Phytosphingosine-based ceramide I analogs

Details Phytosphingosine-based ceramide I analogs Phytosphingosine-based ceramide I analogs

1996-04-29

1999-07-06

Geist, Gary

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

554 63, 554 68, C07C23100

Patent

active

059199601

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

Ceramides are the main lipid component in the upper layer of the skin, the stratum corneum. The stratum corneum has an important barrier function: external compounds are generally kept outside and the loss of moisture is limited.
The addition of ceramides to skin cosmetic products improves the barrier function of the skin, restores lost moisture and has,been found to have "anti-wrinkle" effects. Moreover, ceramides have also found use in pharmaceutical preparations for example for the treatment of atopic eczema (Kerscher et al. (1991) Eur. J. Dermatol., 1, 39-43). European Patent Application EP 0 373 038 describes the therapeutic use of N-acyllysosphingolipids, wherein the acyl group has a chain length of 2-24 carbon atoms and is substituted by one or more polar groups.
In particular, ceramide I, described in European Patent 0 097 059 (Unilever/Conopco) is commonly found in commercial cosmetic preparations. The structure of ceramide I was investigated by Wertz et al. ((1985) J. Invest. Dermatol., 84(8), 410-412--see also Wertz and Downing (1983) J. Lipid Res., 24, 759-765; Wertz et al. (1983) Biochim. Biophys. Acta, 753, 350-355; Kerscher et al. (1991), supra, p. 41) and is depicted below: ##STR1##
Several references postulate that ceramide I has a unique function in relation to other known ceramides. It appears that ceramide I, with its characteristic acyl-ceramide structure, acts as a sort of "molecular rivet" whereby the extracellular lipid bilayers of the stratum corneum are bound to one another, thus maintaining the skin's characteristic barrier function (permeability-regulating) and its moisture-retaining properties (see Melton et al. (1987) Biochim. Biophys. Acta, 921(2), 191-197; Wertz and Downing to (1988) Lipids, 23(5), 415-418; Brooks and Idsen (1991) Int. J. Cosmet. Sci., 13, 103-113; Wertz et al. (1983) Biochim. Biophys. Acta, 753, 350-355; and Kerscher et al. (1991) supra). The analysis of the ceramide composition in the skin disorder psoriasis, a skin disorder which is characterized by an impaired barrier function, showed a significantly decreased content of ceramide I, as compared to normal human stratum corneum (Motta et al. (1993) Biochni. Biophys. Acta 1182, 147-151).
However, it has also been found that-sphingosine-based ceramides such as natural ceramide I are broken down in the skin by the action of ceramidases to liberate sphingosine. Free sphingosine inhibits the activity of protein kinase C and in this way, may affect cell division. It has been proposed that the effects of free sphingosine may be an important factor in the modulation of epidermal cell proliferation in order to balance the rate in which cells are lost from the skin surface (Downing, D. T. (1992) J. Lipid Res., 33, 301-313).
Nevertheless, as mentioned above, natural ceramide I is commonly found in cosmetic preparations containing ceramides. Thus, the application of ceramide I-containing cosmetics to the skin may lead to the accumulation of an excess of free sphingosine due to the subsequent action of the ceramidases endogenous to the statum corneum. As a result, the fine balance of epidermal cell modulation may be upset.
On the other hand, the presence of phytosphingosine could not been demonstrated in the skin, despite efforts to locate it (Wertz and Downing (1990) J. Invest. Dermatol., 94(2), 159-161; Wertz and Downing (1989) Biochim. Biophys. Acta, 1002(2), 213-217). This may indicate that the ceramidases which degrade sphingosine-based ceramides are not active on phytosphingosine-based ceramides.
Another drawback of the use of natural ceramide I in cosmetics is that this ceramide is difficult to obtain in a cost-effective way in the quantities needed for application in cosmetic preparations. Isolation from natural sources is laborious and expensive, resulting in only small amounts of pure ceramide I. A solution to this problem may be the chemical synthesis of ceramide I from its constituents sphingosine and an acyloxyalkanoic acid. However, this is not a very realistic option, because

REFERENCES:
patent: 5627056 (1997-05-01), Casey et al.
Motta, S., et al., "Ceramide Composition of the Psoriatic Scale" Biochem Biophys Acta (1993) 1182(2):147-151.

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