393 The Human Stratum Corneum
PEG ethers showed significant release of inflammatory markers compared to PEG esters.
Two exceptions among their tested esters were a PEG ester (PEG-25 hydrogenated castor
oil), and a sucrose ester (sucrose laurate). The large number of nonionic surfactants allowed
the authors to examine their results for structure-function relationships. Most parameters
such as CMC and HLB did not show any correlation with their impact on cytotoxicity.
However, packing parameter or phase behavior seem to show an interesting correlation with
the higher packing parameter, or the more crystalline or lamellar structure the structure is,
the lower its tendency is to release inflammatory markers. This observation is also consistent
with the previously reported correlation between micelle charge density and skin irritation
potential for ionic surfactants as higher charge density results in lower packing parameters.34
The results presented by Lemery et al. clearly show that certain nonionic surfactants can be
harsher than others.73 Further research to understand the molecular mechanism governing
the effect of nonionic surfactants on skin penetration and their potential for skin irritation
is warranted. With increasing interest in enhancing skin penetration for advanced skin care
benefits, the importance of the delicate balance among enhancing penetration, stabilizing
emulsions, and preventing skin irritation may become important in the coming years.
EFFECT OF PENETRATION ENHANCERS ON SC STRUCTURE
Delivery of drugs and cosmetic actives through skin have been an active area of research
for decades, and it has been reviewed extensively.74–78 It is generally believed that a
molecular weight of 500 Daltons is a cut off for penetration of molecules into skin.78 The
extent of penetration of molecules with molecular weights is very much dependent upon
factors such as charge, polarity, and hydrophobicity. In this context, an approach often
employed to enhance delivery of actives is to use chemical penetration enhancers. Typical
penetration enhancers include surfactants, solvents, terpenes, azone and osmolytes.79
Among the surfactants-class, ionic, amphoteric, and nonionic surfactants are used as
penetration enhancers. Solvents (such as water, ethanol, and propylene glycol), terpenes
(such as menthol and camphor), and osmolytes, (such as glycerol and urea) are also used for
enhancing penetration through the SC. Penetration enhancers may function by multiple
mechanisms including enhancing solubility of actives, modifying the lipid structure, and
enhancing polar pathway by swelling the SC. Mechanisms by which surfactants impact the
penetration has been discussed in earlier sections in the context of skin cleansing. Since the
focus of this paper is on the interaction of ingredients with SC, the effect different types of
penetration enhancers on the structure of SC will be briefly reviewed here.
Moghadam et al. recently reviewed the effect of various types of penetration enhancers
on the SC lipid barrier.80 In their study, they used both SAXS and WAXS to investigate
structural changes to SC upon exposure to various penetration enhancers. Depending upon
the degree of alteration to the lipid structure observed from their SAXS patterns, they
classified the penetration enhancers into five categories. These include minimal changes
to lipid structure, slight disordering, significant disordering, disruption of the lipid layer,
and formation of new lipid structure with incorporation of the enhancers. Some of their
observations are summarized below:
• Solvents such as ethanol and PG had the least impact on the SC lipid structure, even
though both have been shown to enhance skin penetration of actives. Moghadam et al.
attributed this to effect of solvent on solubility and partitioning of actives into the SC.80

394 JOURNAL OF COSMETIC SCIENCE
• In general, surfactants had most impact on disordering the lipid layers and they also
enhanced the penetration of actives to a higher degree than did terpenes and solvents.
Impact was seen in either SPPs or LPPS or in some cases, both.
• Use of dodecyl trimethyl ammonium bromide and benzalkonium chloride, resulted
in the disappearance of the orthorhombic lipid fraction of the SC bilayer, indicating
their strong lipid disruption potential. Similarly, SDS also caused disruption of the lipid
phase, which resulted in the formation of a new lipid phase that incorporated SDS
into the structure. The impact of nonionic surfactants was less than that of their ionic
counterparts.
• Among terpenes and solvents, those with ring structures had less impact on the lipid
structure than those with alkyl chains.
• Authors also concluded that the degree of damage did not always correlate with the extent
of enhancement in penetration suggesting that it may be possible to find penetration
enhancers that are less damaging to the lipid barrier.
Phan et al. also investigated the effect of chemical penetration enhancers on SC structure.81
They used natural abundance 13 C polarization transfer solid-state nuclear magnetic resonance
(NMR) on intact porcine SC to investigate the changes in the mobility of lipid and protein
components upon exposure to chemical penetration enhancers such as monoterpenes, fatty
acids, osmolytes, surfactant, and azone. They also included the effect SC hydration level on
the performance of these penetration enhancers. They used dry SC powder obtained from
porcine skin in their NMR experiments and hydrated them to 20% or 40% by weight of
the SC sample. Their main conclusion was that hydrophobic and amphiphilic compounds
mainly affected the lipid regions, whereas osmolytes and hydrophilic compounds affected
both lipid and protein regions. They also concluded that the effect of penetration enhancers
depended on the hydration level of the SC with higher hydration impacting the structure
more than the lower one.
It is clear from the literature that penetration enhancers influence SC barrier properties.
Importantly, the degree of damage did not necessarily correlate with the magnitude of
penetration enhancement, indicating that it is possible to enhance the penetration without
causing major damage to the corneum. It is also important to ensure that the barrier is
restored to its normal state within a reasonable time. Not much work has been done on
understanding the restoration of barrier properties after exposure to penetration enhancers.
MOISTURIZER ACTIVES AND THEIR IMPACT ON THE SC BARRIER
Typical moisturizer actives include occlusives, humectants, emollients, and lipidic materials
such as fatty acids.65–67 Lately, skin identical lipids such as fatty acids, ceramides, and
sterols in ratios that are likely to form bilayer structures are being used to improve the SC
barrier.66,82,83 The role of moisturizer is to alleviate symptoms of dry skin and to help the SC
rebuild a healthy natural barrier. Moisturizer performance can vary significantly depending
upon the actives in them.
OCCLUSIVES
Petrolatum, a hydrocarbon based occlusive, is still the gold standard when it comes to
preventing water loss from damaged skin.84–86 White purified petrolatum has been shown