(12) Patent Application Publication (10) Pub. No.: US 2014/0134222 A1 Morariu (43) Pub

US 2014O134222A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0134222 A1 Morariu (43) Pub. Date: May 15, 2014

(54) TOPICAL BENFOTIAMINE AND A618/4I (2006.01) PYRDOXAMINE COMPOSITIONS A618/49 (2006.01) (71) Applicant: Tracie Martyn International, Inc., New A61O 19/08 (2006.01) York, NY (US) (52) U.S. Cl. CPC ...... A61K 8/55 (2013.01); A61 K8/4926 (72) Inventor: Marius Morariu, Brooklyn, NY (US) (2013.01 ); A61O I9/08 (201 3 .01): A618/4I (73) Assignee: Tracie Martyn International, Inc., New (2013.01); A61O 19/00 (2013.01) York, NY (US) USPC ...... 424/401: 514/86; 514/18.8; 424/766; 424/732: 514/27; 424/94.1: 514/440; 424/94.4: (21) Appl. No.: 14/158,124 424/94.5; 424/729; 514/47 (22) Filed: Jan. 17, 2014 (57) ABSTRACT Related U.S. Application Data The present invention provides a composition comprising an (63) S.ty R.S.E.N. effective amount of benfotiamine and an effective amount of of application No. 1 1/218 226. filed on Aug. 31, 2005 pyridoxamine in a suitable vehicle for topical application. now Pat. No. 7,666,442. The present compositions are useful in improving the appear (60) Provisional application No. 60/605,750, filed on Aug. ance of aged skin characterized by wrinkles, loss of elasticity, 31, 2004. and hyperpigmentation caused by chronoaging and/or pho toaging of skin, by inhibiting particularly skin damage result Publication Classification ing from reactive carbonyl species (RCS), glycation of skin (51) Int. Cl. proteins, formation of advanced glycation endproducts A6 IK 8/55 (2006.01) (AGEs) and formation of advanced lipoxidation endproducts A61O 19/00 (2006.01) (ALEs). US 2014/0134222 A1 May 15, 2014

TOPCAL BENFOTAMINE AND plaques and tangles of Alzheimer's Disease, thereby acceler PYRDOXAMINE COMPOSITIONS ating neuron death (Brain Research Review 23:134-143 (1997)). When glucose bonds with collagen, many negative 0001. This application claims priority to provisional appli effects can result, including thickened arteries, stiff joints, cation No. 60/605,750 filed Aug. 31, 2004, herein incorpo feeble muscles and failing organs. As collagen molecules in rated by reference. the cartilage and skin have a long lifetime (117 years for FIELD OF INVENTION cartilage and 15 years for skin collagen), they are Susceptible to the accumulation of AGEs since the protein turnover is a 0002 The present invention relates to the topical applica major determinant in AGE accumulation (Verzijl N., et al., J. tion of compositions containing benfotiamine and pyridox Bid. Chem. 275(50):39027-31 (2000)). Reducing glycation amine for the prevention and/or treatment of damage to skin, within the body to slow the aging process has been recom particularly skin damage resulting from reactive carbonyl mended to improve lifestyle and foster a youthful appearance. species (RCS), glycation of skin proteins, formation of This has been done with food, guiding patients in what they advanced glycation endproducts (AGES) and formation of eat, and how they cook. (F. Wilson, Cosmetic Surgery Times, advanced lipoxidation endproducts(ALEs). September, 2004). 0007 Currently, scientists believe there are two major BACKGROUND OF THE INVENTION ways in which AGEs can form inside the body. One way is 0003 Skin is subject to abuse by many extrinsic (environ through a simple series of chemical reactions known as the mental) factors as well as intrinsic factors. A common extrin “Mallard Pathway.” known from food chemistry for more sic factor is exposure to ultraviolet radiation. Whether extrin than a century. During glycation, glucose binds to a protein sic or intrinsic, the abuse results in skin aging. Skin aging bound nitrogen via a hydroxyl or carbonyl group. This inter happens in two ways: (1) through the natural aging process mediate then chemically rearranges to produce an Amadori which dermatologists call chronological aging (also known product having two ketone groups on the second or third as chronoaging); and (2) through UV rays in Sunlight accel carbon of the glucose ring. This Amadori product goes erating the aging process which dermatologists call photoag through other rearrangements through the Maillard reaction. ing. Chronoaging results in thinning, loss of elasticity and This is the basis for atherosclerosis, cataracts and other prob general degradation of skin. As the skin naturally ages, there lems commonly associated with diabetes. is a reduction in the cells and blood vessels that supply the 0008. The second, discovered more recently, is based on a skin. There is also a flattening of the dermal-epidermal junc distinctly biological pathway, which only occurs within the tion which results in weaker mechanical resistance. As a cells because of the body's metabolism of carbohydrates or consequence, older persons are more Susceptive to blister Sugars. It is known that glucose and other saccharides are formation in cases of mechanical traumas or disease pro important glycating agents, but the most reactive glycating cesses (Oikarinen et al., Photodermatal. Photoimmunol. agents are the C-oxoaldehydes, glyoxal, methylglyoxal and Photomed, 7:3-4 (1990)). 3-deoxyglucosone. Tissue-specific metabolic characteristics 0004. By contrast photoaging, or premature aging, is a are understood to be involved in the degree of cellular protein process in which the skin changes in appearance as a result of modification by Maillard reactions, e.g., by modulation of the repeated exposure to Sunlight. Typically, photoaging occurs concentration of glycolysis intermediates or via specific in areas of habitual exposure, Such as the scalp, face, ears, defensive systems in these organs. (Portero-Otin, M., et al. neck, chest, forearms and hands. The changes associated with Biochem. Soc. Trans. (2003)31, 1403-1405. photoaging include elastosis, atrophy, wrinkling, vascular 0009 AGEs are implicated as a major pathogenesis pro changes (diffuse erythema, ecchymoses, and telangiectasias), cess in atherosclerosis, Alzheimer's Disease, the normal pigmentary changes (lentigines, freckles, and areas of hypo aging process, and the pathogenesis of the major microvas and hyper-pigmentation), and the development of seborrheic cular complications of diabetes mellitus: nephropathy, neur keratosis, actinic keratosis, comedones and cysts. opathy and retinopathy. In certain pathophysiological states, 0005 Decreased elasticity of the cardiovascular system is one or more of the following changes to glycation-related one of the hallmarks of the normal aging process of mammals processes occurs: the rate of glycation is increased, the renal and has been linked to an age-related accumulation of clearance of AGES is decreased and/or the expression of advanced glycation endproducts (AGES). Glycation is the AGES receptors is increased leading to AGEs-related mem product of reaction between a Sugar and the free amino group brane thickening, AGES-mediated cell activation, premature of proteins and involves cross-linking. The linking of glyco aging, and amyloidosis. sylation byproducts to proteins results in the development of 0010. In the skin, glycation forms new AGEs in the extra large, cross-linked molecules that inhibit the ability of the cell cellular matrix of the dermis and changes fibroblast shape and to function normally, thereby increasing the aging process. In distribution, alters extracellular matrix molecules and the addition, AGES in tissues increase the rate of free radical dermal-epidermal junction Zone, increases 13 and a integrins production to 50-times the rate of free-radical production by concentration in the epidermal skin layer, and increases col unglycated proteins, even further increasing the rate of the lagenase activity. (Pageon, H., et al., Ann NYAcad Sci. 2005, aging process. 1043:529-32.) 0006. The relationship between sugar and the aging pro 0011. The mechanism of action for AGEs inhibitors is cess is well established and is based upon the observation of understood to include both nucleophilic traps for reactive diabetics, who seem to age rapidly. The irreversible cross carbonyl AGE intermediates and antioxidant activity. AGE linked proteins of AGEs in vessel collagen also contribute to inhibitors are chelators of copper, and potent inhibitors of atherosclerosis, as well as to kidney failure-conditions wors ascorbate oxidation. Because of the strong ascorbate oxidiza ened in diabetes (Diabetes 46(supp2):S 19-25 (1997)). It is tion inhibition properties of AGE inhibitors, these properties also believed AGES aggravate protein cross-linking in are believed to be the primary mechanism for the inhibition of US 2014/0134222 A1 May 15, 2014

AGE formation. (Price DL, et al., JBiol. Chem. 2001 Dec.28; 0018. It is another and more specific object of the inven 276(52):48967-72). AGEs are primarily eliminated from the tion to provide a topical composition and method for an AGES circulation by Scavenger receptor-mediated uptake in hepatic preventive regiment and/or therapy based upon topical appli sinusoidal endothelial cells. (Hansen, B. et Diabetologia. cation to exposed or affected skin areas of an active agent or 2002 October; 45(10): 1379-88). derivative thereof, in association with a dermatologically 0012. There are several drugs that inhibit the formation of acceptable carrier or vehicle. AGES: one such candidate is aminoguanidine. Aminoguani 0019. These and other objects are accomplished by the dine is structurally very similar to guanidine, the active ingre present invention, which provides a method for inhibiting the dient in the herb, goat's rue (galega officinalis). It is believed formation of AGEs in the skin which comprises topical appli that aminoguanidine acts by enhancing the action of nitric cation to the exposed or affected skin areas of an effective oxide (Brownlee, Diabetes, 2:57-60 (1992)). However, amount of a combination of benfotiamine and pyridoxamine recently aminoguanidine has shown signs of toxicity in in a dermatologically acceptable carrier. Also provided is a human trials (Okada et al., J. Nutr. Sci. Vitaminol., 41:43-50 method for the prevention and/or treatment of skin damage (1995)). from AGES, which comprises topical application to the 0013. In addition, it has been shown that thiamine pyro exposed or affected skin areas of an effective amount of a phosphate (TPP), the active coenzyme form of the B-complex combination of benfotiamine and pyridoxamine in a derma vitamin thiamine, can stop late stage AGEs formation. TPP tologically acceptable carrier. The composition for the inhi has also been shown to exert a two-pronged AGES-inhibiting bition of the formation of AGEs and prevention and/or treat effect in the body. Boosting TPP in cells stressed by high ment of skin damage may be administered to a diabetic or a glucose concentrations results in the opening of a 'safety person without diabetes. Preferably, the composition is valve' in the normal metabolism of blood sugar through an administered to anyone with skin damage from AGES, includ enzyme known as transketolase. Activating transketolase ing damage caused by chronological aging and damage allows the body to shunt excess triosephosphates, reactive caused by photoaging. glucose metabolic intermediates, transferring AGES damage 0020. In the preferred practice of the invention, the com inside the cell into a safe alternative metabolic pathway, pre bination of benfotiamine and pyridoxamine is applied in venting their buildup and, concomitantly, preventing the for admixture with a dermatologically acceptable carrier or mation of AGES. Unfortunately, regular thiaminevitamin B is vehicle (e.g., as a lotion, cream, ointment, soap, or the like) so not readily absorbed and metabolized by the body. In addi as to facilitate topical application and, in Some cases, provide tion, taking Supplements comprising TPP is equally futile additional therapeutic effects as might be brought about, e.g., because specific enzymes Strip TPP of its phosphate group, by moisturizing of the affected skin areas. Additionally, other rendering the adulterated TPP ineffective to battle AGEs. ingredients, particularly antioxidants, can be advantageously 0014) Another antiglycation compound, ALT-711, breaks included in the compositions. the specific AGE-derived crosslinks between proteins, but 0021. The amount of benfotiamine and the amount of pyri does not disrupt the natural enzymatic glycosylation sites or doxamine necessary to bring about enhanced prevention and/ peptide bonds of the collagen chain. ALT-711 has been shown or therapeutic treatment of skin damage is not fixed per se, to reduce age-related Ventricular stiffness and improve car and is necessarily dependent upon the identity and form of diac function (Asif M, et al., Proceedings of the National pyridoxamine and benfotiamine employed, the amount and Academy of Sciences USA, 97(6):2809-13; erratum:97(10): type of any additional ingredients used, particularly those that 5679 (2000). ALT 711 also has been used to improve skin appear to exhibit synergistic effects (to be discussed more hydration of aged rats through oral and topical administra fully below), the user's skin type and, where present, the tion. (Vasan, S, et al., Arch Biochem. Biophys. 419(1):89-96 severity and extent of the patient’s pathological skin condi (2003). tion. Generally, the benfotiamine and/or pyridoxamine or 00.15 Benfotiamine and B vitamins have previously been composition containing it is topically applied in effective used in combination for the oral treatment of diabetic poly amounts to skin areas which have been damaged or aged, or neuropathy (Stracke et al. Clin. Endocrinol. Diabetes 1996; which are susceptible to damage because of AGEs. 104(4):311-6) and alcoholic polyneuropathy (Woelk H. et al., 0022. In one embodiment, the composition contains from Alcohol Alcohol. 1998 November-December:33(6):631-8). about 0.001 to 80 weight%, preferably from about 0.1% to However, neither of these references Suggest topical applica tions for treating aging skin. about 5%, of each of benfotiamine and pyridoxamine. 0016 While AGEs-inhibiting drugs have displayed prom DETAILED DESCRIPTION OF THE INVENTION ise in regard to treating a number of conditions, including the reduction in the signs of aging, there is a clear need for the 0023 This invention is based upon the finding that a com identification of new, safe AGE-inhibiting, non-prescription bination of the two AGE inhibitors benfotiamine and pyri topical compositions that can be used to address the signs of doxamine is useful for the treatment and prevention of dam skin aging caused by reactive carbonyl species (RCS), glyca aged or aged skin from reactive carbonyl species (RCS), tion of skin proteins, formation of advanced glycation end glycation of skin proteins, formation of advanced glycation products (AGEs) and formation of advanced lipoxidation endproducts (AGEs) and formation of advanced lipoxidation endproducts(ALEs). endproducts(ALEs).

SUMMARY OF THE INVENTION I. Benfotiamine 0017. It is an object of the present invention to provide a 0024. As used herein the term “a benfotiamine' encom method and composition for treatment and/or prevention of passes benfotiamine (4-(4-amino-2-methyl-pyrimidin-5- skin damage, particularly skin damage from RCS, glycation yl)methyl-formyl-amino-3-benzoylsulfanyl-pent-3-enoxy of skin proteins, and formation of AGEs and ALEs. phosphonic acid), which has the formula: US 2014/0134222 A1 May 15, 2014

Med. 2003 March; 9(3):294-9). Benfotiamine directs hexose O and triose phosphates to the pentose phosphate pathway, and reduces tissue AGEs. Similar improvements in nerve and O C -K) vascular function have been observed (Cameron, N E et al., N I Ann NY Acad Sci. 2005 June:1043:784-92). This enhance ment of energy metabolism is also important for the aging HC-( / ch----chi-ji, process as cellular energy declines with aging. (Squier, TC, N CH O Exp Gerontol. 2001 September, 36(9): 1539-50). Therefore the use of a formulation comprising benfotiamine particularly useful as it has a multipronged effect in targeting the aging NH2 o=-ol process especially when combined with an additional cellular OH energy enhancing agent. 0025. The term a benfotiamine also encompasses benfo II. Pyridoxamine tiamine derivatives such as S-Benzoylthiamine O-monophos 0029. As used herein the term “a pyridoxamine' encom phate and benzoylthiamine, which has the following formula: passes 4-aminomethyl-5-hydroxy-6-methyl-3-py ridinemethanol (pyridoxamine), which has the following O Structure

O C | NH2 N it t HC1 HC-( / cit-s--c-ch-ch, HC N OH N CH3 2 N CH

0026. Benfotiamine is the most potent of the allithiamines, The term a pyridbxamine also encompasses pyridoxamine a unique class of thiamine-derived compounds present in derivatives such as 4-amino-methyl-5-hydroxy-6-methyl-3- trace quantities in roasted crushed garlic and other vegetables pyridinemethanol dihydrochloride, and 4-aminomethyl-5- from the Allium genus (Such as onions, shallots and leeks). hydroxy-6-methyl-3-pyridylmethyl phosphate. 0027 Benfotiamine raises the blood level of thiamine 0030 Pyridoxamine is a vitamin B6 derivative that is pyrophosphate (TPP, or thiamine diphosphate), which is the water-soluble and nontoxic in rats and humans. It inhibits the biologically active co-enzyme of thiamine. TPP plays an formation of AGEs from Amadori proteins and is classified as essential role in the Kreb cycle by removing CO, from pyru a post-Amadori inhibitor (Khalifah et al. Biochem. Biophys. vic acid, making TPP vital to the production of cellular Res. Comm. 199:257, p. 251-258). Other AGE inhibitors such energy. (See Stryer, Biochemistry, 3" ed. W.H. Freeman and as aminoguanidine are primarily scavengers which scavenge Co. New York 1988). Benfotiamine's unique open-ringed reactive dicarbonyl precursors to AGEs (Khalifah RG, et al., structure facilitates its passage directly through cell mem Ann NYAcadSci, 2005 June; 1043:793-806). Pyridoxamine branes, readily crossing the intestinal wall and being taken sequesters catalytic metal ions and blocks oxidative degrada straight into the cell. As a result, the body readily absorbs tion of Amadori intermediate. It also actively scavenges the benfotiamine better than thiamine itself, and plasma levels of toxic carbonyl products of Sugar and lipid degradation and thiamine and thiamine pyrophosphate (TPP) remain higher inhibits reactive oxygen species (Voziyan, PA., Ann NYAcad for longer. Thiamine absorption from benfotiamine is about Sci. 2005: 1043:807-16; Voziyan, PA et al., Cell Mol Life Sci. five times as great as from conventional thiamine Supple 2005; 62(15): 1671-81.) It is also believed that pyridoxamine ments, and benfotiamine is less toxic than conventional thia traps reactive dicarbonyl intermediates in AGE formation and mine supplements. By effectively increasing levels of TPP, may also decrease oxidative stress, which Subsequently benfotiamine decreases the formation of AGES. In one decreases AGE formation from reactive oxygen species (la embodiment, thiamine is added to the topical formulation in covella et al. SCJMM, 2004: 5, p. 73-101). addition to the benfotiamine to enhance the effect. 0031. Pyridoxamine has also been shown to inhibit 0028 Benfotiamine has also been shown to be useful in advanced lipoxidation end products (ALES) (Onorato JM, et treating patients with diabetic neuropathy due to the anti al., J. Biol. Chem. 275(28):21177-84 (2000)). Malondialde glycation effects of the agent (Haupt, E., et al., Int J Clin hyde, (an intermediate in the formation of ALEs during lipid Pharmacol Ther: 200543(2) 11-7.) Both thiamine and benfo peroxidation) is trapped under physiological conditions by tiamine have been shown to prevent the development of pyridoxamine and inhibits the formation of ALEs (Kang, Zet incipient nephropathy by halting the increase in hydroimida al., Amino Acids. 2005 Jul. 5 (epub)). Decreasing ALEs for Zolone AGE residue formation (Karachalias, N, et al., Ann N mation is accomplished by decreasing the concentration of an Y Acad. Sci. 2005 June; 1043:777-83). Additionally, benfo oxidiable substrate such as glucose and blood lipids (Metz. T tiamine has been found to help maintain healthy cells in the O, et al., Arch Biochem Biophys. 419(1):41-9 (2003)). It has presence of blood glucose by stimulating tranketolase, a cel been proposed that the antioxidant properties of pyridoxam lular enzyme essential for maintaining normal glucose meta ine be used for the inhibition of ALE as well as AGE forma bolic pathways (Obrenovich ME etal, Sci. Aging Knowledge tion and development of complications of diabetes and hyper Environ. 2003 Mar. 12; 2003(10):PE6; Hammes, H P Nat. lipidemia (Mene P. et al., Am J Cardiovasc Drugs. 3(5)315-20 US 2014/0134222 A1 May 15, 2014

(2003)). The ALEs inhibiting property of ayridoxamine is 0036 Additionally, benfotiamine, pyridoxamine, and significant as peroxidation of skin lipids is a factor in skin other agents described herein incorporated in the formulation damage and aging. of the present invention provide other benefits as well. For 0032. Pyridoxamine, as well as the other B vitamins pyri example, benfotiamine, as a precursor for TPP, increases the doxine and pyridoxal, is metabolized in the liver to pyridoxal amount of TPP in the blood and decreases pyruvic acid con 5'-phosphate, the active form of the vitamin. For a general centration in a process that converts pyruvic acid into COA. review of the vitamin B complex see The Pharmacological Pyridoxamine lowers the toxicity of agents such as carnosine, Basis of Therapeutics, 8th edition, ed. Gilman, Rall, Nies, and a preferred additional AGEs inhibitor in this invention; Taylor (Pergamon Press, New York, 1990, pp. 1293-4; pp. decreases oxidative stress; and inhibits ALE formation. Car 1523-1540). Although it has long been believed that these nosine, one preferred additional agent, is also a potent anti three forms have equivalent biological properties, this has glycation agent, promotes wound healing, and protects been shown to be incorrect. They have different antioxidant against radiation damage. Additionally, where the formula activities (i.e., the efficacy order is pyridoxal tion induces lower pyruvic acid levels due to the presence of 5'-phosphateapyridoxamine a benfotiamine, carnosine is better able to reduce glycolysis 5'-phosphate-pyridoxamine-pyridoxalapyridoxine. Pyri intermediates compared to other formulations. (Holiday, R. doxamine and the two phosphates have greater antioxidant BrJ Cancer: 1996 April; 73(8):966-71). Therefore a formu activity than Vitamin C (Chumnantana, R., Biochim Biophys lation containing pyridoxamine, benfotiamine and carnosine Acta. 2005, 11; 1722(1): 84-91. Epub 2004 Dec. 19). U.S. Pat. is Superior to a formulation containing benfotiamine or pyri Nos. 6,750,209 and 6,740,668 demonstrate the difference in doxamine alone. Additionally, a formulation combining ben pyridoxamine and the other B6 vitamins as inhibitors of post fotiamine and pyridoxamine is beneficial compared to a for Amadoriantigenic AGE formation. The efficacy of inhibition mulation with only one of these components because of the of overall glycation of protein, in the presence of high con added benefits of the two components. For example, benfo centrations of sugar, was not predictive of the ability to inhibit tiamine increases TPP and therefore contributes to DNA and the post-Amadori steps of AGE formation where free sugar is RNA formation via the transketolase pathway as well as removed. Pyridoxamine has strong antioxidant activity and increasing cellular energy via Coenzyme A, and pyridoxam has been shown to be the strongest AGE inhibitor of the B ine decreases oxidative stress and inhibits ALEs formation. vitamins, and is therefore preferred in the topical formula Adding additional components such as carnosine adds even tions of the present invention (Price, D. L., J. Biol. Chem. more unique functions to the formulation of the present 2001 Dec. 28: 276(52):48967-72.) invention because, for example, carnosine is also a potent 0033 Pyridoxamine is also particularly beneficial due to anti-glycation agent and has other beneficial properties dis its low toxicity compared to pyridoxine. Pyridoxamine does cussed in this application. not cause injury to the primary sensory neurons as does pyri 0037. As used herein, the term “treatment of skin damage' doxine (Levine, S., J Appl Toxicol. 2004 November-Decem means the treatment of the symptoms of skin damage, treat ber;24(6):497-500.) Due to the safety, its strength as an AGE ment of the skin to prevent or reduce the damage from reac inhibitor, and its strength as an antioxidant, pyridoxamine is tive carbonyl species (RCS), glycation of skin proteins, for significantly more useful than pyridoxine (a compound used mation of advanced glycation endproducts (AGES) and extensively as a vitamin B6 agent in topical formulations). formation of advanced lipoxidation endproducts(ALEs) and/ or to prevent or reduce the further accumulation of reactive III. Combinations carbonyl species (RCS), glycated skin proteins, advanced 0034. In accordance with this invention, by combining a glycation endproducts (AGES) and advanced lipoxidation benfotiamine and a pyridoxamine, there is a decrease in their endproducts(ALEs) in the skin. toxicity profiles or the potential of a skin irritation in sensitive 0038. The skin damage from AGEs as well as ALES in the individuals. An enhanced efficacy of AGE inhibiting capa skin include elastosis; atrophy; wrinkling; vascular changes bilities when a benfotiamine and a pyridoxamine are admin including diffuse erythema, ecchymoses, and telangiectasias; istered in combination also occurs. A topical composition and pigmentary changes including lentigines, freckles, and comprising both a benfotiamine and a pyridoxamine is mark areas of hypo- and hyper-pigmentation. This damage is edly Superior to a composition having only a single AGE reduced, and further damage can be reduced or prevented by inhibiting compound. Since the two AGE inhibitors work in the topical administration of benfotiamine and pyridoxamine. different ways by inhibiting the pathway to AGEs at different This damage can be described by the effects of glycation in stages; there is an enhanced effect when pyridoxamine and the skin, which has been shown to (1) modify fibroblast shape benfotiamine are combined compared to the use of a single and distribution; (2) enhance extracellular matrix molecules one of the AGE inhibitors. Therefore, there is a beneficial for and the dermal-epidermal junction Zone; (3) increase B and use on skin, such as on the face, neck, and hands, to relieve the C. integrin concentration in the epidermal cell layer, and (4) effects of damage from reactive carbonyl species (RCS), gly increase collagenase activity. When an AGE inhibitor is topi cation of skin proteins and formation of advanced glycation cally applied to the skin, these markers overexpressed in endproducts (AGEs). glycated skin constructs are reduced and the visible effects of 0035 Benfotiamine and pyridoxamine are both inhibitors (Pageon, H., et al., Ann NY Acad Sci. 2005, 1043:529-32.) of AGE. Additionally, they all have other benefits that, when 0039. Only effective amounts of a benfotiamine and a combined into a formulation, provide AGE inhibition using pyridoxamine are needed to prevent or treat skin damage lower concentrations of the components than would be caused by AGES. Generally, an effective amount of the topical required if a single agent were used. The reduced concentra formulation is applied to exposed or affected skin sites in tions of benfotiamine and pyridoxamine decrease the toxicity association with a carrier, and particularly one in which the effects of these agents and their potential of irritating skin in active ingredient is soluble perse or is effectively solubilized sensitive individuals. (e.g., as an emulsion or microemulsion). It is necessary that US 2014/0134222 A1 May 15, 2014

the carrier be inert in the sense of not bringing about a deac IV. Additional Ingredients tivation of a benfotiamine and/or a pyridoxamine, and in the 0043. Many preferred embodiments of this invention con sense of not causing any adverse effect on the skin areas to tain at least one or more other active ingredients in addition to which it is applied. benfotiamine and pyridoxamine. Such additional active 0040. By the term “an effective amount’ or “amount effec ingredients may include, but are not limited to, compounds tive' of a compound or property, e.g., an amount effective in known to inhibit the formation of AGES, antioxidants, Sun reducing or eliminating the effects of AGE as provided screens glutathione, SOD, r-lipoic acid and its derivatives herein, is meant such amount as is capable of performing the catalase, an energizing ingredient (e.g., mitochondrial resus function of the compound or property for which an effective citants), acetylcholine and choline containing natural ingre amount is expressed. As pointed out above, the exact amount dients, acetylcholine or choline precursors or metabolites, required will vary from case to case, depending on recognized cholinesterase inhibitors and acetyl-cholinesterase inhibi tors, matrix metalloprotease inhibitors, dermorelaxants, anti variables such as the compounds employed and the individual inflammatory agents, molecular film tensors, alpha hydroxy Subject treated. Thus, it is not possible to specify an exact acids, Salicylic acid, ascorbic acid and its derivates and col “effective amount.” However, an appropriate effective lagen protecting or collagen increasing agents. amount may be determined by one of ordinary skill in the art using only routine experimentation. AGE Inhibitors 0041. In one embodiment, one or more of the active com 0044 An additional agent that may be added to the pyri ponents of the formulation, and preferably all of the active doxamine and benfotiamine formulation of the present inven components (including additional agents) are from a natural tion is an anti-glycation agent. As used herein, the term “anti source or are nature-identical. The term “nature-identical glycation agent’ means a compound for preventing and/or includes synthetic compounds having the same chemical reducing the glycation of skin proteins, in particular of dermal structure, regioisomeric form and stereoisomeric form as proteins such as collagen. The anti-glycation agent inhibits compounds produced by either a plant or animal. Natural and the formation of advanced glycation end products (AGES) nature-identical compounds are preferred in a particular and is also known as an AGE inhibitor. embodiment of the present invention since different isomers 0045 Strong antiglycation compounds are preferentially and synthetic chemicals with novel molecular structures can added to the benfotiamine and pyridoxamine formulation as have unpredictable effects on skins metabolism and many are they increase the AGE inhibitory potential of the formulation, unlikely to be biodegradeable. can have a different, and often complementary, inhibitory 0042. The combination of benfotiamine and pyridoxam mechanism, and may have very strong antiglycation proper ine is particularly useful in a topical formulation when the ties regarding collagen specifically. skin and/underlying tissue or the topical and/or oral formu 0046. A non-limiting list of examples of anti-glycation lation contains a high concentration of a Sacharides, Vitamin agents are aminoguanidine, ALT-946, OPB-9195, alage C, amino acids prone to glycation, and the like. In the personal brium chloride, N-phenacylthiazolium bromide, LR-90, care industry, there are many Substances that can lead to plant extracts of the Ericaceae family, such as an extract of AGEs that are increasingly being used for their skin benefits blueberry (Vaccinium angustifolium); ergothioneine and its as functional ingredients (e.g., Sugars as humectants, Sugar derivatives; and hydroxystilbenes and their derivatives, such derived emulsifyers or Surfactants) or actives (ascorbate, as resveratrol and 3.3',5,5'-tetra-hydroxy stilbene. Other pufas, amino acids). The topical benfotiamine and pyridox exemplary inhibitors of AGE formation include, but are not amine formulation eliminates or decreases the potential anti limited to, thiamine, G-rutin (Nagasawa T., Mol Cell Bio glycation effects of these Substances, allowing these nutrients chem. 249(1-2):3-10, 2003); pyridoxal phosphate, ami to open their full beneficial potential. One example of this is noguanidine, a aminoguanidine-pyridoxal adduct, green tea the use of ascorbic acid (i.e., vitamin C) in topical formula (Ouyang P. Di Yi Jun Yi Da Xue Xue Bao 24(3): 247-51, 2004); tions. This easily oxidizable compound is increasingly being extracts of Thymus vulgaris (Morimitsu et al., Biosci Biotech used in topical products. Its oxidized form is dehydroascor nol Biochem 59(11):2018-21, 1995); Ge-132(2-carboxyethyl bate, a species which leads to the formation of AGES. There germanium sequioxide) (Unakar et al., Exp. Eve Res. 61(2): fore, the present invention is particularly useful in combina 155-64, 1995); curcumine (Sajithlal et al., Biochem Pharma tion with topical formulations containing vitamin C. col. 56(12):1607-14, 1998); extracts of Cratoxylum Similarly, these compounds may have been ingested orally to cochinchinense (Tang, SY et al., Free Radic. Biol. Med. create the high concentration of the agents in the skin and/or 36(12): 1575-87, 2004); extracts of Apocynum venetum underlying tissue. For example, Sugars are added to a number Luobuma (Yokozawa et al., Food Chem. Toxicol. 42(6):975 of food products. In particular, fructose is added to products 81, 2004); carnosine; carnosinylated proteins (Hipkiss A Ret to provide a natural Sugar which many consumers feel is al., Cell Mol Life Set 57(5):747-53, 2000); extracts of Euge beneficial. However, fructose glycates four or five times nia bicyclis (Okada et al., Nat. Prod. 67(1): 103-5, 2004); rutin faster than glucose. (Wilson, F. Cosmetic Surgery Times, Sep (Kiho, T et al. Biosci. Biotechnol. Biochem. 68(1):200-5, tember, 2004). Therefore, the topical formulation of the 2004); amadoriase enzymes from Aspergillus fungi (Monnier present invention is particularly useful when the skin, under V Met al., Biochem. Soc. Trans 31:1349-53, 2003: U.S. Pat. lying tissue, a topical administration (either in the same for No. 6,605,642), guanidine rich extracts of Galega officinalis, mulation or in a separate formulation), an oral administration, and extracts of lycopersicon esculentum. The AGE inhibitor or a combination thereof contains a high concentration of as described herein may be incorporated in amounts from agents prone to glycation or agents whose oxidation product about 0.001%-30% by weight. More preferably, the AGE are prone to glycation or agents included for other beneficial inhibitor is incorporated in amounts from about 0.1%-5% by properties that are themselves glycating agents. weight, based on the total weight of the preparation. For US 2014/0134222 A1 May 15, 2014

compounds without a recommended daily dose, the dose will cell stress, and increase the signs of aging in the skin. Pro be within the range commonly accepted as safe and effective duction of the AGE-crosslinked amyloid peptide aggregates for that particular compound. has been shown to be attenuated by carnosine (Munch, G., et 0047 A preferred anti-glycation agent is carnosine. As al., Biochim Biophys Acta, 1997 Feb. 27: 1360(1):17-29). used herein the term "carnosine” encompasses the dipeptide These protective effects are attributed to its anti-glycating and beta-alanyl-L-histidine; it includes D.L-carnosine, D-carnos antioxidant activities (Preston, J. E. et al., Neurosci Lea. 1998 ine, L-carnosine and their derivatives (for example, anserine), Feb. 13:242(2):105-8). as well as their salts (for example, Zinc carnosine, copper 0051 One general problem with the administration of car carnosine, and copper anserine). nosine is that the 3-alanine metabolite can have some toxic 0048 Carnosine has been shown to possess strong and effects on cell growth. Beta-alanine has been shown to reduce specific antioxidant properties. It is a potent anti-glycation skin fibroblast cell growth; however, the co-administration of agent and has unique anti-aging properties. It has a free pyridoxamine can be used to significantly reduce these 3-ala radical scavenging activity and has been shown to extend nine toxic effects (Higgins J. J., et al., Neurology. 1994 Sep human fibroblast life-span, kill transformed cells, protect tember; 44(9): 1728-32). When carnosine is chelated to Zinc cells against aldehydes and amyloid peptide fragments and or copper ions, the presence of the ions enhances carnosines inhibit, in vitro, DNA/protein cross-linking, and act as an activity as a Superoxide radical scavenger (Gulyaeva N.Y. aldehyde scavenger (Hipkiss; A R, Int J Biochem Cell Biol. Biochemistry 57 (7:2) 1051-4, 1987). Therefore, the addition 1998 August:30(8):863-8: Hobartet at Life Sci. 75:1379-89.) of carnosine as an agent in the present invention provides for It also promotes wound healing (Roberts PR, et al., Nutrition Superoxide Scavenger activity as well as the anti-glycation 1998; 14, 266-9), protects against radiation damage, is poten and anti-oxidation properties of carnosine. Carnosine has tially a modulator of enzymatic activities, and has been shown been administered orally at dosages above 500 mg/kg body to beachelator of heavy metals (Quinn, PJ et al., Mol. Aspcts. weight in animal studies and has found to be safe. The addi Med. 1992: 13(5),379-444; (Hipkiss A R. IntJ Biochem Cell tion of carnosine in the formulation of the present invention Biol 1998:30:863-8). Carnosine is degraded by histidine and will be between 0.001-10% by weight. carnosinase to form histamine and B-alanine (Nagai, Ket al., 0052. The salts and derivatives of carnosine are also useful Surgery 1986, 100(5): 815-821.) The B-alanine produced by additions to the present invention and salts and derivatives the degradation of carnosine stimulates the biosynthsis of thereof, which function as a pH buffer and also act as an agent nucleic acids and of collagen. This increased collagen Syn of inhibiting protein cross-linking. One preferred embodi thesis is an important aspect of the present invention, as it ment uses N-acetyl-carnosine as it is highly resistant to provides additional benefit to the skin and reduces the effects hydrolysis by carnosinases and therefore may provide pro of aging. Similarly, the histamine produced by the degrada tection from AGES for a longer period of time in comparison tion process stimulates early effusion at the initial stage of to carnosine. Zinc and copper complexes of carnosine are also tissue inflammation. Researchers have hypothesized that the useful as chelating agents (Kohen at al., Free Radic. Res. effectiveness of carnosine stems from its ability to react with Commun. 991; 12-13 Pt 1:179-85). carbonyl groups on glycated or oxidized proteins (i.e., 0053 A topical composition comprising a carnosine, a camosinylation); this reaction inhibits the glycoxidised pro lipoic acid such as R-lipoic acid or R-dihdyrolipoic acid, and teins from cross-linking with normal macromolecules and a carnitine Such as acetyl-1-carnitine, may be combined with causing the signs of aging (Hipkiss A R, et al., Mech Ageing the formulation of the present invention. This formulation, Dev 2001 Sep. 15: 122(13): 1431-45; Hobart et al. Life Sci. which is useful in improving the appearance of aged skin 75:1379-89). characterized by wrinkles and loss of elasticity, and has been 0049 Carnosine reacts strongly with aldehyde and keto described in U.S. Prov. Pat. Appl. 60/665,206 filed Mar. 24, groups of Sugars by Amadori reaction, and is also theorized to 2005, herein incorporated by reference. deplete certain glycolysis intermediates. Therefore, a reduc 0054 An anti-glycation agent of interest is garcinol. Gar tion of glycolysis intermediates by carnosine depletes their cinol occurs naturally in the latex exudate of the herb Gar energy Supply. But the addition of pyruvate reverses this cinia Cambogia, which is used as a weight loss Supplement. effect (Holliday R Br J. Cancer. 1996 April; 73(8):966-71). Garcinol is a moderate antioxidant, metal chelator, and free Therefore, it is preferable to add carnosine to a formulation radical scavenger. It also is a Superoxide anion scavenger and which also reduces the amount of pyruvate available. Addi has been shown to Suppress glycation in a bovine serum tionally, the reaction between carnosine and aldehydes pro albumin/fructose system. (Yamaguchi F. et al., JAgree Food tects Susceptible macromolecules. Therefore, carnosine Chem. 2000 February; 48(2):180-5) It has also been shown inhibits nonenzymic glycosylation and cross-linking of pro that the (-)-hydroxycitrate from Garcinia fruits may aid teins induced by reactive aldehydes (aldose and ketose Sug endurance during post-absorptive aerobic exercise by pro ars, certain triose glycolytic intermediates and malondialde moting gluconeogenesis. Garcinia is particularly useful as an hyde (MDA), a lipid peroxidation product) (Hipkiss A R, et additional agent because the combination of garcinol with al., Ann NY Acad Set 1998 Nov. 20; 854:37-53). Carnosine carnitine and chromium will have anti-glycation properties has also been shown to be beneficial on growth, morphology, and promote gluconeogenesis (McCarty M F. Med. Hypoth and longevity of cultured human fibroblasts, and has an eses. 1995 September; 45(3):247-54). important role in cellular homeostasis and maintenance (Mc 0055 Aglycal LS 8777, made by Laboratoires Serobi Farland GA, et al. Exp Gerontol. 1999 January:34(1):35-45). ologique (Cognis France), may also be included as an anti 0050 Amyloid beta peptides enhance the expression of glycation agent in the formulation of the present invention. AGE receptors (Chaney, MO, et al., Biochim Biophy's Acta Aglycal LS 8777 is a plant-based complex that retards the 2005 Jun. 30; 1741(1-2): 199-205. Epub 2005 Apr. 19). These glycation of proteins. This photo-complex aids in the long receptors mediate amyloid-beta peptide transport across the term elasticity of the skin and protects against the fragmen blood-brain barrier, suppress cerebral blood flow, exaggerate tation of collagen. (www.laboratoires-serobiologiques.com) US 2014/0134222 A1 May 15, 2014

0056 Aldenine, made by Lipotec (Spain), is a complex of have been shown to be potent inhibitors of glycation, and have a tripeptide and hydrolyzed wheat and soy proteins that been shown to inhibit the glycation of collagen. boosts Collagen III synthesis while protecting cells from 0062). Other AGE inhibitors are described by MTakahashi photo damage. Aldenine detoxifies the skin from harmful et al., who teache the isolation, purification, and character RCS (Reactive Carbonyl Species). ization of amadoriase isoenzymes (fructosylamine-oxygen 0057. Another anti-glycation agent, ANTIGLYSKINR) oxoreductase) (J. Biol. Chem. (1997) J. Biol Chem. 272, from Silab, is rich in phenolic acids and glycopeptides from 3437-3743). Sunflower and inhibits the protein glycation reaction and pre 0063 Additionally, antiglycation compounds may be vents the glyco-oxidation. added to the pyridoxamine and benfotiamine formulation. 0058 Compounds obtained from Pterocarpus marsupium Two types of enzymes, fructosyl lysine oxidase and fructose may also be incorporated into the topical formulation. (-) lysine 3-phosphokinase, catalyze the deglycation reaction Epicatechin, the active ingredient in the Indian herb Ptero and generate free amine groups. The biochemical properties carpus marsupium Roxb, can be obtained from the water of these amadoriase enzymes and their role in protein degly extract of the bark and is insulinogenic. (Ahmad F. et al., Acta cation are described by Wu, X et al., Arch Biochem Biophys. Diabetol Lat. 1989 October-December:26(4):291-300). It 419(1):16-24 (2003). In one embodiment, the compounds has been found to decrease hepatic and skeletal muscle gly described by Wu, Takahasi, and/or Rahbar are used in com cogen (Grover JK, et al., Mol Cell Biochem. 2002 December; bination with the formulation described herein. The com 241(1-2):53-9). In addition, three flavonoid antioxidants are pounds described by Wu, Takahasi, or Rahbar may be used in also present in the heartwood; these flavonoid are marsupsin, combination with the formulation described herein. pterosupin, and liquiritigenin. The gum tannic acid and a 0064. Other AGE inhibitors may be added to the formula non-glucosidal tannin, kino tannic acid, and Pterocarpus tion of the present invention. Extracts of Paeonia suffruticosa marsupium extracts have also been shown to have anti-oxi have been shown to be AGE inhibitors (Okano et al., at dant activity (Katiyar S K, et al., Photochem Photobiol. 1995 www.creative-developments.co.uk/papers/Natural November; 62(5):855-61) and a strong anti-glycation agent %20Ingredients %201998.html). Additionally, AGE inhibi (www.laboratoires-Serobiologiques.com/LSvi/english/ tors have been isolated along with compounds having anti prod 2.html)). oxidant activity from Paeonia suffruticosa; these compounds 0059 N-Acetylcysteine is an N-acetylated cysteine which include the monoterpene glycoside, C.-benzoyloxypaeoni is a thiol containing amino acid, also called O-acetamido-B- florin, B-benzoyloxypaeoniflorin, paeonolide, paeoniflorin mercaptopropanoic acid, which is a preferred additional com and mudanpioside-H. (Ryu G. et al. Arch Pharm Res. 2001 ponent of the present invention. The incorporation of N-ace April; 24(2):105-8). tylcysteine into the topical formulation will improve the signs 0065. Another AGE inhibitor is from extracts of San of aging of the skin. N-acetylcysteine is an antioxidant and guisorba officinalis, which has been shown to reduce chronic also has been indicated as protective against pulmonary oxy photodamage to the skin. (Tsukahara K. Biol Pharm Bull. gen toxicity (Eur: Respir. J. 2: 116-126 (1989)). It is also an 2001 SeP:24(9):998-1003). Pterocarpus marsupium has anti-glycation agent. Preferred forms of N-acetyl cysteine been shown to be an anti-diabetic agent and strong antihyper include: N-acetyl-L-cysteine, N-acetyl-L-cysteine amide, glycemic agent (Babu P S., J. Pharm Pharmacol. 2004 N-acetyl-L-cysteine methyl ester, N-acetyl-L-cysteine ethyl November; 56(11): 1435-42). C. Cochinchinense has been ester, N-acetyl-L-cysteine propyl ester, and N-acetyl-L-cys found to be a particularly potent AGE inhibitor on proteins teine isopropyl ester. See PCT US96/16534 which teaches and also to strongly inhibit hypochlorous acid-induced DNA topical compositions containing N-acetylcysteine, and U.S. damage. (Tang S Y. Free Radic Biol Med. 2004 Jun. 15: App. 20030229141 which discloses the topical use of 36(12): 1575-87). N-acetyl cysteine to alleviate or improve various cosmetic 0066. There are other natural products that are AGE conditions and dermatological disorders. inhibitors, which may be used in the present invention. The 0060 AGE inhibitors that may be added to the formulation screening method described by Matsuura, based on a fluoro include the enzymes, fructosyl lysine oxidase and fructose metric analysis, may be used to determine the inhibitory lysine3-phosphokinase, which catalyze the deglycation reac index of the Maillard reaction and AGE inhibition to deter tion and generate free amine groups. The biochemical prop mine compounds useful to include in the formulation of the erties of these amadoriase enzymes and their role in protein present invention. (Nobuyasu Matsuura et al. J. Health Sci deglycation are described by Wu, X et al., Arch Biochem ence 48(6)520-526 (2002)). In addition new AGE inhibiting Biophys. 419(1):16-24 (2003). See also Takahasi, M. et al., J. compounds may be synthesized by molecular combination of Biol. Chem. 272, 3437-43 (1997). The amadoriase enzymes two or more AGE inhibitors. These newly created molecules are particularly useful since they have strong anti-glycation would need to be tested for their AGE inhibiting properties as activity, and some of these compounds are selective for col well as their safety and efficacy before they can be incorpo lagen. This makes these enzymes particularly useful as com rated into the formulation. RCS(reactive carbonyl species) ponents in the topical formulation of the present invention are detoxified by several enzymatic pathways, such as aldose since they will preferentially act on collagen and therefore reductase, aldehyde dehydrogenases, and the glyoxalase inhibit the glycation of collagen and reduce the signs of aging pathway. These enzymes produced via biotechnology can be in the skin. also incorporated in the formulation. 0061 Another class of AGE inhibitors that may be used in the formulation of the present invention is described by Rah Antioxidants bar et al., Molecular Cell Biology Research Commun. 3, 0067. In particular, preferred embodiments of the addi 360-66 (2000). These compounds are benzoic acid deriva tional active ingredients included in the formulations of the tives, aryland heterocyclic ureido compounds, and aryland present invention are compounds having antioxidative action heterocyclic carboxamido phenoxy isobutyric acids. They due to their known benefit in protecting the skin and the US 2014/0134222 A1 May 15, 2014

implication of oxidative stress in the formation of RCS as marine species (e.g., Bioplasma and monostrama extract well as to protect from the known oxidative stress created by from Secma), roxisomes (from AGI), crocetin, pine pollen AGES. Exemplary antioxidants include, but are not limited to, extracts, beta glucans and the suitable derivatives of the amino acids (e.g. glycine, histidine, tyrosine, and tryptophan) invention (salts, esters, ethers, Sugars, nucleotides, nucleo and their derivatives, imidazoles (e.g. urocanic acid) and their sides, peptides and lipids) of these said active ingredients. derivatives, carotenoids (e.g. lutein, lycopene), carotenes 0068 Anthocyanins and their derivatives are particularly (e.g. C-carotene, B-carotene, lycopene, canthaxantin, cryp preferred antioxidants. Anthocyanins encompasses a class of toxanthin, Zeaxanthin and astaxanthin) and their derivatives, flavonoid compounds that are naturally occurring, water chlorogenic acid and its derivatives, aurothioglucose, propy soluble compounds, responsible for the red, purple, and blue lthiouracil, thiotaurine and other thiols (e.g. thioredoxin, cys colors of many fruits, vegetables, cereal grains, and flowers. teine, cystine, cystamine and their glycosyl-N-acetyl, methyl, Anthocyanins are Susceptible to degradation by light, heat, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, Y-lino oxygen, and other reactants including iron, copper, and tin. leyl, cholesteryl and glyceryl esters) and their salts, aminoet The antioxidant properties of the anthocyanins can be mea hylcysteine, decarboxylated dimmer of aminoethylcysteine sured by their capacity to absorb free radicals. The oxygen ketimine, dilauryl thiodipropionate, distearyl thiodipropi radical absorbance capacity (ORAC) is a measurement of onate, thiodipropionic acid and their derivatives (esters, this. Anthocyanins generally have a high ORAC rating com ethers, peptides, lipids, nucleotides, nucleosides and salts) pared to other antioxidants. Further, for ripe berries, there is a and SulphoXimine compounds (e.g. buthionine SuiphoX linear relationship between ORAC values and anthocyanin imines, homocysteine SulphoXimine, buthionine Sulphones, content. High ORAC ratings include 25-200 umole of Trolox pentathionine SulphoXimine, hexathionine SulphoXimine, equivalents (TE)/g. In most fruits (i.e., not just the fruits with heptathionine SulphoXimine) in very low, acceptable doses; high anthocyanin content), ORAC values ranged from 7.8 to 33.7 umole TE/gg of fresh berries and the ORAC values of also (metal) chelating agents (e.g. C-hydroxy fatty acids, the leaves range from 69.7 to 182.2 Lumole TE/g. (Wang SY. palmitic acid, phytic acid, lactoferrin, tannins, and cur Lin HS.J. Agric Food Chem. 2000 February; 48(2):140-6). cumine), C-hydroxy acids (e.g. citric acid, lactic acid, malic Black raspberries have a very high ORAC of 77 umole TE/g, acid, mandelic acid), humic acid, colic acid, colic extracts, while boysenberries have an ORAC of 48 umole TE/g, and bilirubin, biliverdin, EDTA, EGTA and their derivatives, red raspbererries and blueberries have 24 and 23 umole TE/g, unsaturated fatty acids and their derivatives (e.g. Y-linolenic respectively. (http://www.deckerfarm.com/antioxidants. acid, linolic acid, oleic acid), folic acid and their derivatives, ubiquinone and ubiquinol and their derivatives, vitaminA and html). Acai is another fruit having a high ORAC content. The derivatives (e.g. vitamin A palmitate), the other B vitamins stage at which the plant is harvested affects the ORAC value. and their derivatives, including thiamine, coniferyl benzoate Blackberries have their highest ORAC values during the of benzoin resin, rutinic acid and their derivatives, butylhy green stages, whereas red raspberries have their highest droxy toluene, butylhydroxy anisole, nordihydroguaiacic ORAC values when ripe. In one embodiment, the antioxidant acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, is selected from a natural product having a high ORAC value. uric acid and its derivatives, mannose and its derivatives, The ORAC may be obtained by using the method described sesamol, Sesamolin, Zinc and its derivatives (e.g. ZnO, by the U.S. Department of Agriculture's Agricultural ZnSO) including zinc amino acid chelates(zinc-methionine, Research Service (Prior and Cao, 83(4) J. AOACINT. 950-6 Zinc acetyl-methionate), selenium and its derivatives (e.g. (2000)). Additionally, testing for ORAC, H-ORAC, Selenium methionine), stilbenes and their derivatives (e.g. N-ORAC, S-ORAC, and ORAC-E (high throughput ORAC stilbene oxide, trans-Stilbene oxide), proanthocyanidins, for oil-in-water emulsion) are available from Brunswick ascorbic acid, particularly fat-soluble fatty acid esters of Laboratories (www.brunswicklabs.com). ascorbic acid (e.g. ascorbyl palmitate and tetrahexy decyl 0069. Additionally, anthocyanins are collagenase inhibi ascorbate), quercetin and its derivatives (e.g. quercetingly tors. The inhibition of collagenase helps in the prevention and coside or rutin), hesperidine, Sylimarin, Sylibin, glabridin, reduction of wrinkles, increase in skin elasticity, etc., which Superoxide dismutase and their derivatives, catalase and its are caused by a reduction in skin collagen. derivatives, carnosic acid and its derivatives, apigenin and its 0070 The anthocyanins useful in the present invention derivatives, luteolin and its derivatives, chlorogenic acid and may be obtained from any portion of various plant sources, its derivatives, caffeic acid and its derivatives, ferrulic acid such as the fruit, flower, stem; leaves, root, bark, or seeds. One and its derivatives, resveratrol and its derivatives, green tea of skill in the art will understand that certain portions of the polyphenols and its derivatives, matrix metalloproteinase plant may contain higher natural levels of anthocyanins and, inhibitors (e.g. green tea polyphenols, trans-retinoic acid, therefore, those portions are preferably used to obtain the luteoline, quercetine, ursolic acid, shark cartilage prepara desired anthocyanins. Methods to determine whether and tions, diterpenes and ursolic acid from Siegesbeckia and Cen which portions of a plant contain anthocyanins are known and taurium extracts, and a tocopherol), Coenzyme Q10, glu not discussed herein. The extraction and identification of tathione and its derivatives, myristicin, changkil saponins various anthocyanins are described, for example, in U.S. Pat. (from platycodon grandflorium, which is also known as jie No. 6,818,234, U.S. Pat. No. 6,780,442, and U.S. Pat. No. geng), pomengranate, elagic acid, honokiol (from magnolia 4.413,004. officinalis), magnolol (from magnolia officinalis), maringenin, 0071 Particularly preferred anthocyanins are derived clove essential oil, martynosides, Verbascosides, wolfberry from natural sources having high anthocyanin content. (from lycium barbarum) extracts, cascading antioxidants Approximately 300 anthocyanins have been discovered in including but not limited to carnosic acid, standardized nature, and come from sources including, but not limited to, extract of Phyllanthus emblica (trade named Emblica), pinus acaiberries, aronia berries, apples, bilberries, black carrots, maritima and pinus radiata bark extracts, hydroxytyrosol blueberries, cherries, cranberries, eggplants, elderberries, (from olives), genistein, thiotaurine, antioxidants from grapes, macqui berry, prunes, purple carrots, purple loos US 2014/0134222 A1 May 15, 2014 estrife, purple rice, radishes, raspberries, red cabbage, red DHLA can regenerate endogenous antioxidants and repair currants, red-fleshed potatoes, red raspberries, red onions, oxidative damage. DHLA can regenerate the endogenous species from the Rubus class (e.g., black raspberry, black antioxidants vitamin E. Vitamin C and glutathione as well as berry, and youngbeXry), species from the Ribus class (e.g., provide peptide methionine sulfoxide reductase with reduc black currant and gooseberry), Sea buckthorn, woliberry ing equivalents. The reducing equivalents help in the repair of extract, strawberries tart cherry. Two particularly preferred oxidatively damaged proteins such as C-1 antiprotease. (Bie anthocyanins are macquieberry and aronia berry due to their wenga GP, et al., Gen Pharmacol. 1997 September, 29(3): high ORAC. Wild blueberry is another particularly preferred 315-31). DHLA is a potent sulfhydryl reductant and has also anthocyanin having a high ORAC that may be added to the been shown to act as a strong direct chain-breaking antioxi formulation of the present invention. dant which may enhance the antioxidant potency of other 0072 Other preferred anthocyanins used in the topical antioxidants such as ascorbate and vitamin E. (Kagan V. E., et formulation of the present invention are formed from a com al., Biochem Pharmacol 1992 Oct. 20; 44(8):1637–49). bination of two or more (i.e., 2, 3, 4, 5, or 6) different sources 0077 Retinol and its derivates such as retinyl palmitate of anthocyanins. For example, an embodiment may include and trans-retinoic acid as well as retinols stabilized in lipo anthocyanins derived from both amnia berry and from young Somes and cyclodextrin preparations may be added to the berry. present invention. One retinol derivate of interest is toco 0073. When anthocyanins are used, flavonoid glucu pheryl-retinoate available from Nikko Chemicals Co. LTD. ronides and flavonoid glycuronides may be added to the for 0078. Other agents useful in the topical formulation of the mulation of the current invention as a stabilizer for one or present invention include vitamin C and the vitamin C deriva more anthocyanin. As used herein, the term “flavonoid glu tives including ascorbic acid, Sodium ascorbate, and the fat curonide' encompasses flavonoids that are attached to a glu soluble esters tetrahexyldecyl ascorbate and ascorbyl palmi curonic acid (e.g., glucose having a carboxylic acid at the C6 tate, magnesium ascorbyl phosphate, ascorbyl-glucoside, position on the Sugar ring); the term also encompasses fla glucosamine ascorbate, ascorbyl acetate, etc. Additionally, vonoid glucosides, which are flavonoids attached to glucose. extracts from plants containing a high amount of vitamin C, Similarly, flavonoid glycuronides are flavonoids attached to such as camu berry (Myrciaria dubia), acerola, emblica offi glycuronic acid, and flavonoid glycosides, which are herein cinalis, and bioflavonoids from rose hip and citrus, may be encompassed in the term flavonoid glycuronides, are fla used including water-soluble bioflavonoids such as hesperi vonoids attached to a glycose. One particularly useful fla din methyl chalcone. When vitamin C and/or these related vonoid glucuronide is the glucuronide derived from rose easily oxidiazble compounds are indicated, the combination mary. Other exemplary flavonoid glucuronides can be found with the pyridoxamine and benfotiamine formulation of the in U.S. Pat. No. 5,908,650. present invention is particularly useful for reducing the dam 0.074. In one embodiment, an additional antioxidant aging effects from the potential formation of the oxidation included in the formulations of the present invention is one or product dehydroascorbate (or related compounds), a species more betacyanin. Betacyanins, like anthocyanins, may be which leads to the formation of AGEs. Therefore, the present obtained from natural Sources and are antioxidants. One beta invention is particularly useful in combination with topical cyanin of interest is betanin found in beets. formulations containing vitamin C. 0075 Alipoic acid is a preferred antioxidant for use in the 0079. In one particularly preferred embodiment, the anti topical formulation of the present invention. Lipoic acid is oxidant is superoxide dismutase (SOD) (and derivatives), available in both the R and S forms. R-lipoic acid is a pre catalase (and derivatives), or a mixture thereof. In a particu ferred form. The lipoic acid of the present invention also larly advantageous embodiment, SOD is heterologous SOD includes the reduced form, or dihydrolipoic acid. In aqueous (HSDs), described in U.S. Pat. No. 6,426,068, which no systems, both lipoic acid and MBA show strong antioxidant longer, or practically no longer, exhibit dismutase activity, but activity. Lipoic acid is also useful in treating diseases associ which conserve immuno-redox activity, Stimulate the produc ated with oxidative stress including liver cirrhosis, ath tion of endogenous SOD, as well as the production of catalase eroschlerosis, and polyneuritis of diabetes mellitus. (Maitra, and of glutathione peroxidase. According to another advan I., et al., Free Rad. Biol. Med. 18:823-829 (1995), introduc tageous embodiment includes a plantheterologous SOD that tion). The antioxidative activity of lipoic acid is due, at least has been derived from melon. Any endogenously occurring in part, to its ability to prevent free radical damage to cells and form of SOD may be used as the SOD additive in the present cell components. Free radical damage is most evident in invention. The preferred embodiment uses an encapsulated cellular membranes because of the density of the molecular SOD. For example, a formulation of the present invention structure of the membranes. (R)-Lipoic acid has been shown includes benfotiamine, pyridoxiame, and Superoxide dismu to reverse the age-related decline in oxygen consumption and tase that has been microencapsulated. increase mitochondrial membrane potential. The age-related 0080. Another preferred antioxidant is the mitochondrial decline in hepatocellular glutathione and ascorbic acid levels targeted antioxidant tert-butyl hydroxylamine (NtEHA). is reversed by treatment with (R)-lipoic acid (as an oral NtEBHA reduces the loss of the mitochondrial enzyme supplement in rats). (Hagen T M. et al., FASEB J. 1999 glutamate dehydrogenase (GDH), decreases concentrations February: 13(2):411-8). of glutathione-mixed disulfides compared to free glutathione. 0076 Reduced R-lipoic acid, or R-dihydrolipoic acid NtEBHA is also an inhibitor of AGES. Proteasomal (organelles (R-DHLA), may be used instead of or in addition to R-lipoic within cells that degrade and process proteins through enzy acid. R-DHLA which is formed in situ by the reduction of matic reactions) activity was also higher in cells treated with R-lipoic acid by NADH has more antioxidant properties than NtEBHA than in untreated cells. This is significant since pro lipoic acid. Both DHLA and lipoic acid have metal-chelating teasomes break down lipofuscin. The spin trap PBN is capacity (LA chelates Fe" and Cu"; DHLA chelates Cd") believed to hydrolyze to NtEBHA, and may be used in combi and can scavenge reactive oxygen species. However, only nation with the topical NtEHA-containing formulation. US 2014/0134222 A1 May 15, 2014

0081. Sesame (Sesamum indicum) or sesame lignan may Lipids. 2002 April; 37(4):351-8). One preferred formulation also be added to the present invention. Sesame and its lignans contains d-O-, d-B-, d-y-, and d-Ötocopherol, d-O-, d-B-, d-f-. (the fibrous compounds associated with the sesame) act as and d-ö-tocotrienol in addition to the Sesame lignans. antioxidants, reduce inflammation, normalize blood pressure, I0086 Vitamin A is a preferred addition to formulations of improve lipid levels, and promote fat burning. Sesame has the present invention because of the increased stability it can also been shown to aid in protecting and enhancing the bio impart to lipoic acids. Segall, A.J. Cosmet Sci. 2004 Septem availability of fish oil and conjugated linoleic acid, to enhance ber-October; 55(5):449-61. the anti-inflammatory effects of essential fatty acids, lower I0087. In addition, carotenoids, particularly the xantho total cholesterol and low-density lipoprotein (LDL), block phyll type, are also preferred antioxidants that can be used in oxidative damage implicated in atherosclerosis, and reduce the practice of the instant invention. The xanthopyll type blood pressure. Sesame lignans can dramatically increase carotenoids include molecules Such as lutein, canthaxantin, tissue and serum levels of the vitamin Efractions atocopherol ctyptoxanthin, Zeaxanthin and astaxanthin. Xanthophylls and Y tocopherol, thereby enhancing their protective proper protect compounds such as vitamin A, vitamin E and other, ties. (Yamashita K, et al., J Nutr. 1992: 122(12):2440-6). carotenoids (Demmig-Adamas, B. Biochemica et Biophsvica Studies have shown that sesame can also reduce inflamma Acta, 1020:1-24 (1990)). Xanthophylls can be obtained from tory processes known to promote cancer, Senescence, and a multitude of natural sources, or produced as described, for aging. example, in U.S. Pat. No. 5,916,791. 0082 Sesame seed lignans significantly enhance vitamin I0088 Flavan-3-ols are also preferred antioxidants that E activity and increase a tocopherol concentrations in the may be used in the formulations of the present invention; they blood and tissue of rats fed a diet containing a tocopherol and belong to a class of nutrients known as the flavonoid family. sesame seed or its lignans. (Yamashita K, et at. Lipids. 1995 Particularly preferred flavan-3-ols include the procyanidin December; 30(11):1019-28). Additionally, they elevate mixtures extracted from grape (Vitis vinifera) seed. Proantho gamma tocopherol concentration by inhibiting an enzyme cyanidins play a role in the stabilization ofcollagen and main involved in breaking down tocopherols and tocotrienols. tenance of elastin, two critical proteins in connective tissue (Ikeda S, et al., J. Nutr 2002 June; 132(5):961-6). that Support organs, joints, blood vessels, and muscle 0083. Other preferred antioxidants which may be incorpo (Mitcheva et al. Cell Mol Bio 39:443-8 (1993) and Maffei at rated in the formulations of the present invention include al. Arzneimittefbrschung, 44:592-601 (1994)). Other flavan tocopherols (e.g. d-C-tocopherol, d-B-tocopherol, d-y-toco 3-ols may also be added to the formulation. These include pherol, d-o-tocopherol), tocotrienols (e.g. d-O-tocotrienol, catechin and epicatechin. Procyanidins are the dinners and d-B-tocotrienol, d-y-tocotrienol, d-Ö-tocotrienol.) and Vita oligomers of catechin and epicatechin and their gallic acid min E (C-tocopherol acetate). These compounds added to the esters, and are widely distributed in the plant kingdom and compounds of the present invention may be isolated from may be added to the formulation of the present invention. natural Sources, prepared by Synthetic means, or mixtures Other flavonoids. Such as isoflavin B, quercetin, glabridin, red thereof. Tocotrienol-enriched vitamin E preparations may be clover, and others described in U.S. Pat. Nos. 5,686,082 and obtained by fractionating vitamin E preparations to remove a 5,686,367 may also be included in the formulation. portion of tocopherols and recover a preparation more highly concentrated in tocotrienol. Useful tocotrienols are natural Sunscreen products isolated from, for example, wheat germ oil, grain, or I0089. In particular preferred embodiments, the additional palm oil using high performance liquid chromatography, or active ingredients included in the compositions of the present isolated by alcohol extraction and/or molecular distillation invention are compounds having Sunscreening action. Sun from barley, brewer's grain or oats. As used herein, the term screening agents include, but are not limited to, aminoben “tocotrienols' includes tocotrienol-rich-fractions obtained Zoic acid, avobenzone, dioxybenzone, homosalate, lisadi from these natural products as well as the pure compounds. mate, menthyl anthranilate, octocrylene, octyl The increased glutathione peroxidase activity protects the methoxycinnamate, octyl salicylate, oxybenzone, padimate skin from oxidative damage. (Musalmah M. et al., Asia Pac J O. phenylbenzimidazole, roXadimate, Sulisobenzone, tita Clin Nutr 2002; 11 Suppl 7:S448-51). In one particular nium dioxide, trolamine Salicylate, Zinc oxide, and combina embodiment the tocopherols and tocotrienols are extracted tions thereof (see www.nlm.nih.gov/medlineplus/druginfo/ from Annato. uspdi/202782.html). In one particular embodiment the 0084 Gammatocopherol is one particularly advantageous Sunscreen agent or agents are naturally occurring Substances E vitamin since it is capable of quenching reactive nitrogen Such as: Zinc oxide, coffee oil, leuco-melanin, date palm fruit oxide species such as peroxynitrite and nitrogen dioxide. melanin, galanga extract (available from Symrise). Other (Bole K. M. Front Biosci. 2004 Feb. 1; 9:763-76). Gamma Substances that protect from UV damage that may be used tocopherol and its water-soluble metabolite, gamma-CEHC, include Such as sanguinaria extract Krameria triandra root have been shown to reduce inflammation by inhibiting pros extract (15% neolignans) metallothionein, 1,25-dihydroxyvi taglandin E2 (Jiang Q, et al., Proc Natl. AcadSci USA. 2000 tamin D3, and thymidin dinucleotide. A preferred sun-pro Nov. 10; 97 (20:11494-9) and gammatocopherol administra tective extract is a polypodium leucomotos extract. This com tion correlates with a reduced risk from heart disease. (Kushi pound may be incorporated in the topical formulation, or L. H. et al. NEngl Med 1996 Jun. 2: 334(18): 1156-62). alternatively, it may be provided as an oral Supplement in 0085. When a tocopherol or tocotrienol is added to the addition to the formulation of the present invention for formulation of the present invention, it is also preferable to increased protection from UV damage. (Middlekamp-hup et add sesame oil (or an extract thereof Such as Sesaminol, a al., J. An Acad Dermatol, 2004, 51(6) 910-918). One pre sesame lignans) due to the enhanced antioxidant effect of the ferred Sunscreen agent is isoamyl-p-methoxycinnamate combination. (Ghafoorunissa, Hemalatha S., et al., Mol Cell (from Galanga, available from Symrise, Gmbh & Co); this Biochem. 2004 July; 262(1-2): 195-202; Yamashita K, et al., compound provides an Spf of greater than 30 using only US 2014/0134222 A1 May 15, 2014

natural ingredients (botanicals, antioxidants, coffe oil and Energizing Ingredients microfine Zinc oxide). Additional Sunscreen agents include: allantoin, aloesin, apigenin, caffeic-acid, chlorogenic-acid, 0096 Energizing ingredients may also be combined with ellagic-acid, esculetin, esculin, ferulic-acid, fraxetin, fraxin, the benfotiamine and pyrodixamine topical formulation. lawsone, p-aminobenzoic-acid, paba, procyanidins, rutin, These include the mitochondrial resuscitants and Asian silymarin, squalene, and umbelliferone. botanicals known to tonify Qi such as panax species, 0090. Adding an anti-erythema ingredient to the formula, Polygonum multiflorum, Codonopsis silvestris, Astragalus an additional-effect caused by the damaging UV radiation membranaceus, Poria cocos, or a combination thereof (Chen, besides free radical formation is addressed. The reduction in J. Zhong XiYi Jie He Za Zhi. 1989 April: 9(4):226-7, 198.). redness accomplished by applying the formulation of the present invention is due to an incorporation of aesculin, Mitochondrial Resuscitants colchicines, esculin, glycyrrhetinic-acid, opc, opcs, procya nidin-a-2, procyanidins, rutin, or silymarin into the formula 0097 Mitochondrial resuscitants may also be added to the tion. Another particularly preferred skin-protective agent is benfotiamine and pyridoxamine formulation. Mitochondrial beta glucan, which may be obtained from yeast, oat and decay in aging is a major driving force behind the aging mushroom species. It is a free radical scavenger and stimu process. (Ann NY Acad Sci. 2004 June; 1019:406-11; Proc lates nonspecific immunity. Natl AcadSci USA. 1994.91:10771-8). The mitochondria are 0091 Hyaluronic acid, a component of connective tissue the powerhouses of the cell responsible for producing all whose function is to cushion and lubricate the tissue as well as cellular energy and convert carbohydrates and fatty acids into hyaluronidase inhibitors such as extracts of Echinacea spe ATP ATP is necessary for the production of proteins, which cies are also useful as additional agents in the present formu declines with aging (e.g., collagen and elastin). Therefore, the lation. addition of a mitochondrial resuscitant is useful in the present 0092 Alpha hydroxy acids, known for their exfoliating Agents useful as mitochondrial resuscitants include, but are and resurfacing properties, may be combined as an ingredient not limited to lipoic acid (Ames B. Ann. N.Y. Acad. Scf. 1033: in the topical formulation of the present invention in combi 108-116 (2004), carnitine, COQ10, CoA, NADH, FADH, nation with a saccharide isomerate, green tea, strontium chlo Succinic acid, creatine, D-ribose, Sepitonic M3R (containing ride and/or a COX 2 inhibitor to prevent stinging in sensitive magnesium aspartate, Zinc gluconate, copper gluconate). individuals. pyruvate, gymnostemma pentaphyllum, and cytochrome C. 0.093 Hormonal decline is known to occur with aging adenosine, adenosine monophosphate, adenosine di-phos therefore a class of Substances replenishing and regulating phate and ATP itself. Additionally, agents including phenyl these is useful in combination with the formulation of the butylnitrone (PBN) and other spintraps, such as the nitrone or present invention. A non-exclusive list of agents useful for nitroso spin traps described in U.S. Pat. No. 5,723.502 (N-t- treating hormonal decline is: estriol, 7-keto-dhea, dhea, butyl-O-phenylnitrone, 3,5-dibromo-4-nitrosobenzene estrone, estradiol, progesterone, pregnenolone, melatonin, sulfonic acid, 5,5-dimethyl-1-pyrroline N-oxide, 2-methyl-2- Soy isoflavons, phytoestrogens (back cohosh, red clover, Sage nitroSopropane, nitrosodisulfonic acid, C.-(4-pyridyl-1- etc.) chrysin, diosgenin, Vitex extract, diindolmethane, puer oxide)-N-t-butylnitrone, 3.35.5-tetramethylpyrroline aria mirifica (puresterol available from bio-botanica), B-sito N-oxide, and 2,4,6-tri-t-butylnitrosobenzene) may be used. sterol, B-stigmasterol, betulin and derivatives thereof, These agents are antioxidants as well as mitochondrial resus Conyza Canadensis essential oil, and maca extract standard citants, and therefore have this added benefit when incorpo ized to macamides. rated into the formulation of the present invention. 0094. Anti-acne agents may also be combined with the 0.098 D-ribose is a naturally occurring five-carbon sugar formulation of the present invention. Since both free radicals found-in-all living cells, and is a preferred mitochondrial and inflammation are induced by AGES and are also cofactors resuscitant. It is not an essential nutrient, since it can be made in acne, especially in adult skin, a combination with one or in the body from other Substances, such as glucose. However, more anti-acne ingredient may be Used in the topical formu the application of additional D-ribose can aid in preserving lation of the present invention. A non-limiting list of useful the youthful look of skin. D-ribose, in the form of ribonucleo unit-acne agents includes: (-)-epigallocatechin, (-)-epigallo side diphosphates, is converted to deoxyribonucleoside catechin-gallate, C-pinene, C-terpineol, anacardic-acid, aze diphosphates, precursor molecules for DNA. D-ribose in laic-acid, baicalein, berberastine, berberine, n-carotene, cam RNA and D-deoxyribose in DNA. When D-ribose is added to phor, caryophyllene, cryptotanshinone, B-cadinene, the formulation, it is particularly preferred to additionally Y-linolenic-acid, indole, linoleic-acid, nerolidol, pufa, pufas, include an AGE inhibitor to prevent the potential glycating pyridoxine, resorcinol, selenium, Sulfur, terpinen-4-ol, thy effect of d-ribose. mol, tin, propolis extract and zinc. 0099 R-lipoic acid is implicated in mitochondrial energy 0095 Other skin-protective lipids may be used as well; production and protection from free radicals. It has been these include ceramides, cerebrosides, essential fatty acids shown to maintain microsomal protein thiols, protect against and botanical or marine oils containing these, calophyllum hemolysis, protect against neurological disorders, and protect inophyllum squalene, squalane, botanical oils and butters against ischemia/reperfusion injury. R, not S-lipoic acid is Such as (shea butter, meadowsweet oil and coconut oil) produced by the body and decreases in concentration during phospatidylserine, spingolipids and natural materials con the aging process (Pick U., et al., Biochem Biophy's Res Com taining them Such as Conyza Canadensis, phospholipids and mun. 1995 Jan. 17: 206(2):724–30). The formulation of the sulfatet sterols available from Vincience may also be added to present invention replenishes this vital Substance as well as protect the skin. Another protective lipid is krill oil rich in provides protection to the skin cells. R-lipoic acid is incorpo omega 3 fatty acids and astaxanthin. This oil is preferably rated in the formulation in one preferred embodiment of the deodorized when used in the topical formulation. present invention. US 2014/0134222 A1 May 15, 2014

0100 Acetyl-L-carnitine has a three pronged anti-aging thol, berberastine, huperzine-a, menthone, (+)-piperitenone effect by being a mitochondrial energy boosting agent, help oxide, berberine, isomenthol, p-cymene, (+)-pulegone, car ing to boost acetyl-choline necessary for proper face muscle vone, isomenthone, piperitenone, 1,8-cineole, chellerythrine, tone and being an effective antioxidant. It is useful in the isopulegol, pulegone, akuammicine, d-carvone, 1-carvone, transport of long-chain fatty acids into the mitochondrial sanguinarine, akuammidine, d-limonene, 1-limonene, ter matrix, transport of short- and medium-chain fatty acids away pinen-4-ol, alpha-terpinene, elemol. 1-menthol, viridiflorol, from the mitochondrial matrix, and regulation of energy (+)-menthol, galanthamine, limonenc., yohimbine, (+)-piper metabolism through the modulation of acetyl CoA:CoA itenone-oxide, gamma-terpinene, menthol, and menthone. ratios. For this regulation, the acetyl group of acetyl CoA is 0105 Preferably, the ChE or AChE inhibitor-is-obtained transferred to L-camitine by carnitine acetyl-transferase from a plant source. Some preferred ChE or AChE inhibitors (CAT), freeing CoA to participate in the PDH reaction. The are: arecoline, choline, deoxypeganine, deoxyvasicinone, acetyl-L-carnitine can then be removed from the mitochon eseridine, galanthamine, iridin, irigenin, lecithin, lithium, dria. (Arrigoni-Martelli E, et al., Drugs Exp Clin Res. 2001; nicotine, nobiletin, physostigmine, pilocarpine, pro 27(1):27-49; Rebouche C.J. Carnitine. In: shills ME, et al.eds. nuciferine, and yohimbine. Nutrition in Health and Disease. 9th ed. Baltimore: Williams 0106 Huperzine, an alkaloid derived from the herb & Wilkins: 1999:505-512). This increase of free CoA relative Huperzia Serrata, is a preferred inhibitor of acetylcholinest to acetyl CoA, enhances the activity of pyruvate dehydroge erase (AchE) used in the present invention. Huperzine is nase (PDH) which catalyzes the conversion of pyruvate to useful in the forms huperzine A, huperzine B, 6-3-hydroxy acetyl CoA, a crucial reaction in glucose metabolism. (lpi. huperzine A, and tautomers thereof. Transdermal application oregonstate.edu/-infocenter/othernuts/carnitine/carniti of huperzine has been shown to improve memory and cogni nerefs.html#ref2) tive functions by adding huperzine with a permeation 0101 ATP, adenosine 5'-monophosphate (AMP), and enhancer to increase blood plasma levels of huperzine. (U.S. their degradation products may also be administered directly Pub. 2004/020705). Similarly, huperzine can be administered as agents in the topical formulation of the present invention. transdermally for the treatment of Alzheimer's disease (U.S. U.S. Pat. No. 5,227,371 teaches the oral or topical-adminis Pat. No. 6,352,715) and cholinergic deficient disorders (WO tration of AMP, ATP or their degradation products adenosine 2004 080436). In a preferred embodiment, the huperzine-a in and inorganic phosphate to increase ATP levels. Extracellular the topical formulation is encapsulated in a liposome or nano ATP has been shown to help regulate vascular tone (Burn SO. stock, G. and Kennedy, C Circa. Res. 1986, 58, 319-330), 0107 Galanthamine is a reversibly acting cholinesterase promote muscle contractions (Burnstock, G. Pharmacol. Rev. inhibitor and an acetyleholinesterase inhibitor; it is a tetracy 1972, 24, 509-581), and arresting tumor growth (U.S. Pat. No. clic alkaloid which was initially isolated from galanthus niva 5,049.372). When ATP or other agents susceptible to degra lis. Galanthamine has unique specific properties, for example, dation are used, a stabilized form of the agent is preferred. highly analgesic effects comparable to those of morphine, and is not as toxic as cholinesterase inhibitors such as phys Muscle Toning and Enhancing Agents ostigmine and neostigmine. The principal use in humans has been the postoperative reversal of neuromuscular blockade. It Cholinesterase Inhibitors and Acetyl-Cholinesterase has also been administered in a number of neuromuscular Inhibitors diseases, and has been shown to enhance activation of motor 0102 Cholinesterase (ChE) and acetyl-cholinesterase nerve terminals stimulated electrically, to increase ganglionic inhibitors (AChE) are partially useful as a component in the depolarization induced by acetylcholine, and to protect topical formulation of the present invention because of their against hexamethonium, indicating enhancement of the activ ability to augment the restoring of a youthful tone to the face ity of nicotinic receptors (U.S. Pat. No. 6,670,356). Galan muscles. In one preferred embodiment these ingredients are thamine may be isolated, for example, by the process used on the skin covering a facial muscle that tends to cause described in U.S. Pat. Nos. 6,617,452 and 6,573,376, from facial sagging due to the aging process or the antagonist of a either biological or synthetic material. facial muscle that can cause expression wrinkles causing the facial expression muscle to relax. Such method of facial shap Acetyl Choline, Choline, and Precursors ing is described with the use of injectable botulinum toxin 0108. Additional agents are also useful as muscle toning type A and in this invention these ingredients can be further agents. L-C. glycerylphosphorylcholine, citicoline (a stabi combined with dermorelaxant ingredients used in the formu lized CDPCholine (cytidine 5' diphosphocholine), or a stabi lation on different skin areas corresponding to the described lized form of citicoline (see U.S. Pat. Nos. 3,687,932 and facial muscles. (Stuzin, J Metal. Plastic and Reconstructive 6,057.301) may be added. Formulations having these agents Surgery 112(5) Suppl. October 2003 pp 19S-20S). are particularly useful when acetyl-l-carnitine is also (0103) The ChE inhibitor is preferably obtained from a included in the formulation since the added ingredients plant source. Preferred ChE inhibitors include, for example: enhance the effect of acetyl-l-carnitine and provide the skin (+)-carvone, demissine, 1-carvone, Solanidine, 1,8-cineole, with youthful amounts of acetylcholine to prevent sagging ephedrine, limonene-oxide, Solanine, actinidine, eseramine, and lack of tone to the face. lycorine, Solasodine, allicin, eseridine, palmatine, thymol. 0109 Alkanolamine such as ethylaminoethanol, methy C-chaconine, fenchone, physostigmine, Vasicinol, B-2-cha laminoethanol, dimethylaminoethanol (DMAE), isopro conine, galanthamine, pulegone, bufotenine, huperzine-a, panolamine, triethanolamine, isopropanol-dimethylamine, sanguinarine, d-carvone, huperzine-b, selagine, demissidine, ethylethanolamine, 2-butanolamine, choline, serine, and ibogaine, and serotonin. mixtures thereofare useful as additional agents in the present 0104 AChE inhibitors are preferably obtained from a invention. They have been shown to be useful for treating plant source. Some preferred AChE inhibitors are: (+)-men wounds. (U.S. Pat. No. 6,319,942). These compounds may US 2014/0134222 A1 May 15, 2014 increase acetylcholine levels in the skin, by affecting Smooth Matrix Metalloproease Inhibitors muscle contraction. DMAE is a particularly preferred alkano lamine. 0115 Matrix metalloprotease (MMP) inhibitors may also be added to the formulation of the present invention. MMPs 0110 Anti-elastase ingredients are also beneficial as addi are enzymes that play a major role in physiological and patho tional ingredients which enhance the formulas ability to firm logical destruction of connective tissue, especially collagen. the skin. These agents include, but are not limited to: PRO Most MMPs are thiols or hydroxyamates. Many MMPs are TEASYL(RTPLS8657 (from Laboratories Serobiologique), neutral zinc-dependent endopeptidases that selectively cata anthocyanins, caffeic-acid, isoquercitrin, procyanidin-a-2, lyze the hydrolysis of polypeptide bonds; they degrade and and quercetin. rebuild structural proteins in collagens and are required for 0111 Molecular film tensors for finning and lifting prod the healing of moist skin wounds. (Agren MS. Arch Dermatol ucts may also be used. To help target sagging of skin in Res. 1999 November: 291 (11):583-90). Increased concentra addition to tensing agents, ingredients can be included that tions of MMP 1 (collagenase 1, interstitial collagenase), 3. improve adhesion of cells to the basement membrane and (Stromelysin 1), 7 (Matrilysin, PUMP), 9 (Gelatinase B, 92 among themselves by enhancing synthesis of laminin V and kD gelatinase), and 12 (Macrophage metalloelastase) have integrin alpha 6. One such ingredient is Serilesine from Lipo been found in Sun-exposed skin. Additionally, increased lev tec. els of MMP-1 have been found in smokers. (Lahmann C, et al., Lancet 2001,357:935–936) AMP levels are also known to Collagen Enhancing Agents rise in fibroblasts as a function of age in both photoaging and natural aging. (Varani.J. et al., JInvest Dermatol. 2000 March; 0112 Collagen enhancing agents such as those described 114(3):480-6). Therefore the addition of inhibitors of MMPs, herein may also be added to the present formulation. Agents particularly MMP-1,3, 7, 9, and 11 in the topical formulation having Collagenic activities include the anthocyanidins, of the present invention is contemplated. MIVIP inhibitors ascorbic acid, asiatic acid (such as from centella asiatica), include the tissue inhibitors of metalloproteinases (TIMPs) aucubin, proanthocyanidins, stabilized vitamin C, the amino which are the natural inhibitors of MMP activity (Gomez, D. acids 1-lysine, l-proline and their derivatives (e.g., dipalmi E. et al. (1997) Eur, J. Cell Biol. 74:111) and include com toyl-hydroxy-proline, hydroxyproline, homoproline, and pounds such as Ilomastat (www.chemicon.com/Product). natural raw materials containing these such as apt (Ahnfeltia Other MMP inhitors useful in the topical formulation of the concinna) available from CIR).), and copperpeptides. Agents present invention include those described in U.S. Pat. Pub. having Collagenase-Inhibitor activities include the antho 2005OO58709. cyanidins, extracts of soy, extracts of apple, eicosapentaenoic acid, proanthocyanidins, procyanidins, bovine cartilage extracts and glycosaminoglycans from shark. Agents having Dermorelaxants Collagen-Sparing activities include caffeic acid, chloro 0116 Dermorelaxants, or myo-relaxants that relax the genic acid, cichoric acid, cynarin, and echinacoside. Each of muscles directly beneath the skin, may also be incorporated these may be used in addition to the lipoic acid, carnitine, and into the formulation of the present invention. These com carnosine of the present invention. Alternatively, collagen pounds relax the muscles and reduce wrinkles in the skin. itself may be added to the formulation such as in the form of Dermorelaxants include compounds such as myoxinol from collagen peptides (e.g. Active Collagen Polypeptide available cognis, boswellia extract and hexapeptides (available from from Shanghai UChem. Co. LTD.), soluble avian collagen or Lipotech, Spain) and may be incorporated into the formula in a form adapted for delivery to the skin so that the collagen tion of the present invention. Additional dermorelaxants will penetrate into the skin (e.g., the form described in U.S. include limonoids such as those described in U.S. Pat. No. Pat. No. 6,759,056). 6,866,856. Limonoids are plant alkaloids of the Maliaecae 0113 Additional collagen inducing-agents are growth family, such as toosendanin and azadirachtin, are particularly factors, such as EGF, FGF, TGF, TGF-B, HGH(offered in a useful for relaxing the facial expression muscles. Additional nanoliposome encapsulation by Regernon, NGF, KGF, TOP, myo-relaxant ingredients also include alverine and its salts natural Sources containing growth factors such as colostrums (e.g., alverine citrate), Sapogenins (e.g., diosgenin or diosge (PephaO Nutrix from Centerchem), deer antler preparations nin extract from wild yam), salts of manganese (e.g., manga and peptides designed to increase the production of any of nese gluconate), adenosine, the hexapeptide argireline R (LI these growth factors (e.g., SynR)-col from Centerchem-TGF POTEC), and SynR-Ake, a a synthetic tripeptide that mimics B, Hericium Erinaceus and Idebertone-NGF) or the produc the effect of Waglerin 1, a peptide that is found in the venom tion of collagen itself (e.g. Matrixy1300, Dermaxyl, and Cal of the Temple Viper, Tropidolaemus wagleri. See as described mosensine each from Sederma), and collagen peptides. in U.S. Pat. No. 6,866,856. Additional dermorelaxants Glucosamine, glucoseamine Sulfate, glucosamine HCl, glu include BosweloxTM which is a combination of boswellia cosamine ascorbate, chondroitin Sulfate and other glu Serrata extract and manganese (LOreal). In one preferred cosamine salts and derivatives may be used in the formulation embodiment the dermorelaxant ingredient(s) are used on the to induce collagen. N-acetyl-glucosamine can be used in one skin covering expression muscles or on the antagonist of a preferred embodiment. Manganese gluconate, a common facial muscle that tends to cause facial sagging due to the Source of manganese, may also be included in the formula aging process. Such method of facial shaping is described tion. The enzyme MnSOD is a powerful antioxidant that with the use of injectable botulinum toxin type a. (Stuzin, JM, removes Superoxide radicals. Plastic and Reconstructive Surgery 112(5) Suppl. October 0114. In one embodiment, a silicon, oran ortho silicic acid 2003 pp 19S-20S). described in U.S. Pat. No. 5,922.360 may be used. This ingre 0117. Other agents useful for relaxing the skin that may be dient may be used to boost collagen production. added to the present formulation include 3-O-acetyl-11-keto US 2014/0134222 A1 May 15, 2014

boswellic acid or plant extracts containing this compound crispus extract; chamomile extracts; green tea extracts; lactic (U.S. Pat. Pub 2004/0166178, herein incorporated by refer acid, pearl extract, Tricholoma matsutake extract, magne ence). sium-asorbyl-phosphate, edelweiss extract, Sedum acre extract, arbutine, ergothione, phyllantus emblica extract, Anti-inflammatory Agents C-MSH antagonists such as Undecylenoyl phenylalanine, germanium, and GABA and songyi mushroom. Bowman 0118. The free radicals associated with aging skin will Birk Inhibitors are described in U.S. Pat. No. 6,750.229 (e.g., often also induce inflammation in the skin and lack of skin inhibitors derived from the leguminosae, Solanaceae, immunity. Therefore anti-inflammatory agents including gramineae or cucurbitaceae family). Dermalight(R) and Clar NSAIDS, COX-2 inhibitors (e.g., nexrutine, ursolic acid, iskin3 ID from Silab are also depigmenting agents that can be quercetin, curcumine, and evodia extract. (Kang, S. S., et al., used. Kinetin (N6 furfuryladenine) is a 6-(R-amino)purine Nat. Prod. Sci., 1999, 5(2): 65-69.) can be included in the cytokinin and is described in U.S. Pat. Nos. 5,602,139, 5,164, formulation of the present invention. Ingredients for sensitive 394, and 5,021,422. It has been shown to have anti-aging skin including endorphin modulating ingredients and anti effects on the skin of dogs as well as the depigmenting effects irritants can also be added to the formula. Such one example without adverse effects. (Kimura T. Doi K. Rejuvenation is described in WO 98/07744 and U.S. Pat. No. 6,272,717 Res. 2004 Spring;7(1):32-9). 0119. In one preferred embodiment, the formulation com 0.122 Compounds having “anticapillary-fragility activity prises benfotiamine, pyridoxamine, pyruvate, biotin, and a may also be included as an additional ingredient. Capillary COX-2 inhibitor. This embodiment is particularly useful fragility can cause telangiectasia and spider veins. Further because of the combined properties afforded by these agents. more, AGES and free radicals can cause damage to the fine The pyruvate has a dual function of AHA-like exfoliation and vessels and induce telangiectasia or spider veins; therefore ATP-enhancement. Through co-carboxylase (from benfo this class of agents is also useful to augment the benfotiamine tiamne) and carboxylase (biotin), the pyruvate will convert to and pyridoxamine formulation. These agents include, but are Co-A. Benfotiamine is both an AGE inhibitor and a Co-A not limited to: aescin, aesculetin, aesculetol, aesculin, aescu facilitator. The COX-2 inhibitor is added to minimize any loside, dioSmin, escin, esculetin, esculin, hederagenin, hes potential stinging from the pyruvic acid or other AHA that peridin, hydroxyethylrutoside, hyperoside, inulicin, luteolol. may be included. maniflavone, neoruscogenin, patulin, procyanidin-a-2, quer cetol, quercetoside, rhamnetol, ruscogenin, rutin, rutoside, Other Agents and Xanthorhamnoside. Additionally, microcirculation 0120. An additional antioxidant that may be used in the decreases with age, especially around the eyes. Therefore this present invention is a phenylpropanoid glycosides. Martyno class is also beneficial and includes hydroxysuccinimide, side, a particularly preferred phenylpropanoid glycoside, chrysin(and other bilirubinolytic Substances Such as garde may be isolated from a number of botanical sources such as: nia, gardenoside, berberine) or ingredients containing Such Clerodendron trichotomum (apps 1..niaid.nih.gov/struct Substances eg Haloxyl from Sederma, Nattokinase, and Vita search/); the aerial section of Scutellariaponrica. (ErsoZT, et min K in its forms, including menaquinone-7. al., Turkish J. Chem. “Phenolic Compounds from Scutellaria I0123. In a preferred embodiment, liposomes made by the pontica”, which also provides the isolation of other phenyla process described by AGI Dermatics (New York) may be lkyloid glycosides); transformed root cultures of Catalpa used. These photosomes and ultrasomes are be useful in for ovata (Halina Wysokinska J, et al., Free Radic Res. 2003 mulations used to target DNA repair associated with photo August; 37(8):829-33); Pedicularis plicata (Liao R et al., aging and are described in U.S. Pat. Nos. 6,623,724 and Phytotherapy Research 1999 13(7):621-623; which also pro 6.479.533. A marine-derived photolyase, a DNA-repair vides the isolation of verbascoside); Pedicularis (Wang at al., enzyme from Anacystis nidulans plankton may be added to Sci China C Life Sci (1996)39(2):154-8; which also provides the formulation. These enzymes, encorporated into a lipo the isolation of the phenylpropanoid glycosides: echinaco Some (e.g., PhotosomeR) are adsorbed through the skin and side, Verbascoside, leucosceptoside A, and pediculariosides repair Sun-damaged DNA. Redness and Sunburn-cell-forma A, M and N). Their antioxidant Scavenging activities are tion may also be reduced or prevented by the addition of these similar to those of the o-dihydroxy group of phenylpropanoid enzymes. glycosides (Wang et al., Biochem Pharmacol (1996) 51(5): 0.124 Ethylenediaminetetraacetate (EDTA) or other metal 687-91). The addition of martynoside or verbascoside as an chelators are preferred antioxidants that can be included in ingredient in the formulation of the current invention is par the compositions. Plant tannins are also metal chelators that ticularly advantageous because these phenylpropanoid gly may also be included in the composition. The chelating agent cosides have been shown to reduce fatigue in muscle tissue. forms a complex with metal ions, inactivating them, and This allows for a relaxation and Smoothing in the overlying preventing them from affecting antioxidant activity. Other skin and reduces the signs of aging. (Liao R et al., Phyto chelators include, but are not limited to dihydroxyethylgly therapy Research 1999 13(7):62-623). cine, citric acid, tartaric acid, and mixtures thereof. 0121 Depigmenting agents may be added as an additional 0.125 Glutathione, reduced glutathione, glutathione per agent in the present invention. Depigmenting agents include oxidase, glutathione S-transferase or glutathione reductase tyrosinase inhibitors such hydroquinone and its derivatives may be incorporated in the formulation of the present inven (e.g., hydroquinone monomethyl ether, hydroquinone mono tion. Additionally, synergistic intracellular glutathione induc ethyl ether, arbutin), soy and derivatives thereof, retinoids ers and precursors of glutathione may be used. These include Such as retinol; Kojic acid and its derivatives (e.g., kojic ornithine, C.-ketoglutarate, 1-cystein, 1-glycine, 1-glutamatic dipalmitate); transexamic acid; vitamins such as niacin, Vita acid, glycyl-l-glutamine, n-acetyl-cystein, riboflavin, vitamin min C and its derivatives; azelaic acid; phytic acid, licorice; B6, parsley seed or seed extract, Sylimarin, and cysteine whey mulberry extracts; extracts from ramex species Such as ramex peptides. US 2014/0134222 A1 May 15, 2014

0126 Aldenine, which comprises a vegetal protein weight, preferably from about 0.1 to about 5% by weight, hydrolysate and a synthetic tripeptide, may be included in the based on the total weight of the preparation. formulation of the present invention. Aldenine is able to boost Collagen III production. V Topical Formulations 0127 Centrophenoxine (Lucidril.R.) is another agent that I0131 The formulations of the present invention may also may be added to the pyridoxamine and benfotiamine formu comprise pharmaceutically acceptable topical auxiliaries. lation. It contains both dimethylaminoethanol (DMAE) and Pharmaceutically acceptable auxiliaries are those which, as is p-chlorophenoxyacetate. DMAE is found in food and is also known can be used in the field of pharmacy, food technology a metabolite. pCPA is a synthetic compound related to plant and related fields, in particular, those listed in relevant phar hormones known as auxins. Centrophenoxine has been macopeia (e.g. DAB Ph. Eur. BP NF), and other auxiliaries shown to remove lipofuscin, a cellular residue that accumu whose properties do not impede physiological use. lates over the life of the cell. Additionally, it has been shown (0132 Suitable carriers include water, alcohols, oils and to have an effect as a cognition enhancer. (J. Am. Geriatr. Soc. the like, chosen for their ability to dissolve or disperse the (USA), 1978, 26:2, 74.41.) active ingredients at concentrations of active ingredients most 0128. In one embodiment, the topical benfotiamine and suitable for use in the therapeutic treatment. Generally, even pyridoxamine formulation is taken in conjunction with an low concentrations of active ingredients in the carrier will be oral Supplement containing one or more anti-glycation agent. Suitable, requiring only the more frequent application of the The added benefit of an oral Supplement containing one or topical composition. The present invention provides that the more anti-glycation agent has been demonstrated, for topically applied composition be formulated to contain at example, by Thirunavukkarasu V. et al., who demonstrated least about 0.001% up to about 80% by weight, more prefer that oral consumption of C-lipoic acid affects the content and ably from about 0.01% to about 20% by weight, and even characteristics of the protein collagen from skin of high more preferably from about 0.1% to about 5% by weight, of fructose fed rats. (Exp Diabesity Res. 2004 October-Decem a benfotiamine and at least about 0.001% up to about 80% by ber; 5(4):237-44.) Any AGE inhibitor suitable for oral con weight, more preferably from about 0.01% to about 20% by Sumption may be administered. One particularly preferred weight, and even more preferably from about 0.1% to about oral AGE inhibitor is carnosine. In one example, the oral 5% by weight of a pyridoxamine and, accordingly, carriers Supplement comprises a capsule containing 50-150 mg ben can be chosen which will solubilize or disperse the active fotiamine, 50-500 mg 1-carnosine, 25-150 mg pyridoxamine ingredients at Such concentrations. One particularly effica and 25-150 mg lipoic acid. cious embodiment contains about 2% by weight of a benfo 0129. The ingredients included in the oral formulation tiamine and 3% by weight of a pyridoxamine in a liposomal may also be nutrients for hair, skin and nails (including, for carrier. In another embodiment, the topically applied compo example, stabilized orthosilicic acid, biotin, hyaluronic acid sition is formulated to contain at least about 0.001% up to and essential fatty acids available from plant, animal and about 0.05% by weight, more preferably from about 0.01% to marine sources. Examples of these fatty acids include lipids about 0.05% by weight, of a benfotiamine and at least about such as fish oil and krill oil. Other ingredients include weight 0.001% up to about 80% by weight, more preferably from loss encouraging agents (e.g., carbogen (from Triarco), about 0.01% to about 20% by weight, and even more prefer hoodia gordonii extract, coleus forskholii extract, CLA, ably from about 0.1% to about 5% by weight of a pyridox 7-Beta-Hydroxy-DHEA, carnitine, cholecystokinin releas amine and a carrier. ing agents such as Satise (from Kemin) cognition enhancing 0.133 Suitable auxiliaries may be lubricants, wetting agents (acetyl-1-carnitine, citicholine, huperzine, DMAE, agents, emulsifying and Suspending agents, preservatives, Bacopa Monneiri extract, Sage extract, L-alpha Glyceryl anti-irritants, emulsion stabilizers, film formers, gel formers, Phosphoryl Choline, Ginko Biloba, Vinpocetine, DHA, noo odor masking agents, resins, hydrocolloids, solvents, solubi tropics including Phenyltropin, Pikatropin (from Creative lizers, neutralizing agents, permeation accelerators, pig Compounds). Other agents include sleep and mood enhanc ments, quaternary ammonium compounds, refatting and ing ingredients (e.g., melatonin, S-AME, GABA), probiotics, Superfatting agents, ointment, cream or oil base materials, stabilized probiotics such as Probiocap (Institute Rosell), silicone derivatives, stabilizers, sterilizing agents, propel antioxidants, energizing ingredients, libido enhancing ingre lants, drying agents, opacifiers, thickeners, waxes, emol dients, wellness enhancing ingredients and multivitamin and lients, or white oils. mineral combinations. The use of the benfotiamine and pyri I0134. According to the invention, the formulations are doxamine in conjunction with the oral formulation eliminates administered topically, to the area of skin that is to be treated. or decreases the potential glycation effects of these Sub The topical administration provides the AGE-inhibiting for stances (such as ascorbate and D-ribose or Pufas), allowing mulation to the skin. The composition is administered in a these nutrients to open their full beneficial potential. These Subject Susceptible to or having an accumulation-of-AGE, oral agents may be used, as appropriate (i.e., they must adsorb preferably a human being. It may be administered according through the skin) in the topical formulation as well. Alterna to a dosage and administration regimen defined by routine tively, topical agents as described hereinabove that have gly testing. cating effects may be taken orally, as appropriate nutraceuti I0135) In one embodiment, the topical benfotiamine and cals. pyridoxamine formulation is combined with iontophoresis to 0130. The additional agent can be used as the sole addi enhance permeation. In particular, iontophoresis using less tional active agent in the pyridoxamine and benfotiamine than 1000 LA, or more particularly less than 600 LA. In topical formulation. They also may be used in combination addition, this method of administering the topical formula with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more other agents. tion may be combined with additional oral pyridoxamine and The amount of additional agent in the preparation, alone or in benfotiamine Supplement, which is particularly contemplated combination, is preferably from about 0.001 to about 30% by for use by diabetic patients or where AGES/ALEs inhibition is US 2014/0134222 A1 May 15, 2014

particularly important for treating the skin, and where other 0142. One typical process is to dissolve the shell material uses for AGE/ALE inhibiting may be warranted. in a solvent (in the form of a colloidal or true solution) and to 0136. The area to which the formulation of the present disperse the core material in the resulting solution in the form invention is applied may be determined based on the type of of solids or microdroplets. This dispersion is divided into muscles underlying the skin. For example, the pyridoxamine microdroplets and then heated using, for example, hot air. and benfotiamine formulation containing a dermorelaxant During this process, the solvent evaporates and the shell may be preferably applied to skin that covers expression material re-precipitates in the form of solids and forms a shell muscles. Expression muscles include facial muscles (belly around the core material. This gives crude microcapsules, and muscle attachments). Alternatively, a formulations which can then be subjected to the customary processing including ingredients that have muscle toning properties steps and incorporated into the final formulations. This pro (AChE inhibitors, ChE inhibitors, anti-elastase properties cess utilizes the known phenomenon of coacervation. and/or molecular film tensors), the formulation is preferably 0.143 Another process of microencapsulation uses inter applied to skin areas covering muscles knownto Sagand loose face polymerization to create the microcapsule shell. In this their tone due to the aging process. In one embodiment, a method, precursors of the shell material, for example mono formulation including a dermorelaxant is applied to one part mers, are concentrated onto the core material, where they of the face while a different formulation containing a toning polymerize to give the final shell film. Fat-coating processes agent is applied to another part of the face, dependent upon also may be used. the underlying muscles. 0144. The materials used for microencapsulation are 0.137 While the carrier for the combination of benfo selected from conventional hydrophilic or hydrophobic sub tiamine and pyridoxamine can consist of a relatively simple stances or mixtures thereof. Solids, in particular natural poly Solvent or dispersant such as an oil, it is generally preferred mers for example, starch and other polysaccharides, are pre that the carrier comprise a composition more conducive to ferred. However, synthetic polymers can also be used. topical application, and particularly one which will form a Examples of shell materials are fats and/or waxes, preferably film or layer on the skin to which it is applied so as to localize those having a solidification temperature of approximately the application and provide Some resistance to perspiration, 35°-80° C. and include mixtures of cetyl palmitate and cetyl and/or one which aids in percutaneous delivery and penetra alcohol. Other compounds include polysaccharides and their tion of the active ingredients into lipid layers. Many Such derivatives of natural or partially synthetic origin, (e.g. cellu compositions are known in the art, and can take the form of lose derivatives); further, polymers of C- and/or B-hydroxy creams, gels, ointments, hydrogels, pastes or plasters, and carboxylic acids, in particular polymers of glycolic acid liquid dosage forms, such as Solutions, emulsions, in particu (polyglycolides), lactic acid (polylactides), C-hydroxybu lar oil-in-water emulsions, Suspensions, (for example, tyric acid (polyhydroxybutyrate), C.-hydroxyvaleric acid lotions, etc.), or even solid sticks. If desired, it is also possible (polyhydroxyvalerate) and/or their copolymers, or mixtures to use liposomes or microspheres. of such polymers and/or copolymers. 0.138. To prepare the dermatological compositions accord 0145 Independently of the specific technique for prepar ing to the invention, the active ingredients can be mixed or ing the microcapsules, it is preferred to carry out the process diluted with a suitable auxiliary (excipient). Excipients can be at a temperature which does not cause any of the components Solid, semisolid or liquid material which may serve as vehicle of the formulation to decompose or lose their antioxidant or carrier medium for the active ingredient. The other auxil activity. iaries, if desired, are mixed in the manner known to the person 0146 Similarly, nanoencapsulation may be used. skilled in the art. Nanoemulsions are metastable oil-in-water emulsions having 0.139. If desired, two or more active ingredients can be a globule size is less than 150 nm. They can be stabilized with formulated together. They can, however, also be initially pro amphiphilic lipids Nanoemulsions are structurally distinct cessed separately and then combined in a suitable dosage from microemulsions which are thermodynamically stable form. dispersions comprising micelles of at least one amphiphilic 0140. In one aspect of the present invention, the benfo lipid Swollen with oil and do not require mechanical energy to tiamine and pyridoxamine formulation is stabilized using be prepared. An advantage of using nanoencapsulation is the microencapsulation. Microencapsulation can protect the reduced need for surfactants, which may tend to lead to intol active agents from the Surrounding environment and increase erance and entailing a sticky feel when applied to the skin. the effectiveness as an antiaging agent since more agents will (See U.S. Pat. No. 6,562,356). remain active as the skin layer has been penetrated. Processes 0.147. In one embodiment, the formulation is encapsulated conventionally used for microencapsulation may be in cyclodextrine. Such process is performed, for instance, by employed, and may comprise encapsulation by nanosomes, the Wacker group. liposomes, or other vehicles known in the art. 0.148. In another embodiment, the formulation is encapsu 0141. The microcapsules may be prepared, for example, lated with NADH, R-DHLA, ATP, Glutathione and SOD in by coacervation techniques or by interfacial polymerization, Nano Spheres. Such process is performed, for instance, by for example, hydroxymethylcellulose or gelatin-microcap Salvona Technologies. In another embodiment, biopolymer Sules and poly(methylmethacrylate) microcapsules, respec nanoemulsions from Ivrea-Pak Tech are used to eliminate tively, in colloidal drug delivery systems (for example, lipo undesirable residue ('ghosting) commonly associated with Somes, albumin microspheres, microemulsions, nano porous particulate entrapment formulations. particles and nanocapsules) or in macroemulsions. 0149 One particular embodiment comprises the use of (Remington’s Pharmaceutical Sciences (A. Osol ed., 16th ed. novel dispersions of hydrophobes to yield a surfactant-free (1980)). Microencapsulation is particularly useful for formu formulation, by Subjecting the materials to high pressure, lations containing DHLA, which is prone to degradation and high shear processing. Cold process formulations are also a oxidation. preferred method as they protect certain heat-sensitive agents US 2014/0134222 A1 May 15, 2014

in the formulation; they can be obtained by using self-emul occurs after four or more weeks of treatment, where treatment sifying oleosomes such as Natrulon OSF available from refers to topical application at least once daily. Lonza. In one embodiment, the formulation is processed using the carriers and dry-water process of Aerosil R (De 0154 Each reference cited herein is herby incorporated by gussa), which is based on fumed silica or in a liquid formu reference in its entirety. lation trademarked AERODISP. (See www1.sivento.com/ wps3/portal/en/aerosil/industnes/personal.0.html). EXAMPLES OF TOPICAL COSMETIC 0150. According to the invention, the formulations are PREPARATIONS OF THE INVENTION administered topically in the form of a cream, gel, or liquid. The topical administration provides the benfotiamine and 0155 The following Examples are provided to illustrate pyridoxamine-containing formulation directly to the skin, the invention without being limiting in any way. which is preferably provided with the use of a dermatologi cally acceptable carrier. While the carrier may consist of a relatively simple solvent or dispersant, such as an oil, it is Example 1 generally preferred that the carrier comprise a material more conducive to topical application, and particularly one which 0156 will form a film or layer on the skinto which it is applied. This localizes the application and provides some resistance to perspiration and/or aids in percutaneous delivery and penetra tion of the active ingredients into lipid layers. Many Such Ingredient % by weight compositions are known in the art, and can take the form of creams, gels, ointments, hydrogels, pastes or plasters, and pyridoxamine 3.00 liquid dosage forms, such as Solutions, emulsions, in particu benfotiamine 2.OO lar oil-in-water emulsions, Suspensions, for example lotions, carnosine 1.OO etc., or even Solid Sticks. Liposomes or microspheres may astaxanthin 1.OO also be used. tocotrienols OSO 0151. In some embodiments, the topical formulation will tocopherols OSO be administered using a device or method designed to more readily break the skin barrier and provide the agents in the grape proanthocyanidins OSO topical formulation with a faster or more effective means E.D.T.A. (ethylenediamine tetracetic acid) O.OS through the stratum corneum. This nanosomal delivery includes, for example, oxygen nebulizers and nanosomal mist in conjunction with iontophoresis. A spray or nebulizer may be used to create the nanosomal mist. In one embodiment, the Example 2 micro-electronic cosmetic delivery mechanism described as PowerCosmeticsTM may be used for delivery of the topical O157 agent to the skin. This method is useful for delivering ioniz able compounds to the skin and aids the penetration of Small molecules through the stratum corneum. (www.powerpaper. com). Ingredient % by weight 0152 The method of the present invention is particularly pyridoxamine O.S benfotiamine O.2 useful for the prevention of skin damage which may result billberry anthocyanins 1.O from the formation of AGES. shark derived glycosaminoglycans 1.O 0153 Generally, the composition is topically applied to green tea polyphenols 2.0 the affected skin areas in a predetermined or as-needed regi tocopherols O.S men to bring about improvement, it generally being the case C. G-rutin 1.O that gradual improvement is noted with each Successive *o-G-rutin can be obtained from Toyo Sugar Refining Co.,LTD. Japan. application. The presence of AGEs in the skin can be deter mined by a relatively simple test. Since several AGEs exhibit fluorescence, a noninvasive autofluorescence reader can be Example 3 used to measure the relative concentration of these fluores cent AGEs in the skin. Therefore, the effectiveness of the 0158 AGE-inhibition properties of the topical formulation of the present invention may be measured. (Meerwaldt, R., et al., Ann NY Acad. Sci. 2005, 1043:290-8; Meerwaldt, R., et al., Ann NYAcad. Sci. 2005, 1043:911). Particularly, the concen Ingredient % by weight tration of AGEs in a certain location of the skin can be mea Pyridoxamine 1.O sured by fluorescence spectroscopy before treatment with the Benfotiamine 1.O formulation of the present invention. After treatment, the Lutein O.S Tetrahexyldecylascorbate 3.0 fluorescence is measured again and compared to the first Lycopene O.S measurement. The formulation may inhibit the formation of coenzyme Q10 (ubiquinone) O.1 AGES by reducing the AGE concentration by at least 20%, or Curcumine O.S more particularly 30%, 40%, or even more particularly 50%. In one measurement regimen, the second measurement US 2014/0134222 A1 May 15, 2014 18

Example 4 (ii) a pyridoxamine or a dermatologically acceptable salt thereof, and 0159) (iii) a dermatologically acceptable carrier; the pyridoxamine and benfotiamine components being incorporated in amounts effective in the treatment of Ingredient % by weight skin damage. 2. The composition of claim 1, which comprises compo Pyridoxamine 3.0 Benfotiamine 3.0 nent (i) in an amount of from about 0.001 to 80% by weight, Carnosine 3.0 based on the total weight of the composition. Carnosol O.O1 3. The composition of claim 1, which comprises compo aminoguanidine O.1 nent (ii) in an amount of from about 0.001 to 80% by weight, Tocotrienols O.1 Tocopherols O.S based on the total weight of the composition. retynyl palmitate O.S 4. The composition of claim 1, further comprising an anti tetrahydrocurcuminoids 1.O oxidant. (a curcumin derivative) 5. The composition of claim 4, wherein the antioxidant is selected from the group consisting of grape seed procyani dins, tocopherols, tocotrienols, astaxanthin, carnosol or car Example 5 nosic acid, macqui berry anthocyanins, billberry anthocya nins, blueberry anthocyanins, pomegranate extract, ellagic (0160 acid, honokiol, magnolol, silymarin, quercetin, maringenin, roSmarinic acid, clove essential oil, emblica extract, thiotau rine, acai extract, aronia extract, mangosteen and camellia Sinensis eXtract. Ingredient % by weight 6. The composition of claim 4, wherein the antioxidant is pyridoxamine 1.O an endogenous antioxidant or antioxidant enzyme selected benfotiamine 1.O from the group consisting of a Superoxide dismutase, glu pyridoxanine 1.O pyridoxal 5'-phosphate 1.O tathione, reduced glutathione, glutathione peroxidase, glu pyridoxamine 5'-phosphate 1.O tathione S-transferase, glutathione reductase, thioredoxin, thiamine 1.O NADH/NADPH, r-lipoic acid, R-dihydrolipoic acid, and catalase. 7. The composition of claim 1, further comprising an addi tional AGE inhibitor. Example 6 8. The composition of claim 6, wherein the additional AGE (0161 inhibitor is selected from the group consisting of carnosine, a carnosine derivate, a carnosine salt, a thiamine or a coenzy mated thiamine, thiamine pyrophosphate, pyridoxamine-5- phosphate and pyridoxamine-5-phosphate. Ingredient % by weight 9. The composition of claim 1, further comprising an pyridoxamine 1.O anthocyanin and a glutathione. benfotiamine 1.O 10. The composition of claim 1, further comprising a pyruvate 1.O hydroxylamine biotin 1.O 11. The composition of claim 10 wherein that hydroxy quercetin 1.O lamine is an anti-glycation agent and/or lipofuscin inhibitor. 12. The composition of claim 12 wherein the hydroxy 0162 This particular formulation is useful for the combi lamine is N-tert-butyl hydroxylamine. nation of the benfotiamine and pyridoxamine as discussed 13. The composition of claim 1, further comprising a spin above with pyruvate providing exfoliation and ATP-enhanc trap. ing activity. Additionally, through cocarboxylase (from ben 14. The composition of claim 1, further comprising an fotiamine) and carboxylase (biotin) the pyruvate would be acetyl-choline precursor or an acetylcholinesterase inhibitor. converted to Co-A and provide additional anti-aging activity. 15. The composition of claim 13 wherein the acetyl-cho The quercetin is added to minimize any potential stinging line precursor or acetylcholinesterase inhibitor is from pyruvic or other aha that may be included. Huperzine-A or an extract containing Huperzine-A. 0163 Having described the invention with reference to 16. The composition of claim 1, further comprising a der particular compositions, it will be apparent to those skilled in morelaxant. the art that it is not intended that the invention be limited by 17. The composition of claim 1 further comprising centro Such illustrative embodiments, and that the modifications can phenoxine be made without departing from the scope or spirit of the 18. The composition of claim 1 wherein the formulation invention, as defined by the appended claims. It is intended contains only natural or nature-identical ingredients. that all modifications and variations be included with the 19. The composition of claim 18, further comprising a Scope of the invention. botanical or plant-derived preservative. What is claimed is: 20. The composition of claim 1, further comprising a con 1. A topical composition comprising: tainer, wherein the container is airtight, the container Substan (i) a benfotiamine or a dermatologically acceptable salt tially blocks light between 450 and 720 nm, or a combination thereof; thereof. US 2014/0134222 A1 May 15, 2014

21. The composition of claim 1 whereas the components 26. The method of claim 23, wherein the composition are encapsulated in liposomes or nanosomes. further comprises an additional AGE inhibitor, 22. The composition of claim 1 further contains ascorbic 27. The method of claim 23, further comprising orally acidora derivative of ascorbic acid, wherein theascorbic acid administering an AGE inhibitor. is stabilized by encapsulation with emblica tannins, NADH, 28. The method of claim 23, wherein inhibition of the r-DHLA, glutathione, anthocyanins, or a combination formation of advanced glycation endproducts occurs after or thereof. concurrently with the oral ingestion or topical application of 23. A method of inhibiting the formation of advanced gly cation endproducts in the skin, said method comprising topi a Sugar, amino acid, or vitamin C derivative, wherein the cally applying to skin areas to be treated a composition com Sugar, amino acid, or vitamin C derivative is either prone to prising: glycation or has an oxidation product that is prone to glyca (i) a benfotiamine or a dermatologically acceptable salt tion or is itself a glycating agent. thereof; 29. The method of claim 23, wherein the composition (ii) a pyridoxamine or a dermatologically acceptable salt further comprises a dermorelaxant, and wherein the skin thereof, and areas to be treated are skin areas covering expression muscles. (iii) a dermatologically acceptable carrier; 30. The method of claim 23, wherein the composition the pyridoxamine and benfotiamine components being incor further comprises an ingredient having muscle toning prop porated in amounts effective in the inhibition of the formation erties wherein the skin areas to be treated are skin areas of advanced glycation endproducts. covering muscles known to Sagand loose their tone due to the 24. The method of claim 23, wherein the composition aging process. further comprises an antioxidant. 31. The method of claim 23, wherein the composition is 25. The method of claim 24, wherein the antioxidant is applied in a makeup. selected from the group consisting of grape seed procyani 32. The method of claim 23, wherein inhibiting the forma dins, tocopherols, tocotrienols, astaxanthin, carnosine or car tion of advanced glycation endproducts comprises reducing nosic acid, macqui berry anthocyanins, billberry anthocya nins, blueberry anthocyanins, pomegranate extract, ellagic the advanced glycation endproduct formation in the skin by at acid, honokiol, magnolol, silymarin, quercetin, naringenin, least 50%. roSmarinic acid, clove essential oil, emblica extract, thiotau 33. The method of claim 23, further comprising inhibiting rine, acai extract, aronia extract, mangosteen and camellia the formation of advanced lipoxidation end products. Sinensis eXtract. k k k k k