JP2009137927A - Physiologically active composition containing thioctic acid derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a thioctic acid derivative having high safety and physiological activity at a low cost. <P>SOLUTION: A method is provided for the low-cost synthesis of a derivative obtained by bonding an 8-22C hydrocarbon group which may have branches or unsaturated bonds, an acyl group or a 9-100C polycyclic aromatic hydrocarbon to a thioctic acid derivative. A physiologically active composition contains the derivative. The physiologically active composition containing the thioctic acid derivative has high safety and stability compared with conventional thioctic acid derivative, is easily absorbable in cells and tissues to increase the thioctic acid concentration in the cells and tissues after absorption, keeps high thioctic acid activity in the cells and tissues for a long time and exhibits a wide range of physiological effects greatly exceeding the effects of existing derivatives. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

Detailed Description of the Invention

The present invention relates to a physiologically active composition containing a thioctic acid derivative.

The technology of division, promotion and regeneration of living cells and tissues has greatly advanced and is widely applied in fields such as industrial medicine, pharmaceuticals, cosmetics, foods and feeds. In particular, research on cell culture media and matrix compositions has progressed, and recently, the use of artificial media and matrices has made basic research easier. In addition, cost reduction, elimination of lot differences, and maintenance of quality and the like are facilitated.
In addition, factors such as EGF (Epidmal Growth Factor) and GM-CSF (Granular Macrophage-Colony Stimulating Factor) have been discovered as cell growth promoters.

Reference 1

Marchese C.M. Rubin J., et al. Ron D. , Faggioni A. , Torrisi M. et al. . R. Messina A .; Frati L. , Aaronson S. A. , J .; Cell Physiol. 144 (2) 326-332, 1990,

Reference 2

Braunstein S.M. Kaplan G., et al. , Gottlieb A .; . B. , Schwartz M .; Walsh G .; , Abalos R .; M,. Fajardo T. T.A. Guido L., et al. S. , Krueger J. et al. G. , J .; Invest. Dermatol. , 103 (4) 601-604, 1994,

Reference 3

Paus R. , Luftl M. et al. , CzarnetzkiB. M.M. , Br. J. et al. Dermatol. 130 (2) 174-180. , 1994).

Since these factors promote wound healing in humans and various animals, they have been studied for the treatment of wounds and burns and have been used as cell culture growth factors in cell biology experiments. Accordingly, the provision of an excellent cell growth and tissue formation promoter and cell culture composition is useful for medical, beauty, health maintenance, anti-aging, wound healing, animal husbandry, fermentation production and cell biological experiments. It occupies a very important position.

It is known that oxygen toxicity is due to the formation of reactive oxygen species (ROS) in the body, and this ROS includes free radicals and non-radicals that induce oxidative damage to anatomy. ROS has been shown to be involved in over 100 diseases and aging processes, aging of organisms, growth inhibition, wound healing in many organisms including humans, farmed and fermented organisms.

Thioctic acid (also known as lipoic acid: hereinafter abbreviated as LA) is an antioxidant molecule that is required in vivo like vitamin C and vitamin vitamin E, and is present in many organisms from humans to bacteria. Known as thioctic acid, 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3-valeric acid or 6,8-thioctic acid. Thioctic acid has one asymmetric carbon atom and results in two enantiomeric forms.

Reduced forms of lipoate, such as dihydrothioctic acid (dihydrolipoic acid), have two —SH groups that provide a very low oxidation potential (−0.29 V) for the molecule. Thus, the redox conjugate of thioctic acid and DHLA interacts with almost all forms of ROS, recycles other antioxidants, and can further reduce the oxidized disulfide groups of biological systems. It is an agent. These molecules can then restore their biological reducing power and function. All of these properties of LA also make it one of the most important molecules in redox signaling. For this reason, thioctic acid is used as an antiaging agent and a radical disease preventive or therapeutic agent.

Many derivatives of thioctic acid (including reduced forms) are already known. For example, US Pat. Nos. 5,650,429 and 5,532,269 are applications of thioctic acid to cardiovascular disease, and US Pat. No. 5,621,117 is an anti-inflammatory function of thioctic acid. US Pat. No. 5,569,670 is an analgesic, anti-inflammatory, anti-necrotic and anti-diabetic, US Pat. No. 5,334,612 is an application to retroviral diseases. U.S. Pat. No. 5,084,481 is anti-inflammatory, U.S. Pat. No. 5,693,664 is a diabetic application, and U.S. Pat. No. 5,508,275 already has thioctic acid derivatives. Disclosure.

ROS is known to be able to activate NF-κB, and ROS is thought to be the last common signal for many stimuli that activate NF-κB.

Reference 4

Sen and Packer, The FASEB Journal, 10, 709-720 (1996). Activation of NF-κB is believed to be at least partially involved in the cause or progression of a number of disease states.

Reference 5

Packer et al., Advances in Pharmacology, 38, 79-101 (1997) Tocotrienyl thioctic acid is NF-κB activated in US Provisional Application No. 60 / 055,433, Aug. 4, 1997. Has been proposed to adjust.

On the other hand, in surgical operations, wound closure / joining of the skin, organs, blood vessels, etc., protection and reinforcement of the excised part, and substitute tissue are one of the most basic procedures. The use of polymer compositions for tissue regeneration such as bioimplants such as adhesive films, gauze, bandages, bandages, and fracture reinforcing materials has become common. The polymer composition for tissue regeneration is used to create conditions under which wounds can be joined and healed, and tissue can be easily regenerated. When using a tissue regeneration polymer composition for wound closure, bonding, and regeneration, especially when it is a suture thread or adhesive tape, reinforcing bone, or a substitute tissue, biocompatibility that can withstand moderate external force, It is conceivable to use a polymer composition for tissue regeneration with good regenerative properties, and several tissue regeneration polymer compositions are clinically used. In particular, the absorbable polymer composition absorbed in the living body, after absorption, the tissue regeneration site recovers to a normal state without leaving a foreign body. In addition, a polymer composition for bioresorbable tissue regeneration is used as a bioreinforcing material and a biological tissue substitute material. Causes of delaying rapid healing of wounds due to large amounts of active oxygen such as hydroxyl radicals due to infiltration of neutrophils, which are likely to cause an inflammatory reaction in surgical and wound sites where these polymer compositions for tissue regeneration are used It has become. It is also effective for detoxification of heavy metals. The administration of antioxidants such as thioctic acid is likely to be effective against the wound healing delay caused by these radical species, and the search for thioctic acid derivatives that express thioctic acid activity efficiently in the living body has been conducted. It was.

However, these conventional thioctic acids are unstable and have problems with safety, contrary to high antioxidant activity, are poorly absorbed into tissues and cells, are consumed in a short time in vivo, and the effect of thioctic acid is sufficient There was a problem that could not be demonstrated. In addition, there is a problem that even a stable thioctic acid derivative does not convert to thioctic acid in cells or in vivo and does not exhibit the effect of thioctic acid. In order to change the effect of a thioctic acid derivative that is stable in vitro to an active form in vivo, it is necessary to involve in vivo chemical changes such as a hydrolysis reaction in an in vivo enzyme having stereospecificity. For this reason, the thioctic acid derivative is designed if it is not evaluated in a cell system or biological system, even if the inherent chemical structure of the thioctic acid derivative molecule changes, a slight change in the three-dimensional structure, a change in the chiral structure, etc. The effect of can not be estimated. In order to confirm the intracellular and in vivo effects of the thioctic acid derivative, there is a problem that the thioctic acid derivative must actually be synthesized and evaluated in the cell system and the actual ecology. Therefore, even if thioctic acid alone has a preventive, ameliorating, or therapeutic effect on aging, adult disease, cerebral infarction, myocardial infarction, cardiovascular disorder, pain, inflammation, necrosis, toxin, diabetes, skin disease, it is newly synthesized. The effect cannot be estimated and guaranteed with the thioctic acid derivative. Moreover, it is unclear whether the effect of the new derivative exhibits the effect of the conventional thioctic acid. The same applies to the following cosmetic effects of known thioctic acid. That is, the effect of suppressing, reducing and preventing skin pigmentation, the sufficient effect of suppressing, reducing and preventing acne on the skin, the effect of improving seborrhea related disorders, the suppression, reduction and prevention of wrinkles and sagging of the skin Diseases that inhibit, reduce or prevent skin wrinkles and sagging, promote hair growth, prevent hair loss, reduce pores, improve texture, slimming, and active oxygen. The problems of these conventional thioctic acid derivatives are summarized as follows.

Some known thiocto derivatives have safety issues, and are cytotoxic, irritating, and allergic. Even if it is a known thioctic acid derivative, its actual effect cannot be predicted unless it is actually evaluated in cells or in vivo. Known thiocto derivatives are prone to degradation when stored in formulations and have low stability. Known thiocto derivatives are not easily absorbed by cells and tissues. Even if a known thiocto derivative is absorbed by a cell or tissue, it cannot increase the concentration of thioctic acid sufficient to exert a sufficient effect in the cell or tissue. Known thiocto derivatives are not easily converted to thioctic acid and cannot exhibit high thioctic acid activity in cells and tissues. Known thiocto derivatives cannot exert thioctic acid activity for a long time in cells and tissues. In particular, known thiocto derivatives cannot sufficiently exhibit the effects of the following known thioctic acids. It cannot promote the proliferation and tissue formation of various cells, which are the effects of known thioctic acid. Known thiocto derivatives cannot sufficiently shorten the culture time for cell and tissue formation. With known thiocto derivatives, the effect of increasing the passage number of cultured cells is low. With known thiocto derivatives, many target cells cannot be obtained in a short time. With known thiocto derivatives, the antioxidant activity cannot be continuously exerted in cells and tissues. With known thiocto derivatives, the effect is limited by a specific species or cell type, and the effect cannot be exerted in common for a wide range of species and cell types. A wide range of industrially useful aquaculture pet animals and a wide range of industrially useful single-cell organisms used in the fermentative production industry are not sufficiently effective against growth inhibition and stress. The following effects that can be expected as the effect of thioctic acid cannot be sufficiently exhibited. Radical disease, adult disease, cerebral infarction, myocardial infarction, cardiovascular disorder, analgesic effect, inflammation, necrosis, diabetes, pigmentation, acne, seborrhea, wrinkles, sagging, obesity, swelling, hair loss, pore enlargement, rough skin. In addition, in order to synthesize these known thioctic acid derivatives, the raw material cost is high, the equipment cost is high, the production energy cost is high, the reaction is complicated and difficult to control, and the purity of the obtained thioctic acid derivative is low. In addition, there is a problem that high cost is required to obtain a high concentration thioctic acid derivative.

In addition, as described above, there is a demand for a tissue regeneration polymer composition that can withstand moderate tension and breaking force, has no tissue damage, and has good biocompatibility. However, since the conventional polymer composition for tissue regeneration has low strength, problems such as failure of tissue regeneration after surgery, biotoxicity to living tissue, and hindering tissue regeneration of the tissue. There is also a point. Until now, there has been no polymer composition for tissue regeneration that has the effect of more actively promoting tissue regeneration, and a polymer composition for tissue regeneration that promotes tissue regeneration and enhances tissue regeneration power is desired. Yes. In addition, wounds often involve inflammation and are susceptible to infectious diseases, causing cellular tissue damage due to active oxygen generated from immune cells, antibiotics, etc., making it difficult to repair wounds. At present, there is no polymer composition for tissue regeneration for body tissue that comprehensively solves the problems such as inflammation, infection and active oxygen generation of these wounds. The present invention solves the above-mentioned problems, and its purpose is higher than that of comprehensively solving problems such as anti-inflammatory action, anti-infective action, and active oxygen generation as well as having a higher tissue regeneration promoting action. The object is to provide a polymer composition for tissue regeneration having an effect for tissue regeneration.

The antioxidant properties of thioctic acid are due in particular to its function as a strong reducing agent, along with its ability to form chelates with metal ions and directly remove radicals.

Problems to be solved by the invention

The problems to be solved by the present invention are described below.
To provide a derivative having a safety, irritation, and allergenicity lower than those of existing thioctic acid derivatives, although it is a novel derivative. To provide a highly stable thioctic acid derivative with little degradation even when stored in a preparation. To provide a thioctic acid derivative that is easily absorbed by cells and tissues. It must be a thioctic acid derivative that can increase the thioctic acid concentration in cells and tissues after being absorbed by cells and tissues. Able to exert high activity of thioctic acid in cells and tissues. Able to exert thioctic acid activity for a long time in cells and tissues. Derivatives that can exhibit the following effects of thioctic acid to a higher degree. To provide a thioctic acid derivative that promotes proliferation and tissue formation of various cells. To provide a thioctic acid derivative capable of shortening the culture time of cell and tissue formation. To provide a thioctic acid derivative that increases the passage number of cultured cells. To provide a thioctic acid derivative capable of exerting an effect in common with a wide range of biological species and cell types whose effects are not limited by specific biological species or cell types. To provide a thioctic acid derivative capable of obtaining a large number of target cells in a short time. To provide a thioctic acid derivative that can continuously exert high antioxidant activity in cells and tissues. To provide a thioctic acid derivative that can sufficiently exhibit the following effects, which are the effects of a conventional known thioctic acid, and to select a synergistic curing agent for exhibiting the highest effect. Radical disease, anti-aging activity, adult disease prevention activity, cerebral infarction, myocardial infarction, cardiovascular disorder, analgesic effect, anti-inflammatory sclerosis, anti-necrosis effect, anti-diabetic disease, detoxification, skin disease prevention, improvement, treatment effect. The effect of suppressing, reducing and preventing skin pigmentation, the effect of suppressing, reducing and preventing skin acne, the effect of improving seborrhea related disorders, the effect of suppressing, reducing and preventing skin wrinkles and sagging, Diseases involving skin wrinkles and sagging, reducing hair, preventing hair growth, promoting hair growth, preventing hair loss, reducing pores, improving texture, slimming, and active oxygen. The effects are not limited by specific species and cell types, and can be exerted in common with a wide range of species and cell types, especially in a wide range of industrially useful aquaculture pet animals and fermentation production industries. To provide a thioctic acid derivative capable of sufficiently exerting effects on growth inhibition and stress of industrially useful single-cell organisms. Moreover, in order to reduce the cost of these known thioctic acid derivatives, to establish a synthesis method that reduces raw material costs, facility costs, and production energy costs. Establish a production method for obtaining a highly pure thioctic acid derivative with high purity of the thioctic acid derivative that is easy to control and not complicated.

Means for solving the problem

As a result of diligent research based on the above problems, the present inventors have found that a special thioctic acid derivative having a carbon chain with a certain length range among many thioctic acid derivatives is safe, stable, As a result of investigating each of the effects of various thioctic acids, it was found that the effects of absorption, thioctic acid activity, and sustainability were all satisfactory, and the present invention was completed.

The present inventors first collected a large amount of known thioctic acid derivatives and conducted a stability test in a high temperature state. As a result, a group of thioctic acid derivatives having a hydrocarbon group having 2 to 35 carbon atoms in thioctic acid and dihydrothioctic acid. Was found to be extremely stable.

Next, these thioctic acid derivatives having a hydrocarbon group having 2 to 35 carbon atoms are subjected to titer change after 6 months, cytotoxicity test, absorbability to cells and tissues, enzymatic degradation property and anti-degradability of skin tissue homogenate. Results of oxidative activity and skin irritation test, continuous skin irritation test, skin sensitization test, phototoxicity test, mutagenicity test, chromosomal aberration test, and thioctic acid derivative having a hydrocarbon group having 8 to 22 carbon atoms It was found that the group cleared all safety and showed high effect at the same time.

Further, when various effect tests were conducted with the thioctic acid of the present invention, a group of thioctic acid derivatives having a hydrocarbon group having 8 to 22 carbon atoms (said specimen numbers: 37 to 40, 46 to 48, particularly preferably 41 to 41). 45) and the dihydrothioctic acid derivative group of the present invention, specimen numbers 57-60, 66-68, particularly preferably 61-65) were found to exhibit extremely high effects, and the present invention was completed.

Furthermore, when the above thioctic acid derivatives were tested in many industrially useful animal species, species, and single-cell organisms, the effects were not limited by specific species or cell types, and they were common to a wide range of species and cell types. It is effective against a wide range of industrially useful aquaculture pet animals and a wide range of industrially useful single-cell organisms used in the fermentation production industry, detoxification effects such as harmful metals such as mercury, and stress. It was found that the derivative is a thioctic acid derivative that can sufficiently exhibit the effect.

Furthermore, when the manufacturing method of these thioctic acid derivatives was examined, in the conventional manufacturing method of binding a fatty acid to thioctic acid, the production cost, reaction cost, and raw material cost are high, but intermediate alcohol is reacted with thioctic acid to obtain a thioctic acid derivative. As a result of honest opinion about the method, 1 ± 0.5 molecular equivalent of thioctic acid and physiologically acceptable medium chain, long chain monovalent, divalent, or trivalent alcohol 1 ± 0.5 having 8 to 22 carbon atoms. Dissolve the molecular equivalent in a dehydrated methylene chloride solvent under an inert gas atmosphere, add 0.05 ± 0.025 molecular equivalent of a catalytic amount of dimethylaminopyridine and stir at 0 ± 10 ° C. while stirring at 1.1 ± 0.00. After adding 5 molecular equivalents, the reaction is stirred for 1 to 48 hours at 25 ± 10 ° C., thereby reducing the production cost and producing a very high reaction yield It could be established. As for the purification method, after separating the reaction mixture, the solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was separated and purified by a silica gel column (hexane weight% / ethyl acetate weight% = 10 ± 5). In this way, high purity can be obtained and the present invention has been completed.

That is, the present invention is a composition for promoting cell growth and tissue formation containing a thioctic acid derivative as an active ingredient. The claims of the present invention are as follows.

Claim 1

（式（１）中、Ｒ１は、分岐または不飽和結合を有していてもよい炭素数８〜２２、さらに好ましくは炭素数１４から１８の炭化水素元基、又は、アシル基、又は炭素数９〜１００のポリサイクリックアロマティクハイドロカーボン又は炭素連続体を示す。）An industrially useful physiologically active composition comprising a thioctic acid derivative represented by the following general formula (1).

(In Formula (1), R1 may have a branched or unsaturated bond, C8-22, more preferably a C14-18 hydrocarbon primary group, acyl group, or carbon number. 9 to 100 polycyclic aromatic hydrocarbons or carbon continuums are shown.)

Claim 2

（式（２）中、Ｒ１は、分岐または不飽和結合を有していてもよい炭素数８〜２２、さらに好ましくは炭素数１４から１８の炭化水素元基、又は、アシル基、又は、炭素数９〜１００のポリサイクリックアロマティクハイドロカーボン又は炭素連続体を示す。）An industrially useful physiologically active composition comprising a dihydrothioctic acid derivative represented by the following general formula (2).

(In Formula (2), R1 is a hydrocarbon group having 8 to 22 carbon atoms, more preferably 14 to 18 carbon atoms, which may have a branched or unsaturated bond, or an acyl group or carbon. A polycyclic aromatic hydrocarbon or carbon continuum having a number of 9 to 100 is shown.)

Claim 3

（式（３）中、Ｒ６〜Ｒ８はそれぞれ独立に水素原子、アリール基、又は分岐、不飽和結合もしくは置換基を有していてもよい、炭素数８〜２２、さらに好ましくは炭素数１４〜１８の炭化水素基を表す。）。The industrially useful physiologically active composition according to claim 1 or 2, wherein in the formulas (1) and (2), R1 is a group selected from any of the following formulas (3): object.

(In Formula (3), R6 to R8 each independently have a hydrogen atom, an aryl group, or a branched, unsaturated bond or substituent, and preferably have 8 to 22 carbon atoms, more preferably 14 to 14 carbon atoms. Represents 18 hydrocarbon groups).

Claim 4

In the formula (3), R 6 is a chain hydrocarbon group having 8 to 22 carbon atoms, more preferably 14 to 18 carbon atoms, which may have a branch, an unsaturated bond or a substituent, and R 7 And R8 are each independently a hydrogen atom or a chain hydrocarbon group having 8 to 22 carbon atoms, more preferably 14 to 18 carbon atoms, which may have a branched, unsaturated bond or substituent. The industrially useful physiologically active composition according to claim 3.

Claim 5

Tedecanoylthioctic acid (n = 14), isotetradecanoylthioctic acid (n = 14), pentadeca having the following chemical structure, which may have a branched, unsaturated bond or substituent: Noylthioctic acid (n = 15), isopentadecanoylthioctic acid (n = 15), hexadecanoylthioctic acid (n = 16), isohexadecanoylthioctic acid (n = 16), heptadecanoylthioctic acid ( The industrially useful physiologically active composition according to claim 1, comprising any one of n = 17) and isoheptadecanoyl thioctic acid (n = 17).

Claim 6

Tedecanoyl dihydrothioctic acid (n = 14), isotetradecanoyl dihydrothioctic acid (n = 14) having the following chemical structure, which may have a branched, unsaturated bond or substituent: Pentadecanoyl dihydrothioctic acid (n = 15), isopentadecanoyl dihydrothioctic acid (n = 15), hexadecanoyl dihydrothioctic acid (n = 16), isohexadecanoyl dihydrothioctic acid (n = 16), The industrially useful physiologically active composition according to claim 1, comprising any one of heptadecanoyl dihydrothioctic acid (n = 17) and isoheptadecanoyl dihydrothioctic acid (n = 17).

Claim 7

The industrially useful physiologically active composition according to any one of claims 1 to 6, wherein the thioctic acid derivative concentration is added so that the cell culture medium concentration or tissue concentration is 50 to 3200 ppm.

Claim 8

Sodium L-ascorbic acid-2-phosphate, magnesium L-ascorbic acid-2-phosphate, L-ascorbic acid-2-glucoside, sodium L-ascorbic acid-2-phosphate-6-palmitic acid, sodium L- Ascorbic acid-2-phosphate-6-isopalmitic acid, L-ascorbic acid-2,3,5,6-tetrahexyldecanoic acid, L-ascorbic acid-3-ethyl, ascorbic acid-3-glucoside, sodium tocopheryl The industrially useful physiologically active composition according to any one of claims 1 to 7, comprising at least one compound selected from phosphoric acid, sodium tocopheryldimethylglycine, and tocopheryl retinoic acid at the same time.

Claim 9

Industrially useful physiological activities include high sustained activity, high absorbability to cells, high enzyme conversion activity in living organisms, high activity in living organisms, low cytotoxicity, cells The industrially useful physiologically active composition according to any one of claims 1 to 8, which has one or more physiologically active effects selected from high growth promoting activity.

Claim 10

10. The industrially useful physiologically active composition according to claim 9, wherein the cell is any one selected from prokaryotic cells, eukaryotic cells, protist cells, fungal cells, animal cells, and plant cells.

Claim 11

Cells are stem cells, neurons, glandular fibroblasts, keratinocytes, pigment cells, cardiomyocytes, hepatocytes, oral mucosal epithelial cells, enamel blasts, odontoblasts, hair matrix cells, vascular endothelial cells, hematopoietic stem cells, many The industrially useful physiologically active composition according to claim 11, which is a potent stem cell or an adipocyte.

Claim 12

The industrially useful physiologically active composition according to any one of claims 9 to 11, wherein the cell is a plurality of cell aggregates which are tissues or organs.

Claim 13

The physiologically active composition is a pharmaceutical product having a physiological effect according to any one of the following: Industrially useful physiologically active composition according to any one of claims 1 to 12, a therapeutic disease preventive effect on an adult disease, Preventive effect on cerebral infarction, preventive effect on myocardial infarction, preventive effect on treatment of cardiovascular disease, preventive effect on anti-infective treatment, wound healing effect, analgesic effect, anti-inflammatory effect, detoxification effect, anti-necrosis effect, preventive effect on diabetes treatment, pigment Anti-deposition treatment effect, acne treatment prevention effect, seborrhea treatment prevention effect, UV irradiation disorder treatment prevention effect, wrinkle treatment prevention effect, sagging treatment prevention effect, obesity treatment prevention effect, swelling treatment prevention effect, hair loss treatment prevention effect, Prevention of pore enlargement treatment, prevention of rough skin treatment, prevention of growth inhibition treatment, anti-stress effect.

Claim 14

The physiologically active composition is a cosmetic product having any of the following physiological effects: Industrially useful physiologically active composition according to any one of claims 1 to 12, analgesic effect, antipruritic effect, detoxification effect, wound healing effect Anti-necrosis effect, pigmentation treatment prevention effect, acne treatment prevention effect, seborrhea treatment prevention effect, ultraviolet irradiation disorder treatment prevention effect, wrinkle treatment prevention effect, sagging treatment prevention effect, swelling treatment prevention effect, hair loss treatment prevention effect , Pore expansion treatment prevention effect, rough skin treatment prevention effect, anti-stress effect.

Claim 15

The industrially useful physiologically active composition according to any one of claims 1 to 14, wherein the physiologically active composition is a polymer composition for tissue regeneration.

Claim 16

The physiologically active composition according to any one of claims 1 to 14, wherein the physiologically active composition is a food additive.

Claim 17

The industrially useful physiologically active composition according to any one of claims 1 to 14, wherein the physiologically active composition is a feed additive.

Claim 18

The following manufacturing method of the thioctic acid derivative in any one of Claims 1-6.
1 ± 0.5 molecular equivalent of thioctic acid and 1 to 0.5 molecular equivalent of physiologically acceptable medium chain, long chain monovalent, divalent, or trivalent alcohol having 8 to 22 carbon atoms as inert gas Under atmosphere, dissolved in dehydrated methylene chloride solvent, a catalytic amount of 0.05 ± 0.025 molecular equivalent of dimethylaminopyridine was added. While stirring at 0 ± 10 ° C., 1.1 ± 0.5 molecular equivalent of dicyclohexylcarbodiimide was added, followed by stirring at 25 ± 10 ° C. for 1 to 48 hours to separate and purify the reaction mixture.

Claim 19

The following purification method of the thioctic acid derivative according to any one of claims 1 to 6.
After separating the reaction mixture obtained in claim 24, the solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was separated and purified on a silica gel column (hexane weight% / ethyl acetate weight% = 10 ± 5).

（式（９）中、Ｒ１は、分岐または不飽和結合を有していてもよい炭素数８〜２２、さらに好ましくは炭素数１４から１８の炭化水素元基、又は、アシル基、又は炭素数９〜１００のポリサイクリックアロマティクハイドロカーボン又は炭素連続体を示す。）The thioctic acid derivative as the composition for promoting cell growth and tissue formation of the present invention is represented by the following general formula.

(In Formula (9), R1 is a C8-C22 hydrocarbon group which may have a branched or unsaturated bond, more preferably a C14-C18 hydrocarbon radical, an acyl group, or a carbon number. 9 to 100 polycyclic aromatic hydrocarbons or carbon continuums are shown.)

The polycyclic aromatic hydrocarbon having 9 to 100 carbon atoms is a carbon continuum composed of only carbon, hydrogen, and a hydroxyl group represented by the following general formula.

（上式１０，１１，１２中、Ｃは炭素原子を示し、好ましくは隣接する炭素と共有結合で結ばれた複数の環状構造体をとり、Ｒｎは、Ｃに結合するｎ個の置換基であり、それぞれ独立して、同一又は別異に、水素原子、炭素原子、酸素原子、窒素原子、リン原子、水酸基、その水酸基と無機酸もしくは有機酸とのエステル基、その水酸基と糖との配糖体基、その水酸基とケトンとのケタール基又はその水酸基とアルデヒドのアセタール基を示す。ｎは１以上の整数を示す。Ｒｎが炭素の場合は、隣接した炭素と共役系で結ばれた炭素のみからなる連続した環状構造体であることが望ましい。）The polycyclic aromatic hydrocarbon having 9 to 100 carbon atoms may be a continuous cyclic structure of a plurality of carbons represented by the following general formula.

(In the above formulas 10, 11, and 12, C represents a carbon atom, preferably takes a plurality of cyclic structures covalently bonded to adjacent carbon, and Rn is an n number of substituents bonded to C. Each independently or independently, a hydrogen atom, a carbon atom, an oxygen atom, a nitrogen atom, a phosphorus atom, a hydroxyl group, an ester group of the hydroxyl group with an inorganic acid or an organic acid, and the coordination of the hydroxyl group with a sugar. A saccharide group, a ketal group of a hydroxyl group and a ketone, or an acetal group of the hydroxyl group and an aldehyde, n represents an integer of 1 or more, and when Rn is carbon, carbon bonded to adjacent carbon in a conjugated system It is desirable that it is a continuous annular structure consisting only of

Specific examples of the cyclic aromatic hydrocarbon that can be used in the present invention include pyrene, coronene, naphthalene, phenanthrene, perylene, benzoperylene, tetraphen, chrysene, antanthrene, ovarene, pentaphen, Examples include pentacene, triindane, corannulene, dodecahedrane, and decacyclene.

Reference 6

Douglas M.M. etc. The Astrophysical Journal, 632: 316-332, 2005 October 10

Reference 7

L. T.A. Scott et al Science 295, 1500 (2002)

Reference 8

G. Mehta et al Tetrahedron 54, 13325 (1998)

（式（１３）中、Ｒ１は、分岐または不飽和結合を有していてもよい炭素数８〜２２、さらに好ましくは炭素数１４から１８の炭化水素元基、又は、アシル基、又は、炭素数９〜１００のポリサイクリックアロマティクハイドロカーボン又は炭素連続体を示す。）Furthermore, the thioctic acid derivative as the composition for promoting cell growth and tissue formation of the present invention is represented by the following general formula.

(In the formula (13), R1 is a hydrocarbon group having 8 to 22 carbon atoms which may have a branched or unsaturated bond, more preferably 14 to 18 carbon atoms, or an acyl group or carbon. A polycyclic aromatic hydrocarbon or carbon continuum having a number of 9 to 100 is shown.)

（式（３）中、Ｒ６〜Ｒ８はそれぞれ独立に水素原子、アリール基、又は分岐、不飽和結合もしくは置換基を有していてもよい、炭素数８〜２２、さらに好ましくは炭素数１４〜１８の炭化水素基を表す。）。In the formulas (1) and (2), R1 may be a group selected from any of the following formulas (3).

(In Formula (3), R6 to R8 each independently have a hydrogen atom, an aryl group, or a branched, unsaturated bond or substituent, and preferably have 8 to 22 carbon atoms, more preferably 14 to 14 carbon atoms. Represents 18 hydrocarbon groups).

Further, in the formula (3), R6 is a chain hydrocarbon group having 8 to 22 carbon atoms, more preferably 14 to 18 carbon atoms, which may have a branch, an unsaturated bond or a substituent. , R7 and R8 are each independently a hydrogen atom or a branched hydrocarbon group having 8 to 22 carbon atoms, more preferably 14 to 18 carbon atoms, which may have a branched, unsaturated bond or substituent. The composition for promoting cell growth and tissue formation according to claim 3 may be used.

同時に本発明は、以下の化学構造を有する新規物質であるテトラデカノイルジヒドロチオクト酸（ｎ＝１４）、イソテトラデカノイルジヒドロチオクト酸（ｎ＝１４）、ペンタデカノイルジヒドロチオクト酸（ｎ＝１５）、イソペンタデカノイルジヒドロチオクト酸（ｎ＝１５）、ヘキサデカノイルジヒドロチオクト酸（ｎ＝１６）、イソヘキサデカノイルジヒドロチオクト酸（ｎ＝１６）、ヘプタデカノイルジヒドロチオクト酸（ｎ＝１７）、イソヘプタデカノイルジヒドロチオクト酸（ｎ＝１７）を含むものである。

さらに、本発明は、チオクト酸誘導体濃度が細胞培地濃度又は組織中濃度を５０〜３２００ｐｐｍになるように添加することを特徴とする請求項１〜６のいずれかに記載の細胞増殖及び組織形成促進用組成物がより好ましく。Further, the present invention is a novel substance having the following chemical structure: tetradecanoyl thioctic acid (n = 14), isotetradecanoyl thioctic acid (n = 14), pentadecanoyl thioctic acid (n = 15), Isopentadecanoyl thioctic acid (n = 15), hexadecanoyl thioctic acid (n = 16), isohexadecanoyl thioctic acid (n = 16), heptadecanoyl thioctic acid (n = 17), isoheptadecanoyl Contains thioctic acid (n = 17).

At the same time, the present invention relates to tetradecanoyl dihydrothioctic acid (n = 14), isotetradecanoyl dihydrothioctic acid (n = 14), pentadecanoyl dihydrothioctic acid (n = 15) which are novel substances having the following chemical structures. ), Isopentadecanoyl dihydrothioctic acid (n = 15), hexadecanoyl dihydrothioctic acid (n = 16), isohexadecanoyl dihydrothioctic acid (n = 16), heptadecanoyl dihydrothioctic acid (n = 17) ), Isoheptadecanoyl dihydrothioctic acid (n = 17).

Furthermore, this invention is added so that a thioctic acid derivative density | concentration may become a cell culture medium density | concentration or tissue density | concentration to 50-3200 ppm, The cell growth and tissue formation promotion in any one of Claims 1-6 characterized by the above-mentioned. More preferred is a composition for use.

Furthermore, the present invention relates to sodium L-ascorbic acid-2-phosphate, magnesium L-ascorbic acid-2-phosphate, L-ascorbic acid-2-glucoside, sodium L-ascorbic acid-2-phosphate-6- Palmitic acid, sodium L-ascorbic acid-2-phosphate-6-isopalmitic acid, L-ascorbic acid-2,3,5,6-tetrahexyldecanoic acid, L-ascorbic acid-3-ethyl, ascorbic acid-3 The cell growth and tissue according to any one of claims 1 to 7, which simultaneously contains one or more compounds selected from glucoside, sodium tocopheryl phosphate, sodium tocopheryl dimethylglycine, and tocopheryl retinoic acid. A composition for promoting formation is more preferred.

Furthermore, the cell that is the subject of the present invention may be any one selected from prokaryotic cells, eukaryotic cells, protist cells, fungal cells, animal cells, and plant cells.
Among these cells, stem cells, neurons, glandular fibroblasts, keratinocytes, pigment cells, cardiomyocytes, hepatocytes, oral mucosal epithelial cells, enamel blasts, odontoblasts, hair matrix cells, vascular endothelial cells, hematopoiesis Desirable are stem cells, pluripotent stem cells, and adipocytes.

Furthermore, the present invention includes a collection of cells in which the cells are tissues or organs. Specific embodiments of the present invention include a tissue regeneration promoting pharmaceutical comprising the above-described composition for promoting cell proliferation and tissue formation, and cosmetics, a polymer composition for tissue regeneration, and a polymer composition for tissue regeneration. Things are included.

Furthermore, this invention includes the following manufacturing methods of the thioctic acid derivative described above.
1 ± 0.5 molecular equivalent of thioctic acid and 1 to 0.5 molecular equivalent of physiologically acceptable medium chain, long chain monovalent, divalent, or trivalent alcohol having 8 to 22 carbon atoms as inert gas Under atmosphere, dissolved in dehydrated methylene chloride solvent, a catalytic amount of 0.05 ± 0.025 molecular equivalent of dimethylaminopyridine was added. While stirring at 0 ± 10 ° C., 1.1 ± 0.5 molecular equivalent of dicyclohexylcarbodiimide was added, followed by stirring at 25 ± 10 ° C. for 1 to 48 hours to separate and purify the reaction mixture.

The present invention further includes the following purification method of the thioctic acid derivative described above.
After separating the reaction mixture obtained in claim 24, the solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was separated and purified on a silica gel column (hexane weight% / ethyl acetate weight% = 10 ± 5).

The following high effects could be confirmed in the thioctic acid and dihydrothioctic acid derivatives of the present invention. Radical disease, adult disease, cerebral infarction, myocardial infarction, cardiovascular disorder, analgesic effect, inflammation, necrosis, diabetes, pigmentation, acne, seborrhea, wrinkles, sagging, obesity, swelling, hair loss, pore enlargement, rough skin, Wounds, growth inhibition, stress.

Specific examples of the above radical diseases include skin aging, pigmentation, wrinkles, cancer, seborrhea, sunburn, cancer, acne, burns, sagging skin, obesity, hair loss, stress, psychosis, dementia, Parkinson's disease, HIV, cold, influenza, infection, myocardial infarction, ischemic heart disease, heart failure, angina, arrhythmia, arteriosclerosis, liver lipid metabolism disorder, hyperlipidemia, essential hypertension, hypertension, arteriosclerosis, Coronary sclerosis, thrombosis, obstructive arteriosclerosis, vascular disorder, peripheral vascular disorder, cholestasis, hypercholesterolemia, pancreatic disorder, organ failure, acute chronic hepatitis, gastric ulcer, duodenal ulcer, ulcerative colitis, Gastrointestinal disorders cholecystosis, diabetes, arthritis treatment, rheumatism, liver failure, liver disorders, ischemic liver disorders, liver lipid metabolism disorders, gallbladder disorders, organ transplant disorders, diabetes, addiction, organ transplant disorders, ischemic reperfusion Obstacle , Is ischemic disease.

It is known from the following references and references cited in the references that these radical diseases are caused by radicals or one of the causative factors thereof is an in vivo radical.

References

"Reactive oxygen and disease state" edited by Inoue, Academic Publishing Center, 1992 and "Antioxidant" Futaki et al., Academic Publishing Center, 1994

References

“Contemporary Medicine” vol. 25, no. 10, 1993

Specific examples of the radical disease related to the present invention include the following diseases. That is, the radical diseases that are the targets of the drug of the redox control composition of the present invention include organ failure and tissue damage at the time of organ transplantation performed for tissue replacement. That is, cells and tissues due to heart transplantation surgery such as heart, liver, kidney, pancreas, gallbladder, thymus, stomach, lung, intestine, skin, coronary artery recanalization and the like, bypass surgery, and diseases and events described below And organ damage associated with the stoppage or delay of blood flow flowing into the body, and damage to cells and tissues that occur during or after reperfusion after the stop of blood flow, or damage to death or organ failure. The present invention is effective for these diseases. In addition, the present invention relates to vascular thrombosis, anemia, ischemia, vascular sclerosis, vasoconstriction, hemorrhage (OBAYASHI, PROC. SOC. EXP. BIOL. WED., 196, 196, 164-169, 1990). Examples include, for example, damage to cells and tissues associated with physical reduction or cessation of blood flow velocity caused by the above, death, and diseases and insufficiency of organs including blood vessels. The redox control composition of the present invention includes oxygen deficiency caused by a decrease in oxygen pressure in blood vessels, and temporary deficiency of oxygen deficient tissues in cells or tissues caused by chemical substances such as agricultural chemicals and carbon monoxide poisoning. Organs including cell death, blood vessel damage, death or blood vessels found when blood flow is sent to cells or tissue under normal or close conditions by appropriate treatment or event such as blood transfusion Diseases and insufficiency, and the like are also effective. The redox control composition of the present invention is also effective for ischemic reperfusion diseases, and examples thereof include ischemic reperfusion myocardial injury (NARITA.WJ, J.LAB.CLIN.MED., 110, 153-158, 1987, Smith, LL Phil. Trans. R. Soc., 311, 647-657, 1985), ischemia-reperfusion liver injury (INOUE, M, INMUCOSAL IMMUNOLOGY, 527-530, ELSEVIER, AMSTERDAM, 1990, Nakahama, Liver, 32: 1110-1123, 1991, Takekawa, Liver, 30: 459-467, 1989, Shirasugi, Nissho Gaijin, 26: 358, 1993) Ischemia / Reperfusion Kidney Disorder , Ischemia-reperfusion pancreatic injury (ISAJI, S .: MIE MED. J., 35: 109-123 1985), ischemia-reperfusion gallbladder disorder (TAOKA, GASTROENT.JPN, 26: 633-644, 1991), ischemia-reperfusion cardiovascular disorder, ischemia-reperfusion gastrointestinal disorder (Iwai, Nisshokai, 87) 1662-1669, 1990, NAITO, Y., FREE RED. RES. COMMS, 16: 13.5, 1992), ischemia-reperfusion myopathy, ischemia-reperfusion vascular disorder, ischemia-reperfusion ophthalmopathy book Also effective for ischemia-reperfusion skin disorders such as The redox control composition of the present invention is also effective in the following various disorders induced by active oxygen. Specific examples include Behcet's disease, radiation damage, side effects of anticancer drugs, bacterial shock, cachexia, autoimmune disease, burns, herpes virus, adult T cell leukemia, thioredoxin syndrome, traumatic shock, fungal atrophy Such as lateral sclerosis, asexual myocardial infarction. Furthermore, the present invention provides the human epidermal keratinization as described above for growing human epidermal keratinocytes by adding to a serum-free medium for human epidermal keratinocytes, or for treating burns, wounds or aza A composition for promoting cell proliferation and tissue formation is included.

The composition for promoting human epidermal keratinocyte proliferation and tissue formation of the present invention can, for example, cultivate cells obtained from humans and propagate them to tissues. In addition, the cell growth and tissue formation promoting composition of the present invention can be added to a commercially available cell culture kit to prepare a culture solution, which can be used to promote cell growth.

The effective concentration of the thioctic acid derivative of the composition for promoting cell growth and tissue formation according to the present invention is 1 ppm to 10000 ppm in a solvent or a tissue culture medium such as a culture solution. In order to continuously obtain an effect that is superior to that of thioctic acid, the cell culture medium concentration or tissue concentration must be 50 to 3200 ppm. The existence of a highly effective effective concentration range of the thioctic acid derivative is considered to be due to the equilibrium reaction characteristic of the thioctic acid derivative-acting enzyme of the cell as well as the safe concentration for the cell.

In addition, when the composition for promoting cell proliferation and tissue formation of the present invention is applied as a pharmaceutical, the subject is not particularly limited as long as it is for the purpose of treating or improving various diseases or symptoms by activating human epidermal keratinocytes. . For example, treatment for burns, wounds, aza, etc. can be used as a specific purpose. Moreover, the method of administration is performed parenterally, and the dosage form includes creams, ointments, cataplasms and the like. The dosage varies depending on whether it is an animal or a human, and also varies depending on the age, administration route, and number of administrations, and can vary widely. In this case, an effective amount administered as a composition of the composition for promoting cell growth and tissue formation of the present invention and an appropriate diluent and a pharmaceutically usable carrier is 0.01-100 mg / It is cm2 skin / day, and it is administered once or several times a day for 2 days or more.

The polymer used in the polymer composition for tissue regeneration used in the present invention is not particularly limited, but a biodegradable polymer is preferable. As the biodegradable polymer, any of those conventionally used as a polymer composition for tissue regeneration can be used. For example, polyglycolic acid (PGA), polylactic acid (PLA), poly (α-hydroxy) Acid) polymer, poly-β-hydroxybutyric acid (PHB), poly (β-hydroxyalkanoate) polymer, poly-ε-caprolactone (PCL), poly (ω-hydroxyalkanoate), polybutylene succinate (PBS), polyethylene succinate (PES), polyalkylene alkanoate, polyester polymer, polypropylene polymer, polyamide polymer, polytetrafluoroethylene polymer, PGA-PLA polymer, polydioxanone polymer Chitin / chitosan polymer, polyamino acid polymer, polysaccharide chain polymer, Examples include biodegradable polymers such as polynucleic acid polymers, hydroxyapatite polymers, and calcium phosphate polymers, but are not particularly limited. In the case where the polymer composition for tissue regeneration is a biodegradable polymer, it is absorbed after wound healing, and is therefore particularly suitable when it is preferable for a living body not to remain as a foreign body. In addition, the polymer composition of the present invention has a porous structure in which fine holes or spaces having a diameter of 1 nm to 1 mm are present, such as a commercially available membrane filter for removing bacteria, thereby allowing more anti-inflammatory factors, This is effective because it can incorporate a simple substance or a complex molecule selected from a free radical scavenging factor, a cell growth factor, an anti-infective factor, and a tissue formation inducing factor. In the case where the present invention is a fiber, a hollow fiber structure having a single molecule or a complex molecule thereof selected from more anti-inflammatory factors, free radical scavenging factors, cell growth factors, anti-infective factors, and tissue formation inducing factors It is effective because it can be captured.

The biodegradable polymer may be any material that can be decomposed and absorbed by the forces of enzymes, cells, bacteria, etc. in the living body. Examples include molecules, PGA-PLA-based polymers, polydioxanone-based polymers, chitin / chitosan-based polymer compositions, and the like, but are not particularly limited as long as they are biodegradable polymer compositions.

The biodegradable polymer is preferably an aliphatic polyester biodegradable resin. Examples thereof include, for example, poly (α-hydroxy acids) such as polyglycolic acid (PGA) and polylactic acid (PLLA); poly (β-hydroxyalkanoates) such as poly-β-hydroxybutyric acid (PHB); Poly (ω-hydroxyalkanoates) such as -ε-caprolactone (PCL); polyalkylene alkanoates such as polybutylene succinate (PBS) and polyethylene succinate (PES). These resins may be homopolymers or copolymers with copolymerizable components. These resins can be synthesized by a known method. The weight average molecular weight of these resins is, for example, at least 50,000, preferably at least 70,000, and more preferably 100,000 to 300,000.

In claim 22 of the present invention, as the polymer other than the biodegradable polymer, various known polymers can be used without any particular limitation. Typical examples are polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyethylene naphthalate (PEN), a copolymer of polyethylene terephthalate, a copolymer of polybutylene terephthalate, and a copolymer of polyethylene naphthalate. Examples thereof include polyester resins such as coalescence; nylon resins; styrene resins; polyolefin resins such as polyethylene and polypropylene. Polyethylene includes very low density polyethylene, low density polyethylene, linear low density polyethylene, medium density polyethylene, and high density polyethylene. The inclusion of the polymer improves practical problems such as the brittleness of the biodegradable polymer. In particular, when a polyolefin resin is contained, a hydrophobic effect can be obtained, and the hydrolysis resistance of the biodegradable polymer can be improved.

In the present invention, a compatibilizing agent for compatibilizing these polymers can be contained by a conventional method. Examples thereof include ionomer resins, oxazoline-based compatibilizing agents, elastomer-based compatibilizing agents, and reactive phases. There are, but not limited to, a solubilizer and a copolymer-based compatibilizer. By containing the compatibilizing agent, the compatibility between the biodegradable polymer and the other polymer is improved, and the action of the highly degradable polymer becomes more effective.

If necessary, ions can be added to these polymer compositions.
For example, alkali metal ions such as Li +, Na +, K +, alkaline earth metal ions such as Mg2 +, Ca2 +, Sr2 +, Ba2 +, transition metal ions such as Zn2 +, Cu2 +, Mn2 +, Ni2 +, Co2 +, Co3 +, Fe3 +, Cr3 + are used. It is done. In addition, an anion such as C1-, Br-, I- or the like can be blended with the cation host polymer.

The polymer that can be added to the present invention is not particularly limited. For example, ethylene-methacrylic acid copolymer ionomer, ethylene-acrylic acid copolymer ionomer, propylene-methacrylic acid copolymer ionomer, propylene-acrylic acid copolymer. Combined ionomer, Butylene-acrylic acid copolymer ionomer, Ethylene-vinylsulfonic acid copolymer ionomer, Styrene-methacrylic acid copolymer ionomer, Sulfonated polystyrene ionomer, Fluorinated ionomer, Telechelic polybutadiene acrylic acid ionomer, Sulfonated ethylene -Propylene-diene copolymer ionomers, hydrogenated polypentamer ionomers, polypentamer ionomers, poly (vinylpyridium salt) ionomers, poly (vinyltrimethylammonium) (Monium salt) ionomer, poly (vinylbenzylphosphonium salt) ionomer, styrene-butadiene acrylic acid copolymer ionomer, polyurethane ionomer, sulfonated styrene-2-acrylamido-2-methylpropane sulfate ionomer, acid-amine ionomer, aliphatic System ionene, aromatic ionene, polyethylene-polyamide graft copolymer (PE-PA GP), polypropylene-polyamide graft copolymer (PP-PA GP) and the like. Further, it contains at least one group selected from the group consisting of alkoxy groups, amino groups, mercapto groups, vinyl groups, epoxy groups, acetal groups, maleic acid groups, oxazoline groups and carboxylic acid groups, and has a melt flow rate of 1 or more Specifically, methyl methacrylate-butadiene-styrene resin, acrylonitrile-butadiene rubber, EVA / PVC / graft copolymer, vinyl acetate-ethylene copolymer resin, ethylene- Examples include α-olefin copolymers, propylene-α-olefin copolymers, hydrogenated styrene-isopropylene-block copolymers, and the like.

If necessary, a reactive compatibilizing agent can be added to the polymer composition of the present invention. Specific examples thereof include a compound having a double bond, a carboxyl group, an epoxy group, an isocyanate group, etc. (low molecular compound or Polymer), which reacts with one or both of the polymers to be compatibilized in the molding process and acts as a surfactant based on the graft or block structure to function as a compatibilizer. Yes (Reference: "Polymer Roy" Fundamentals and Applications, edited by Polymer Society, published in 1993). Examples of the reactive compatibilizer that can be used in the present invention include ethylene glycidyl methacrylate copolymer (E-GMA; copolymer weight composition, for example, E / GMA = 100/6 to 12), ethylene glycidyl methacrylate-vinyl alcohol copolymer. Polymer (E-GMA-VA; copolymer weight composition, for example, E / GMA / VA = 100/3 to 12/8 to 5), ethylene glycidyl methacrylate-methacrylate copolymer (E-GMA-MA; copolymer weight) Composition, for example, E / GMA / MA = 100/3 to 6/30). Specifically, Sumitomo Chemical, Bond First E, Bond First 2C; Nippon Polyolefin, Lexpearl RA, Lexpearl ET, Lexpearl RC, ethylene maleic anhydride ethyl acrylate copolymer (E-MAH-EA; Sumitomo) Chemical, Bondine), ethylene glycidyl methacrylate-acrylonitrile styrene (EGMA-AS; copolymer weight composition, eg EGMA / AS = 70/30), ethylene glycidyl methacrylate-polystyrene (EGMA-PS; copolymer weight composition, eg EGMA / PS = 70/30) ethylene glycidyl methacrylate-polymethyl methacrylate (EGMA-PMMA, for example, EGMA / PMMA = 70/30), acid-modified polyethylene wax (APEW; manufactured by Mitsui Chemicals, high wax), OOH polyethylene graft polymer, COOH polypropylene graft polymers, polyisocyanates containing 5-30% by weight of isocyanate groups. Specifically, Degussa (VESTANAT T1890) is mentioned. Only one of these reactive compatibilizers may be used, or two or more thereof may be mixed and used as necessary.

In the present invention, the compatibilizer is preferably blended in an amount of 0.1 to 100 parts by weight, more preferably 1 to 20 parts by weight with respect to 100 parts by weight of the biodegradable polymer. In the case where a plurality of compatibilizers are used, the total amount thereof should be within the above range. When the blending amount of the compatibilizer is less than 0.1 parts by weight, it is difficult to obtain a compatibilizing effect between the biodegradable polymer and the other polymer, and an improvement effect due to the polymer is hardly exhibited. On the other hand, when the amount of the compatibilizer exceeds 100 parts by weight, the compatibilizing effect is saturated and the biodegradability of the resulting biodegradable polymer material is lowered. In consideration of the use of the biodegradable polymer material, the amount of the compatibilizer used may be appropriately determined.

In the present invention, the biodegradable polymer material further includes other additives such as organic or inorganic fillers, flame retardants, anti-blocking agents, crystallization accelerators, gas adsorbents, anti-aging agents (esters, amides, etc.) ), Antioxidants, ozone degradation inhibitors, UV absorbers, light stabilizers, tackifiers, plasticizers (fatty acids such as stearic acid and oleic acid or their metal salts), softeners (mineral oil, wax, Paraffins, etc.), stabilizers, lubricants, mold release agents, antistatic agents, modifiers, colorants, coupling agents, preservatives, antifungal agents and the like may be appropriately blended.

The blending method is not particularly limited and can be carried out by an ordinary melt kneading method. For example, a biodegradable polymer, a polymer other than a biodegradable polymer, a compatibilizer, and other optional components are kneaded in a roll kneader, a Banbury mixer, an intermix, a single screw extruder, a twin screw extruder, etc. Kneading with a machine is recommended. Kneading may be performed using one kind of kneader selected from the kneaders, or may be performed using two or more kinds of kneaders.

A biodegradable polymer, a polymer other than a biodegradable polymer, and a biodegradable polymer material containing a compatibilizing agent are molded by conventional methods to form various molded articles. Moreover, it is also possible to add an additive to the biodegradable polymer material as necessary to obtain a coating material, a coating material, or an adhesive material.

Various molded products from the biodegradable polymer material can be produced by a conventional molding method. For example, extrusion molded products, injection molded products, blow molded products, sheets or films extruded from T dies, inflation films, fibers by melt spinning, yarns, strings, ropes, multifilaments, monofilaments, flat yarns, staple fibers , Fibrous structures such as spunbond nonwoven fabrics and flash-spun nonwoven fabrics, and various foam-molded articles can be obtained.
Sodium L-ascorbic acid-2-phosphate, magnesium L-ascorbic acid-2-phosphate, L-ascorbic acid-2-glucoside, sodium L-ascorbic acid-2 that exhibits a synergistic effect with the thioctic acid derivative of the present invention -Phosphoric acid-6-palmitic acid, sodium L-ascorbic acid-2-phosphate-6-isopalmitic acid, L-ascorbic acid-2,3,5,6-tetrahexyldecanoic acid, L-ascorbic acid-3- The amount of ethyl, ascorbic acid-3-glucoside, sodium tocopheryl phosphate, sodium tocopheryl dimethylglycine, and tocopheryl retinoic acid is not particularly limited and is appropriately selected over a wide range, but preferably in the composition of the present invention. Is in the range of 10-6 to 10% by weight, more preferably 0.001% to 1% by weight. It is in the range of.

In addition to the thioctic acid derivative described above, the composition for promoting cell growth and tissue formation of the present invention and the pharmaceutical, cosmetic, medical material, polymer composition for tissue regeneration, and polymer composition for tissue regeneration of the present invention include In general, components used for promoting cell growth and tissue formation, or pharmaceuticals, medical materials, and cosmetics can be blended in amounts that do not impair the effects of the present invention. Examples of materials that can be added to the production of the present invention (for example, oil, higher alcohol, fatty acid, ultraviolet absorber, powder, pigment, surfactant, polyhydric alcohol / sugar, polymer, physiologically active ingredient, solvent, antioxidant Agents, fragrances, preservatives, etc.) are listed below, but of course the present invention is not limited to these examples. Although it does not specifically limit as a component which can be mix | blended with this invention, For example, the component as described in the following references is mentioned.

Public number

Ingredients described in JP-A-2005-343880 (P2005-343880A), paragraph numbers [0050] to [0062]

The composition for promoting cell growth and tissue formation of the present invention and the pharmaceutical and cosmetic containing the same may be in any dosage form and form as long as they are used in contact with the skin at the time of use. It is more preferable to use it in contact with the skin in the vicinity of the site where metabolism is desired. Specifically, for example, skin milk, skin cream, foundation cream, massage cream, cleansing cream, shaving cream, cleansing foam, lotion, lotion, pack, lipstick, blusher, eye shadow, nail polish, soap, body shampoo, hand Soap, shampoo, rinse, hair tonic, treatment, hair cream, hair spray, hair restorer, hair nourishing agent, hair dye, hair conditioner, hair removal agent, anti-dandruff agent, toothpaste, denture adhesive, gargle, permanent wave agent, curling Cosmetics, styling agents, ointments, poultices, tape bathing agents, antiperspirants, sunscreen agents, etc. are included in a broad sense. It is preferable that it is a form which can be used as. Regardless of the gender and age of the user. Furthermore, in addition to humans, those that come into contact with animal skin are also included. Moreover, the composition for promoting cell growth and tissue formation of the present invention and the cosmetic containing the composition may be in any shape, and in addition to solid, liquid, semi-solid, gas, powder, granule, tablet shape Although many forms, such as a gel form and a foam form, are mentioned, it is not limited to this in particular. In addition, the cosmetics of this invention can use what can generally be used as cosmetics among the other components mentioned above, In addition to these, the existing cosmetic raw material can also be used further. For example, Cosmetic Material Standards Second Edition Annotation, edited by Japan Standards Association, 1984 (Pharmaceutical Daily Report), Cosmetic Raw Material Standards Ingredient Standard, Ministry of Health and Welfare Pharmaceutical Affairs Bureau Examination Division Supervision, 1993 (Pharmaceutical Daily Report), Cosmetic Raw Material Standards Ingredients Standards supplement, supervised by the Ministry of Health and Welfare Pharmacy Examination Division, 1993 (Pharmaceutical Daily), permission standards by cosmetic type, supervision by the Ministry of Health and Welfare Pharmacy Examination Division, 1993 (Pharmaceutical Daily), formulation standard by cosmetic variety, Ministry of Health and Welfare Pharmacy Examination Division All cosmetic raw materials described in Supervision, 1997 (Pharmaceutical Daily), Cosmetic Raw Material Dictionary, Heisei 3 (Nikko Chemicals), and new cosmetic functional materials 300, 2002 (CMC Publishing) can be used. The composition for promoting cell growth and tissue formation and the cosmetic of the present invention are prepared by dissolving, mixing, or dispersing the above-described components according to a conventional method according to the mode using the above-described components so as to have a predetermined content. Can be manufactured.

When the composition for promoting cell growth and tissue formation of the present invention is administered parenterally, additives such as a stabilizer, a buffer, a preservative, and an isotonic agent can be contained.

Action

When the thioctic acid derivative and dihydrothioctic acid derivative used in the present invention were examined, a thioctic acid derivative having a hydrocarbon group having 8 to 22 carbon atoms, particularly a thioctic acid derivative having a hydrocarbon group having 14 to 18 carbon atoms, Comprehensive evaluation that summarizes the results of titer changes after months, tissue absorption, skin tissue homogenate solution enzymatic degradation and antioxidant activity, and skin irritation. In comparison, it has been confirmed that all have extremely excellent performance in any evaluation of titer change over time, absorption into tissue, enzymatic degradation and antioxidant activity of skin tissue homogenate, and skin irritation. . It is presumed that these combined actions could have a very useful action in the industry compared to the conventionally known thioctic acid.

EXAMPLES Hereinafter, although this invention is demonstrated further more concretely based on an Example, this invention is not limited to these Examples.

Synthesis Example 1-1
<Synthesis of heptadecanoyl thioctic acid>
Thioctic acid (2.06 g, 10 mmol) and 1-heptadecanol (2.56 g, 10 mmol) are dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) is dissolved. Was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.31 g of light yellow solid heptadecanoylthioctic acid. The yield was about 75%.
The structure of this target product was confirmed by the following 1H-NMR spectrum.
1H NMR (400 MHz, CDCl3) d4.06 (t, J = 6.8 Hz, 2H), 3.57 (quin, J = 6.4 Hz, 1H), 3.17 (m, 1H), 3.13 ( m, 1H), 2.46 (sex, J = 6.4 Hz), 2.32 (t, J = 7.2 Hz, 1H), 1.89 (sex, J = 6.8 Hz, 1H), 1. 75-1.61 (m, 1H), 1.26 (bs, 33H), 0.88 (t, J = 6.0 Hz, 3H);
The structure of this target product was confirmed by the following 13C-NMR spectrum.
13C NMR (75 MHz, CDCl3) d173.5, 64.5, 56.3, 55.7, 40.2, 38.4, 34.9, 34.6, 34.1, 31.9, 29.7 29.6, 29.5, 29.3, 29.2, 28.7, 28.6, 25.9, 25.4, 24.7, 22.7, 14.1; Was confirmed by the following IR (KBr) spectrum.
IR (KBr) 2918, 2850, 2120, 1730, 1472, 1238, 1178 cm <-1>

Synthesis Example 1-2
α-Lipoic acid (2.06 g, 10 mmol) and oleyl alcohol represented by the following chemical formula [Chemical Formula 17] (2.68 g, 10 mmol) were dissolved in dehydrated methylene chloride solvent (50 mL) in an argon atmosphere, and a catalytic amount of dimethylamino was dissolved. Pyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain α-lipoic acid ester [Chemical Formula 18] represented by the following chemical formula as a yellow liquid (4.4 g, yield 96). %).

The structure of this target product was confirmed by the following 1H-NMR spectrum.
¹ H NMR (400 MHz, CDCl ₃ ) δ 5.34-5.29 (m, 2H), 4.01 (t, J = 6.8 Hz, 2H), 3.52 (dquin, J = 6.4, 1 .6 Hz, 1H), 3.17 to 3.04 (m, 2H), 2.42 (sex, J = 6.8 Hz), 2.27 (t, J = 7.2 Hz, 1H), 1.97. (Bsex, J = 7.2 Hz, 2H), 1.84 (sex, J = 7.2 Hz, 1H), 1.69 to 1.54 (m, 4H), 1.43 (m, 1H), 1 .24 (bm, 30H), 0.83 (t, J = 6.8 Hz, 3H);
The structure of this target product was confirmed by the following 13C-NMR spectrum.
¹³ C NMR (75 MHz, CDCl ₃ ) δ 173.5, 129.9, 129.7, 64.5, 56.3, 40.2, 38.4, 34.6, 34.1, 32.6, 31 .9, 29.7, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 29.2, 28.7, 28.6, 27.2, 27.2 , 25.9, 24.7, 22.6;
The structure of the target product was confirmed by the following IR (KBr) spectrum.
IR (KBr) 2925, 2854, 1736, 1458, 1175 cm ⁻¹ ; MS (ESI) positive, m / z = 457.4 (M + H) ⁺ , 479 (M + Na) ⁺ , 495 (M + K) ⁺ .

<Synthesis of hexadecanoyl thioctic acid>
Thioctic acid (2.06 g, 10 mmol) and hexadecanol (2.58 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.29 g of yellow solid hexadecanoylthioctic acid.

Synthesis example 3
<Synthesis of octadecanoyl thioctic acid>
Thioctic acid (2.06 g, 10 mmol) and hexadecanol (2.57 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.15 g of a light yellow solid of octadecanoylthioctic acid.

Synthesis example 4
<Synthesis of pentadecanoyl thioctic acid>
Thioctic acid (2.06 g, 10 mmol) and pentadecanol (2.55 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 2.85 g of a pale yellow solid of pentadecanoylthioctic acid.

Synthesis Example <Synthesis of tetradecanoyl thioctic acid>
Thioctic acid (2.06 g, 10 mmol) and tetradecanol (2.51 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.25 g of a light yellow solid of tetradecanoylthioctic acid.

Synthesis Example <Synthesis of icosanoyl thioctic acid>
Thioctic acid (2.06 g, 10 mmol) and icosanol (2.45 gl) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain icosanoylthioctic acid as a pale yellow solid (3.11 g was obtained).

Synthesis Example <Synthesis of docosanoylthioctic acid>
Thioctic acid (2.06 g, 10 mmol) and docosanol (2.39 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.54 g of a light yellow solid of docosanoyl thioctic acid.

Synthesis Example <Synthesis of dodecanoyl thioctic acid>
Thioctic acid (2.06 g, 10 mmol) and dodecanol (2.34) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.15 g of dodecanoylthioctic acid as a pale yellow solid.

Synthesis Example <Synthesis of Decanoyl Thioctic Acid>
Thioctic acid (2.06 g, 10 mmol) and decanol (2.29 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 2.99 g of a light yellow solid of decanoylthioctic acid.

Synthesis Example <Synthesis of Octanoylthioctic Acid>
Thioctic acid (2.06 g, 10 mmol) and octanol (2.23 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.10 g of a light yellow solid of octanoylthioctic acid.

Synthesis Example <Synthesis of hexanoylthioctic acid>
Thioctic acid (2.06 g, 10 mmol) and hexanol (2.20 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.08 g of hexanoylthioctic acid as a pale yellow solid.

Synthesis Example <Synthesis of Pentanoylthioctic Acid>
Thioctic acid (2.06 g, 10 mmol) and pentanol (2.17 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.34 g of a pale yellow solid pentanoylthioctic acid.

Synthesis Example <Synthesis of butanoylthioctic acid>
Thioctic acid (2.06 g, 10 mmol) and butanol (2.12 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.24 g of a light yellow solid of butanoylthioctic acid.

Synthesis Example <Synthesis of propanoylthioctic acid>
Thioctic acid (2.06 g, 10 mmol) and propanol (2.05 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.09 g of propanoylthioctic acid as a pale yellow solid.

Synthesis Example <Synthesis of Ethanoylthioctic Acid>
Thioctic acid (2.06 g, 10 mmol) and ethanol (1.99 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.20 g of ethanoylthioctic acid as a yellow solid.

Synthesis Example <Synthesis of methanoyl thioctic acid>
Thioctic acid (2.06 g, 10 mmol) and methanol (1.97 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 2.96 g of methanoylthioctic acid as a pale yellow solid.

Synthesis Example <Synthesis of Butylene Glycoyl Thioctic Acid>
Thioctic acid (2.06 g, 10 mmol) and 1,3-butylene glycol (5.12 g) are dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) is added. added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 2.54 g of light yellow solid butyleneglycol thioctic acid.

Synthesis Example <Synthesis of Propylene Glycoyl Thioctic Acid>
Thioctic acid (2.06 g, 10 mmol) and propylene glycol (4.23 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 2.98 g of propyleneglycol thioctic acid as a yellow solid.

Synthesis Example <Synthesis of Isohexadecanoylthioctic Acid>
Thioctic acid (2.06 g, 10 mmol) and isohexadecanol (2.55 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. . Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.31 g of isohexadecanoylthioctic acid as a pale yellow solid.

Synthesis Example <Synthesis of Hydroxyisohexadecanoylthioctic Acid>
Thioctic acid (2.06 g, 10 mmol) and hydroxyhexadecanol (2.76 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. . Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 2.98 g of hydroxyisohexadecanoylthioctic acid as a yellow solid.

Synthesis Example <Synthesis of mercaptohexadecanoyl thioctic acid>
Thioctic acid (2.06 g) and mercaptohexadecanol (3.14 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 3.11 g of a light yellow solid mercaptohexadecanoylthioctic acid.

Synthesis Example <Synthesis of mercaptohexadecanoyl thioctic acid>
Thioctic acid (2 g) and an alcohol selected from the following alcohol group (3 g) were dissolved in dehydrated methylene chloride solvent (50 ml) under an argon atmosphere, and a catalytic amount of dimethylaminopyridine (60 mg, 0.5 mmol) was added. . Dicyclohexylcarbodiimide (2.26 g, 11 mmol) was added while stirring at 0 ° C., and then stirred at room temperature for 1 day. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain thioctic acid derivatives.

A novel substance containing the present invention which is a thioctic acid derivative having the following sample number was produced by the above production method, and the structure of the target product was confirmed by 1H-NMR spectrum, 13C-NMR spectrum and IR (KBr) spectrum.
33) butanoylthioctic acid, 34) pentanoylthioctic acid, 35) hexanoylthioctic acid, 36) heptanoylthioctic acid, 37) octanoylthioctic acid, 38) nonanoylthioctic acid, 39) decanoylthioctic acid, 40) dodecanoylthioctic acid, 41) tetradecanoylthioctic acid, 42) pentadecanoylthioctic acid, 43) hexadecanoylthioctic acid, 44) heptadecanoylthioctic acid, 45) octadecanoylthioctic acid, 46) nona Decanoylthioctic acid, 47) Icosanoylthioctic acid, 48) Docosanoylthioctic acid, 49) Tetracosanoylthioctic acid, 50) Hexacosanoylthioctic acid, 51) Octacosanoylthioctic acid, 52) Triacontanoylthiocto Acid, 53) butanoyl dihydrothioc Acid, 54) pentanoyl dihydrothioctic acid, 55) hexanoyl dihydrothioctic acid, 56) heptanoyl dihydrothioctic acid, 57) octanoyl dihydrothioctic acid, 58) nonanoyl dihydrothioctic acid, 59) decanoyl dihydrothioctic acid, 60) dodecanoyl dihydrothioctic acid, 61) tetradecanoyl dihydrothioctic acid, 62) pentadecanoyl dihydrothioctic acid, 63) hexadecanoyl dihydrothioctic acid, 64) heptadecanoyl dihydrothioctic acid, 65) octadecanoyl dihydro Thioctic acid, 66) Nonadecanoyl dihydrothioctic acid, 67) Icosanoyl dihydrothioctic acid, 68) Docosanoyl dihydrothioctic acid, 69) Tetracosanoyl dihydrothioctic acid, 70) Hexacosanoyl dihydro Octoic acid, 71) octacosanoyl dihydrothioctic acid, 72) triacontanoylthioctic acid, tetradecanoylthioctic acid, isotetradecanoylthioctic acid, pentadecanoylthioctic acid, isopentadecanoylthioctic acid, hexadecanoylthiocto Acid, isohexadecanoylthioctic acid, heptadecanoylthioctic acid, isoheptadecanoylthioctic acid, 93) isobutanoylthioctic acid, 94) isopentanoylthioctic acid, 95) isohexanoylthioctic acid, 96) isohepta Noylthioctic acid, 97) isooctanoylthioctic acid, 98) isononanoylthioctic acid, 99) isodecanoylthioctic acid, 100) isododecanoylthioctic acid, 101) isotetradecanoylthioctic acid, 102) isopentadeca Neulch Octocic acid, 103) Isohexadecanoylthioctic acid, 104) Isoheptadecanoylthioctic acid, 105) Isooctadecanoylthioctic acid, 106) Isononadecanoylthioctic acid, 107) Isoicosanoylthioctic acid, 108) Isodocosanoylthioctic acid, 109) isotetracosanoylthioctic acid, 110) isohexacosanoylthioctic acid, 111) isooctacosanoylthioctic acid, 112) isotriacontanoylthioctic acid, 113) isobutanoyldihydrothioctic acid , 114) isopentanoyl dihydrothioctic acid, 115) isohexanoyl dihydrothioctic acid, 116) isoheptanoyl dihydrothioctic acid, 117) isooctanoyl dihydrothioctic acid, 118) isononanoyl dihydrothioctic acid, 11 ) Isodecanoyl dihydrothioctic acid, 120) isododecanoyl dihydrothioctic acid, 121) isotetradecanoyl dihydrothioctic acid, 122) isopentadecanoyl dihydrothioctic acid, 123) isohexadecanoyl dihydrothioctic acid, 124) iso Heptadecanoyl dihydrothioctic acid, 125) Isooctadecanoyl dihydrothioctic acid, 126) Isononadecanoyl dihydrothioctic acid, 127) Isoicosanoyl dihydrothioctic acid, 128) Isodocosanoyl dihydrothioctic acid, 129) Isotetra Cosanoyl dihydrothioctic acid, 130) isohexacosanoyl dihydrothioctic acid, 131) isooctacosanoyl dihydrothioctic acid, 132) isotriacontanoyl thioctic acid

In the present invention, an effect test confirming that the thioctic acid derivative is effective as a composition for promoting cell growth and tissue formation is described below.

(Stability test)
The thioctic acid derivative group having the hydrocarbon group having 8 to 22 carbon atoms of the present invention produced above (specimen number: 37-40, 46-48, 41-45) and the dihydrothioctic acid derivative group of the present invention, specimen Nos. 57-60, 66-68, 61-65) and existing thioctic acid derivatives (carbon numbers 4-7 and 23-30, specimen numbers 29-36, 49-52), and existing dihydrothioctic acid (sample) Each test substance containing No. 53-56, 69-72) and an existing vitamin derivative was dispersed in Dulbecco's PBS (−) to obtain 1% by mass of each test substance solution or dispersion. Each test substance obtained is stored at 40 ° C. for 6 months, and each titer is measured by high performance liquid chromatography and gas chromatography. The average value is obtained and the titer after 6 months is defined as 0% as 100%. Expressed in weight percent.

1) Thioctic acid, 8% or less, 2) Dihydrothioctic acid, 12% or less, 3) Sodium L-ascorbic acid-2-phosphate, 57%, 4) Magnesium L-ascorbic acid-2-phosphate, 68% 5) L-ascorbic acid-2-glucoside, 79%, 6) Sodium L-ascorbic acid-2-phosphate-6-palmitic acid, 48%, 7) Sodium L-ascorbic acid-2-phosphate-6 Isopalmitic acid, 32%, 8) L-ascorbic acid-2,3,5,6-tetrahexyldecanoic acid, 75%, 9) L-ascorbic acid-3-ethyl, 78%, 10) Sodium tocopheryl phosphorus Acid, 75%, 11) sodium tocopheryl dimethylglycine, 21%, 12) tocopheryl retinoic acid, 65%, 13) butanoic acid, 98%, 14) pentanoic acid, 9 %, 15) hexanoic acid, 91%, 16) heptanoic acid, 90%, 17) octanoic acid, 85%, 18) nonanoic acid, 86%, 19) decanoic acid, 85%, 20) dodecanoic acid, 83%, 21) Tetradecanoic acid, 82%, 22) Pentadecanoic acid, 80%, 23) Hexadecanoic acid, 79%, 24) Heptadecanoic acid, 74%, 25) Octadecanoic acid, 77%, 26) Nonadecanoic acid, 75%, 27) Icosanoic acid, 76%, 28) docosanoic acid, 73%, 29) tetracosanoic acid, 70%, 30) hexacosanoic acid, 66%, 31) octacosanoic acid, 65%, 32) triacontanoic acid, 73%, 33) pig Noylthioctic acid, 85%, 34) pentanoylthioctic acid, 83%, 35) hexanoylthioctic acid, 78%, 36) heptanoylthioctic acid, 77%, 37) Turanoylthioctic acid, 72%, 38) nonanoylthioctic acid, 73%, 39) decanoylthioctic acid, 72%, 40) dodecanoylthioctic acid, 70%, 41) tetradecanoylthioctic acid, 69%, 42 ) Pentadecanoyl thioctic acid, 67%, 43) Hexadecanoyl thioctic acid, 66%, 44) Heptadecanoyl thioctic acid, 61%, 45) Octadecanoyl thioctic acid, 64%, 46) Nonadecanoyl thioctic acid , 62%, 47) Icosanoyl thioctic acid, 63%, 48) Docosanoyl thioctic acid, 60%, 49) Tetracosanoyl thioctic acid, 57%, 50) Hexacosanoyl thioctic acid, 53%, 51) Octa Cosanoyl thioctic acid, 52%, 52) Triacontanoyl thioctic acid, 60%, 53) Butanoyl dihydrothioc Acid, 90%, 54) pentanoyl dihydrothioctic acid, 88%, 55) hexanoyl dihydrothioctic acid, 83%, 56) heptanoyl dihydrothioctic acid, 82%, 57) octanoyl dihydrothioctic acid, 77%, 58) nonanoyl dihydrothioctic acid, 78%, 59) decanoyl dihydrothioctic acid, 77%, 60) dodecanoyl dihydrothioctic acid, 75%, 61) tetradecanoyl dihydrothioctic acid, 74%, 62) pentadecanoyl Dihydrothioctic acid, 72%, 63) Hexadecanoyl dihydrothioctic acid, 71%, 64) Heptadecanoyl dihydrothioctic acid, 66%, 65) Octadecanoyl dihydrothioctic acid, 69%, 66) Nonadecanoyl dihydrothiocto Acid, 67%, 67) Icosanoyl dihydrothioctic acid 68%, 68) docosanoyl dihydrothioctic acid, 65%, 69) tetracosanoyl dihydrothioctic acid, 62%, 70) hexacosanoyl dihydrothioctic acid, 58%, 71) octacosanoyl dihydrothioctic acid, 57%, 72) Triacontanoyl thioctic acid, 65%.

(Comparison of absorbability to tissues)
The thioctic acid derivative group having the hydrocarbon group having 8 to 22 carbon atoms of the present invention produced above (specimen number: 37-40, 46-48, 41-45) and the dihydrothioctic acid derivative group of the present invention, specimen Nos. 57-60, 66-68, 61-65) and existing thioctic acid derivatives (carbon numbers 4-7 and 23-30, specimen numbers 29-36, 49-52), and existing dihydrothioctic acid (sample) No. 53-56, 69-72) and each sample containing thioctic acid and an existing vitamin derivative were dispersed in a polyacrylic acid-based hydrophilic gel at a concentration of 5%, and the skin tissue absorbability (%) was determined as the skin tissue of hairless mice. Was measured by high performance liquid chromatography and gas chromatography. The concentration after 3 hours of the skin tissue of the mouse from which the stratum corneum had been removed was taken as 100%, and each concentration after 3 hours in the skin tissue (epidermis and dermis) was measured, and the average value was determined and expressed in weight% below.

1) thioctic acid 23%, 2) dihydrothioctic acid 25%, 3) sodium L-ascorbic acid-2-phosphate 79%, 4) magnesium L-ascorbic acid-2-phosphate 85%, 5) L-ascorbine Acid 2-glucoside 74%, 6) sodium L-ascorbic acid-2-phosphate-6-palmitic acid 95%, 7) sodium L-ascorbic acid-2-phosphate-6-isopalmitic acid 99%, 8 ) L-ascorbic acid-2,3,5,6-tetrahexyldecanoic acid 87%, 9) L-ascorbic acid-3-ethyl 91%, 10) sodium tocopheryl phosphate 89%, 11) sodium tocopheryl dimethylglycine 93%, 12) tocopheryl retinoic acid 91%, 13) butanoic acid 71%, 14) pentanoic acid 69%, 15) hexanoic acid 68%, 16 Heptanoic acid 65%, 17) octanoic acid 66%, 18) nonanoic acid 70%, 19) decanoic acid 81%, 20) dodecanoic acid 83%, 21) tetradecanoic acid 85%, 22) pentadecanoic acid 88%, 23) hexadecane Acid 89%, 24) Heptadecanoic acid 89%, 25) Octadecanoic acid 84%, 26) Nonadecanoic acid 83%, 27) Icosanoic acid 82%, 28) Docosanoic acid 80%, 29) Tetracosanoic acid 80%, 30) Hexacosanoic acid 75%, 31) octacosanoic acid 72%, 32) triacontanoic acid 70%, 33) butanoylthioctic acid 75%, 34) pentanoylthioctic acid 70%, 35) hexanoylthioctic acid 78%, 36) heptanoylthiocto Acid 75%, 37) Octanoyl thioctic acid 76%, 38) Nonanoyl thioctic acid 80%, 39) Decanoy Thioctic acid 90%, 40) Dodecanoylthioctic acid 93%, 41) Tetradecanoylthioctic acid 95%, 42) Pentadecanoylthioctic acid 98%, 43) Hexadecanoylthioctic acid 99%, 44) Heptadecanoylthiocto Acid 99%, 45) octadecanoyl thioctic acid 94%, 46) nonadecanoyl thioctic acid 93%, 47) icosanoyl thioctic acid 92%, 48) docosanoyl thioctic acid 49, 49) tetracosanoyl thioctic acid 90%, 50) 85% hexacosanoyl thioctic acid, 51) 82% octacosanoyl thioctic acid, 52) 80% triacontanoyl thioctic acid, 53) 79% butanoyl dihydrothioctic acid, 54) pentanoyl dihydrothioctic acid 78%, 55) Hexanoyl dihydrothioctic acid 80%, 56) Hep Tanoyl dihydrothioctic acid 85%, 57) Octanoyl dihydrothioctic acid 87%, 58) Nonanoyl dihydrothioctic acid 88%, 59) Decanoyl dihydrothioctic acid 91%, 60) Dodecanoyl dihydrothioctic acid 93%, 61) Tetradecanoyl dihydrothioctic acid 97%, 62) Pentadecanoyl dihydrothioctic acid 96%, 63) Hexadecanoyl dihydrothioctic acid 98%, 64) Heptadecanoyl dihydrothioctic acid 97%, 65) Octadecanoyl dihydrothioctic acid 95%, 66) Nonadecanoyl dihydrothioctic acid 92%, 67) Icosanoyl dihydrothioctic acid 91%, 68) Docosanoyl dihydrothioctic acid 89%, 69) Tetracosanoyl dihydrothioctic acid 89%, 70) Hexacosa Noyl dihydrothiocto 83%, 71) 81% octa Kosa octanoyl dihydrothiazole octoate, 72) triacontanyl alkanoyl Chi octoate 78%

(Enzymatic degradation and antioxidant activity of skin tissue homogenate)
The thioctic acid derivative group having the hydrocarbon group having 8 to 22 carbon atoms of the present invention produced above (specimen number: 37-40, 46-48, 41-45) and the dihydrothioctic acid derivative group of the present invention, specimen Nos. 57-60, 66-68, 61-65) and existing thioctic acid derivatives (carbon numbers 4-7 and 23-30, specimen numbers 29-36, 49-52), and existing dihydrothioctic acid (sample) No. 53-56, 69-72) and each sample containing thioctic acid and an existing vitamin derivative, each sample was added to the skin tissue homogenate solution of hairless mice at a concentration of 500 ppm, and the reduction rate of hydroxy radicals generated in the Fenton reaction system Was measured by the ESR method. The positive control was set with thioctic acid, the reduction rate of hydroxy radicals at this time was taken as 100%, the reduction rate of other samples was measured, and the average value was obtained and shown below.

1) Thioctic acid 100%, 2) Dihydrothioctic acid 82%, 3) Sodium L-ascorbic acid-2-phosphate 59%, 4) Magnesium L-ascorbic acid-2-phosphate 49%, 5) L-ascorbine Acid-2-glucoside 23%, 6) sodium L-ascorbic acid-2-phosphate-6-palmitic acid 51%, 7) sodium L-ascorbic acid-2-phosphate-6-isopalmitic acid 59%, 8 ) L-ascorbic acid-2,3,5,6-tetrahexyldecanoic acid 14%, 9) L-ascorbic acid-3-ethyl 25%, 10) sodium tocopheryl phosphate 45%, 11) sodium tocopheryl dimethylglycine 49%, 12) tocopheryl retinoic acid 12%, 13) butanoic acid 1%, 14) pentanoic acid 1%, 15) hexanoic acid 1%, 16) Tanoic acid 1%, 17) Octanoic acid 1%, 18) Nonanoic acid 1%, 19) Decanoic acid 1%, 20) Dodecanoic acid 1%, 21) Tetradecanoic acid 1%, 22) Pentadecanoic acid 1%, 23) Hexadecane Acid 1%, 24) Heptadecanoic acid 1%, 25) Octadecanoic acid 1%, 26) Nonadecanoic acid 1%, 27) Icosanoic acid 1%, 28) Docosanoic acid 1%, 29) Tetracosanoic acid 1%, 30) Hexacosanoic acid 1%, 31) octacosanoic acid 1%, 32) triacontanoic acid 1%, 33) butanoylthioctic acid 73%, 34) pentanoylthioctic acid 75%, 35) hexanoylthioctic acid 71%, 36) heptanoylthiocto Acid 69%, 37) Octanoyl thioctic acid 75%, 38) Nonanoyl thioctic acid 79%, 39) Decanoyl thioctic acid 80%, 40) Dodecanoyl 84% Octoic acid, 41) 87% Tetradecanoylthioctic acid, 42) 89% Pentadecanoylthioctic acid, 43) 95% Hexadecanoylthioctic acid, 44) 92% Heptadecanoylthioctic acid, 45) Octadecanoyl Thioctic acid 90%, 46) Nonadecanoylthioctic acid 88%, 47) Icosanoylthioctic acid 85%, 48) Docosanoylthioctic acid 80%, 49) Tetracosanoylthioctic acid 72%, 50) Hexacosanoylthiocto Acid 74%, 51) octacosanoyl thioctic acid 67%, 52) triacontanoyl thioctic acid 59%, 53) butanoyl dihydrothioctic acid 69%, 54) pentanoyl dihydrothioctic acid 61%, 55) hexanoyl dihydrothiocto Acid 65%, 56) heptanoyl dihydrothioctic acid 63%, 57 ) Octanoyl dihydrothioctic acid 67%, 58) nonanoyl dihydrothioctic acid 62%, 59) decanoyl dihydrothioctic acid 67%, 60) dodecanoyl dihydrothioctic acid 68%, 61) tetradecanoyl dihydrothioctic acid 82%, 62) Pentadecanoyl dihydrothioctic acid 70%, 63) Hexadecanoyl dihydrothioctic acid 73%, 64) Heptadecanoyl dihydrothioctic acid 74%, 65) Octadecanoyl dihydrothioctic acid 71%, 66) Nonadecanoyl dihydro Thioctic acid 68%, 67) Icosanoyl dihydrothioctic acid 58%, 68) Docosanoyl dihydrothioctic acid 55%, 69) Tetracosanoyl dihydrothioctic acid 43%, 70) Hexacosanoyl dihydrothioctic acid 48%, 71) Octacosanoyl dihydr Thioctic acid 39%, 72) triacontanyl alkanoyl Chi octoate 32%

見られなかった皮膚を１００％とした。以下の値は刺激により赤みが増すほど

(Skin irritation test)
The thioctic acid derivative group having the hydrocarbon group having 8 to 22 carbon atoms of the present invention produced above (specimen number: 37-40, 46-48, 41-45) and the dihydrothioctic acid derivative group of the present invention, specimen Nos. 57-60, 66-68, 61-65) and existing thioctic acid derivatives (carbon numbers 4-7 and 23-30, specimen numbers 29-36, 49-52), and existing dihydrothioctic acid (sample) No. 53-56, 69-72) and for each sample containing thioctic acid and existing vitamin derivatives, the skin irritation of each sample to humans was measured using the skin of the subject.
The measurement is to measure the red intensity of erythema after 24 hours patching on the skin using a color difference meter.

Unseen skin was taken as 100%. The following values increase as redness increases with stimulation.

1) 83% thioctic acid, 2) 78% dihydrothioctic acid, 3) 79% sodium L-ascorbic acid-2-phosphate, 4) 86% magnesium L-ascorbic acid-2-phosphate, 5) L-ascorbine Acid 2-glucoside 75%, 6) sodium L-ascorbic acid-2-phosphate-6-palmitic acid 69%, 7) sodium L-ascorbic acid-2-phosphate-6-isopalmitic acid 79%, 8 ) L-ascorbic acid-2,3,5,6-tetrahexyldecanoic acid 82%, 9) L-ascorbic acid-3-ethyl 65%, 10) sodium tocopheryl phosphate 75%, 11) sodium tocopheryl dimethylglycine 81%, 12) tocopheryl retinoic acid 59%, 13) butanoic acid 50%, 14) pentanoic acid 53%, 15) hexanoic acid 55%, 16 Heptanoic acid 57%, 17) octanoic acid 60%, 18) nonanoic acid 63%, 19) decanoic acid 65%, 20) dodecanoic acid 68%, 21) tetradecanoic acid 70%, 22) pentadecanoic acid 73%, 23) hexadecane Acid 75%, 24) Heptadecanoic acid 78%, 25) Octadecanoic acid 80%, 26) Nonadecanoic acid 83%, 27) Icosanoic acid 87%, 28) Docosanoic acid 90%, 29) Tetracosanoic acid 93%, 30) Hexacosanoic acid 96%, 31) octacosanoic acid 98%, 32) triacontanoic acid 99%, 33) butanoylthioctic acid 32%, 34) pentanoylthioctic acid 35%, 35) hexanoylthioctic acid 44%, 36) heptanoylthiocto Acid 49%, 37) Octanoyl thioctic acid 75%, 38) Nonanoyl thioctic acid 80%, 39) Decanoy Thioctic acid 85%, 40) Dodecanoylthioctic acid 88%, 41) Tetradecanoylthioctic acid 90%, 42) Pentadecanoylthioctic acid 93%, 43) Hexadecanoylthioctic acid 94%, 44) Heptadecanoylthiocto Acid 95%, 45) Octadecanoylthioctic acid 93%, 46) Nonadecanoylthioctic acid 87%, 47) Icosanoylthioctic acid 87%, 48) Docosanoylthioctic acid 91%, 49) Tetracosanoylthioctic acid 93%, 50) hexacosanoyl thioctic acid 96%, 51) octacosanoyl thioctic acid 98%, 52) triacontanoyl thioctic acid 97%, 53) butanoyl dihydrothioctic acid 50, 54) pentanoyl dihydrothioctic acid 53%, 55) Hexanoyl dihydrothioctic acid 55%, 56) Hep Tanoyl dihydrothioctic acid 60%, 57) Octanoyl dihydrothioctic acid 68%, 58) Nonanoyl dihydrothioctic acid 71%, 59) Decanoyl dihydrothioctic acid 70%, 60) Dodecanoyl dihydrothioctic acid 75%, 61) Tetradecanoyl dihydrothioctic acid 79%, 62) pentadecanoyl dihydrothioctic acid 82%, 63) hexadecanoyl dihydrothioctic acid 82%, 64) heptadecanoyl dihydrothioctic acid 84%, 65) octadecanoyl dihydrothioctic acid 87%, 66) Nonadecanoyl dihydrothioctic acid 85%, 67) Icosanoyl dihydrothioctic acid 87%, 68) Docosanoyl dihydrothioctic acid 92%, 69) Tetracosanoyl dihydrothioctic acid 93%, 70) Hexacosa Noyl dihydrothiocto 95%, 71) octa Kosa 96% noil dihydrothiazole octoate, 72) triacontanyl 96% alkanoyl Ji octoate

(Comprehensive evaluation index)
The thioctic acid derivative group having the hydrocarbon group having 8 to 22 carbon atoms of the present invention produced above (specimen number: 37-40, 46-48, 41-45) and the dihydrothioctic acid derivative group of the present invention, specimen Nos. 57-60, 66-68, 61-65) and existing thioctic acid derivatives (carbon numbers 4-7 and 23-30, specimen numbers 29-36, 49-52), and existing dihydrothioctic acid (sample) No. 53-56, 69-72) and each sample containing thioctic acid and an existing vitamin derivative, titer change after 6 months, tissue absorbability, skin tissue homogenate solution enzymatic degradability and antioxidant activity Based on the results of skin irritation, a comprehensive evaluation index was calculated from the following formula and comprehensive evaluation was performed. The overall evaluation index was evaluated according to the following method of evaluating the effect in five stages: A + rank effect, A rank effect, B rank effect, C rank effect, and no effect. Potency change (%) / 100x absorbency (%) / 100x enzyme degradability and antioxidant activity (%) 100x skin irritation (%) / 100x100 = overall evaluation index 50 (A + rank effect) = A effect 40 or more (A rank effect) = significantly higher than B rank effect, 30 or more (B rank effect) = C rank effect 10 or less and less than 30 (C rank effect) = effect similar to control of conventional product, less than 10 = no effect

1) Thioctic acid 1.5, 2) Dihydrothioctic acid 1.9, 3) Sodium L-ascorbic acid-2-phosphate 21.0, 4) Magnesium L-ascorbic acid-2-phosphate 24.4, 5 ) L-ascorbic acid-2-glucoside 10.1,6) Sodium L-ascorbic acid-2-phosphate-6-palmitic acid 16.0,7) Sodium L-ascorbic acid-2-phosphate-6-iso Palmitic acid 14.8,8) L-ascorbic acid-2,3,5,6-tetrahexyldecanoic acid 7.5,9) L-ascorbic acid-3-ethyl 11.5,10) Sodium tocopheryl phosphate 22 5,11) sodium tocopheryldimethylglycine 7.8, 12) tocopheryl retinoic acid 4.2, 13) butanoic acid 0.3, 14) pentanoic acid 0.4, 15) hexane 0.3, 16) Heptanoic acid 0.3, 17) Octanoic acid 0.3, 18) Nonanoic acid 0.4, 19) Decanoic acid 0.4, 20) Dodecanoic acid 0.5, 21) Tetradecanoic acid 5, 22) pentadecanoic acid 0.5, 23) hexadecanoic acid 0.5, 24) heptadecanoic acid 0.5, 25) octadecanoic acid 0.5, 26) nonadecanoic acid 0.5, 27) icosanoic acid 0.5, 28) docosanoic acid 0.5, 29) tetracosanoic acid 0.5, 30) hexacosanoic acid 0.5, 31) octacosanoic acid 0.5, 32) triacontanoic acid 0.5, 33) butanoylthioctic acid 12.8 , 34) pentanoylthioctic acid 13.8, 35) hexanoylthioctic acid 18.5, 36) heptanoylthioctic acid 19.5, 37) octanoylthioctic acid 30.8, 38) nonanoylthiocto 36.9, 39) Decanoyl thioctic acid 44.1, 40) Dodecanoyl thioctic acid 48.1, 41) Tetradecanoyl thioctic acid 51.3, 42) Pentadecanoyl thioctic acid 54.3, 43) Hexadeca Noylthioctic acid 58.3, 44) Heptadecanoylthioctic acid 52.8, 45) Octadecanoylthioctic acid 50.4, 46) Nonadecanoylthioctic acid 44.1, 47) Icosanoylthioctic acid 42.9 , 48) docosanoyl thioctic acid 41.3, 49) tetracosanoyl thioctic acid 34.4, 50) hexacosanoyl thioctic acid 32.0, 51) octacosanoyl thioctic acid 28.0, 52) triacontanoyl thioc Acid 27.5, 53) butanoyl dihydrothioctic acid 21.35, 54) pentanoyl dihydrothioctic acid 20. 2,55) Hexanoyl dihydrothioctic acid 23.2, 56) Heptanoyl dihydrothioctic acid 26.3, 57) Octanoyl dihydrothioctic acid 30.5, 58) Nonanoyl dihydrothioctic acid 30.2, 59) Decanoyl Dihydrothioctic acid 32.9,60) dodecanoyl dihydrothioctic acid 35.6,61) tetradecanoyl dihydrothioctic acid 47.1,62) pentadecanoyl dihydrothioctic acid 39.7,63) hexadecanoyl dihydrothioctic acid 41.7, 64) Heptadecanoyl dihydrothioctic acid 44.0, 65) Octadecanoyl dihydrothioctic acid 40.5, 66) Nonadecanoyl dihydrothioctic acid 35.6, 67) Icosanoyl dihydrothioctic acid 31. 2,68) docosanoyl dihydrothioctic acid 30.6, 9) tetracosadione noil Dihydrothiazol octoate 22.1,70) hexacosanol hexanoyl Dihydrothiazol octoate 22.0,71) octa Kosa octanoyl Dihydrothiazol octoate 17.3,72) triacontanyl alkanoyl Chi octoate 15.6.
(A + rank effect) = significantly higher effect than A effect (A rank effect) = significantly higher effect than B rank effect (B rank effect) = Significantly higher effect compared to C rank effect (C rank effect) = Same effect as control of conventional product, Less than 10 = No effect

The thioctic acid derivative having a hydrocarbon group having 8 to 13 carbon atoms and 19 to 22 carbon atoms synthesized above from the above result section (the sample numbers: 37 to 40 and 46 to 48) is a titer change after 6 months, Thiocto having a hydrocarbon group having 14 to 18 carbon atoms, which is A or B in a comprehensive rank evaluation that summarizes the results of absorption into tissue, enzymatic degradation and antioxidant activity of skin tissue homogenate, and skin irritation The acid derivative (the sample number: 41 to 45) is A + in the overall evaluation, and the thioctic acid derivative of the present invention is the existing thioctic acid derivative synthesized above (carbon number 4 to 7 and 23 to 30, the sample number 29 to 36, 49-52) with superior performance in any evaluation of changes in titer over time, absorption into tissues, enzymatic degradation and antioxidant activity of skin tissue homogenate, and skin irritation. Have Theft has been confirmed.

Similarly, dihydrothioctic acid derivatives having the hydrocarbon groups having 8 to 13 and 19 to 22 carbon atoms synthesized above from the above result section (the sample numbers: 57 to 60 and 66 to 68) are obtained after 6 months. Is a comprehensive rank evaluation that summarizes the results of changes in titer, absorbability to tissue, enzymatic degradation and antioxidant activity of skin tissue homogenate, and skin irritation, and is a hydrocarbon group having 14 to 18 carbon atoms The dihydrothioctic acid derivative having the above (sample number: 61-65) is A in the overall evaluation, and the thioctic acid derivative of the present invention is the same as the existing dihydrothioctic acid (sample numbers 53-56, 69-72) synthesized above. In comparison, it has been confirmed that it has extremely excellent performance in all of the evaluations of titer change over time, absorbability to tissue, enzymatic degradation and antioxidant activity of skin tissue homogenate, and skin irritation. It was.

The same test was performed on fatty acids and thioctic acid derivatives having the following branched chains. As a result, isothioctic acid derivatives having a hydrocarbon group having 8 to 13 carbon atoms and 19 to 22 carbon atoms were changed in titer after 6 months, Isothioc having a hydrocarbon group of 14 to 18 carbon atoms with A or B in the overall rank evaluation that summarizes the results of absorption to tissue, enzymatic degradation and antioxidant activity of skin tissue homogenate, and skin irritation The acid derivative is A + in the overall evaluation, and the isothioctic acid derivative of the present invention has a change in titer with time, absorbability to tissue, enzymatic degradation and antioxidant activity of skin tissue homogenate compared to the existing isothioctic acid derivative, In addition, it was confirmed to have extremely excellent performance in both evaluations of skin irritation.

1)

With respect to the thioctic acid derivatives of the present invention in the subject areas of the following 37) to 48), which have already been tested above to investigate the influence of carbon having an unsaturated bond, Rn or Cn (claims 1 to 6) of the present invention n is an integer) The following test group (A) having an unsaturated bond (A) 237) to 248) The effect of a thioctic acid derivative containing one unsaturated bond is compared with the stability test described above, comparison of absorbability to tissues, The overall evaluation index was calculated by the same method as described above in the same manner as in the experiment of the enzyme degradability, antioxidant activity and skin irritation test of the skin tissue homogenate solution.

Target group (B) 37) Octanoylthioctic acid, 38) Nonanoylthioctic acid, 39) Decanoylthioctic acid, 40) Dodecanoylthioctic acid, 41) Tetradecanoylthioctic acid, 42) Pentadecanoylthioctic acid, 43 ) Hexadecanoylthioctic acid, 44) heptadecanoylthioctic acid, 45) octadecanoylthioctic acid, 46) nonadecanoylthioctic acid, 47) icosanoylthioctic acid, 48) docosanoylthioctic acid,

Test Group (A) 237) Octanoylthioctic acid, 238) Nonanoylthioctic acid, 239) Decanoylthioctic acid, 240) Dodecanoylthioctic acid, 241) Tetradecanoylthioctic acid, 242) Pentadecanoylthioctic acid, 243 ) Hexadecanoylthioctic acid, 244) heptadecanoylthioctic acid, 245) octadecanoylthioctic acid, 246) nonadecanoylthioctic acid, 247) icosanoylthioctic acid, 248) docosanoylthioctic acid.

The results are shown below. In the following calculation formula, the value of (b) is the value of the thioctic acid derivative 37) to 48) of the above experiment. As shown in the following results, the thioctic acid derivative (a) of the present invention containing an unsaturated bond is more particularly enzyme-active X antioxidant activity than the thioctic acid derivative (b) of the present invention that does not contain an unsaturated bond of the present invention. It was proved that an excellent effect was exhibited in the evaluation index and a higher effect was exhibited in the evaluation index. The effect of this unsaturated fatty acid was shown to be the same as that of a molecule having one unsaturated bond even in the case of a molecule having two or more unsaturated bonds in the molecules of thioctic acid derivatives 37) to 48).

In order to examine the relationship between the thioctic acid derivative concentration and the cell growth rate and tissue formation rate of human epithelial gland fibroblasts, the culture solution was prepared to have the following thioctic acid derivative concentration so that the carbon number of the present invention was 8-22. Thioctic acid derivative group having the hydrocarbon group (the sample numbers: 37 to 40, 46 to 48, 41 to 45) and the dihydrothioctic acid derivative group of the present invention, sample numbers 57 to 60, 66 to 68, 61 to 65. ) And existing thioctic acid derivatives (carbon number 4-7 and 23-30, sample numbers 29-36, 49-52) and existing dihydrothioctic acid (sample numbers 53-56, 69-72) are different from each other. After adding at a concentration and culturing for 3 days, the relationship between the concentration of each derivative and the cell growth rate was examined. As a result, when the cell culture medium concentration or tissue concentration of the thioctic acid derivative of the present invention was 50 to 3200 ppm, it was found that the cell growth rate and tissue formation rate increased 1.2 times.

In order to examine the combined effect of the thioctic acid derivative of the present invention and the following existing vitamin derivatives, the cell proliferation rate and skin tissue formation rate of human epithelial gland fibroblasts were compared with those obtained when the thioctic acid derivative of the present invention was administered alone. Comparison was made between the combination of the thioctic acid derivative of the invention and the following existing vitamin derivatives. As a result, in the combined use of the thioctic acid derivative of the present invention and the following existing vitamin derivatives as compared with the single administration of the thioctic acid derivative of the present invention, the combined use group is up to 1.3 times as much as the single administration group. It was found that cell proliferation rate and skin tissue formation rate were exhibited.
Existing vitamin derivatives used in the experiment: sodium L-ascorbic acid-2-phosphate, magnesium L-ascorbic acid-2-phosphate, L-ascorbic acid-2-glucoside, sodium L-ascorbic acid-2-phosphate -6-palmitic acid, sodium L-ascorbic acid-2-phosphate-6-isopalmitic acid, L-ascorbic acid-2,3,5,6-tetrahexyldecanoic acid, L-ascorbic acid-3-ethyl, ascorbine Acid-3-glucoside, sodium tocopheryl phosphate, sodium tocopheryl dimethylglycine, tocopheryl retinoic acid. A group of thioctic acid derivatives having a hydrocarbon group having 8 to 22 carbon atoms according to the present invention prepared as described above in a culture solution so as to obtain a thioctic acid derivative concentration in order to examine the relationship between the thioctic acid derivative concentration and the cell growth rate of various cells. (The sample numbers: 37 to 40, 46 to 48, 41 to 45) and the dihydrothioctic acid derivative group of the present invention, sample numbers 57 to 60, 66 to 68, 61 to 65) and existing thioctic acid derivatives (carbon number) 4-7 and 23-30, the above sample numbers 29-36, 49-52), and existing dihydrothioctic acid (sample numbers 53-56, 69-72) were added, respectively, and cultured for 3 days. The relationship between concentration and cell growth rate was investigated. In addition, the formation rate of the tissue forming material was also examined.
As a result, baker's yeast, lactic acid bacteria for foods, bifidobacteria, natdecocco-producing bacteria, natto bacteria, koji mold, koji mold for sake, penicillin-producing bacteria, human-derived cells, silkworm-derived cells, prawn-derived cells, rainbow trout-derived cells, chicken-derived Cells, pig, cow, sheep, horse, dog, cat embryo-derived cells, Xenopus embryo-derived cells, suppon embryo-derived cells, abalone-derived cells, human and cow, pig, chicken-derived stem cells, nerve cells, glandular fibroblasts Promotion of cell growth of cells, keratinocytes, pigment cells, cardiomyocytes, hepatocytes, oral mucosal epithelial cells, enamel blasts, odontoblasts, hair matrix cells, vascular endothelial cells, hematopoietic stem cells, pluripotent stem cells, adipocytes It has been found that the action is increased up to 1.3 times by the thioctic acid derivative of the present invention compared to the existing thioctic acid derivative. In addition, regarding the cells forming the tissue, the tissue formation rate increased up to 1.5 times. These effects were further increased up to 1.2 times by adding the existing vitamin derivatives.

The thioctic acid derivative group having the hydrocarbon group having 8 to 22 carbon atoms of the present invention produced above (the specimen number: 37-48) and the dihydrothioctic acid derivative group of the present invention, the specimen number 57-68, respectively. The following preparations were prepared and used as pharmaceuticals, cosmetics, feed additives, food additives, biological tissue regeneration polymer compositions, and tissue regeneration polymer compositions, respectively.

Oily liquid formulation:
The thioctic acid derivative group of the present invention, the specimen numbers: 37 to 48, and the dihydrothioctic acid derivative group of the present invention and the specimen numbers 57 to 68 were each dissolved in olive oil at a concentration of 30% by weight.

Gel formulation:
9% by weight of glycerin was mixed well with 1% by weight of surfactin sodium, and 90% by weight of the above oily liquid preparation was gradually added thereto to make 100% by weight to obtain a liquid oil gel.

Aqueous emulsion dispersion formulation:
60% by weight of water was added to 40% by weight of the gel-like preparation and dispersed. This was used to obtain an emulsified particle dispersion having an average particle size of 30 μm using a microfluidizer.

Aqueous gel:
The above aqueous emulsified dispersion preparation was added to the aqueous gel produced by adding 99.5% by weight of water to 0.5% by weight of xanthan gum and mixed well to prepare an ointment-like aqueous gel.

Powder:
5% of the oily liquid preparation produced above was permeated and dispersed in 95% of dextrin to obtain a powder.

Solid material:
A porous sheet-like polylactic acid molding was impregnated with the same weight of the above aqueous emulsion-dispersed preparation under reduced pressure and then dried under reduced pressure to obtain a solid material.

[Human epidermal keratinocyte proliferation and tissue formation test]
Using a normal human epidermal keratinocyte culture kit manufactured by Morinaga Bioscience Institute, the thioctic acid derivative group having a hydrocarbon group having 8 to 22 carbon atoms of the present invention produced above, the specimen number: 37 to 48, and The effect of the composition for promoting growth of human epidermis keratinocytes on the dihydrothioctic acid derivative group of the present invention, specimen Nos. 57 to 68 (hereinafter collectively referred to as the thioctic acid derivatives of the present invention) In order to investigate, the following tests were conducted.

[Test Example 1] Frozen normal human epidermal keratinocytes were thawed, cultured in a serum-free medium for epidermal keratinocytes, and subcultured twice. At the third passage, the thioctic acid derivative of the present invention (concentration 1 mg / ml) sterilized by filtration is added to the above serum-free medium, and the number of cells is measured over time, and the state of cell proliferation is observed. Observed. In addition, the thing which did not add the thioctic acid derivative of this invention was compared as a control.

As a result, in the thioctic acid derivative-containing culture medium of the present invention, a remarkable cell increase of up to 1.5 times was recognized as compared with the control culture medium.
As described above, the proliferation activity of human epidermal keratinocytes could be increased by adding the thioctic acid derivative of the present invention.

[Test Example 2] Frozen normal human epidermal keratinocytes were thawed and cultured in a serum-free medium for epidermis keratinocytes in a medium supplemented with the thioctic acid derivative of the present invention (0.10 mg / ml). -Passage was performed when it reached confluence (a state in which adherent cells occupy about 80% of the area of the incubator). The number of days to reach semi-confluence in the third passage was investigated and the average value of the results was calculated. In addition, what did not add the thioctic acid derivative of this invention was compared as a control group. The semi-confluent days achieved are shown below.

Table 2

Control group 2.5 days, 37) Octanoylthioctic acid 1.7 days, 38) Nonanoylthioctic acid 1.5 days, 39) Decanoylthioctic acid 1.6 days, 40) Dodecanoylthioctic acid 1.4 days 41) tetradecanoylthioctic acid 1.1 days, 42) pentadecanoylthioctic acid 1 day, 43) hexadecanoylthioctic acid 1 day, 44) heptadecanoylthioctic acid 1 day, 45) octadecanoylthioctic acid 1.2 days, 46) nonadecanoyl thioctic acid 1.3 days, 47) icosanoyl thioctic acid 1.5 days, 48) docosanoyl thioctic acid 1.5 days, 49) tetracosanoyl thioctic acid, 50) Hexacosanoyl thioctic acid, 51) octacosanoyl thioctic acid, 52) triacontanoyl thioctic acid, 53) butanoyl dihydrothioctic acid, 54) pentano Ludihydrothioctic acid, 55) Hexanoyl dihydrothioctic acid, 56) Heptanoyl dihydrothioctic acid, 57) Octanoyl dihydrothioctic acid 1.5 days, 58) Nonanoyl dihydrothioctic acid 1.4 days, 59) Decanoyl dihydro Thioctic acid 1.5 days, 60) Dodecanoyl dihydrothioctic acid 1.3 days, 61) Tetradecanoyl dihydrothioctic acid 1.5 days, 62) Pentadecanoyl dihydrothioctic acid 1 day, 63) Hexadecanoyl dihydrothiocto Acid 0.9 days, 64) Heptadecanoyl dihydrothioctic acid 1.1 days, 65) Octadecanoyl dihydrothioctic acid 1.2 days, 66) Nonadecanoyl dihydrothioctic acid 1.1 days, 67) Icosanoyl Dihydrothioctic acid 1.4 days, 68) docosanoyl dihydrothioctic acid 1.5 days

(Example A) 1.0 g of a product name “Dexon” manufactured by Davis & Greck, which is a suture made of a PGA polymer, was immersed in the aqueous emulsion-dispersed preparation prepared in the above Example and then taken out. After air drying, a suture which is an example of the polymer composition for tissue regeneration of the present invention was obtained. The yarn weight increase was 5 mg.
(Example B) 1.0 g of a trade name “Vicryl” manufactured by Ethicon, which is a suture made of a PGA polymer, was immersed in the aqueous emulsion-dispersed preparation prepared in the above Example and then taken out. After air drying, a suture which is an example of the polymer composition for tissue regeneration of the present invention was obtained. The weight increase of the yarn was 5 mg each.
Example C 1.0 g of a trade name “PDS” manufactured by Ethicon, which is a suture made of a polydioxanone-based polymer, was immersed in the aqueous emulsion-dispersed preparation prepared in the above Example and then taken out. After air drying, a suture which is an example of the polymer composition for tissue regeneration of the present invention was obtained. The yarn weight increase was 5 mg.
Example D 1.0 g of a trade name “Vicryl” manufactured by Ethicon, which is a suture made of a PGA polymer, was immersed in the aqueous emulsion-dispersed preparation prepared in the above Example and then taken out. After air drying, a suture which is an example of the polymer composition for tissue regeneration of the present invention was obtained. The yarn weight increase was 5 mg each.
(Example E)
A gauze was woven from the fabric of Example A as a raw material by a conventional method. This gauze was sterilized with ethylene oxide gas by a conventional method to obtain a gauze as an example of the polymer composition for tissue regeneration of the present invention.
(Example F)
A nonwoven fabric was prepared from the yarn of Example B as a raw material by a conventional method to prepare a gauze. This gauze was sterilized with ethylene oxide gas by a conventional method to obtain a nonwoven fabric gauze as an example of the polymer composition for tissue regeneration of the present invention.

(Comparative Examples 1 to 3) As a control for the following tensile strength tests, only sutures that were not immersed in the aqueous emulsion-dispersed preparation prepared in the above example were used. That is, the product name “Dexon” manufactured by Davis & Greck was used as Comparative Example A ′, the product name “Vicryl” was used as Comparative Example B ′, the product name “PDS” was used as Comparative Example C ′.
Performance evaluation Examples A and B described above. The performance of the sutures for tissue regeneration of C and the sutures of Comparative Examples A ′, B ′, and C ′ were evaluated by the following methods.
The back of a 10-week old guinea pig was shaved and a 2 cm long cut was made with a scalpel in a direction perpendicular to the midline of the back. Using the yarns of each example and comparative example, the wound was repaired by regenerating the tissue at five locations at regular intervals. One week after this treatment, a strip-like skin tissue having a width of 1 cm from the center of the cut was excised from the center of the cut under ether anesthesia, and the tensile strength (g / cm) of the cut was measured using a rheometer. Ten guinea pigs were used for each example and comparative example, and the tensile strength (g / cm) was the average of the values obtained for these guinea pigs. The results are shown in Table 1.

表１より、本発明のチオクト酸誘導体を含有する組織再生用高分子組成物の実施例である縫合糸を使用した群では、それを含まない縫合糸を使用した群よりも、耐抗張力が大きく上昇したことが分かる。

From Table 1, the group using the suture which is an example of the polymer composition for tissue regeneration containing the thioctic acid derivative of the present invention has a higher tensile strength than the group using the suture not containing the suture. You can see that it has risen.

(Example 8)
Polybutylene succinate PBS (Bionore 1001, Showa High) for 1 part by weight of each of the thioctic acid derivative group of the present invention, the specimen numbers: 37 to 48, and the dihydrothioctic acid derivative group of the present invention, and specimen numbers 57 to 68. 84 parts by weight of molecule), 10 parts by weight of polyethylene terephthalate PET (Dianite PA-500, manufactured by Mitsubishi Rayon), and ethylene glycidyl methacrylate copolymer E-GMA (reactive compatibilizer, Bond First E, manufactured by Sumitomo Chemical) 1 part by weight was added to each, using a twin screw extruder (manufactured by Technobel Co., Ltd., KZW15-30MG), melted and kneaded at 240 ° C. in a conventional manner, extruded and solidified in water at a diameter of about 3 mm, and then Each resin chip was obtained by cutting to a length of 3 mm. The extrusion conditions at this time were as follows.

<Extrusion conditions>
Temperature setting: feed 180 ° C., kneading section 240 ° C., head 180 ° C., rotation speed: 60 rpm
Each of the obtained chips was press-molded (press-molding machine: manufactured by Shindo Metal Industry Co., Ltd.), and the femur reinforcing material and the fracture repairing screw which are examples of the respective tissue regeneration polymer compositions of the present invention were obtained. Produced.
<Press molding conditions>
After pressing at 10 MPa for 1 minute at a press temperature of 180 ° C., pressing was performed at 20 MPa for 2 minutes. Then, it cooled for 3 minutes with the cooling press.

Hydroxyapatite (HA) prepared to a particle size of about 50 μm by spray drying was mixed with 1 wt% sodium alginate aqueous solution so as to be 10 wt% to obtain a uniform slurry. This slurry was formed into a spherical shape by dropping 3 μl each into a 1 wt% calcium chloride aqueous solution. The spherical HA molded as described above was dried at 60 ° C. for 12 hours and then sintered at 1250 ° C. for 1 hour to obtain porous spherical aggregate particles having a diameter of 0.8 ± 0.2. A solution obtained by sterilizing an aqueous solution prepared by dissolving each of the aqueous emulsified dispersion preparations prepared in the above examples in ultrapure water at 10% by weight with a 0.2 μm membrane filter by vacuum decompression of the porous spherical aggregate particles was 1: After the addition in 1, freeze-dried porous spherical aggregate particles for bone repair were obtained as examples of the tissue regeneration polymer composition of the present invention containing the thioctic acid derivative of the present invention.
On the other hand, by kneading with a mixture of equimolar amounts of quaternary calcium phosphate (TeCP) and dicalcium phosphate (DCP) with ultrapure water containing 10% by weight of each aqueous emulsified dispersion preparation prepared in the above Example. A self-hardening calcium phosphate cement paste for bone repair, which is an example of the polymer composition for tissue regeneration of the present invention, was prepared.

Next, the self-hardening calcium phosphate cement paste mixed with the aggregate particles so as to be 80 vol% was kneaded so as to incorporate air bubbles into the paste, and prepared based on the CT data of the bone defect portion. It was filled in an impression mold having a bone defect site shape and allowed to stand at room temperature in the air for 24 hours to obtain a cemented body having a bone defect site shape. By the above method, a calcium phosphate porous body having a bone defect site shape as an example of the polymer composition for tissue regeneration of the present invention could be obtained. In this calcium phosphate porous body, macropores of about 100 μm and micropores of several microns were distributed. Moreover, the said macropore was couple | bonded by the micropore in adjacent aggregate particle | grains, and formed the communicating-hole network. When tested in a guinea pig bone defect model, it was compared with the same material without a single substance or a combination thereof selected from conventional anti-inflammatory factors, free radical scavenging factors, cell growth factors, anti-infection factors, and tissue formation inducers As a result, the bone shape repair speed was healed about 3.5 times faster than the conventional one.

Examples in the field of food production. Production of liquor 0.1 kg of the heptadecanoyl dihydrothioctic acid prepared in the above example was added to 10,000 liters of the shochu-baked Satsuma Kirishima black label and mixed for 20-30 minutes. The obtained mixed solution was passed through a charcoal filter at a flow rate of 30 dl / hour to separate insoluble matters, and the final product was bottled. The resulting shochu was soft, smooth and had a good scent; the hangover after drinking this shochu was mild compared to the normal one.

Example. The dried beverage mixture and its manufacturing method 700 g of sugar was ground into a beverage mixture-like powder. 17 g ground salt, all in dry form, 17.5 g ground citric acid, 0.5 g disodium salt, heptadecanoyl dihydrothioctic acid made in the previous example followed by 1/3 of the sugar powder. Added to. The mixture was shaken well each time. While continuing stirring, 2.6 cm3 of orange flavor was added to the powder mixture. 260 g of dried gummy fruit powder and the remainder (2/3) of the sugar powder were added to the flavored product. The obtained mixture was divided into 20 g portions and packaged. Each package is for obtaining a 200 cm3 beverage.
The prepared dry mixture had a uniform orange color with a sweet and sour flavor and a fruity aroma. The beverage regenerated from the dried mixture had a refreshing effect, and when 20 g was taken every day and the body weight was measured after 3 months, the body weight was significantly reduced.

Example. Edible vegetable oil and its production method 9: 1 by weight of a mixture of heptadecanoyl dihydrothioctic acid prepared in the above example and 0.02 kg of heptadecanoyl thioctic acid prepared in the above example Added to bean oil. The solution was shaken and filtered. Soybean oil was bottled, sealed and stored. The obtained soybean oil can be used as a health food for preventing adult diseases. This edible oil has heat stress mitigating effects, so it is useful not only for humans but also for cattle, horses, chickens, pigs, fish, shrimp, crab, abalone, silkworms, frogs, earthworms, brewer's yeast, and baker's yeast It could also be used to increase the production of animal and economic microorganisms.

Example. Biscuits Manufacturing Method For making biscuits, traditional ingredients are mixed with a predetermined amount of water to obtain a butter emulsion. As a flavoring agent, several types of powder are added to the emulsion, such as Zilla. The amount of ingredients per 100 kg of flour was as follows: margarine 15 kg, flavoring additive 4.5 kg, sugar 7.0 kg, salt 2.3 kg, edible soda 0.58 kg, carbon-ammonium salt 4 kg, citric acid 0 0.021 kg, 5 kg starch, and 0.01 kg heptadecanoyl thioctic acid prepared in the previous example. Subsequently, the mixture was shaken, formed into a biscuit shape, and baked. Biscuits are recommended for the elderly as a traditional bread substitute; this is due to the food characteristics of this product and has a high physiological effect with heat stress mitigation.

Examples of cosmetic and dermatological applications, scalp care cosmetics Scalp care cosmetics were prepared to have the following weight percent composition weight percent: about 10% isopropyl palmitate, about 3 with lecithin % Concentrated phosphatide, about 3% bentonite clay, about 2% keratin hydrolyzate, about 2% silicone wax, about 0.5% alpha-tocopherol oil essence, about 0.5% fragrance, About 0.5% emulsified aqueous solution containing 49% heptadecanoyl dihydrothioctic acid and 1% surfactin prepared in the above example, about 0.5% preservative, and the rest (about 78%) from marine products It is an emulsified liquid glyceride of mammalian subcutaneous fat. The obtained scalp care cosmetics gave hair growth stimulating action to the skin and hair. The scalp care cosmetic was applied to normal wet hair and scalp; it was evenly distributed along the hair and lightly rubbed into the skin for 2-3 minutes. Ten minutes after the action, the head was washed with warm water. Scalp care cosmetics make the skin healthy, promote hair growth, reanimate hair, and eliminate dandruff.

Example. Sunburn skin treatment composition For treatment of skin exposed to prolonged sunlight (ultraviolet radiation), an ointment having the following composition (% by weight) was prepared: about 2% magnesium salt of aspartic acid, about 5 % Chamomile flower extract water-alcohol solution, about 1% vitamin A, B1, D, E, C, PP, about 4% lecithin, about 1% magnesium sulfate, about 2% sodium lactate, about 1% heptadecanoyl dihydrothioctic acid in 50% ethanol, about 5% glycerol, about 0.5% preservative, about 3% emulsifier, and the remainder ethanol. In the composition and presence of heptadecanoyl dihydrothioctic acid, which binds to peroxide radicals formed in the burned skin layer and actively restores water-salt parallel in skin cells by moving magnesium ions Due to the action of other active ingredients, skin damaged by UV irradiation was quickly recovered. A composition in the form of an emulsion or lotion according to the present invention was applied to the exposed skin area every 3-4 hours using a soft absorbent cotton.

Embodiments of the invention relating to animals and poultry. A mixture of physiologically active substances including amino acids or derivatives thereof, vitamins or derivatives thereof, enzymes, pharmaceuticals, hormones, carbohydrates, microorganisms and mineral substances is prepared; then heptadecanoyl thioctic acid is added to the mixture, The mixture was stirred; the resulting composition was coated with a protective layer and granulated. The resulting granular composition was used as an animal feed additive; the composition can significantly increase the level of antioxidant activity and immunoglobulin G in the milk of cow, pig, dog and cat mothers. did it.

Example. For the purpose of preventing premature aging of pet dogs and cats, an injection solution was prepared by adding an aqueous solution of heptadecanoylthioctic acid and other known active ingredients belonging to the amino acid and vitamin group to physiological saline. The preparation was injected intraperitoneally into the animals.

Example. The broiler formula feed contained feed additives containing high levels of heavy metals and arsenic. To reduce the level of the substance in broiler meat, a mixture of heptadecanoyl thioctic acid and heptadecanoyl dihydrothioctic acid in a ratio of 2: 3 was added to their formula feed one week before slaughter. Formula feed had a positive effect: the mercury, cadmium, lead and zinc contents of broiler white and red meat were significantly reduced compared to controls.

Example. The hamachi formula feed was deliberately impregnated with feed additives containing high levels of mercury. In order to reduce the level of the substance in the adipose tissue of hamachi, a mixture of heptadecanoyl thioctic acid and heptadecanoyl dihydrothioctic acid in a ratio of 2: 3 was added to their formula feed one month before dissection.
Formulated feed had a positive effect: mercury content in hamachi adipose tissue was significantly reduced compared to control.

The invention's effect

The effects obtained by the present invention are summarized below. The composition for promoting cell growth and tissue formation containing the thioctic acid derivative of the present invention is extremely safe because it is less irritating and allergenic than existing thioctic acid derivatives. The bioactive composition containing the thioctic acid derivative of the present invention is stable and stable even when stored in a preparation, and is easily absorbed by cells and tissues. The concentration of thioctic acid can be increased, the activity of thioctic acid can be exhibited highly in cells and tissues, and the activity of thioctic acid can be exhibited in cells and tissues for a long time. In particular, the following effects can be exhibited more highly. Promotes the proliferation and tissue formation of various cells, shortens the culture time of cells and tissue formation, increases the number of passages of cultured cells, and has a wide range of effects that are not limited by specific species or cell types The effect can be exerted in common with biological species and cell types, a large number of target cells can be obtained in a short time, and the antioxidant activity can be exerted continuously and highly in cells and tissues. Furthermore, it is a composition for promoting cell proliferation and tissue formation that can sufficiently exhibit the following effects. Its effects include radical disease, anti-aging activity, adult disease prevention activity, cerebral infarction, myocardial infarction, cardiovascular disorder, analgesic effect, anti-inflammatory sclerosis, anti-necrosis effect, anti-diabetic disease, detoxification, skin disease prevention, Improvement, therapeutic effect. The effect of suppressing, reducing and preventing skin pigmentation, the effect of suppressing, reducing and preventing acne on the skin, the effect of improving seborrhea related disorders, the effect of suppressing, reducing and preventing skin wrinkles and sagging, Diseases involving skin wrinkles and sagging, reducing hair, preventing hair growth, promoting hair growth, preventing hair loss, reducing pores, improving texture, slimming, and active oxygen. Furthermore, the effects are not limited by specific species and cell types, and the effects can be exerted in common with a wide range of species and cell types, and are used in a wide range of industrially useful aquaculture pet animals and fermentation production industries. It can fully exert its effects on growth inhibition and stress of a wide range of industrially useful single-cell organisms. Furthermore, in order to reduce the production cost of the thioctic acid derivative used in the present invention, a synthesis method with reduced raw material cost, equipment cost, and production energy cost is established, and the reaction is not complicated and can be easily controlled. In addition, the purity of the thioctic acid derivative is high, and a production method for obtaining a high-purity thioctic acid derivative was established.

Claims (19)

An industrially useful physiologically active composition comprising a thioctic acid derivative represented by the following general formula (1).

(In Formula (1), R ¹ is a hydrocarbon group having 8 to 22 carbon atoms, more preferably 14 to 18 carbon atoms, which may have a branched or unsaturated bond, or an acyl group, or carbon. A polycyclic aromatic hydrocarbon or carbon continuum having a number of 9 to 100 is shown.) An industrially useful physiologically active composition comprising a dihydrothioctic acid derivative represented by the following general formula (2).

(In Formula (2), R ¹ is a hydrocarbon group having 8 to 22 carbon atoms, more preferably 14 to 18 carbon atoms which may have a branched or unsaturated bond, or an acyl group, or A polycyclic aromatic hydrocarbon or carbon continuum having 9 to 100 carbon atoms is shown.) The industrially useful physiological activity according to claim 1 or 2, wherein R ^{1 in the} formulas (1) and (2) is a group selected from any of the following formulas (3): Composition.

(In Formula (3), R ^{6 to} R ⁸ may each independently have a hydrogen atom, an aryl group, or a branched, unsaturated bond or substituent, having 8 to 22 carbon atoms, more preferably a carbon number. Represents 14 to 18 hydrocarbon groups). In the formula (3), R ⁶ is a chain hydrocarbon group having 8 to 22 carbon atoms, more preferably 14 to 18 carbon atoms, which may have a branch, an unsaturated bond or a substituent, R ⁷ and R ⁸ are each independently a hydrogen atom or a branched hydrocarbon chain having 8 to 22 carbon atoms, more preferably 14 to 18 carbon atoms, which may have a branched, unsaturated bond or substituent. The industrially useful physiologically active composition according to claim 3, which is a group. Tedecanoylthioctic acid (n = 14), isotetradecanoylthioctic acid (n = 14), pentadeca having the following chemical structure, which may have a branched, unsaturated bond or substituent: Noylthioctic acid (n = 15), isopentadecanoylthioctic acid (n = 15), hexadecanoylthioctic acid (n = 16), isohexadecanoylthioctic acid (n = 16), heptadecanoylthioctic acid ( The industrially useful physiologically active composition according to claim 1, comprising any one of n = 17) and isoheptadecanoyl thioctic acid (n = 17).

Tedecanoyl dihydrothioctic acid (n = 14), isotetradecanoyl dihydrothioctic acid (n = 14) having the following chemical structure, which may have a branched, unsaturated bond or substituent: Pentadecanoyl dihydrothioctic acid (n = 15), isopentadecanoyl dihydrothioctic acid (n = 15), hexadecanoyl dihydrothioctic acid (n = 16), isohexadecanoyl dihydrothioctic acid (n = 16), The industrially useful physiologically active composition according to claim 1, comprising any one of heptadecanoyl dihydrothioctic acid (n = 17) and isoheptadecanoyl dihydrothioctic acid (n = 17).

The industrially useful physiologically active composition according to any one of claims 1 to 6, wherein the thioctic acid derivative concentration is added so that the cell culture medium concentration or tissue concentration is 50 to 3200 ppm. Sodium L-ascorbic acid-2-phosphate, magnesium L-ascorbic acid-2-phosphate, L-ascorbic acid-2-glucoside, sodium L-ascorbic acid-2-phosphate-6-palmitic acid, sodium L- Ascorbic acid-2-phosphate-6-isopalmitic acid, L-ascorbic acid-2,3,5,6-tetrahexyldecanoic acid, L-ascorbic acid-3-ethyl, ascorbic acid-3-glucoside, sodium tocopheryl The industrially useful physiologically active composition according to any one of claims 1 to 7, comprising at least one compound selected from phosphoric acid, sodium tocopheryldimethylglycine, and tocopheryl retinoic acid at the same time. Industrially useful physiological activities include high sustained activity, high absorbability to cells, high enzyme conversion activity in living organisms, high activity in living organisms, low cytotoxicity, cells The industrially useful physiologically active composition according to any one of claims 1 to 8, which has one or more physiologically active effects selected from high growth promoting activity. 10. The industrially useful physiologically active composition according to claim 9, wherein the cell is any one selected from prokaryotic cells, eukaryotic cells, protist cells, fungal cells, animal cells, and plant cells. Cells are stem cells, neurons, glandular fibroblasts, keratinocytes, pigment cells, cardiomyocytes, hepatocytes, oral mucosal epithelial cells, enamel blasts, odontoblasts, hair matrix cells, vascular endothelial cells, hematopoietic stem cells, many The industrially useful physiologically active composition according to claim 11, which is a potent stem cell or an adipocyte. The industrially useful physiologically active composition according to any one of claims 9 to 11, wherein the cell is a plurality of cell aggregates which are tissues or organs. The physiologically active composition is a pharmaceutical product having a physiological effect according to any one of the following: Industrially useful physiologically active composition according to any one of claims 1 to 12, a therapeutic disease preventive effect on an adult disease, Preventive effect on cerebral infarction, preventive effect on myocardial infarction, preventive effect on treatment of cardiovascular disease, preventive effect on anti-infective treatment, wound healing effect, analgesic effect, anti-inflammatory effect, detoxification effect, anti-necrosis effect, preventive effect on diabetes treatment, pigment Anti-deposition treatment effect, acne treatment prevention effect, seborrhea treatment prevention effect, UV irradiation disorder treatment prevention effect, wrinkle treatment prevention effect, sagging treatment prevention effect, obesity treatment prevention effect, swelling treatment prevention effect, hair loss treatment prevention effect, Prevention of pore enlargement treatment, prevention of rough skin treatment, prevention of growth inhibition treatment, anti-stress effect. The physiologically active composition is a cosmetic product having any of the following physiological effects: Industrially useful physiologically active composition according to any one of claims 1 to 12, analgesic effect, antipruritic effect, detoxification effect, wound healing effect Anti-necrosis effect, pigmentation treatment prevention effect, acne treatment prevention effect, seborrhea treatment prevention effect, ultraviolet irradiation disorder treatment prevention effect, wrinkle treatment prevention effect, sagging treatment prevention effect, swelling treatment prevention effect, hair loss treatment prevention effect , Pore expansion treatment prevention effect, rough skin treatment prevention effect, anti-stress effect. The industrially useful physiologically active composition according to any one of claims 1 to 14, wherein the physiologically active composition is a polymer composition for tissue regeneration. The physiologically active composition according to any one of claims 1 to 14, wherein the physiologically active composition is a food additive. The industrially useful physiologically active composition according to any one of claims 1 to 14, wherein the physiologically active composition is a feed additive. The following manufacturing method of the thioctic acid derivative in any one of Claims 1-6.
1 ± 0.5 molecular equivalent of thioctic acid and 1 to 0.5 molecular equivalent of physiologically acceptable medium chain, long chain monovalent, divalent, or trivalent alcohol having 8 to 22 carbon atoms as inert gas Under atmosphere, dissolved in dehydrated methylene chloride solvent, a catalytic amount of 0.05 ± 0.025 molecular equivalent of dimethylaminopyridine was added. While stirring at 0 ± 10 ° C., 1.1 ± 0.5 molecular equivalent of dicyclohexylcarbodiimide was added, followed by stirring at 25 ± 10 ° C. for 1 to 48 hours to separate and purify the reaction mixture. The following purification method of the thioctic acid derivative according to any one of claims 1 to 6.
After separating the reaction mixture obtained in claim 24, the solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was separated and purified on a silica gel column (hexane weight% / ethyl acetate weight% = 10 ± 5).