4

3(2004)

&
(254-0073

1-14-11)

,
,
,
(2S,3R)

(D-erythro),"

"

, (2S,3R)
,

(= )Vol.4,No.3,105(2004)

89

105

3(2004)

Development

and Properties

of the Optically

Active

Ceramides

&
254-0073
1--14-11

Kenya
ISHIDA
Fine & Aroma Chemical Laboratory, Fine Chemical
Division Takasago International Corporation
4-11, 1-Chome, Nishi-Yawata, Hiratsuka City, Kanagawa
254-0073, JAPAN

Abstract:
The most important and principal function of the skin is to provide a protective interface
between human body and external environment. Ceramides exist as main components of intercellular
lipids of stratum corneum, and play an essential role of a barrier function of the skin. It is well known
that natural ceramides are optically active, and consist of (2S, 3R)-configuration
(D-erythro configuration) at the sphingosine moiety. Thus, the optically active (2S, 3R)-ceramides have been developed
based on the strategy of asymmetric synthesis. The solubility of the ceramides in various solvents is
low due to its amphiphatic structure consisting of hydrophobic long-chained hydrocarbon unit and
hydrophilic amide-diol moiety. In order to embody the function of the ceramides in various cosmetic
products, effective and stable novel formula of the ceramides have been devised with consideration of
lamellar structure of natural intercellular lipids. As a consequence of studies especially focused on stereochemistry,
compositions containing the optically active ceramides showed significant recovering
effect of water-holding capacity and barrier function of the skin, and also hair care properties.
The following article reviews recent developments in the functional properties of the optically active
ceramides as well as various formulating techniques of these materials.
Key words:
Optically Active Ceramides, Asymmetric Synthesis, (2S, 3R)-form, Barrier Function,
Skin and Hair Care Property.

,Fig.1

,




1980
,

i-5), ,

Fig. 1

General

Structure

of Ceramides.

BSE(

, ,

,1990

:
E-mail : kenya _ishida@takasago.com

( :

19

106

3(2004)

(NaturalMoisturizingFactor)

Imokawa

6),

50%

, ,

),

(Fig.3) 2

7)

2((2S,3R)

2)

8"10), 5 11)
,

) ,

(TEWL:TransEpidermalWaterLoss)
,

, ,

13-14), ,

(Fig.2)

20m
Elias

12)(Fig.3)

15

Fig.4

(SPT)
L CoA

Fig.2SectionalStructureofHumanEpidermis.
( ,

,3,

20

(1990)

Fig. 3

Schematic

Representation

for Human

Stratum

and Lamellar

3(2004)

107

Structure.

Downing
,
,7
(Type17)2
(TypeA,B)

(Fig.5)19)

Fig. 4

Metabolism

of Ceramides

in Human

Epidermis.

,

, ,

,
,

15)
,

SPT

16),L 17),
18)

21

Fig. 5

General
Human

Structure
Stratum

and Composition
Corneum.

of Ceramides

in

108

3(2004)

20)

"

"

3R) ( :D-erythro)

(Fig.1),

1,3-dio1]

[(2S,3R)-2-(2-hydroxyhexadecanoyl)aminooctade-

(2S,

cane-1,3-diol]

BINAP

"SEGPHOS"(4
,4bi-1,3-benzodioxole)-5,5
diy1-bis

21)

(Fig.6)

(diarylphosphine)s)

PHOS

22-23), SE(}-

L D

(2S,3S)

BINAP

(2)
,

(2R,3S) ,

(2R,3R)

,
5

Fig.7

BINAP(2,2'-bis(diphenylphosphino)-1,1

binaphtyl)

(suMlcHIRALoA-4600)

2HPLC

:(2S,3S):(2R,3R):(2S,3R):(2R,3S)=15:

,2

15:35:35(

(1)
(2)

3-

(2R,3S)

,3

(3)

97%

(2S,3R)

2[(2S,3R)-2-octadecanoylaminooctadecane

Synthetic

Procedure

of Optically

22-

Fig. 6

:threo/erythro=3/7)]

(2R,3R)

Active

Ceramides.

Fiq. 7

Optical

Resolution

of Ceramide

61

3(2004)

109

2 by Chiral-HPLC.

101

82

72

, 1 ,

4 ,

106

99 ,88

5 , ,

(DSC)

(Fig8)

68,92,101

17

Fig. 8

DSC Analysis

23

of Ceramide

2.

110

62

3(2004)

,2

,
/
)

, ,)

(Fig.9)

X
Braggsangle

A,10.2A

,41.8A,20.6A,13.4
,

( )

4.5A

, (

(Fig.10)

24)
, (
,

),

/
Akasaki

26) ,
(Fig.11)

,
(

),

64

(L.L.C.:LamellarLi(1-

uidCrystallinephase)

, L.L.C

, ,

, ,

27)

Elias ,
,
,

25),




63

,



2

24

Fig. 9

Polarized
Ceramide

Microphotograph
2 and Cholesterol.

for Contact

Test between

3(2004)

111

Fig. 10 X-ray Diffraction for Ceramide 2 with Cholesterol (1/1 mol ratio).

Fig. 11 Time Courses of Water Evaporating Rate through

the Membrane Consists of Ceramide 2 (Chiral and
Racemate) and Cholesterol.

Fig.12

/
( )

(pH=6.86)=1/1

(40)

28)

Fig. 12 Phase Diagrams for the Ceramide 2/Cholesterol/

Choresteryl sulfate/Phosphate
buffer (pH=6.86)
System.
,

gel

Fig.13

LL.c.

65'nv'tro

(L.L.C.)

3
L.L.C.

25

(
:3.0%)

,(2S,3R)

(Fig.14)

(2S,3R)

112

3(2004)

,
,

,Fig.15

(2S,3R)

ModelSC

Lipids ( )
, ModelSCLipids
,

,
,

ModelSCLipids

, (
)
7

Fig. 13 Polarized Microscope

Observation
of
Lamellar Liquid Crystalline phase (L.L.C.)as
Maltese Cross Image.

71

(SDS:SodiumDodecylSulfate)

, ,

(mp:74)

L.L.

30

(2S,3R)

120

(ModelSCLipids)

8090

, L.L
(
SDS

:4%)
(

),

:TEWL)

(Flg.16,Fig.
17) TEWL

, ,
(2S,3R)

inuitro

,
,
Fig. 14

Water

Holding

Capacity

Fig. 15

on Various

201,

Ceramides.

Effect of Various

Ceramides

26

on Natural

Water

Barrier

Function.

Fig. 16

Recovery

Fig. 17

455%

30

Ratio of Conductance

Recovery

Values on SDS Induced

Ratio of TEWL

on SDS Induced

3(2004)

113

Dry Skin.

Dry Skin.

, ,

(n=9)

72

, 0.5%

Fig. 18

Time

Courses

of Conductance

Lotion.

27-

,14

(Fig.18,Fig.19)

Values

Treated

with

0.5% Ceramide

114

3(2004)

Fig. 19

(12)

Time

Courses

of TEWL

Values Treated

with 0.5% Ceramide

Lotion.

73

(CMC:CellMembraneComplex)

50%

(
(

2(88%),
Hussler

,
5(12%),

29)

Effect
of Water
Vesicles.

:4%)

(0.5%)

Effect
Vesicles.

of Water

Holding

Capacity

2 2

(Fig.22)

Ceramide

for

21)30)

5/

Synergy

Function

(Fig.20,Fig.

(MIU)

Fig. 20

Barrier

(2-hydroxyhexadecanoyl)aminooctadecane-1,3-diol]

Synergy
Ceramide

5[(2S,3R)-2-

Fig. 21

SEM

for

Fig. 22 Recovery of Hair Surface as Friction Score (MIU).

28

Fig. 23

3(2004)

115

SEM Images for Hair Surface (X 240).

, (Fig.23)
,
,
,

(5cm/min)

, 5/

2
(Fig.24)
4%

C.M.C

Recovery

of Hair Breaking

Strength

under

Strain.

Fig. 24

,
,

1,

5,

,
,

,L.L.C.

, ,

,

, ,

,
,

29

1) P.W. Wertz & D.T. Downing., J. Lipid Res., 24, 759

(1983).
2) P.W.Wertz, M.C. Miethke, S.A. Long, J.S. Strauss & D.T.
Downing, J. Invest. Dermat, 84, 410 (1985).
3) P.M. Elias, J. Invest Dermatol., 80 (Supp),44 (1983).
4) P.W.Wertz, E.I. Cho & D.T. Downing, Biochem. Biophy.
Acta, 753, 350 (1983).

116

5)

3(2004)

98,40(1988).

6) G. Imokawa, Y. Yada, K. Higuchi, M. Okuda, Y. Ohhashi

& A. Kawamata, J. Clin. Invest., 94, 89 (1994).
7) R. Noyori, T. Ikeda, T. Ohkuma, M. Widohalm, M. Kitamura, H. Takaya & S. Akutagawa, J. Am. Chem. Soc.,
111,9134 (1989).
8)

,FrgrnceJ.,10,75

18)
19)
20)
21)

(1999).
9)

22)

9-235259.
10)

118
11)

23)

,2,25(1998).

,Frgr1zceJ.,6,60

24)

(2002).

12) P.M. Elias & D.S. Friends, J. Cell Biol., 65,180(1975).

13) K. Akimoto, N. Yoshikawa, Y. Higaki, M. Kawashima &
G. Imokawa, J. Dermatol. (Tokyo),20, 1 (1993).
14) G. Imokawa, A. Abe, K. Jin, Y. Higaki, M. Kawashima &
A. Hidano, J. Invest. Dermatol., 96, 523 (1991).
15)

Zhang, R. Kosturko, P. Verdejo, C. Feinberg, L. Nguyen

& P. Chandar, Arch. Dermatol. Res., 288, 383 (1996).
M. Hara, Y. Uchida, A. Haratake, K. Mimura & S.
Hamanaka, J. Dermatol. Sci., 16, 111 (1998).
K.J. Robson, M.E. Stewart, S. Michelsen, N.D. Lazo &
D.T. Downing, J. lipid Res. 35, 2060 (1994).
G. Nemes & P.M. Steinert, Exp. Mol. Med., 31, 5 (1999).
H.E. Carter & D. Shapiro, J. Am. Chem. Soc., 75, 5131
(1953).
T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T.
Miura & H. Kumobayashi, Adv. Synth. catal., 343, 264
(2001).
H. Kumobayashi, T. Miura, N. Sayo, T. Saito & X. Zhang,
Synlett., SI, 1055 (2001).

.,

2000-169359.

16) 0. Tanno, Y. Ota, N. Kitamura, T. Katsube & S. Inoue,

Br. J. Dermatol., 143, 524 (2000).
17) A.V. Rawlings, A. Davies, M. Carlomusto, S. Pillai, K.

30

,1107

(1993).

25) M.Q. Man, K.R. Feingold, C.R. Thornfeldt & P.M. Elias,
J. Invest. Dermat, 106, 1096 (1996).
26)

,Frgrnce.,13,64(1994).

27) T. Kaneko & H. Sagitani, Colloids Surf., 69, 125 (1992).

28)

10-182401.

29) G. Hussler & G. Kaba, Int. J. Cosmet. Sci., 17, 197

(1995).
30)

2001-348320.