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1. WO2007147370 - PSEUDOCERAMIDES AND PHARMACEUTICAL AND/OR COSMETIC COMPOSITIONS DESIGNED FOR ADMINISTRATION TO THE SKIN CONTAINING THE SAME

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Pseudoceramides and pharmaceutical and/or cosmetic compositions designed for
administration to the skin containing the same

Technical Field

The invention concerns pharmaceutical and cosmetic preparations containing pseudoceramides that are designed for topical administration to the skin and skin adnexa with the purpose of relipidization, improving hydration or damage prevention.

Background Art

The main function of the skin is to prevent entry of exogenous substances to the organism and loss of water. The uppermost skin layer, the stratum corneum (SC), in particular, is responsible for said function. Said layer is composed of cells in the terminal stage of keratinization, the corneocytes, deposited in a complex lipid mixture. The corneocytes are very poorly permeable; they are completely filled with keratin and their cell walls are thickened with deposition of highly cross-linked proteins into a corneocyte envelope. Intercellular lipids consist mostly of a mixture of ceramides, fatty acids and cholesterol in the equimolar ratio and are organized in multilayer lamellae. The high content of ceramides and very tight packing of the lipid lamellae are the basis of exceptional resilience of the skin against chemical as well as mechanical damage and its low permeability both outwards for body's intrinsic substances, e.g. water, and inwards, for xenobiotics.
Lowered amount of and changes in the composition of SC lipids, especially ceramides, is encountered in skin diseases such as for example atopic dermatitis or psoriasis. In the case of atopic dermatitis, a lower content of ceramides in the SC leads to higher permeability of the skin for allergens, toxic and irritating substances, or microbes. These substances subsequently cause or worsen the inflammation, which further degrades the barrier function of the skin and closes the so-called vicious circle of atopic dermatitis. Lowered content of ceramides is also encountered in dry or ageing skin, in people working for example with solvents, exposed to stresses, and the like. It is not yet known whether a decrease of the ceramide content is the primary factor or a secondary result of the above mentioned pathological effects.

Based on the current knowledge of biochemistry of these abnormalities, it is a logical correction and therapeutic procedure to supply missing ceramides by topical administration, i.e. by relipidization of the SC. This approach allows restoring of intercellular equilibriums between the lipid and aqueous phases in the SC and helps subsequent regeneration and optimization of physiological processes going on in the SC and lower layers of the epidermis. Topically administered formulation containing lipids with the structure similar to skin lipids, especially ceramides, improve homeostasis and overall condition of the skin. (Coderch L, Lopez O, de Ia Maza A, Parra JL. Am J Clin Dermatol. 2003 ;4(2): 107-29. Elias PM, Feingold KR. US Pat. 5,643,899, 1997).

Relipidization, therefore, represents a safe and effective form of adjuvant or alternative therapy for atopic dermatitises, xerodermas and other undesirable skin conditions. It can, for example, decrease need for corticosteroids, the use of which is always accompanied with a certain risk, especially in children (Chamlin SL, Kao J, Frieden IJ, Sheu MY, Fowler AJ, Fluhr JW, Williams ML, Elias PM. J Am Acad Dermatol. 2002;47(2): 198-208). The most frequently used method of evaluation of damage of the barrier function of the skin and relipidization by means of topic formulations is measuring of transepidermal losses of water (TEWL) and skin hydration. The TEWL value determines the rate of water permeation through the skin and is increased when the skin is damaged or in skin deseases (Pinnagoda J, Tupker RA, Agner T, Serup J. Contact Dermatitis. 1990;22: 164-78). Effective relipidization of damaged or diseased skin reduces the TEWL value (Chamlin SL, Kao J, Frieden IJ, Sheu MY, Fowler AJ, Fluhr JW, Williams ML, Elias PM. J Am Acad Dermatol. 2002;47(2): 198-208).

Ceramides and pseudoceramides have already been used in cosmetic as well as therapeutic formulations for about 15 years. Currently, the therapeutic ceramide formulations that are commercially available include for example Lipobase® Repair (LR, Astellas) and TriCeram (Osmotics). Their high price still remains a main limitation for wider use of ceramides and pseudoceramides. According to recent studies, certain chemical modifications in the structure of ceramides can lead to similarly active analogs or pseudoceramides with advantageous properties . For example, Philippe et al. have described the capacity of 2-oleoylaminooctadecane-l,3-diol to decrease the TEWL of isolated SC damaged by extraction with solvents (Philippe M, Garson JC, Guard P, Hocquaux M, Hussler G, Leroy F et al. Int J Cosmet Sci 1995;17: 133-145). Fukunaga et al. have described the capacity of N-octadecanoyl-O-galactosyl-(L)-serine hexylamide to decrease the TEWL in mice exposed to UV radiation (Fukunaga K, Yoshida M, Nakajima F, Uematsu R, Hara M, Inoue S, Kondo H, Nishimura S. Bioorg Med Chem Lett. 2003;13(5): 813-5). Imokawa et al. have described pseudoceramides derived from N-(2-hydroxyethyl)-N-(3-alkoxy-2-hydroxypropyl)amides of substituted fatty acids that were able to decrease the TEWL in rats with essential fatty acid deficiency and which reduced epidermal hyperplasia in guinea-pigs exposed to UV radiation (Imokawa G, Yada Y, Higuchi K, Okuda M, Ohashi Y, Kawamata A. J Clin Invest. 1994;94(1): 89-96).

Esters of acylated L-serine have been described in literature, of general formula



wherein Ra is an alkyl with the chain length of from C12 to Ci8; R is an alkyl with the chain length of from Ci5 to Ci8, which were patented as intermediates for preparation of surface active substances or amphiphilic substances (Shimizu T, Namikawa H, Murakami T, Hado M. JP 06080618 A2, 1994). Our work group has already prepared N-tetracosanoyl-(L)-serine tetradecyl ester and its capacity to in vitro decrease the permeability of pig skin for theophylline after acute damage with solvents has been described (Vavrova K, Zbytovska J, Palat K, Holas T, Klimentova J, Hrabalek A, Dolezal P. Eur J Pharm Sci. 2004;21(5): 581-7). N-Hexadecanoyl-(L)-serine hexadecyl ester and N-oleoyl-(L)-serine hexadecyl ester have been patented as transdermal permeation enhancers, i.e. the substances accelerating permeation of medicaments through the skin (Vavrova K, Hrabalek A, Dolezal P. WO 2004/074235, 2004, CZ 293 989). None of these substances has been tested as a part of pharmaceutical and/or cosmetic formulation designed for skin relipidization, decreasing the TEWL and increasing hydration.

Disclosure of Invention

The subject-matter of the invention consists in pharmaceutical and/or cosmetic compositions designed for administration to the human or animal skin, characterized in comprising a pseudoceramide of general formula (I),

(I)
wherein R1 is an alkyl with the chain length of from Ci2 to C20; R2 is an alkyl or alkenyl with the chain length of from Ci5 to C29 with the exception of (£)-heptadec-8-enyl, the minimal number of carbons in the molecule being 36, in amounts of from 0.01 to 20 weight %, based on the total weight of the composition, in a pharmaceutically acceptable vehicle.

The pharmaceutical and/or cosmetic compositions according to the invention are designed for relipidization of the skin as well as for supplementary treatment of skin diseases associated with reduced lipid content and increased skin permeability. Another subject-matter of the invention consists in the use of these compositions for the treatment of damaged, dry or ageing skin and skin adnexa or for the prevention of skin and skin adnexa damage.

The essence of the compositions according to the present the invention consists in the use of pseudoceramides based on esters of N-acylated L-serine. These substances differ from the natural ceramides only by replacement of the allylic hydroxyl of the ceramides with the ester bond.

Another subject-matter of the invention consists in novel pseudoceramides of general formula (H)


(H) wherein R3 is an alkyl with the chain length of from C]2 to C20; R4 is an alkyl or alkenyl with the chain length of from C15 to C29, the minimal number of carbons in the molecule being 36, with the following provisos:
a) if R3 is an alkyl with the chain length of from Ci2 to Cig, R4 can only be an alkyl with the chain length of from C 19 to C29 or an alkenyl with the chain length of from Cj5 to C29;
b) if R3 is the alkyl with the chain length C]6, R4 can only be an alkyl with the chain length of from C19 to C29 or an alkenyl with the chain length of from Ci6 to C29, except for (E)-heptadec-8-enyl;
c) if R3 is the alkyl with the chain length Ci4, R4 can only be an alkyl with the chain length of from C)9 to C22 or Cj4 to C29 or an alkenyl with the chain length of from Ci8 to C29;
d) if R4 is an alkyl with the chain length Ci5 to Ci8, R3 can only be an alkyl with the chain length Ci9 to C20;
e) if R4 is (£)-heptadec-8-enyl, R3 can only be an alkyl with the chain length Ci2 to Ci5 and Cn to C20; and
f) if R4 is the alkyl with the chain length C23, R3 can only be an alkyl with the chain length Ci2 to Ci3 and Ci5 to C20.

The following are preferable new compounds of general formula (II), which are duly described in the examples:
N-docosanoyl-(L)-serine hexadecyl ester,
N-docosanoyl-(L)-serine tetradecyl ester,
N-oleoyl-(L)-serine octadecyl ester,
N-hexadecanoyl-(L)-serine eicosyl ester,
N-triacontanoyl-(L)-serine tetradecyl ester,
N-tetracosanoyl-(L)-serine dodecyl ester,
N-tetracosanoyl-(L)-serine hexadecyl ester,
N-hexacosanoyl-(L)-serine tetradecyl ester,
N-eicosanoyl-(L)-serine tetradecyl ester.

The above-defined pseudoceramides of general formula (II) are substances not yet described in literature. None of the substances has been tested as a part of pharmaceutical and/or formulation designed for skin relipidization, decreasing the TEWL and increasing hydration.

Preferred pseudoceramides in the compositions according to the invention include N-eicosanoyl-(L)-serine tetradecyl ester, N-docosanoyl-(L)-serine tetradecyl ester, N-tetracosanoyl-(L)-serine tetradecyl ester, N-eicosanoyl-(L)-serine hexadecyl ester, and N-docosanoyl-(L)-serine hexadecyl ester.

The compositions according to the invention have the advantage of the pseudoceramides contained in them having approximately the same chain length as the natural ceramides in the skin, in contrast to other pseudoceramides. An optimal length of the chains is essential for the function of the ceramides in the skin and is associated with the high capacity of relipidization of damaged skin using the compositions according to the invention. This capacity is, under the given experimental conditions, even higher than that of the reference commercially-available formulation. Skin relipidization using the compositions according to the invention is demonstrated by reduction in the TEWL and improvement of its hydration. Specific results are given in the Examples section.

The invention is advantageous, compared with physiological ceramides and with prior pseudoceramides, in being possible to prepare the pseudoceramides contained therein in a simple and cheap manner in two-step synthesis. The synthesis has been described for N-tetracosanoyl-(L)-serine tetradecyl ester in our previous paper (Vavrova K, Zbytovska J, Palat K, Holas T, Klimentova J, Hrabalek A, Dolezal P. Eur J Pharm Sci. 2004;21(5): 581-7). The first step comprises esterifi cation of L-serine with the respective alcohol R1OH, where R1 is an alkyl with the chain length of from Ci2 to C20, in the presence of dry hydrogen chloride according to Limanov (Limanov VE, Svitova IR, Kruchenok TB, Tsvirova IM, Yaroslavskaya LA. Pharm. Chem. J. 1984; 18:708-11). In the second reaction step, L-serine ester is acylated with a fatty acid of general formula R2COOH, where R2 is an alkyl or alkenyl with the chain length of from Ci5 to C29, in the presence of dicyclohexylcarbodiimide. Yields of both steps of the synthesis are high, the synthesis does not require protection of the primary hydroxyl, the reactants are relatively cheap and easily available substances. The synthesis can be used for the preparation of all pseudoceramides of general formula (II); detailed description of the synthesis and characterization of the product are given in the Examples section.

Another advantage of the invention, compared with the previously described pseudoceramides, includes the fact that the structure of the pseudoceramides contained in the compositions according to the invention allows biodegradation of these substances to nontoxic metabolites - the amino acid L-serine, a fatty acid (i.e. a carboxylic acid with the chain length of Cj6 - C30) and a fatty alcohol (i.e. an alcohol with the chain length of C]2 - C20).

The pharmaceutical and/or cosmetic compositions according to the present invention contain one or more pseudoceramides of general formula (1) in the amount of from 0.01 to 20 weight %, based on the total weight of the composition, in a suitable vehicle.

The pharmaceutical and/or cosmetic compositions according to the present invention can be formulated in any administration form suitable for administration to the skin including its adnexa, e.g. creams, ointments, lotions, foams, aerosols, sprays, roll-on formulations, etc.

The pharmaceutical and/or cosmetic compositions according to the present invention are administered externally, topically to the human, or alternatively animal, skin.

The pharmaceutical and/or cosmetic compositions according to the present invention are characterized by high capacity to optimize the composition of skin lipids in diseases and conditions associated with decreased content of ceramides inthe SC.

Examples

The invention is illustrated using the following examples of pharmaceutical and/or cosmetic bases, or compositions which, however, do not limit its extent in any respect.

Example 1 - Synthesis of N-docosanoyl-(L)-serine hexadecyl ester

a) (L)-2-Hydroxy-l-hexadecyloxycarbonylethylammonium chloride
L-Serine (0.1 g, 1 mmol) and hexadecanol (0.7 g, 3 mmol) were heated at 70 0C under nitrogen under continuous stirring for 8 hours. Every 2 hours, dry hydrogen chloride was introduced into the reaction mixture for 15 minutes according to Limanov (Limanov VE, Svitova IR, Kruchenok TB, Tsvirova IM, Yaroslavskaya LA. Pharm. Chem. J. 1984; 18: 708-11). The product was crystallized from boiling acetone and crystals were washed with hexane to remove remaining hexadecanol. Yield: 0.32 g (88 %); colorless crystals; melting point = 92

- 94 °C; [αg = -6.4° (1.0; ethanol); IR (KBr): vmax 3428, 2920, 2851, 1745, 1468, 1237, 1025, 721 cm"1; 1H NMR (300 MHz, DMSO): δ 8.57 (3H; s; NH3+); 5.61 (IH; s; OH); 4.20 - 4.10 (2H; m; COOCH2); 4.05 (IH; t; J = 3.4 Hz; CHN); 3.81 (2H; d; J = 2.7 Hz; CH2OH); 1.70 -1.50 (2H; m; CH2); 1.40 - 1.10 (22H; m; 1 ICH2); 0.83 (3H; t; J= 6.6 Hz; CH3); 13C NMR (75 MHz, DMSO): δ 168.3; 65.7; 59.7; 54.6; 31.5; 29.3; 29.2; 29.2; 28.9; 28.9; 28.2; 25.4; 22.3; 14.2.

b) N-Docosanoyl-(L)-serine hexadecyl ester
(L)-2-Hydroxy-l-hexadecyloxycarbonylethylammonium chloride (290 mg, 0.8 mmol) and 4-dimethylaminopyridine (107 mg, 0.88 mmol) were stirred in 10 ml of dry chloroform. Separately, docosanoic acid (270 mg, 0.8 mmol) and dicyclohexyl carbodiimide (165 mg, 0.8 mmol) were mixed in dry chloroform and the solution was added to the reaction. The reaction mixture was stirred at lab temperature for 20 hours and then concentrated under reduced pressure. The crude product was suspended in hexane and crystals were filtered out after 1 hour. Dicyclohexylurea was removed by suspending crystals in methanol and filtering them out after 1 hour. The pure product was obtained via chromatography on silica gel using the mobile phase chloroform/ethyl acetate 8:2. Yield: 458 mg (92 %); colorless crystals; melting point = 83 - 86 °C;
6.3° (0.8; CHCl3); IR (KBr): vmax 3428, 2919, 2850, 1734, 1647, 1541, 1468, 1235, 720 cm'1; 1H NMR (300 MHz, CDCl3): δ 6.41 (IH; d; J = 6.9 Hz; NH); 4.70 - 4.60 (IH; m; CHN); 4.17 (2H; t; J= 6.7 Hz; OCH2); 3.95 (2H; dd; J1 = 6.1 Hz; J2 = 3.9 Hz; CH2OH); 2.62 (IH; t; J= 5.9 Hz; OH); 2.26 (2H; t; J= 7.6 Hz; COCH2); 1.75 - 1.50 (4H; m; 2CH2); 1.50 - 1.05 (62H; m; 31 CH2); 0.87 (6H; t; J= 6.7 Hz; 2CH3); 13C NMR (75 MHz, CDCl3): δ 173.8; 170.5; 66.2; 64.0; 54.9; 36.5; 31.9; 29.7; 29.7; 29.6; 29.5; 29.4; 29.2; 29.2; 28.5; 25.8; 25.6; 22.7; 14.1.

Example 2: N-Docosanoyl-(L)-serine tetradecyl ester

The substance was prepared by the procedure described in Example 1. Yield: 89 %; colorless crystals; melting point = 79.5 - 81.5 °C;
6.4° (0.8; CHCl3); IR (KBr): vmax 3428, 2918, 2850, 1734, 1648, 1540, 1468, 720 cm"1; 1H NMR (300 MHz, CDCl3): δ 6.41 (IH; d; J= 6.9 Hz; NH); 4.70 - 4.60 (IH; m; CHN); 4.17 (2H; t; J= 6.7 Hz; OCH2); 3.95 (2H; dd; J1 = 6.1 Hz; J2= 3.9 Hz; CH2OH); 2.62 (IH; t; J= 5.9 Hz; OH); 2.26 (2H; t; J= 7.6 Hz; COCH2); 1.75 - 1.50 (4H; m; 2CH2); 1.50 - 1.05 (6OH; m; 30 CH2); 0.87 (6H; X; J = 6.1 Hz; 2CH3); 13C NMR (75 MHz, CDCl3): δ 173.8; 170.5; 66.2; 64.0; 54.9; 36.5; 31.9; 29.7; 29.7; 29.6; 29.5; 29.4; 29.2; 29.2; 28.5; 25.8; 25.6; 22.7; 14.1.

Example 3 : N-Oleoyl-(L)-serine octadecyl ester

The substance was prepared by the procedure described in Example 1. Yield: 75 %; colorless crystals; melting point = 63 - 66.5 0C; [αg = 9.9° (1; CHCl3); IR (KBr): vmax 3428, 3311, 3007, 2917, 2850, 1738, 1645, 1551, 1468, 1214, 720 cm"1; 1H NMR POO MHZ5 CDCI3)^ 5.92 (IH; bs; NH); 5.40 - 5.25 (2H; m; CH=CH); 4.12 (2H; t; J = 6.6 Hz; COO-CH2); 4.02 (2H; d; J = 5.0 Hz; CH2NH); 2.21 (2H; t; J = 7.5 Hz; COCH2); 2.05 - 1.90 (4H; m; 2
CH2CH=); 1.70 - 1.50 (4H; m; 2 CH2); 1.40 - 1.10 (52H; m; 26 CH2); 0.85 (6H; t; J= 6.6 Hz; 2 CH3); 13C NMR (75 MHz, CDCl3): δ 173.2; 170.3; 130.0; 129.7; 65.7; 41.3; 36.4; 31.9; 31.9; 29.8; 29.7; 29.6; 29.6; 29.5; 29.5; 29.3; 29.3; 29.2; 29.2; 29.1; 28.5; 27.2; 27.2; 27.2; 25.8; 25.6; 22.7; 14.1

Example 4: N-Hexadecanoyl-(L)-serine eicosyl ester

The substance was prepared by the procedure described in Example 1. Yield: 77 %; colorless crystals; melting point = 81.5 - 84 °C; [α]2D5= 6.3° (0.8; CHCl3); IR (KBr): vmax 3426, 2919, 2850, 1733, 1648, 1540, 1468, 720 cm"1; 1H NMR (300 MHz, CDCl3): δ 6.41 (IH; d; J= 6.9 Hz; NH); 4.70 - 4.60 (IH; m; CHN); 4.17 (2H; t; J= 6.7 Hz; OCH2); 3.95 (2H; dd; J, = 6.1 Hz; J2= 3.9 Hz; CH2OH); 2.62 (IH; t; J= 5.9 Hz; OH); 2.26 (2H; t; J= 7.6 Hz; COCH2); 1.75 - 1.50 (4H; m; 2CH2); 1.50 - 1.05 (6OH; m; 30 CH2); 0.87 (6H; t; J = 6.7 Hz; 2CH3); 13C NMR (75 MHz, CDCl3): δ 173.8; 170.5; 66.2; 64.0; 54.9; 36.5; 31.9; 29.7; 29.7; 29.7; 29.6; 29.5; 29.4; 29.2; 29.2; 28.5; 25.8; 25.6; 22.7; 14.1.

Example 5: N-Triacontanoyl-(L)-serine tetradecyl ester

The substance was prepared by the procedure described in Example 1. Yield: 69 %; colorless crystals; melting point = 91 - 95 °C; [αg = 4.9° (0.5; CHCl3); IR (KBr): vmax 3430, 2918, 2850, 1733, 1648, 1546, 1468, 720 cm"1; 1H NMR (300 MHz, CDCl3): δ 6.41 (IH; d; J= 6.9 Hz; NH); 4.70 - 4.60 (IH; m; CHN); 4.17 (2H; t; J= 6.7 Hz; OCH2); 3.95 (2H; dd; J, = 6.1 Hz; J2 = 3.9 Hz; CH2OH); 2.62 (IH; t; J= 5.9 Hz; OH); 2.26 (2H; t; J= 7.6 Hz; COCH2); 1.75

- 1.50 (4H; m; 2CH2); 1.50 - 1.05 (76H; m; 38 CH2); 0.87 (6H; t; J= 6.7 Hz; 2CH3); 13C NMR (75 MHz, CDCl3): δ 173.8; 170.5; 66.2; 64.0; 54.9; 36.5; 31.9; 29.7; 29.7; 29.6; 29.6; 29.6; 29.5; 29.4; 29.2; 29.2; 28.5; 25.8; 25.8; 25.6; 22.7; 14.1.

Example 6: N-Tetracosanoyl-(L)-serine dodecyl ester

The substance was prepared by the procedure described in Example 1. Yield: 90 %; colorless crystals; melting point = 78 - 80,5 0C; [αg = 6.4° (0.8; CHCl3); IR (KBr): vmax 3428, 2919, 2850, 1734, 1648, 1546, 1468, 720 cm"1; 1H NMR (300 MHz, CDCl3): δ 6.41 (IH; d; J= 6.9 Hz; NH); 4.70 - 4.60 (IH; m; CHN); 4.17 (2H; t; J= 6.7 Hz; OCH2); 3.95 (2H; dd; J, = 6.1 Hz; J2= 3.9 Hz; CH2OH); 2.62 (IH; t; J= 5.9 Hz; OH); 2.26 (2H; t; J= 7.6 Hz; COCH2); 1.75

- 1.50 (4H; m; 2CH2); 1.50 - 1.05 (6OH; m; 30 CH2); 0.87 (6H; t; J= 6.7 Hz; 2CH3); 13C NMR (75 MHz, CDCl3): δ 173.8; 170.5; 66.2; 64.0; 54.9; 36.5; 31.9; 29.7; 29.7; 29.6; 29.5; 29.4; 29.2; 29.2; 28.5; 25.8; 25.6; 22.7; 14.1.

Example 7: N-Tetracosanoyl-(L)-serine hexadecyl ester

The substance was prepared by the procedure described in Example 1. Yield: 86 %; colorless crystals; melting point = 84 - 86.5 °C;
6.4° (0.8; CHCl3); IR (KBr): vmax 3428, 2919, 2850, 1734, 1648, 1546, 1468, 720 cm"1; 1H NMR (300 MHz, CDCl3): δ 6.41 (IH; d; J= 6.9 Hz; NH); 4.70 - 4.60 (IH; m; CHN); 4.17 (2H; t; J= 6.7 Hz; OCH2); 3.95 (2H; dd; J1 = 6.1 Hz; J2 = 3.9 Hz; CH2OH); 2.62 (IH; t; J= 5.9 Hz; OH); 2.26 (2H; t; J= 7.6 Hz; COCH2); 1.75

- 1.50 (4H; m; 2CH2); 1.50 - 1.05 (68H; m; 34 CH2); 0.87 (6H; t; J= 6.7 Hz; 2CH3); 13C NMR (75 MHz, CDCl3): δ 173.8; 170.5; 66.2; 64.0; 54.9; 36.5; 31.9; 29.8; 29.7; 29.7; 29.6; 29.5; 29.4; 29.2; 29.2; 28.5; 25.8; 25.6; 22.7; 14.1.

Example 8: N-Hexacosanoyl-(L)-serine tetradecyl ester

The substance was prepared by the procedure described in Example 1. Yield: 86 %; colorless crystals; melting point
6.3° (0.8; CHCl3); IR (KBr): vmax 3428, 2919, 2850, 1734, 1648, 1546, 1468, 720 cm"1; 1H NMR (300 MHz, CDCl3): δ 6.41 (IH; d; J= 6.9 Hz; NH); 4.70 - 4.60 (IH; m; CHN); 4.17 (2H; t; J= 6.7 Hz; OCH2); 3.95 (2H; dd; J, = 6.1 Hz; J2 = 3.9 Hz; CH2OH); 2.62 (IH; t; J= 5.9 Hz; OH); 2.26 (2H; t; J= 7.6 Hz; COCH2); 1.75

- 1.50 (4H; m; 2CH2); 1.50 - 1.05 (68H; m; 34 CH2); 0.87 (6H; t; J= 6.7 Hz; 2CH3); 13C NMR (75 MHz, CDCl3): δ 173.8; 170.5; 66.2; 64.0; 54.9; 36.5; 31.9; 29.8; 29.7; 29.7; 29.7; 29.6; 29.5; 29.4; 29.2; 29.2; 28.5; 25.8; 25.6; 22.7; 14.1.

Example 9: N-Eicosanoyl-(L)-serine tetradecyl ester

The substance was prepared by the procedure described in Example 1. Yield: 84 %; colorless crystals; melting point = 76.5 - 79 °C;
6.4° (0.8; CHCl3); IR (KBr): vmax 3428, 2918, 2850, 1734, 1648, 1540, 1468, 720 cm"1; 1H NMR (300 MHz, CDCl3): δ 6.41 (IH; d; J= 6.9 Hz; NH); 4.70 - 4.60 (IH; m; CHN); 4.17 (2H; t; J= 6.7 Hz; OCH2); 3.95 (2H; dd; J1 = 6.1 Hz; J2= 3.9 Hz; CH2OH); 2.62 (IH; t; J= 5.9 Hz; OH); 2.26 (2H; t; J= 7.6 Hz; COCH2); 1.75

- 1.50 (4H; m; 2CH2); 1.50 - 1.05 (46H; m; 28 CH2); 0.87 (6H; t; J= 6.7 Hz; 2CH3); 13C NMR (75 MHz, CDCl3): δ 173.8; 170.5; 66.2; 64.0; 54.9; 36.5; 31.9; 29.7; 29.7; 29.6; 29.5; 29.4; 29.2; 29.2; 28.5; 25.8; 25.6; 22.7; 14.1.

Example 10 - Protective relipidization cream (I)

Composition in weight percents:
N-tetracosanoyl-(L)-serine tetradecyl ester 5.0
Cetostearyl alcohol 5.7
Cetostearomacrogol 2.9
Liquid paraffin 17.1
White petrolatum 39.9 Methylparaben 0.2
40 mM citrate buffer pH 3 ,7 ad 100

Example 11 - Effect of cream (I) according to Example 10 on the TEWL of skin damaged by extraction of lipids

Fresh human skin from abdominal plastic surgery (number of donors = 11 , 44 ± 9 years) was experimentally damaged by extraction of barrier lipids with a mixture chloroform/methanol 2:1. The tested compositions (pseudoceramide containing cream according to Example 10, analogous cream base without pseudoceramide and commercially available product LR as the positive standard) were applied to the surface of the damaged skin, excess of the composition was removed and evaluation was performed after 2 hours. Evaporimeter EPl (Servo Med) was used for TEWL evaluation at room temperature of 23 °C and relative humidity of 30 %.

Damage of the skin barrier by extraction of lipids resulted in a 60 % increase of the TEWL. Single administration of cream (I) according to Example 10 to thus damaged skin reduced the TEWL in a statistically significant manner. The relipidization effect of cream (I) is statistically significantly higher than that of product LR and that of the cream base without pseudoceramide (Table 1).

Table 1 : TEWL of the healthy skin and the skin damaged by extraction of lipids and relipidization by means of cream (I), comparison with commercially available product LR.
Healthy Damaged τ „ Cream _ ,TN
. . . . LR , Cream (I)
skin skin base
Skin damage by
+ + + + extraction of lipids
Administration of
+ + + composition
Number of repetitions 11 11 11 11 11

TEWL (g/m2/h) ± S.D. 3.3 ± 0.2 5.1 ± 0.5+ 4.5 ± 0.3* 4.4 ± 0.4* 3.8 ± 0.6*-LR L S.D. - standard deviation, Statistically significant difference compared to healthy skin (p < 0.05), * statistically significant difference compared to damaged skin (p < 0.05), Statistically significant difference compare to the cream base (p < 0.05), LRstatistically significant difference compared to LR (p < 0.05)

Example 12 - Effect of cream (I) according to Example 10 on the TEWL of skin damaged by partial removal of SC

Fresh human skin from abdominal plastic surgery (number of donors = 11 , 44 ± 9 years) was damaged by partial removal of the SC by means of an adhesive tape (repeated 20 times). Administration of the compositions and evaluation were the same as in Example 11.
Damage of the skin barrier by partial removal of the SC resulted in a 5.6-fold increase of the TEWL. Single administration of cream (I) according to the Example 10 to thus damaged skin reduced the TEWL in a statistically significant manner. The relipidization effect of cream (I) is statistically significantly higher than that of product LR and that of the cream base without pseudoceramide (Table 2).

Table 2: TEWL of the healthy skin and the skin damaged by partial removal of SC and relipidization by means of cream (I), comparison with commercially available product LR.
Healthy Damaged τ „ Cream „ ,
. . J . .6 LR , Cream (I)
skin skin base ___

Skin damage by partial
+ + + + removal of SC
Administration of
+ + + composition
Number of repetitions 11 11 11 11 11

TEWL (g/m2/h) ± S.D. 3.3 ± 0.2 18.5 ± 3.3+ 13.3 ± 2.5* 11.3 ± 2.7* 8.9 ± 1.6* LR L S. D. - standard deviation, Statistically significant difference compared to healthy skin (p < 0.05), * statistically significant difference compared to the damaged skin (p < 0.05), Statistically significant difference compared to the cream base (p < 0.05), LRstatistically significant difference compared to LR (p < 0.05)

Example 13 - Protective relipidization cream (H)

Composition in weight percents:
N-docosanoyl-(L)-serine tetradecyl ester 3.0
Cetostearyl alcohol 5.8
Cetostearomacrogol 3.0
Liquid paraffin 17.5
White petrolatum 40.7
Methylparaben 0.2
40 mM citrate buffer pH 3.7 ad 100

Example 14 - Effect of cream (II) according to Example 13 on the TEWL of skin damaged by a detergent

Fresh human skin from abdominal plastic surgery (n = 12, 46 ± 9 years) was experimentally damaged by 3-hour application of 2 % sodium laurylsulfate. The skin was then washed with water and cream (II), LR and a cream base without ceramides were administered after two hours. Administration of the compositions and evaluation was the same as in Example 11.

Damage of the skin barrier by extraction of lipids resulted in a 67 % increase of the TEWL. Single administration of cream (II) according to the Example 13 o thus damaged skin reduced the TEWL in a statistically significant manner. The relipidization effect of cream (II) is statistically significantly higher than that of product LR and that of the cream base without pseudoceramide (Table 3).

Table 3: TEWL of the healthy skin and the skin damaged by partial removal of SC and relipidization by means of cream (II), comparison with commercially available product LR.
Healthy Damaged τ „ Cream „ .
. . . . LR , Cream (I)
skin skin base
Skin damage by partial
- + + + + removal of SC
Administration of
- - + + + composition
Number of repetitions 12 12 12 12 12

TEWL (g/m2/h) ± S.D. 3.3 ± 0.2 5.5 ± Ll+ 4.9 ± 0.4* 5.3 ± 0.9 4.6 ± 0.6*'L

S.D. - standard deviation, Statistically significant difference compared to healthy skin (p < 0.05), * statistically significant difference compared to damaged skin (p < 0.05), Statistically significant difference compared to the cream base (p < 0.05), LRstatistically significant difference compared to LR (p < 0.05)

Example 15 - Protective relipidization cream (III)

Composition in weight percents:
N-eicosanoyl-(L)-serine tetradecyl ester 1.0
Cetostearyl alcohol 5.9
Cetostearomacrogol 3.0
Liquid paraffin 17.8
White petrolatum 41.6
Methylparaben 0.2
40 mM citrate buffer pH 3.7 ad 100 Example 16 - Effect of cream (III) according to Example 15 on the TEWL of skin damaged by a detergent

Model skin damage and administration of cream (III) were performed in the same way as in Example 14. Hydration of the skin was measured with Corneometer CM 820 (Courage&Khazaka) and is expressed as hydration index (HI).
HI of the healthy skin is 72 ± 5 units; damage with a detergent statistically significantly decreases hydration to 57 ± 4 units. Administration of cream (III) increased HI to 67 ± 7 units in a statistically significant manner.

Example 17 - Base for a daily cream

Composition in weight percents:
N-tetracosanoyl-(L)-serine hexadecyl ester 0.30
Bis-PEG/PEG- 14/14 Dimethicone/Cyclomethicone 35.00
Capryloyl/caprinoyl triglyceride 4.50
Cyclomethicone 3.00
Dimethicone 2.00
Glycerol 85% 7.50
Glyceryl stearate/citrate 2.00
Microcrystalline wax 2.00
Paraffin oil 2.00
Octyl dodecanol 2.00
Preservatives q.s.
Water ad 100

Example 18 - Base for a protective barrier cream

Composition in weight percents:
N-docosanoyl-(L)-serine octadecyl ester 0.56
Methoxy PEG/PPG-7/3 aminopropyl dimethicone 35.00
Beeswax 3.00
C(12-15)alkyl benzoate 1.00 Cyclomethicone 3.00

Decyl pentanoate 3.00

Dicaprylyl ether 1.00

Glycerol 85% 4.00

Glyceryl stearate 6.00

PEG-2-stearate 1.00

PEG-40-stearate 3.00

Petrolatum 2.50

Phenoxyethanol/Methy lparaben/Ethy lparaben 4:2:1 0.60

Polyacrylamide/C(13-14)isoparaffin/Laureth-7 0.50

Sorbitan tristearate 1.85

Sunflower oil 2.00

Preservatives q.s. Water ad 100

Example 19 - Base for a moisturizing lotion

Composition in weight percents:

N-tetracosanoyl-(L)-serine dodecyl ester 1.21

Cetyl PEG/PPG 10/1 Dimethicone 24.00

Glycerol 85% 10.00

Alkyl modified carboxyvinyl polymers 0.05

Carboxyvinyl polymer 0.10

Cetyl isooctanoate 5.00

Ethanol 60 % 5.00

Methylparaben 0.20

Propylene glycol 4.00

Preservatives q.s.

Water ad 100 Example 20 - Base for a protective cream

Composition in weight percents:
N-hexacosanoyl-(L)-serine tetradecyl ester 1.20

Cholesterol 2.00

2-Ethylhexyl-p-methoxy cinnamate 0.10

Cetyl alcohol 5.00

Decyl oleate 20.00

Glyceryl oleate 1.50

Ozokerit 1.50

Stearyl alcohol 3.80

Sunflower oil 5.00

White petrolatum 30.00

White wax 4.40

Preservatives q.s.

Water ad 100

Example 21 - Vehicle for an emollient handkerchief

Composition in weight percents:
N-oleoyl-(L)-serine octadecyl ester 0.85

Propyleneglycol/PEG-55-propyleneglycol oleate 27.00

Glycerol 85% 5.00

Glyceryl stearate 3.00

Tocopheryl acetate 0.30

Preservatives q.s.

Water ad 100

Example 22 - Base for a protective gel

Composition in weight percents:
N-docosanoyl-(L)-serine tetradecyl ester 0.50

PEG- 18-glyceryl-oleate/cocoate 19.00 Pectin 0.50

Calcium chloride 0.03

Dipropyleneglycol 8.97

Glycerol 85% 6.00

Cholesterol 0.30

Lecithin 0.50

Preservatives q.s. Water ad 100

Example 23 - Base for a make-up-removal lotion

Composition in weight percents:
N-(2-hydroxyhexadecyl)-(L)-serine eicosyl ester 0.10

Capryloyl/caprinoyl glycerides 2.50

Olive oil 5.00

Sodium cocoyl lactylate 2.50

Glyceryl stearate 2.50

Cetearyl alcohol 1.00

Isohexadecane 0.50

Polyacrylamide / C(13-14)isoparaffin / Laureth-7 0.40

Preservatives q.s.

Water ad 100

Example 24 - Base for an absorption regeneration serum

Composition in weight percents:
N-hexacosanoyl-(L)-serine dodecyl ester 1.80

PEG- 18 Glyceryl oleate/cocoate 10.00

Propane- 1,3-diol 3.00

Glycerol 85% 4.70

Sodium hyaluronate 0.10

Preservatives q.s.

Water ad 100 Example 25 - Replenishing cream

Composition in weight percents:
N-triacontanoyl-(L)-serine dodecyl ester 0.55

Cholesterol 2.55

Glycerol 85% 5.00

Polysorbate 0.50

Polyglyceryl-3-caprate 15.00

Cetostearyl alcohol 5.00

Citric acid 0.50

Dexpanthenol 1.00

Glyceryl caprylate/caprinate 1.00

Glyceryl behenate 0.00

Chlorophenesine 5.00

Magnesium sulfate 5.00

Macrocrystalline wax 3.00

Paraffin oil 0.20

Olive oil 10.00

Octyl-stearate 0.50

Solid paraffin 2.00

PEG-22-dodecylglycol copolymer 13.50

PEG-30-dipolyhydroxy stearate 12.00

Phenoxyethanol 1.50

Propylene glycol 3.00

Sodium chloride 3.90

Preservatives q.s.

Water ad 100

Example 26 - Regeneration cream

Composition in weight percents:
N-eicosanoyl-(L)-serine hexadecyl ester 1.50 PEG-I δ-glyceryl-oleate/cocoate 15.00

Cholesterol 1.50

Glycerol 85% 7.00

Polyacrylamide/C(13-14)isoparaffin / Laureth-7 2.50

Saccharose sorbitan-stearate/cocoate 1.00

Diethylhexyl carbonate 7.00

Polysorbate 20 0.10

Stearyl alcohol 0.40

Cetyl alcohol 0.90

Isopropyl isostearate 1.50

Isohexadecane 1.00

D-panthenol 0.50

Niacinamide 2.00

EDTA disodium salt 0.10

Tocopheryl acetate 0.50

Preservatives q.s.

Water ad 100

Example 27 - Replenishing gel

Composition in weight percents:
Dodecylester N-tetracosanoyl-(L)-serine 1.25

Niacinamide 2.50

Retinyl propionate 0.20

Titanium dioxide 1.50

Polyacrylamide/Isoparaffin/Laureth-7 1.00

Xanthan gum 0.25

Glycerol 85% 8.00

Urea 2.00

Panthenol 3.00

Allantoin 1.50

Tocopheryl acetate 0.05

Cetyl alcohol 0.05 Stearyl alcohol 0.05

Cyclomethicone/Dimethiconol 1.25

Steareth-21 1.25

Steareth-2 0.50

Saccharose cocoate 0.30

PPG- 15-stearyl ether 1.50

Ethylhexyl palmitate 7.00

Dimethicone 7.60

EDTA disodium salt 3.00

Sodium lactate 1.10

Preservatives q.s.

Water ad 100

Example 28 - Emollient gel

Composition in weight percents:
N-docosanoyl-(L)-serine tetradecyl ester 2.30

Bis-PEG/PEG-14/14 Dimethicone/Cyclomethicone 7.00

Allantoin 1.50

Cetyl alcohol 0.05

Cyclomethicone 1.25

Dimethicone 7.60

EDTA disodium salt 3.00

Ethylhexyl palmitate 7.00

Glycerol 85% 8.00

Niacinamide 2.50

Panthenol 3.00

Polyacrylamide / Isoparaffϊn / Laureth-7 1.00

PPG- 15 -stearyl ether 1.50

Retinyl propionate 0.20

Sodium lactate 1.10

Steareth-2 0.50

Steareth-21 1.25 Stearyl alcohol 0.05

Saccharose cocoate 0.30

Titanium dioxide 1.50

Tocopheryl acetate 0.05

Urea 2.15

Xanthan gum 0.10

Preservatives q.s. Water ad 100

Example 29 - Reparation cream

Composition in weight percents:
N-octacosanoyl-(L)-serine tetradecyl ester 2.50

Glycerol 85% 4.50

Almond oil (Prunus amygdalus dulcis) 5.00

Capryloyl/caprinoyl triglyceride 6.00

Cyclomethicone 2.00

Dimethicone 0.50

Grape seed (Vitis vinifera) oil 4.00

Hydroxyethylcellulose 0.50

Cholesterol 0.10

Imidazolidinylurea 0.20

Methoxy-PEG/PPG-7/3-aminopropyldimethicone 5.00

Methylparaben 0.20

Panthenol 0.50

Propylparaben 0.10

Sodium hyaluronate 0.10

Tocopheryl acetate 0.50 Water ad 100

Example 30 - Relipidization shampoo

Composition in weight percents:

N-oleoyl-(L)-serine hexadecyl ester 0.10

Propyleneglycol / PEG-55 -propyl eneglycol oleate 0.50

Sodium laurylether sulfate 0.40

C( 12- 14)alkyl-polyglucoside 5.00

Sodium lauryl ether sulfosuccinate 8.50

PolyquaterniumlO PEG-55 3.00

Propyleneglycol oleate 1.00

PEG-I -glyceryl oleate/cocoate 0.20

PEG-160-sorbitan triisostearate 1.00

Sodium chloride 1.00

Lactic acid 0.30

Citric acid 1.80

2-Oxopyrrolidine-5 -carboxylic acid 0.10

Propylene glycol 0.10

Glycerol 85% 0.50

Preservatives q.s.

Water ad 100

Example 31 - Foam for sensitive skin

Composition in weight percents:
N-hexadecanoyl-(L)-serine eicosyl ester 0.10

Cholesterol 0.10

Ethylhexyl palmitate 12.00

Glycerol 54.00

Cetyl alcohol 0.10

Stearic acid 0.10

Talc 0.20

Diglycerol monooleate 0.20

Castor oil 1.00

Cetyl palmitate 1.00

Diglyceryl laurate 4.20

Paraffin oil 6.00 Isobutane 10.50 Propane 10.50

Example 32 - Cleansing hydrolotion

Composition in weight percents:
N-triacontanoyl-(L)-serine dodecyl ester 0.20

PEG-120-methylglucosyl dioleate 14.00

Xanthan gum 0.25

Ceteareth-30 0.25

Lactic acid 0.40

Olive oil 7.50

Panthenol 4.20

Sodium lactate 0.90

Tocopherol 0.10

Urea 8.00

Preservatives q.s.

Water ad 100

Example 33 - Hair serum

Composition in weight percents:
N-docosanoyl-(L)-serine tetradecyl ester 15

Propyleneglycol; PEG-55-propyleneglycol oleate 10

Sodium lauryl ether sulfosuccinate 15

Sodium lauryl ether sulfate 15

Cocoamidopropyl betaine 7

Preservatives q.s.

Water ad 100 Industrial applicability

The invention can be utilized in pharmaceutical and cosmetic industries for manufacturing compositions designed for treatment of skin diseases associated with changes in lipidic composition or with damage of skin lipids and of the function of the skin, and cosmetic composition designed for skin care, or alternatively for preventing undesirable permeation of xenobiotics into the organism. Pharmaceutical and cosmetic compositions according to the invention can be used as vehicles for any dermatological and cosmetological active substances.