A High Throughput Method to Predict Skin Penetration and Screen Topical Formulations

Mar 1, 2013 | Contact Author | By: Konstantin Tsinman, PhD, Pion Inc.; B:aacute;lint Sinkó, PhD, SinkoLAB Scientific Bt
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Title: A High Throughput Method to Predict Skin Penetration and Screen Topical Formulations
skin permeabilityx high throughputx transdermal penetrationx artificial membranex transdermal formulationsx
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Keywords: skin permeability | high throughput | transdermal penetration | artificial membrane | transdermal formulations

Abstract: This work studies the applicability of a 96-well-based skin-mimetic artificial membrane permeability model to differentiate between topical pharmaceutical and cosmetic formulations. Results are compared with data obtained from in vitro Franz cell permeability measurements and reveal the applicability of this method to assess cosmetic formulation permeation and speed the discovery process.

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K Tsinman and B Sinkó, A high throughput method to predict skin penetration and screen topical formulations, Cosm & Toil 128(3) 192-199 (Mar 2013)

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  • Smoking is a major contributor to skin discoloration, ECM breakdown, deep wrinkling, premature skin aging, poor wound-healing and the formation of abnormal skin growths.
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In past decades, the understanding of mechanisms for skin penetration has significantly improved. Studies have identified the stratum corneum (SC), the outermost layer of the skin, as the main barrier for penetration of pharmaceutical and cosmetic ingredients, and due to its unique composition—i.e., about 50% ceramides, 35% free fatty acids and 15% cholesterol—the SC differs from other biological membranes. To facilitate the development of transdermal delivery for the compounds of interest, estimations of skin penetration rates and comparisons of dermatological formulations have become crucial to pharmaceutical and cosmetics research.

Several methods have been developed for the prediction of skin penetration. Although the most useful data is obtained from in vivo studies in humans, such measurements are expensive, labor-intense and slow to perform. This makes their application in lead selection and optimization impractical. In vivo measurements using rodents are well-known to overestimate the penetration rate since compounds can permeate down the hair follicle, and although pig ear skin is also used for in vitro tests based on its structural equivalence to human skin, the most generally accepted in vitro permeation models are based on human skin as the membrane.

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This content is adapted from an article in GCI Magazine. The original version can be found here.

 

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Figure 1. Schematic view of the PAMPA sandwich

Figure 1. Schematic view of the PAMPA sandwich

This method uses a 96-well microtitre “sandwich” plate assembly to form 96, two-chamber cells used as donor/receiver compartments for permeability studies.

Figure 2. Adapting the Skin PAMPA method to formulation testing

Figure 2. Adapting the Skin PAMPA method to formulation testing

Formulations were placed in the top compartment (30 ± 5 mg per well) of the 2-chamber PAMPA sandwich while the bottom compartment was filled with 180 µL pH 7.4 buffer, serving as the receiver chambe.

Figure 3. Permeability values and standard deviations for the eight test compounds

Figure 3. Permeability values and standard deviations for the eight test compounds

Averaged effective permeability (Pe in 10-6 cm/sec) and standard deviations for the set; the standard deviation for the measurements was within 0.2 logarithm permeability units, which is consistent with historic data from other PAMPA models.

Figure 4. UV spectrum of ibuprofen in different receiver compartments of the skin PAMPA assembly

Figure 4. UV spectrum of ibuprofen in different receiver compartments of the skin PAMPA assembly

UV spectrum of ibuprofen in different wells of the receiver compartment of the skin PAMPA plate assembly after 60 min of incubation; top left, top right, bottom left and bottom right graphs correspond to Formulas A, B, C and slurry formulations in donor wells (n ≥ 12 for each form). Note: the same absorbance scale for all forms eases the comparison.

Figure 5. Concentration of ibuprofen measured

Figure 5. Concentration of ibuprofen measured

Concentration of ibuprofen measured at 30 min and 60 min time points in the PAMPA assay (left Y-axis), and averaged flux measured at 1 hr time point of Franz cell permeability assay using human epidermis (right Y-axis)

Figure 6. Amount of diclofenac per unit area that permeated

Figure 6. Amount of diclofenac per unit area that permeated

Amount of diclofenac per unit area permeating from the test formulas at 20 min, 40 min and 60 min; Formula A included diclofenac c; Formula B, diclofenac d; and Formula C, diclofenac e (see Footnotes for c, d, e); 1% w/v of diclofenac was used for comparison.

Footnotes [Tsinman 128(3)]

a All chemical compounds used for the described studies were purchased from Sigma-Aldrich.
b The silicone based anhydrous gel formulation was provided by Dow Corning Corp.
c Voltaren is a product of Novartis.
d Diclofenac-ratiopharm is a product of SkyePharma.
e Flector is a product of Pfizer.
f The Prisma HT buffer used is a product of Pion Inc.
g Spectroscopic grade DMSO was obtained from Burdick and Jackson.
h The PAMPA Evolution system was developed by Pion Inc.
j The 96-well Stirwell PAMPA sandwiches are manufactured by Pion Inc.
k The UV plates were from Greiner Bio-one(UV-star micro plate, clear, flat bottom, half area)
m The Gut‑Box stirring device is manufactured by Pion Inc.

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