TW200817039A - Compositions and methods for skin lightening - Google Patents

Abstract

The invention relates to compounds and methods for inhibiting production and function of tyrosinase in the skin of a mammal. The invention further relates to compounds and methods for inhibiting darkening of the skin of a mammal, as well as lightening the skin of a mammal and reducing pigmentation in the skin of a mammal.

Description

200817039 IX. INSTRUCTIONS: [Background of the Invention] There are two different types of skin aging, because the aging caused by the genetic gene is called a genus, (internal) aging, and another type of aging is known as eve A.琢 search (external) old / 6 and is caused by environmental factors, such as exposure to the sun's rays. Internal aging, also known as natural aging, is a continuous process that generally begins in the middle of 2 years of age. In the skin, collagen is produced slowly, and elastin, the skin restores the original position of the substance, with a little less elasticity, dead skin cells will not fall off quickly and the renewal of new skin cells may be slightly reduced, although these changes are always in When we were in our twenties, the signs of natural aging were typically not visible for decades. The 4 signs of natural aging are · fine wrinkles, thin and transparent skin, resulting in reduced fat under the cheeks and bags under the eyes and a significant reduction in hand and neck firmness and dry skin that may cause itching, there are cells supplying the skin And reduction of blood vessels, there is also a flattening of the epidermal-dermal junction, which results in weak mechanical resistance at this joint, and as a result, older people are more susceptible to blisters in the case of mechanical trauma or disease processes. (0ikarinen et al., 199〇

Photodermatal· Photoimmunol· Photomed·, 7:3-4) 〇 Gene Control How fast the normal aging process begins. Several external factors, or external factors, act together with the normal aging process to age our skin early. Most of the early aging is caused by twilight exposure, and other external factors that age our skin early are repetitive. Facial expressions, gravity, sleeping position, and smoking. If sun exposure is not prevented, only a few minutes of exposure per day will lead to significant changes in the skin, freckles, age spots, vascular changes (diffuse red ecchymoses and vasodilatation, varicose veins), rough and Skin-like skin, 3 peels, fine wrinkles, loose skin, spotted skin, photochemical horn fiber (thick sarcoma of the skin, rough, red spots), pigmentation changes (d, view, and hypopigmentation) Hyperpigmentation of the hyperpigmentation area or) monthly keratotic keratinization, actinic keratinization, development of acne, cysts, elastic tissue, miscellaneous, atrophy, and skin cancer can all be traced back to twilight. In addition, protein saccharification is more common in photo-aging skin, ie ea_ire c·, etc.

Br J Dermatol. 2001 July; 145(1): 1〇,. Photoaging is a name used by dermatologists to describe this form of aging caused by exposure to the sun's rays. The development of photoaging is based on, 1) human skin color and illusory long-term or dense sun. The history of exposure is that people who are skin-skinned with a history of sun exposure have more signs of photoaging than those with dark skin. In the darkest skin, signs of photoaging are generally limited to fine wrinkles and variegated skin tone. Ageing occurs over several years, with repeated exposure to the sun, the ability of the skin to lose self-repair, and the accumulation of damage. Scientific research has shown repeated ultraviolet (UV) exposure surfaces (4) original and damage-induced quality = The sun will also attack our elastin. The skin weakened by the sun is more likely to stop bounce back from the skin that is protected from UV rays, and it is more relaxed with the unprotected skin exposed to the sun. And the signs of the aging of the raw sugar, which are visible overnight, are virtually invisibly located beneath the surface of the skin for several years. 'UV photography makes us see signs of photoaging. 6 years before the accumulation of damage on the surface of the skin. 6 200817039 When the skin ages, there is an increase in oxidative stress, an increase in inflammation, a decrease in collagen content, an excessive expression of enzymes, a protein glycation & Increased body attenuation. The additional aging method includes the self-consumption rate of the material leakage across the inner granular gland membrane, reduced film fluidity, and reduced content and function of cardiolipin. Granular glands, which are converted by drinking and others. The energy required for cell-induced ATP-producing cells is negatively affected by these aging processes. The oxidant produced by her glands has been shown to be the main source of oxidative damage in the glandular glands, which accumulates with age (eight brain BN, # , Biochim Biophys Acta. 1995 May 24; 1271(1): 165-70)〇# When the skin ages, the glands become severely damaged, which leads to a decrease in ATp production and greater oxidative damage. Acidase is necessary for the conversion of amino acid tyrosinase into melanin in the skin. When too much melanin is produced, it will cause excessive pigmentation. Components such as hydroquinone with glucose, tannic acid, and Aromatine inhibits or inhibits tyrosinase, which prevents the appearance of additional pigmentation. The skin color is formed by melanin, a natural pigment that also determines the color of the hair and eyes. In the skin, enzyme tyrosinase It relates to the biochemical pathway responsible for the conversion of amino acid tyrosinase into melanin, which occurs when excessive melanin is produced and formed in the deposition of skin. The cells that produce pigment are called melanocytes, which are located in the epidermis. At the bottom, melanocytes produce melanin granules, which are transmitted to other cells of the epidermis and up to the top layer of the skin. The synthesis of melanin occurs exclusively in melanin. When too much melanin is produced, deposition and hyperpigmentation occur. In the skin. 200817039, ammonia _ is a kind of _ plus monooxygenase, which catalyzes the single-age phase, the ortho-hydrolysis reaction of the ortho-diphenol (monophenolase or methylesterase activity), and the single 1 is the corresponding neighbor _ Awakening oxidation reaction (diphenyl expectantase or methylesterase activity). These functions of melanin to produce its lysinase are important in the formation of melanin powder, which is responsible for skin imperfections in black silk and plays an important role in preventing skin damage from being too entangled. However, melanin products are in the stomach and stomach. Cumulative causes of dark spots, brown spots, freckles, and age spots, which can be a serious aesthetic problem (Jeon et al. (2005) Bull. Κ_η Chem· S〇c Vol. 26·1135_1137 ).

Taking close to the global market demand & development of skin beauty agents, several kinds of road ammonia 曰 inhibitors have been used in the cosmetics industry as skin whitening agents, unfortunately. At noon, these inhibitors have not been proven to be clinically effective, when heart control, research pills are critically analyzed. 'So, many efforts are still being made to screen the skin whitening agents that have been tested and the correct research methods are effective. The development of the road ammonia system is important. Recently, these skin whitening agents have been tested for DOPA oxidation by (iv) acid conversion for commercial y, but these tests did not use human caseinase, and the domain was made up of human ammonia and acid. A comparative study of the inhibitory effect of skin whitening agents has not been completed. Natural plants (4) are extracts that exhibit interference with the process of causing melanin to appear on the skin to prevent excessive melanin and further discoloration. Although hyperpigmentation is typically not harmful to medicine, except in the case of certain skin cancers, this is a common clinical condition for many people seeking treatment because they are considered aesthetically unpleasant. Hyperpigmentation affects 200817039 People with skin color and ethnicity, and tend to increase with age, for example, almost all African-American babies become darker shortly after birth. Freckles anywhere in the body during the first or second decade of life, small, flat, brown to black spots become more permanent and increase with the number of sun exposures. It is often rumored that freckles turn black with sunlight and fade with less exposure to sunlight. Black cockroaches, known as age spots or liver spots, are small, motley or blackened skin spots that appear in older adults, especially in the faces of the individual who have been exposed to the sun, the back of the hand, And the arm. Hyperpigmentation also results from inflammation or other skin irritation, for example, skin conditions such as acne or banding may leave black spots. The courts that have suffered from skin injuries or surgery have also become hyperpigmented. Cosmetic procedures - which include laser mites, laser hair removal, and chemical peeling - also cause the affected area to be darker than normal. All of these conditions can be classified as postoperative inflammatory pigmentation. In addition to hyperpigmentation, many women suffer from dark spots, also known as brown spots, a hormone-like skin condition that is often obtained from birth control pills and/or pregnancy. Most of the black spots appear on the cheeks, foreheads, and temples of the face, but they also appear in the abdomen and other areas. There are several compositions currently available on the market to prevent and/or treat aging skin that is chronically aged and photoaged. Hydroquinone is a skin whitening agent that can be provided without a concentration of up to 2%, and can be as much as 4% of the concentration of the drug, however, hydroquinone is very irritating at high concentrations, long-term use can cause yellow brown disease, and is a tumor-producing in rats (Maeda and Fukada, J Pharmacol Exp Ther, 1996). 200817039 Phenylene is a kind of plant glycoside and skin whitening agent found in natural plants, Uva_Ursi (which also has antioxidant properties). The phenanthrene-glucose is a natural hydroquinone molecule attached to a sugar molecule (qj^O6), which makes it water-soluble. Hydroquinone with glucose helps prevent the formation of extra brown spots by stopping the production of black pigment. In particular, it is a melanin in the skin towel. On the side of the enzyme, UVa_Ufsi also contains three strong antioxidants, ferulic acid, caffeic acid, and chlorogenic acid. These antioxidants neutralize the oxygen free radicals that damage the skin. These three acids are also used as a kind of intermediate acid. It produces a double-faced _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _麴酉文 is a skin whitening agent produced by sputum sputum, which was found in the year-month. It has been used and shows excellent results from skin and brown spots. _ two ugly _, the collection of melanin in the formation of skin cells. Thyme is a vanilla plant inherent in the Mediterranean region. Thyme extract contains thyme, which has strong (iv) and antioxidant properties, and helps prevent cell oxidative breakdown. Thyme lysine inhibits the production of melanin by the inhibition of the mystery from the milk to 3,4_two silks ton _-), which is the first step in the biochemical pathway to form melanin. Importantly, 'Berry Spices harm melanocytes, and melanin synthesis occurs here. Cucumber, the bitter part of the strain contains cucurbitacin (forms A, b, c and D), which has traditionally been used to remove dark circles from the area under the eyes. 200817039 Despite the availability of these skin lightening agents, there is still an effective topical anti-aging formula that requires = 'and no limits' to treat hyperpigmentation, unwanted pigmentation, other related skin diseases, and skin damage. The utility. The present invention emphasizes and meets these needs. Summary of the Invention

A specific embodiment of the sputum m contains a method for inhibiting the activity of serotonin H in mammalian skin, which comprises administering a composition comprising meglumine to the extract. In one aspect, the composition further comprises a medically acceptable carrier. In another aspect, the composition further comprises at least one decolorizing agent, and in another aspect, the decolorizing agent is selected from the group consisting of capric acid, terephthalene, glucosamine, and N-ethylglucosamine. In another aspect, the '5 hai composition further comprises at least one additional active ingredient, which is based on old, reduced wrinkle remover, skin whitening agent, skin lightening agent, skin bleaching anti-moon spring cancer sputum, sebum reducing agent, and sunscreen The list of ingredients is selected. In another aspect, the mammal is a human. Another embodiment of the invention comprises a method of inhibiting the activity of benzalkonium oxidase comprising administering a drug comprising (iv) an amine conjugate to a mammal. In the aspect, the composition further comprises a pharmaceutically acceptable carrier. In another aspect, the composition further comprises at least one decolorizing agent, and in another aspect, the decolorizing vessel is selected from the group consisting of citric acid, d dextrose, and < In another aspect, the ^^ step further comprises at least one additional active ingredient, which is an anti-aging agent: a sensitizing agent, a skin whitening agent, a skin lightening agent, a skin bleaching sword, an anti-chokepox agent A list of sebum reducing agents and sunscreens is selected. In another: 200817039, the mammal is human. Another embodiment of the invention comprises a method of brightening the skin of a mammal comprising administering (4) a composition to a mammal. In the aspect of the composition, the composition further comprises a medical receiving carrier. In another aspect, the composition further comprises at least one decolorizing agent, and in another aspect, the decolorizing agent is composed of tannic acid, phenylidene glucosamine, and acetophene glucosamine. The list is selected. In the other-step-by-step, it contains at least a kind of lining sand, which is composed of fine anti-silk == less wrinkle agent, skin whitening agent, skin lightening agent, skin bleaching agent, anti-myomic tincture, sebum reducing agent, and sunscreen agent. The list is selected. In another aspect, the mammalian system is a human. Another embodiment of the invention comprises a composition for reducing pigmentation in the skin of a mammal, the method comprising administering a composition comprising an amine to a mammal. In one aspect, the composition further comprises a pharmaceutically acceptable carrier. In another aspect, the composition further comprises at least one decolorizing agent, and in another aspect, the decolorizing agent is selected from the list consisting of capric acid, hydroquinone, glucosamine, and N-acetylglucosamine. In another aspect, the composition further comprises at least one additional active ingredient which is resistant to ageing, wrinkle reducing agents, skin lightening agents, skin lightening agents, skin bleaching agents, anti-acne agents, sebum reducing agents, and sunscreens. The list of ingredients is selected. In another aspect, the mammal is a human. Another embodiment of the invention comprises a method of preventing skin blackening in a mammal' which comprises administering a composition comprising meglumine to the mammal. In one aspect, the composition further comprises a pharmaceutically acceptable 12 200817039 vector. In another aspect, the composition further comprises at least one decolorizing agent, and in another aspect, the decolorizing agent is selected from the group consisting of decanoic acid, terephthalic acid, glucosamine, and N-acetylglucosamine. In another aspect, the composition further comprises at least one additional active ingredient which is an anti-aging agent, a wrinkle reducing agent, a skin lightening agent, a skin lightening agent, a skin bleaching agent, an anti-acne agent, a sebum reducing agent, and a sunscreen. The list of ingredients is selected. In another aspect, the mammal is a human. Another embodiment of the present turtle includes a method of preventing melanin accumulation in the skin of a mammal, the method comprising administering to the mammal a composition comprising meglumine. In one aspect, the composition further comprises a pharmaceutically acceptable carrier. In another aspect, the composition further comprises at least one decolorizing agent, and in another aspect, the decolorizing agent is selected from the list consisting of capric acid, hydroquinone, glucosamine, and N-acetylglucosamine. In another aspect, the composition further comprises at least one additional active ingredient which is an anti-aging agent, a wrinkle reducing agent, a skin lightening agent, a skin lightening agent, a skin bleaching agent, an anti-acne agent, a sebum reducing agent, and a sunscreen. The list of ingredients is selected. In another aspect, the mammal is a human. Another embodiment of the present invention comprises a method of preventing browning of a fruit, the method comprising applying a composition comprising glucosamine to the fruit. Another embodiment of the invention comprises a method of preventing browning of a vegetable, the method comprising applying a composition comprising glucosamine to the vegetable. [Embodiment] The present invention is generally directed to compounds and methods for treating deleterious and/or undesirable conditions, which are directed to inhibiting the activity of at least one enzyme responsible for the deposition or staining of the skin responsible for the skin in mammalian skin tissue. Because it has now been discovered, as described in detail elsewhere, glucosamine inhibits the activity of phenanthryl oxidase, and tyrosinase and other tyrosinase enzymes. Unless he is determined by A, all technical and scientific names made here are the same as those commonly known to those skilled in the art, although any method and substance f described may be used in this month's month. Or testing, preferred methods and materials are described herein. With the use of the three places, each of the following names has the article in the section, and -(8)" or "one (four)" means one in this article (that is, it means that at least one sub-table cannot be over Yuan f silk - a yuan money (four) - a t ride,,, a ϋ ϋ 本文 本文 本文 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓Word, or _ miscellaneous - word; by relative to it: subcode, as shown in the table below, the full name of aspartic acid glutamic acid arginine arginine histidine

D E K R H

Asp

GJU

Lys

Arg

His 14 200817039 η

Tyrosine Tyr Cysteine / Cys Aspartic Acid Asn Glutamine Gin Serine Seric Acid Thr Glycine Gly Alanine Ala α-Amino Isovalerate Val Leucine Leu Isoleucine lie Methionine Met Proline Pro Phenylalanine Phe Tryptophan Trp Υ C Ν Qs

τ G A V L I Μ Ρ F W name, biological sample, when used herein, refers to a sample of living organisms that contains skin, hair 'tissue, blood, blood, cells, sweat, and urine. The term "clear, as used herein, refers to a physiological method of removing a compound or molecule, such as by diffusion, shedding, removal via blood, secretion in urine, or through other perspiration or other fluids. 'Compound', as used herein, means any form of substance or agent that is generally considered to be a drug, or a candidate for use as a drug, and combinations and mixtures thereof, or modified compounds. Or a derivative. "Disease" is an animal's state of health in which the animal is unable to maintain the balance of the body, and if the disease does not improve, the animal's health continues to deteriorate. When used herein, normal aging is included as a disease. The "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in this state the state of the animal's health is less favorable than the absence of the disorder. If left untreated, the disorder does not necessarily result in further deterioration of the animal's health status. A compound, an effective amount, or, a medically effective amount, is an amount sufficient to provide an effective effect on the individual of the desired pharmaceutical composition or to impart a medically effective appearance (e.g., in a cosmetic product). As used herein, "instruction material," includes a publication, a record, a figure, or any other representation medium that can be used in a traffic kit to tuse the usefulness of the amino acid of the invention to produce the reference herein. Various diseases or disorders _ slow. Alternatively, or alternatively, the instructional material may describe one or more methods of slowing the disease or disorder in mammalian cells or tissues. The instructional material of the kit of the present invention may for example Attached to a container containing the identification compound invention or shipped with a contained compound containing the identified compound. Alternatively, the instructional material may be shipped separately from the container for use as a guide material and a compound to be used by the recipient. The designation "amino acid" typically refers to a short polypeptide. "Field" as used herein, the designation "pharmaceutically acceptable carrier, means a chemical composition" suitable compound or derivative may be combined therewith and after combining It can be used to administer the appropriate compound to an individual. As used herein, the designation "physiologically acceptable," or "ester" or "salt" means an active ingredient, or a salt form, which is in any other form with the pharmaceutical composition.

200817039 parts are compatible, and it is not harmful to the drug to be administered. "Polypeptide" means a naturally occurring structural change associated with an amino acid residue, a related naturally occurring structural change, and its heterozygous non-self-initiating analogy linked by her bond, and its synthesizing A polymer composed of non-naturally occurring analogs.单 'Multi-core Wei' silk machine single-stranded or parallel and anti-parallel strands, so the polynucleotide can be single-stranded or double-stranded nucleic acid. The preventive treatment system is - noodles until the appearance of He (four) or only Treatment of an individual exhibiting early signs of disease to achieve the goal of reducing the risk of developing a pathology associated with the disease. The name "protein," typically refers to a large polypeptide. The name "skin, when listening to this article, the silk is defined throughout the skin, for example, the epidermis and dermis, and the cells, glands, mucous membranes, and connective tissue containing the skin. The same name "standard, when this article , silk shows the secret of comparison - some things. For example, it may be a known standard reagent or compound, when administered; 1 conjugate is shot and 峨, or a standard parameter or function for measuring two doses to a control value is measured. Function = when acting. "Standard" may also mean a type, an internal standard, or, for example, a reagent or a compound that has been added to a sample in the head and a sample thereof that is used for comparison with the squama or gas. Purify or extract the step by step. Internal standard _ common, but not limited to, if the radioactive isotope has been used to indicate that the impurity-purified label 1j is distinguished from the endogenous substance in the sample. 17 200817039 Synthetic amino acids or polypeptides" are meant to represent non-naturally occurring amino acids or oxime peptides, and synthetic, methionine or polypeptides can be synthesized using, for example, automated polypeptide synthesizers. Those skilled in the art are aware of various solid states. A method of synthesizing a retinoic acid. A therapeutic treatment is a treatment for the treatment of an individual who develops a symptom of the disease to achieve the purpose of reducing or eliminating these signs. The tooth-permeable skin is transmitted as a skin-penetrating (or The administration of the skin, and the transmucosal, that is, the passage of the drug through the skin or mucosal tissue and the passage into the bloodstream. Penetrating the skin also means using the skin as a drug to which the drug or compound is topically applied. Or the administration of a compound. The term "topical administration" as used herein refers to administration to a surface, such as the skin. This name can be used interchangeably with, dermal administration, and the name "treatment" as used herein. When it is used to reduce the frequency of patients or individuals experiencing symptoms or to administer a compound or compound to reduce the frequency of symptoms experienced in this article, ' Treating a disease or disorder, is indicative of reducing the frequency with which a patient experiences symptoms of a disease or disorder. Diseases and disorders are used interchangeably herein. I. Compositions The present invention relates to compounds and compositions, and compounds and compositions thereof. Use as a skin lightening agent. In one embodiment, the present compositions and compositions can be used to reduce total skin pigmentation. In another embodiment, the compounds and compositions of the invention can be used to reduce individual skin pigmentation For example, freckles, dark spots, and liver spots can also be used to reduce inflammation-induced pigmentation.

(, '

In an embodiment, the inhibitor composition comprises meglumine, or a salt thereof. In another embodiment, the inhibitor composition comprises a Portuguese, a derivative or an adduct. In another embodiment, the second composition comprises 1-deoxy-H-amino group > D-xylitol (DYN3〇). In another embodiment, the composition consists of meglumine. In another embodiment, the composition is (4) an analog, modification, derivative or addition of methylamine. In another embodiment, the composition comprises 1-deoxy-1-(methylamino)-D-xylitol (DYN3®). 200817039 The present invention comprises an inhibitor composition comprising meglumine, or a salt thereof, wherein the composition inhibits tyrosinase activity. In a specific embodiment of the invention, there is provided an inhibitor composition comprising meglumine, wherein the composition inhibits the activity of benzophenanthion oxidase. In a specific embodiment, the inhibitor composition comprises glucosamine, or money. In another embodiment, the inhibitory chelate comprises an analog, a modification, a derivative or an adduct of a meglumine comprising 1·deoxy·kappamethylglycolitol. For example, the composition consists of a further specific form of the meglumine group, a derivative system (IV) guanamine ugly, a == organism or an adduct. In another one, «_, the inhibition = compound contains 丨-deoxy-H methylamino group > D_xylitol _3 〇). Another specific embodiment of the invention provides a combination of inhibitors - a specific disaccharide inhibits the accumulation of melanin in the skin of a mammal. In the other /, gamma = inhibitor composition comprises meglumine, or a salt thereof. In another embodiment, the inhibitory chelate comprises a similar 19 200817039, modification, derivative or adduct of glucosamine. In another embodiment, the inhibitor composition comprises 1-deoxy-1-(methylamino)-D-xylitol (DYN3®). In another embodiment, the composition consists of meglumine. In another embodiment, the composition consists of an analog, modification, derivative or adduct of meglumine. In another embodiment, the inhibitor composition comprises 1-deoxy small (methylamino)-D-xylitol (DYN30). In one embodiment of the invention, an inhibitor composition is a decolorizing agent. In another embodiment, glucosamine, or a salt thereof, is a decolorizing agent. In another embodiment, an analog, modification, derivative or adduct of glucosamine is a decolorizing agent. In another embodiment, the inhibitor composition comprises 1-deoxy-1-(methylamino)_D-xylitol (DYN3®). In another embodiment, the composition consists of meglumine. In another embodiment, the composition consists of an analog, modification, derivative or adduct of meglumine. In another embodiment, the inhibitor composition comprises 1-deoxy-1(methylamino)-D-xylitol (DYN30). In another embodiment, a decolorizing agent may be added as an additional agent of the present invention, and the decolorizing agent comprises a tyrosinase inhibitor such as hydroquinone and a derivative thereof (for example, a desired monomethyl ether, a paraphenylene Monoethyl _, p-benzoquinone with glucose), glucosamine and N-acetyl glucosamine, and derivatives thereof, soybeans and their derivatives, vitamin A such as vitamin A; citric acid and its derivatives (such as strontium) Acid palmitate, tranexamic acid; vitamins such as niacin, vitamin C and its derivatives; azelaic acid; phytic acid, licorice; mulberry extract; extracts from the genus Syzygium, such as sorrel extract; Chrysanthemum extract; green leaf extract; lactic acid, pearl extract, Tricholoma matsutake extract, vitamin C phosphate town, 20 200817039 Alpine Edelweiss extract, Brassica extract, Arbutin, Camellia extract, α-MSH antagonist For example, enol phenylalanine, guanidine, and GABA and mulberry mushrooms. Bowman-Birk inhibitors are described in U.S. Patent No. 6,750,229 (e.g., an inhibitor from the genus Corydalis, Solanaceae, Gramineae or the Gypsaceae family). DermalightTM and ClariskinTM from Silab are also available as decolorants. Cain Court (N6-glycosylglycan) is a 6-(r-amino)u-counter cytokinin and is described in U.S. Patents 5,6,2,139, 5,164,394, and 5,021. , number 422. It has been shown to have anti-aging effect and decolorization effect on dog skin without negative effects (Kimura T., Doi Κ" RejuvenatiQn

Res· 2004 Spring; 7(1): 32-9). The compositions of the present invention are those suitable for application to human skin in accordance with the methods of the present invention, optionally comprising a further skin benefit agent, suitable additional skin benefit agents comprising an anti-aging agent, a wrinkle reducing agent, a skin lightening agent, Anti-acne agents, and sebum reducing agents. These examples include: hydroxy acid, beta-hydroxy acid, polyhydroxy acid, betulinic acid, hyaluronic acid, hydroquinone, dibutyl hydroquinone, vitamin Β derivatives, vitamin C derivatives, allantoin, placenta Diacids, vitamins, and resorcinol derivatives. A solderable agent can be used as a diluent, dispersant or dough for the beneficial components of the skin of the composition towel to promote the distribution of these ingredients when the compound is applied to the skin. ° The vehicle can be aqueous, anhydrous or emulsion. Preferably, the composition is aqueous or in the form of a water-in-oil or oil-in-water, preferably an oil-in-water emulsion. The water may be present in an amount ranging from 5 S to 99%, preferably from 20 to 70%, most preferably between 4 and 7 % by weight. Other acceptable carriers useful in soils ',, 200817039 include, but are not limited to, glycerin, water, physiological saline, ethanol, and other pharmaceutically acceptable salts of tetrahydrogenates such as acid salts and organic acids. Examples of these and other medical acceptance aspects are described in Remingtons Pharmaceutical Science (1991, Mack Publication Co., New Jersey). In addition to water, a relatively volatile solvent can also be used as the carrier in the composition of the present invention, preferably as a CjC:3 alcohol monohydrate, which comprises ethanol, methanol and isopropanol. The amount of monoalcohol monohydrate may range from hydrazine to hydrazine, preferably from 10 to 5 % by weight, most preferably between 15 and 40% by weight. Samarium sulphate can also be used as an acceptable carrier, which can be in the form of an oxime oil and a synthetic resin. The softening agent may vary anywhere from 1 to 5 % by weight, preferably between 丨 and 2% by weight. Iridinone / can be divided into volatile and non-volatile. As used herein, the name "," is used to mean which substances have a measurable vapor pressure at atmospheric temperatures. The volatile ketone oil is preferably derived from a cyclic or linear polydimethyl thief containing from 3 to 9 daisy atoms, preferably from 4 to 5 cerium atoms. Linear Volatile Stones = Substance - generally has a viscosity of less than about 5 cents towed, but the ring has a viscosity of less than about 1 Torr. The non-volatile gas ketone oil used as a softening substance comprises polysilax oxy-fired, poly-fired aryl sulphur-oxygenated gas, and rich in oxygen. Here, _ = oxygen, for example, a polymethyl oxane having a viscosity of from about 5 to about 25 million 'c, in the preferred non-volatile softener for use in the compositions of the present invention is viscous About 1 〇 to about 4 〇〇 拖 于 乃 乃 乃 乃 乃 乃 乃 乃 乃 乃 乃 乃 乃. , 22 200817039 Γ,.

The softening of the s oxime is (1) an alkenyl group or a silk 贞 of a fatty acid having 1 〇 to 2 碳 carbon atoms, and examples thereof include isopentyl succinic acid, isodecanoic acid, and meat. Stem Wei oil _ _, hard linoleene _, and oleic acid oleyl vinegar, ether marriage, such as B - the fat of the fat alcohol, (3) polyterpene esters 'ethylene glycol mono- and di-fatty acid esters Classes, diethylene glycol mono- and di-fatty acid noodles, polyethylene glycol (fine_6_)- and two-fat coffee, propylene glycol- and di-fat _ target, propylene glycol L-monooleic acid _, polypropylene glycol-2_ Mono-oil, B-(4) two-material hard fat turtle, glyceryl-di-di-fatty acid vinegar, polyglycerol poly fat noodle, ethanol glycerin, hard fat, purpose, 1,3 · Ding Alcohol monostearic acid 0, with butanediol distearate, water, oxygen, ethylene glycol fatty acid, sorbitan fatty acid vinegar: and polyoxyethylene sorbitan fatty acid Satisfactory polyol vinegar '(4) _ for example, natural Wei, medlar, fourteen stalk vinegar, stearic acid stearin _ and twenty-two burning twenty-six, (10) alcohol, of which Fatty acid from the purpose of the class as an example . Fatty acids having 10 i 3 (M solid carbon atoms may also be included as cosmetically acceptable conjugates of the compositions of the invention, examples of which are citric acid, lauric acid, myristic acid, palmitic acid, stearic acid, iso-hard Fatty acid, stearic acid, oleic acid, linoleic acid, oleic acid, peanut-acid, twenty-two ship and boundary acid. ^%%-form of the tonation can also be used as a cosmetically acceptable composition of the present invention. Carrier, sorption _ help to increase the effectiveness of the softener, reduce the disease, stimulate the accumulation, fine removal and improve the catch. The formula alcohol contains glycerin, polyglycol and more preferably olefin diol and its touch, Containing propylene di-, dipropylene glycol, polypropylene glycol, polyethylene glycol and its derivatives, Yamanashi 23 200817039 Sugar alcohol, propyl sorbitol, hexanediol, 1,3-butanediol, 1, 2 6-hexanediol, ethanol esterified glycerol, propanol esterified glycerol and mixtures thereof. For best results, the moisture absorbent is preferably propylene glycol or sodium hyaluronate. The amount of moisture absorbent can range from 0.5 to 30. Any range of %, preferably between 1 and 5% by weight of the composition. Thickeners may also be used as the composition according to the invention In part, typical thickeners include crosslinked acrylates (eg, Kappa 982), hydrophobically modified I acrylates (eg, Kappa 1382), cellulose derivatives, and natural gums. Useful in the field of methyl cellulose, carbaryl, propyl cellulose, ethyl cellulose, ethyl cellulose. Suitable for this hair _ days _ containing guar, Huangyuan Glue, white fungus, carrageenan, pectin and a combination of these gums. The amount of thickener can range from _01 to 5%, generally from 0.001 to 1%, optimally between 〇·〇 1 to 0. 5 wt%. (J collectively, water, solvent, linaloic acid, vinegar, fatty acid, sputum and/or thickener may be from 1 to 99.9%, preferably from 80 to 99. The amount by weight of the composition constitutes an acceptable carrier. The oil or oily substance may be present together with the emulsifier to provide a water-in-oil emulsion. The emulsification used in this sub-domain may also be present in the present invention. The total concentration of the surfactant ranges from 〇1 to 4π〇/1 main 40/°, preferably from 1 to 20%, most preferably from 2 to 5%. The surfactant can be selected from the group consisting of anions, heteros, cations and two steep activators. The best surfactants are those of the 2008 20087039 and some of the Ethylene Ethylene or Ethylene C with 2 S 100 Moules. a C1GC2G fatty alcohol or acid hydrophobic compound condensed with a hydrophobic compound; a qcw-based alcohol condensed with from 2 to 20 moles of an olefin oxide; a mono- and mono-fatty acid ester of ethylene glycol; a fatty acid monoglyceride Ester; sorbitan, mono- and di-QC8 fatty acids; block copolymers (epoxyethylene oxide/propylene oxide), and polyoxyethylene sorbose rides and combinations thereof. Silk Town Poly (4) and Home Sugar Fatty amines such as methyl glucosamine are also suitable nonionic surfactants. Preferred anionic surfactants include soap, alkyl ether sulfate and sulfonate, alkyl sulfate and pyruvate, alkyl benzene sulfate, alkyl and dialkyl sulfosuccinate, C8C2G fluorenyl Isethionate, mercaptoglutamic acid, C8c2 alkyl ether phosphate, and combinations thereof. Other accompanying secondary ingredients may also be incorporated into the compositions of the present invention, such as coloring agents and/or pigments, opacifiers, perfumes, other thickeners, plasticizers, calamine, antioxidants; chelating agents; An additional sunscreen, such as an organic sunscreen. These other accompanying minor ingredients are in any amount from the range of (8) 1% up to 20% of the composition reset, for use as a sunscreen, the metal oxides may be used alone or in admixture or combined with an organic sunscreen Examples of organic sunscreen agents used include, but are not limited to, benzophenone _1 (uvinul 400; BASF Chemical Company), benzophenone _2 (uviNULD-50; chemical company), benzophenone-3 (UVINUL M- 40 ; BASF Chemical Company), benzophenone-4 (UVINUL MS_40; BASF Chemical Company), benzophenone-6 (UVINUL D-49; BASF Chemical Company), benzophenone -8 (SPECRA_SORB UV- 24; American Cyanamide), dimercaptoketone-12 (UVINUL 408; BASF Chemical Company), methoxycinnamate 25 200817039 (BERNEL HYDRO; Bernel Chemical), ethyl dihydroxypropyl-PABA (AMERSCREEN P; Amerchol Corp.), glyceryl PABA (NIPA GMPA; Nipa Labs), methyl salimentol (KEMESTER HMS; Hunko Chemicals), methyl benzoate (SUNAROME UVA; Felton Worldwide), octoline (UVINULN_539; BASF) Chemical company), octyl dimethyl PABA (AMERSCOL; Amerchol Corp.), oxime meat Octyl cinnamate (PARSOL MCX; Bemel Chemical), octyl salicylate (SUNAROME WMO; Felton Worldwide), PABA (PABA; National Starch), 2-phenylbenzimid-5-thereic acid (EUSOLEX 232; EM Industries), TEA Salicylate (SUNAHOME W; Felton Worldwide), 3-(4-methylbenzylidene)-camphor (EUSOLEX 6300; EM Industry), 40 isopropyldiphenylmethane (EUSOLEX 8020; EM industry), butyl decyl benzophenone (PARSOL 1789; Givaudan Corp.), elerichin (UVINULN-35; BASF Chemical Company). The amount of organic sunscreen agent in the composition is preferably at about 1 weight. It is in the range of about 10% by weight, more preferably in the range of about 5% by weight to 5% by weight. As will be appreciated by those skilled in the art, the compositions useful in the present invention may comprise an active ingredient when disclosed as disclosed herein. Alternatively, compositions useful in the present invention may comprise at least two active ingredients. On the one hand, multiple heterogeneous components can be paired to live. On the one hand, the multiple active ingredients can be activated in a synergistic manner, that is, the multiple active ingredients in the compositions of the present invention can provide a greater additive effect than the medical effects provided by each of the active ingredients alone. Medical effect. 26 200817039 Composition and administration method η υ The present invention relates to the administration of an identified compound in a pharmaceutical or cosmetic composition for carrying out the method of the invention, the composition comprising the compound or a suitable derivative or analog of the compound and a pharmaceutical Accept the carrier. For example, a chemical composition which is a suitable inhibitor of at least one of tyrosinase, benzoin oxidase, aloinase, and benzo-di-g-oxygenase, is a pure drug of the appropriate compound To the animal. The present invention should be constructed to include one of the inhibitors of lysinase, phenodiene oxidase, tyrosinase, and benzene-like, 妓 more than one while = more than one used In the case of inhibitors, they can be administered or they can be administered individually. In a specific embodiment, a pharmaceutical composition for practicing the present invention can be administered to deliver a dose between 1 ng/kg/day and (10) mg/kg/day. In another embodiment, a pharmaceutical composition (10) for use in the practice of the present invention can be administered at a dose of 丨Nick/対/day and (10) gram/room. The pharmaceutical composition may be prepared, packaged, or sold in the form of a bactericidal injectable aqueous or oily suspension or solution. The suspension or solution may be formulated according to known techniques and may contain additional ingredients in addition to the active ingredient, for example A dispersing, wetting, or suspending agent as described. Such bactericidal injectable formulations may be prepared using non-toxic parenterally acceptable diluents or solvents such as water or 1,3-butanediol 'preparation' with other acceptable diluents or solvents, but are not limited to Ringer, s solution , physiological saline solution, and such as synthetic mono- or di-glycerides. 27 200817039 9 Pharmaceutical compositions useful in the methods of the present invention may be suitable for use in oral, topical, buccal, ocular, or another route of administration. 22 Preparation, packaging, and/or sale. Other contemplated formulations include non-rice granules, liposome preparations, re-closures containing the bismuth component, hemocytocytes, and immunologically based formulations. The compositions of the present invention can be administered via a number of routes including, but not limited to, a parenteral, topical, buccal, or ocular, route of administration. It is obvious that these two factors are based on several factors, including the form and severity of the disease to be treated, the beast or human being, the age and age, and the like. A pharmaceutical composition having a method for the present month can be formulated with an oral solid, 1 eye, a gas-transfer, a topical or other similar formulation, and a drug in addition to a compound such as heparin sulfate or its biological equivalent. : Such pharmaceutical compositions may comprise peony and other ingredients known to enhance and promote drug administration. Other possible formulations, such as nanoparticles, microlenses, blister-bound red blood cells, and systems with immunofilaments, can also be used to administer compounds in accordance with the methods of the present invention. Compounds identified for use in any of the methods described herein can be formulated and (4) to mammals for treatment of skin aging and skin related conditions as described herein. The present invention comprises the preparation and use of a pharmaceutical composition comprising a compound for the treatment of various skin-related conditions (including skin aging and photoaging) as described herein, which pharmaceutical composition may comprise only active ingredients, which are suitable for use In the form of administration to an individual, or the pharmaceutical composition may comprise 28 200817039 at least one active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or a combination of some of these. The active ingredient may be in the form of a physiologically acceptable ester or salt, e.g., in combination with a physiologically acceptable cation or anion, in a pharmaceutical composition, as is well known in the art. The disorder of local administration of the pharmaceutical composition is the stratum corneum of the epidermis, which is the southern obstruction I, which is shouted by protein, cholesterol, scorpion, free fatty acids and various other fine substances, and contains the cells. And living cells. One factor limiting the rate of penetration of a compound through the stratum corneum is the amount of active substance that can be loaded or applied to the surface of the skin. The greater the amount of active applied per unit area of the skin, below the surface of the skin and under the skin. The greater the concentration gradient between the layers, and the greater the active material f through the skin, the greater the concentration of the active substance, the more active the substance may be, the more likely the active substance penetrates through the skin, and especially The rate of fixation is equal to that of other formulations with a lower concentration. The formulations of the pharmaceutical compositions described herein can be prepared by any of the methods known in the pharmaceutical arts or developed thereafter, and such preparations involve the encapsulation of the active ingredient with the carrier or - or more of its components, and Next, if necessary or desired, the step of forming or packaging the product is the desired unit or unit. While the conflation of the pharmaceutical compositions provided herein is primarily related to the suitability of the person for aesthetic administration to a human pharmaceutical composition, it is well known to those skilled in the art that such compositions are generally suitable for secret distribution to all types of animals. It is well known to modify pharmaceutical compositions suitable for administration to humans such that compositions useful for administration to various animals are well known, and generally have technology 29 29170039. The medical practitioner can design and execute using only ordinary experiments (if needed). Such improved pharmaceutical compositions for administration of the present invention include, but are not limited to, humans and other primates, including mammals of commercial-related mammals such as cows, pigs, horses, sheep, cats, and dogs. The pharmaceutical composition for use in the method of the present invention may be prepared, packaged, or formulated for oral, direct, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ocular, intracytolic or other routes of administration. Or, the other desired formulation comprises a planned nanoparticle, a liposome preparation, a heavy red blood cell containing the active ingredient, and a formulation of an immunofilament. % The pharmaceutical compositions of the present invention may be prepared, packaged, or sold in a single unit dose, or in a plurality of single unit doses 1. As used herein, the unit dosage is the amount of individual n-components of a pharmaceutical composition comprising a predetermined amount of active ingredient - the amount of active ingredient that can be administered to an individual or the convenience of such a dose. The ratio is, for example, one-half or one-third of such a dose. The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any of the external ingredients in the pharmaceutical compositions of the present invention may vary depending on the identity, size, and condition of the individual being treated, and further depending on the route of administration of the composition. As a general example, a 5 liter composition may contain between 1 (8)% by weight of active ingredient. The pharmaceutical composition of the present invention may further comprise or more additional pharmaceutically active ingredients in addition to the active ingredient. The controlled release or sustained release formulations of the pharmaceutical compositions of the present invention can be made using conventional techniques. 30 200817039 Formulations suitable for topical administration include, but are not limited to, liquid or liquid, biliary, emulsified, oil-in-water, oil-in-water emulsions such as rituals, and solutions or secrets. The topical dosage may comprise (iv) from 1% to about 1% by weight of the constituents, although the active ingredient may be as long as the riding age limit. For the topical administration, one or more additional components are recited herein. Infiltration enhancers may be used which increase the rate of penetration of the drug through the skin. Typical enhancers in the art include ethanol, glycerol monolaurin, PGML (dodecyl phthalate), Dimethyl sulfoxide, and its analogs. Other strengthening vessels include returning, riding, ethoxylated triethanol, laurel, alkyl carboxylic acid, dimethyl hydrazine, polar lipids, or hydrazine methyl hydrazine. An acceptable carrier for the topical delivery of some of the compositions of the present invention may comprise a liposome. The liposome compositions and their use are known in the art (for example, see constanza, U.S. Patent No. 6,323,219). ~ The active ingredient surface to be formulated depends on the specific compound form, and the small organic molecules and the amino acid or oligomer fragments can be chemically synthesized and provided in a pure form suitable for medical/cosmetic purposes. The product of the natural extract is purified according to techniques known in the art and the recombinant source of the compound is also available to those skilled in the art. In an alternative embodiment, the topical active pharmaceutical or cosmetic composition can be remotely selected with other ingredients such as wetting agents, cosmetic adjuvants, antioxidants, chelating agents, skin bleaches, skin lightening agents, tyrosinase Inhibitors and other decolorizing agents, surfactants, foaming agents, conditioners, fish attractants, wet 200817039 agents, emulsifiers, fragrances, tackifiers, buffers, antiseptic sunscreens and the like combination. In another embodiment, a penetration enhancer or introduction enhancer is included in the composition and is effective to improve penetration of the active ingredient into the perforating stratum corneum, relative to a composition lacking the penetration enhancer. Various permeation enhancers' which are known to those skilled in the art - eucalyptol, ethoxyethylene glycol, laurel, ruthenium, dimethyl sulphur, polar lipids, or hydrazine Methyl bismuth is slightly the same. On the other hand, the 兮= compound can further comprise a water-soluble _, which is made to increase the irregularity in the horn/belt structure, and thus allows the increase over the stratum corneum to be conveyed: various water-soluble aids Agents such as isopropanol, propylene glycol, or sodium xylene sulphate are known to those skilled in the art. The compositions of the present invention may also comprise an active amount of a vitamin (i.e., any compound that is linked to a vitamin to the stomach) which comprises, for example, vitamin A acid, vitamin A, vitamin: acid and/or Or esters of vitamin A and their analogues. The pharmaceutical or cosmetic composition of the u"Hui Bureau activity shall be administered in an amount effective to effect the formation of the skin. When it is herein, "effective amount" shall mean an amount sufficient to cover the surface area of the skin from which the slave is produced. The active compounding amount is present in an amount of the composition, more preferably, the amount of the composition is present in an amount of from 5% to about 5% to about 5% of the composition, and most preferably, it should be: Approximately 5%, % to about 1% of the composition is present. Such a composition may be: synthetic or naturally obtained. ... mouth = liquid derivative made from biological sources and natural extract = from = to about 99% of the concentration (weight/volume) is used in the composition of the present invention, and the fraction of the day subtractive and the -inhibitor may have a different preferred range from about 001% to about 32 200817039 20% and, more preferably, From about i% to about 1% by weight of the composition. Of course 'mixtures of the active agents of the invention may be combined and used together in the same formulation, or in a series of different formulations. The compositions of the invention may comprise self-approximately 0.005% to about 2.0% of the total weight of the composition of the preservative, the preservative is used to prevent in the case of aqueous glue Corrosion caused by repeated patient use when exposed to contaminants in the environment from exposure to air or patient skin, including contact with a finger used to administer a composition of the invention, such as a medical gel or cream. Permissible examples of preservatives useful in accordance with the present invention include, but are not limited to, preservatives selected from the group consisting of stilbene, sorbic acid, p-benzoic acid esters, imidazolidine ureas, and combinations thereof. A combination of from 5% to about 2.0% benzyl alcohol and from 0.05% to about 0.5% sorbic acid. The composition preferably comprises an antioxidant and a chelating agent which inhibits the use of the aqueous gel formulation for the compounds of the invention. Degradation, preferred oxidizing agents for some compounds are Βητ, bha, alpha tocopherol and ascorbic acid in a preferred range of from about 1% to about 3%, and more preferably in the range of from 3% to 〇1% by weight. Preferably, the chelating agent is present in an amount from 1% to 5% by weight of the total composition of the composition, and the preferred chelating agent comprises an edetate (e.g., edetate II) Sodium) and citric acid in about 1% to 〇·2〇% by weight The weight range of the total weight of the composition and more preferably from 002% to 1% by weight of the composition to the weight range '5 chelating agent is used to chelate the metal in the composition which is harmful to the use period of the formulation. Ions, and some of the compounds and sedatives are particularly good antioxidants and chelating agents, and can be replaced by other suitable and equivalent antioxidants and chelating agents, as is well known to those skilled in the art 33 200817039 It is also known to use controlled release formulations and methods of using such formulations, as is well known to those skilled in the art. In some cases, the form of administration to be used may be, for example, propylmethylcellulose, other polymerizations. System, condensate, osmotic membrane, osmotic system, multi-layer coating, microparticles, microlipids, or microspheres or combinations thereof to provide sustained release η ο controlled release type or more active ingredients provided to use varying The ratio provides the desired data. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use in the pharmaceutical compositions of the present invention. Thus, single tablets, dosage forms such as controlled release tablets, capsules, gelatinous, and long tablets suitable for oral administration are included in the present invention. The object view type (4) product shape good (4) release type relative, to achieve the common goal of music therapy. Ideally, there is a minimum amount of medicine: including extension; giving = two days of obedience. In addition, controlled release formulations can be used to affect the timing of the game or other characteristics, such as blood drug levels, and the occurrence of side effects. Han Yu j’s desire for the grain is immediately produced in a fresh day, and the drug content is gradually and continuously released: Second:: The medical effect of this level, in order to maintain this fixed The rate at which the amount of the drug that is metabolized and secreted by the body 34 200817039 is replaced is released from the form of administration. The controlled release of the lingual component can be stimulated by various inducers, for example, yang, temperature, _, water, and his physiological condition. In the present invention, the name, the controlled release component, is defined herein as a compound, or a compound which includes, but is not limited to, a polymer, a polymer, a gel, a permeable membrane. , a liposome, or a microsphere or a combination thereof that promotes controlled release of the active ingredient. Liquid suspensions can be prepared using conventional methods to achieve suspension of the active ingredient in aqueous or oily vehicle. Aqueous carriers include, for example, water, and physiological saline. The oily carrier comprises, for example, almond oil, oily ester, ethanol, vegetable oil such as peanut, eucalyptus, sesame, or coconut oil, sesame oil, mineral oil such as liquid paraffin. The liquid suspension may further comprise one or more additional ingredients including, but not limited to, agents, dispersing or wetting agents, emulsifying agents, moisturizers, preservatives, buffers, salts, flavoring agents, coloring agents, ^ Sweetener. The oily suspension may further comprise a thickening agent, which is known to be suspended, but not limited to, mountain thief, hydrogenated edible fat, sodium alginate, polyvinyl decyl ketone, gum tragacanth, arabic Gums, and cellulose derivatives such as sodium carboxy F-based cellulose, methyl cellulose, hydroxypropyl methyl, halogen. It is known that dispersed or wet lakes include, but are not limited to, naturally occurring phospholipids such as lecithin, condensation products of dilute hydrocarbon oxides with fatty acids, condensation products with long chain aliphatic alcohols, and derivatives derived from fatty acids and hexitols. a partial ester, a sink, and a product, or a condensation product with a partial ester derived from a fatty acid and a hexitol anhydride (for example, respectively, with polyethylene oxide stearate, heptavinyloxy cetyl alcohol, poly Ethylene oxide sorbitan monooleate, and polyoxyethylene dehydration 35 200817039 ... ι人二单极(五)° known ritual agents include, but are not limited to, lecithin, • and & Acacia. Known preservatives included However, it is not limited to methyl, ethyl, or naphthyl formic acid, ascorbic acid, and sorbic acid. It is known that sweeteners include, for example, glycerin, propylene glycol, sorbitol, ruthenium, and saccharin. Known thickeners for liquids include, for example, natural beeswax, hard stone butterfly, and cetyl alcohol. η #Active ingredient in aqueous or miscible _(tetra) solution can be prepared in a substantially liquid suspension phase, mainly The difference is that the active ingredient dissolves earlier, rather than suspended in the auxiliary The present day (10) composition body solution contains each of the ingredients described in relation to the liquid suspension, it being understood that the suspending agent does not necessarily aid in the dissolution of the active ingredient in the solvent. The aqueous solvent comprises, for example, water, and physiological saline. The oily solvent includes, for example, almond oil, oily alcohol, vegetable oil such as peanut, eucalyptus, sesame, or coconut oil, fractionated vegetable oil, and mineral oil such as liquid paraffin. UI invention powder and granules of pharmaceutical preparations Formulations can be prepared using known methods, which can be administered directly to the subject, which can be used, for example, to form an oxime, a gelatin, or an aqueous or oily carrier to prepare an aqueous or oily suspension. Or a solution. Each of these formulations may further comprise one or more dispersing or wetting agents, suspending agents, and preservatives, additional excipients such as fillers and sweet, aroma, or coloring agents, which may also be included in these The pharmaceutical composition of the present invention may also be prepared, packaged, and sold in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as Laminate or peanut oil, mineral oil such as liquid paraffin, or a combination of these. Such a composition 36 200817039 The composition may further comprise one or more emulsifiers such as naturally occurring gums such as gum arabic or gum tragacanth, naturally occurring phospholipids For example, soy or lecithin phospholipids, esters or partial esters derived from a combination of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxidation Ethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetness or aroma. § For use herein, the 'oily' liquid is a liquid containing carbonaceous liquid and appears to be watery. Liquids with less polar characteristics. Formulations of the pharmaceutical compositions of the present invention suitable for oral administration can be prepared, packaged, and sold in the form of dispersed solid dosage units including, but not limited to, lozenges, hard or soft capsules. , a cachet, an ingot, or a sugar spin, the parent of which contains a predetermined amount of active ingredient. Other formulations suitable for oral administration include, but are not limited to, powdered or granulated formulations, aqueous or oily suspensions, aqueous or oily solutions, pastes, gels, toothpastes, shore water, coatings, Oral sputum, or lotion. The names of oral sputum and mouthwash are used interchangeably herein. The pharmaceutical compositions of the present invention may be prepared, packaged, or sold for use in formulations for oral or buccal administration, and may include, but are not limited to, gels, liquids, suspensions, pastes, toothpastes, Mouthwash or oral sputum, and coating. For example, the oral sputum of the present invention may comprise about 14% of the compound of the present invention, 2% of sputum, 1% by weight of ethanol, saccharin (15%), FD&C; ), peppermint oil (0.5%), glycerin (1% by weight), Tween 60 (0.3%), and water to 1%. In another embodiment, the toothpaste of the present invention may comprise about 5.5% of a compound of the invention, sorbitol, 7% by weight in water 37 200817039 (25.0%), sodium saccharin (0.15%), sodium lauryl sulfate (175%) , Kappo State, 6% dispersion (m), spearmint oil (10)%), sodium hydroxide, 5〇% in water (0.76%) '二县咖_dihydrate (45%), and water to Said %. The actual wealth of the formulations described above is perforated and it is to be understood that the invention includes additional modifications not described herein, but which are well known to those skilled in the art. The ingot containing the active ingredient is prepared, for example, by - or molding the active ingredient 'optionally with - or more additional ingredients, and the test agent can be applied in a suitable package by pressure-self-domain (for example, powder or granules) The active ingredient of the conditioned preparation is optionally prepared by mixing with - or more binders, emollients, excipients, surfactants, and dispersing agents.郷 = a key agent may be provided by a suitable device, a brain component, a medically acceptable carrier, and at least one sufficient amount of liquid that can wet the mixture. a pharmaceutically acceptable agent for the manufacture of tablets, but

Limited to 'inert diluents, granulating and disintegrating agents, binders, and lubricants. It is known that the dispersion is chiral, but is sparse, and the potato and surfactants include, but are not limited to, sodium lauryl sulfate. The release agent has been included, but not limited to, carbon_, sodium carbonate, milk is not limited to, jade fine powder and alginic acid. It is known that the binder includes, but is not limited to, gel, gum arabic, pre-gelatinized jade flour, sputum, and sylvestre. Known sagging agents = limited to magnesium stearate, stearic acid, dioxide, and talc. The binders may be uncoated or they may be coated with known methods to achieve delayed disintegration in the gastrointestinal tract of the individual 38 200817039, thereby providing sustained release and absorption of the active ingredient. As an example, a substance such as glyceryl monostearate or glyceryl distearate may be used to coat the tablet, further as an example, and the tablet may be used as described in U.S. Patent No. 4,256,1,8; 〇, 452; and 4,265,874 The method described in the above is applied to form an osmotic controlled release lozenge, lozenge

Sweetening agents, flavoring agents, coloring agents, preservatives, or some combination of these may be further included to provide aesthetically pleasing and palatable preparations for use in medicine. Hard capsules containing the active ingredient can be prepared using physiologically degradable compositions, such as gels. Such a hard capsule contains the active ingredient, and may further comprise 3 external components, which comprise, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin. Soft capsules containing the active ingredient may be prepared using a physiologically degradable composition, for example, / by Susie. Such a soft capsule contains the active ingredient, which may be mixed with an aqueous or oily medium such as peanut oil, liquid stone fiber, or eucalyptus oil. Suitable for oral administration of lining_The invention is a pharmaceutical body preparation: packaged, packaged, and sold in liquid form or in the form of a dry product intended to be reconstituted with water or other suitable carrier prior to use. The plug __ can be made by combining brain _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Appropriate medical music can be included in the frigate, but secret, oil glycerides. Suppository formulations can be further included, but not _, antioxidants, gambling; 3) Chemical composition impregnation or coating material used in the art 39 200817039 It is known that 'and including' but not limited to the Shencheng adhesion chemical composition method, where the substance is mixed (ie, for example, using a physiologically degradable substance) And absorption of water; Suspension ^ Suction "Materials, its shirts with money Weiling sputum or § used in this article, peony composition, non-intestinal administration, package for individual tissue physical rupture of drug administration and medicine Composition via group (10)

Any _, parenteral administration of the drug then includes, but is not limited to, by injecting the composition, by administering the composition via surgery, by permeating the non-surgical fine-working composition via tissue, and the like. The administration of the pharmaceutical composition. In particular, parenteral administration is intended to include, but not: subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and infusion techniques. Formulations of pharmaceutical compositions suitable for parenteral administration comprise the active ingredient in association with a pharmaceutically acceptable carrier such as sterilizing water or bactericidal physiological saline. Such formulations may be suitable for manufacture, packaging, or sale in the form of dosage administration or continuous administration. The injectable formulations may be presented in unit dosage form, for example, in a kit containing a preservative or in a multi-dose container, packaged, or sold. Formulations for parenteral administration include, but are not limited to, sap suspensions, solutions, emulsions in aqueous or oily vehicles, pastes, and implantable sustained release or physiologically degradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending agents, stabilizers, or dispersing agents. In a specific embodiment of the formulation for parenteral administration, the active ingredient is provided in a dry (i.e., powdered or granulated form) form for use with a suitable carrier prior to parenteral administration of the reconstituted composition ( For example, sterile non-heat source 200817039 quality water) reconstituted. The pharmaceutical composition can be manufactured, packaged, or sold in the form of a bactericidal injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to known techniques, and may contain, in addition to the additional ingredients, additional ingredients such as such dispersing agents, wetting agents, or suspending agents as described herein. Such bactericidal injectable formulations may be prepared using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol, and other acceptable diluents and solvents include, but are not limited to, Ringer, s solution Physiological saline solutions, and fixed oils such as synthetic mono- or di-glycerides, useful other parenterally administrable formulations include those which are included in microcrystalline form, liposome preparations, or as biodegradable polymers Formulations of the active ingredient of the system, sustained release excipient or implanted compositions may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as emulsions, ion exchange resins, poorly soluble polymers, or poorly soluble salts. The pharmaceutical compositions of the present invention may be suitable for the manufacture, packaging, or sale of formulations for buccal administration. Such a formulation may be in the form of, for example, a tablet or lozenge made using conventional methods, and may comprise, for example, from 1 to 2% by weight of active ingredient, with the balance comprising orally dissolvable or degradable. The compositions and, optionally, one or more additional ingredients recited herein. Alternatively, formulations suitable for buccal administration may comprise a powder or an aerosolized or nebulized solution or suspension comprising the active ingredient. Such powdered, aerosolized, or atomized formulations, when dispersed, preferably have an average particle size or droplet size in the range of from about 1 to about 200 nanometers, and may further comprise One or more additional ingredients in this article. As used herein, the additional ingredients, including, but not limited to, one or more of the following: 200717039 are more than the following: excipients; surfactants; dispersing agents; inert diluents; granulating and disintegrating agents; Lubricating agent; sweetener; flavoring agent; coloring agent; preservative; physiologically degradable composition such as gel; aqueous carrier and solvent; oily carrier and solvent; suspending agent; dispersing or wetting agent; , moisturizing agent; buffer; salt; thickener; filler; emulsifier; antioxidant; antibiotic; antifungal agent; stabilizer; and pharmaceutical acceptable polymerizable or hydrophobic plant, quality. Other, additional ingredients that may be included in the pharmaceutical compositions of the present invention are known and described in the art, for example, Genaro, ed. (1985, Remington, s

Pharmaceutical Sciences, Mack Publishing Co., Easton, PA), which is incorporated herein by reference. Typically, the compositions of the present invention are administered, which can be administered to an animal, preferably a human, which will depend on several factors including, but not limited to, the type of animal and the form in which the condition is to be treated, the animal's Age and route of administration. υ The compound can be administered to the animal several times a day, or it can be administered less frequently, for example once a day, once a week, every two weeks _; times, once a month, or even less frequently, for example every few months Or even a year - times or less. The frequency of administration is well known to the skilled artisan and will depend on, and depending on, the subject matter, such as, but not limited to, the form and severity of the disease to be treated, the type and age of the animal, and the like. The method of the present invention is characterized in that the method of whitening a mammalian skin, in a method of whitening a mammalian skin, comprises administering a composition to a drug, wherein the composition comprises meglumine, or a salt thereof. In another embodiment, the composition contains an analog, a modification, a derivative or an adduct of glucosamine. In another embodiment, the composition comprises meglumine. In another embodiment, the composition comprises an analog, a modification, a derivative or an adduct of meglumine. In another embodiment, the composition comprises 1-deoxy-1-(methylamine) xylitol (DYN30). In another specific embodiment, the inhibitor composition comprises 丨-deoxy(methylamine) heptaitol (DYN30). Ο The present invention is also a method for reducing pigmentation of mammalian hides. The method of reducing pigmentation in mammalian skin comprises administering a composition to a mammal, wherein the composition comprises meglumine, Or its salts. In another embodiment, the composition comprises an analog, a modification, a derivative or an adduct of meglumine. In another embodiment, the composition comprises meglumine. In another embodiment, the composition comprises an analog, a modification, a derivative or an adduct of meglumine. In another embodiment, the composition comprises 丨-deoxy]-(methylamine)-d-2 alcohol (D^N3G). In another embodiment, the inhibiting composition L 3 1-deoxy_1_(methylamine)_D_xylitol (DYN3〇). A further feature of the invention is a method of preventing skin darkening in a mammal' a method of preventing darkening of a mammalian skin comprising administering a drug'extract' wherein the composition comprises meglumine, or a salt thereof. Specifically, the composition comprises an analog of meglumine, a modified: 3 or an adduct. In another embodiment, the LI-like modification of the combination amine is a specific embodiment. The composition comprises a scorpion, a living organism or an adduct. In another specific embodiment of WO 200817039, the composition comprises 丨_deoxy-H methylamine)_D_xylitol (DYN30). In another embodiment, the inhibitor composition comprises "deoxy-1-(methylamine)-D-xylitol (DYN30>). The invention is also a method of inhibiting tyrosinase in mammalian skin, In a specific embodiment, the method of inhibiting leucine transduction in mammalian skin comprises administering a composition to a mammal, the composition comprising meglumine, or a salt thereof. In another embodiment, The composition comprises an analog, a modification, a derivative or an adduct of meglumine. In another embodiment, the composition comprises meglumine. In another embodiment, the composition comprises meglumine. Analogous, amelioration, derivative or adduct: In another embodiment, the composition comprises iota-deoxy-l-(methylamine at xylitol (DYN30). In another embodiment, The inhibitor composition comprises 1-deoxysuccinate (methylamine)-D-xylitol (DYN30). In another aspect, the invention features a method of inhibiting the activity of a phenanthryl oxidase, in one embodiment, inhibiting Method for benzoin oxidase activity in mammalian skin comprising administration To a mammal, wherein the composition comprises glucosamine or a salt thereof. In another embodiment, the composition comprises a meglumine oxime, a enhancer, a touch or an adduct. In another embodiment, the composition comprises meglumine. In another embodiment, the composition comprises an analog, a enhancer, a derivative or an adduct of glucosamine. In another embodiment The composition comprises dideoxy-1-(methylamine)-D-xylitol (DYN3®). In another embodiment, the inhibitor composition comprises 丨_deoxy-丨_(decylamine) VII _ xylitol (DYN30) 〇44 200817039 辛 剌 剌 is characterized by a method for inhibiting melanin accumulation in the skin of a mammal, and in a specific embodiment, a method for inhibiting melanin accumulation in a mammalian skin comprises administering a composition to a mammal Financial test

Ο t contains ® methylamine, or its crane. In another embodiment, the assay comprises a lysine, an enhancer, a mosquito or an adduct. In another embodiment, the composition comprises meglumine. In another embodiment, the composition comprises an analog, a modification, a derivative or a secret of meglumine. In another embodiment, the composition comprises i-deoxy small (methylamine)-D-xylose-plus 0). In another embodiment, the inhibitor composition comprises 丨-deoxy-(A(DYN30). ^ 药剂. Pharmacy kit. The invention encompasses tissue, preferably mammals, and even better humans, skin Various types of whitening _ cleavage. The _ kit comprises a cosmetically acceptable or pharmaceutically acceptable composition comprising at least one skin lightening agent. In a specific embodiment, the skin whitening agent is meglumine, or: a salt In other specific embodiments, the present invention relates to a plate-like substance comprising meglumine, or a salt thereof, wherein the composition inhibits benzene; hops oxidase riding property. In another embodiment For example, the conjugate comprises an analog, a modification, a derivative or an adduct of glucosamine. In another embodiment, the composition comprises meglumine, or a face thereof. In another embodiment For example, the composition comprises (iv) an analog, a modification, a derivative or an adduct of an amine. In another embodiment, the composition comprises if deoxy-1-(f-amine)-D-xylose Alcohol (DYN3〇). In another embodiment 45 200817039, the inhibitor composition comprises Oxygen Small (Methylamine) _ In the aspect of the present invention, the pharmaceutical kit comprises an adduct which is a decolorizing agent, and in another aspect, meglumine, or a salt thereof, is a decolorizing agent. In one aspect, the analog, the enhancer, the derivative or the adduct of the meglumine is a decolorizing agent. In another embodiment, the μ deoxygenated seven (methylamine)-p-xylitol (DYN30) is A decolorizing agent. Soil, on the other hand, the decolorizing agent of the present invention can be added as an additional reagent. The decolorizing agent comprises a cap that is called a cap and a derivative thereof (for example, p-methoxybenzene, ethoxylate) Phenol, p-benzoquinone with glucose, soy and its derivatives, vitamin A _ such as miscellaneous cockroach; face and its derivatives (such as palmitate palmitate); tranexamic acid; vitamins > , vitamins and their derivatives; azelaic acid; phytic acid; licorice; mulberry extract; extracts from 'sorrel substances such as sorrel extract; chamomile extract, · green tea extract; lactic acid, Pearl extract, Tricholoma matsutake extract, vitamin C magnesium phosphate, alpine velvet extract, sage extract Arbutin, oleracea extract, α-MSH antagonists such as undecenol phenylalanine, guanidine, and GABA and mulberry mushrooms. The Bowman-Birk inhibitor is described in U.S. Patent No. 6,750,229 (eg derived from the eucalyptus , Youke, Gramineae or Cucurbitaceae inhibitors. DermalightTM and ClariskinTM from Silab are also available as decolorizers. Kayin Ting (N6_mercapto adenine) is a 6-(R-amine) The sputum cytokinin and its system are described in U.S. Patent Nos. 5,602,139, 5,164,394, and 5,021,422, which have been shown to have anti-aging benefits. The guidance material is used in accordance with the intent provided herein. Without further elaboration, it is common for those skilled in the art to make and utilize the compounds of the present invention and practice the methods of the present invention using the foregoing description and the following illustrative examples. The following examples of the invention are set forth to illustrate the preferred embodiments of the invention, and are not intended to be limited in any way. The invention is now described with reference to the following examples, which are intended to be illustrative only and the invention should not be construed as being limited to the examples. All changes.遂Skin drug 偻i off

, and the transmission of compounds from the skin, including drugs or other medical agents, has several advantages in entering the body. This method is called the delivery of the skin. Transdermal medications, which provide an alternative to injectable and oral medications, ^, the ability to provide multiple days of treatment to improve patient compliance, and the transmission of drugs present in the delivery system The extension has a short half activity and its controlled release characteristics. Transdermal drug delivery

Tausnitz, difficulty, no:: or the interaction between ί and =, the gastrointestinal tract and portal veins /, avoid the first one, that is, the drug substance through the system for the low skin ^ initial channel ϋ transdermal drug delivery Application due to 'stomach permeability' is limited to only a few drugs [Pj 47 200817039 MR· et al. Current status and future potential of transdermal drug delivery, 2004, Nat Rev Discov 3(2): ρ·115-24 ].经 Ο The transdermal delivery of solute is mostly controlled by the stratum corneum bilayer lipid, and the solute transport in the stratum corneum bilayer lipid, similar to other bilayer lipid systems, is highly heterogeneous and size dependent, specifically The double-layered lipid exhibits strong structural heterogeneity, which causes spatial variability in the distribution of solute and diffusion coefficient. As a result, the salty molecule follows the molecular group at the tail end (for hydrophobic molecules) or the apical molecular group (for hydrophilicity). The tortuous pathway in the region of the molecule diffuses through the skin, where the transmission between the two layers can occur in the bilayer-double layer interface or other structural disordered parts [Marrink, SJ· and Berendsen, HJ is studied by molecular turbulence simulation The penetration of small molecules across the lipid layer, 19% Physical Chemistry Journal 100 (41): 16729_16738 pages]. A small number of drugs can effectively penetrate the skin, nicotine, estrogen, guanamine, phenanthrene, and glycerol as a few drugs can be self-medicated successfully: the secret side transmitted by the skin is their phase #小和在A small dose of αι mg to ^mg/day is effective [Kanikka job, Ν. et al., percutaneous = = Shen Hui chemist's structural rhyme _, 2_, contemporary pharmacology to 7 (6): 593__ ]. Many other drugs are only available when there are additional methods for face-to-face, super-sonic, _(ring), and micro-shop. Any of the 经由μμ 48 200817039 liposome via the skin delivery method is a microscopic, fluid-filled capsular bag whose wall system is made of the same phospholipid as the phospholipid layer constituting the cell membrane. They are well known and their structure and properties have been thoroughly studied. Basically, they are small single or multi-layer lipid/water structures having diameters ranging from nanometers to micrometers. The liposomes can be formed from a variety of natural phospholipids, such as cholesterol, stearylamine, or phospholipid choline, which can be formulated to incorporate a wide range of materials as a payload in water or in a lipid compartment. The liposomes are very diverse and variable due to their composition and can be used to deliver vaccines, proteins (enzymes), nucleotides, plasmids, drugs, or cosmetics to the body. The liposome can be used as a carrier for anti-tumor and anti-viral derivatives of lipophilic drugs such as Αζτ [Kamps, JA· et al., (modified) conjugates of human serum proteins and liposomes; Drug carrier with essential anti-hiv activity, 1996· Bi〇chim Bi〇phys 八伽12,··183' page]. Insulin can also be transmitted via liposome [_ job_, κ·etc.] in rabbits after intranasal administration of liposomes modified with insulin-containing enhancers, and the relationship between liposome and tensin absorption. chat·

Drug Dev IndPharm 25(10): 1099.105 1] For medical purposes, liposomes can also be injected intravenously and when they are lipid-like, their surfaces become more hydrophilic and then in the blood. Between = can be significantly increased, such a general term, hidden, the micro-lipid system is particularly a hydrophilic (water-soluble) anticancer drug such as doxorubicin carrier. The disease that wakes up the onion and its cells in the mouth is special. They tend to accumulate in the swallowing cells, and swallow the cell touches = ^[Ren^ 49 200817039

Blood and different _ towel Mito t mosquito, 1996, ^ Ch_atogr B

Bi〇medAPP16 guide 2): 185_92], they have also been used experimentally to carry normal base 0 into human cells to replace Gu, silk due to [Gu. , ^ and Lee, R.I. Use of anionic microlipids. Effective gene delivery of complex polymers (LPDII), 2000· Biosci Rep 20(5): 419-32]. The liposomes are sometimes used in cosmetics because of their moisturizing qualities, and it has been found that the combination with water immediately forms a spherical shape because one end of each molecule is water-soluble, while the other end is insoluble in water. Ultrasonic introduction Ultrasonic introduction or ultrasound introduction has been widely used in sports medicine since the 60th century. In vivo control studies in humans have confirmed the use of the currently used parameters (frequency 1-3 megahertz, intensity 丨_2 Watt / cm (7), the period of 5-10 minutes 'continuous or pulse mode' of the technology has no effect or mild effect. However, in 1995, the intestines used the low-frequency ultrasound in animals to cast a large biological activity. Molecules are feasible. This led to a new study of this dermal administration method [Machet, L. and Boucaud, a• Ultrasound introduction: efficiency, mechanism and skin tolerance, International Journal of Medicine 2002 243 (1_2)··Μ5 pages]. In this method, the transient application of ultrasonic waves is used to penetrate the skin for a long time, and the enhancement induced by the ultrasonic waves is particularly remarkable at a low frequency (f < 1 kHz). During this time, the ultrasonically infiltrated skin can be utilized for drug delivery, and in addition, samples of tissue fluid or components thereof can be taken through the permeated skin for diagnostic applications. Detailed studies in drug delivery have been performed using insulin and mannitol as model drugs, and diagnostic studies have been performed using glucose as a model drug [Mitrag〇tri, s• and K〇st,; • low frequency supersonic 50 200817039 Wave. Non-invasive method for drug delivery and diagnosis, 2000. Biotechnol Prog 16(3): 488-92]. In vitro, in vivo, and clinical studies have also demonstrated the success of low-frequency ultrasound in transdermal drug delivery and lysine extraction. Important clues obtained through several studies have also been studied [Mitragotri, S. and Kost, J. Low Frequency Ultrasound: Retrospective, 2004. Adv Dmg Ddiv Rev 56(5): 589_6〇1 page]. ^ School 〇f Pharmacy, Faculty of Sciences, University of Geneva 'A study to demonstrate low-frequency ultrasound (9) kHz) Strengthening the skin's money-based mechanism is to study the physical role of the transmission path in the K-waveguide The amount of lipids removed from the intercellular region of the stratum corneum was determined by the infrared spectrum. Under the influence of ultraviolet light, the transmission of the glory probe Nile Red and Yellow was evaluated by a t-scan common-focus microscope. #魏(四)Data and a significant ratio (about 30%) of the interstitial lipids in the sacral layer responsible for skin spasm in principle compared with the spur data obtained from the skin only exposed to the thermal effects of ultrasound treatment Low frequency ultrasound introduction was removed during application. Although the common image from the Nile Red experiment is not hydrophilic, the isoflavin is particularly beneficial in the individual infiltration areas, and the ultrasound is clearly and significantly (again, relative to the corresponding control) facilitating the transmission, while other resistances are Obviously unaffected. The removal of lipids from the stratum corneum suggests a factor contributing to the penetration enhancement effect of the observed low-frequency ultrasound [Alvarez_R〇man, R, et al., enhanced skin permeability by low-frequency supersonic waveguides: _ material extraction ^ Path, 2003 Journal of Medical Sciences 92 (6): 1138_46].忠51 200817039 Effects of low-frequency ultrasound introduction The effect of higher-frequency ultrasound introduction is more important, with a significant increase in delivery into and out of the skin after application, although the mechanism is still not fully defined However, it strongly suggests the hole # and the thermal process [Merino, G, et al., Ultrasound-enhanced transdermal delivery, 2003 Journal of Medical Sciences 92 (6): 1125-37]. In another study, the application of low frequency ultrasound has been shown to increase skin permeability, thereby facilitating the delivery of macromolecular low frequency ultrasound introduction. This study sought to determine the theoretical transmission of hydrophilic permeate induced by low-frequency ultrasound introduction through the skin. Parameters such as pore size distribution, absolute porosity, and the dependence of effective tortuosity on solute properties were investigated. Pig skin is violent at low-frequency ultrasound at 58 kHz to achieve different skin impedance, measuring the presence of four permeates [mannitol, luteinizing hormone releasing hormone (LHRH), insulin, dextran] in ultrasound Transmoid # under the absence of ultrasound. The porous hetero-models improve the S-permeability characteristics of the sputum type and the path responsible for the transport of hydrophilic permeates. The log kp(p) ratio of the individual solute is determined by the slope of the solute molecular area. It is suggested that the permeability-impedance correlation of each permeate is related to its size, and the degree of reorientation of the permeate in the skin is also based on its size, and the larger molecule undergoes a smaller tortuosity path. Improved porous road = pull type can be independently calculated for effective resilience and skin porosity. The results of this study are not low frequency ultrasonic introduction to produce a wide range of pore size permeate transmission, the path, the solute paste The optimal pore size is based on their molecular half ^rTezel, A. et al. 'Based on the improved porous path model, the description of hydrophilic solute transport on the skin during low frequency ultrasound introduction. ·Medical Science 52 200817039 Journal 92 (2): 318-93 pages]. In vitro experiments using full thickness pig skin to measure skin conductivity and drug permeability have been performed and ultrasound has been applied to pretreat the skin using an ultrasonic pulverizer operating at a frequency of 20 or 40 kHz. It also noticed the pitting of aluminum foil to measure cavitation, which is the main mechanism of low-frequency ultrasonic introduction. It is found that the enhancement of skin conductivity is inversely proportional to the distance from the skin keratin. When the intensity is increased, the skin conductivity is also increased. A certain forbidden limit, and then a decrease, the maximum intensity of occurrence (I(max)) is about 14 watts/cm 2 to 20 kHz and 17 watts/cm 2 to 4 kHz, these findings are optimized at low Frequency ultrasound introduction is useful. In summary, the dependence of the parameters transmitted on the ultrasonic parameters is similar to that of aluminum foil pitting, so these results support the role of cavitation in low-frequency ultrasound introduction [Terahara, T. et al., introduction of low-frequency ultrasound The dependence of ultrasonic parameters, the distance and intensity of keratin, 2002 Medical International Journal 235 (1-2): 35-42 pages]. The enhancement of drug delivery via low-frequency ultrasound introduction is considered to be fine 1 by the formation and rupture of cavitation 'gas bubbles, while the medium has assumed that the utility of low-frequency ultrasound introduction can be significant due to the provision of cavitation nuclei strengthen. In a special study, 'a porous resin, Diaion HP20 and Diaion HP2MG (2MG), used as cavitation nucleus, used cavitation of aluminum foil to measure the effect of these resins on cavitation. Compared with Diaion HP20, 2MG showed strengthening For the more efficient use of pitting, 2MG is also effective in enhancing transdermal mannitol delivery. The results confirmed that the addition of a null-nuclear nucleus such as a porous resin further increases the effect of low-frequency ultrasound on skin permeability [Terahara, τ• et al., multi-53 200817039 Porous resin as a cavitation enhancer for low-frequency ultrasound introduction, 2002 Journal of Medical Sciences 91 (3): 753-9 pages]. Electroporation is a transient structural perturbation of a bilayer lipid film due to the application of a very short (<1 second) high voltage pulse, the application to the skin has not increased the number of transdermal drug delivery by several orders of magnitude, and Electroporation, either alone or in combination with other intensive methods, extends the range of drugs (small to macromolecular, lipophilic or hydrophilic, charged or neutral) that can be delivered through the skin. Molecular delivery via transient electroporation by electroporation is primarily produced by self-enhancing diffusion and electroporation. The utility of the transmission depends on the electrical parameters and physiochemical properties of the drug. The in vivo application of high voltage pulses is tolerable but always induces muscle contraction. Electrodes and patches are designed as an important issue to reduce the human electrotherapy. Comfort [Denet, AR· et al., Skin Electroporation via Skin and Local Delivery, 2004, Adv Drug Deliv

Rev 56(5): 659-74]. Patelite electroosmotic therapy Iontophoresis or electrokinetic administration (EMDA) is a very effective method of delivering drug-affected sites. This method is commonly used in many countries to include the United States. Instead of directly injecting a drug (usually a steroid) into the site of inflammation, applying a low-density current several times (ranging from a few minutes to a few hours) iontophoresis can evenly distribute a high concentration of drug to the tissue, which is attracted to the drug molecule. Ions and drives them through the skin to be absorbed by the inflamed tissue. ^ Hydrogenation of a solution of carboxypropyl-β-cyclodextrin (ΗΡ-β-CyD) in aqueous solution by transdermal iontophoresis has been studied and compared with the formulation of latent solvents 54 200817039 Chang, SL· and Banga, Transdermal Iontophoresis of Hydrocortisone from Cyclodextrin Solution, 1998, J pharm Pharmac〇1 50(6): 635_40 pp.]. The passive penetration of nitnitoxone through dead human cadaver skin when transported from propylene glycol was higher than that after dissolution in HP4_CyD aqueous solution, however, the iontophoretic transport of 1% hydrogenated cortisone _9% HP_p_CyD solution was higher. The amount of 1% hydrocortisone-propylene glycol formulation passively transported, even if oleic acid is used as a chemical enhancer. The iontophoretic transport of 1% hydrocortisone with 3% or 15% HP+CyD is lower than that of the -9% Hp_j3_CyD solution. This data suggests that free deuterated cortisone rather than complexes are mainly via Skin iontophoresis and HP_(3_CyD complex is used as a carrier to supplement the consumption of sputum cortisone, Hp_(3_CyD prevents hydrocortisone from forming skin storage. Iontophoresis provides better chemical methods) Enhancement of hydrocortisone transdermal delivery when only sufficient amount of HP_p_CyD is added to dissolve hydrocortisone [Chang, SL· and Banga, Α·Κ·hydrocortisone from cyclodextrin solution for transdermal iontophoresis, 1998, J Pharm Pharmacol 50(6): 635-40 pages. Introduction of an enhancer Another long-term method of improving transdermal drug delivery is the use of an introduction enhancer (also known as a sorption cocatalyst or accelerator) that is worn. Transdermally reversibly reduces barrier impedance. Several compounds have been evaluated for their penetration enhancing activity, including sulfoxides (eg, disulfoxide, DMSO), azones (eg, azone), and sulphonone Classes (eg 2-° piroxime, 2P), alcohols and alcohols Ethanol, or sterol), glycols (such as propylene glycol, PG, a common excipient for topical administration), surfactants (also commonly used in the form of administration) 55 200817039 η υ and olefins Many potential sites and modes of action are identified for use in skin-introducing enhancers. Intercellular lipid matrixes in this accelerator can interrupt the accumulation of phantoms, cells, keratin regions or by increasing the drug by acting as a solvent for the intramembrane permeate. ^ Assignment to the organization. Further potential mechanisms, such as the use of a cell bridge between the cells, or altering the metabolic activity in the skin, or the effect of the thermodynamic activity/solubility of the drug in the vehicle , the agent is also feasible _iamS, AC and Barry, Bw lead two increase ^ ^ ' 2004. Adv Drug Deliv Rev 56 (5): 603-18 page]. ^ % dextrin is a hydrophilic external surface and slightly Lipophilic central empty = % oligosaccharides, cyclodextrin can form a water-soluble inclusion complex with many lipophilic water-insoluble substances. In aqueous solution, the drug molecules in the central cavity and free drugs Molecular formation Dynamic equilibrium, and the pro-inspective molecules in the 错t-mismatched medium compete with each other in the space of the cavity. Because of their size and hydrophilicity, only a significant amount of cyclodextrin and drug 精2 fine complex (4) Wear a biological barrier of a relative, such as a complete cutaneous stomach. - The 'cyclodextrin can provide sputum by increasing the surface of the barrier, and: strong local drug delivery' on the surface of drug molecules from cyclodextrin hole distribution = See the lipid barrier, so the drug transfer from the aqueous cyclodextrin solution is == and _ control _, it is difficult to transfer in the lower cyclodextrin only 2 local music transfer _ surface, τ · and face, Μ • cyclodextrin In the local Chinese ship. Theory and implementation, facial medicine __ 225 (four): Bei] 0 through, 2 know that dextrin can enhance the penetration of poorly soluble drugs through the bio-thinning, ..., permeability will be reduced if more than solvated The concentration of the drug required for the addition of 56,170,390 degrees to the cyclodextrin, cyclodextrin, the role of the increase in the degree of rotation in the dance body is also explained by the music in the water supply enhancer, that is, by reducing lipophilic (four) Typical infiltrations have used a hybrid barrier (which contains, ... self-explanatory interpretation. To study the role of cyclodextrin, = phase-controlled diffusion, the diffusion of the entire donor is slow, and this = the diffusion of the diffuse layer is more than the existence of the Ο 胁 及 and the system of the system (four) constants Fine and _ compound mixed with the fortune (4) money skin penetration =: = = ' With the increase of cyclodextrin wrong side s clothing dextrin flux reduction can be accurately predicted. The permeation data of the cast-through model is combined with the equation = "cyclodextrin used as a penetration enhancer to carry the drug through the aqueous screen in M. t from the bulk solution to the lipophilic surface of the biofilm, this Drug molecules are distributed from the complex into the lipophilic film [Μ_, - etc.] cyclodextrin as a penetration enhancer: some theoretical evaluation and in vitro testing, 1999. Controlled Release Journal 59(1)·1〇7_18] . Tyrosine 醢13⁄4 A variety of studies can be used in accordance with the present invention, such studies

Jeon #((2005)Bull.K〇rean Chem. Soc.? Vol. 26:1135-1137), in a nutshell, the study can be tested and/or standardized using the mushroom tyrosinase to obtain ^3 , 4_Dihydroxyphenylalanine 仄-dopa), and citric acid (Sigma, St. Louis, MO). Human tyrosinase can be obtained from the expression of cDNA in E. coli as described in the art. Weight 57 200817039 Group of humans shouting _ can be controlled in the tae promoter τ expressed in the large intestine purified by DEAE-Sephacd column and fixed metal affinity column, the:: and group of human tyrosinase should appear to correspond to the molecule on SDS_pAGE A single-protein band of 66 ribs, which is consistent with the reporter's tyrosine i, purified recombinant human alanine enzyme followed by an L-dopa oxidation reaction system for inhibiting the action of small tyrosinase _ is known in the art. In the method, the inhibition of the activity of the methioninase was carried out by using one: the agent to pre-culture the enzyme for 2 minutes and measuring the reaction by adding 3 millimoles of L-dopa to 37qc, resulting in 5〇. The inhibitory concentration of % 抑 C C5 〇) is determined by the plot of residual activity versus inhibitor concentration. d 31 cases 1 ’ t) f amine salvation suppression of stupid o-phenol oxygen &

Apple (RedDelici〇us) was purchased and cut into two pieces, half of which was soaked in water sideways for 10 seconds and the other half soaked in 1%% meglumine in the same manner. The two >} were placed at room temperature for more than 2 hours, the first photo was taken in 2 hours, the left half (A) was soaked in water, but the right half (B) was soaked in 1〇 % meglumine _ Η α. These data confirm that meglumine prevents normal browning of apples, which is an enzymatic phenanthryl oxidase, an enzyme similar to the enzyme tyrosinase, an enzyme required for the production of melanin in the skin. O-di-synthase is routinely used in the literature as a substitute for hydrazine = S#. — Example 2 · Methylamine worms are made of benzophenone oxidized bismuth oxime and defensively. Just buy the potato and cut into two pieces, and half of the potato skin is soaked in the side. 58 200817039 10 seconds in water The other half was soaked in 1 〇〇/〇 glucosamine _HC1 in the same manner. " Put the two pieces at room temperature for more than 2 hours, the photo taken in Figure 2 is taken - 2 hours, half (A) on the left is soaked in water, but half on the right (B ) was immersed in 1 〇〇 / 0 meglumine _HC1. These data confirm that meglumine prevents the normal browning of the potato, which is oxidized by the enzyme benzophenone, which is an enzyme similar to the enzyme lysinase, an enzyme required for the production of melanin in the skin. Secondary oxidase is routinely used in the literature as a substitute for Lucase. Width _ Example 3 · Glucosamine inhibits stupid dioxin oxidase protein extract containing phenanthryl oxidase in a 15 ml cell homogenizer by homogenizing 5 g of mature but not soft bananas in 1 ml ml 5〇 Prepared by a millimolar concentration of catechin buffer, pH 7.2. The homogenized banana extract was transferred to an Oak Ridge type screw cap centrifuge tube and centrifuged at 12 minutes on a Beckman JA20 rotor for 15 minutes, extracted before use, and the supernatant was concentrated at 50 millimolar. The phospho-methyl buffer was diluted to 1/10, and benzoic acid (Fisher #Acl58981000) was prepared in water at a concentration of 1 Torr, and all other compounds were dissolved in water to a molar concentration. The phthalic acid oxidase converts the phenanoic phenol (clarified) to benzoquinone (yellow). The ability of several compounds to prevent this conversion is tested as described in the following table (Table 丨). The post-volume volume of Yanjiu is about 2· 〇ml. Table 1 ---- Number of tubes 1 ----- 2 3 4 5 6 7 8 Final concentration 59 200817039 Millenol concentration phthalic acid '''Ϊ ------— "... 0.5 0.5 0.5 0.5 0.5 0.5 ~ 0.5 0.5 -------- 2·5 mM concentration of banana extract (1/10 dilution) —— . 1.0 1.0 1.0 1.0 1.0 1.0 — 1.0 1.0 ----- 1 Molar concentration of meglumine ~~_ 0.01 0.01 —----- 5 millimolar concentration 1 mole concentration of meglumine-HC1 —— 0.01 o.oT 5 millimolar concentration Γ 1 molar concentration arginine ^^S--- 0.01 0.01 0.01 5 millimolar concentration 1; 1 molar concentration sorbitol ^-~~~~~-- 0.01 —---. 5 millimolar concentration 1 molar concentration N-B Brewing base_-----0.01 5 millimolar concentration of grape glutamine - Lil2〇_ 0.5 0.5 0.5 0.5 0.5 0.5 — 0.5 0.5 Reactant deducted banana extract mixed at room temperature, added banana extract

And the reaction was incubated at room temperature. Figure 3 shows the reaction at 1 minute, lane 1 ^ inhibitor _ system reaction; note yellow. Lanes 2 and 3 clearly demonstrate that glucosamine or meglumine _HC1 inhibits benzo-II activity because these tubes are clear. Arginine is not an inhibitor (lane 4) and is not represented by Portuguese

Methylamine enhances benzophenone oxidized bismuth as a heart... J wants to ferment benzene argon (clear) to be awkward (yellow ^ _ is dopa pigment) and its conversion force is as follows (Table 2) ^ =, ,) 'Several compounds to prevent this conversion of T3824-25KU) diluted in i, ancient K just try, shiitake lysinase (Sigma soaring 50 home molar concentration of serotonin buffer 60 200817039 solution, pH 7.2, A concentration of 10% glycerol to 25 thousand units/ml, which was diluted 1000 times with 50% molar concentration of potassium phosphate buffer, pH 7.2 before use in the reaction. Table 2 Number of wells 1 2 3 4 5 6 7 8 9 10 11 Final concentration k25 unit / ml tyrosinase 20 20 20 20 20 20 20 20 20 20 20 2.5 units / ml 10 mmol concentration phthalic acid 5 5 5 5 5 5 5 5 5 5 250 micromolar concentration H2o 25 20 100 millimolar concentration meglumine-HC1 20 10 millimolar concentration 100 millimolar concentration arginine 20 10 millimolar concentration 100 millimolar concentration tannic acid 20 10 millimolar concentration 61 200817039 100 milli Mo 1 ear concentration anti-ascorbic acid 20 10 millimolar concentration 100 millimolar concentration sorbitol 20 10 millimolar concentration ^100 millimolar concentration xylitol 20 10 millimolar concentration 100 millimolar concentration glucosamine 20 10 millimolar concentration 100 millimoles lee concentration hydroquinone 20 10 millimolar concentration 100 millimolar concentration Ν-phenyl-sulfur pulse 20 10 millimolar concentration phosphate buffer 150 150 150 150 150 150 150 150 150 150 150 62 200817039 final reaction 200 200 200 ~ 2 〇Γ ¥ volume, micro > 200 200 200 200 η Reactant decarboxylation to room temperature, add the addition of methioninase and react at room temperature. All the reverse side is performed twice. The fourth step is shown in the reaction for 2 minutes. Β is a negative control reaction (no benzophenanthrene or inhibitor) 'well 2A and B as positive control; note yellow. meglumine _ fertilizer clearly inhibits lysinase (pore 3 Α and Β), lysine The enzyme also showed inhibition by citrate (pore 5 Α and Β), ascorbic acid (pore 6 Α and Β), benzodiazepine (pore 〇α and β), and Ν-phenyl-sulfur gland (pore 11 a and Β) . Arginine (pores 4 Α and Β) and glucosamine (Hole 9 Α and Β) produce an unknown source of red, and sorbitol (pore 7α and xylitol (pore 8 a and Β) do not inhibit spect. The determination of the concentration of the methionin is determined by the concentration of the molidinase inhibition of meglumine-HC1, and the reagents are as described above and the ability of meglumine to inhibit the amino-amine is 0.5 small 5, 10 The determination of the concentration of 50, and the molar concentration is as detailed in Table 3. Table 3 Τ^η ----- 7 ------ 8 The final concentration of 20 20 ---- 2.5 units / ml --- -- 5 —--- 5 250 micromoles concentration of pores ~ --- _ 1 2 — 3 4 5 25 units / ml of lysinase ' ^ ^ a 20 20 20 20 ~ 20 ~ ~ io millimolar concentration 5 5 5 5 63 200817039 f phthalic acid -------- 25 20 _ .10 millimolar concentration of meglumine-HC1 _--^ 100 millimolar concentration of glucosamine-HC1 -- ---- 1 molar concentration of s-methylamine-HC1 .- phosphate buffer 150 150 final meglumine XX-HC1 concentration, millimolar concentration

/in / heart W < 3 0 U G chain tray mixed at room temperature, add tyrosine _ and react to temperature incubation for 20 minutes. Figure # shows the reaction at 2 minutes, when the concentration of glucosamine is increased from 〇5m: to 10Θmmol (well 8), and the inhibition is increased in 2〇, / 辰. This effect is characteristic of enzyme inhibition. Contains the next measurement 'Preparation of 500 ml of mixture, L. dopa or 3 potassium buffer 1^7·6; 600 millimolar concentration and melamine concentration tyrosine substrate; 250, 500 or 1000 mM Dudou glucosinolate 酴 ς ς ς # 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Unit Xiangyi 64 200817039 Prolinease Enzyme (Sigma). The blank reaction was also set to be no glutamate enzyme, and the mixture was incubated at 37QC for 48 hours. After the culture period, the melanin system was subjected to various steps and extractions described by D. S. Kim et al. (Cell Science Journal 115: 1699; 2003). The meglumine-HC1 was added in 0.5 ml portions to a final concentration of 50 mM potassium phosphate buffer ΡΗ 7·6 to 500 mM, and the mixture was vortexed and then rotated at 7500 X g for 20 minutes. The supernatant, and a 250 ml solution containing 1 molar concentration of NaOH and 10% DMSO, is added to the mass, the precipitate is vortexed, and the suspension is placed at 10 〇〇 QCl hours and vortexed every 30 minutes, and then After centrifugation at 7500 x g for 5 minutes, a portion of 200 ml of the supernatant was placed in a 96-well styrene porous disk and the absorbance was read at 415 nm using a multi-well disk reader. The percentage value indicates (test substance - blank A415 / 'control blank 8 415) \ 100 (Table 4). Table 4 % control a415 L-dopa tyrosinase substrate control 100 100 250 millimolar concentration meglumine-HC1 32 84 500 millimolar concentration meglumine-HC1 20 63 1000 millimolar concentration Methylamine-HC1 -------- 4 33 Citrate 9 2 Hydroquinone 106 9 N-Acetyl Glucosamine 81 126 65 200817039 The results show that the black formed by tyrosinase:) boast in Portugal: : The child is reduced in the next and more than he: _ enzyme inhibitor citric acid, benzoate and N_ acetaminophen less matrix. Q paper and N_(4) lysine which reduces the polyp of p: nn [~ukai" is produced as a methioninase from L_dopa (10), which then spontaneously forms siba pigment, which is A precursor of black insoluble, dark precipitates. Measurement of the effect of meglumine on lysase activity and melanin appearance. Contains 5 〇 莫 莫 麟 麟 麟 缓 缓 缓 pH 7.6, _ 胄 Mo Er concentration L-dopa and 10 please meglumine surface, touch or ascorbic acid (final concentration is 2GG millimolar concentration, 5 millimoles The ear concentration and 5 mM concentration of the 9 〇 ml study mixture were prepared. Add 1 ml of tyrosinase to a final concentration of 12.5 units/ml, and mix the mixture at 37QC for 72 hours.

At the time, the additional reaction was also carried out in the absence of a protease. The above reaction was repeated except that glucosamine hydrochloride, citric acid or ascorbic acid was added 2 hours after the start of the reaction by the addition of tyrosinase. After the culture period, melanin was precipitated and extracted using various procedures as described by D S. Kim et al. (Cell Science Journal 116: 1699; 2003). After the 72 hour incubation period, 2 ml of 50% glycerol was added to 50 mmol of potassium phosphate buffer pH 7.6, and the mixture was vortexed and spun at 7500 X g for 20 minutes to remove the supernatant and will contain 1 A 250 ml solution of molar concentration NaOH and 1% DMSO was added to the pellet, the sediment was vortexed, and the suspension was placed at 100 QC for 1 hour and vortexed every 30 minutes, and then centrifuged at 66 200817039 7500 χ g for 5 minutes. The separation of 2 ml of the supernatant was placed in a porous styrene disk and the absorbance was read at 415 nm. All 'test' Α '5 values minus the background (1〇% DMS 工 、, degree NaOH) value, the percentage value indicates (test material A# 昭耳浓 A415) x100 (Table 5). 5 ---- %Control A415 ^^ —---- No tyrosinase added to the control at time 0 ~ ~~ ~~~ 100 4 * and knife into the Too-^ meglumine-HC1 16 ~ 21 麴Acid 4 7 hydroquinone 1 110 "18 ascorbic acid --~2~---------------- η

The results showed that the presence of tyrosinase and the absence of tyrosine §|^^^ melanin (shown by a415 value) decreased in the presence of meglumine = the amount of melanin in the formation of the tyrosinase __ also reduced in the presence of p-phenylene and ascorbic acid, and meglumine also reduced the amount of tiredness. When the lysinase was added from the L-dopa, the skin pigmentation was caused by the sulphate. Two skin cream preparations to test their ability to alter pigmentation in freckle skin' - seeds containing meglumine and liposome and another not containing (placebo), the placebo (base cream) Purchased from FMI (Allent_, PA) and containing Pauli wax, Jojoba oil, glycerin, Shuang Mi 67 200817039 Oral carbazide II, Crodofos SG, NaOH, Lipex 205, Dimethoate DC200, Triethanolamine NF , Kappa 1 〇, Ucare Polymer LK, Juniper

Blend and purified deionized water. Another preparation (test cream) contains 82 grams of base cream from FMI, with 8 grams of meglumine hydrochloride, and 10 grams of mixture containing 8 grams of Natipide II (American Lecithin Company) and 2 grams of meglumine hydrochloride (by Stirring together to prepare a homogeneous emulsion 0 This is a double-blind, placebo-controlled trial in which 16 individuals participated in the experiment. These individuals have a itz_ΠΙ Fitzpatrick skin form between the ages of 18-65 years and show at least moderate pigmentation. At the edge of the upper arm, each participant is given an active and placebo product (one for each arm) for the designated side portion of the upper arm according to a random assignment schedule, and the participant applies the cream twice daily. The side portions of the upper arm are treated for three weeks. During the study period, participants are indicated as follows: Do not use any moisturizer or topical medicine (applied to the skin) on the upper lateral arm. Avoid sunburn, sun exposure or other direct sun exposure. _Do not use phototherapy beds, = Do not sand the arm test area, do not use loofah or bath cotton to wash the arm or apply other products to the test site. The product guides are given to participants and placebo cream products (each arm-species) according to a random assignment schedule. The product guidelines are as follows: ^ On the designated arm twice a day, - in the morning and - in the evening. The heart knows to use the product designated for the left arm in the left arm and the product designated for the right arm of 68 200817039 in the right arm. The skin erythema is based on the standardized tristimulus system recommended by the CIE (Commission Intematioiml de L Eclairage) using a reflectance technique, which uses the 8 mm measurement area Minolta using Dm illumination conditions closest to normal daylight conditions. CR-200b colorimeter, a hand-held I placed gently by the surface to be characterized by color. When triggered, the pulsed light source emits a flash and the light reflects off the surface and returns to the device and is measured. Within this device, there are six sanding cells that are filtered to detect the main stimulus values for the red, green, and blue wavelengths of light. For color reading, this value is converted to the L*a*b coordinate, the interval of which is associated with the color meal perceived by the human eye. This is an international cognitive practice for numerically representing the color difference established by CIE. The l* value represents the density value from black to white, and the a* and b* values represent the range from green to red and from blue to yellow, respectively. Color axis. [Babulak, SW·, Rhein, LD” Scala, DD” Simion, AF· and Grove, GL·, using Minolta Chroma (reflectance) for erythema quantification in soap room tests: comparison of instrument results with visual assessment, cosmetic chemistry Journal of the Association 37: 475-479, 1986]. Ten sets of L*, a*, and b* readings were taken for each test site at the beginning of the study and after 3 weeks. Using L*, a*, and b* readings, the following equations are also used for ΔΕ and AC calculations: = λ/[(ΔΙ*)2 +(Δα*)2 +(Δ6*)2 △C = Λ/[ (Δα*) 2 + (Δ6*) 2 ΔΕ is used to describe the distance between two colors and AC is chromaticity. 69 200817039 Table 6 ----------- Placebo Cream Test Cream AC ΔΕ ------------—— ^1.0010.57 1·36±0·91 Τ74ΤΓΠ~ T-test 0.0171

The calculation of the ΔE and AC values (which are linear changes in the color space) confirms that the test cream produces a significantly larger change than the placebo cream (iv) 〇5 hemp 6). As understood from the disclosure herein, other non-glycolamine compounds are useful in accordance with the present invention, including, but not limited to, sorbitol lysine, mannitol lysine, galacto (four) , _ octyl glucosamine Marlene ^, Marlene & sorbitol, Marlene mannitol.嗍9: The influence of Portuguese on melanin formation

The effect of meglumine analogues on melanin formation was tested and the hydrochloride salt of this compound was prepared using general procedures, for example, 丨_deoxy-丨-(methylamino)-D-xylose (DYN30) using D _ xylose production, D_xylose (2 mM) dissolved in 10 _ liters of methanol, adding 5 ml of 2 molar concentration of methylamine to methanol followed by 1 ml of active hydrazine to the slurry, which is under 28 psi of hydrogen After shaking for six hours, the catalyst was removed by filtration and the filtrate was evaporated to remove excess methylamine. The residue was dissolved in 2 ml of water and the pH was reduced to 7 using a 丨 equivalent concentration Ηα, and the solution was concentrated to about 1 ml. And 1 ml of isopropanol was added, and the resulting precipitate was collected by filtration and dried. Contains 50 home molar concentration potassium citrate buffer pH 7.6, 600 亳 molar concentration L-dopa and 1 〇〇 millimolar concentration of meglumine hydrochloride or 1 〇 () millimolar concentration DYN30 190 ml study mixture Two parts were prepared on a styrene 96-well plate. At half the number of wells, ten milliliters of tyrosinase enzyme was added to a final concentration of U 5 units/ml, and the mixture was incubated at 37 ° C for 72 hours. 200817039 The other half of the wells were placed in 10 ml of % millimolar phosphoric acid, buffer 7.6 〇p. After 72 hours of incubation, the plate was photographed (Fig. 6), and the result was not lysinase (ammonia-enriched surface). The amount of meglumine (dark black precipitate) formed in the presence of or in the presence of smectic acid ((tetraosinase) is reduced in the presence of meglumine and in the presence of the meglumine analog DYN30. The disclosure of each of the patents, patent applications, and publications is hereby incorporated by reference in its entirety. While the invention has been described with reference to the specific embodiments thereof, it is understood that The scope of the appended claims is intended to cover all such specific embodiments and modifications. '' 71 200817039 [Simple description of the schema] The following detailed description of the S-type ί is easier to understand. For the purpose of illustrating the invention, the invention is not limited to the arrangement and instrument shown. In the drawings: Π The first ® is an image, which is said to be gambling. Half of the fruit on the left (eight) was treated with water and =2 with 10% meglumine-HC1. W thousand frequency results Fig. 2 is a kind of image 'It shows that the root county is half-belled with water, and the right side = potato is treated with 10% meglumine _HC1. ^ 3 is a kind of image, which illustrates the invention of the benzoic acid inhibition of the present invention. The general description is described in this paper, and the channel 3 and the channel 3, the package of 3 glucosamine and the meglumine-HC The conversion of benzophenone oxime from benzophenanthrene oxidization to hydrazine is _. Figure 4 is a kind of image, which says that the county ammonia _ confuses ^ this article. In the pores 3Α^, it contains meglumine. The conversion of benzophenone to benzoquinone is prevented. Figure 5 is a kind of image, which is called the titration of the system, which is described in this paper. (4) When the concentration of methylamine increases from G5 = ear concentration to 1GG (four) ear concentration, the degree of inhibition increases by 2 in 2Q minutes. [Main component symbol description] None

Claims (1)

200817039, the scope of application for patents: 1. A method for inhibiting the activity in the skin of a mammal, the method of ritual includes a method of applying the group of the genus (4), such as the patent application, wherein: Lai. And the towel is further provided as in the method of the patent scope range w, wherein the combination contains at least one decolorizing agent.匕 办 Do two & the third method, the towel is decolorized by a list of = two: expectant, glucose woven glucosamine, or a combination thereof. 5. The method of claim 3, wherein the composition further comprises at least one additional active ingredient, which is an anti-aging agent, a wrinkle reducing agent, a skin whitening agent, a skin lightening agent, a skin A list of bleaching agents, primary anti-acne agents, sebum reducing agents, and anti-axis or combinations thereof is selected. 6. The method of claim 1, wherein the mammal is a human. 7. A method for inhibiting benzodiazepine oxidase activity in a mammalian skin, the method comprising administering a composition comprising meglumine to the mammal. 8. The method of claim 7 Wherein the composition further comprises a pharmaceutically acceptable carrier. 9. The method of claim 7, wherein the composition further comprises at least one decolorizing agent. The method of claim 9, wherein the decolorizing agent is selected from the group consisting of capric acid, hydroquinone, glucosamine, and guanidine-glucamine, or a combination thereof. The method of claim 7, wherein the composition further comprises at least one additional active ingredient, which is an anti-aging agent, a wrinkle reducing agent, a skin whitening agent, a skin lightening agent, and a skin bleaching. A list of the composition of the agent, the primary anti-puberal agent, the sebum reducing agent, and a sunscreen agent, or a combination thereof. 12. The method of claim 7, wherein the mammal is a human. 13. A method of brightening a mammalian skin, the method comprising administering to the mammal a composition comprising meglumine. 14. The method of claim π, wherein the composition further comprises a pharmaceutically acceptable carrier. The method of claim 13, wherein the composition further comprises at least one decolorizing agent. The method of claim 15, wherein the decolorizing agent is selected from the group consisting of citric acid, hydroquinone, glucosamine, and guanidine-glucamine, or a combination thereof. The method of claim 13, wherein the composition further comprises at least one additional active ingredient, which is an anti-aging agent, a reducing agent, a skin whitening agent, a skin lightening agent, a skin A list of bleaching agents, primary anti-acne agents, a sebum reducing agent, and a sunscreen, or a combination thereof is selected. 74. The method of claim 13, wherein the mammal is a human. 19. A method of brightening the skin of a mammal, the method comprising administering to the mammal a composition comprising 1-deoxy-indole-(methylamino)-D-xylitol (DYN30). 20. A method of reducing pigmentation in the skin of a mammal, the method comprising administering to the mammal a composition comprising meglumine. The method of claim 20, wherein the composition further comprises a pharmaceutically acceptable carrier. The method of claim 2, wherein the composition further comprises at least one decolorizing agent. 23. The method of claim 22, wherein the decolorizing agent is selected from the group consisting of citric acid, hydroquinone, glucosamine, and N-acetylglucosamine, or a combination thereof. The method of claim 2, wherein the composition further comprises at least one additional active ingredient, which is an anti-aging agent, a reducing agent, a granule, a skin whitening agent, a skin lightening agent, A list of skin bleaches, primary anti-acne agents, sebum reducing agents, and anti-, or combinations thereof is selected. [25] The method of claim 2, wherein the mammal is a human. 26. A method of reducing pigmentation in the skin of a mammal, the method comprising administering to the mammal a composition comprising x-oxygenated hepta-(methylamino) xylitol (steroid 3). 75 200817039 27. A method of preventing darkening of a mammalian skin, the method comprising administering to a mammal a composition comprising meglumine. 28. The method of claim 27, wherein the composition further comprises a pharmaceutically acceptable carrier. The method of claim 27, wherein the composition further comprises at least one decolorizing agent. 30. The method of claim 29, wherein the decolorizing agent is selected from the group consisting of 麴@文, the second g component, glucosamine, and bismuth-ethyl glucosamine, or a combination thereof. The method of claim 27, wherein the composition further comprises at least one additional active ingredient comprising an anti-aging agent, a reducing crepe agent, a skin whitening agent, a skin lightening agent, and a skin bleaching A list of agents, primary anti-acne agents, a sebum reducing agent, a sunscreen, or a combination thereof is selected. 32. The method of claim 27, wherein the mammal is a human. 33. A method of inhibiting melanin accumulation in a mammalian skin, the method comprising administering to the mammal a composition comprising glucosamine. 34. A method of inhibiting melanin accumulation in a mammalian skin, the method comprising administering to a mammal a composition comprising 1-deoxysuccinate (D-amino)-D-xylitol (DYN30). 35. The method of claim 33, wherein the composition further comprises a pharmaceutically acceptable carrier. 36. The method of claim 33, wherein the composition further comprises 76 200817039 comprising at least one decolorizing agent. 37. The method of claim 36, wherein the decolorizing agent is selected from the group consisting of capric acid, hydroquinone, glucosamine, and N-acetylglucosamine, or a combination thereof. 38. The method of claim 33, wherein the composition further comprises at least one additional active ingredient comprising an anti-aging agent, a wrinkle reducing agent, a skin whitening agent, a skin lightening agent, and a skin bleaching agent. A list of primary anti-acne agents, a sebum reducing agent, a sunscreen, or a combination thereof is selected. 39. The method of claim 33, wherein the mammal is a human. 40. A method of preventing browning of a fruit, the method comprising applying a composition comprising meglumine to the fruit. 41. A method of preventing browning of a vegetable, the method comprising applying a composition comprising meglumine to the vegetable. 77 200817039 VII. Designation of Representative Representatives (1) The representative representative of the case is: (4). (2) A brief description of the symbol of the representative figure: None 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: