JP5306688B2 - Apoptosis inhibitor - Google Patents

Description

  The present invention is applied to viral infections such as rough skin, dry skin, inflammation, pruritus, sensitive skin, eczema, pigmentation symptoms or rheumatoid arthritis, hepatitis B and hepatitis C caused by increased apoptosis of cells constituting the skin. Associated hepatitis, fulminant hepatitis, diabetes, myocardial infarction, ulcerative colitis, chronic nephritis, alopecia, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, ischemic brain damage, acquired immune deficiency syndrome, dilated cardiomyopathy The present invention relates to a pharmaceutical, a food, a cosmetic composition, and a beauty method that are useful for prevention or improvement.

Apoptosis (apoptosis) is a “physiological cell death” caused not only by pathological factors but also by various physiological factors such as development, immunity, and hormonal action. It occurs randomly and plays an important role as cell death essential for life phenomena. Abnormal apoptosis is deeply involved in the development of various diseases.
It has been shown that a part of caspases responsible for apoptosis is involved in the onset and progression of lesions including inflammation (Non-patent Document 1). Therefore, an inhibitory effect on certain inflammatory reactions is expected by suppressing apoptosis. In fact, it has been reported that Fas L (Fas ligand) neutralizing antibody has an excellent effect on experimental inflammatory pulmonary fibrosis and inflammatory bowel disease model animals (Non-patent Document 2). Is expected to have excellent effects in the prevention or treatment of symptoms, pathologic conditions, and tissue disorders in various inflammatory diseases.

In skin, expression of Fas molecules on keratinocytes is remarkably induced by the action of IFN-γ produced by lymphocytes infiltrating the skin during acute and chronic inflammation, and apoptosis is caused by reaction with FasL expressed by lymphocytes. It has been clarified that this is caused (Non-patent Document 3). In addition, keratinocytes are strongly bound to each other by a binding device called desmosome, and it is thought that sponge-like blister formation is caused by keratinocyte apoptosis, resulting in characteristic pathological changes called spongy state and eczema symptoms. (Non-Patent Document 4). It is considered that such barrier dysfunction of the epidermis due to apoptosis facilitates the entry of various stimulating substances from the outside into the living body and causes a further inflammatory reaction and causes symptom deterioration. In addition, when the epidermis is damaged, the turnover of keratinocytes is promoted, but the regularity of the turnover is lost in a chronic inflammatory state, and an undifferentiated stratum corneum is easily formed. On such undifferentiated keratinocytes, the production of water-soluble amino acids that are moisturizing decreases, and the skin's moisturizing ability tends to be lost. (Non-Patent Document 5).

In vivo, for example, Fas antibody, FasL, TNF-α, TGF-β, and the like induce apoptosis through a receptor even when stimulated from outside such as radiation, ultraviolet rays, and anticancer drug treatment. Compounds that suppress apoptosis are various diseases caused by excessive apoptosis, such as rough skin, dry skin, inflammation, pruritus, sensitive skin, eczema, pigmentation, etc. Neurodegeneration such as rheumatoid arthritis, hepatitis associated with viral infections such as hepatitis B and hepatitis C, fulminant hepatitis, diabetes, myocardial infarction, ulcerative colitis, chronic nephritis, alopecia, Alzheimer's disease and Parkinson's disease It can be a prophylactic / therapeutic agent for diseases, ischemic encephalopathy, acquired immune deficiency syndrome, dilated cardiomyopathy, and the like (see Non-Patent Document 6). For example, antibodies that suppress the function of Fas receptor, which plays an important role in the apoptosis-inducing pathway, are being developed. However, because of proteins, there are problems in administration methods, in vivo stability, side effects, etc. Has been.

Daemen M.M. A. et al. , Clin. Invest. , 104, 541-549 (1999); et al. , At. Med. , 4, 1287-1292 (1998); Lawson J. et al. A. et al. , Hepatol. , 28, 761-767 (1998) Via C.I. S. et al. , J .; Immunol. 157, 5387-5393 (1996); et al. , Int. Immunol. 11,925-931 (1999); KuwanoK. et al. , J .; Clin. Invest. 104, 13-19 (1999) Trautmann A.M. etal. , J .; Clin. Invest. 106, 25-35 (2000); Takahashi H. et al. et al. , J .; Invest. Dermatol. , 105, 810-815 (1995); et al. , Int. J. et al. Cancer, 80, 564-572 (1999) Trautmann A.M. etal. , J .; Allergy Clin. Immunol. , 108, 839-846 (2001) Fragrance Journal, vol. 10 (2002); Hachiro Tagami, Medicine of the skin, Chuko Shinsho (1999) Nature Med. 6, 389-395 (2000). Science, 267, 1456-1462 (1995).

An object of the present invention is to provide a safe and highly stable substance having an activity of suppressing apoptosis. Such substances include skin diseases such as rough skin caused by increased apoptosis of cells constituting the skin, hepatitis associated with viral infections such as rheumatoid arthritis, hepatitis B and hepatitis C, fulminant hepatitis, diabetes, myocardial infarction, ulcers Drugs and foods useful as preventive and therapeutic agents for neurodegenerative diseases such as ulcerative colitis, chronic nephritis, alopecia, Alzheimer's disease and Parkinson's disease, ischemic encephalopathy, acquired immune deficiency syndrome, and dilated cardiomyopathy It can be a cosmetic composition, or is considered useful as a cosmetic method.

Epithelial cells, such as the epidermis of the skin, gastrointestinal epithelium, and hair matrix cells, are repeatedly supplied with new cells and maintain their functions as tissues. In order to observe the apoptotic reaction caused by various cells of living tissues, it was considered appropriate to use skin keratinocytes as representative of epithelial cells. In order to solve the problem, the present inventors searched for an apoptosis inhibitor in nature by screening an anti-apoptotic active substance using a skin keratinocyte cell line, and extracted a seaweed extract of Sargassum (for example, (At least one or more extracts selected from the group consisting of Sargassum ringgoldianum, Sargassum horneri, and Sargassum fulvellum), or Psyllium extract and Ginkgo biloba extract and Chlorella extract and β- The present inventors have found the activity of glycyrrhetinic acid to suppress apoptosis of a skin keratinocyte cell line and have completed the present invention.

Since the substance of the present invention has anti-apoptotic activity as shown in the following test examples, for example, a pharmaceutical composition used as an anti-inflammatory agent for apoptosis-related inflammation, or skin for preventing and improving rough skin It is useful as an external preparation.

Such a pharmaceutical composition of the present invention includes hepatitis associated with viral infections such as rheumatoid arthritis, hepatitis B and hepatitis C, fulminant hepatitis, diabetes, myocardial infarction, ulcerative colitis, chronic nephritis, alopecia, Alzheimer It can be used as a prophylactic / therapeutic agent for apoptosis-related diseases such as neurodegenerative diseases such as Parkinson's disease and Parkinson's disease, ischemic encephalopathy, acquired immune deficiency syndrome, and dilated cardiomyopathy. Moreover, such a skin external preparation of this invention can be used as a skin external preparation which prevents and improves rough skin, dry skin, inflammation, pruritus, sensitive skin, eczema and pigmentation symptoms.
Further provided by the present invention is a method comprising the step of administering a therapeutically effective amount of the compound to a mammal, including a human, and a step comprising contacting the cell with an effective amount of the substance.

In the pharmaceutical composition containing the substance of the present invention as an active ingredient, the administration method, dosage form and dosage can be appropriately determined according to the purpose of use. For example, the dosage form of a pharmaceutical comprising the substance of the present invention as an active ingredient may be oral administration or parenteral administration. Examples of the dosage form include oral administration agents such as tablets, powders, capsules, granules, extracts and syrups, and parenteral administration agents such as injections, drops, and suppositories. These preparations can be produced by known methods using pharmaceutically acceptable additives such as excipients and binders. The dosage of the pharmaceutical composition containing the substance of the present invention as an active ingredient varies depending on the age, weight, sensitivity, symptom level, etc. of the patient, but the effective amount is usually administered orally per day as an active ingredient. Then, 0.1
mg to 100 mg
/ Kg, preferably about 1 mg to 20 mg / kg, and for parenteral administration, 0.01 mg to 10 mg / kg, preferably 0.1 mg to 2
It is about mg / kg. It is also possible to administer the above dose once or several times a day. Further, if necessary, an amount outside the above range can be used.

  The dosage form of the external preparation for skin according to the present invention can be provided in various dosage forms such as a lotion, emulsion, gel, cream, ointment, powder, granule and the like. In addition, skin cosmetics such as skin lotion, milky lotion, cream, cosmetic liquid, and packs, foundation cosmetics such as makeup base lotion and makeup base cream, foundations for each dosage form such as emulsion, oily, solid, and eye It can be provided as makeup cosmetics such as color, body cosmetics such as lip balm, hand cream, leg cream, neck cream, and body lotion.

The composition according to the invention can also be packaged as an aerosol composition containing a compression propellant. The composition according to the present invention may also be used in the oral cavity as a quasi-drug and specifically can be added to a toothpaste. In this case, the composition may contain conventional toothpaste paste additives, in particular surfactants, thickeners, abrasives, fluorides such as sodium fluoride, and sweeteners.
When the compound of the present invention is used as a research reagent, it can be dissolved in an organic solvent or a water-containing organic solvent, and examples of usable organic solvents include methanol, ethanol, dimethyl sulfoxide and the like. Can do. Examples of the dosage form include a solid agent such as powder, or a liquid agent dissolved in an organic solvent or a water-containing organic solvent. Usually, the effective use amount for exhibiting apoptosis inhibitory activity using the above compound as a research reagent is 0.1 to 100 μg / mL in a cultured cell system. It depends on the type of system and purpose of use, and can be selected as appropriate. Further, if necessary, an amount outside the above range can be used. The administration mode of the inhibitor of apoptosis of the present invention and the preventive and / or therapeutic agent for diseases caused by the promotion of apoptosis is not particularly limited, and can be administered orally or parenterally. Preferably, it may be administered parenterally, intravenously by injection or infusion, or transdermally. An extract of the seaweed of the genus Sargassum, which is an active ingredient as an inhibitor of apoptosis of the present invention and a preventive and / or therapeutic agent for diseases caused by the promotion of apoptosis, such as Sargassum ringgoldianum, At least one or more extracts selected from the group consisting of Sargassum horneri and Sargassum fulvellum, or Ginkgo biloba extract and Chlorella extract and β-glycyrrhetinic acid and Psyllium extract are administered directly to the patient. However, it should preferably be provided as a well-known form of preparation by adding the active ingredient and pharmacologically and pharmaceutically acceptable additives.

The anti-apoptotic agent of the present invention is useful for the prevention or treatment of tissue damage, disease or pathological condition in which apoptotic death of cells is involved or due to increased apoptosis. Furthermore, it is useful for the prevention or treatment of skin diseases, symptoms, pathological conditions, and tissue disorders resulting from normalization of metabolism of cells constituting the skin, that is, the balance between apoptosis and cell neogenesis, and increased apoptosis of cells constituting the skin. .

Embodiments of the present invention will be described below.
Examples of the seaweeds of the genus Honda walla used in the present invention include, for example, sarcasum tosaense, sargassum patens, sargassum horneri, sargassum filicinum, sawgassum serratifolium, ygassum , Sargassum giganteifolium, Sargassum ringgoldianum, Sargassum sagamianum, Sargassum confusum, Sargassum thunberg, Sargassum thunberg, Sargassum thun Isomak (Sargassum hemiphyllum), Togemoku (Sargassum micracanthum), Narasasum (Sargassum nigrifolium), Usbamok (Sargassum tenuifolium), Nagashimasumoku (Sargassum racemosum), Pea (Sargassum yendoi), Argosum (c) Imoku (Sargassum sandei), and the like, but not particularly limited to this plant as long as seaweeds belonging to Sargassum.

The leaf extract used in the present invention may be extracted from a whole plant of Sargassum ringgoldianum (hereinafter referred to as “original”) after being dried with a solvent at room temperature or under heating, or It can be obtained by extraction using an extraction tool such as a Soxhlet extractor.

The red mushroom extract used in the present invention may be extracted from a whole plant of the genus Sargassum horneri (hereinafter referred to as “raw material”) and then extracted with a solvent at room temperature or under heating, or It can be obtained by extraction using an extraction tool such as a Soxhlet extractor.

The Honda wallra extract used in the present invention may be extracted with a solvent at room temperature or under warming after drying the whole plant (hereinafter referred to as “original”) of the genus Sargassum fulvellum. It can be obtained by extraction using an extraction tool such as a Soxhlet extractor.

Here, examples of the solvent used include water and / or an organic solvent, and an organic solvent is particularly preferable. Specific examples of the organic solvent include polyhydric alcohols such as glycerin, polyethylene glycol, and propylene glycol, a mixed solution of these polyhydric alcohols and water (preferably 5 to 30% aqueous solution); an anionic surfactant aqueous solution. , Nonionic surfactant aqueous solution, amphoteric surfactant; alcohols such as methanol, ethanol, butanol; mixed solution of these alcohols and water (10-99.5%, preferably 20-90% aqueous solution); hexane, Hydrocarbons such as benzene, toluene, xylene and petroleum ether; Halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane; Ethers such as diethyl ether and tetrahydrofuran; Esters such as ethyl acetate and isopropyl myristate Liquid paraffin, soybean oil, sesame Various mineral oils and the like, animal oils, vegetable oils, and the like and mixtures thereof.

Specific examples of a preferred method for extracting from the active ingredient include: (a) a method in which the active ingredient is crushed and then extracted with an ethanol solvent, and the solvent is distilled off; (b) the extract obtained in (a) is decolorized. A method of treating with one or more selected from activated carbon, polyamide resin, polystyrene resin such as HP-20, and polyethylene methacrylate resin; (c) after pulverizing the raw material, A method of extracting with a solvent, and then subjecting the extract to liquid-liquid extraction using a hydrous lower alcohol and hydrocarbons, and further distilling off the solvent from the hydrocarbon phase to which the active component has been transferred; And then extracted with a solvent such as anhydrous or hydrous lower alcohol, and the extract is subjected to liquid-liquid extraction using water and a solvent immiscible with water such as ethyl acetate, and further from the organic phase or aqueous phase. Remove the solvent (E) A method in which the aqueous phase obtained in (d) is subjected to liquid-liquid extraction using butanol and water, and the solvent is distilled off from the butanol phase; (f) (d) or (e) In this method, the liquid extract is treated with one or more selected from activated carbon, polyamide resin, polystyrene resin such as HP-20 and polyethylene methacrylate resin before or after liquid-liquid extraction; (g) After pulverizing the body, it is extracted with a suitable solvent, and then the extraction phase is treated with one or more selected from polystyrene methacrylate resins such as activated carbon, polyamide resin, and HP-20 to adsorb active ingredients, and then methanol. , Ethanol, acetone, or a mixture of these and water to extract the active ingredient and distill off the solvent. These methods may be appropriately selected depending on the purpose and application. For example, when ethanol, water, hydrous ethanol or the like is used as an extraction solvent, the concentration can be adjusted by appropriately adding ethanol, water or the like without completely distilling off the solvent. Further, impurities can be generated at room temperature or lower, which can be used after being removed by filtration or the like.

The extract can be used as it is as an active ingredient of the present invention, but the extract is further subjected to appropriate separation means such as gel filtration, silica gel column chromatography, or reversed-phase or normal-phase high-performance liquid chromatography. A highly active fraction can also be fractionated and used.

As the chlorella (Chlorella vulgaris) extract, a dried product of chlorella extract (water extract) manufactured by Ichimaru Falcos Co., Ltd. was used.

Ginkgo biloba leaf extract used Ginkgo biloba extract (50% ethanol extract) manufactured by Tokiwa Phytochemical Laboratories.

β-glycyrrhetinic acid manufactured by Maruzen Pharmaceutical Co., Ltd. was used.
Hereinafter, the present invention will be described in more detail with reference to examples, but it goes without saying that the present invention is not limited to such examples.

<Example 1> To 121 g of dried seaweed Oobamoku (chopped), 1210 g of 50% (wt / wt) aqueous ethanol solution or 95% (wt / wt) aqueous ethanol solution was added and extracted at room temperature for 5 days. Filter with. Collect the filtrate (concentration 0.5% wt / v solids). The solution is extracted at 5 ° C. for 2 days and filtered through a filter paper to obtain a leaf extract (50% EtOH) and a leaf extract (95% EtOH), respectively.
Example 2 1000 g of 50% (wt / wt) ethanol aqueous solution was added to 100 g of dried seaweed akamoku (thinned), extracted at room temperature for 5 days, and filtered through filter paper. Collect the filtrate (concentration 0.5% wt / v solids). Take 2 days at 5 ° C and filter with filter paper to obtain Akamoku extract.
<Example 3> 1000 g of 50% (wt / wt) ethanol aqueous solution is added to 100 g of dried seaweed Honda Walla (chopped), extracted at room temperature for 5 days, and filtered through filter paper. Collect the filtrate (concentration 0.5% wt / v solids). Take 2 days at 5 ° C and filter with filter paper to obtain HONDAWALA extract.
The various substances were subjected to the tests described below.

<Example 4>
(1) Induction of apoptosis Epilife medium using normal human neonatal foreskin keratinocytes (Keratinocytes) (Kurabo Corp .: 4 passage PDL24) so that TGF-β1 and TGF-β2 have the concentrations shown in Table 1. In addition to the above, we confirmed whether apoptosis was induced. Apoptosis is evaluated by ELISA (ApoStrand ELISA Apoptosis
Detection Kit AK-120: manufactured by BIOMOL). ApoStrand ELISA Apoptosis
In the detection kit AK-120, if apoptosis is promoted, the absorbance value increases.
The results are shown in Table 1.

From the results in Table 1, when TGFβ-1 1000 pg / mL and TGFβ-2 1000 pg / mL were added, promotion of apoptosis was observed in keratinocytes.

<Example 5>
(2) Evaluation method of anti-apoptotic activity ELISA is used to search for components that induce apoptosis in keratinocytes (passage 4 PDL24) with TGF-β1 1000pg / mL and suppress the apoptosis.
Detection Kit AK-120: manufactured by BIOMOL).

From the results shown in Table 2, when TGF-β1 1000 pg / mL was added and apoptosis was induced in keratinocytes, 10 ppm Honda extract (50% EtOH) and 10 ppm red peach extract (50% EtOH) were added to TGF-β1. Significantly inhibited apoptosis induced by. Moreover, apoptosis was significantly suppressed when Oberamok 50% EtOH 0.001 ppm was added to TGF-β1 300 pg / mL. Moreover, when TGF-β1 1000 pg / mL was added to induce apoptosis, there was a tendency to suppress apoptosis induced by adding 10 ppm of Obermok 50% EtOH. However, when the concentration of obermok 50% EtOH was lowered to 0.1 ppm or 0.001 ppm, the induction of apoptosis was not observed. On the other hand, when Ginkgo BG extract (100 ppm) + Chlorella extract (100 ppm) + Glycyrrhetinic acid (10 ppm) was added to TGFβ-1 300 pg / mL, no inhibition of apoptosis was observed. When 0.001 ppm of% EtOH was added, apoptosis was significantly suppressed. Furthermore, when TGF-β1 1000pg / mL was added to induce apoptosis, Ginkgo BG extract (100ppm) + Chlorella extract (100ppm) + Glycyrrhetinic acid (10ppm) + Oberamok 50% EtOH 0.001ppm was added to induce apoptosis of keratinocytes It became clear that it was suppressed markedly. Since the inhibitory effect of minoxidil on apoptosis is reported, TGF-β1 1000pg / mL was added and 0.1ppm of minoxidil was added to the state in which apoptosis was induced by keratinocytes, but apoptosis induced by TGF-β1 was not suppressed. It was. From the above, it was revealed that the seaweed extract of the genus Honda walla markedly inhibits apoptosis of keratinocytes.

<Example 6>
Table 3 summarizes the prescriptions for the skin suppression lotion of the present invention and the skin lotion of the comparative product.

<Production method>
An activator (polyoxyethylene sorbitan monolaurate (20E.O)) and preservative are added to ethyl alcohol and dissolved uniformly. To this, an aqueous layer portion (purified water, test substance, glycerin) dissolved in advance is added and dissolved.

<Example 7>
<Use test>
Subsequently, a use test was performed on the examples and comparative examples of the present invention. Since it is presumed that rough skin is improved when apoptosis is suppressed, the following test was performed. Twenty panelists who felt rough skin were made into one group, and each group was made to use Examples and Comparative Examples on the face blindly, and the improvement of the rough skin and the change in the amount of moisture were observed or measured with a ski control and evaluated. The period of use was one month. For rough skin, it was evaluated in three levels: “Improved”, “Slightly improved”, “No change”, “Slightly worse” and “Deteriorated”, and the water content was evaluated in three levels: “Increase”, “No change” and “Decrease” The panel numbers obtained for each evaluation are shown in Table 4 below.

As shown in Table 4, it was recognized that rough skin was improved and the amount of water was remarkably increased by using the example of the present invention containing the extract of Oberomoku as compared with the comparative example.

Next, examples of cosmetics, external preparations for skin preparations, and examples of foods and pharmaceuticals containing the various components of the present invention are shown, but the present invention is not limited thereto.
Examples of cosmetic formulations

(1) Cosmetic cream (wt%)
a) Beeswax ... 2.0
b) Stearyl alcohol ... 5.0
c) Stearic acid: 8.0
d) Squalane ... 10.0
e) Self-emulsifying glyceryl monostearate ... 3.0
f) Polyoxyethylene cetyl ether (20E.O.) ... 1.0
g) Obermoku extract ... 2.5
h) Potassium hydroxide ... 0.3
i) Preservatives / Antioxidants ...
j) 1,3-butylene glycol ... 5.0
k) Purified water: remainder <Production method>
Heat up to a) to f) and keep at 80 ° C. i) to k) are dissolved by heating,
Maintain at 80 ° C., emulsify in addition to a) to f) and add h). Add g) at 40 ° C and cool to 35 ° C with further stirring.

(2) Emulsion (wt%)
a) Beeswax ... 0.5
b) Petrolatum ... 2.0
c) Squalane ... 8.0
d) Sorbitan sesquioleate ... 0.8
e) Polyoxyethylene oleyl ether (20E.O.) ... 1.2
f) Akamoku extract ... 1.0
g) Carboxyvinyl polymer ... 0.2
h) Potassium hydroxide ... 0.1
i) 1,3-Butylene glycol ... 7.0
j) Purified water: remaining
k) Preservatives / Antioxidants ...
l) Ethanol ... 7.0
<Production method>
Heat up to a) to e) and keep at 80 ° C. f) to k) (except h) are heated and dissolved,
Keep at 80 ° C., emulsify in addition to a) to e) and add h). Cool to 50 ° C with stirring. Add l) at 50 ° C and cool to 40 ° C.

(3) Lotion (wt%)
a) Akamoku extract ... 5.0
b) Glycerin ... 5.0
c) Polyoxyethylene sorbitan monolaurate (20E.O.) 0.5
d) Preservatives / Antioxidants ...
e) Purified water: remainder <Production method>
Mix a) to e) and dissolve uniformly.

(4) Packing agent (wt%)
a) Oberamok extract ... 0.5
b) Akamoku extract ... 0.1
c) Vinyl acetate resin emulsion ... 15.0
d) Polyvinyl alcohol ... 10.0
e) Olive oil ... 3.0
f) Glycerin ... 5.0
g) Titanium oxide ... 8.0
h) Kaolin ... 7.0
i) Ethanol ... 8.0
j) Perfume ... appropriate amount
k) Preservatives / Antioxidants ...
l) Purified water: remainder <Production method>
Mix a) to l), stir and disperse well to make uniform.

(5) Hair tonic (% by weight)
a) Ethanol ... 60
b) Akamoku extract ... 5.0
c) Glycerin ... 3.0
d) Menthol 0.2
e) Purified water: remainder <Production method>
Mix a) to e), stir and disperse well to make uniform.

(6) Ointment (wt%)
a) Ascorbyl palmitate ... 2.0
b) Polyoxyethylene hydrogenated castor oil (60E.O.) ... 10.0
c) Polyoxyethylene cetyl ether (2E.O.) ... 10.0
d) Stearyl alcohol ... 10.0
e) Propylene glycol ... 30.0
f) Glycerin ... 34.6
g) β-glycyrrhetinic acid ... 0.1
h) Chlorella extract ... 1.0
i) Ginkgo biloba extract ... 2.0
j) Oobamoku extract ... 0.1
j) Paraben ... 0.2
<Production method>
a) to j) are heated and dissolved, and cooled to 35 ° C. with stirring.

(7) Capsule (wt%)
a) Extract of Psyllium ... 5.0
b) β-glycyrrhetinic acid ... 0.1
c) Chlorella extract ... 2.0
d) Ginkgo biloba extract ... 2.0
e) Glucose ... balance
<Production method>
Mix a) to e) well and form into capsules.

(8) Drink (wt%)
a) Extract of Honda Walla ・ ・ ・ 1.0
b) β-glycyrrhetinic acid ... 0.1
c) Chlorella extract ... 1.0
d) Ginkgo biloba extract ... 2.0
e) Fragrance: appropriate amount
f) Preservatives / Antioxidants ... appropriate amount
g) Purified water: appropriate amount <Production method>
a) to g) are mixed and dissolved.

(9) Powdered glucose 5 so as to contain 10 mg of injection / instillation Honda Walla extract
After adding g, the vial was aseptically distributed and sealed, sealed with an inert gas such as nitrogen and helium, and stored in a cool dark place. Before use, dissolve in ethanol and add 0.85% physiological saline 100
Add ml to make an intravenous injection, and administer 10 to 100 ml per day by intravenous injection or infusion depending on the symptoms.

(10) Take 1 g of granule obomak extract, 98 g of lactose and 1 g of hydroxypropyl cellulose, mix well, then shape into granules according to the usual method, dry well, and suitable for bottles and heat seal packaging Granules were produced. 100-1000 per day
mg can be administered orally depending on the symptoms.

The apoptosis-suppressing agent of the present invention is useful for the prevention or treatment of tissue damage, disease, or pathological condition in which apoptosis death of cells is involved or due to increased apoptosis.

Claims (1)

An apoptosis inhibitor containing 50% (wt / wt) ethanol water extract of Sargassum horneri as an active ingredient (except for wrinkles and dullness due to hyaluronidase activity inhibitory action) .