JP6437291B2 - Maillard reaction inhibitor - Google Patents

Description

  The present invention relates to a preparation that inhibits the Maillard reaction, maintains skin firmness and gloss, and is effective for diabetes, Alzheimer's disease, arteriosclerosis and the like.

Skin aging occurs due to the complex action of various factors. Recently, it has been reported that the Maillard reaction is deeply involved in natural aging among skin aging.
Maillard reaction is a complex reaction of amino groups of amino acids, peptides, proteins, etc. with ketones, aldehydes or reducing sugars, and substances called AGEs (Advanced Glycation End Products) are also generated in the body. It has been confirmed that (See Non-Patent Documents 1 and 2).
It is known that when a Maillard reaction is caused to protein and skin collagen which are the main components of the skin, it causes a decrease in skin elasticity and dullness. Moreover, it has been reported that the degeneration of collagen accompanying aging is a cause of disappearance of skin elasticity and gloss. Therefore, it can be expected that the skin protein and collagen are protected by inhibiting the Maillard reaction in the skin, and the firmness and gloss of the skin are maintained.

In addition, an increase in AGEs in in vivo proteins is a phenomenon that is also seen by aging of healthy individuals, but it is known that the degree of increase is high in patients with diabetes, Alzheimer's disease, arteriosclerosis and the like. AGEs create disordered cross-links within and between protein molecules, causing physical and physiological changes (degeneration), and it is clear that AGEs are a direct cause of these diseases and associated complications It is being made.
Maillard reaction inhibitors that inhibit the production of AGEs are likely to be therapeutic or preventive agents for these diseases and symptoms. Therefore, aminoguanidine, a Maillard reaction inhibitor, has already been used as a preventive agent for diabetic complications (non- Patent Document 3) and ALT-711 are used in clinical trials as a therapeutic agent for aging diseases (Non-Patent Document 4).
In addition, as an extract of a plant having a Maillard reaction inhibitory action, for example, an extract selected from calcade, hibiscus, chazenshi, tonin, maronier, keishi, trash, shikon, senna, toshishi, and sandalwood (see Patent Document 1) An extract of yew, extract of goldfish, or extract of moktenryo (see Patent Document 2), an extract of Kashiwagi (see Patent Document 3), an extract of papaya (see Patent Document 4), an extract of Simoniro (See Patent Document 5) and the like.

  However, to date, Maillard reaction inhibitors and aging-improving agents that have excellent Maillard reaction inhibitory activity, are easily available, inexpensive, and are highly safe natural products, and can be used widely. Is not yet fully provided, and there is a strong demand for prompt provision.

JP-A-11-106336 Japanese Patent No. 3695472 JP 2009-67747 A JP 2006-298812 A JP 2006-219447 A

Z. Ernaehrunswiss, Vol. 30, p29-45 Science, Vol. 211, no. 4481, p491-493, 1981 Am J Nephrol. 2004, 24, 32-40 J Card Fail. 2005, 11 (3), 191-195

  The object of the present invention is to inhibit the Maillard reaction, maintain the firmness and gloss of the skin, and further obtain a preparation effective for diabetes, Alzheimer's disease, arteriosclerosis and the like.

  As a result of intensive studies by the present inventors, it has been found that glycyrrhizic acid and its salt and / or an extract of neem leaves achieve the above object.

The Indian Sendang (Melia azadirachta aka Azadirachta indica) is a plant belonging to the family Sendanidae and is distributed in temperate regions of India, Sri Lanka and Myanmar. This bark is used for fever, vomiting and thirst. . Known for its English name “Neeme”, it has long been prized as a mysterious medicine that is indispensable for Indian Ayurvedic.
In consideration of efficiency, the extraction is preferably performed after processing such as chopping, drying, and pulverization.
Drying may be performed in the sun or using a commonly used dryer.
As the solvent used for the extraction, water, a hydrophilic organic solvent, or a mixture thereof is used.
Examples of water that can be used as the extraction solvent include pure water, tap water, well water, mineral spring water, mineral water, hot spring water, spring water, fresh water, and the like, as well as water that has been subjected to various treatments. Examples of the treatment applied to water include purification, heating, sterilization, filtration, ion exchange, adjustment of osmotic pressure, buffering, and the like. Therefore, the water that can be used as the extraction solvent in the present invention includes purified water, hot water, ion-exchanged water, physiological saline, phosphate buffer, phosphate buffered saline, and the like.
Examples of the hydrophilic organic solvent include lower alcohols having 1 to 5 carbon atoms such as methanol, ethanol, propyl alcohol, and isopropyl alcohol; lower aliphatic ketones such as acetone and methyl ethyl ketone; 1,3-butylene glycol, propylene glycol, Examples thereof include polyhydric alcohols having 2 to 5 carbon atoms such as glycerin, and a mixed solvent of these hydrophilic organic solvents and water can be used.

In addition, when using the mixed solvent of the said water and a hydrophilic organic solvent, in the case of a lower alcohol, it is 1-20 mass parts with respect to 10 mass parts of water, and in the case of a lower aliphatic ketone, it is 10 mass parts of water. On the other hand, it is preferable to add 1 to 15 parts by mass. In the case of a polyhydric alcohol, it is preferable to add 1 to 20 parts by mass with respect to 10 parts by mass of water.
The amount of the organic solvent used for the extraction is preferably about 5 to 100 times, more preferably about 10 to 50 times the amount of the plant (seaweed) as the raw material. Furthermore, in order to raise extraction efficiency, you may stir or homogenize in an extraction solvent. The extraction temperature is suitably about 5 ° C. to the boiling point of the extraction solvent. The extraction time varies depending on the type of extraction solvent and the extraction temperature, but it is appropriate to set it to about 1 hour to 14 days.
The extraction operation is not limited to a single operation. A fresh solvent can be added again to the residue after extraction to perform an extraction operation, or the extraction solvent can be brought into contact with the extraction raw material a plurality of times.
If necessary, purification treatment such as deodorization and decolorization may be further added within a range that does not affect the effect, and concentration can be performed by a vacuum concentrator such as an evaporator or solvent removal by heating.
Further, this extract can be further purified using a synthetic adsorbent (Diaion HP20, Sephabies SP825, Amberlite XAD4, MCIgelCHP20P, etc.), dextran resin (Sephadex LH-20, etc.), ultrafiltration and the like. is there.

  Glycyrrhizic acid is a component contained in licorice root, and is a triterpene glycoside that is 30 to 50 times sweeter than sugar. In general, dipotassium salt is often used.

The preparation of the present invention exhibits drug efficacy for oral, injection, and external use, but is preferably used as a skin external preparation. Skin external preparations include skin cosmetics, external quasi-drugs, and medical skin external preparations.
In addition to the above ingredients, the preparations of the present invention include surfactants, oily ingredients, moisturizers, polymer compounds, ultraviolet absorbers, anti-inflammatory agents, bactericides, and other agents used in various pharmaceutical and cosmetic preparations. Antioxidants, sequestering agents, preservatives, vitamins, pigments, fragrances, water and the like can be blended.

  As the surfactant, any of anionic, cationic, nonionic, natural, and synthetic surfactants can be used, but it is preferable to use a nonionic surfactant in consideration of irritation to the skin. Examples of the nonionic surfactant include glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene glycol. , Polyoxyethylene polyoxypropylene alkyl ether, polyethylene glycol fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, alkylglycoside and the like.

  Examples of the oil component include fats and oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, essential oils, silicone oils, and the like. Examples of the fats and oils include soybean oil, nutka oil, jojoba oil, avocado oil, almond oil, olive oil, cacao oil, sesame oil, persic oil, castor oil, coconut oil, mink oil, beef fat, pork fat and the like, and these Hardened oil obtained by hydrogenation of natural fats and oils and synthetic triglycerides such as myristic acid glyceride and 2-ethylhexanoic acid triglyceride; waxes include, for example, carnauba wax, whale wax, beeswax, lanolin and the like; hydrocarbons For example, liquid paraffin, petrolatum, paraffin microcrystalline wax, ceresin, squalane, bristan etc .; higher fatty acids include, for example, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, Linolenic acid, lanolinic acid, isostearic acid, etc .; Examples of the class alcohols include lauryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, lanolin alcohol, cholesterol, 2-hexyldecanol, etc .; examples of the esters include cetyl octanoate, triglyceride octanoate, myristyl lactate, cetyl lactate, Examples of essential oils include mint oil, jasmine, isopropyl myristate, myristyl myristate, octyldodecyl myristate, isopropyl palmitate, isopropyl adipate, butyl stearate, decyl oleate, cholesterol isostearate, POE sorbite fatty acid ester, etc. Oil, pepper brain oil, cypress oil, spruce oil, ryu oil, turpentine oil, cinnamon oil, bergamot oil, mandarin oil, ginger oil, pine , Lavender oil, bay oil, clove oil, hiba oil, rose oil, eucalyptus oil, lemon oil, thyme oil, peppermint oil, rose oil, sage oil, menthol, cineole, eugenol, citral, citronellal, borneol, linalool, geraniol, Camphor, thymol, spirantol, pinene, limonene, terpene compounds, etc .; examples of silicone oils include dimethylpolysiloxane. These oily components described above can be used alone or in combination of two or more. In the present invention, among these, myristic acid glyceride, 2-ethylhexanoic acid triglyceride, lanolin, liquid paraffin, petrolatum, paraffin microcrystalline wax, squalane, lauric acid, myristic acid, palmitic acid, linoleic acid, linolenic acid, isostearic acid , Cetyl alcohol, stearyl alcohol, oleyl alcohol, cholesterol, cetyl octanoate, triglyceride octanoate, isopropyl myristate, octyldodecyl myristate, cholesterol isostearate, POE sorbite fatty acid ester, peppermint oil, spruce oil, cinnamon oil, rose Oil, menthol, cineol, eugenol, citral, citronellal, geraniol, pinene, limonene, dimethylpolysiloxane It is preferable to use.

The following components can be further added to the preparation of the present invention, but the components are not limited thereto.
Colors: Yellow color No. 4, Blue No. 1 and Yellow No. 202 are recognized as food additives such as tar color dyes I and II, chlorophyll, riboflavin, crocin, safflower, anthraquinone, etc. Natural pigments.
Vitamins; vitamin A, vitamin C, vitamin D, vitamin E, etc.
Others: bactericides, preservatives, other ingredients necessary for formulation.

The preparation of the present invention can be produced according to a conventional method by adding the optional components to the essential components as necessary, and can be in the form of cream, emulsion, lotion or the like.
The amount of dipotassium glycyrrhizinate is 0.0001 to 5% by weight, preferably 0.001 to 2.0% by weight, and the extract of neem leaves is 0.00001 to 1.0% by weight, preferably as a solid. Is 0.0001 to 0.5% by weight.

Maillard reaction inhibition test 50 μl of test product solution, 100 μl of purified water, 500 μl of 0.1 M phosphate buffer (pH 7.2), 200 μl of 4 mg ml BSA, and 100 μl of 2M glucose solution were incubated at 60 ° C. for 30 hours. (A reaction solution in which the same operation was performed as an object was incubated at 4 ° C. for 30 hours, respectively.)
200 μl of the reaction solution was put into a 96-well plate for fluorescence measurement, and the fluorescence value of the final glycation product (AGEs) was measured with a fluorescence plate reader (Ex / Em = 340/420 nm).
The obtained measurement value calculated the inhibition rate according to the following formula.


Inhibition rate = ((AC) − (BD)) × 100 / (AC)

A: 60 ° C reaction, no test product B: 60 ° C reaction, test product present C: 4 ° C reaction, no test product D: 4 ° C reaction, test product present The results are shown in Table 1.

  When the extract of dipotassium glycyrrhizinate and neem leaves was used as an external preparation for skin, it was found that the firmness and gloss of the skin were improved.

Claims (1)

Maillard reaction inhibitor as an active ingredient an extract of the leaves of Lee Ndosendan.