JPH0881382A - Lipolytic medicine - Google Patents

Abstract

PURPOSE: To obtain a medicine having obvious lipolytic action in adipose tissue and excellent effect of suppressing, inhibiting and improving of obesity by using a plant of family Citrus as an active component. CONSTITUTION: This lipolytic medicine contains a raw material, a squeezed solution, dried powder or a solvent-extracted material, etc., of a plant of family Citrus, preferably Citrus tangerina Tanaka or Citrus erythrosa Tanaka of genus Citrus as an active component. Said accelerating medicine is blended with a xanthine derivative (preferably aminophylline or theophylline, etc.), a β- adrenergic stimulant (preferably isoproterenol or dobutamine, etc.), an α2 - adrenergic depressant (preferably yohimbine or phentolamine, etc.) or a bipyridine derivative (preferably amrinone or milrinone, etc.) of preferably 0.01-20% to enhance the effect.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a lipolysis promoter useful for suppressing or preventing obesity, improving obesity constitution, and reducing local or systemic adipose tissue, and a skin external preparation composition containing the same.

Obesity is caused by excessive intake of energy with respect to consumed energy, which is accumulated as neutral fat in white adipocytes. It has been pointed out that obesity, which has a large accumulation as visceral fat, is associated with pathological conditions such as insulin resistance and arteriosclerosis, and obesity, which has a large accumulation as subcutaneous fat, is a major problem from a cosmetic perspective regardless of gender. Has become. Conventionally, it has been considered preferable to always drink oolong tea and eucommia tea to suppress, prevent and improve obesity. Also,
For the purpose of suppressing calorie intake, dietary restrictions, low energy foods, appetite suppressants, digestive absorption suppressants and the like have been used. However, the usual drinking of oolong tea and eucommia tea and the suppression of caloric intake do not always have the effect of preventing and improving obesity and are not acceptable as a habit, and they also promote the decomposition of accumulated fat. It wasn't something, so it wasn't a fundamental solution.

[0003]

Therefore, the present invention is intended to provide a lipolysis promoting agent which promotes the decomposition of accumulated adipose tissue and can sufficiently suppress, prevent and improve obesity. is there.

[0004]

[Means for Solving the Problems] In view of such a situation,
As a result of repeated intensive studies by the present inventors, citrus plants for topical or oral administration promote the decomposition of neutral fat accumulated in adipose tissue, and can suppress, prevent and improve obesity, And a xanthine derivative,
The inventors have found that the above-mentioned effects are further enhanced by incorporating a β-adrenergic stimulant, an α ₂ -adrenergic inhibitor or a bipyridine derivative, and completed the present invention.

That is, the present invention provides a lipolysis promoter containing a plant of the Rutaceae family. The present invention also provides a skin external preparation containing this lipolysis promoter.

Furthermore, the present invention provides a skin external preparation composition containing a lipolysis promoter and one or more selected from xanthine derivatives, β-adrenergic stimulants, α ₂ -adrenergic inhibitors and bipyridine derivatives. It is provided.

The Rutaceae plant used in the present invention includes the citrus genus Citrus
unshiu Marcov), Ovenimikan (C
itrus tangerina Tanaka), cobenimikan (Citrus erythrosa Ta
naka), mandarin orange (Citrus aurantiu)
m L subsp. nobilis Makin
o), Citrus aurantium L., Daidai (Citrus aurantium L., va
r. daidai Makino), Marubushkan (Citrus medica L), Natsumikan (C
itrus Natsudaidai Hayat
a), pomelo (Citrus grandis Osb)
eck), Yuzu (Citrus Junos Tana)
ka), Ponkan (Citrus reticulat)
a Blanco), lemon (Citrus limo)
n Burmann), Karatachi (Citrus tr)
ifoliata L), a Fortunella genus Malchincan (Fortunella japonica)
Swingle), Xanthoxium piperium D
C. ), The genus Evodia (Evodia r)
utaecarpa Hook. fil et Tho
ms. ), As well as Aegle m.
armelos Corr), Bukkokinoki (Agat)
hosma betulina Pill), Chinese cabbage (Dictamnus albus L), Indica Zinsho (Fragara mante churica H)
onda), European heron (Orixa japonica)
Thunb), Yellowfin (Phellodendron)
amurense Rupr, Pilocarpus penna
tifolius Lan), Phellodendron chinense
Schneido, Henruda (Ruta gra)
veolens L), Miyamaximi (Skimmia)
Japana Thunb) and the like. Among these, Obeni mandarin and Coben mandarin are especially preferable.

[0008] As such citrus plants, mature,
Or immature fruits, peels, seeds, leaves, petioles, branches, roots,
Flowers and the like are used as a raw material, and among them, fruits, peels and leaves are preferable. However, the above Rutaceae plants are distributed in Kampo prescriptions for the purpose of stomach ache, antitussive and carminative, and those used internally or for external use / bath include Chenpi (skin) and orange peel (spruce). . The rind is mainly unshiu mandarin orange (Citrus unshiu Marcov), and the orange rind is Citrus aurantium L or daidai (Citrus aurantium L., va).
r. It is a matured pericarp of daidai Makino), and when these are used as a raw material, the effect intended by the present invention is small. Therefore, it is preferable to use immature fruits or leaves for these three species. In addition, mandarin orange (Citrus aurantiu) that has been eaten conventionally
m L subsp. nobilis Makin
o), Natsumikan (Citrus Natsuid)
ai Hayata), pomelo (Citrus gra)
ndis Osbeck, Yuzu (Citrus Ju)
nos Tanaka, lemon (Citrus li)
Mon Burmann mature flesh and salmon (Xanthoxyum piperitum D)
C. With respect to the matured fruit of (1), since the effect of the present invention is small, it is preferable to use an immature fruit, or a pericarp or leaf.

The Rutaceae plant in the present invention is used as a raw juice, a dry powder, a solvent extract or the like as it is.

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

The amount of citrus plants mixed can be selected from a wide range, although it varies depending on the addition form and administration form. For example, in the case of an external preparation, it is preferable to add 0.005% by weight (hereinafter referred to simply as%) or more, particularly 0.01 to 30%, in terms of a solvent-extracted dry product. Also, in the case of oral preparations, in terms of solvent-extracted dry matter,
It is preferable that the daily dose of an adult is 0.01 to 5 g, especially 1 to 2 g.

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, R ² represents a hydrogen atom, a hydroxy group having 1 to 2 carbon atoms or an alkanoyl group having 2 to 10 carbon atoms, which may be substituted. To 12 alkyl groups] or a salt thereof.

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

The β-adrenergic stimulant used in the present invention is not particularly limited, and for example, isoproterenol, epinephrine, norepinephrine, dobutamine, dopamine, butopamine, salbutamol, terbutaline, isoethalin, protoxylol, fenoterol, metaproterenol, chlor. Plenalin, 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 pharmacologically acceptable salts thereof. Examples of the pharmaceutically acceptable salt include pharmaceutically 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 more selected from the group consisting of isoproterenol, dobutamine, salbutamol and pharmacologically acceptable salts thereof. As the salt in this case, hydrochloride or sulfate is used. Is preferred. The amount of the β-adrenergic stimulant added is 0.
It is preferably 005% or more, and particularly preferably 0.01 to 20%.

The α ₂ adrenergic inhibitor used in the present invention is not particularly limited, and examples thereof include yohimbine, phentolamine, phenoxybenzamine, tolazoline, ergotamine, ergotoxin, dihydroergotamine, ergomethrin, methylergomethrin, dihydroergotoxin, lauorcin, Examples thereof include piperoxane and pharmacologically acceptable salts thereof. Examples of the pharmacologically acceptable salt include those similar to the above. In the present invention, it is preferable to use one or more selected from the group consisting of yohimbine, phentolamine, ergotamine and pharmaceutically acceptable salts thereof. As the salt in this case, a mesylate salt or a tartrate salt, The hydrochloride salt is preferred. The blending amount of the α ₂ adrenergic inhibitor is preferably 0.005% or more, and particularly preferably 0.01 to 20% in the total amount of the composition.

The bipyridine derivative used in the present invention is not particularly limited, and examples thereof include compounds represented by the following general formula (2) and pharmacologically acceptable salts thereof.

[0019]

Embedded image

[Wherein R ³ is a hydrogen atom or a methyl group,
An alkyl group such as an ethyl group is shown, and Q is NH ₂ , NC, H ₂
Indicates NCO, etc.]

Examples of such bipyridine derivatives include amrinone, milrinone, 5-cyano- [3,4'-bipyridin] -6 (1H) -one and 5-carbamyl- [3,3.
4'-bipyridin] -6 (1H) -one and pharmacologically acceptable salts thereof and the like can be mentioned. Examples of the pharmacologically acceptable salt include the same as those mentioned above. In the present invention, it is preferable to use one kind or two or more kinds selected from the group consisting of amrinone, milrinone, and pharmacologically acceptable salts thereof. The blending amount of the bipyridine derivative is 0.005% or more, especially 0.0
It is preferably 1 to 20%.

In addition to the above-mentioned components, the lipolysis promoter and external skin preparation composition of the present invention include a surfactant, an oily component, which is 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, the nonionic one 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 sorbit fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene glycol. , Polyoxyethylene polyoxypropylene alkyl ether, polyethylene glycol fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, alkyl glycoside and the like.

The lipolysis promoter and external skin preparation composition of the present invention may further contain the following components, but the components are not limited to these. (A) Pigments: Tar dyes such as Yellow No. 4, Blue No. 1, Yellow No. 202, etc. recognized as a food additive such as the pigments of Tables I and II of the tar list, chlorophyll, riboflavin, crocin, safflower, anthraquinone, etc. Natural pigments that are used. (B) Vitamins; vitamin A, vitamin C, vitamin D, vitamin E and the like. (C) Others: bactericides, antiseptics, and other components necessary for formulation.

The lipolysis-promoting composition and external skin preparation composition of the present invention can be produced by a conventional method by adding the above-mentioned optional components to the above-mentioned essential components as necessary. In addition, by adding an appropriate amount of water in the range of 0.01 to 90% to the lipolysis promoter and skin external preparation composition of the present invention prepared as described above, the stability of the preparation is increased, or the preparation is prepared. It can also be emulsified.

The lipolysis-promoting composition and the skin external preparation composition of the present invention may be in the form of a bath preparation. In this case, the amount used once is in terms of solvent-extracted dried product of citrus plants. It is preferable that the concentration in the bath water be 0.01 ppm to 200 ppm.

The dosage form of the lipolysis promoter and the external skin preparation composition 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, paps, plasters, sticks, sheets, tea bags and the like can be used.

[0028]

The lipolysis-promoting agent and the external skin preparation composition of the present invention have a clear lipolysis-promoting action in adipose tissue, and have excellent effects in suppressing, preventing and improving obesity.

[0029]

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

Invention 1 Citrus tangerina
100 g of dried young fruits (Tanaka) were 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 Scutellaria baicalensis.

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

Inventive product 3 Evodia rutaecarpa Ho
ok. fill etThoms. ) Dried fruit 100g
Was extracted with hot water by a conventional method, filtered, concentrated under reduced pressure, and then freeze-dried. This was used as a goshuyu hot water extract.

Inventive Product 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 then freeze-dried. This was used 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 designated as 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 designated as an oolong tea 30% ethanol extract.

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

Example 1 Inventive products 1 to 4 and comparative products 1 to 3 were used to examine their lipolysis promoting action by the following test method. The results are shown in Table 1.

Test Method Rodbell's method [Rodbell, M .; J. Bio
l. Chem. , 239, 375 (1964)], male Wistar rats (weight 150 to 200 g).
Free adipocytes were prepared from five epididymal adipose tissues using a collagenase solution. Hanks (H) containing bovine serum albumin adjusted to a test substance concentration of 100 μg / ml
ank's) buffer, the above cells are incubated at 37 ° C. for 2 hours, and the released fatty acid is analyzed by the method of Okuda et al.
kuda, H .; et al. , Pharmacol. R
es. Commun. , 18, 877 (1986)].

[0039]

[Table 1]

From Table 1, it is possible to measure 100 μl
When g / ml was applied, the invention products 1 to 4 showed a clear lipolysis promoting action, whereas the comparative products 1 to 3 did not show this action.

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

Test Method The abdominal skin tissue of 5 male Wistar rats (body weight 250-350 g) was peeled together with the subcutaneous fat tissue at a diameter of 4 cm, and set in a cylindrical diffusion cell having a diameter of 2.6 cm. Table 2
0.5 g of the skin external preparation composition shown in 1) was uniformly applied to the skin surface, and the lower cell was filled with Hank's buffer. After standing at 37 ° C. for 3 hours, glycerol released in the buffer solution in the lower cell was measured by an enzymatic method (F-kit glycerol; Boehringer Mannheim used).

[0043]

[Table 2]

From Table 2, inventive products 5 to 6 show a clear lipolysis promoting action in the subcutaneous adipose tissue when applied to the skin, as compared with the comparative product 4 in which the invention products are not blended. Inventive products 7 to 10 in which the extract and the xanthine derivative, β-adrenergic stimulant, α ₂ adrenergic suppressor or bipyridine derivative are mixed, the action is further enhanced as compared with Comparative products 5 to 8 in which no Rutaceae plant is not mixed. Was done.

Example 3 Oral tablets

[Table 3] (%) Daidai peel skin powder 25 Theophylline 10 Lactose 30 Dextrin 25 Glucose 10 Dye Trace amount

Example 4 Gel cream

[Table 4] (%) Extract of Invention 1 5 Liquid paraffin Squalane 20 Microcrystalline wax 5 Cetyl isooctanoate 5 Polyoxyethylene (20) glycerol tri-isostearate 1 Perfume Trace dye Pigment

Example 5 Massage Agent with Scrub Agent

[Table 5] (%) 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 Acyl methyl taurine 6 Polyoxyethylene (60) octyldodecyl alcohol ether 8 Purified water Appropriate amount Perfume Trace amount

Example 6 Foam pack

[Table 6] (%) Inventive product 2 extract 5 Yohimbine hydrochloride 2 1,3-butylene glycol 10 glycerin 10 methylparaben 0.2 potassium hydroxide 0.2 stearic acid 1 butyl alcohol 2 polyoxyethylene (60) hardening Castor oil 3 Liquefied petroleum gas (propellant) 5 Dimethyl ether (propellant) 3 Perfume Trace amount Purified water Appropriate amount

Example 7 Tablet type bath agent

[Table 7] (%) Inventive product 3 extract 12 Amrinone 2 Sodium hydrogen carbonate 20 Sodium carbonate 10 Fumarate 30 Polyethylene glycol (average molecular weight 6000) 20 Dextrin Appropriate amount Perfume Trace amount Pigment amount Trace amount

Example 8 Liquid bath agent

[Table 8] (%) Extract of Invention 4 10 Triglyceride octanoate 33 Octyldodecyl myristate 33 Liquid paraffin Appropriate amount Polyoxyethylene sorbit fatty acid ester (40E.O.) 9 Polyoxyethylene sorbit fatty acid ester (20E.O.O.) ) 3 Fragrance

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[Procedure amendment]

[Submission date] March 20, 1995

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0043

[Correction method] Change

[Correction content]

[0043]

[Table 2]

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Claims (7)

[Claims] 1. A lipolysis promoter comprising a plant of the Rutaceae family as an active ingredient. 2. A skin external preparation composition containing the lipolysis promoter according to claim 1. 3. The skin external preparation composition according to claim 2, further comprising one or more selected from xanthine derivatives, β-adrenergic stimulants, α ₂ adrenergic inhibitors and bipyridine derivatives. 4. The xanthine derivative is aminophylline,
The external skin preparation composition according to claim 3, which is selected from the group consisting of theophylline, caffeine and salts thereof. 5. The external skin preparation composition according to claim 3, wherein the β-adrenergic stimulant is selected from the group consisting of isoproterenol, dobutamine, salbutamol and salts thereof. 6. The external skin preparation composition according to claim 3, wherein the α ₂ adrenergic inhibitor is selected from the group consisting of yohimbine, phentolamine, ergotamine and salts thereof. 7. The external skin preparation composition according to claim 3, wherein the bipyridine derivative is selected from the group consisting of amrinone, milrinone and salts thereof.