Formulating Cleansers for Sensitive Skin:creating a skin compatible cleanser

Russel Waltersrwalter2@its.jnj.com

TeamWorks, Chicago, IL

31 March 2010

Sensitive Skin Cleanser brief

Design a skin cleanser that is….

1) Non-irritating

2) Ideal for sensitive skin

3) Smells great

4) High foaming

5) Clear

6) Preservative free

7) “Cures Eczema”

XYZsensitive

skin facial cleanser

Cleansing for Sensitive Skin

What is sensitive skin…?

www.Drugstore.com : “Sensitive skin” = 265 products

Sensitive skin is many things…Dermatitis, atopic dermatitis (eczema), rosacea, psoriasis, ichthyosis, seborrhea, contact dermatitis, surfactant-induced, poison ivy, xerosis, acne, diaper rash,

inflammation of the skin with many causes: allergenic response, contact with irritants, retinol, many others

reduced skin barrier: compromised skin or thinner skin: Aging skin & infant & toddler skin

involves some kind of impaired barrier, burning and stinging, swollen red itchy skin

Skin that requires less aggressive, milder cleansing

Formulation Strategies for sensitive skin…

1) Add sensitive skin to the label the of a current facial skin cleanser

2) Product forms: creamy non-foaming, ~non-cleansing

3) Create a well designed skin compatible cleansers• skin & surfactant interactions with skin• tradeoffs• other components to add: anti-inflammatory ingredients• and not to add: allergens, unnecessary ingredients

XYZfacial

cleanser

XYZsensitive

skin facial cleanser

Skin & skin lipidsCeramides Cholesterol Surfactant Fatty acid

Bouwstra et al J Lipid Res. 42, 1759 (2001)

EM

Jiang et al, J Derm Sci, 32, 243 (2003)

Gonneke, Bouwstra et al Soc Invest Derm, 117, 710 (2001)

X-ray scattering

Domain mosaic model, SC lipid organization (Forslind, 1994, Acta Derm Venereo)

• 3 lipid phases (orthorhombic, hexagonal, disordered or liquid)

Crystalline domainsDisordered regions

X-ray diffraction

Study of skin lipids

Cleanser(Surfactant monomers & micelles)

Skin(Surface layers)

Inflammation Oxidative Stress

Cell Signaling

2) Remain in skin and alter/ disrupt skin structure

Surfactants, cleansers, interact with skin

1) RemoveBarrier Components (lipids, NMF, cerimides, enzymes)

ImpairedBarrier

Redness Dryness, Itchy

SensorialIrritation

Uncomfortable

www.themomsbuzz.com/moms_buzz/health/index.html

Surfactant have many effects on skin

• lipid removal

• NMF removal

• enzyme disruption

• protein denaturation

• lipid disorganizations

• penetrate into skin

• membrane disruption

• inflammation

because surfactants can interact with skin in many ways there are many properties of surfactant that are important in achieving a mild skin cleanser.

there are dozens of measurement to asses cleanser mildness- all measure some aspect of surfactant/skin compatibility – hopefully.

Understanding of physical chemistry of surfactant systems

Surfactant at Air / Water @ equilibrium

Whilemy tensiometry

Surfactant penetration into SC: IR, Raman

Size of micelles –light scattering

Thermodynamics of micelle disassociation -μcalorimetry

Surfactant dynamicsPendant drop

micelle surface chargeZeta potential

Sensitive Skin Cleanser briefDesign a skin cleanser that is….

1) Non-irritating

2) Ideal for sensitive skin

3) Smells great

4) High foaming

5) Clear

6) Preservative free

7) “Cures Eczema”

XYZsensitive

skin facial cleanser

target

R. Walters, M. Fevola, Cosm. & Tol. 123 (2008) 53-60.

A cleanser for sensitive skin cannot be all things

“Monomer theory” of surfactant-induced irritation:• Surfactant Monomer causes irritation. Micelles are too large to penetrate into tissue

• Surfactant systems with low CMCs are less irritating; lower monomer concentration

• Led to desire to decrease the CMC; Mixed surfactant systems (e.g. anionic + amphoteric).

High CMC surfactant

Micelle

Low CMC surfactantMonomer

Starting point was usually SLS, adding a co-surfactant does reduce irritation

Monomer theory not the full story…1) High CMC surfactant are not necessarily irritating: 2) Surfactant systems CMC << conc. that causes irritation3) Irritation = f(concentration)

“…mixed micelles of [surfactant] mixtures reduce the concentration of the irritating monomeric surfactant species.” Surfactants: Strategic Personal Care Ingredients, 2005

Monomer theory: problems… 1) Surfactant systems CMC << conc. that causes irritation

CMC ~ 0.1wt% surfactant, while concentration in contact with skin ~2 wt%the vast majority of surfactant exist in micelle (a small fraction as monomer)

Patent US6468614

2) Irritation = f(concentration > CMC) 3) No correlation between CMC &

surfactant aggressiveness

?

4) Time dependence

0.0

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0.5

0.6

0.7

0.0 1.0 2.0 3.0 4.0 5.0

Cleanser Concentration (% formula)

Dye

Lea

kage

(a.u

.)adult shampoo

adult body wash

baby cleanser

Transepithelial Permeation (TEP), surfactant aggressiveness

Cottin, M.; Zanvit, A. Toxicology in Vitro 1997 11(4), 399-405.Clothier, R. et al. Toxicology in Vitro 1999 13(4/5), 713-717.

• EC50: % concentration of formula at which 50% of maximum dye leakage occurs

• Mildness increases with increasing EC50

Diluted formula and fluorescein dye are applied to MDCK cell monolayer 15 min

epithelial monolayer

Dye leakage quantified via UV absorbance

0.0

0.2

0.4

0.6

0.8

1.0

1.2

0.1 1 10 100Concentration (% formula)

Dye

leak

age

(a.u

.)

EC50

Idealized TEP data

R. Walters, M. Fevola, J. LiBrizzi, K. Martin, Cosmetics and Toiletries (2008)

It is not just monomer… micelles size is important

Micelle size (nm) 3 4 6

Mildness (TEP) 0.1 0.5 3.5

Foam (ml): 820 720 350

Adult Body Face / Baby

Milder – more tissue compatible

Micelle size and mildness

Average Micelle (nm)

TEP Score (%) Mildness

Adult Shampoo 3.7 0.76

Baby Shampoo 7.1 3.89

0.0

0.1

0.2

0.3

0 2 4 6 8 10 12 14

Frac

tion

of m

icel

les

Hydrodynamic Diameter, dH (nm)

PANTENE

JBS Surfactant micelles can penetrate through aqueous pores in the stratum corneum…

pore size of SC = 2.0 – 5.6nm

By making lager micelles, cleanser are more mild…

Adult ShampooMild baby/face cleanser

Dynamic light scattering

Moore, Blankschtien, J Cosmet. Sci. 54 29 (2003)

Blends of traditional surfactant systems

SLS sodium lauryl sulfate

SLES sodium lauryl ethyl sulfate

CAPB Cocamidol propyl betaine

PEG-80 sorbitane Laurate

body wash

SLES, CAPB

adult shampoo

SLS

face / babySLES, CAPB, PEG-80SL

Blending larger & larger surfactants… to create larger more stable micelles

R. Walters, M. Fevola, J. LiBrizzi, K. Martin. “Designing Cleansers for the Unique Needs of Baby Skin”, Cosm. & Tol. 123 (2008) 53-60.

addition of hm-polymer; new surfactant architecture

Anionic (SLS)

Ethoxylated anionic (SLES, TDES)

Amphoteric(CAPB)

Non-ionic(PEG-80 sorbitane Laurate)

D. Discher, F. Ahmed, Polymersomes, Annual Review of Biomedical Engineering, 8, 323 (2006)

PEGylation creates invisible “stealth vesicles”

PEO covered micelles

NMT’s micelle model Fevola, Walters

PEG-80 Sorbitan Laurate

Lipid Biophysics:PEG phospholipid interactions suggest , the PEG lays down on the phospholipid surface, covering the bilayer

also fits light scattering micelle size results

G. Wu, et al. Interaction between Lipid Monolayers and Poloxamer 188: An X-Ray Reflectivity and Diffraction Study, Biophys J. 5, 3159 (2005).

Minimizing surfactant irritation potential with polymers• Water-soluble polymers (e.g. PEO, PVP) proposed for irritation mitigation

– Explained in context of “monomer theory”– When CAC < CMC, polymer-surfactant aggregation results in lower monomer

activity

• Blankschtein et al.: PEO minimizes SDS micelle penetration– Roadblocks to commercialization: Efficiency & Cost

Goddard, E. D. In Principles of Polymer Science and Technology in Cosmetics and Personal Care; Eds. Marcel Dekker, Inc.: New York, 1999; pp 181-215.

Cabane, B. J. Phys. Chem 1977, 81 1639.Maltesh_somasundarian, J Coll. Interface Sci, 157, 14 1993.

PEO / SDS pearl necklace model

Moore, Blankschtien, J Cosmet. Sci. 54 29 (2003)

Micelle charge – Zeta potential

A Lips, Role of Surfactant Charge in Protein Denaturation and Surfactant-Induced Skin Irritation, Surfactants in Personal Care Products and Decorative Cosmetics 177-187 CRC Press (2006)

SDS: anionic surfactants

high negative charge

SLES/CAPB: anionic/amphoteric surfactants

moderate negative charge

APG

high (-) charge pushes head groups apart, and creates smaller more dynamics micelles – more aggressive

Addition of glycerin

S. Ghosh, et al., “Visualization and quantification of skin barrier perturbation induced by surfactant-humectant systems using two-photon fluorescence microscopy”, J. Cos. Sci. 59 263 (2008)

1% SDS

1% SDS + 10% glycerine

S. Ghosh, et al.“Ranking of aqueous surfactant-humectant systems based on an analysis of in vitro and in vivo skin barrier perturbation measurements” J. Cosmet Sci. 2007;58(6):599

Two-photon microscopy (TPM)

Addition of glycerin has been shown in many models to improve cleanser compatibility with skin.

This has long been known, glycerin was added to soaps to create milder soap.

Why…proposed that glycerin blocks or closes the aqueous channels in the SC.

also, glycerin alters the aqueous phase, likely changing micelle properties.

Low Mw Hydrophobically-modified polymers (HMPs) to mitigate surfactant irritation

Hydrophobically-modified polymers (HMPs)…

Hydrophobic group

Hydrophilic polymer backbone

…added to surfactant based cleansers… Mammalian Tissue

HMP-Surfactant Complex Surfactant

Micelle

…bind surfactant to form HMP-surfactant complexes. Excess surfactant forms micelles.

HMPs reduce surfactant penetration

Surface tensiometry and “delta CMC”

Idealized plot of surface tension vs. surfactant concentration

10 100 1000 10000

Surfactant Concentration (mg/L)

Surfactant

HMP + Surfactant

20

30

40

50

60

70

1

Surf

ace

Tens

ion

(dyn

/cm

)

CMC CMCPΔCMC

CAC

LiBrizzi, J.; Protz, A.; Ganopolsky, I.; Walters, R. US 7,157,414, 2007. Goddard, E. D. In Principles of Polymer Science and Technology in Cosmetics and Personal Care; Goddard, E. D.; Gruber, J. V., Eds. Marcel Dekker, Inc.: New York, 1999; pp 113-180.

Wilhelmy plate tensiometry

ΔCMC and irritation reduction

Importance of ΔCMC:

• Measure of HMP surfactant binding efficiency

• Correlates to irritation mitigation and reduced surfactant penetration

LiBrizzi, J.; Protz, A.; Ganopolsky, I.; Walters, R. Methods of reducing irritation in personal care compositions. US 7,157,414, 2007.

Addition of hmp results in decreased surfacatnt aggressiveness

TEP, Surfactant aggressiveness

Surfactant Penetration into Skin, Clinical ModelStudy Population

Adults aged 21-50, with no history of skin condition, n=9-10 subjects/cellStudy Design

Expose volar forearms to diluted cleanser solution under occlusive patch for 4 hours; rinse/dry skin, take 10 consecutive tape strips

Quantify surfactant & total protein concentration on each individual tape stripEvaluations

Surfactant concentration, via colorimetric detection on each tapeTotal protein concentration on each tape

(μg

surfa

ctan

t / μ

g pr

otei

n)

~depth into skin; (# of tapes; 1 = skin surface)

0

0.1

0.2

0.3

1 2 3 4 5 6 7 8 9 10

6% TDES

6% TDES + 1.8% hm-polymer

Control

Inflammatory Response (in vitro):Surfactant w/ and w/o hmp

PlaceboTDES/CAPB TDES/CAPB/

hm-polymer

43% reduction vs placebo

** p < 0.05 vs Placebo Control

**

In Vitro:

Skin cultures, Epiderm (Mattek) skin equivalence

Study Design

Exposure: 10% dilution for 1 hr, then rinses

Cytokine response measured after 24 hours

Inflammatory Mediators (IL-1a, IL-1ra)

6 independent wells for each cleanser

Summary• New understanding of surfactant tissue penetration (i.e. micelle

penetration model) offers new insight for design of mild cleansers

• Cleanser can be designed to suite sensitive skin consumers, but there are limitations on fomrulation

• HMPs can be used to effectively reduce free micelle concentration, enabling milder more tissue compatible cleanser (reduced surfactant penetration, reduced inflammation markets, etc.)

Acknowledgements:Johnson & Johnson

Michael J. Fevola Joseph J. LiBrizzi

Neena TierneyKatharine Martin

Lisa GandolfiHuda Jerri

Aaron Nelson

Rutgers UniversityRichard Mendelsohn

Carol FlachGuangru Mao