JP2005132847A - Oral administration composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a lipolysis promoting agent promoting decomposition of accumulated fatty tissue, and sufficiently suppressing, preventing and improving obesity. <P>SOLUTION: The lipolysis promoting agent containing a plant of the family Piperaceae as an active ingredient and a skin care preparation for external use containing the promoting agent are provided. The lipolysis promoting agent and the skin care preparation for external use have each apparent lipolysis promoting action in fatty tissue and have each excellent suppressing, preventing and improving effects on obesity. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a lipolysis promoter useful for the suppression or prevention of obesity, improvement of obesity constitution, reduction of local or systemic adipose tissue, and a skin external preparation composition containing the same.

  Obesity is a result of excessive intake energy relative to energy consumed, which accumulates as neutral fat in white fat cells. Obesity with a large accumulation of visceral fat has been pointed out to be associated with pathologies such as insulin resistance and arteriosclerosis, and obesity with a large accumulation of subcutaneous fat is a major problem for both men and women from a cosmetic standpoint. It has become. Conventionally, regular drinking of oolong tea and tochu tea has been preferred for the suppression, prevention and improvement of obesity. For the purpose of suppressing caloric intake, dietary restrictions, low energy foods, appetite suppressants, digestion absorption inhibitors, and the like have been used. However, there is a problem that the prevention and improvement effect of obesity is not always sufficient in the regular consumption of oolong tea and Tochu tea and the suppression of calorie intake, and it is difficult to accept as a habit, and these promote the decomposition of accumulated fat It was not a fundamental solution because it was not a thing.

  Therefore, the present invention intends to provide a lipolysis promoter capable of promoting the degradation of accumulated adipose tissue and sufficiently suppressing, preventing and improving obesity.

In view of such a situation, the present inventors have conducted intensive research, and as a result, a pepper plant that has not been considered to have a physiological action on fat cells until now can be used for topical or oral administration. It has been found that the neutral fat accumulated in the tissue can be decomposed and obesity can be suppressed, prevented and ameliorated. In addition, the present inventors have found that the above action is further enhanced when a xanthine derivative, β-adrenergic stimulant, α ₂ adrenergic inhibitor or bipyridine derivative is added thereto, and the present invention has been completed.

  That is, this invention provides the lipolysis promoter containing the plant of a pepper family. Moreover, this invention provides the skin external preparation containing this lipolysis promoter.

Furthermore, the present invention provides a skin external preparation composition comprising one or more selected from a lipolysis accelerator and a xanthine derivative, a β-adrenergic stimulant, an α ₂ adrenergic inhibitor and a bipyridine derivative. It is.

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

The pepper plant of the family to be used in the present invention, pepper (Piper nigrum L.), long pepper (Piper longum L.), Sadasou (Peperomia japonica Makino), Shimagoshou (Peperomia buninsimensis Makino), Tizimi bus Shima Aoi saw (Peperomia caperata Ruiz .et Pav.), Watageaoisou (Peperomia incana A.Dietr), white Shima Aoi Saw (Peperomia magnolifolia A.Dietr.var variegata R.et P.) , Sasabaaoisou (Peperomia puteolata Trel.), Shimaaoisou (Peperomia sandersii C. DC.var. Argyreia Bailey), betel (Piper betele L.), Kubeba (Piper cubeba L.), birch (Piper methysticum Forst), Java Naga Gore Shaw (Piper retrofractum Vahl), Nantes Hugo Shaw (Piper aurantiacum Wall.var hupehense C .DC.), Piper Kadsura (Piper kadzura Ohwi), Piper Beme Rie Folie Umm wall (Piper boehmeriaefolium wall), Piper Hainaneze Hemuru (Piper hainanense Hemsl), Pipahausei Maxim. (Piper haucei Maxim.), Such as pin parser Instrument Sam Rochus (Piper sarmentosum Roxb) and the like. Among these, pepper and hihatsu are particularly preferable.

As such a pepper plant, mature or immature fruits, fruit skins, seeds, leaves, petioles, branches, roots, flowers and the like are used as raw materials, among which fruits, fruit skins and leaves are preferable. However, among the above-mentioned pepper family plants, pepper ( Pipe nigrum L.) is widely used as a spice and is known to have sweating and gastric action. It is called dried black pepper and white pepper that has been dried by removing the pericarp of mature fruits. On the other hand, when used for the purpose of the present invention, it is preferable to use an immature green fruit further than an immature fruit used for black pepper.

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

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

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

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

[Wherein, R ¹ represents a methyl group or a hydrogen atom, and R ² represents a hydrogen atom, 1 to 2 hydroxy groups, or an alkanoyl group having 2 to 10 carbon atoms which may be substituted. A compound represented by the following formula: or a salt thereof.

  Such xanthine derivatives include xanthine, aminophylline, theophylline, choline theophylline, caffeine, theobromine, oxtriphyrin, diprofylline, proxyphylline and the like. These can be used individually by 1 type or in combination of 2 or more types. 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 compounding amount of the xanthine derivative is preferably 0.005% or more, particularly 0.01 to 20% in the composition. In addition, these xanthine derivatives can be used synthetically or substantially purely isolated from plants such as tea leaves.

The β-adrenergic stimulant used in the present invention is not particularly limited. Hexoprenalin, trimethoquinol, procaterol hydrochloride, prenalterol, forskolin, disodium (R, R) -5- [2-[[2- (3-chlorophenyl) -2-hydroxyethyl] -amino] propyl] -1 , 3-Benzodioxol-2,2-dicarboxylate, (R ^* , R ^* )-4- [2-({2-[(3-chlorophenyl) -2-hydroxyethyl] amino} propyl) phenyl ] Phenoxyacetic acid, {2-hydroxy-5- [ -({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 pharmacologically 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 kinds selected from the group consisting of isoproterenol, dobutamine, salbutamol and pharmacologically acceptable salts thereof, and the salt in this case is hydrochloride or sulfate. Is preferred. The blending amount of the β-adrenergic stimulant is preferably 0.005% or more, particularly 0.01 to 20% in the composition.

The α ₂ adrenergic inhibitor used in the present invention is not particularly limited, and examples thereof include yohimbine, phentolamine, phenoxybenzamine, trazoline, ergotamine, ergotoxin, dihydroergotamine, ergomethrin, methylergomethrin, dihydroergotoxin, lauorcine, piperoxane and these And pharmacologically acceptable salts thereof. Examples of the pharmacologically acceptable salt include those 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 pharmacologically acceptable salts thereof. In this case, the salt is mesylate or tartrate, Hydrochloride is preferred. The blending amount of the α ₂ adrenergic inhibitor is preferably 0.005% or more, particularly preferably 0.01 to 20%, based on the total amount of the composition.

  The bipyridine derivative used for this invention is not specifically limited, For example, the compound represented by following General formula (2), these pharmacologically acceptable salts, etc. are mentioned.

[Wherein R ³ represents a hydrogen atom or an alkyl group such as a methyl group or an ethyl group, and Q represents NH ₂ , NC, H ₂ NCO or the like]

  As such bipyridine derivatives, amrinone, milrinone, 5-cyano- [3,4'-bipyridine] -6 (1H) -one, 5-carbamyl- [3,4'-bipyridine] -6 (1H)- And pharmacologically acceptable salts thereof. Examples of the pharmacologically acceptable salt include those described above. In the present invention, it is preferable to use one or more selected from the group consisting of amrinone, milrinone and pharmacologically acceptable salts thereof. The blending amount of the bipyridine derivative is preferably 0.005% or more, particularly preferably 0.01 to 20%, based on the total amount of the composition.

  In addition to the above components, the lipolysis accelerator and skin external preparation composition of the present invention include surfactants, oily components, moisturizers, polymer compounds, UV absorbers used in various pharmaceutical and cosmetic preparations. Agents, anti-inflammatory agents, bactericides, antioxidants, sequestering agents, preservatives, vitamins, pigments, fragrances and the like can be blended.

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

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

The following components can be further blended in the lipolysis promoter and skin external preparation composition of the present invention, but the components are not limited thereto.
(A) Pigments: recognized as food additives such as tar pigments I and II, chlorophyll, riboflavin, crocin, safflower, anthraquinone, etc. stipulated in the Ordinance of the Ministry of Health and Welfare such as Yellow No. 4, Blue No. 1, Yellow No. 202, etc. Natural pigments that are used.
(B) Vitamins; vitamin A, vitamin C, vitamin D, vitamin E, etc.
(C) Others: bactericides, preservatives, other ingredients necessary for the preparation, etc.

  The lipolysis promoter and skin external preparation composition of the present invention can be produced according to a conventional method by adding the optional components to the essential components as necessary. In addition, an appropriate amount of water is added 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 to increase the stability of the formulation, It can also be made into the emulsified form.

  In addition, the lipolysis promoter and the skin external preparation composition of the present invention can be in the form of a bath preparation. In this case, the amount of use once is as follows: The medium concentration is preferably 0.01 ppm to 200 ppm, preferably 0.1 to 100 ppm, and more preferably 0.5 to 50 ppm.

  The dosage form of the lipolysis promoter and skin external preparation composition of the present invention is not particularly limited. For example, tablets, capsules, liquids, powders for oral administration, foods, externals, baths, showers, body washings, etc. Granules, creams, emulsions, gels, pastes, pops, plasters, sticks, sheets, tea bags and the like can be used.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples. Inventive products 1 to 3 and comparative products 1 to 3 used in the examples are as follows.

Invention 1
Pepper ( Pipe nigrum L.) green dried young fruit 100 g was extracted with hot water by a conventional method, filtered, concentrated under reduced pressure, and then freeze-dried. This was made into a pepper hot water extract.

Invention 2
100 g of dried green pepper ( Pipe nigrum L.) green fruit was extracted with a 30% aqueous ethanol solution by a conventional method, filtered, concentrated under reduced pressure, and then lyophilized. This was a 30% ethanol extract of pepper.

Invention 3
100 g of dried fruit of Piper longum L. was extracted with hot water by a conventional method, filtered, concentrated under reduced pressure, and then freeze-dried. This was taken as a Hihatsu 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 lyophilized. This was used as oolong tea hot water extract.

Comparison 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 defined as an oolong tea 30% ethanol extract.

Comparison 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 used as Tochu tea hot water extract.

Example 1
Inventive products 1 to 3 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 method [Rodbell, M .; , J .; Biol. Chem. , 239, 375 (1964)], free adipocytes were prepared from 5 Wistar male rats (body weight 150-200 g) using the collagenase solution. The cells were incubated at 37 ° C. for 2 hours in Hank's buffer containing bovine serum albumin prepared so that the concentration of the test substance was 100 μg / ml, and the released fatty acid was analyzed by the method of Okuda et al. [Okuda et al. , H .; et al. Pharmacol. Res. Commun. , 18, 877 (1986)].

  From Table 1, when 100 μg / ml of the test substance was allowed to act on the free fat cells, the inventive products 1 to 3 showed a clear lipolysis promoting effect, whereas the comparative products 1 to 3 did not show 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 action was examined by the following test method. The results are also shown in Table 2.

Test Method Five abdominal skin tissues of Wistar male rats (body weight 250 to 350 g) were exfoliated with a subcutaneous fat tissue at a diameter of 4 cm and set in a cylindrical diffusion cell having a diameter of 2.6 cm. The skin external preparation composition 0.5 g shown in Table 2 was uniformly applied to the skin surface, and the lower cell was filled with Hank's buffer. After leaving 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; using Boehringer Mannheim).

From Table 2, Inventions 4 to 5 show a clear lipolysis promoting action in subcutaneous adipose tissue when applied to the skin, compared with Comparative Product 4 in which this is not blended, and Pepperaceae plant extract and Inventive products 6 to 9 containing a xanthine derivative, a β-adrenergic stimulant, an α ₂ adrenergic inhibitor or a bipyridine derivative were further enhanced in action compared to comparative products 5 to 8 not containing a pepper family plant.

Example 3 Oral tablets (Table 3)
(%)
Pepper fruit powder 20
Theophylline 10
Lactose 30
Dextrin appropriate amount glucose 15
Dye trace amount

Example 4 Gel cream (Table 4)
(%)
Extract 1 of Invention 1
Liquid paraffin appropriate amount Squalane 20
Microcrystalline wax 5
Cetyl isooctanoate 5
Polyoxyethylene (20) glycerol triisostearate 1
Perfume Trace pigment Trace amount

Example 5 Massage agent with scrub agent (Table 5)
(%)
Hihatsu fruit powder 5
Isoproterenol hydrochloride 1
Polyethylene beads (particle size 20μm or less 7%, particle size 5000μm or more 0%) 10
Liquid paraffin 14
2-Ethylhexanoic acid triglyceride 37
Sorbitol 8
Polyethylene glycol (average molecular weight 400) 6
Acylmethyl taurine 6
Polyoxyethylene (60) octyldodecyl alcohol ether 8
Purified water Appropriate amount of fragrance Trace amount

Example 6 Foam Pack (Table 6)
(%)
Extract 2 of Invention 2
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) hydrogenated castor oil 3
Liquefied petroleum gas (propellant) 5
Dimethyl ether (propellant) 3
Perfume Trace amount of purified water

Example 7 Tablet type bath preparation (Table 7)
(%)
Extract 3 of Invention 3
Amrinon 2
Sodium bicarbonate 20
Sodium carbonate 10
Fumaric acid 30
Polyethylene glycol (average molecular weight 6000) 20
Dextrin Appropriate amount of perfume Trace pigment Trace amount

Example 8 Liquid bath agent (Table 8)
(%)
Extract 4 of Invention 4
Octanoic acid triglyceride 33
Octyldodecyl myristate 33
Liquid paraffin appropriate amount Polyoxyethylene sorbite fatty acid ester (40E.O.) 9
Polyoxyethylene sorbite fatty acid ester (20E.O.) 3
Perfume

Claims (7)

An orally administered composition comprising an immature green fruit of pepper ( Pipe nigrum L.) or Hibatsu ( Pipe longum L.) as an active ingredient. Pepper ( Pipe nigrum L.) immature green fruit or baboon ( Pipe longum L.) is contained as an active ingredient, and has a lipolysis-promoting action. Orally administered composition. Furthermore, the oral administration composition of Claim 2 which mix | blended 1 type (s) or 2 or more types chosen from a xanthine derivative, a beta adrenergic stimulant, an alpha ₂ adrenergic action inhibitor, and a bipyridine derivative.   The oral administration composition according to claim 3, wherein the xanthine derivative is selected from the group consisting of aminophylline, theophylline, caffeine and salts thereof.   The composition for oral administration according to claim 3, wherein the β-adrenergic stimulant is selected from the group consisting of isoproterenol, dobutamine, salbutamol and salts thereof. The composition for oral administration according to claim 3, wherein the α ₂ adrenergic inhibitor is selected from the group consisting of yohimbine, phentolamine, ergotamine and salts thereof.   The composition for oral administration according to claim 3, wherein the bipyridine derivative is selected from the group consisting of amrinone, milrinone and salts thereof.