Back to Basics

Journal of Cosmetic Dermatology, 11, 310--317

Stability, transdermal penetration, and cutaneous effects of ascorbic

acid and its derivatives
Nicholas P J Stamford, BSc(Hons), MA, MMngt, PhD
Ultraceuticals Pty Ltd, Gladesville, NSW, Australia

Summary Topically applied antioxidants exert their benefits by offering protection from
damaging free radicals and over-the-counter cosmeceuticals incorporating
antioxidants are among the most popular anti-aging products available. One potent
antioxidant of particular note, vitamin C, has been extensively utilized because it
possesses a variety of other cutaneous benefits including photoprotection from UV A
& B, neocollagenesis, inhibition of melanogenesis and improvement of a variety of
inflammatory skin disorders. However, the instability of this water-soluble vitamin,
together with difficulties associated with its topical delivery, has presented issues for
the formulation chemist. This article reviews the scientific data and clinical studies
that underpin the stability, percutaneous absorption, and cutaneous effects of vitamin
C together with its commonly utilized, commercially available derivatives.
Keywords: ascorbic acid, vitamin C, topical, photoprotection, melanogenesis, neocollagenesis

have been recorded after topical application.27 For

Introduction
L-Ascorbic acid (AA, 1; Scheme 1) has many important
biochemical functions but is most typically identified as
the primary water-soluble nonenzymic antioxidant in
human tissue.1 As such much of the research on AA
has focused on its role as a free-radical scavenger.
Antioxidants, like AA, act by scavenging and reducing
free radicals to less reactive species, thus reducing oxida-
tive damage to critical cellular components. In this pro-
cess, AA is oxidized to dehydro-L-ascorbic acid 2 which
can be re-reduced to AA by the endogenous antioxidant
pool or decay irreversibly to diketogulonic acid 3.
Stability and percutaneous delivery
Due to AAs inherent hydrophilicity, penetration of AA
across the skin might be expected to be poor. Neverth-
eless, significantly enhanced cutaneous levels of AA
Correspondence: Dr N P J Stamford, Suite 2, Level 4, 436-484 Victoria Rd,
Gladesville NSW 2111, Australia. E-mail: pats@ultraceuticals.com.au
Accepted for publication August 23, 2012
optimal penetration of the epidermal barrier,6 aqueous
formulations of AA (including its sodium salt) must be
at a pH which is below the pKa of AA itself (pKa 4.2),
thus reducing the charge density on the molecule. In
porcine skin models, under these conditions, applica-
tion of up to 20% AA in an aqueous formulation
increased the underlying AA concentration 20-fold.6
The resultant tissue saturation was achieved with only
3 days of application and the half-life for AA decline
was approximately 4 days.
Unfortunately, the beneficial antioxidant effect of AA
also underscores the primary challenge in developing
AA formulations, ensuring its stability. Oxidation of
AA is triggered by its ionization in aqueous solution.
Other factors that increase the rate of degradation of
AA are high pH or temperature, the presence of dis-
solved oxygen, and catalytic amounts of metal ions.810
Indeed, the degradation of AA, most often accompanied
by a yellowish discolouration, can proceed rapidly
depending on formulation, packaging and storage
conditions.1114 Various stabilization strategies can be
attempted to address the issue, such as exclusion of

310 2012 Wiley Periodicals, Inc.

 Ascorbic acid review . N P J Stamford

HO HO HO
6
5 O O O O OH
4 1
HO 2H+ , 2e- HO H2O HO CO2H
H 3 2 H H

1 HO OH 2 O O 3 O O

SCHEME 1

oxygen during formulation, oxygen-impermeable packag-
ing, encapsulation, low pH, minimization of water, and
inclusion of electrolytes and other antioxidants.1517
Despite these strategies AA stability remains a challenge,
and some of these approaches can lead to cost and diffi-
culty in formulation. A summary of the salient stability,
percutaneous absorption, and therapeutic dermalogical
characteristics of AA and its derivatives is given in
Table 1.
Ascorbyl 2-phosphates, usually formulated as their
sodium (SAP) and magnesium (MAP; 4) salts, are sta-
strated that topically applied ascorbyl phosphate salts
are, at very best, poorly absorbed in comparison with
AA.3,6 In one study, SAP was not observed to pene-
trate the epidermis.18 In another experiment, only AA
and not MAP improved skin barrier function in vivo
suggesting a difference in rates of skin penetration.19
However, skin treatment with lasers, microdermabra-
sion, or by sonophoresis has been shown to dramati-
cally improve topical delivery of both vitamin C and
derivatives that normally demonstrate poor dermal
penetration.2022

HO O

O O O O O
HO HO
-
O
H Mg 2+ H

4 HO O 5 HO OH
O-
O
HO

O O
HO O
O O O
H H O

HO O O O
O
OH O
O
O

HO OH
6 7
OH

ble in solution at ~pH 7. Introduction of the phosphate
group in the second position of the cyclic ring protects
the enediol system of the molecule from oxidation;
ascorbyl phosphate salts are therefore not in them-
selves antioxidant agents.13 As a consequence, their
effectiveness depends upon their conversion in vivo to
AA (presumably accomplished by an alkaline phospha-
tase). Confirmation of trans-dermal penetration and
conversion to AA has been demonstrated for MAP.18
Although the stability of the ascorbyl phosphate
salts is significantly greater than for AA, with their
increased charge density, skin penetration presents an
even greater challenge. Indeed, it has been demon-
The most frequently commercially utilized nonsalt deriva-
tives of AA such as ascorbyl 6-palmitate23,24 (AA-Pal; 5),
ascorbyl 2-glucoside25 (AA-2G; 6), and tetra-isopalmitoyl
ascorbate26,27 (VC-IP; 7) to a greater or lesser extent all dem-
onstrate superior stability and ease of formulation to AA.
Unlike the ascorbyl phosphate salts, AA-2G and VC-IP
(which are all modified at the carbon 2 of the cyclic ring), the
chemical modification of AA-Pal is located on carbon 6 and
as such provides no protection to AA from oxidative degra-
dation. AA-Pal is therefore less stable than these other forms
in solutions and topical formulations. The stability of AA-Pal
over AA therefore depends largely on the structural proper-
ties of the formulations in which it is incorporated.13,23

2012 Wiley Periodicals, Inc. 311

Ascorbic acid review . N P J Stamford

Table 1 Summary of the stability, percutaneous absorption, and therapeutic characteristics of AA and its derivatives.

Sodium Magnesium Ascorbyl Ascorbyl

ascorbyl ascorbyl Ascorbyl tetraiso- Ascorbyl 2-phosphate 3-O-Ethyl
Ascorbic acid phosphate phosphate palmitate palmitate glucoside 6-palmitate ascorbate
(AA) (SAP) (MAP) (AA-PAL) (VC-IP) (AA-2G) (APPS) (EAC)

Stability If pH < 3.5 in Yes Yes Similar to AA Yes Yes Yes No data
aqueous at pH7 at pH7 pH < 5 at pH7
solutions;
Anhydrous

Percutaneous Yes Yes Yes Yes Yes Yes Yes Yes

absorption Human ex vivo Animal Animal Animal in vivo Human ex in vitro Animal Animal
(as solution or ex vivo ex vivo (formulation vivo > MAP in vivo ex vivo
microparticles) (but limited) (but limited) dependent) (trade > AA-2G
publication)

Conversion N/A No data Yes No data Yes Yes Yes No data

to AA in vitro in vitro in vitro in vitro

Photoprotection Yes Yes No data Yes In vitro data Yes No data No data
Human in vivo Human Animal in vivo Human
in vivo in vivo
< AA < SAP

Cutaneous Yes Yes Yes Yes Yes Yes No data No data

neocollagenesis Human in vivo in vitro in vitro in vitro in vitro in vitro
< MAP AA (trade
publication)

Inhibition of Yes Yes Yes No data Yes Yes Yes Yes

melanogenesis Human in vivo Human Human in vivo Human in vitro Human Human
in vivo in vivo in vivo in vivo
(trade (trade
publication) publication)

O HO In contrast to AA-Pal, the stable AA derivative AA-

O O O O
HO
O- 2+
H Mg
HO O O
8
O
O-
With the addition of a lipid-soluble group, it might
be expected that AA-Pal should provide a marked
increase in AA levels in the skin compared to topically
applied AA alone. However, one study has shown that
topical application of AA-Pal did not increase skin lev-
els of AA.6 Although AA-Pal appears to readily enter
the skin,28 and microemulsions were able to deliver
AA-Pal to the skin,29 it is possible that its conversion
to AA may be limited.
However, this observation is incongruous with those
made with a similar derivative, ascorbic 2-phosphate
6-palmitate (APPS, 8). APPS has been shown to pene-
trate into the skin30 and it appears it can be converted
to ascorbic acid after delivery.31 Nonetheless, like SAP,
the ability of APPS to penetrate the skin by topical
application does seem very limited.32
O
2G25 6 is hydrolyzed by cellular a-glucosidase to release
HO
AA.33 Topically applied AA-2G has also been shown to
H
exhibit the physiological effects of AA.34,35 AA-2G does
OH
9
penetrate the skin,22 but the rate of penetration and in
vivo conversion to AA has not yet been determined. In
comparison, and possibly unsurprisingly, the permeabil-
ity of the lipophilic derivative 3-O-ethyl ascorbic acid
(EAC; 9)36 appears to be greater than for AA-2G.22 The
3-alkyl-ascorbic acids like EAC have been tested as
antioxidants and were found to be potent chain-breaking
agents with a high affinity for biomembranes.36
The other stable AA analog used in cosmeceutical for-
mulation is VC-IP 7 in which four isopalmitic acid esters
are located at the 2, 3, 5, and 6 carbon positions. When
topically applied, it exhibited the physiological effects of
AA which leads to the suggestion that, like AA-2G, it
both penetrates the dermis and is converted in vivo to
AA.26 In addition, in reconstructed skin models, VC-IP
does penetrate and is converted efficiently to AA.27
However, a trade publication26 suggests percutaneous
absorption on excised human skin (on a molar

312 2012 Wiley Periodicals, Inc.


equivalent basis) was only about 4-fold greater than
that for the poorly absorbed MAP. Furthermore, the
manufacturer (Nikko Chemicals Co Ltd, Tokyo, Japan)
indicates that in formulations where pH > 5, VC-IP is
not stable and discolouration was observed to be propor-
tional to the degree of VC-IP degradation.
Photoprotection
Among the many important biochemical functions of
AA, it is its potent antioxidant ability which is princi-
pally acknowledged. The generation of reactive oxygen
species and other free radicals by normal cellular pro-
cesses, UV irradiation and pollutants are associated
with carcinogenesis and aging. In this regard, several
clinical studies showing the benefits of topically applied
vitamin C against the biochemical and physically iden-
tifiable processes of aging due to oxidative stress have
recently been reviewed.7,37
As noted earlier, the topical application of AA has
been shown to significantly elevate cutaneous levels of
this vitamin, and this correlates with protection of the
skin from UVB-induced oxidative damage as measured
by a decrease in UVB erythema and sunburn cell forma-
tion.3,38,39 However, as already suggested, AA does not
act independently of other cellular processes in its role
as an antioxidant. Importantly AA is also capable of
recycling photo-oxidized a-tocopherol thereby regenerat-
ing vitamin E and contributing to an antioxidant reser-
voir in the skin.40 AA therefore not only acts through
scavenging reactive oxygen species itself but also poten-
tiates the antioxidant activity of a-tocopherol for protec-
tion against free-radical damage.4143 In fact, topical AA
combined with a-tocopherol provided notably increased
photoprotection against UV-induced erythema and
diminished the number of sunburn cells as compared to
that seen for each antioxidant individually39 which
underlines the synergistic effect, particularly in protection
against UV-induced oxidative damage. The presence of a-
tocopherol in formulations may also have a stabilizing
effect on the photo-degradation of ascorbic acid.44
Like AA, AA-Pal is itself biologically active. It can
directly generate the ascorbyl radical, an action that
also drives the radical scavenging process by AA.45
However, topical treatment with AA-Pal was not as
effective as AA in providing protection against UVB
radiation exposure in mouse models,28 although when
applied to porcine skin did provide protection against
ultraviolet-induced free radicals.29 However, another
study in human keratinocyte cell culture has suggested
that despite its antioxidant properties, AA-Pal may
potentiate skin damage following UVB irradiation.46,47
2012 Wiley Periodicals, Inc.
Ascorbic acid review . N P J Stamford
The protective effect of SAP on UVB-induced cutane-
ous damage in mouse skin in vitro is due to the main-
tenance of a normal AA level by conversion of SAP to
AA in skin tissue.48 However, topically applied SAP
was less effective than identically applied AA in reduc-
ing oxidative stress in human skin in vivo.11 Nonethe-
less, MAP did repress mortality of UVB irradiated
mouse keratinocytes in vitro more markedly than
AA.49 Keratinocytes are known to actively uptake vita-
min C and possess efficient systems to maintain high
intracellular levels of vitamin C.50 The apparent differ-
ence between the in vitro and ex vivo effects of ascorbyl
phosphate salts may therefore further underscore the
difficulty associated with their dermal penetration.
AA-2G reduced UV-induced damage of human skin
keratinocytes and fibroblasts more effectively than
ascorbyl 2-phosphate51 and demonstrated a photopro-
tective effect against UVB.41 VC-IP was found to sup-
press the elevation of intracellular peroxide after UVB
irradiation and provide enhanced cellular tolerance
against UVB and reactive oxygen species.27 It also
showed antioxidant activity comparable with retinyl
palmitate and tocopheryl acetate in an in vitro chemi-
luminescence assay.52
Neocollagenesis
Apart from its role as a potent antioxidant, it has also
been demonstrated that AA functions as an essential
cofactor for the enzymes lysyl hydroxylase and prolyl
hydroxylase both of which are required for the post-
translational processing of types I and III collagen.
Because AA stimulates collagen production in the der-
mis (Fig. 1),5355 and can cause a dramatic increase in
fibroblast proliferation potentially resulting in greater
collagen production,56 it might be presumed that AA
possesses the potential to also increase collagen pro-
duction for wrinkle appearance reduction.
AA-2G increased collagen production on normal
human fibroblasts in vitro to a significantly lesser extent
than either ascorbyl 2-phosphate or AA, but did
enhance three-dimensional collagen mesh reorganiza-
tion at a lower concentration.57 However, an alterna-
tive study demonstrated that AA-2G successfully
stimulated collagen synthesis in cultured human fibro-
blasts with an effectiveness comparable to that of AA,35
while VC-IP is purported to increase collagen synthesis
greater than twofold over AA at the same dosage.26 In
other cultured human fibroblast experiments, MAP was
found to be equivalent to AA in stimulating collagen
synthesis, while SAP required at least a tenfold greater
concentration to produce the same effect as AA.58
313
Ascorbic acid review . N P J Stamford

AA-Pal augmented human intestinal smooth muscle
cells procollagen synthesis in vitro more effectively than
AA but induced similar increases in the amounts of
newly synthesized collagen secreted into the medium.59
AA also plays a role in collagen synthesis at the level
of gene expression.60,61 It has been shown to up-regu-
late collagen synthesis and increase the synthesis of
the inhibitor of metalloproteinase-I62 which decreases
UV-induced collagen degradation.
Inhibition of melanogenesis
Finally, AA has been shown to suppress melanin pro-
duction by reducing orthoquinones (such as dopaqui-
none) so that tyrosinase-dependent melanin formation
is prevented.63 In this way, AA has proven to be useful
for skin depigmentation.64 In the only comparative
study available, the melanin synthesis in B 16 mela-
noma cells was inhibited more by AA-2G than by
ascorbyl 2-phosphate.51 That these AA derivatives can
be transformed into the active antioxidant is the
most likely basis for their ability to suppress melanin
biosynthesis. It is therefore not surprising that clinical
effects have also been noted for MAP,6467 VC-IP,26,27
APPS,68 and EAC,69 although there is no comparative
data for these compounds.
Conclusions and outlook
Ascorbic acid and its derivatives have been ascribed
antiaging effects in several cosmetic studies in which
overall reduced facial photoaging (Fig. 2), improved
skin texture (Fig. 3), and improvement in skin collagen
and elastin have been well documented.11,52,70,71 Fun-
damental to these observations are the neocollegenic,
skin lightening, and antioxidant properties of AA for
which there is substantial evidence.
The instability and aqueous solubility of AA has his-
torically presented issues for formulation. Nevertheless,
the current understanding of AA now enables formula-
tion for more than acceptable transdermal penetration.
Unfortunately, it seems, many products in the market
still fail even the most rudimentary analysis (e.g. rapid
discolouration). However, the advent of chemically

a b

Figure 1 A high concentration anhydrous ascorbic acid preparation was applied topically onto the surface of freshly excised human
abdominal skin. Following an exposure time of 48 h with appropriate controls, skin discs were cut into sections, placed on slides, and
assessed using immunohistochemical (collagen type I) staining (details published previously55). Analysis was performed using micros-
copy. (a) Control 200; (b) Anhydrous ascorbic acid formulation 200.

a b

Figure 2 Photo-damaged skin (a) before and (b) 6 months after treatment with a high concentration anhydrous ascorbic acid cream
preparation applied once daily demonstrating reduction in facial redness, fine lines, and melasma.

314 2012 Wiley Periodicals, Inc.


a b
Figure 3 Facial skin (a) before and (b) 6 months after treatment with a high concentration anhydrous ascorbic acid cream preparation
applied once daily demonstrating reduction in hyperpigmentation and general improvement in skin quality.
modified analogs of AA has also helped to improve this
formulation issue and, with the exception of AA-Pal,
the oxidative stability of AA has been greatly improved.
Still, on current available evidence in the scientific liter-
ature, the effective transdermal penetration of these
analogs (especially the phosphate analogs), their con-
version to active AA and, ultimately, their comparative
clinical effectiveness still needs to be fully ascertained.
These concerns aside, cosmeceuticals containing appro-
priately formulated AA or its analogs for topical applica-
tion should play an essential role in the treatment of
aging skin.
Acknowledgments
The author would like to thank The University of
Technology Sydney for providing generous access to
their library facilities and to Ultraceuticals Pty Ltd who
provided Figures 1, 2, and 3.
References
1 Colven RM, Pinnell SR. Topical vitamin C in aging. Clin
Dermatol 1996; 14: 22734.
2 Kaplan MD, Moloney SJ, Troy WR et al. A new stabilized
ascorbic acid solution: percutaneous absorption and effect
on realtive collagen synthesis. J Cut Aging Cos Derm
1989; 1: 11521.
3 Darr D, Combs S, Dunston S et al. Topical vitamin C pro-
tects porcine skin from ultraviolet radiation induced dam-
age. Br J Dermatol 1992; 127: 24753.
4 Lee ARC, Tojo K. Characterization of skin permeation of
vitamin C: theoretical analysis of penetration profiles and
differential scanning calorimetry study. Chem Pharm Bull
1998; 46: 1747.
5 Leveque N, Muret P, Makki S et al. Ex vivo cutaneous
absorption assessment of a stabilized ascorbic acid formu-
lation using a microdialysis system. Skin Pharmacol Phys-
iol 2004; 17: 298303.
2012 Wiley Periodicals, Inc.
Ascorbic acid review . N P J Stamford
6 Pinnell SR, Yang H, Omar M et al. Topical L-ascorbic
acid: percutaneous absorption studies. Dermatol Surg
2001; 27: 13742.
7 Farris PK. Topical vitamin C: a useful agent for treating
photoaging and other dermatologic conditions. Dermatol
Surg 2005; 31: 8147.
8 Buettner GR, Jurkiewicz BA. Chemistry and biochemistry
of ascorbic acid. In: L Packer, ed. Handbook of Antioxi-
dants, Vol. 5. New York: Dekker; 1996; pp. 96100.
9 Tsao CS, Young M. A stabilised ascorbic acid solution.
Med Sci Res 1996; 24: 4735.
10 Ahmad I, Sheraz MA, Shaikh RH et al. Photostability of
ascorbic acid in aqueous and organic solvents. J Pharm
Res 2010; 3: 12379.
11 Raschke T, Koop U, Dusing HJ et al. Topical activity of
ascorbic acid: from in vitro optimization to in vivo efficacy.
Skin Pharmacol Physiol 2004; 17: 2006.
12 Gallarate M, Carlotti ME, Trotta M et al. On the stability
of ascorbic acid in emulsified systems for topical and cos-
metic use. Int J Pharm 1999; 188: 23341.
13 Austria R, Semenzato A, Bettero A. Stability of vitamin C
derivatives in solution and topical formulations. J Pharm
Biomed Anal 1997; 15: 795801.
14 Ahmad I, Sheraz MA, Ahmed S et al. Photostability and
interaction of ascorbic acid in cream formulations. AAPS
PharmSciTech 2011; 12: 91723.
15 Yang JH, Lee SY, Han YS et al. Efficient transdermal pen-
etration and improved stability of L-ascorbic acid. Bull
Korean Chem Soc 2003; 24: 499503.
16 Lee JS, Kim JW, Han SH et al. The stabilization of L-ascor-
bic acid in aqueous solution and water-in-oil-in-water
double emulsion by controlling pH and electrolyte con-
centration. J Cosmet Sci 2004; 55: 112.
17 Sheraz MA, Ahmed S, Ahmad I et al. Formulation and
stability of ascorbic acid in topical preparations. Sys Rev
Pharm 2011; 2: 8690.
18 Kobayashi S, Takehana M, Itoh S et al. Protective effect of
magnesium-L-ascorbyl-2 phosphate against skin damage
induced by UVB irradiation. Photochem Photobiol 1996;
64: 2248.
315
Ascorbic acid review . N P J Stamford
19 Maia Campos PMBG, Goncalves GMS, Gaspar LR. In vitro
antioxidant activity and in vivo efficacy of topical formula-
tions containing vitamin C and its derivatives studied by
non-invasive methods. Skin Res Technol 2008; 14: 37680.
20 Lee WR, Shen SC, Kuo-Hsien W et al. Lasers and micro-
dermabrasion enhance and control topical delivery of
vitamin C. J Invest Dermatol 2003; 121: 111825.
21 Hakozaki T, Takiwaki H, Miyamoto K et al. Ultrasound
enhanced skin-lightening effect of vitamin C and niacin-
amide. Skin Res Technol 2006; 12: 10513.
22 Hsiao CY, Huang CH, Hu S et al. Skin pretreatment with
lasers promotes the transdermal delivery of vitamin C
derivatives. Lasers Med Sci 2011; 26: 36976.
23 Spiclin P, Gasperlin M, Kmetec V. Stability of ascorbyl
palmitate in topical microemulsions. Int J Pharm 2001;
222: 2719.
24 Segall AI, Moyano MA. Stability of vitamin C derivatives
in topical formulations containing lipoic acid, vitamins A
and E. Int J Cosmet Sci 2008; 30: 4538.
25 Yamamoto I, Muto N, Murakami K et al. L-Ascorbic acid
a-glucoside formed by regioselective transglycosylation
with rat intestinal and rice seed a-glucosidases: Its
improved stability and structure determination. Chem
Pharm Bull 1990; 38: 30203.
26 Barnet Products Corp. BV-OSC (tetrahexyldecyl ascor-
bate); a stable, oil-soluble form of vitamin C. Technical
Bulletin. Englewood Cliffs NJ: Barnet Products Corp.
27 Ochiai Y, Kaburagi S, Obayashi K et al. A new lipophilic
pro-vitamin C, tetra-isopalmitoyl ascorbic acid (VC-IP),
prevents UV-induced skin pigmentation through its anti-
oxidative properties. J Dermatol Sci 2006; 44: 3744.
28 Bisset DL, Chatterjee R, Hanlon DP. Photoprotective
effect of superoxide scavenging antioxidants against
ultraviolet radiation-induced chronic skin damage in
hairless mouse. Photodermatol Photoimmunol Photomed
1990; 7: 5662.
29 Jurkovic P, Sentjurc M, Gasperlin M et al. Skin protection
against ultraviolet induced free radicals with ascorbyl
palmitate in microemulsions. Eur J Pharm Biopharm
2003; 56: 5966.
30 Murakami K, Inagaki J, Saito M et al. Skin atrophy in
cytoplasmic SOD-deficient mice and its complete recovery
using a vitamin C derivative. Biochem Biophys Res Com-
mun 2009; 382: 45761.
31 Liu JW, Kayasuga A, Nagao N et al. Repressions of actin
assembly and RhoA localization are involved in inhibition
of tumor cell motility by lipophilic ascorbyl phosphate. Int
J Oncol 2003; 23: 15617.
32 Watanabe Y, Suzuki H, Ueda T. HLB number of vitamins
C, E, coenzyme Q10 derivatives and their transportation
efficiency into skin. Vib Spectrosc 2006; 42: 195200.
33 Ichiyama K, Mitsuzumi H, Zhong M et al. Promotion of IL-4-
and IL-5-dependent differentiation of anti-l-primed B cells by
ascorbic acid 2-glucoside. Immunol Lett 2009; 122: 21926.
34 Yamamoto I, Suga S, Mitoh Y et al. Antiscorbutic activity
of L-ascorbic acid 2-glucosode and its availability as a
316
vitamin C supplement in normal rats and guinea pigs.
J Pharmacobio-Dyn 1990; 13: 68895.
35 Yamamoto I, Muto N, Murakami K et al. Collagen synthe-
sis in human skin fibroblasts is stimulated by a stable
form of ascorbate. J Nutr 1992; 122: 8717.
36 Nihro Y, Miyataka H, Sudo T et al. 3-O-Alkylascorbic acids
as free-radical quenchers: synthesis and inhibitory effect
on lipid peroxidation. J Med Chem 1991; 34: 21527.
37 Humbert P, Messikh R, Try C. The action of vitamin C for
treating wrinkles and protecting skin from photodamage.
Eur J Dermatol 2010; 5: 3640.
38 Murray J, Darr D, Reich J et al. Topical vitamin C treat-
ment reduces ultraviolet B radiation-induced erythema in
human skin. J Invest Dermatol 1991; 96: 587.
39 Lin JY, Selim MA, Shea CR et al. UV photoprotection by
combination topical antioxidants vitamin C and vitamin
E. J Am Acad Dermatol 2003; 48: 86674.
40 Chan AC. Partners in defence, vitamin E and vitamin C.
Can J Physiol Pharmacol 1993; 71: 72531.
41 Miyai E, Yanagida M, Akiyama J et al. Ascorbic acid
2-O-alpha-glucoside-induced redox modulation in human
keratinocyte cell line, SCC: mechanisms of photoprotective
effect against ultraviolet light B. Biol Pharm Bull 1997;
20: 6326.
42 Quevedo WC Jr, Holstein TJ, Dyckman J et al. The
responses of the human epidermal melanocyte system to
chronic erythemal doses of UVR in skin protected by topi-
cal applications of a combination of vitamins C and E.
Pigment Cell Res 2000; 13: 1902.
43 Burke K. Interaction of vitamins C and E as better cosme-
ceuticals. Dermatol Ther 2007; 20: 31421.
44 Ahmad I, Sheraz MA, Ahmed S et al. Photochemical
interaction of ascorbic acid with riboflavin, nicotinamide
and alpha-tocopherol in cream formulations. Int J Cosmet
Sci 2012; 34: 12331.
45 Perricone NV. The photoprotective and anti-inflammatory
effects of topical ascorbyl palmitate. J Geriatr Dermatol
1993; 1: 510.
46 Meves A, Stock SN, Beyerle A et al. Vitamin C derivative
ascorbyl palmitate promotes ultraviolet-B-induced lipid
peroxidation and cytotoxicity in keratinocytes. J Invest
Dermatol 2002; 119: 11038.
47 Pinnell SR. Ascorbyl-6-palmitate is not ascorbic acid.
J Invest Dermatol 2002; 119: 991.
48 Nayama S, Takehana M, Kanke M et al. Protective effects
of sodium-L-ascorbyl-2 phosphate on the development of
UVB-induced damage in cultured mouse skin. BioI Pharm
Bull 1999; 22: 13015.
49 Sugimoto M, Okugawa Y, Miwa N. Preventive effects of
phosphorylated ascorbate on ultraviolet-B induced apop-
totic cell death and DNA strand cleavage through enrich-
ment of intracellular vitamin C in skin epidermal
keratinocytes. Free Radic Res 2006; 40: 21321.
50 Catani MV, Savini I, Rossi A et al. Avigliano L. Biological
role of vitamin C in keratinocytes. Nutr Rev 2005; 63:
8190.
2012 Wiley Periodicals, Inc.

51 Kumano Y, Sakamoto T, Egawa M et al. In vitro and in vivo
prolonged biological activities of novel vitamin C deriva-
tive, 2-0-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G),
in cosmetic fields. J Nutr Sci Vitaminol 1998; 44: 34559.
52 Maia Campos PMBG, Gianeti MD, Kanashiro A et al.
In vitro antioxidant and in vivo photoprotective effects of
an association of bioflavonoids with liposoluble vitamins.
Photochem Photobiol 2006; 82: 6838.
53 Nusgens BV, Humbert P, Rougier A et al. Stimulation of
collagen biosynthesis by topically applied vitamin C. Eur J
Dermatol 2002; 4: 324.
54 Humbert PG, Haftek M, Creidi P et al. Topical ascorbic
acid on photoaged skin. Clinical, topographical and ultra-
structural evaluation: doubleblind study vs. placebo. Exp
Dermatol 2003; 12: 23744.
55 Heber GK, Markovic B, Hayes A. An immunohistological
study of anhydrous topical ascorbic acid compositions on
ex vivo human skin. J Cosmet Dermatol 2006; 5: 1506.
56 Phillips CL, Combs SB, Pinnell SR. Effects of ascorbic acid
on proliferation and collagen synthesis in relation to the
donor age of human dermal fibroblasts. J Invest Dermatol
1994; 103: 22832.
57 Boyera N, Galey I, Bernard BA. Effect of vitamin C and its
derivatives on collagen synthesis and cross-linking by nor-
mal human fibroblasts. Int J Cosmet Sci 1998; 20: 1518.
58 Geesin JC, Gordon JS, Berg RA. Regulation of collagen
synthesis in human dermal fibroblasts by the sodium and
magnesium salts of ascorbyl-2-phosphate. Skin Pharmacol
1993; 6: 6571.
59 Rosenblat G, Willey A, Zhu Y-N et al. Palmitoyl ascorbate:
selective augmentation of procollagen mRNA expression
compared with L-ascorbate in human intestinal smooth
muscle cells. J Cell Biochem 1999; 73: 31220.
60 Tajima S, Pinnell SR. Ascorbic acid preferentially
enhances type I and III collagen gene transcription in
human skin fibroblasts. J Dermatol Sci 1996; 11: 2503.
61 Belin S, Kaya F, Burtey S et al. Ascorbic acid and gene
expression: another example of regulation of gene expres-
sion by small molecules? Curr Genomics 2010; 11: 527.
2012 Wiley Periodicals, Inc.
Ascorbic acid review . N P J Stamford
62 Nusgens BV, Humbert P, Rougier A et al. Topically
applied vitamin C enhances the mRNA level of collagens
I and III, their processing enzymes and tissue inhibitor of
matrix metalloproteinase 1 in the human dermis. J Invest
Dermatol 2001; 116: 8539.
63 Ando H, Kondoh H, Ichihashi M et al. Approaches to
identify inhibitors of melanin biosynthesis via the quality
control of tyrosinase. J Invest Dermatol 2007;
127: 75161.
64 Kameyama K, Sakai C, Kondoh S et al. Inhibitory effect of
magnesium L-ascorbyl-2-phosphate (VC-PMG) on melano-
genesis in vitro and in vivo. J Am Acad Dermatol 1996; 34:
2933.
65 Kim S, Oh SY, Lee SH. Comparative study of glycolic acid
peeling versus vitamin C iontophoresis in melasma. Kor-
ean J Dermatol 2001; 39: 135663.
66 Kawada A, Kameyama H, Asai M et al. A new approach
to the evaluation of whitening effect of a cosmetic using
computer analysis of video-captured image. J Dermatol Sci
2002; 29: 108.
67 Miyamoto K, Takiwaki H, Hillebrand GG et al. Utilization
of a high-resolution digital imaging system for the objec-
tive and quantitative assessment of hyperpigmented spots
on the face. Skin Res Technol 2002; 8: 737.
68 Inui S, Itami S. Perifollicular pigmentation is the first tar-
get for topical vitamin C derivative ascorbyl 2-phosphate
6-palmitate (APPS): randomized, single blinded, placebo-
controlled study. J Dermatol 2007; 34: 2213.
69 Maeda K, Hatao M. Method of preventing darkening of
skin or inhibiting melanisation of melanin monomer and
polymerization inhibitor of biological dihydroxyindole
compound. U.S. Patent 6,861,050, filed June 6, 2002,
and issued March 1, 2005.
70 Traikovich SS. Use of topical ascorbic acid and its effects
on photodamaged skin topography. Arch Otolaryngol Head
Neck Surg 1999; 125: 10918.
71 Fitzpatrick RE, Rostan EF. Double blind, half face study
comparing topical vitamin C and vehicle for rejuvenation
of photodamage. Dermatol Surg 2002; 28: 2316.
317
 -

www.xuebalib.com

24 IP