TOPICAL COMPOSITIONS CONTAINING SIALYL SUGARS AND THEIR DERIVATIVES

Abstract: Sialyl oligosaccharides and derivatives useful for regulating inflammatory responses, and treating related disorders and conditions, and/or improving the texture or appearance of the skin, as well as topical pharmaceutical and cosmetic compositions containing sialyl oligosaccharide or derivatives and methods for their use are described. The sialyl oligosaccharides or derivatives of the present invention are also useful in topical compositions suitable for prophylactic or therapeutic treatment of disorders associated with the inflammatory response of cells in the skin.

Description: TOPICAL COMPOSITIONS CONTAINING SIALYL SUGARS AND THEIR DERIVATIVES 1. FIELD OF THE INVENTION _ The invention relates to sialyl oligosaccharides and derivatives thereof that are useful for regulating inflammatory responses and treating skin irritation. The invention further relates to topical pharmaceutical and cosmetic compositions containing such oligosaccharides, and to methods for their use. 2. BACKGROUND OF THE INVENTION 2.1. SKIN IRRITATION AND ASSOCIATED INFLAMMATORY RESPONSES 15 Skin irritation can have any of several causes, for example, skin irritation can result from diseases, such as psoriasis, eczema, and seborrheic dermatitis. Psoriasis is a chronic skin condition that is characterized by red plaques with thick, flaking, silvery scales. Affected areas can _ 0 range from localized patches of skin to the entire body. Psoriasis is not presently curable and even temporary relief requires long-term treatment. Eczema and seborrheic dermatitis are also inflammatory conditions of the skin, and typically involve scaling or blisters. Eczema may affect up to 10% of the adult population and as many as 20% of children at any given time. Exposure to an irritant or allergen can also result in skin irritation and inflammation. These allergic conditions are often referred to as contact dermatitis and can be caused 30 by ( for example, exposure to substances found in cosmetics, clothing, plants and household items. Administration of certain drugs and by particular means of administration, e.g., transdermal delivery, can also cause irritation. Atopic dermatitis is typically associated with a family 35 history of allergic rhinitis, asthma, or atopic eczema. Skin irritation can also result from exposure to certain plants. For example, exposure to oils from poison ivy, poison oak, the poison sumac can result in redness and swelling, followed by blisters and severe itching, in persons who are sensitive to these plants. Another cause of skin irritation is insect bites and stings, which can cause reactions such as hives, inflammatory papulae, and blisters. Inflammatory responses, including those that are associated with many forms of skin irritation, are usually caused by activation of the immune system. Recent research indicates that specific cell surface oligosaccharide structures are involved in the activation and regulation of immune responses. Specific sialylated oligosaccharides function as ligands for intercellular adhesion receptors, matrix proteins and growth factors. For example, compounds bearing the oligosaccharide moiety sialyl-LewisX(SLeX; NeuAcoc2-3Gal/3l-4 (Fucoc 1-3) GlcNAc l were recently found to play an important role in the inflammatory response, mediating the cell adhesion of leukocytes to endothelial cells (see, e.g., US Patent No. 5,753,631). After binding to endothelial cells, the leukocytes are able to squeeze past gaps between them to enter the adjoining tissue, where they help repair injury. Sialylated oligosaccharide structures are also involved in macrophage-mediated immune responses. Macrophage cell surfaces display sialoadhesin, which is a 185 kDa transmembrane glycoprotein that mediates cell-cell interactions through recognition of glycoproteins and glycolipids that contain the terminal oligosaccharide NeuAcoc2-3GalNac (van den Berg et al . , 1992, J. Exp . Med . 176: 647-755; Crocker et al . , 1991, EMBO .J 10; 1661-1669). Sialoadhesin, which binds preferentially to granulocytic cells (Crocker et al . , 1995, J. Clin . Invest . 95: 635-643), is a member of the immunoglobulin superfamily (Crocker et al . , 1994, EMBO J . 13: 4490-4503). The amino acid sequence of sialoadhesion is similar to those of CD22 and the myelin- associated glycoprotein (MAG) , both of which also bond sialylated oligosaccharides (Kel et al . , 1994, Cur . Biol . 4; 965-972). These three molecules, which have been termed the "sialoadhesin family" of the immunoglobulin superfamily (Id . ) , are selective in the cell types that are bound. This selectivity is due at least in part to the preference of each member of the sialoadhesin family for a specific oligosaccharide structure. While sialoadhesin preferentially binds N- and O-linked oligosaccharides that terminate in oc2 , 3-linked sialic acid, MAG preferentially binds O-linked oc2 , 3-sialylated oligosaccharides and 22 binds to N-linked cχ2 , 6-sialylated oligosaccharides (Id . ) For a review of the role of sialoadhesin in macrophage recognition, see e.g., Crocker et al . , 1997, Glycoconjugate J. 14: 601-609). 2.2. OLIGOSACCHARIDES AND THEIR ROLE IN CELL ADHESION Cell surface oligosaccharides have recently been found to have important regulatory roles in cell biological and immunologic processes. Specific oligosaccharides have been shown to function as ligands for intercellular adhesion receptors, matrix proteins and growth factors. In particular, compounds bearing the oligosaccharide moiety, sialyl-Lewis X (SLeX) , were recently found to play an important role in the inflammatory response, mediating the cell adhesion of leukocytes to endothelial cells. Leukocytes migrate into tissues during an inflammatory response. Vascular endothelial cells' participation in the recruitment of leukocytes to injured tissue occurs by the expression of cell adhesion molecules in response to cytokines (Pober et al., 1986, J . Immunol . 136:1680; Bevilacqua et al., 1987, Proc . Natl . Acad . Sci . 84:9236). The cell adhesion molecules make the endothelial cells recognizable to SLeX containing white blood cells. After binding to endothelial cells, the leukocytes are able to squeeze past gaps between them to enter the adjoining tissue, where they help repair injury. Sometimes too many leukocytes are recruited and normal tissue is destroyed. This can occur in septic shock, in chronic inflammatory diseases such as psoriasis and rheumatoid arthritis, and in reperfusion tissue injury that occurs following heart attack, stroke or organ transplant, (Malech et al., 1987, N . Engl . J . Med . 317:687; Cotran et al., 1986, J . Exp . Med . 164:661). The biological mechanism of leukocytes binding to activated endothelial cells involves binding by SLeX to the endothelial leukocyte adhesion molecule-1 (ELAM-1) , the cell adhesion molecule synthesized and expressed on endothelial cell surfaces in response to cytokines, interleukin-1 and tumor necrosis factor (Phillips et al., 1990, Science 250:1130). ELAM-1 is produced within 2 to 4 hours of cytokine induction and mediates binding of neutrophils at endothelial foci (Bevilacqua et al., 1987, Proc . Natl . Acad . Sci . U . S . A . 84:9238) . ELAM-1 (E-selectin) is a member of the selectin family of cell adhesion molecules including Mel-14/LAM-l (L- selectin) and GMP-140/PADGEM (P-selectin) , which also mediate cell-cell interactions (Bevilacqua et al., 1989, Science 243:1160; Lasky et al., 1989, Cell 56:1045). Because the NH 2 terminal domains of all three selections have a lectin motif they were postulated to recognize a carbohydrate motif. The SLeX group has been found to serve as a common ligand for P- and E-selections and is a component of glycosphingolipids and glycoproteins which are also found on the surface of the leukocyte membrane. The ligand for L-selectin has also been proposed to contain an SLeX type structure in which the sialic acid is replaced with a sulfate group. (Yuen et al., 1992, Biochemistry 31:7549). The increased understanding of the role of carbohydrates as cell surface recognition elements, particularly in the immune response, has led to increased interest in the production of carbohydrate molecules of defined structure in order to regulate those interactions upon systemic administration. The use of SLeX carbohydrate groups has been proposed to block cell-cell adhesion for the treatment of acute and chronic inflammation (Paulson et al., 1990, Science 250:1130-1132). SLeX compounds have also been shown to inhibit binding to E-selectin (DeFrees et al., 1993, J . Am. Chem . Soc . 115:7549). 2.3. SIALYL OLIGOSACCHARIDES WITH IMMUNOMODULATING ACTIVITY Much of the focus in the art has been directed to developing large SLeX analogs with immunomodulating properties for use as systemic anti-inflammatories. International Publication No. WO 92/22564, published December 12, 1992, discloses sulfate, phosphate and carboxylate derivatives of Lewis X oligosaccharides that lack a sialyl group, but are said to provide enhanced immunosuppressing or tolerogenic properties over derivatives lacking the sulfate, phosphate or carboxylate substituents. These compounds have utility in suppressing a cell-mediated immune inflammatory response to an antigen, and therefore reduce sensitization of a mammal to an immune response. Other groups have focused on inhibiting specific cellular interactions. In particular, Nashed et al. (see U.S. Patent No. 5,326,752, issued July 5, 1994) has developed substituted lactose and lactosamines that specifically bind to the ELAM-1 receptor and thus modulate inflammatory responses. Pharmaceutical compositions containing these compounds, are reported to have utility in the treatment of inflammation, allergic reactions and autoimmune disease upon parenteral administration. In particular, International Publication No. WO91/19501, published December 26, 1991, and International Publication No. WO91/19502, published December 26, 1991, disclose that oligosaccharides containing the pentameric and hexameric structures shown below inhibited the selective intracellular binding between cells containing the ligand (below) and those containing a selectin receptor and that the penta- and hexasaccharides provided better inhibition than did SLeX: NeuAcα2-3/3Gal/3l-4(Fucαl-3)GlcNACj3l,3Galj3-; NeuAcc.2-3jSGal/3l-4(Fucαl-3)GlcNAci3l-3Gal3l-4Glc-; and NeuAcc.2-3βGalj8l-4(Fucαl-3)GlcNAc = SLeX. These oligosaccharides have utility in inhibiting selectin- mediated cell adhesion related to inflammatory disease and tumor metastasis, when administered intravenously, orally or as an aerosol. Other research groups have extended the area of interest to compositions containing sialyl oligosaccharides derivative for use as systemic anti-inflammatories and cosmetics. For example, two Japanese patent applications, Yoshihiro et al. JP163110A, published June 27, 1989, and Yoshihiro et al., JP163125A, published June 27, 1989, describe the use of sialyl oligosaccharide derivative compounds in both systemic and topical applications. In both of these applications the sialic acid compounds are crudely extracted from milk preparations, resulting in complex mixtures of sialyl sugars with other sugars, proteins and fats. The isolation procedures described in the patent publications and the basis of the identification of sialic acid as part of the "sialic acid containing complexes" is based solely on the allegation that the isolated complex mixtures contained charged oligosaccharide functionalities. The patent publications describe the use of these crude preparations in a topical composition which allegedly has activity as a skin aging preventive medication and as a systemic anti-inflammation medication. In addition, large oligosaccharides containing two copies of the SLeX group have been designed for use as anti- inflammatory agents. International Publication No. WO 95/03059, published February 2, 1995, discloses the use of bivalent SLeX compounds to inhibit cellular binding to a selectin receptor. These large oligosaccharides are used in compositions to inhibit adhesion between cells that express a selectin receptor such as the E selectin receptor and cells that express SLex on their surfaces. Synthetic SLeX derivatives which are modified at the C-2 and/or C-6 position of the N-acetylglucosamine (GlcNAc) residue with immunomodulating properties have also been disclosed in the art. International Publication No. WO 92/22565, published December 23, 1992, describes methods for the synthesis of SLeX derivatives with such modifications made to the galactose and/or GlcNAc units of SLeX, employing specified sialyl and fucosyl transferases so that these derivatives are readily prepared by sequential enzymatic methods in vitro . These SLeX derivatives have use in compositions to systemically treat and prevent disease by modulating the immune response. The development of topical compositions containing SLeX derivatives previously has attracted little interest which is probably due to the size of the molecule and the cost and difficulty in synthesizing, purifying and formulating such molecules into compositions suitable for topical application. In view of the above, it would be particularly beneficial to develop commercially feasible compounds which possess anti-inflammatory properties, while being effective upon topical applications. 3. SUMMARY OF THE INVENTION The present invention provides novel sialyl oligosaccharides and their derivatives useful in regulating inflammatory responses, reducing skin irritation, and treating skin reddening, compositions containing the sialyl oligosaccharides and their derivatives, and methods for their use. The invention provides carbohydrate compounds that are capable of treating and preventing undesirable inflammatory responses and skin irritation. The compounds can be used in pharmaceutical compositions and methods of treatment. The anti-inflammatory compounds are generally sialic acids or glycosides of sialic acids. The sialyl glycosideε typically have a formula: sialic acid-Z-R-P, wherein: Z is a member selected from the group consisting of alpha- or beta- linked O, S, and N-A, wherein A is a member selected from the group consisting of H, Acetyl ("Ac") , alkylacyl, aryl and acyl; R is a member selected from the group consisting of a carbohydrate, an aglycon, a polysaccharide, a polymer, an oligosaccharide, a lipid, a ceramide, and a sphingosine; and P is H or a member selected from the group consisting of a polysaccharide, a polymer, and an oligosaccharide. These sialylated structures include both monovalent and polyvalent forms as shown in Compounds I and II below: Compound I Compound II wherein Z, R and P are set forth above, and X is a member selected from the group consisting of OH, NH 2 , NHAc, and N-A, wherein A is a member selected from the group consisting of H, Ac, alkylacyl, aryl and acyl; and Y is a member selected form the group consisting of H, Ac, alkyl, aryl, alkylaryl, alkylacyl, arylalkylacyl, glycoyl, and an amino acid; and M is a member selected from the group consisting of NH or O. In Compound II, each X can be selected independently. Included among the anti-inflammatory compounds are sialyl galactosides, such as, for example, the sialyl lactosides, which typically have the formula as shown in Compound III, Compound IV, Compound VI and sialic acids and sialic acid glycosides as shown in Compound V: NeuAcoe(2-3) Gal/5 (1-4) Glc-Z-R-P Compound III NeuAc (2-6) Gal/3 (1-4) Glc-Z-R-P Compound IV NeuAc-Z-R-P Compound V NeuAcα(2-6)Gal-Z-R-P Compound VI In these formulas, Z, R, and P are set forth above. In Compound V, where R is a sugar, Z is typically an o-linkage between the 2' position of the sialic acid and a 3' or 6' hydroxy1 group of the sugar. In some embodiments, R is an aglycon group having at least one carbon atom, such as alkyl or acyl from 1-18 carbons, 5, 6,7, 8-tetrahydro-2- naphthamido; benzamido; 2- naphthamido; 4-aminobenzamido; or 4-nitrobenzamido. The term "aglycon group having at least one carbon atom" refers to a group A-Z, in which A represents an alkylene group of from 1 to 18 carbon atoms optionally substituted with halogen, thiol, hydroxy, alkyl, aryl, arylalkylacyl, arylalkyl, alkylacyl, arylacyl, a linker arm, oxygen, sulfur, amino, i ino, or alkoxy; and Z is hydrogen, -OH, -SH, -NH 2 , -NHR 1 , - N(R') 2 , -COOH, -C0 2 R', -CONH 2 , -CONHR 2 , -C0N(R') 2 , -CONHNH 2 or - OR 1 wherein each R 1 is independently alkyl of from 1-5 carbons atoms. When R is an aglycon, P is a hydrogen, a saccharide, an oligosaccharide, a polysaccheride, a polymer, or a lipid, or an aglycon group having at least one carbon atom. When R is not an aglycon as defined herein, P is a hydrogen. In addition, P can be (CH 2 ) n CH(CH 2 ) m CH 3 (CH 2 )oCH 3ι where n,m,o = 1-18; (CH 2 )„-R 2 (in which n = 0-18), wherein R 2 is a variously substituted aromatic ring, preferably, a phenyl group, being substituted with one or more alkoxy groups, preferably methoxy or 0(CH 2 ) m CH 3 , (in which = 0-18), or a combination thereof. In some embodiments, when M is oxygen and Y is hydrogen, the sialic acid is 2-keto-3-deoxy-nonulosonic acid (KDN) . In preferred embodiments of the invention, the compounds are selected from the group consisting of 3 '-sialyl and 6'- sialyl derivatives. Additional embodiments are described below. The invention also encompasses novel sialyl oligosaccharide derivatives, including, but not limited to, 3 '-sialyl melibiose, 3 '-sialyl lactulose, 3 '-sialyl GAL arabinose, 3 '-sialyl raffinose and 3 '-sialyl stachyose and pharmaceutically or cosmetically acceptable salts thereof. The invention further encompasses the use of chemically modified sialyl oligosaccharide derivatives, including, but not limited to, benzyl sialyl lactose and ethyl sialyl lactose. In particular, the compounds of the present invention are typically disaccharides, trisaccharides or derivatives thereof. Thus, the present invention encompasses novel sialyl oligosaccharide derivatives which have utility in regulating inflammatory responses. The invention also encompasses pharmaceutical compositions containing the novel oligosaccharide derivatives of the present invention, suitable for administration or application to animals and humans. The present invention further encompasses sialyl oligosaccharide derivatives in topical pharmaceutical and cosmetic compositions. It is to be pointed out that the pharmaceutical compositions of the present invention are those which, when administered, render a benefit or an effect of treating or preventing an abnormal or biological condition or a disease. Benefits or effects of treating or preventing such abnormal condition or disease are the reduction in severity or disappearance of the abnormal condition or disease. The reduction in severity or disappearance of the abnormal condition or disease may be either in the short- or long- term. Such abnormal biological conditions or diseases to be treated by administering a composition of the present invention include treatment of disorders related to anti- inflammatory responses. The topical pharmaceutical compositions of the present invention are suitable for prophylactic or therapeutic treatment of disorders associated with the inflammatory response of cells in the. skin (epidermal and dermal layers) , including but not limited to atopic dermatitis, chronic urticaria lesions, inflammatory dermatoses, facial edema, Well's syndrome, psoriasis, eczema, pruritus, thrombolytic disorders, xerosis, and dry skin. In another embodiment, the topical pharmaceutical compositions of the present invention have utility in treating skin irritation and skin reddening associated with an inflammatory response, for example, skin irritation and skin reddening resulting from extrinsic events including, but not limited to chemicals, pollutants, such as cigarette smoke, irritants, and intrinsic events such as aging, allergants and sun exposure; and immunodeficiency effects. The method comprises administering to a subject a safe and effective amount of a topical composition comprising of one or more of the sialyl oligosaccharide derivatives of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The cosmetic compositions of the present invention are adapted for topical application. The cosmetic compositions of the present invention can be used to improve the aesthetic quality of the skin, and to protect the skin from causes of inflammation. Cosmetic compositions containing the sialyl oligosaccharide derivatives can be used to improve dry skin, acne, age spots, wrinkles (both coarse and fine, caused by intrinsic as well as extrinsic damage) , warts, blemished skin, hyper-pigmented skin, hyper-keratotic skin, inflammatory dermatoses, age-related skin changes and skin in need of cleansers. The cosmetic compositions of the present invention can also be utilized to improve skin irritation, for example skin irritation resulting from chemicals, pollutants, smoke, sunburn and allergies. In addition, the invention encompasses the topical use of sialyl oligosaccharide derivatives, including, but not limited to: 3 '-sialyl melibiose, 3 '-sialyl lactulose, 3'- sialyl GAL arabinose, 3 '-sialyl raffinose, 3'-sialyl stachyose, 3 '-sialyl lactose, 6 '-sialyl lactose, 3 '-sialyl-N- acetyl-lactosamine, 6 '-sialyl-N-acetyl-lactosamine, 3 '-sialyl LNnT (lacto-N-neo-tetraose) , 6'-sialyl LNnT, 3 ' -sialyl-LNT (lacto-N-tetraose), 6 ' -sialyl-LNT, benzyl sialyl lactose and ethyl sialyl lactose and pharmaceutically or cosmetically acceptable salts thereof. The present invention may be understood more fully by reference to the detailed description and illustrative examples which are intended to exemplify non-limiting embodiments of the invention. 4. DETAILED DESCRIPTION OF THE INVENTION 4.1. DEFINITIONS As used herein "inflammation" refers to a reaction of either the specific and/or non-specific defense systems. A specific defense system reaction is a specific immune system reaction to an antigen. Exemplary of specific defense system reactions include antibody response to antigens, such as viruses, and delayed-type hypersensitivity. A non-specific defense system reaction is an inflammatory response mediated by leukocytes generally incapable of immunologic memory. Such cells include macrophages, eosinophils, and neutrophils. Examples of non-specific reactions include the immediate swelling after a bee sting, and the collection of PMN leukocytes at sites of bacterial infection. As used herein, "oligosaccharide" refers to a carbohydrate structure having from 2 to about 10 saccharide units. The particular saccharide units employed are not critical and include, by way of example, all natural and synthetic derivatives of glucose, galactose, N- acetylglucosamine, N-acetylgalactosamine, fucose, sialic acid, and the like. As used herein, "sialic acid" or "sialyl" refers to all naturally occurring structures of sialic acid and analogs of sialic acid including those wherein the sialic acid unit has been chemically modified so as to introduce and/or remove one or more functionalities. For example, such modifications can result in the removal of an -OH functionality, the introduction of an amine functionality, the introduction of a carboxylic acid or ester functionality, the introduction of a halo functionality, and the like. The term "sialic acid" refers to any member of a family of nine-carbon carboxylated sugars. The most common member of the sialic acid family is N-acetyl-neuraminic acid (2-keto-5-acetamindo-3-5-dideoxy-D- glycero-D-galactononulopyranos-1-onic acid (often abbreviated as NeuδAc, NeuAc or NANA) . A second member of the family is N-glycolylneuraminic acid (Neu5Gc or NeuGc) , in which the N- acetyl group of NeuAc is hydroxylated. A third sialic acid family member is 2-keto-3-deoxy-nonulosonic acid (KDN) (Nadano et al . (1986) J. Biol . Chem . 261: 11550-11557; Kanamori et al., (1990) J. Biol. Chem. 265: 21811-21819. Also included are 9-substituted sialic acids such as a 9-O-C 1-C6 acyl-Neu5Ac like 9-0-lactyl- NeuδAc or 9-0-acetyl- NeuSAc, 9-deoxy-9-fluoro-Neu5Ac and 9-deoxy-Neu5Ac. For review of the sialic acid family, see, e . g. , Varki (1992) Glycohiology 2 : 25-40; Sialic Acids : Chemistry, Metabolism and Function, R. Schauer, Ed. (Springer-Verlag, New York (1992) . The synthesis and use of sialic acid compounds in a sialylation procedure is disclosed in international application WO 92/16640, published October 1, 1992, incorporated herein by reference in its entirety. As used herein, "fructose" or "fru" refers to L- and D- fructose and analogs thereof. Analogs of fructose refer to naturally occurring and synthetic analogs of fructose including those where the fructose unit has been chemically modified so as to introduce and/or remove one or more functionalities from this structure. For example, such modification can result in the removal of an -OH functionality, the introduction of an amine functionality, the introduction of a carboxylic acid or ester functionality, the introduction of a halo functionality, and the like. As used herein, "galactose" or "GAL" refers to all naturally occurring structures of galactose and analogs of galactose including those wherein the structure has been chemically modified so as to introduce and/or remove one or more functionalities. For example, such modifications can result in the removal of an -OH functionality, the introduction of an amine functionality, the introduction of a carboxylic acid or ester functionality, the introduction of a halo functionality, and the like. As used herein, "arabinose" or "ara" refers to all naturally occurring structures of arabinose and analogs of arabinose including those wherein the structure has been chemically modified so as to introduce and/or remove one or more functionalities. For example, such modifications can result in the removal of an -OH functionality, the introduction of an amine functionality, the introduction of a carboxylic acid or ester functionality, the introduction of a halo functionality, and the like. As used herein, "safe and effective amount" means an amount of the oligosaccharide, compound or composition, sufficient to significantly induce a positive modification in the condition to be treated. The safe and effective amount of the compound or composition may vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the nature of concurrent treatment, the specific compound, compounds or composition employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge, and expertise of the attending physician or health care provider. As used herein, "substantially pure" means that an object species, e.g. , a sialyl glycoside, is the predominant species present and is essentially free of other components with which it is associated in its natural state. Preferably, a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present. More preferably, a substantially pure species is at least 90 to 95%, or is purified to essential homogeneity wherein the composition consists essentially of a single carbohydrate or macromolecular species. As used herein, "cosmetic" means a formulation to be applied to the skin which improves the texture or appearance thereof, without necessarily affecting the structure or function of the skin, or rendering a benefit or an effect of treating or preventing an abnormal biological condition or a disease. A safe and effective amount of a cosmetic means an amount of the cosmetic sufficient to render a beneficial effect to the skin. As used herein, "pharmaceutical" means a prophylactic or therapeutic formulation to be applied to the skin which renders a benefit or a therapeutic effect of treating or preventing an abnormal biological condition or disease. 4.2. SIALYL GLYCOSIDES The present invention provides novel sialyl oligosaccharide derivatives with anti-inflammatory properties and utility in pharmaceutical and cosmetic applications, especially topical applications. The invention provides carbohydrate compounds that are capable of treating and preventing undesirable inflammatory responses and skin irritation. The compounds can be used in pharmaceutical compositions and methods of treatment. The anti-inflammatory compounds are generally sialic acids or glycosides of sialic acids. The sialyl glycosides typically have a formula: sialic acid-Z-R-P, wherein: Z is a member selected from the group consisting of alpha- or beta-linked O, S, and N-A, wherein A is a member selected from the group consisting of H, Ac, alkyl acyl, aryl and acyl; R is a member selected from the group consisting of a carbohydrate, a polysaccharide, a polymer, an oligosaccharide, a lipid, a ceramide, and a sphingosine; and P is H or a member selected from the group consisting of a polysaccharide, a polymer, and an oligosaccharide. These sialylated structures include both monovalent and polyvalent forms as shown as Compounds I and II below: Compound I Compound II wherein Z, R and P are set forth above, and X is a member selected from the group consisting of OH, NH 2 , NHAc, and N-A, wherein A is a member selected from the group consisting of H, Ac, alkylacyl, aryl and acyl; and Y is a member selected form the group consisting of H, Ac, alkyl, aryl, alkylaryl, alkylacyl, arylalkylacyl, glycoyl, and an amino acid; and M is a member selected from the group consisting of NH or O. In Compound II, each X can be selected independently. Included among the anti-inflammatory compounds are sialyl galactosides, such as, for example, the sialyl lactosides, which typically have formula as shown in Compound III, Compound IV, Compound VI and sialic acids and sialic acid glycosides as shown in Compound V: NeuAcoc(2-3) Gal/3 (1-4) Glc-Z-R-P Compound III NeuAco(2-6) Gal/3 (1-4) Glc-Z-R-P Compound IV NeuAc-Z-R-P Compound V NeuAcα (2-6) Gal-Z-R-P Compound VI In these formulas, Z, R, and P are set forth above. In Compound V, where R is a sugar, Z is typically an α-linkage between the 2' position of the sialic acid and a 3' or 6 ' hydroxy1 group of the sugar. In some embodiments, R is an aglycon having at least one carbon atom, such as alkyl or acyl from 1-18 carbons, 5, 6,7, 8-tetrahydro-2- naphthamido; benzamido; 2-naphthamido; 4-aminobenzamido; or 4-nitrobenzamido. The term "aglycon group having at least one carbon atom" refers to a group A-Z, in which A represents an alkylene group of from 1 to 18 carbon atoms optionally substituted with halogen, thiol, hydroxy, alkyl, aryl, arylalkylacyl, arylalkyl, alkylacyl, arylacyl, a linker arm, oxygen, sulfur, amino, imino, or alkoxy; and Z is hydrogen, -OH, -SH, -NH 2 , -NHR 1 , -N(R') 2 , - COOH, -CO^ 1 , -CONH 2 , -CONHR 2 , -CON(R') 2 , -CONHNH 2 or -OR 1 wherein each R 1 is independently alkyl of from 1-5 carbons atoms. When R is an aglycon, P is a hydrogen, a saccharide, an oligosaccharide, a polysaccharide, a polymer or a lipid, or an aglycon group having at least one carbon atom. When R is not an aglycon as defined herein, P is a hydrogen. In addition, P can be (CH 2 ) n CH(CH 2 ) m CH 3 (CH 2 ) 0 CH 3 where n,m,o = 1-18; (CH 2 ) n -R 2 (in which n = 0-18), wherein R 2 is a variously substituted aromatic ring, preferably, a phenyl group, being substituted with one or more alkoxy groups, preferably ethoxy or 0(CH 2 ) m CH 3 , (in which m = 0-18), or a combination thereof. In some embodiments, when M is oxygen and Y is hydrogen, the sialic acid is 2-keto-3-deoxy-nonulosonic acid (KDN) . In the above descriptions, the terms are generally used according to their standard meanings. The term "alkyl" as used herein means a branched or unbranched, saturated or unsaturated, monovalent or divalent, hydrocarbon radical having from 1 to 20 carbons, including lower alkyls of 1-8 carbons such as methyl, ethyl, n-propyl, butyl, n-hexyl, and the like, cycloalkyls (3-7 carbons) , cycloalkylmethyls (4-8 carbons) . and arylalkyls. The term "alkoxy" refers to alkyl radicals attached to the remainder of the molecule by an oxygen, e . g . , ethoxy, methoxy, or n-propoxy. The term "alkylthio" refers to alkyl radicals attached to the remainder of the molecule by a sulfur. The term "acyl" refers to a radical derived from an organic acid by the removal of the hydroxy1 group. Examples include acetyl, propionyl, oleoyl, myristoyl. The term "aryl" refers to an aromatic monovalent carbocyclic radical having a single ring (e . g . , phenyl) or two condensed rings (e . g . , naphthyl) , which can optionally be mono-, di-, or tri-substituted, independently, with alkyl, lower-alkyo, cycloalkyl, hydroxylower-alkyl, aminolower- alkyl, hydroxy1, thiol, amino, halo, nitro, lower-alkyulthio, lower-alkoxy, mono-lower-alkylamino, di-lower-alkylamino, acyl, hydroxycarbonyl, lower-alkoxycarbonyl, hydroxysulfonyl, lower-alkoxysulfonyl, lower-alkylsuylfonyl, lower- alkyulsulfinyl, triffluoromethyl, cyano, tetrazoyl, carbamoyl, lower-alklcarbamoyl, and di-lower-alkylcarbamoyl. Alternatively, two adjacent positions of the aromatic ring may be substituted with a methylenedioxy or ithylenedioxy group. The invention also encompasses novel sialyl oligosaccharide derivatives, including, but not limited to: 3 '-sialyl melibiose, 3 '-sialyl lactulose, 3 '-sialyl gal arabinose, 3 '-sialyl raffinose and 3 '-sialyl stachyose, benzyl sialyl lactose and ethyl sialyl lactose and pharmaceutically or cosmetically acceptable salts thereof. All of the sialyl oligosaccharide derivatives of the present invention have utility in topical applications, both pharmaceutical and cosmetic compositions, in the treatment of disorders associated with the inflammatory response of cells in the skin and skin irritation. 4.3. SYNTHESIS The compounds of the present invention can be synthesized in a number of ways, including in accordance with standard organic chemical techniques using readily/commercially available starting materials. Alternatively, the sialyl oligosaccharides derivative of the present invention can be prepared from semisynthetic methods or completely from enzymatic synthesis. The sialyl oligosaccharide derivatives of the present invention may also be synthesized by a number of glycosyl transferase cycles, for example utilizing sialyl transferase, as described in U.S. Patent Nos. 5,374,541, 5,728,554, 5,753,631, EPO Publication No. 319,253, W096/32492 and Paulson, et al., 1992, J. Am. Chem. Soc. 114:9283, each of which are incorporated herein by reference in their entirety. In a preferred method (Scheme I below) , a compound containing one or more carbohydrate acceptor units (Z-R-P in Scheme I) can be reacted sequentially with a galactosyltransferase (e.g., N-acetylglucosamine /3l-4 galactosyltransferase (E.C. 2.4.1.90)), a sialytransferase (Galj8l-4GlcNAcc.2-3 sialytransferase (E.C. 2.4.99.6) or Gal/31- 3GalNAcα2-3 sialytransferase (E.C. 2.4.99.4) and, optionally, a fucosyltransferase (e . g. , N-acetylglucosaminide αl-3 fucosyltransferase (E.C. 2.4.1.152)) to yield the desired sialyl galactoside structures. In this case, R can be a carrier moiety or activatable intermediate that will allow attachment to a suitable carrier moiety. Each enzymatic reaction uses the appropriate nucleotide sugar as a donor substrate to generate the following intermediates in the synthesis of the sialyl galactoside. The glycosyl transfer reactions may optimally be carried out with added alkaline phosphatase (e.g., from calf intestine, CIAP) to consume the nucleotide phosphate byproduct which may inhibit the reaction. NeuAcα2,3Gal-Z-R-P Scheme I As shown in Scheme I , the steps for these methods typically include: (a) galactosylating a suitable acceptor compound with a galactosyltransferase in the presence of a UDP-galactose under the conditions sufficient to form the compound: Gal-Z-R-P; and (b) sialylating the compound formed in (a) with a sialyltransferase in the presence of a CMP derivative of a sialic acid using an α(2-3) or an α(2-6) sialyltransferase under conditions in which sialic acid is transferred to the non-reducing sugar to form the compound: NeuAcα (2-3) Gal-Z-R-P or NeuAc (2-6) Gal-Z-R-P. In these formulas, Z is a member selected from the group consisting of alpha- or beta- linked O, S, and N-A, wherein A is a member selected from the group consisting of H, Acetyl ("Ac") , alkylacyl, aryl and acyl; R is a member selected from the group consisting of a carbohydrate, an aglycon, a polysaccharide, a polymer, an oligosaccharide, a lipid, a ceramide, and a sphingosine; and P is H or a member selected from the group consisting of a polysaccharide, a polymer, and an oligosaccharide. The general conditions for preparative enzymatic synthesis of sialyl galactosides are known (see, e . g. , Toone et al . , 1989, Tetrahedron 45:5365-5422; Wong et al . , 1982, J. Am . Chem . Soc . 47:5416-5418; Unverzagt et al . , 1990, J " . Am . 5 Chem . Soc. 112:9308-9309; Prieels et al . , 1981, J. Biol . Chem . 256:10456-10463. Each of the key enzymatic reactions has been demonstrated (Beyer et al . , 1981, Adv . Enzymol . 52:23; Toone et al . , supra ; and Howard et al . , 1981, J . Biol . Chem . 262:16830-16837). For preparative reactions, the 10 galactosyltransferase and the sialytransferase (s) are purified from natural sources (Beyer et al . , supra , and Weinstein et al . , 1982, J. Biol . Chem . 257:13835:13844). Fucosyltransferases may also be identified from natural sources, as generally described in Crawley and Hindsgaul, 15 1989, Carhohyde . Res . 193:249-256). The cDNAs of the galactosyltransferase and a sialytransferase have been cloned (Paulson and Colley, 1989, J . Biol . Chem . 264:17615-17618), allowing the production of soluble recombmant enzymes for large-scale preparative synthesis (Colley et al . , 1989, J . 20 Biol . Chem . 264:17619-17622). 4.4. COMPOSITIONS The present invention provides both pharmaceutical and cosmetic compositions suitable for topical application and 25 methods for their preparation. The present invention also provides both pharmaceutical and cosmetic compositions suitable for topical applications comprising known sialyl oligosaccharides, derivatives thereof and pharmaceutically or cos etically acceptable salts thereof. In addition, the 30 present invention provides both pharmaceutical and cosmetic preparations of novel sialyl oligosaccharide derivatives suitable for topical applications. The compositions of the present invention can be used topically to treat inflammatory responses and related disorders. The compositions containing 35 the sialyl oligosaccharide derivatives of the present invention can also be used topically as a skin protectant, an anti-inflammatory agent and as an agent to improve the aesthetic quality of the skin. The compositions containing the sialyl oligosaccharide derivatives of the present invention have both pharmaceutical and cosmetic utility. The cosmetic compositions of the present invention will generally 5 contain lower concentrations of the sialyl oligosaccharide derivatives than required in the pharmaceutical compositions of the present invention. For example, compositions of the present invention encompass concentrations from about 0.01 to about 5.0 wt. % 10 of the sialyl oligosaccharide derivatives of the present invention. 4.4.1. PHARMACEUTICAL COMPOSITIONS AND THEIR PREPARATION __ The pharmaceutical compositions of the present invention for topical application can be used to treat inflammatory disorders of the skin. Thus, the pharmaceutical compositions of the present invention are suitable for topical treatment of skin. _ The present invention also encompasses pharmaceutical compositions containing one or more novel sialyl oligosaccharides derivative thereof useful to treat inflammatory related disorders. Suitable routes of administration of such pharmaceutical compositions of the present may for example include oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Alternatively, one may administer the compound in a local rather than systemic manner, for example via injection of the compound directly into a site of inflammation. By way of example, the pharmaceutical compositions of __ the present invention are particularly useful in treating inflammatory skin disorders, including atopic dermatitis and chronic urticaria lesions. The pharmaceutical compositions of the present invention can also be used to treat skin disorders related to anti- inflammatory responses in addition to, but not limited to skin irritation, dry skin, dandruff, acne, keratoses, psoriasis, eczema, pruritus, age spots, lentigines, melasmas, wrinkles, warts, blemished skin, hyperpigmented skin, hyperkeratotic skin, and inflammatory dermatoses. The pharmaceutical compositions of the present invention can also be utilized to treat skin irritation for example skin irritation resulting from chemicals, pollutants, allergies, sunburn and smoke. In treating anti-inflammatory disorders of the skin, as described above, topical pharmaceutical compositions containing 0.01 to 5.0 wt.%, preferably 0.1 to 2.0 wt.%, and most preferably 1.0 to 2.0 wt.% of the sialyl oligosaccharide derivative can be employed. It should be understood that two or more sialyl oligosaccharide derivatives may be used in combination so that the combined weight % of those sialyl derivatives used in the above-mentioned compositions is within those ranges mentioned above. The most preferable mode of administering the pharmaceutical compositions of the present invention for treating skin disorders related to anti-inflammatory responses as described above, is topical. Such compositions are preferably applied topically, so as to minimize undesirable systemic side effects. The compounds of the present invention can be formulated into suitable pharmaceutical compositions depending on the particular use for which it is to be intended. The pharmaceutical compositions can comprise one or more sialyl oligosaccharide derivative of the instant invention and a pharmaceutically acceptable carrier or excipient. The compositions of the present invention useful for topical application may contain additional ingredients such as carrier, excipient or vehicle ingredients such as, for example, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1, 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically or dermatologically acceptable. Additionally moisturizers or humectants can be added to the present composition if desired. Examples of such additional ingredients can be found in Remington's Pharmaceutical Sciences, Eighteenth Edition, A.R. Gennaro, Ed., Mack Publishing Co. Easton Pennsylvania, 1990. In addition to these and other vehicles which will be obvious to those of ordinary skill in the art, it will be understood that the pharmaceutical compositions of the present invention may include other ingredients such as those that improve or eradicate age spots, keratoses, wrinkles; the compositions may include analgesics, anesthetics, anti-acne agents, antibacterials, antiyeast agents, antifungal agents, antiviral agents, antidandruff agents, antidermatitis agents, antipruritic agents, other anti-inflammatory agents, antihyperkeratolytic agents, anti-dry skin agents, antiperspirants, antipsoriatic agents, antisebborrheic agents, hair conditioners and hair treatment agents, sunscreen agents, antihistamine agents, skin lightening agents, depigmenting agents, vitamins, corticosteroids, tanning agents, hormones, retinoids, topical cardiovascular agents, clotrimazole, ketoconazole, miconozole, griseofulvin, hydroxyzine, diphenhydramine, pramoxine, lidocaine, procaine, mepivacaine, monobenzone, erythromycin, tetracycline, clindamycin, eclocyline, hydroquinone, minocycline, naproxen, ibuprofen, theophylline, cromolyn, albuterol, retinoic acid, 13-cis retinoic acid, hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, betamethasone valerate, betamethasone diproprionate, triamcinolone acetonide, fluocinonide, clobetasol, proprionate, benzoyl peroxide, crotamiton, propranolol, promethazine, vitamin A palmitate, vitamin E acetate and mixtures thereof. The sialyl oligosaccharide derivatives of the present invention can be used as their pharmaceutically or cosmetically acceptable salts. Such salts include, but are not limited to, sodium, potassium, lithium, calcium, magnesium, iron and zinc salts. Most compositions of the present invention may be formulated as solution, gel, lotion, cream, or ointment in a pharmaceutically acceptable form. Actual methods for preparing pharmaceutical compositions are known or apparent to those skilled in the art and are described in detail in for example, Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA (1990) , which is incorporated herein by reference. 4.4.2. COSMETIC COMPOSITIONS AND THEIR PREPARATION The cosmetic compositions of the present invention are adapted for topical application. The cosmetic compositions of the present invention can be used to improve the aesthetic quality of the skin, and to protect the skin from causes of inflammation. Cosmetic compositions containing the sialyl oligosaccharide derivatives of the present invention can be used to improve dry skin, acne, age spots, wrinkles (both coarse and fine, caused by intrinsic as well as extrinsic damage) , warts, blemished skin, hyper-pigmented skin, hyperkeratotic skin, inflammatory dermatoses, age-related skin changes and skin in need of cleansers. The cosmetic compositions of the present invention can also be utilized to improve skin irritation, for example skin irritation resulting from chemicals, pollutants, smoke, sunburn and allergies. In regulating skin disorders as described above, cosmetic compositions will generally contain lower concentrations of the sialyl oligosaccharide derivatives than required in the pharmaceutical compositions of the present invention. The cosmetic compositions of the present invention can contain 0.01 to 5.0 wt.%, preferably 0.1 to 2.0 wt.% and most preferably 0.1 to 1.0 wt.% of the sialyl oligosaccharide derivatives. It should be understood that two or more sialyl oligosaccharide derivatives may be used in combination so that the combined weight % of those sialyl oligosaccharide derivatives used in the above-mentioned compositions is within those ranges mentioned above. The compounds of the present invention can be formulated into suitable cosmetic compositions depending on the particular use for which it is intended, for example cosmetic or therapeutic. The cosmetic compositions can comprise one or more sialyl oligosaccharide derivative of the instant invention and a cosmetically acceptable carrier or excipient. The compositions of the present invention useful for topical application may contain additional ingredients such as carrier, excipient or vehicle ingredients such as, for example, water, acetone, ethanol, ethylene glycol, alphahydroxy acids, propylene glycol, butane-1, 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, fragrances, preservatives, vitamins and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically or dermatologically acceptable. Additionally moisturizers, humectants, emollients, fragrances and pigments can be added to the present composition if desired. Examples of such additional ingredients can be found in Remington's Pharmaceutical Sciences, Eighteenth Edition, A.R. Gennaro, Ed., Mack Publishing Co. Easton Pennsylvania, 1990, or in the CTFA International Cosmetics Ingredients Dictionary (4th Edition) . In addition to these and other vehicles which will be obvious to those of ordinary skill in the art, it will be understood that the cosmetic compositions of the present invention may include other ingredients such as those that improve or eradicate age spots, keratoses and wrinkles, analgesics, anesthetics, anti-acne agents, antibacterials, antiyeast agents, antifungal agents, antiviral agents, antidandruff agents, antidermatitis agents, antipruritic agents, antiemetics, antimotion sickness agents, anti- inflammatory agents, antihyperkeratolytic agents, anti-dry skin agents, antiperspirants, antipsoriatic agents, antisebborrheic agents, hair conditioners and hair treatment agents, antiaging agents, antiwrinkle agents, antiasthmatic agents and bronchodilators, sunscreen agents, antihistamine agents, skin lightening agents, depigmenting agents, vitamins, corticosteroids, tanning agents, hormones and retinoids. The sialyl oligosaccharide derivatives of the present invention can be used as their cosmetically acceptable salts. Such salts include, but are not limited to, sodium, potassium, lithium, calcium, magnesium, iron and zinc salts. Most compositions of the present invention may be formulated as solution, gel, lotion, cream, or ointment in a cosmetically acceptable form. Actual methods for preparing cosmetic compositions are known or apparent to those skilled in the art and are described in detail in for example, Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA (1990) , which is incorporated herein by reference. 4.4.3. METHODS FOR TREATING DISORDERS RELATED TO ANTI-INFLAMMATORY RESPONSES The present invention also relates to a method for treating disorders treated by anti-inflammatory responses and skin inflammatory responses, including but not limited to those described herein. Such a method comprises applying to the skin a safe and effective amount of one or more of the sialyl oligosaccharide derivatives of the present invention. While the present invention relates to novel sialyl oligosaccharides derivatives to treat disorders by regulating anti-inflammatory responses, the present invention further relates to the use of topical compositions, such as those discussed above, comprising one or more sialyl oligosaccharides derivatives, to be used for treating skin disorders, as described above. The invention encompasses the topical use of sialyl oligosaccharide derivatives, including, but not limited to: 3' -sialyl melibiose, 3 '-sialyl lactulose, 3 '-sialyl GAL arabinose, 3 '-sialyl raffinose, 3 '-sialyl stachyose, sialyl lactose, sialyl N-acetyl lactosamine, 3 ' -sialyl-LNnT, 6'- sialyl-LNnT, 3 ' -sialyl-LNT, 6 ' -sialyl-LNT, benzyl sialyl lactose and ethyl sialyl lactose and pharmaceutically or cosmetically acceptable salts thereof. A preferred method of treating skin disorders related to anti-inflammatory responses is via chronic topical application of a safe and effective amount of the sialyl oligosaccharide derivative to regulate the anti-inflammatory response. The amount of a composition containing the sialyl oligosaccharide derivatives of the present invention and frequency of topical application to the skin can vary widely, depending upon the particular skin disorder and the severity thereof. It is well within the purview of the skilled artisan, such as the dermatologist or other health care provider, to regulate dosages according to the patient needs. It is suggested as an example that the topical application range from about once per week to about four or five times daily, preferably from about three times per week to about three times daily, most preferably about once or twice per day. The composition for topical application will comprise from about 0.01% to about 5.0%, preferably from about 0.1% to about 2%, most preferably from about 0.1% to about 2% of the active compound or mixture of the compounds. By "chronic" application, it is meant herein that the period of topical application may be over the lifetime of the patient, preferably for a period of at least about one month, more preferably from about three months to about twenty years, more preferably from about six months to about ten years, more preferably still from about one year to about five years, thereby resulting in regulation of the anti- inflammatory response. 4.4.4. METHODS FOR IMPROVING THE TEXTURE OR APPEARANCE OF THE SKIN The present invention also relates to a method for improving the texture or appearance of the skin. Improving the texture or appearance of the skin is meant to encompass improving the aesthetic quality of the skin by providing a natural-looking and/or -feeling so as to enhance the beauty and/or smoothness of the skin from its pre-treated state and to protect the skin from causes of inflammation. Such cosmetic uses include but are not limited to moisturizing skin; masking skin blemishes or other undesired attributes; highlighting the skin as, for example, an eye shadow; improving skin texture; and the line. Such abnormal biological conditions or diseases include, but are not limited to dry skin, severe dry skin, dandruff, acne, keratoses, psoriasis, eczema, skin flakiness, pruritus, age spots, lentigines, melasmas, wrinkles (both moisturizing skin; masking skin blemishes or other undesired attributes; highlighting the skin as, for example, an eye shadow; improving skin texture; and the like. The amount of sialyl oligosaccharide derivative and frequency of topical application to the skin can vary widely, depending upon desirability of use. Thus, the invention also encompasses unsupervised home use, i.e. , outside of the supervisor of a dermatologist or health care provider. Most compositions of the instant invention may be formulated as solution, gel, lotion, cream, ointment, or other pharmaceutically acceptable form. To prepare a composition in solution form for general use, at least one sialyl oligosaccharide derivative of the present invention is dissolved in a solution prepared from ethanol, water, propylene glycol, butylene glycol, acetone or other pharmaceutically acceptable vehicle. The concentration of the sialyl oligosaccharide derivative of the present invention may range from 0.01 to 2.0 percent, the preferred concentration ranges being from about 0.1 to about 1.0 percent for home use, with higher ranges. In another embodiment of the invention, improving the texture or appearance of the skin involves administering both a safe and effective amount of the sialyl oligosaccharide derivative and optionally, one or more of a sunscreening agent, an anti-inflammatory agent, an anti-oxidant/radical scavenging agent, a chelating agent, a retinoid and/or a benzofuran derivative to the skin simultaneously. As used herein, "simultaneous application" or "simultaneously" means administering the agents to the skin at the same sites on the body at about the same time. Though this can be accomplished by administering the agents separately to the skin, preferably a composition comprising all the desired agents commingled is administered to the skin. If present, the amount of sunscreening agent administered is generally from about 0.02 mg to about 1.0 mg per cm 2 skin; the amount of anti-inflammatory agent administered is generally from about 0.005 mg to about 0.5 mg, preferably from about 0.01 mg to about 0.1 mg per cm 2 skin; the amount of chelating agent generally administered is from about 0.001 mg to about 1.0 mg, preferably from about 0.01 mg to about 0.5 mg, more preferably from about 0.05 mg to about 0.1 mg per cm 2 skin; the amount of retinoid administered is generally from about 0.00001 mg to about 0.02 mg per cm 2 skin; and the amount of benzofuran derivative administered is generally from about 0.001 mg to about 1.0 mg/cm 2 skin per application, preferably from about 0.01 to about 0.5 mg/cm 2 skin per application. The amount of sialyl oligosaccharide derivative (s) administered is generally from about 0.001 mg to about 1.0 mg per cm 2 skin per application, preferably from about 0.001 mg to about 1.0 mg per cm 2 skin per application, preferably from about 0.001 mg to about 01. mg per cm 2 , more preferably from about 0.001 to about 0.05 mg/cm 2 skin per application coarse and fine, caused by intrinsic as well as extrinsic damage) , warts, blemished skin, hyperpigmented skin, hyperkeratotic skin, inflammatory dermatoses, age-related skin changes and skin in need of cleansers, as well as the effects of skin atrophy. Such a method comprises administering to the skin a safe and effective amount of one or more of the sialyl oligosaccharide derivatives of the present invention. The amount of sialyl oligosaccharide derivatives and frequency of topical application to the skin can vary widely, depending upon desirability of use by the skilled artisan, e.g., a user of cosmetics. While the present invention relates to sialyl oligosaccharide derivatives used to treat skin disorders, the present invention further relates to the use of compositions, such as those discussed above, comprising one or more of the sialyl oligosaccharide derivatives of the present invention, to be used for treating skin disorders. A preferred method of treating the skin is via occasional topical application of a safe and effective amount of the sialyl oligosaccharide derivative to improve the texture or appearance of the skin. The amount of sialyl oligosaccharide derivative and frequency of treatment will vary widely depending upon the desired level of improvement of the appearance or texture of the skin and/or the extent of an abnormal skin condition of disease, if one such exists. It is suggested as an example that topical application range from about once per week to about 4 or 5 times daily, preferably from about 3 times a week to about 3 times daily, most preferably about once or twice per day. The composition for topical application will comprise from about 0.01 to 5.0 wt. %, preferably 0.05-5 wt. % and most preferably 0.01-2 wt. % of the sialyl oligosaccharide derivative. By "occasional" application, it is meant herein that the period of topical application may be as often as desired and/or needed to improve the texture or appearance of the skin. 5. EXAMPLES EXAMPLE NO. 1 The following in vitro assay illustrates the effectiveness of the sialyl oligosaccharide derivative, 3' sialyl lactose, in inhibiting the adhesion of cells that express SLeX on their surfaces to cells expressing a selectin receptor. The ability of 3 '-sialyl lactose to inhibit cell adhesion was tested using an in vitro assay system. Neutrophils were activated with either interleukin-1 or phorbol ester, TPA, to induce expression of selections and binding to endothelial cells. The activated neutrophils were treated with either 3 '-sialyl lactose at 0.01 and 0.02%, sucrose at 4% or a positive control, and then assayed for their ability to bind to PMN-endothelial cells. TABLE 1 Test Compound % Inhibition of Adhesion 3 '-Sialyl lactose 0.01% 39% 3 '-Sialyl lactose 0.02% 61% Sucrose 4.0% 40% Positive Control 100% Treating activated neutrophils with 0.02% 3' sialyl lactose effectively inhibited the ability of IL-1 induced neutrophils to bind PMN-endothelial cells. Therefore, in an in vitro assay 0.02% 3 '-sialyl lactose is very effective in inhibiting the adhesion of cells that express SLeX on their surfaces to cells expressing a selectin receptor. EXAMPLE NO. 2 The following in vivo assay illustrates the effectiveness of sialyl oligosaccharide derivatives, 3'- and 6' -sialyl lactose, in preventing skin irritation. The in vivo assays used to assess efficacy of topical anti-irritants are known to those skilled in the art, examples of such assays may be found in Muizzuddin et al., 1990, J. Soc. Cosmet. Chem. 41:369-378, and Lubach et al. in Topical Corticoids, Maibach & Surber (eds.) Basel, Karger, 1992, pp. 26-41, both of which are incorporated herein by reference in their entirety. The skin anti-irritancy effects of 3'- and 6'- sialyl lactose were tested on 7 volunteers with a history of skin sensitivity to Balsam of Peru. The test compounds were applied to the ventral forearms of the panelists. The material was allowed to absorb for twenty minutes and then Balsam of Peru, an irritant, was applied to the test sites. Skin irritation was measured in terms of increase in skin redness. The degree of redness was measured with the Minolta chromameter and compared with the positive and negative controls. The positive control was the color of skin treated with Balsam of Peru alone and the negative control was the skin treated with cola material challenged like the test material. TABLE 2 Test Compound % Decrease In Redness 3 '-Sialyl lactose 0.1% 69% 3 '-Sialyl lactose 0.1% 67% 6'-Sialyl lactose 0.1% 57% Sialic Acid 0.1% 31% Lactose 0.1% 45% CONTROLS Cola 10.0% 65% Hydrocortisone 0.5% 66% Sialyl Lewis X 0.1% 66% Balsam of Peru 0% Topical use of solutions containing 3' -sialyl lactose (3'-N acetylneuraminyl-lactose) showed significant activity in preventing irritation caused by a topical irritant. At one- hundredth the concentration of cola, 3 '-sialyl lactose was more effective in preventing skin irritation, illustrating the extra ordinary beneficial effects of using sialyl oligosaccharide derivatives in topical compositions. The structural analog 6 '-sialyl lactose at 0.1% was not as active as 3 '-sialyl lactose, however showed significant activity in preventing skin irritation when compared to 10% cola. The building blocks of 3 '-sialyl lactose; namely sialic acid and lactose, when tested alone, were ineffective at preventing irritation. EXAMPLE NO. 3 The following in vivo assay illustrates the effectiveness of analogs of 3 '-sialyl lactose in preventing skin irritation. The skin anti-irritancy effects of analogs of 3 '-sialyl lactose were tested on 7 volunteers with a history of skin sensitivity to Balsam of Peru. The test compounds were applied to the ventral forearms of the panelists. The material was allowed to absorb for twenty minutes and then Balsam of Peru, an irritant, was applied on the test sites. Skin irritation was measured in terms of increase in skin redness. The degree of redness was measured with the Minolta chromameter and compared with the positive and negative controls. The positive control was the color of skin treated with Balsam of Peru alone and the negative control was the skin treated with cola material challenged like the test material. TABLE 3 Test Compound % Decrease In Redness Sialyl lactulose 0.1% 44% (3 '-sialyl-gal-l,4-fru) Sialyl Gal Ara 0.1% 42% (3 '-sialyl-gal-l,4-Ara) Sialyl melibiose 0.1% 47% (3 ' -sialyl-gal-1, 6-glu) CONTROLS Cola 10.0% 70% Hydrocortisone 0.5% 60% Balsam of Peru 0% Topical use of solutions containing the lactulose, Gal- Ara and melibiose analogs of 3 '-sialyl lactose showed significant activity in preventing irritation caused by a topical irritant. At one-hundredth the concentration of cola, the 3 '-sialyl lactose analogs demonstrated significant activity in reducing the development of skin irritation. Thus illustrating the beneficial effects of using these compounds in compositions suitable for topical application for the treatment of skin irritation. EXAMPLE NO. 4 The following in vivo assay illustrates the effectiveness of 3 '-sialyl oligosaccharide derivatives in preventing skin irritation. The skin anti-irritancy effects of various derivatives of 3 '-sialyl lactose were tested on 7 volunteers with a history of skin sensitivity to Balsam of Peru. The test compounds benzyl sialyl lactose and ethyl sialyl lactose were applied to the ventral forearms of the panelists. The material was allowed to absorb for twenty minutes and then Balsam of Peru, an irritant, was applied on the test sites. Skin irritation was measured in terms of increase in skin redness. The degree of redness was measured with the Minolta chromameter and compared with the positive and negative controls. The positive control was the color of skin treated with Balsam of Peru alone and the negative control was the skin treated with cola material challenged like the test material. TABLE 4 Test Compound % Decrease In Redness Benzyl Sialyl lactose 0.1% 42.47% Ethyl Sialyl lactose 0.1% 40.6% CONTROLS Cola 10.0% 68.7% Balsam of Peru 0% At one-hundredth the concentration of cola, the 3'- sialyl lactose derivatives, lactose ethyl and benzyl sialyl lactose, demonstrated significant activity in reducing the development of skin irritation due to chemical irritant, exhibiting 40.6% and 42.47% activity respectively. Thus, demonstrating the beneficial effects of using these compounds in compositions suitable for topical application for the treatment of skin irritation. The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments which are functionally equivalent are with the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the appended claims. All references cited herein are incorporated herein by reference in their entirety for all purposes.

Claims: CLAIMS What is claimed: 1. A topical composition useful for treating skin disorders or skin irritation which comprises a cosmetically acceptable vehicle and an effective amount of a substantially purified sialic acid glycoside. 2. The composition of Claim 1, wherein the sialic acid glycoside is not a naturally occurring component of milk or rennet casein. 3. The composition of Claim 1, wherein the sialic acid is selected from the group consisting of NeuAc, NeuGc and KDN. 4. The composition of Claim 1, wherein the sialic acid glycoside comprises a sialic acid-alpha2-3-glycoside or a sialic acid-alpha2-6 glycoside. 5. The composition of Claim 1, wherein the sialic acid glycoside is a compound having a formual: sialic acid-Z-R-P wherein Z is a member selected from the group consisting of alpha- or beta-linked 0, S, and N-A, wherein A is a member selected from the group consisting of H, Acetyl, alkylacyl, aryl and acyl; R is a member selected from the group consisting of a carbohydrate, an aglycon, a polysaccharide, a polymer, an oligosaccharide, a lipid, a ceramide, and a sphingosine; and P is H or a member selected from the group consisting of a saccharide, a polysaccharide, a polymer, and an oligosaccharide . 6. The composition of claim 5, wherein R is a carbohydrate selected from the group consisting of glucose, galactose, fructose, N-acetylglucosamine, glucosamine, Gal- Glc, Gal-Fruc, Glu-Fruc, and Gal-Glc-Fruc. 7. The composition of Claim 6, wherein the compound has a formula: Compound I wherein X is a member selected from the group consisting of OH, NH 2 , NHAc, and N-A, wherein A is a member selected from the group consisting of H, Ac, alkylacyl, aryl and acyl; Y is a member selected from the group consisting of H, Ac, alkyl, aryl, alkylaryl, alkylacyl, arylalkylacyl, glycoyl, and an amino acid, and M is a member of the group consisting of O and NH. 8. The composition of Claim 5, wherein the compound has a formula: Compound II wherein each X is a member independently selected from the group consisting of OH, NH 2 , NHAc, and N-A, wherein A is a member selected from the group consisting of H, Ac, alkyl acyl, aryl and acyl; and M is a member of the group consisting of 0 and NH. 9. The composition of Claim 5, wherein R is selected from the group consisting of Glc-O-alkyl, GlcNAc-alkyl, Glc- O- (CH 2 ) n -NH 2 , wherein n is an integer between 0-24. 10. The composition of Claim 5, wherein R is Gal (αi- 6)-Glc or Gal (ocl-6)-Gal. 11. The composition of Claim 1, wherein the sialic acid glycoside is selected from the group consisting of sialyl melibiose, sialyl raffinose, and sialyl stachyose. 12. The composition of Claim 1, wherein the sialic acid glycoside is selected from the group consisting of sialyl lactose, sialyl lactulose, sialyl galactose arabinose, sialyl benzyl lactoside, sialyl ethyl lactoside, sialyl lacto-N- tetraose, sialyl lacto-N-neotetraose, ganglioside GM3 , and sialyl lactosyl-sphingosine. 13. The composition of Claim 1, wherein the composition comprises a lotion, a tincture, a cream, an emulsion, a gel, and an ointment. 14. A compound selected from the group consisting of: 3-sialyl melibiose, 3-sialyl lactulose, 3-sialyl galactose arabinose, 3-sialyl raffinose, and 3-sialyl stachyose. 15. The composition of Claims 1 or 14 wherein said compound is present in an amount of about 0.01 to about 5.0 wt % of the composition. 16. The composition of Claims 1 or 14 wherein said composition comprises about 0.1 to about 2 wt % of the said compound. 17. The composition of Claims 1 or 14 wherein said composition comprises about 0.1 to about 1 wt % of the said compound. 18. A topical composition which comprises a compound selected from the group consisting of: 3 '-sialyl lactose; and 6 '-sialyl lactose; or a cosmetically acceptable salt thereof. 19. A topical composition useful for regulating inflammatory responses, which comprises a pharmaceutically or cosmetically acceptable vehicle and a compound selected from the group consisting of: benzyl sialyl lactose; and ethyl sialyl lactose; or a cosmetically acceptable salt thereof. 20. The composition of Claim 18 or 19 wherein said compound is present in an amount of about 0.01 to about 5.0 wt % of the composition. 21. The composition of Claim 18 or 19 wherein said compound is present in an amount of about 0.1 to about 2 wt % of the composition. 22. A method for treating skin irritation, inflammation or inflammatory response in a mammal, the method comprising topically administering an effective amount of a sialic acid or a sialic acid glycoside. 23. The method of Claim 22, wherein the sialic acid glycoside is a compound having a formula: Sialic acid-Z-R-P wherein Z is a member selected from the group consisting of alpha- or beta- linked 0, S, and N-A, wherein A is a member selected from the group consisting of H, Ac, alkyl acyl, aryl and acyl; R is a member selected from the group consisting of a carbohydrate, an aglycon, a polysaccharide, a polymer, an oligosaccharide, a lipid, a ceramide, and a sphingosine; and P is H or a member selected from the group consisting of a saccharide, a polysaccharide, a polymer, and an oligosaccharide. 24. The method of Claim 22, wherein the skin irritation or inflammation is associated with a skin condition selected from the group consisting of atopic dermatitis, chronic urticaria lesions, inflammatory dermatoses, facial edema, Well's syndrome, psoriasis, eczema, pruritis, hyperkeratotic skin, dry skin, wrinkles, blemished skin, age-related skin changes, acne, and skin irritation. 25. The composition of Claim 22, wherein the sialic acid glycoside is substantially purified. 26. The method of Claim 22 wherein said inflammatory response is skin reddening. 27. The method of Claim 22 wherein said compound is selected from the group consisting of: 3 '-sialyl lactose; and 6 ' -sialyl lactose; or a cosmetically acceptable salt thereof. 28. The method of treating an inflammatory response or disorder which comprises topically administering a compound selected from the group consisting of: 3 '-sialyl melibiose; 3 '-sialyl lactulose; 3 '-sialyl GAL arabinose; sialyl LNnT; sialyl LNT; sialyl N-acetyl lactosamine; 3 '-sialyl raffinose; and 3 '-sialyl stachyose; or a cosmetically acceptable salt thereof. 29. A method for treating an inflammatory response or disorder which comprises topically administering an effective amount of a compound selected from: benzyl sialyl lactose; and ethyl sialyl lactose; or a cosmetically acceptable salt thereof. 30. A method for improving the texture or appearance of skin, which comprises topically applying an effective amount of a sialic acid or a sialyl galactoside. 31. The method of Claim 30, wherein the sialyl galactoside is selected from the group consisting of sialyl benzyl lactose and sialyl ethyl lactose. 32. The method of Claim 31, wherein the sialic acid glycoside is substantially purified. 33. The method of Claim 31 wherein said compound is selected from the group consisting of: 3 '-sialyl lactose; and 6 '-sialyl lactose; or a cosmetically acceptable salt thereof. 34. The method of Claim 31 wherein said compound is selected from the group consisting of: 3 '-sialyl melibiose; 3 '-sialyl lactulose; 3 '-sialyl GAL arabinose; 3 '-sialyl raffinose; sialyl LNnT; sialyl LNT; sialyl N-acetyl lactosamine; 3 '-sialyl stachyose, or a cosmetically acceptable salt thereof. 35. The method for improving the texture or appearance of the skin which comprises topically applying an effective amount of either benzyl sialyl lactose or ethyl sialyl lactose or a cosmetically acceptable salt thereof. 36. The method of Claim 31 wherein said compound is present in an amount of about 0.01 to about 5.0 wt % of the composition. 37. The method of Claim 31 wherein said compound is present in an amount of about 0.01 to about 2 wt % of the composition. 38. The method of Claim 31 wherein said vehicle is selected from the group consisting of lotions, tinctures, creams, emulsions, gels and ointments. 39. The method of Claim 31 wherein said compound is present in an amount of about 0.1 to about 1 wt % of the composition. 40. The method of Claim 31 wherein said vehicle is selected from the group consisting of lotions, tinctures, creams, emulsions, gels and ointments.

Inventors: ANDERSON JON E, DEFREES SHAWN, ANDERSON, JON, E., DEFREES, SHAWN
Applicants: ANDERSON JON E, DEFREES SHAWN, ANDERSON, JON, E., DEFREES, SHAWN
Application year: 1999
Main classification: A61K7
IPC codes: A61K8, A61K31, A61P17, A61Q17, A61Q19, C07H3, C07H5, C07H15