JP2002326947A - Lipolysis promoter - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a lipolysis promoter that has obvious lipolysis promotive action in the adipose tissue and shows excellent effect for inhibition, prevention and amelioration of obesity. SOLUTION: The objective lipolysis promoter comprises peels or leaves of citrus fruits or extract thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a lipolysis-promoting agent useful for suppressing or preventing obesity, improving obesity constitution, reducing local or systemic adipose tissue, and an external preparation for skin containing the same.

[0002] Obesity is caused by excess energy intake relative to energy expenditure accumulated as neutral fat in white fat cells. Obesity, which has a large accumulation as visceral fat, has been pointed out to be related to pathological conditions such as insulin resistance and arteriosclerosis.In addition, obesity, which has a large accumulation as subcutaneous fat, is a major problem for both men and women from the viewpoint of beauty. It has become. Conventionally, it has been considered that oolong tea and Tochu tea are preferably drunk for suppressing, preventing and improving obesity. Also,
For the purpose of suppressing calorie intake, dietary restrictions, low-energy foods, appetite suppressants, digestion and absorption suppressants, and the like have been used. However, oolong tea and Tochu tea are not always effective in preventing and improving obesity and are difficult to accept as a habit in suppressing normal calorie intake and calorie intake, and they promote the breakdown of accumulated fat. It was not a fundamental solution because it was not.

[0003]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a lipolysis promoter capable of promoting the decomposition of accumulated adipose tissue and sufficiently suppressing, preventing and improving obesity. is there.

[0004]

In view of such circumstances,
The present inventors have made intensive studies, and as a result of external or oral administration, Rutaceae plants promote the degradation of triglycerides accumulated in adipose tissue, and can suppress, prevent and improve obesity, And a xanthine derivative,
β-adrenergic stimulants, further when blended alpha ₂ adrenergic inhibitors or bipyridine derivatives found that the above effect is enhanced, and have completed the present invention.

[0005] That is, the present invention provides a lipolysis promoter comprising the pericarp or leaves of an Rutaceae plant or an extract thereof.

[0006] Furthermore, the present invention is, lipolysis promoter and xanthine derivatives, beta-adrenergic stimulants, alpha ₂ adrenergic inhibitors and one or skin external preparation composition containing two or more selected from bipyridine derivative To provide.

The Citrus plants used in the present invention include Citrus genus Citrus (Citrus)
unshiu Marcov)
itrus angelina Tanaka, covenimican (Citrus erythrosa Ta)
naka), mandarin orange (Citrus aurantiu)
ML subsp. nobilis Makin
o), Citrus aurantium L, die dai (Citrus aurantium L., va)
r. daidai Makino), Marbuscan (Citrus medica L), Natsumikan (C)
itrus Natsudaidai Hayat
a), pomelo (Citrus grandis Osb)
eck), Yuzu (Citrus Junos Tana)
ka), Ponkan (Citrus reticulat)
a Blancco, lemon (Citrus limo)
n Burmann), Karatachi (Citrus tr)
ifoliata L), a martin can of the genus Fortunella (Fortunella japonica)
swingle), Xanthoxium piperium D
C. ), Goshyu of the genus Evodia (Evodia
utaecarpa Hook. fill et Tho
ms. ), And Maegul Malmeros (Aegle m
armelos Corr), Bukkokinoki (Agat)
hosma betulina Pill), daffodil (Dictamnusalbus L), dog flies (Fragara mante churica H)
onda), Egret (Orixa japonica)
Thunb), Yellowfin (Phello dendron)
amurense Rupr), Pilocarpus pennatiforius (Pilocarpus penna)
tifolius Lan), Phellodendron chinense
Schneido), Henruuda (Ruta gra)
veolens L), Miyamimi (Skimmia)
japonica Thunb) and the like. Of these, Obenimican and Cobenimican are particularly preferred.

As such citrus plants, mature,
Or immature fruits, peels, seeds, leaves, petiole, branches, roots,
Flowers and the like are used as raw materials, and among them, fruits, pericarp, and leaves are preferable. However, among the above-cited Rutaceae plants, those that are distributed in Kampo formulas for the purpose of healthy stomach, antitussive and carminative, and that are used internally, or for external use and bathing, include cinnamon (thinpi) and orange peel (spruce). . Chen skin is mainly Citrus unshiu Marcov, and orange skin is Citrus aurantium L or Daidai (Citrus aurantium L., va).
r. is a mature pericarp, and when these are used as a raw material, the effect of the present invention is small. Therefore, it is preferable to use immature fruits or leaves for these three species. In addition, conventionally used citrus (citrus aurantiu)
ML subsp. nobilis Makin
o), Natsumikan (Citrus Natsudaid)
ai Hayata), Pomelo (Citrus gra)
ndis Osbeck), Yuzu (Citrus Ju)
nos Tanaka), Lemon (Citrus li)
mon Burmann's mature pulp and salmon (Xanthoxyum piperitum D)
C. Regarding the mature fruit of the above), it is preferable to use an immature fruit, or use pericarp or leaves, since the effect aimed at by the present invention is small.

The citrus plant of the present invention is used as it is, as a juice, a dry powder or a solvent extract.

Examples of the solvent extract include those extracted with water or an organic solvent such as a lower alcohol or a polyol or a mixture thereof, which is appropriately concentrated, purified, sterilized, dried and used. You.

The amount of the Citrus plant varies depending on the form of administration and the form of administration, but can be selected from a wide range. For example, in the case of an external preparation, it is preferably incorporated in the composition in an amount of 0.005% by weight or more (hereinafter simply referred to as%), particularly 0.01 to 30% in terms of a solvent-extracted dry product. In the case of oral preparations, in terms of dry solvent extract,
It is preferable that the amount be 0.01 to 5 g, particularly 1 to 2 g per day for an adult.

The xanthine derivative used in the present invention is not particularly limited. For example, the following general formula (1):

[0013]

Embedded image

[In the formula, R ¹ represents a methyl group or a hydrogen atom, and R ² represents a hydrogen atom or a carbon atom which may be substituted by one or two hydroxy groups or alkanoyl groups having 2 to 10 carbon atoms. Or a salt thereof.

[0015] Examples of such xanthine derivatives include xanthine, aminophylline, theophylline, choline theophylline, caffeine, theobromine, oxtriphylline, diprofylline and proxyphylline. These can be used alone or in combination of two or more. In the present invention, it is preferable to use one or a combination of two or more selected from the group consisting of aminophylline, theophylline and caffeine. The amount of the xanthine derivative is preferably 0.005% or more, particularly preferably 0.01 to 20%, in the composition. Further, as these xanthine derivatives, those which are substantially pure or isolated from plants such as synthetic or tea leaves can be used.

[0016] The β-adrenergic stimulant used in the present invention is not particularly limited. Prenaline, hexoprenaline, trimethoquinol, procaterol hydrochloride, prenalterol, forskolin, disodium (R, R) -5- [2-
[[2- (3-chlorophenyl) -2-hydroxyethyl] -amino] propyl] -1,3-benzodioxole-2,2-dicarboxylate, (R ^* , R ^* )-4-
[2-({2-[(3-chlorophenyl) -2-hydroxyethyl] amino} propyl) phenyl] phenoxyacetic acid, {2-hydroxy-5- [2-({2-hydroxy-3- [4- ( 1-methyl-4-trifluoromethyl) -1H-imidazol-2-yl] phenoxy {propyl) amino] ethoxy} -benzamide monomethanesulfonate, erythro-DL-1- (7-methylindan-4-yloxy ) -3-isopropylaminobutan-2-ol and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. In the present invention, it is preferable to use one or two or more selected from the group consisting of isoproterenol, dobutamine, salbutamol, and a pharmaceutically acceptable salt thereof. Is preferred. The amount of the β-adrenergic stimulant is 0.1% in the composition.
005% or more, particularly preferably 0.01 to 20%.

The α ₂ -adrenergic inhibitor used in the present invention is not particularly limited. And piperoxane and pharmaceutically acceptable salts thereof. Examples of the pharmacologically acceptable salt include the same as described above. In the present invention, it is preferable to use one or two or more selected from the group consisting of yohimbine, phentolamine, ergotamine and a pharmaceutically acceptable salt thereof. Hydrochloride is preferred. alpha ₂ The amount of adrenergic drugs is the total amount of the composition of 0.005% or more and particularly 0.01 to 20%.

The bipyridine derivative used in the present invention is not particularly restricted but includes, for example, compounds represented by the following general formula (2) and pharmaceutically acceptable salts thereof.

[0019]

Embedded image

Wherein R ³ is a hydrogen atom or a methyl group,
Represents an alkyl group such as an ethyl group, and Q represents NH ₂ , NC, H ₂
Indicates NCO etc.)

Examples of such bipyridine derivatives include amrinone, milrinone, 5-cyano- [3,4'-bipyridine] -6 (1H) -one, and 5-carbamyl- [3,
4'-bipyridin] -6 (1H) -one and pharmaceutically acceptable salts thereof. Examples of the pharmacologically acceptable salt include the same as described above. In the present invention, it is preferable to use one or more selected from the group consisting of amrinone, milrinone, and a pharmaceutically acceptable salt thereof. The compounding amount of the bipyridine derivative is 0.005% or more, especially 0.0
It is preferable to set it to 1 to 20%.

In addition to the above components, the lipolysis accelerator and the external preparation for skin of the present invention may further contain surfactants, oily components used in various pharmaceutical and cosmetic preparations,
Moisturizers, polymer compounds, ultraviolet absorbers, anti-inflammatory agents, bactericides, antioxidants, sequestering agents, preservatives, vitamins, pigments, fragrances, and the like can be added.

As the above-mentioned surfactant, any of anionic, cationic, nonionic, natural and synthetic surfactants can be used, but in consideration of skin irritation, nonionic ones should be used. Is preferred. Examples of the nonionic surfactant include glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene glycol , Polyoxyethylene polyoxypropylene alkyl ether, polyethylene glycol fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hardened castor oil, alkyl glycoside and the like.

The lipolysis accelerator and the external preparation composition for skin of the present invention may further contain the following components, but the components are not limited thereto. (A) Dyes: Recognized as food additives such as tar 4, specified in the Ministry of Health and Welfare Ordinance I and II, chlorophyll, riboflavin, crocin, safflower, anthraquinone, etc. Natural pigments, etc. (B) vitamins; vitamin A, vitamin C, vitamin D, vitamin E and the like. (C) Others: bactericides, preservatives, and other components necessary for preparation.

The composition for promoting lipolysis and the external preparation for skin of the present invention can be produced according to a conventional method by adding the above-mentioned optional components to the above-mentioned essential components, if necessary. The lipolysis accelerator and the external preparation for skin of the present invention prepared as described above may be added with an appropriate amount of water in the range of 0.01 to 90% to increase the stability of the preparation, It may be in an emulsified form.

The lipolysis promoter and skin external preparation composition of the present invention can be in the form of a bath preparation. In this case, the amount used at a time is in terms of a solvent extract dry product of an Rutaceae plant. It is preferable that the concentration in the bath water is 0.01 ppm to 200 ppm.

The dosage form of the lipolysis promoter and the external preparation composition for skin of the present invention is not particularly limited, and examples thereof include tablets for oral administration, food, external use, bath, shower, body wash, etc.
Capsules, liquids, powders, granules, creams, emulsions, gels, pastes, pups, plasters, sticks, sheets, tea bags and the like can be used.

[0028]

EFFECT OF THE INVENTION The lipolysis promoter and the skin external preparation composition of the present invention have a clear lipolysis promoting action in adipose tissue, and are excellent in suppressing, preventing and improving obesity.

[0029]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. Inventive products 1-4 and comparative products 1 used in Examples
3 is as follows.

Inventive product 1 Citrus tangerina
100 g of dried young fruits of Tanaka) was extracted with hot water by a conventional method, filtered, concentrated under reduced pressure, and then freeze-dried. This was used as a hot water extract of Ovenimican.

Invention 2 Die Dye (Citrus aurantium L.v.)
100 g of dried fruits of ardaii Makino)
Was extracted with a 30% aqueous ethanol solution by a conventional method, filtered, concentrated under reduced pressure, and then freeze-dried. This is die die 30
% Ethanol extract.

Inventive product 3 Evodia rutaecarpa Ho
ok. file et Thoms. 100g of dried fruit
Was extracted with hot water by a conventional method, filtered, concentrated under reduced pressure, and then freeze-dried. This was designated as Goshuyu hot water extract.

Invention 4 100 g of dried leaves of citrus junos tanaka were extracted with hot water by a conventional method, filtered, concentrated under reduced pressure, and freeze-dried. This was designated as a Yuzu hot water extract.

Comparative product 1 100 g of dried leaves of oolong tea were extracted with hot water by a conventional method, filtered, concentrated under reduced pressure, and then freeze-dried. This was used as the oolong tea hot water extract.

Comparative Product 2 100 g of dried leaves of oolong tea were extracted with a 30% aqueous ethanol solution by a conventional method, filtered, concentrated under reduced pressure, and then freeze-dried. This was used as a 30% ethanol extract of oolong tea.

Comparative product 3 100 g of dried leaves of Tochu tea was extracted with hot water by a conventional method, filtered, concentrated under reduced pressure, and freeze-dried. This was designated as Tochu tea hot water extract.

Example 1 Using the invention products 1 to 4 and the comparison products 1 to 3, the lipolysis promoting effect was examined by the following test methods. Table 1 shows the results.

Test Methods Rod Bell Method [Rodbell, M .; , J. et al. Bio
l. Chem. 239, 375 (1964)], male Wistar rats (body weight 150-200 g).
Free adipocytes were prepared from 5 epididymal adipose tissues using a collagenase solution. Hanks (H) containing bovine serum albumin prepared to give a test substance concentration of 100 μg / ml
ank's) Incubate the cells at 37 ° C. for 2 hours in a buffer and release the released fatty acids according to the method of Okuda et al.
kuda, H .; et al. , Pharmacol. R
es. Commun. , 18, 877 (1986)].

[0039]

[Table 1]

From Table 1, it was found that the free adipocytes had 100
When g / ml was applied, invention products 1 to 4 exhibited a clear lipolysis promoting effect, whereas comparative products 1 to 3 did not exhibit this effect.

Example 2 A skin external preparation composition having the composition shown in Table 2 was prepared by a conventional method, and its lipolysis promoting effect was examined by the following test method. The results are shown in Table 2.

Test Method Five abdominal skin tissues of 5 male Wistar rats (body weight: 250 to 350 g) were peeled together with subcutaneous adipose tissue to a diameter of 4 cm and set in a columnar diffusion cell having a diameter of 2.6 cm. Table 2
Was applied uniformly to the skin surface, and the lower cell was filled with Hank's buffer. After leaving at 37 ° C. for 3 hours, glycerol released into the buffer in the lower cell was measured by an enzyme method (F-kit glycerol; using Boehringer Mannheim).

[0043]

[Table 2]

According to Table 2, invention products 5 to 6 showed a clear lipolysis promoting effect on subcutaneous adipose tissue when applied to the skin, as compared with comparative product 4 not containing the same. extract and xanthine derivatives, beta-adrenergic stimulants, the inventions 7-10 blended with alpha ₂ adrenergic inhibitors or bipyridine derivatives, their action is further compared with the comparative products 5-8 without blending Rutaceae plants enhanced Was done.

Example 3 Oral Tablet (%) Daidai Peel Powder 25 Theophylline 10 Lactose 30 Dextrin 25 Glucose 10 Pigment Trace

Example 4 Gel cream (%) Extract of invention 1 5 Liquid paraffin suitable amount Squalane 20 Microcrystalline wax 5 Cetyl isooctanoate 5 Polyoxyethylene (20) glycerol tri isostearate 1 Perfume Trace pigment Trace trace

Example 5 Massage Agent with Scrub Agent (%) Karatachi Leaf Powder 2 Isoproterenol Hydrochloride 1 Polyethylene Beads (Particle Size: 20 μm or Less 7%, Particle Size 5000 μm or More 0%) 10 Liquid Paraffin 14 2-Ethylhexanoic Acid Triglyceride 37 Sorbitol 8 Polyethylene glycol (average molecular weight 400) 6 Acylmethyltaurine 6 Polyoxyethylene (60) octyldodecyl alcohol ether 8 Purified water Appropriate amount Fragrance Trace amount

Example 6 foam pack (%) Extract of invention 2 5 yohimbine hydrochloride 2 1,3-butylene glycol 10 glycerin 10 methyl paraben 0.2 potassium hydroxide 0.2 stearic acid 1 butyl alcohol 2 polyoxyethylene (60) hydrogenated castor oil 3 liquefied petroleum gas (propellant) 5 dimethyl ether (propellant) 3 fragrance trace amount purified water suitable amount

Example 7 Tablet Bath Agent (%) Extract of Invention Product 3 12 Amrinone 2 Sodium Bicarbonate 20 Sodium Carbonate 10 Fumaric Acid 30 Polyethylene Glycol (Average Molecular Weight 6000) 20 Dextrin Appropriate Amount Perfume Minute Pigment Minute

Example 8 Liquid Bath Agent (%) Extract of Inventive Product 4 10 Triglyceride octoate 33 Octyldodecyl myristate 33 Liquid paraffin Appropriate amount Polyoxyethylene sorbite fatty acid ester (40E.O.) 9 Polyoxyethylene sorbite fatty acid ester (20E.O.) 3 Fragrance trace

Continuation of the front page (72) Inventor Norihiro Tanaka 1746-93, Nishisweat, Kami-Mikawa-cho, Kawachi-gun, Tochigi Prefecture (72) Inventor Yuji Ichii 16-3-1-403, Northeast 24 East, Higashi-ku, Sapporo, Hokkaido, Japan (72) Invention Person Hidenori Mann 423-4 Hiramatsumotocho, Utsunomiya-shi, Tochigi F-term (reference) 4B018 MD52 MD61 ME01 MF01 4C083 AA111 AA112 AB032 AB312 AC012 AC022 AC102 AC112 AC122 AC182 AC242 AC422 AC432 AC482 AC792 AD022 AD042 CC05 CC07 CC25 DD08 DD15 DD23 4 AB62 AC04 AC05 BA08 NA14 ZA70

Claims (2)

[Claims] 1. A lipolysis promoter comprising pericarp or leaf of a Citrus plant or an extract thereof. 2. The citrus plant of the genus Citrus.
The lipolysis accelerator according to the above.