HK40031765B - Mild surfactant preparation and method therefor - Google Patents

Description

Preparation and methods of mild surfactants

Technical Field

This invention relates to the development of mild surfactant systems, specifically mild surfactant systems for infants or young children, while simultaneously assessing the level of skin irritation through analysis of adult skin tests. This invention allows for the evaluation of the irritation level of surfactant systems using objective data, without the need for testing on young children or infants.

Background Technology

Skin cleansers contain surfactants that can impair the skin's integrity against external invaders, leading to skin irritation. Assessing the mildness of cleansers on the skin is typically done clinically by evaluating and measuring changes in transepidermal water loss (TEWL) according to exaggerated patch or exaggerated wash test protocols. These methods are partially subjective and often yield variable results.

The mildness of skincare products is typically assessed in adults using normal use tests, exaggerated (repeated) use tests, or patch tests (especially for cleansing products containing potentially irritating surfactant systems). Even for baby products, evaluation is first conducted in adults, and once approved, normal use tests are sometimes performed in infants. Mildness is rated as non-irritating (usually manifested as erythema (redness)). The effectiveness of the product as a skin barrier is usually assessed instrumentally by measuring transepidermal water loss (TEWL). The effectiveness of the product as a skin barrier can also be studied in vitro using a Franz cell and by measuring skin impedance.

However, previous methods have many drawbacks and problems. For example, normal use testing often requires large panel sizes to differentiate between different levels of mildness, which can be costly and time-consuming. In patch testing, surfactants can respond differently under closed conditions compared to normal use conditions. Arm immersion test results can be climate-dependent. In flexure wash testing, the skin area tested may not represent other areas of the body.

Furthermore, subjective evaluation of each of the aforementioned projects (clinical observations) can lead to variations. Finally, most of these tests are either designed for adult skin and completely irrelevant to infant skin, or these studies are conducted on infants/toddlers, but clinical research on infants raises ethical and technical issues. As noted, the validity of directly transferring data collected from adults to infant skin conditions is questionable. For example, infant skin is not typically used in the Franz pool, and the transfer of this data to infant skin is problematic. The use of these methods always involves a safety factor magnitude (typically 10-fold) reflecting the uncertainty.

Developing a method to evaluate the effects of surfactant systems on the skin barrier of infants and/or young children by objectively assessing the concentration distribution of markers (such as caffeine) that penetrate the skin of adult subjects would be useful. This invention seeks to assess the effects on adult skin using biomarker testing, evaluate the effects on infant/young child skin using computational models, and develop surfactant systems as a result of these tests and analyses.

Moisturizers are mixtures of chemical agents specifically designed to soften the outer layer of skin or hair. Personal care compositions with moisturizing properties are known. Consumers expect such compositions to meet a range of requirements. In addition to determining the intended skin/hair care effects, values are set for various parameters such as dermatological compatibility, appearance, sensory impression, storage stability, and ease of use. Another beneficial effect provided by many moisturizers is protection of the skin from exposure to external environmental factors and agents.

Detailed Implementation

This invention relates to a method for evaluating the mildness of skincare products on infant skin, and specifically, for evaluating the effect of topical application of substances and/or formulations on the barrier function of infant skin, and a method for preparing and/or using surfactant systems based on this evaluation. As used herein, the term "infant skin" refers to the skin of a human newborn, but also includes the skin of children up to 12 months of age. The term "infant" refers to infants aged 12 to 36 months, but also includes children.

The object of this invention is to enable the evaluation of the safety, mildness, etc., of products applied to infants' and/or young children's skin by safely evaluating products applied to adult skin. The method involves applying a substance to adult skin, collecting penetration data of the marker on the treated adult skin, transmitting this information to a computational model of adult skin, extracting penetration parameters from the model, transmitting these parameters to a computational model of infant skin, visualizing the penetration of the marker in the infant skin model, and drawing conclusions about the effect of the topical product on infant skin. Finally, the method then includes preparing a surfactant system as a result of the evaluation, and/or using the surfactant system based on the evaluation and the final preparation of the system.

U.S. Patent Application 20150285787, published to Laboratoires Expanscience, discloses a method for identifying at least one biomarker for children's skin, the method comprising: a) measuring the expression level of a candidate biomarker in at least one skin cell sample (A), said sample being obtained from a donor under the age of 16; b) measuring the expression level of said candidate biomarker in at least one control sample (B) of skin cells; c) calculating the ratio between the expression level of step a) and the expression level of step b); and d) determining whether the candidate biomarker is a biomarker for children's skin.

Laboratoires Expanscience's WO2015150426 and WO2017103195 disclose methods for evaluating in vivo formulations, comprising: a) contacting an active reagent or formulation with a reconstructed skin model derived from a child's skin sample; b) contacting the reconstructed skin model after step a) with urine; and c) measuring the expression level of at least one biomarker from a list of specified biomarkers in the skin model after step b.

U.S. Patent Application 20180185255, granted to Procter & Gamble, discloses a method for screening mild cleansers, the method comprising: a) measuring the level of one or more ceramides on a skin area prior to application of the cleanser; b) applying the cleanser to the skin area for at least 7 days; c) after applying the product to the skin area for at least 7 days, measuring the level of one or more ceramides; wherein the cleanser is mild if the level of the one or more ceramides is at least 10% relative to an untreated control.

U.S. Patent 10,036,741 to Procter & Gamble discloses a method for evaluating the effects of interferons on skin homeostasis and formulating skincare compositions containing interferons. The method includes causing a computer processor to query a stored data architecture of skin cases associated with interferons that have unhealthy skin gene expression characteristics. The query includes comparing unhealthy skin gene expression characteristics with each stored skin case and assigning an association score to each case.

EP 1248830A1, granted to Procter & Gamble, discloses the use of forearm controlled application testing to evaluate the mildness of surfactants.

Saadatmand et al.'s paper, "Skin hydration analysis by experiment and computer simulations and its implications for diapered skin" (Skin Res. Technol., 2017: 1-14), discloses a reversible hydration model for the stratum corneum that simulates evaporative water loss and changes in stratum corneum thickness with exposure conditions such as time-dependent relative humidity, air temperature, skin temperature, and wind speed.

Maxwell et al.’s “Application of a systems biology approach for skinallergy risk assessment” (Proc. ^6th World Congress on Alternatives & Animal Use in Life Sciences, pp. 381-388, 2007) discloses a computer simulation model of skin sensitization induction to characterize and quantify the contribution of each pathway to the overall biological process.

Strube et al.'s "The flex wash test: a method for evaluating the mildness of personal washing products" (J. Soc. Cosmet. Chem., 40: 297-306 (1989)) disclosed the use of a flex arm for sixty seconds of washing (three times daily) to assess the potential irritation of washing products.

Keswick et al.'s "Comparison of exaggerated and normal use techniques for accessing the mildness of personal cleaners" (J. Soc. Cosmet. Chem., 43: 187-193 (1992)) disclosed a comparison between the forearm test and the flexion wash test and home use to determine how close the tests are to casual use.

Frosch et al.’s “Journal of the American Academy of Dermatology” (Vol. 1, No. 1, pp. 35-41, 1979) disclosed a laboratory test for evaluating the irritant properties of soap, which required exposure to an 8% solution for five working days and showed scaling and redness.

For experimental use on infant skin, many in vivo tests are unacceptable. The cited references do not disclose or propose evaluating adult skin or using computational models to correlate how ingredients will affect infant skin. Therefore, this invention does not require in vivo testing on infant skin.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, all publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. Unless otherwise specified, all percentages are by weight as used herein. Moreover, all ranges shown herein are intended to include any combination of values between two endpoints (inclusive).

In this invention, the method can be used to differentiate different cleanser formulations based on their effectiveness in blocking external penetration through the skin. This invention proposes a method for analyzing formulations that objectively evaluates the effectiveness of topical cleansers in blocking external invaders through the skin and can be used to assess the mildness of cleansers. The results of this analysis can be used to provide or prepare suitable formulations considered mild for the skin of infants and/or young children.

This invention relates to a predictive method for assessing the mildness of a topical substance on the skin of a subject (preferably an infant). The invention also relates to a predictive method for assessing the permeation of a compound (marker) through an infant's skin. Furthermore, the invention provides a method for assessing the effect of a topically applied substance on the permeation of a compound (marker) through an infant's skin. Additionally, the invention can provide a method for measuring and/or predicting the barrier enhancement effect of a topical substance.

In one aspect, the invention may include multiple method steps. It may include a phase 1 (in vivo) and a phase 2 (computer simulation), and optionally a phase 3 (intellectual process), and the method may conclude by preparing a suitable surfactant system that has been analyzed to pass the above tests, or by applying the surfactant system to the skin of an infant and/or young child.

Stage I, within the body

A. Applying topical substances to adult skin, such as by direct application or application to patches or other delivery systems.

B. The marker is applied locally to adult skin, and data on the penetration of the marker into the treated adult skin are collected. This step includes applying the marker and then acquiring its concentration distribution across the skin, for example, using confocal Raman microscopy (CRM).

Phase II, Computer Simulation

C. Transfer this information (permeability data) to a computational model of adult skin and extract permeability parameters from the model.

This step can also be described as using a computational adult skin permeability model to visualize the permeability of the marker by optimizing permeability parameters (e.g., local surface concentration and permeability coefficient) so that the model permeability distribution matches the experimental data.

D. Transfer the permeation parameters (after appropriate transformation) to a computational model of infant skin and visualize the permeation of the marker in the infant skin model.

(Optional), Stage III, Intellectual Processes

E. Based on the amount of markers in the infant skin model that has been penetrated, conclusions were drawn regarding the mildness (effectiveness) of topical products on infant skin.

Once the above method steps have been completed and a conclusion has been reached in step E, the surfactant system can be prepared, applied, or dispensed by the user.

Topical substances

This invention includes one or more topical substances to be evaluated, wherein the topical substances are intended to be used in a final surfactant system. The topical substance is any type of substance applied to the skin that has an effect on the permeability of the stratum corneum. The topical substance will alter the permeation of the marker through the skin. The effect of the topical substance can be evaluated by measuring the marker permeation. Typically, for the tests outlined above, the topical substance is immersed in a patch that remains in contact with the skin for 30 minutes prior to application of the marker. The patch may include one or more topical substances for application testing.

Different types of topical substances can be evaluated within the scope of this invention. For example, a topical substance may be an irritant that reduces skin barrier properties and increases marker penetration. In this case, the invention allows for the creation of a mildness classification of substances and helps in selecting gentler solutions when designing new skin product compositions without in vivo or in vitro testing. In other aspects, topical substances may include barrier substances designed to help protect the skin and increase its barrier properties, thereby reducing marker penetration through the skin. As described above, the invention can help in selecting the most effective solution without the need for in vitro or in vivo testing on infant skin.

markers

This invention utilizes one or more markers or biomarkers in its evaluation methods. Any type of marker is suitable as long as a method exists to track the marker and generate concentration distributions (e.g., osmotic data). In the example using confocal Raman microscopy, the marker should have a traceable signal in the Raman spectrum. Alternatively, confocal fluorescence microscopy can be used to track fluorescent markers. Ideally, the osmotic kinetics of the marker should allow a steady-state concentration distribution to be reached within a reasonable timeframe (e.g., at most one hour).

The marker can be hydrophilic, lipophilic, or amphoteric, which will limit the type of barrier effect the evaluator is examining. For example, a suitable marker is caffeine. In the case of caffeine, the analysis examines the barrier effect against hydrophilic substances.

The markers according to the invention may include any molecule that is toxicologically and dermatologically safe, has reasonable permeation kinetics, and can be traced by confocal analysis.

- Safety; Some previously used labels were unacceptable for toxicity reasons (dansyl chloride (mentioned in Paye et al., “Dansyl chloride labelling of stratum corneum: its rapid extraction from skin can predict skin irritation due to surfactants and cleaning products”, Contact Dermatitis 30(2), 91-96, 1994), which has been discontinued due to the risk of sensitization and skin corrosion upon contact with skin).

- Osmotic kinetics; molecules that penetrate the skin, for example, are fast enough but not too fast. For example, molecules with an osmotic coefficient close to that of caffeine can be used: kp = 1.16 × ^10⁻⁴ cm/h, as reported in Dias M et al., “Topical delivery of caffeine from some commercial formulations” Int J Pharm 1999 182(1):41-7.

- Confocal analysis is non-invasive and provides data on the depth of marker penetration. In contrast, for example, tape application is invasive and destroys the barrier; this is unacceptable in this invention.

Penetration data

This invention analyzes permeation data. Permeation data is a concentration distribution; this means that the concentration of the marker is a function of the depth through which it penetrates the skin. This invention can use any desired analytical method suitable for measuring the variation of the marker concentration distribution with depth in the skin, more precisely, depth in the epidermis, and especially depth in the stratum corneum. Any desired method can be used, but non-invasive methods are preferred. Confocal techniques are preferred because they are non-invasive and provide reasonable resolution, for example, 3 μm to 5 μm resolution in the direction perpendicular to the skin surface, at a depth of up to 200 μm. One such method includes confocal Raman microscopy, but other methods, including confocal fluorescence microscopy, can also be used.

Computational models of adult/infant skin

This invention uses computational models to evaluate the components of a tested surfactant system. Any model capable of producing a concentration distribution of markers that penetrate the skin can be used. Users can choose any type of computational skin penetration model that produces a concentration distribution of markers that penetrate the skin given penetration parameters. The use of both adult skin and skin models requires the model to consider the structure of the skin architecture and the differences between the two.

For example, the physiological model published in Sutterlin et al., “A 3D self-organizing multicellular epidermis model of barrier formation and hydration with realistic cellmorphology based on EPISIM,” (Scientific Reports, Vol. 7, No. 43472, 2017), can be used and modified to integrate substances (e.g., markers) diffusing through the skin layer. Sutterlin et al. disclosed a cell behavior model (CBM) that encompasses the regulatory feedback loop between epidermal barriers, water loss from the environment, and water and calcium flow within tissues. The EPISIM platform consists of two ready-to-use software tools: (i) EPISIMModellar (a graphical modeling system) and (ii) EPISIM Simulator (a reagent-based simulation environment). Each EPISIM-based model consists of at least a cell behavior model and a biomechanical model (CBM and BM). The BM encompasses all spatial and biophysical cellular properties. The CBM is a cell-determined model. The model can be used in 2D or 3D form according to the present invention (the form of the 2D model (but without the stratum corneum component) is described in: Suetterlin et al. "Modeling multi-cellular behavior in epidermal tissue homeostasis via finite state machines in multi-agent systems" (Bioinformatics, 25(16), 2057-2063, 2009).

In one approach, the process begins with the user allowing the simulation to reach a steady state corresponding to epidermal homeostasis. Then, at a given time point corresponding to the local application of a marker, the evaluator introduces a user-defined variable corresponding to the skin surface concentration of the marker (C _{_surface} ). The value of this parameter is defined by the concentration distribution obtained experimentally and corresponds to the marker concentration at depth 0 (skin surface). A cellular variable is introduced into the model to define the concentration of the marker in cells (C _{_cell} ). This parameter is modified at each step based on Fick's law of diffusion, as this allows the marker to diffuse from each cell to its immediate neighbors. To apply Fick's law, a permeability coefficient parameter (P) is introduced into the model. This permeability coefficient parameter inherently takes into account the diffusion coefficient, the diffusion resistance due to the partition coefficient, and the diffusion resistance due to the path distance the substance must traverse from one cell to the next. The permeability coefficient of the stratum corneum (PSC) differs from that of the living epidermis (P_{_VE} ). If the substance reaches the bottommost part of the epidermis, it is allowed to diffuse into the epidermal compartments, which are modeled as permeable "grooves."

These modifications apply to both adult skin and infant skin models.

An infant skin model was created by modifying the parameters of an adult model to reflect the higher conversion rates (proliferation and shedding) in infant skin.

Permeability parameters

Permeability parameters characterize permeability kinetics, the ease with which a substance crosses a surface and penetrates deep into the skin. These can be, for example, partition coefficients, diffusion coefficients, and/or permeability coefficients.

Mildness Index

Under steady-state conditions, the concentration distribution of the marker in the adult skin model is compared with the experimental concentration distribution. If the distributions do not match, the permeability parameters (C_surface, P_sc, and P_ve) are adjusted and the simulation is repeated. Once the two distributions match, the parameters are used to calculate the corresponding parameters for marker permeability in the infant skin model. Due to the higher hydrophilicity of infant skin, the C_surface parameter is higher (typically twice that of adult skin*), while other permeability parameters remain the same between the two models. *See, for example, Nikolovski et al., “Barrier function and water-holding and transport properties of infant stratum comeum are different from adult and continue to develop through the first year of life” (Journal of Investigative Dermatology, Vol. 128, 2008), which uses tools such as transepidermal water loss (TEWL), skin capacitance, adsorption-desorption, and Raman confocal spectroscopy to confirm that the water storage and transport properties of the infant stratum corneum differ from those of adults. Specifically, this reference discloses the observation of externally applied water absorption by Raman confocal microscopy 10 seconds after application of water to the skin of the lower ventral arm. Figure 5a (and reproduced below) shows significant water absorption in the stratum corneum of infants under 12 months of age. Figure 5b (and reproduced below) shows, in contrast, no significant water absorption was observed in adult skin after water application. It is expected that highly hydrophilic caffeine penetration will behave similarly to water penetration.

The markers were then allowed to penetrate to reach a steady state in an infant skin model (approximately 1000 steps, each step corresponding to 30 minutes of physiological time). At steady state, the average concentration distribution of the markers (average concentration as a function of depth) was calculated. The area under the curve (AUC, integral) was calculated for the concentration distribution down to a defined depth (e.g., 20 μm).

The mildness index scale can be defined by the AUC values corresponding to different product treatments. This is an agreed-upon scale used to classify the mildness of topical substances.

This mildness index allows evaluators to compare the mildness of a tested topical substance relative to two reference substances: water (mild) and sodium lauryl sulfate (SLS) 0.1% (irritating). Using water and SLS 0.1% as two reference points, it is possible to establish a scale to measure the mildness of other topical substances.

It should be noted that the mildness index is optional, and one can ignore the mildness index and directly compare the relative mildness of different local materials based on the integral of its predicted permeability curve (i.e., the calculated AUC value).

Example

1- Comparison between experiments (adults), models (adults), and predictions (infants)

Target:

• This study demonstrates the predictive effects of two extreme topical solutions: an irritating solution (containing 0.1% SLS) and a mild solution (water) on infant skin.

• This indicates that the adult model is consistent with the experimental data.

• This indicates that topical substances have different effects on adult and infant skin, and that markers penetrate infant skin more easily.

Figure 1: Comparison between experimental, model, and prediction methods of water on adult and infant skin and SLS .

Vertical axis: Caffeine concentration, expressed in mmol/g keratin.

Horizontal axis: Depth, in μm

Line reference:

ο Vertical cross line (+): Experiment (in vivo), adult skin, water.

ο Triangle (Δ): Model (computer simulation), adult skin, water.

ο Diagonal (x): Model (computer simulation), baby skin, water

ο circle (ο): experimental (in vivo), adult skin, SLS.

ο Diamond line (◇): Model (computer simulation), adult skin, SLS.

ο Square line (□): Model (computer simulation), baby skin, SLS.

Figure 1 above shows the penetration depth (in μm) of caffeine (a marker) expressed in mmol/g keratin, obtained through in vivo experiments on adult skin (lines + and ○) or computer simulation prediction models (lines Δ, ×, ◇, and □).

The effects of two topical solutions on caffeine penetration are shown in Figure 1: water and 0.1% SLS. Model calculations for adults are represented by lines Δ and ◇, respectively, for water and SLS. Predicted data for infants are represented by lines × and □, respectively, for water and SLS.

In vivo experimental data were collected on adult skin and then transferred to an adult skin model to simulate the depth of caffeine penetration in adult skin. The prediction of caffeine penetration in infant skin proposed by the model of this invention is indicated by a diagonal line (×) when the skin is treated with a water patch before caffeine application, and by a square line (□) when the skin is treated with a 0.1% SLS patch before caffeine application.

The area under the curve (AUC) for skin depths ranging from 0 μm to 20 μm indicates the gentleness level of a topical substance. A smaller AUC is gentler on the skin. The AUC is a key parameter for comparing different treatments.

2- Comparison of several surfactant formulations .

Target:

• Create a predictive surfactant formulation classification based on the gentleness of surfactant formulations on baby's skin.

Step 2.1: Experimental data, caffeine penetration in adult skin, and its effect on the body.

Figure 2: Caffeine penetration from adult skin and its effect on the body.

Vertical axis: Caffeine concentration, expressed in mmol/g keratin.

Horizontal axis: Depth, in μm

The formula tested:

οWater: diamond-shaped line (◇); mildness reference.

Formula 1: Square line (□); 0.1% sodium lauryl sulfate

Formula 2: Triangle line (Δ); 4.45% PEG 80 dehydrated sorbitol laurate, 8.41% 15% cocoaminopropyl betaine, 3.7% sodium tridecyl polyoxyethylene ether sulfate; 50% diluent

Formula 3: Diagonal (x); 0.75% (Poloxamer 184; BHT); 50% dilution

Formula 4: Star-shaped line (*); 6% (cocoaminopropyl betaine; aqueous solution; sodium chloride), 1% (aqueous solution; cocoyl glucoside; citric acid; hydrogenated palm oil citrate glyceryl ester; tocopherol; palmitic ascorbate; lecithin; glyceryl oleate), 0.6% (acrylate/C10-30 alkyl acrylate crosspolymer), 16% (aqueous solution; cocoyl glucoside); 50% diluent

Formula 5: Round line (○); 5% hydrolyzed potato starch sodium dodecenyl succinate; 50% diluent

The experimental protocols are disclosed in the materials and methods of Stamatas et al.'s article "Development of a non-invasive optical method for assessment of skin barrier to external penetration" (Biomedical Optics and 3D Imaging OSA (2012)). Stamatas et al. disclosed the use of the characteristic Raman spectrum of caffeine to track the penetration of caffeine through adult skin to demonstrate the effects of (1) sodium lauryl sulfate and (2) barrier cream on the barrier function of the stratum corneum.

Step 2.2: Modeling experimental data from adult epidermal models, computer simulation

Figure 3: A computer simulation model of caffeine penetration in adult skin.

Vertical axis: Caffeine concentration, expressed in mmol/g keratin.

Horizontal axis: Depth, in μm

Line reference:

οWater: Rhombus (◇)

Formula 1: Square line (□)

Formula 2: Triangle Line (Δ)

Formula 3: Diagonal (x)

Recipe 4: Star-shaped line (*)

Recipe 5: Circular Line (○)

The experimental caffeine penetration data collected in step 2.1 were transferred to a computational model of adult skin. Skin penetration simulations were performed for each topical substance; a single simulation per substance was sufficient. Caffeine penetration parameters (local surface concentration and permeability coefficient) were extracted.

Step 2.3: Predicted Caffeine Permeation Curve after Surfactant Treatment

Figure 4: Prediction of caffeine penetration in infant skin, computer simulation

Vertical axis: Caffeine concentration, expressed in mmol/g keratin.

Horizontal axis: Depth, in μm

Line reference:

οWater: Rhombus (◇)

Formula 1: Square line (□)

Formula 2: Triangle Line (Δ)

Formula 3: Diagonal (x)

Recipe 4: Star-shaped line (*)

Recipe 5: Circular Line (o)

The caffeine penetration parameters obtained from the adult skin model in step 2.2 were transferred to the computational model of infant skin. Infant skin penetration simulations were performed for each topical substance. The predicted caffeine penetration results were extracted and displayed in Figure 4 above.

Step 2.4: Predicted absorption in the infant's stratum corneum, area under the curve (mmol/L) at a depth of 0 μm-10 μm. (due to /g keratin)

Figure 5: Predicted amount of caffeine absorbed in the stratum corneum of infants

Integrate the predicted curves for each topical agent shown in Figure 4 in step 2.3 to obtain the predicted amount of caffeine absorbed in the infant's stratum corneum for each topical agent. These values are shown in the bar chart above (Figure 5).

In other words, this prediction chart shows how much caffeine will penetrate within the first 10 μm (not mm) of the SC. The more caffeine penetrates, the more corrosive the localized substance will be.

result

Surprisingly, this figure suggests that topical agents will not possess the mildness index value for infant skin that is always reflected in experimental values obtained on adult skin:

Formula 3 will be milder than Formula 5.

Formula 4 will be milder than Formula 2.

As a result of this experiment, compositions comprising the formulations in formulations 3 and/or 4 can be prepared and applied to the skin of infants and/or young children, which are correspondingly more preferred than formulations 5 and 2.

In a next embodiment, the present invention relates to the development of a barrier system, specifically a barrier system for infants or young children, while assessing the level of barrier effectiveness by analyzing adult skin tests.

This invention allows for the evaluation of the protection level of a barrier system using objective data, without the need to test on toddlers or infants.

method

Steps I and II disclosed above remain the same. Predictive data on infant skin penetration of the markers are generated.

The difference in step III is that the data involves using markers to measure low permeability and diffusion through the skin to predict the barrier effect of the topical substance applied in step IA on the skin of infants or young children.

This method can be used to evaluate no-rinse products (such as creams/moisturizers).

experiment

Example 3

Materials and methods

We collected skin data from healthy volunteers with normal skin who agreed not to use any other skin care treatments on their forearms for at least 24 hours before and during the study.

The instruments used:

In vivo confocal Raman spectroscopy (Model 3510 skincare composition analyzer, River Diagnostics, Rotterdam, The Netherlands)

Caffeine patch: 180mg caffeine in 10mL deionized water, 1.8%

Example 4: Barrier Cream Simulation

Experimental data were collected from five female volunteers aged between 20 and 35.

The localized substance tested :

Barrier cream: Cream (diaper rash cream)

US INCI list: Zinc oxide 10%, Inactive ingredient (aloe vera leaf juice), Cyclic polymethylsiloxane, Dimethylsiloxane, Fragrance, Methylparaben, Microcrystalline wax, Mineral oil, Propylparaben, Purified water, Sodium borate, Sorbitol sesquioleate, Vitamin E, White petrolatum, White wax.

plan

1. Allow yourself 5 minutes in a room with controlled temperature and humidity.

2. Apply topical medication to the forearm.

3. Allow yourself 30 minutes in a room with controlled temperature and humidity.

4. Apply the caffeine patch to the forearm (same location) and leave it on for 30 minutes.

5. Measurements were taken in the Raman fingerprint region.

result

1- Experimental data on adult skin

Data obtained from Desitin-treated skin (square) was compared with data obtained from untreated reference skin (circle) (i.e., no topical substance was applied in step 2 of the protocol).

Vertical axis: Caffeine concentration, expressed in mmol/g keratin.

Horizontal axis: Skin depth, in μm

Permeation data were extracted from the experimental results and transferred to a computational model of adult skin.

2-Adult Skin Modeling

The next step is to define skin permeability parameters on a computational model of adult skin so that it can accurately simulate the experimental data provided above.

These parameters are calculated from the slope of the caffeine osmotic distribution. The results for the adult model are shown below.

Skin treated with the barrier cream (square) was compared with untreated skin as a reference (circle).

Vertical axis: Caffeine concentration, expressed in mmol/g keratin.

Horizontal axis: Skin depth, in μm

Osmotic parameters were extracted from a computational adult model.

3-Predictions on Infant Skin

The final step involves using appropriate transformations to transfer caffeine penetration parameters into a computational model of infant skin to simulate predicted caffeine penetration in infant skin.

The predicted caffeine penetration on skin treated with the barrier cream (square) and untreated reference skin (circle) are shown below.

Vertical axis: Caffeine concentration, expressed in mmol/g keratin.

Horizontal axis: Skin depth, in μm

Finally, from the ratio of the area under the curve (AUC) of untreated skin to the AUC of skin treated with the barrier cream shown below, we can calculate the predicted percentage of protection of the barrier cream: Protection % = 100 × (AUC(untreated) - AUC(product)) / AUC(untreated) = 89.18%

Example 5: Moisturizer Simulation

Experimental data were collected from six volunteers aged between 18 and 40.

The localized substance tested :

- Moisturizer A: An emulsion containing glycerin (12%), petrolatum (4%), distearate dimethyl ammonium chloride, and water.

- Moisturizer B: A structured emulsion containing petrolatum (40%), glycerin (12%), distearate dimethyl ammonium chloride, and water.

plan

1. Allow yourself 5 minutes in a temperature/humidity controlled room.

2. Apply a topical substance to the forearm and leave it on for 30 minutes.

3. Apply the caffeine patch to the forearm (same location) and leave it on for 30 minutes.

4- Take measurements in the fingerprint area

result

1- Experimental data on adult skin

Data from skin treated with moisturizer A (square) were compared with data from skin treated with moisturizer B (triangle) and reference untreated skin (circle) (i.e., no topical substance was applied in step 2 of the protocol).

Vertical axis: Caffeine concentration, expressed in mmol/g keratin.

Horizontal axis: Skin depth, in μm

Permeation data were extracted from the experimental results and transferred to a computational model of adult skin.

2-Adult Skin Modeling

The next step is to define skin permeability parameters on a computational model of adult skin so that it can accurately simulate the experimental data provided above.

These parameters are calculated from the slope of the caffeine osmotic distribution.

The results for the adult model are shown below.

Skin treated with moisturizer A (square) was compared with skin treated with moisturizer B (triangle) and with untreated skin as a reference (circle).

Vertical axis: Caffeine concentration, expressed in mmol/g keratin.

Horizontal axis: Skin depth, in μm

Osmotic parameters were extracted from a computational adult model.

3-Predictions on Infant Skin

The final step involves using appropriate transformations to transfer caffeine penetration parameters into a computational model of infant skin to simulate predicted caffeine penetration in infant skin.

The predicted results of caffeine penetration on skin treated with moisturizer A (square), skin treated with moisturizer B (triangle), and reference untreated skin (circle) are shown below.

Vertical axis: Caffeine concentration, expressed in mmol/g keratin.

Horizontal axis: Skin depth, in μm

Finally, from the ratio of the area under the curve (AUC) of untreated skin to the AUC of moisturized skin shown below, we can calculate the predicted percentage of protection provided by the moisturizer:

For moisturizer A

Protection %: Not applicable

The area under the curve (AUC) for moisturizer A was better than that for the untreated reference. The simulation predicted no protective effect on infant skin.

For moisturizer B

Protection % = 100 × (AUC(untreated) - AUC(product)) / AUC(untreated) = 17.72%.

It should be understood that although various aspects of this disclosure have been shown and described by way of example, the invention protected by the claims herein is not limited thereto, but may be practiced in other ways differently according to the scope of the claims set forth in this patent application and/or any derivative patent applications.

Claims (5)

1. A method for evaluating the potential effects of a surfactant system on infant skin, comprising: a) Apply the surfactant system topically to adult skin; b) Apply the marker topically to adult skin treated with the surfactant system; c) Measure the penetration of the marker into adult skin treated with the surfactant system; d) Visualize the permeation of the marker by optimizing permeation parameters using a computational model of adult skin permeation, so that the model of adult skin permeation distribution matches experimental data, wherein the permeation parameters are selected from: skin surface concentration C _{_surface}, stratum corneum permeability coefficient P _{_SC} , and active epidermal permeability coefficient P _{_VE} ; and; e) The optimized permeation parameters are transferred to the computational model of infant skin, resulting in a higher skin surface concentration (C _{_surface}) in the infant skin model compared to the adult skin permeation model, and ensuring that the stratum corneum permeability coefficient (PS _{_SC)} and the living epidermal permeability coefficient (PS_{_VE}) are identical between the two models; and f) Determine the penetration of the marker in a computational model of the infant's skin. The EPISIM platform is used as a computational model for skin penetration in the adults. 2. The method according to claim 1, wherein the marker is caffeine. 3. The method according to claim 1, wherein the calculation model for adult skin permeability is a reagent-based model. 4. The method according to claim 1, wherein the skin surface concentration C _surface parameter in the calculation model of infant skin is twice the skin surface concentration C _surface parameter in the calculation model of adult skin permeability. 5. A surfactant system selected by the method of claim 1.