primary epidermal keratinocytes. We topically applied various concentrations of AAT protein with a constant volume of 50 µl, prepared in Hank’s balance solution, HBSS, to epiCS cultured under bas\al condition or when culture medium supplemented with 100 µg/ml of a combined bacterial lipopolysaccharide (LPS) and peptidoglycan (PGN) mixture. AAT freely diffused across epidermis layers in a concentration and time-dependent manner. Within 18 h topically provided 0.2 mg AAT penetrated well the stratum corneum and localizes within the keratinocytes. The treatments with AAT did not induce obvious morphological changes and damages in keratinocyte layers. As expected, LPS/PGN triggered a strong pro-inflammatory activation of epiCS. AAT exhibited a limited capacity to neutralize the effect of LPS/PGN, but more importantly, it lowered expression of IL-18 and IL-8, and preserved levels of filaggrin, a key protein for maintaining the epidermal barrier integrity. Our findings suggest that the transepidermal route for delivering AAT is worthwhile to explore further. If successful, this approach may offer an easy-to-use therapy with AAT for skin inflammatory diseases.

show abstract

Alternatives to Biological Skin in Permeation Studies: Current Trends and Possibilities

Cited by 212 publications

References 113 publications

Ex Vivo Human Skin is not a Barrier for Cyclic Siloxanes (Cyclic Silicones): Evidence of Diffusion, Bioaccumulation, and Risk of Dermal Absorption Using a New Validated GC-FID Procedure

Ex Vivo Human Skin is not a Barrier for Cyclic Siloxanes (Cyclic Silicones): Evidence of Diffusion, Bioaccumulation, and Risk of Dermal Absorption Using a New Validated GC-FID Procedure

Novel In Vitro Investigational Methods for Modeling Skin Permeation: Skin PAMPA, Raman Mapping

The Delivery of α1-Antitrypsin Therapy Through Transepidermal Route: Worthwhile to Explore

Contact Info

Product

Resources

About